MDPI AG Acta Medica Okayama 1422-0067 27 5 2026 Aerobic Exercise Attenuates Epidermal Hyperplasia in an Obesity-Associated Psoriasiform Dermatitis Model 2308 EN Yoshihiro Matsuda Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Shin Morizane Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Daiki Takezaki Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Yuma Sakamoto Department of Immunology and Molecular Genetics, Kawasaki Medical School Nobuyasu Baba Department of Immunology and Molecular Genetics, Kawasaki Medical School Masanori Iseki Department of Immunology and Molecular Genetics, Kawasaki Medical School Yoshio Kawakami Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Tatsushi Shiomi Department of Pathology, Kawasaki Medical School Tomoyuki Mukai Department of Immunology and Molecular Genetics, Kawasaki Medical School Obesity is an important risk factor for psoriasis, and clinical studies indicate that exercise interventions can improve disease severity. However, the mechanisms by which exercise influences psoriatic pathogenesis remain insufficiently understood. To investigate the effects of aerobic exercise on obesity-associated psoriasis, wild-type mice were fed a high-fat diet (HFD) for 7 weeks to induce obesity and subsequently underwent moderate-intensity treadmill running for 3 weeks. Psoriasiform dermatitis was induced by daily topical application of imiquimod (IMQ) to the skin for five consecutive days. HFD increased body weight, epididymal fat mass, and serum cholesterol. HFD-fed mice developed more severe IMQ-induced psoriatic skin changes compared with normal diet-fed mice. Treadmill exercise modestly reduced body weight gain and attenuated epidermal hyperplasia in HFD-fed mice. In contrast, inflammatory cytokine expression, including Tnfa, Il17a, and Il23a, showed modest increases in the skin of HFD-fed exercised mice, which did not parallel the improvement in epidermal hyperplasia. Overall, these findings indicate that while obesity exacerbates psoriasiform dermatitis, aerobic exercise ameliorates epidermal hyperplasia in obese mice without corresponding changes in inflammatory cytokine expression in the skin, suggesting that exercise may influence psoriatic skin changes through multiple metabolic and immunological pathways. No potential conflict of interest relevant to this article was reported.

The Company of Biologists Acta Medica Okayama 1754-8403 19 2 2026 A genetic model of congenital intestinal atresia implicates Mypt1 in epithelial organisation dmm052605 EN Daisuke Kobayashi Department of Anatomy and Developmental Biology, Kyoto Prefectural University of Medicine Akihiro Urasaki Department of Anatomy and Developmental Biology, Kyoto Prefectural University of Medicine Tetsuaki Kimura Medical Genome Center, Research Institute, National Center for Geriatrics and Gerontology Satoshi Ansai Ushimado Marine Institute, Okayama University Kazuhiko Matsuo Department of Anatomy and Developmental Biology, Kyoto Prefectural University of Medicine Hayato Yokoi Graduate School of Agricultural Science, Tohoku University Shigeo Takashima Institute for Glyco-core Research (iGCORE)/Life Science Research Centre, Gifu University Tadao Kitagawa Program in Environmental Management, Graduate School of Agriculture, Kindai University Takahiro Kage Department of Biological Sciences, Graduate School of Science, The University of Tokyo Takanori Narita Laboratory of Molecular Biology, Department of Veterinary Medicine, College of Bioresource Sciences, Nihon University Tomoko Jindo Department of Biological Sciences, Graduate School of Science, The University of Tokyo Masato Kinoshita Department of Applied Biosciences, Graduate School of Agriculture, Kyoto University Kiyoshi Naruse Laboratory of Bioresources, National Institute for Basic Biology Yoshiro Nakajima Department of Anatomy and Developmental Biology, Kyoto Prefectural University of Medicine Masaki Shigeta Department of Anatomy and Developmental Biology, Kyoto Prefectural University of Medicine Shinichiro Sakaki Department of Anatomy and Developmental Biology, Kyoto Prefectural University of Medicine Satoshi Inoue Department of Anatomy and Developmental Biology, Kyoto Prefectural University of Medicine Rie Saba Department of Radiology, Kyoto Prefectural University of Medicine Kei Yamada Department of Radiology, Kyoto Prefectural University of Medicine Takahiko Yokoyama Department of Anatomy and Developmental Biology, Kyoto Prefectural University of Medicine Yuji Ishikawa Research Centre for Radiation Protection, National Institute of Radiological Sciences Kazuo Araki Research Center for Aquatic Breeding, National Research Institute of Aquaculture, Fisheries Research Agency Yumiko Saga Department of Biological Sciences, Graduate School of Science, The University of Tokyo Hiroyuki Takeda Department of Biological Sciences, Graduate School of Science, The University of Tokyo Kenta Yashiro Department of Anatomy and Developmental Biology, Kyoto Prefectural University of Medicine Congenital intestinal atresia (IA) is a birth defect characterised by the absence or closure of part of the intestine. Although genetic factors are implicated, mechanistic understanding has been hindered by the lack of suitable animal models. Here, we describe a medaka (Oryzias latipes) mutant, generated by N-ethyl-N-nitrosourea (ENU) mutagenesis, that develops IA during embryogenesis. Positional cloning identified a nonsense mutation in mypt1, encoding myosin phosphatase target subunit 1. Mutant embryos exhibited ectopic accumulation of F-actin and phosphorylated myosin regulatory light chain (Mrlc) in the intestinal epithelium, consistent with disrupted actomyosin regulation. These cytoskeletal abnormalities were accompanied by epithelial disorganisation, without notable alterations in cell proliferation, motility or apoptosis. Inhibition of myh11a, encoding smooth muscle (SM) myosin heavy chain, ameliorated the IA phenotype, whereas blebbistatin treatment completely rescued the defect, suggesting a non-contractile role prior to SM maturation. Together, these findings demonstrate that mypt1 loss disrupts intestinal morphogenesis through actomyosin dysregulation. Given the recent clinical identification of IA associated with MYPT1 variants, this medaka model offers a valuable platform to investigate the developmental and molecular basis of MYPT1-associated IA in humans. No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 0964-2633 70 3 2025 Prevalence and Modifiable Risk Factors of Dementia in People With Down Syndrome: Cross‐Sectional Study of Japan in Collaboration With the Intellectual Diversity for Goodness Research Consortium (INDIGO‐2019) 329 336 EN Shintaro Takenoshita Department of Neuropsychiatry, Okayama University Hospital Seishi Terada Department of Neuropsychiatry, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Tomokazu Inoue Asahigawaso Research Institute, Social Welfare Corporation Asahigawaso Taku Kurozumi Asahigawaso Research Institute, Social Welfare Corporation Asahigawaso Manabu Takaki Department of Neuropsychiatry, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Ryozo Kuwano Asahigawaso Research Institute, Social Welfare Corporation Asahigawaso Shigeru Suemitsu Asahigawaso Research Institute, Social Welfare Corporation Asahigawaso Background: People with Down syndrome (DS) have a strong genetic predisposition to Alzheimer's disease (AD). However, the clinical burden and associated risk factors in diverse, non-Western populations remain less understood. This study aimed to investigate the prevalence of dementia in Japanese adults with DS and to identify modifiable clinical factors associated with dementia. Methods: This cross-sectional multicentre study surveyed 133 adults with DS (mean age 50.1 years) residing in 45 welfare facilities across Japan in 2019. Dementia was diagnosed by a consensus panel of physicians using established criteria (DSM-5, ICD-10, DC-LD) after comprehensive assessments, including the Japanese version of the Dementia Screening Questionnaire for Individuals with Intellectual Disabilities (DSQIID-J). Logistic regression analysis was performed to identify factors independently associated with dementia. Results: Forty-six participants (34.6%) were diagnosed with dementia. The prevalence rose sharply with age: 0% in their 30s, 30.8% in their 40s, 31.6% in their 50s and 65.5% in their 60s. After adjusting for covariates, older age, female sex, dyslipidaemia and visual impairment were independently associated with dementia. Conclusions: This study, the largest of its kind in Asia, confirms a high prevalence of dementia in institutionalized Japanese adults with DS. Crucially, this study is the first to identify dyslipidaemia and visual impairment as independent and potentially modifiable risk factors in this population. These findings highlight tangible targets for clinical interventions aimed at mitigating dementia risk in people with DS. No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 1347-9032 2026 Clinical and Genetic Landscape of Glioblastoma, IDH-Wildtype With FGFR Gene Family Alterations EN Yasuhito Kegoya Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Yoshihiro Otani Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Ryo Mizuta Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Ryosuke Ikemachi Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Mako Kamiura Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Joji Ishida Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Shinichi Toyooka Center for Comprehensive Genomic Medicine, Okayama University Hospital Daisuke Ennishi Center for Comprehensive Genomic Medicine, Okayama University Hospital Shuta Tomida Center for Comprehensive Genomic Medicine, Okayama University Hospital Shota Tanaka Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Glioblastoma, isocitrate dehydrogenase wildtype (GBM, IDH-wt), is a highly aggressive brain tumor with a poor prognosis. Alterations in the fibroblast growth factor receptor (FGFR) gene family—such as FGFR::TACC fusions and FGFR1 mutations—have emerged as potential therapeutic targets; however, their clinical and genetic features in GBM, IDH-wt remain unclear. We analyzed 1076 GBM, IDH-wt cases using comprehensive genomic profiling data from the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database in Japan. FGFR alterations were detected in 8.0% of patients, including FGFR::TACC fusions (3.3%) and FGFR1 mutations (2.9%). The FGFR::TACC fusion-positive group was older at diagnosis and showed higher frequencies of TERT promoter mutation and MDM2 amplification, and lower frequencies of EGFR amplification and TP53 mutation, compared with the fusion-negative group. The FGFR1 mutation-positive group was enriched for ATRX, NF1, and PIK3CA mutations and had significantly fewer TERT promoter and PTEN mutations, compared with the mutation-negative group. No significant differences in overall survival were observed, although both groups tended to have longer median overall survival compared with their respective negative groups. This study represents the largest genomic cohort to date of FGFR alterations in GBM, IDH-wt. FGFR::TACC fusion-positive and FGFR1 mutation-positive GBMs exhibited distinct genetic profiles, highlighting the clinical relevance of molecular subclassification and providing insight for future therapeutic strategies. No potential conflict of interest relevant to this article was reported.

Springer Science and Business Media LLC Acta Medica Okayama 1746-6148 22 1 2026 Genetic and phenotypic identities of Staphylococcus coagulans isolated from pustules of dogs with superficial bacterial folliculitis 98 EN Takafumi Osumi Animal Medical Center, Faculty of Agriculture, Tokyo University of Agriculture and Technology Yuuki Shinomiya Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology Thamonwan Wanganuttara Department of Bacteriology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Ichiro Imanishi Kimberly and Eric J. Waldman Department of Dermatology, Icahn School of Medicine at Mount Sinai Yotaro Shimazaki Animal Medical Center, Faculty of Agriculture, Tokyo University of Agriculture and Technology Keita Iyori 1sec Co. Ltd. Yoichi Toyoda 1sec Co. Ltd. Kaori Ide Animal Medical Center, Faculty of Agriculture, Tokyo University of Agriculture and Technology Jumpei Uchiyama Department of Bacteriology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Koji Nishifuji Animal Medical Center, Faculty of Agriculture, Tokyo University of Agriculture and Technology Background Staphylococcus coagulans, formerly called Staphylococcus schleiferi subsp. coagulans is the second most common isolate from skin lesions of dogs with superficial bacterial folliculitis (SBF). However, the clinical significance of S. coagulans in pustules of canine SBF remains uncertain. This study aimed to investigate the prevalence and genotypic and phenotypic diversity of S. coagulans isolated from pustules in two dogs with SBF. Results Two dogs with SBF were included in this study. S. schleiferi/coagulans was isolated as the sole organism from three pustules in case #1, whereas it coexisted with S. pseudintermedius in two of seven pustules in case #2. S. pseudintermedius was the sole organism in the remaining five pustules in case #2. Whole genome sequences revealed that all isolates tested were annotated as S. coagulans. The isolates from the same pustules exhibited identical genotypic and phenotypic profiles, indicating clonal multiplication. S. coagulans isolated from different pustules exhibited similar yet distinct genotypic and phenotypic profiles. Conclusions S. coagulans with identical genetic and phenotypic profiles can be identified as the sole pathogen or coexist with S. pseudintermedius in the pustules of the same dogs with SBF. No potential conflict of interest relevant to this article was reported.

眼科臨床紀要会 Acta Medica Okayama 1882-5176 19 02 2026 斜視の遺伝子研究 113 125 EN Toshihiko Matsuo Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University 共同性斜視は遺伝要因と環境要因からなる多因子疾患で、内斜視と外斜視に大別される。遺伝要因は家族歴、一卵性双生児の表現型一致率から推定され、環境要因には妊娠・分娩時の低酸素状態がある。一方、遺伝要因がある非共同性（麻痺性）斜視として上斜筋腱低形成を呈する特発性上斜筋麻痺がある。遺伝統計学の連鎖解析を使って、内斜視と外斜視の小家系群で4番染色体MGST2を疾患感受性遺伝子候補と同定し、MGST2ノックアウトマウスを作成した。小動物用MRIで解析すると、そのホモ接合体では野生型と比べて眼球形状が有意に横長で体積が大きいことを見出した。次いで遺伝統計学別法の全ゲノム関連解析を内斜視、外斜視、特発性上斜筋麻痺を対象として行った。Infinium Asian Screening Array-24 v1.0でSNPを決めた内斜視253検体、外斜視356検体、上斜筋麻痺102検体を疾患群とした。対照集団としては、バイオバンクジャパン (BBJ) の疾患群とは違うアレイ(OmniExpress)でSNPを決めた182,476検体「BBJ (180K)」、疾患群と同じアレイでSNPを決めたBBJの53409検体「BBJ (ASA)」および長浜コホート3570検体を使った。３対照集団との比較で共通して検出された遺伝子は、上斜筋麻痺群で神経細胞移動に関与するDAB1であった。最も大きい対照集団「BBJ (180K)」との比較では内斜視、外斜視、上斜筋麻痺を含む疾患群全体で眼発生に関与するRARB (retinoic acid receptor β) が検出された。斜視関連遺伝子は眼球形態に関与する可能性がある。特発性上斜筋麻痺は共同性斜視とは独立した疾患と理解されるが、共通の遺伝基盤もあるかもしれない。 No potential conflict of interest relevant to this article was reported.

Elsevier BV Acta Medica Okayama 1341-321X 31 12 2025 Whole-genome sequencing and in vitro characterization of a disseminated ST398 Staphylococcus aureus infection: A case report 102845 EN Yosuke Sazumi Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shinnosuke Fukushima Department of Bacteriology, Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hideharu Hagiya Department of Infectious Diseases, Okayama University Hospital Atsushi Kato Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Atsuhito Suyama Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kohei Oguni Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kazuyoshi Gotoh Department of Medical Laboratory Science, Okayama University Graduate School of Health Sciences Shoko Kutsuno Antimicrobial Resistance Research Center, National Institute of Infectious Diseases, Japan Institute for Health Security Junzo Hisatsune Antimicrobial Resistance Research Center, National Institute of Infectious Diseases, Japan Institute for Health Security Motoyuki Sugai Antimicrobial Resistance Research Center, National Institute of Infectious Diseases, Japan Institute for Health Security Shuma Tsuji Department of Bacteriology, Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Koji Iio Microbiology Division, Clinical Laboratory, Okayama University Hospital Fumio Otsuka Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Staphylococcus aureus potentially causes systemic infections such as disseminated abscesses and bloodstream infections, leading to high mortality rates. We herein describe a case of disseminated muscle abscesses caused by sequence type (ST) 398 methicillin-sensitive S. aureus (MSSA), along with in vitro investigation results for potential pathogenic factors. A 67-year-old healthy woman was admitted to our hospital with complaints of systemic body pain. Blood cultures identified MSSA and contrast-enhanced computed tomography revealed multiple muscle abscesses extending from her neck to her soles. She received antibiotic treatment with intravenous cephazolin and underwent repeated surgical drainage, and was finally discharged. Notably, the MSSA strain exclusively affected her muscle tissues, prompting us to perform genetic analysis to uncover the underlying reason. Short-read genome analysis revealed the isolate to be ST398, harboring chp and scn genes known for immune evasion from human immunity. However, no other known pathogenic factors were identified despite rigorous assays for biofilm formation, surface and cell wall proteins, protease production, and hyaluronidase activity. ST398 S. aureus is commonly isolated from livestock, and her prior experience of being flooded could be related to the disease onset. The present case underscores the possibility of severe ST398 MSSA infections in humans, even in the absence of direct animal exposure. No potential conflict of interest relevant to this article was reported.

Elsevier BV Acta Medica Okayama 1341-321X 31 12 2025 Clinical and molecular characteristics of urinary catheter-associated Pseudomonas aeruginosa prostatic infection: A case series of four postoperative nosocomial infections 102853 EN Shinnosuke Fukushima Department of Bacteriology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takayuki Sano Laboratory of Veterinary Public Health, School of Veterinary Medicine and Animal Sciences, Kitasato University Takashige Kashimoto Laboratory of Veterinary Public Health, School of Veterinary Medicine and Animal Sciences, Kitasato University Hideharu Hagiya Department of Infectious Diseases, Okayama University Hospital Pseudomonas aeruginosa is a causative pathogen of nosocomial catheter-associated urinary tract infections (CAUTI), but prostate involvement, including prostatitis and prostatic abscess, is rare. The clinical characteristics of P. aeruginosa-associated CAUTI with prostatic lesions, as well as the contribution of genetic backgrounds remain unclear. We describe four cases of urinary catheter-associated prostatic infection caused by P. aeruginosa following postoperative catheterization. All patients developed fever within 10 days after surgery, and three of the four patients developed bacteremia. Three patients were diagnosed with prostatic abscess by contrast-enhanced computed tomography or magnetic resonance imaging, while one case presented with prostatitis without abscess formation. Prostate-specific antigen levels were elevated over 20 ng/mL in all three measured cases. All patients were treated successfully with prolonged antibiotic therapy (28–39 days) without surgical drainage. Notably, all three abscess cases were successfully managed with fluoroquinolone-based combination therapy, highlighting its potential role in the management of prostatic abscesses. Three of four isolates were submitted for molecular investigations. All isolates harbored exoT and exoY, whereas exoU was absent. Biofilm-associated genes were detected in two cases, but not in the remaining case. Our findings suggested that P. aeruginosa strains carrying T3SS genes (exoT and exoY) potentially develop prostatic infections, independent of biofilm-associated genes. Host and iatrogenic factors, such as catheter manipulation, may play more critical roles in the development of prostatic pathology than strain-specific determinants. Assessment of prostate-specific antigen levels and early imaging may facilitate appropriate diagnosis and effective management when P. aeruginosa is detected as a cause of CAUTI. No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 1347-9032 2025 Genotype–Phenotype Correlations of Li–Fraumeni Syndrome in Japan Children's Cancer Group LFS20 Study Cohort EN Fumito Yamazaki Department of Pediatrics, Keio University School of Medicine Yoshiko Nakano Department of Genetic Medicine and Services, National Cancer Center Hospital Masashi Sanada Department of Advanced Diagnosis, Clinical Research Center, NHO Nagoya Medical Center Hiroki Kurahashi Division of Molecular Genetics, Center for Medical Science, Fujita Health University Shunsuke Miyai Division of Molecular Genetics, Center for Medical Science, Fujita Health University Arisa Ueki Department of Clinical Genetic Oncology, Cancer Institute Hospital of Japanese Foundation for Cancer Research Yuko Watanabe Department of Pediatric Oncology, National Cancer Center Hospital Daisuke Hasegawa Department of Pediatrics, St. Luke's International Hospital Shuhei Karakawa Department of Pediatrics, Hiroshima University Hospital Toshifumi Ozaki Department of Orthopaedic Surgery, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University Akira Hirasawa Department of Clinical Genomic Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Akiko M. Saito Clinical Research Center, NHO Nagoya Medical Center Eisuke Inoue Showa Medical University Research Administration Center, Showa Medical University Motohiro Kato Department of Pediatrics, The University of Tokyo Hiroyoshi Hattori Department of Clinical Genetics, NHO Nagoya Medical Center Li–Fraumeni syndrome (LFS) is a cancer predisposition syndrome caused by germline pathogenic variants in the TP53 gene. With the increasing use of multi-gene panel testing, TP53 variants have been identified in individuals who do not meet established TP53 testing criteria, such as the Chompret criteria. The term “attenuated LFS” has been proposed for some of these cases, particularly those with adult-onset cancer. We analyzed participants of the Japanese nationwide prospective clinical trial of the cancer surveillance program (Japan Children's Cancer Group LFS-20), along with clinical information including their family histories, to better understand their genotypic and phenotypic characteristics. We identified 32 distinct TP53 variants from 41 families (45 participants), including four missense variants with conflicting classifications of pathogenicity in ClinVar. Among these families, 36 (88%) met the LFS criteria (hereafter referred to as “LFS” in contrast to attenuated LFS), while 5 (12%) were classified as attenuated LFS. Including 30 additional family members carrying the same variant, we analyzed 75 individuals with TP53 variants. Of these, 40 with LFS and 6 with attenuated LFS had cancer. Multiple primary cancers occurred in 22 individuals (21 LFS, 1 attenuated LFS). LFS-core tumors accounted for 66% (58/88) of cancers in the LFS group and 63% (5/8) in the attenuated LFS group; of note, all core tumors in the attenuated group were limited to breast cancer. Hotspot missense variants were detected in 11 of 36 LFS families and in none of 5 attenuated LFS families, and non-hotspot null variants were found in 14 and 1, respectively. Our study revealed genotype–phenotype correlations in several respects. UMIN-CTR: UMIN000045855. No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 2050-0904 13 12 2025 Experience and Insight Into Genetic Diagnosis of Infective Aortic Aneurysm e71586 EN Shinnosuke Fukushima Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hideharu Hagiya Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takumi Fujimori Microbiology Division, Clinical Laboratory, Okayama University Hospital Koji Iio Microbiology Division, Clinical Laboratory, Okayama University Hospital Culture-negative infected aneurysms possibly occur in various clinical situations, including prior antibiotic exposure. Accurate microbial identification is crucial for an optimal antimicrobial strategy. 16S ribosomal RNA gene sequence analysis would provide a useful tool for precise bacterial identification. No potential conflict of interest relevant to this article was reported.

Elsevier BV Acta Medica Okayama 2772-7076 14 2025 Genetic variability in Neisseria meningitidis strains isolated in a Japanese hospital 100511 EN Kazuyoshi Gotoh Department of Medical Laboratory Science, Okayama University Graduate School of Health Sciences Shinnosuke Fukushima Department of Bacteriology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hideharu Hagiya Department of Infectious Diseases, Okayama University Hospital Shuma Tsuji Department of Medical Laboratory Science, Okayama University Graduate School of Health Sciences Koji Iio Microbiology Division, Clinical Laboratory, Okayama University Hospital Osamu Matsushita Department of Bacteriology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Objectives: Neisseria meningitidis is a significant pathogen causing invasive meningococcal disease, posing clinical and public health concerns worldwide. This study aimed to investigate the genetic characteristics of N. meningitidis clinical isolates at Okayama University Hospital in Japan. Methods: Between 2018 and 2023, five clinical strains were isolated, of which three were subjected to the antimicrobial susceptibility testing and whole genetic analysis using MiSeq platform (Illumina, San Diego, CA, USA). Results: One non-groupable isolate, belonging to sequence types (STs)-11026 (ST-32 complex), exhibited non-susceptibility to penicillin G, with a five-mutation pattern (F504L, A510V, I515V, H541N, and I566V) in the penA amino acid sequence and additional mutations (XXXIV and N513Y) characteristic of a mosaic penA gene. The other two isolates, ST-1655 (ST-23 complex) with serogroup Y and ST-2057 with serogroup B, were susceptible to penicillin G, neither of which contained the five-mutation pattern. Levofloxacin resistance was observed in two isolates carrying the T91I mutation in the gyrA protein. Conclusion: Our findings suggest the presence of antimicrobial-resistant N. meningitidis in Japan, underscoring the necessity for continuous local surveillance. Additional research is crucial for clarifying the ongoing spread of resistance mechanisms and for establishing effective countermeasures to reduce the clinical burden of invasive meningococcal disease. No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 137 3 2025 遺伝性腫瘍に関する大学生の知識と意識調査 126 131 EN Reimi Sogawa Department of Clinical Genetics and Genomic Medicine, Kagawa University Hospital Takahito Wada Department of Genomic Medicine, Kyoto University Graduate School of Medicine Akira Hirasawa Department of Clinical Genomic Medicine, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kensuke Kumamoto Department of Clinical Genetics and Genomic Medicine, Kagawa University Hospital Iori Ohmori Special Needs Education, Faculty of Education, Okayama University 　Genomic information plays a critical role in the diagnosis and treatment of various diseases, as well as in the management of asymptomatic individuals. This study assessed the knowledge and understanding of genetics and hereditary cancer among college students who received cancer education in Japan. The study subjects were students from fields such as education, medicine, law, and economics who participated during the period from February to December 2023. The students attended in-person lectures on genomic medicine, and they were then asked to complete an anonymous survey via Google Forms. Over 90％ of the participants reported understanding the content of the lectures, and >80％ indicated that they found the lecture's content understandable at a junior high school level. Over 60％ felt that the appropriate time to begin such education would be in late elementary or junior high school. These results indicate a high level of acceptance of hereditary cancer education among young people. However, challenges remain in their understanding of the roles of genetic factors in cancer development and the mechanisms by which inheritance and phenotype are manifested. The relevant educational programs need to be further refined and strengthened. No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 1347-9032 2025 Genomic Profiling of Pediatric Solid Tumors With a Dual DNA/RNA Panel: JCCG-TOP2 Study EN Kayoko Tao Department of Pediatrics, National Cancer Center Hospital Takako Yoshioka Department of Pathology, National Center for Child Health and Development Miho Kato Department of Childhood Cancer Data Management, National Center for Child Health and Development Kazuyuki Komatsu Department of Pediatrics, Hamamatsu University School of Medicine Shinichi Tsujimoto Department of Pediatrics, Yokohama City University Kenichi Sakamoto Department of Pediatrics, Shinshu University School of Medicine Kazuki Tanimura Department of Pediatrics, National Cancer Center Hospital Minako Sugiyama Department of Pediatrics, National Cancer Center Hospital Masahiro Sekiguchi Department of Pediatrics, The University of Tokyo Yoshiko Nakano Department of Pediatrics, The University of Tokyo Yoshihiro Otani Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yasushi Yatabe Department of Diagnostic Pathology, National Cancer Center Hospital Akihiko Yoshida Department of Diagnostic Pathology, National Cancer Center Hospital Hajime Okita Department of Pathology, Keio University School of Medicine Junko Hirato Department of Pathology, Public Tomioka General Hospital Kenichi Kohashi Department of Pathology, Graduate School of Medicine, Osaka Metropolitan University Yukichi Tanaka Department of Pathology, Kanagawa Children's Medical Center Shinji Kohsaka Division of Cellular Signaling, National Cancer Center Research Institute Takashi Kubo Department of Clinical Genomics, National Cancer Center Research Institute Kuniko Sunami Department of Laboratory Medicine, National Cancer Center Hospital Makoto Hirata Department of Genetic Medicine and Services, National Cancer Center Hospital Shuichi Tsutsumi Genome Science & Medicine Division, Research Center of Advanced Science and Technology, The University of Tokyo Hiroyuki Aburatani Genome Science & Medicine Division, Research Center of Advanced Science and Technology, The University of Tokyo Katsuyoshi Koh Department of Hematology and Oncology, Saitama Children's Medical Center Masahiro Hirayama Department of Pediatrics, Mie University Graduate School of Medicine Shuhei Karakawa Department of Pediatrics, Hiroshima University Hospital Yukayo Terashita Department of Pediatrics, Hokkaido University Hospital Hiroyuki Fujisaki Department of Pediatric Hematology and Oncology, Osaka City General Hospital Takeshi Yagi Okinawa Prefectural Nanbu Medical Center & Children's Medical Center Akihiro Yoneda Department of Pediatric Surgery, National Center for Child Health and Development Shinji Mochizuki Department of Pediatrics, National Center for Global Health and Medicine, Japan Institute for Health Security Hiroyuki Shichino Department of Pediatrics, National Center for Global Health and Medicine, Japan Institute for Health Security Tatsuya Suzuki Department of Hematology, National Cancer Center Hospital Tetsuya Takimoto Department of Childhood Cancer Data Management, National Center for Child Health and Development Koichi Ichimura Department of Pathology, Kyorin University Faculty of Medicine Chitose Ogawa Department of Pediatrics, National Cancer Center Hospital Kimikazu Matsumoto Children's Cancer Center National Center for Child Health and Development Hitoshi Ichikawa Department of Clinical Genomics, National Cancer Center Research Institute Motohiro Kato Department of Pediatrics, The University of Tokyo To develop an optimized genomic medicine platform for pediatric cancers, a nationwide cancer genome profiling project was conducted from January 2022 to February 2023 in collaboration with the Japan Children's Cancer Group. This prospective observational study analyzed matched blood and FFPE tumor samples from patients aged 0–29 years with solid tumors. Genomic analysis used the TOP2 hybrid capture–enrichment system, targeting 737 and 455 genes in the DNA and RNA panels, along with allele-specific genome copy number alterations. A total of 210 patients from 50 institutions were enrolled across Japan (median age, 8 years; range, 0–25). Of these, 154 (77%) were enrolled at diagnosis or during/after initial treatment and 56 (27%) at disease progression or relapse. The TOP2 findings had great benefits in clarifying the diagnosis of pediatric solid tumors. Among the 204 patients with genomic results, 147 (72%) had potentially actionable findings, including diagnostic, prognostic, and therapeutic findings in 111 (54%), 61 (30%), and 64 (31%), respectively. Oncogenic fusions were noted in 45 (23%) patients. A copy number alteration was identified in at least one genomic region in 170 (83%) patients. Two patients exhibited a high tumor mutation burden. Seventeen (8%) patients harbored a germline pathogenic/likely pathogenic variant in cancer-predisposing genes. This study highlighted the feasibility of implementing a nationwide precision medicine platform and the clinical utility of the TOP2 system for pediatric cancers. The results support the integration of genomic data into the standard clinical care of pediatric patients with cancer, both at diagnosis and at relapse. No potential conflict of interest relevant to this article was reported.

Springer Science and Business Media LLC Acta Medica Okayama 1472-6831 25 1 2025 Evaluation of Streptococcus mutans strains possessing genes encoding collagen-binding proteins in the Japanese population 1908 EN Makoto Okuda Department of Pediatric Dentistry, Graduate School of Dentistry, The University of Osaka Yuto Suehiro Department of Pediatric Dentistry, Graduate School of Dentistry, The University of Osaka Jinthana Lapirattanakul Department of Oral Microbiology, Faculty of Dentistry, Mahidol University Shuhei Naka Department of Pediatric Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Michiyo Matsumoto-Nakano Department of Pediatric Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ryota Nomura Department of Pediatric Dentistry, Graduate School of Biomedical and Health Sciences, Hiroshima University Rena Okawa Department of Pediatric Dentistry, Graduate School of Dentistry, The University of Osaka Kazuhiko Nakano Department of Pediatric Dentistry, Graduate School of Dentistry, The University of Osaka Background Streptococcus mutans harbors collagen-binding protein genes, namely cnm and cbm, which are implicated in its virulence and pathogenicity in both oral and extraoral infections. Although both genes were initially identified in S. mutans isolated from Japanese populations, their geographical prevalence, distribution, and genetic relatedness within Japan remain largely unexplored. This study investigates the prevalence of S. mutans strains carrying cnm and cbm genes across Japan, correlates these findings with clinical data, and analyzes the genetic relatedness of cnm-positive and cnm-negative strains using multilocus sequence typing (MLST). Methods Dental plaque specimens were collected from 1248 individuals from eight Japanese cities (Hiroshima, Fukuoka, Nagasaki, Niigata, Okayama, Osaka, Tokushima, and Tokyo) and plated on selective medium for S. mutans isolation. S. mutans was confirmed in 523 subjects by colony morphology and PCR using species-specific primers, and the presence of the cnm and cbm genes was determined by PCR with gene-specific primers. Demographic (age, sex) and oral examination (caries prevalence, caries experience, number of teeth) data were recorded. MLST was employed to genotype selected cnm-positive and cnm-negative S. mutans strains to assess their clonal relationships. Results Among 523 subjects possessing S. mutans (aged 3–90 years), we detected cnm-positive strains in all cities; specifically, the prevalence ranged from 5.5% in Okayama to 25.0% in Tokushima. In contrast, cbm-positive strains were less common and undetectable in some regions. Furthermore, subjects harboring cnm-positive S. mutans were significantly older (p = 0.002) and had higher caries prevalence and experience (p < 0.001). MLST revealed evolutionary relationships among cnm-positive strains across the cities but no discernible region-specific clustering. Clonal relationships partially reflected cnm gene distribution, particularly for exclusively cnm-positive or cnm-negative clonal complexes, but inconsistencies involving serotypes and cnm presence within some clonal complexes and sequence types were also noted. Conclusions The cnm-positive S. mutans strains are widely distributed throughout Japan and are associated with increased age and caries burden. Although core genome analysis revealed some clonal patterns, the non-uniform distribution of the non-core cnm gene is likely influenced by horizontal gene transfer, providing S. mutans with adaptive advantages irrespective of its core genetic background or serotype. No potential conflict of interest relevant to this article was reported.

Springer Science and Business Media LLC Acta Medica Okayama 2399-3642 8 1 2025 A genome-wide association study identifies the GPM6A locus associated with age at onset in ALS 1720 EN Ryoichi Nakamura Department of Neurology, Aichi Medical University School of Medicine Genki Tohnai Division of ALS Research, Aichi Medical University School of Medicine Naoki Atsuta Department of Neurology, Aichi Medical University School of Medicine Yumi Matsuda Public Health Informatics Unit, Department of Integrated Health Sciences, Nagoya University Graduate School of Medicine Satoru Morimoto Keio University Regenerative Medicine Research Center, Kawasaki Daisuke Ito Department of Neurology, Nagoya University Graduate School of Medicine Masahisa Katsuno Department of Neurology, Nagoya University Graduate School of Medicine Yuishin Izumi Department of Neurology, Tokushima University Graduate School of Biomedical Sciences Mitsuya Morita Division of Neurology, Department of Internal Medicine, Jichi Medical University Ikuko Iwata Department of Neurology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University Ichiro Yabe Department of Neurology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University Tomoko Nakazato Department of Neurology, Juntendo University School of Medicine Nobutaka Hattori Department of Neurology, Juntendo University School of Medicine Takehisa Hirayama Department of Neurology, Toho University Faculty of Medicine Osamu Kano Department of Neurology, Toho University Faculty of Medicine Asako Tamura Department of Neurology, Mie University Graduate School of Medicine Naoki Suzuki Department of Neurology, Tohoku University Graduate School of Medicine Masashi Aoki Department of Neurology, Tohoku University Graduate School of Medicine Kazumoto Shibuya Department of Neurology, Graduate School of Medicine, Chiba University Satoshi Kuwabara Department of Neurology, Graduate School of Medicine, Chiba University Masaya Oda Department of Neurology, Vihara Hananosato Hospital Rina Hashimoto Department of Neurology, NHO Higashinagoya National Hospital Ikuko Aiba Department of Neurology, NHO Higashinagoya National Hospital Tomohiko Ishihara Department of Neurology, Brain Research Institute, Niigata University Osamu Onodera Department of Neurology, Brain Research Institute, Niigata University Toru Yamashita Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hiroyuki Ishiura Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kota Bokuda Department of Neurology, Tokyo Metropolitan Neurological Hospital Toshio Shimizu Department of Neurology, Tokyo Metropolitan Neurological Hospital Yoshio Ikeda Department of Neurology, Gunma University Graduate School of Medicine Kazuko Hasegawa Division of Neurology, NHO Sagamihara National Hospital Fumiaki Tanaka Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine Takanori Yokota Department of Neurology and Neurological Science, NucleoTIDE and PepTIDE Drug Discovery Center (TIDE), Institute of Science Tokyo Kazuaki Kanai Department of Neurology, Fukushima Medical University School of Medicine Yu-ichi Noto Department of Neurology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine Ryuji Kaji Department of Neurology, Tokushima University Graduate School of Biomedical Sciences Hirohisa Watanabe Department of Neurology, Fujita Health University Tomoko Konishi Division of ALS Research, Aichi Medical University School of Medicine Mikiko Hasegawa Division of ALS Research, Aichi Medical University School of Medicine Hozuki Fukaya Division of ALS Research, Aichi Medical University School of Medicine Jun-ichi Niwa Department of Neurology, Aichi Medical University School of Medicine Manabu Doyu Department of Neurology, Aichi Medical University School of Medicine Yohei Okada Department of Neurology, Aichi Medical University School of Medicine Shiho Nakamura Keio University Regenerative Medicine Research Center, Kawasaki Fumiko Ozawa Keio University Regenerative Medicine Research Center, Kawasaki Hideyuki Okano Keio University Regenerative Medicine Research Center, Kawasaki Masahiro Nakatochi Public Health Informatics Unit, Department of Integrated Health Sciences, Nagoya University Graduate School of Medicine Gen Sobue Division of ALS Research, Aichi Medical University School of Medicine Amyotrophic lateral sclerosis (ALS) exhibits considerable clinical variability, such as differences in age at onset (AAO). Multiple factors, including genetic factors, may underlie this variability; however, the specific determinants remain unclear. To identify genes affecting AAO, we have conducted a genome-wide association study in Japanese patients with ALS (discovery cohort: n = 1808; replication cohort: n = 207). Here, we show that the minor A allele of rs113161727 at the ADAM29-GPM6A locus is associated with a younger AAO in the discovery cohort (effect, -4.27 years; p = 4.60 × 10-8); this finding has been confirmed in the replication cohort (p = 0.0068) and meta-analysis (p = 1.08 × 10−9). Among 65 ALS patients with a SOD1 mutation, the AAO has been found to be 10.2 years younger in those with the A allele than in those without it (p = 0.002). This variant correlates with GPM6A upregulation in iPSC-derived motor neurons, suggesting GPM6A as a candidate AAO modifier. Overall, our study highlights the impact of genetic modifiers on ALS heterogeneity and provides a potential target for delaying disease onset. No potential conflict of interest relevant to this article was reported.

Informa UK Limited Acta Medica Okayama 2167-8421 2025 Novel in-frame duplication variant of SOD1 in a Japanese family with familial amyotrophic lateral sclerosis EN Masanori Nakajima Department of Neurology, Kyorin University School of Medicine Hiroya Naruse Department of Neurology, Graduate School of Medicine, The University of Tokyo Yuichi Riku Department of Neuropathology, Institute for Medical Science of Aging, Aichi Medical University Kunihiro Ueda Department of Neurology, Graduate School of Medicine, The University of Tokyo Takashi Matsukawa Department of Neurology, Graduate School of Medicine, The University of Tokyo Jun Mitsui Department of Neurology, Graduate School of Medicine, The University of Tokyo Yoshitsugu Nakamura Division of Neurology, Department of Internal Medicine IV, Osaka Medical and Pharmaceutical University Shimon Ishida Division of Neurology, Department of Internal Medicine IV, Osaka Medical and Pharmaceutical University Takashi Yamada Department of Pathology, Osaka Medical and Pharmaceutical University Naoki Moro Department of Neurology, Kyorin University School of Medicine Naoki Kotsuki Department of Neurology, Kyorin University School of Medicine Kentaro Nagai Department of Neurology, Kyorin University School of Medicine Shin-ichi Tokushige Department of Neurology, Kyorin University School of Medicine Ayumi Uchibori Department of Neurology, Kyorin University School of Medicine Chizuko Oishi Department of Neurology, Kyorin University School of Medicine Hiroyuki Yabata Department of Neurology, Shiga University of Medical Science Makoto Urushitani Department of Neurology, Shiga University of Medical Science Yasushi Iwasaki Department of Neuropathology, Institute for Medical Science of Aging, Aichi Medical University Hiroyuki Ishiura Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan;Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tatsushi Toda Department of Neurology, Graduate School of Medicine, The University of Tokyo Shoji Tsuji Department of Neurology, Graduate School of Medicine, The University of Tokyo Yaeko Ichikawa Department of Neurology, Kyorin University School of Medicine Objectives: To analyze the cases of a family with a novel in-frame duplication variant (NM_000454.5:c.357_357 + 2dup, p.Val120dup) of SOD1 and a structural model of the mutated SOD1 protein. Methods: The clinical profiles of three patients in the family were analyzed, including the neuropathological findings of the proband’s mother. Genetic analyses were conducted for three patients. cDNA and in silico structural analyses were performed to evaluate the effects of duplication variants on the structure of SOD1. Results: The clinical features of the patients included predominant involvement of the lower motor neurons, asymmetric onset of motor symptoms in the lower limbs, and a relatively rapid progression of muscular weakness and respiratory insufficiency. Neuropathological findings revealed severe loss of spinal cord motor neurons, and immunohistochemistry using an anti-misfolded SOD1 antibody revealed aggregates in the spinal cord. Genetic analyses revealed a c.357_357 + 2dup at the exon 4–intron 4 boundary of SOD1 in three patients. cDNA analysis of the proband suggested the presence of a valine (p.Val120dup) duplication in the heterozygous state, and the SOD1 transcript level showed no significant differences from those of healthy controls. In silico structural analyses predicted that p.Val120dup could affect the structure of the β-barrels and copper ion binding site of SOD1, suggesting an abnormal conformation of SOD1 that is predicted to interfere with the binding of copper ions. Conclusion: We identified a novel in-frame duplication variant in the C-terminus of β7 of SOD1. This genotype–structure–phenotype study of SOD1 provides valuable insights into disease-causing mechanisms. No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 2049-4173 13 4 2025 Identification of New Repeat Expansion Diseases 244 249 EN Hiroyuki Ishiura Department of Neurology, Okayama UniversityGraduate School of Medicine, Dentistry and Pharmaceutical Sciences Through a genetic study of benign adult familial myoclonus epilepsy (BAFME) type 1, TTTCA and TTTTA repeat expansions have been identified in intron 4 of SAMD12. Lengths of expanded repeats inversely correlated with age at onset of epilepsy. Gain-of-toxic function mechanisms are suggested by the presence of UUUCA-repeat-containing RNA foci. From families with BAFME who did not have repeat expansions in SAMD12, we identified expanded TTTCA and TTTTA repeats in TNRC6A and RAPGEF2. These findings indicated a strong correlation between the repeat motif and the phenotype, leading to the identification of other types of BAFME. We then conducted genetic analysis of neuronal intranuclear inclusion disease (NIID), oculopharyngeal myopathy with leukoencephalopathy (OPML), and oculopharyngodistal myopathy (OPDM). From the observation that NIID, OPML, and OPDM, in addition to fragile X-associated tremor/ataxia syndrome, have shared clinical features, a direct search for CGG repeat expansions successfully led to the identification of the causative genes. Here, I review recent studies on repeat expansions. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 79 6 2025 Effects of Thoron Inhalation and Cyclosporin A Treatment on Dextran Sulfate Sodium-Induced Oxidative Damage in Mice 421 429 EN Ayumi Tanaka Graduate School of Health Sciences, Okayama University Shota Naoe Graduate School of Health Sciences, Okayama University Reiju Takenaka Graduate School of Health Sciences, Okayama University Norie Kanzaki Ningyo-toge Environmental Engineering Center, Japan Atomic Energy Agency Akihiro Sakoda Ningyo-toge Environmental Engineering Center, Japan Atomic Energy Agency Kiyonori Yamaoka Faculty of Health Sciences, Okayama University Takahiro Kataoka Faculty of Health Sciences, Okayama University Original Article 10.18926/AMO/69844 Radon (222Rn; Rn) and thoron (220Rn; Tn) inhalation have been reported to enhance antioxidant activity in various organs. However, the effects of Tn on the colon have not been investigated. This study aimed to clarify the effects of Tn inhalation, alone and in combination with cyclosporin A (CsA), on dextran sulfate sodium (DSS)-induced colitis, and the accompanying oxidative stress, in mice. Male BALB/c mice were subjected to continuous 8-day Tn inhalation (c-Tn, 533±128 Bq/m3) or alternate-day Tn inhalation over the same period (f-Tn, 577±63Bq/m3), followed by treatment with 3% DSS and either CsA or vehicle for 7 days. Although the disease activity index (DAI) decreased significantly by day 2 in the c-Tn group, scores remained significantly higher than those in the f-Tn group. In the c-Tn group, superoxide dismutase and catalase activity in the colon were significantly elevated compared with those in sham controls. Thus, DSS-induced damage was effectively inhibited in the earlier stages by the c-Tn mode of inhalation than by the f-Tn mode. These findings suggest that continuous Tn inhalation more effectively attenuated early colitis symptoms than alternate-day inhalation, potentially through upregulation of antioxidant defenses. Tn and CsA showed no combined effects. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 79 6 2025 COVID-19 and the Risks of Migraine and Headache: A Mendelian Randomization Study 413 419 EN Zhiyun Jiang Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University Ying Xi Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University Original Article 10.18926/AMO/69843 Several observational studies suggested that migraine headache attacks were associated with coronavirus disease 2019 (COVID-19). We investigated genetic causal links between COVID-19 phenotypes and the development of headache and migraine, including migraine with aura (MA) and migraine without aura (MO). We conducted a two-sample Mendelian randomization (MR) analysis to estimate the genetic association in European populations. The inverse-variance weighted (IVW) method was used as the main approach in the MR analyses, together with weighted median and MR-Egger methods. We also performed a series of sensitivity tests to assess the robustness of the MR results. The MR results demonstrated that COVID-19 severity, hospitalization, and susceptibility had no causal effect on the risks of headache, migraine, MA, or MO. No horizontal pleiotropy was detected, and the results were robust as supported by the sensitivity analysis findings. Our analyses identified no casual effect of COVID-19 severity, hospitalization, or susceptibility on the risks of headache or migraine in European populations. No potential conflict of interest relevant to this article was reported.

Elsevier BV Acta Medica Okayama 0732-8893 114 3 2026 Molecular epidemiological investigation of the carbapenemase-producing Enterobacterales isolates in Okayama prefecture, Japan 117209 EN Shuma Tsuji Department of Medical Laboratory Science, Okayama University Graduate School of Health Sciences Shinnosuke Fukushima Department of Bacteriology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kazuyoshi Gotoh Department of Medical Laboratory Science, Okayama University Graduate School of Health Sciences Koji Iio Microbiology Division, Clinical Laboratory, Okayama University Hospital Mayu Sato Department of Clinical Laboratory, Okayama City Hospital Yasurou Inoue Department of Clinical Laboratory, Okayama City Hospital Sayaka Sakita Department of Clinical Laboratory, Okayama Rosai Hospital Tomoko Fudeyasu Department of Clinical Laboratory, Microbiology Division, Tsuyama Chuo Hospital Fumio Otsuka Department of Infectious Diseases, Okayama University Hospital Hideharu Hagiya Department of Infectious Diseases, Okayama University Hospital We investigated the genetic characteristics of non-IMP type carbapenemase-producing Enterobacterales isolates detected in Japan. The isolates were found to carry diverse plasmids with high sequence similarity to those previously reported in other countries, underscoring the critical imperative for comprehensive nationwide epidemiological surveillance for the silent pandemic of the nightmare pathogen. No potential conflict of interest relevant to this article was reported.

Japanese Society of Internal Medicine Acta Medica Okayama 0918-2918 64 23 2025 A Prompt Diagnosis of Ascites and Dramatic Effect of Alectinib for Advanced Lung Adenocarcinoma Harboring EML4-ALK Fusion 3413 3418 EN Takahiro Baba Department of Respiratory Medicine, Okayama University Hospital Hirofumi Inoue Department of Medical Support, Okayama University Hospital Hiromi Matsuoka Department of Medical Support, Okayama University Hospital Mio Kyakuno Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine Yusuke Yoshinaga Department of Respiratory Medicine, Okayama University Hospital Tetsuya Takeguchi Department of Respiratory Medicine, Okayama University Hospital Miho Fujiwara Department of Respiratory Medicine, Okayama University Hospital Kotaro Yamada Department of Respiratory Medicine, Okayama University Hospital Eri Nakamura Department of Respiratory Medicine, Okayama University Hospital Ayako Morita Department of Respiratory Medicine, Okayama University Hospital Naofumi Hara Department of Respiratory Medicine, Okayama University Hospital Kiichiro Ninomiya Center for Comprehensive Genomic Medicine, Okayama University Hospital Hisao Higo Department of Respiratory Medicine, Okayama University Hospital Masanori Fujii Department of Geriatric Medicine, Okayama University Hospital Eiki Ichihara Center for Clinical Oncology, Okayama University Hospital Kammei Rai Center for Innovative Clinical Medicine, Okayama University Hospital Kadoaki Ohashi Department of Respiratory Medicine, Okayama University Hospital Katsuyuki Hotta Center for Innovative Clinical Medicine, Okayama University Hospital Masahiro Tabata Center for Clinical Oncology, Okayama University Hospital Yoshinobu Maeda Department of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Yosuke Togashi Department of Respiratory Medicine, Okayama University Hospital Go Makimoto Department of Respiratory Medicine, Okayama University Hospital A 75-year-old never-smoker woman presented with dyspnea and loss of appetite. A mass was identified in the left upper lobe of the lung, and the patient was referred to our hospital. Despite the diagnosis of lung adenocarcinoma via bronchoscopy, anaplastic lymphoma kinase (ALK) immunostaining was negative. Rapid weight gain and abdominal distension caused by ascites prompted fluid testing using the AmoyDx® Pan Lung Cancer PCR Panel. EML4-ALK fusion was confirmed, and alectinib therapy was initiated immediately. The tumor size had decreased significantly, and the patient was discharged on day 34. This case highlights the necessity of multiplex genetic testing even when ALK immunostaining is negative. No potential conflict of interest relevant to this article was reported.

Oxford University Press (OUP) Acta Medica Okayama 1465-3621 55 4 2025 Current management of neurotrophic receptor tyrosine kinase fusion-positive sarcoma: an updated review 313 326 EN Yuta Kubota Department of Orthopaedic Surgery, Faculty of Medicine, Oita University Masanori Kawano Department of Orthopaedic Surgery, Faculty of Medicine, Oita University Tatsuya Iwasaki Department of Orthopaedic Surgery, Faculty of Medicine, Oita University Ichiro Itonaga Department of Orthopaedic Surgery, Faculty of Medicine, Oita University Nobuhiro Kaku Department of Orthopaedic Surgery, Faculty of Medicine, Oita University Toshifumi Ozaki Department of Orthopaedic Surgery , Science of Functional Recovery and Reconstruction, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kazuhiro Tanaka Department of Orthopaedic Surgery, Faculty of Medicine, Oita University In recent years, pembrolizumab has demonstrated significant efficacy in treating tumors characterized by a high tumor mutational burden and high microsatellite instability. Tropomyosin receptor kinase (TRK) inhibitors have shown considerable efficacy against tumors harboring neurotrophic receptor tyrosine kinase (NTRK) fusion genes, highlighting the growing importance of personalized medicine in cancer treatment. Advanced sequencing technologies enable the rapid analysis of numerous genetic abnormalities in tumors, facilitating the identification of patients with positive biomarkers. These advances have increased the likelihood of providing effective, tailored treatments. NTRK fusion genes are present in various cancer types, including sarcomas, and the TRK inhibitors larotrectinib and entrectinib have been effectively used for these malignancies. Consequently, the treatment outcomes for NTRK fusion-positive tumors have improved significantly, reflecting a shift toward more personalized therapeutic approaches. This review focuses on NTRK fusion-positive sarcomas and comprehensively evaluates their epidemiology, clinical features, and radiological and histological characteristics. We also investigated the treatment landscape, including the latest methodologies involving TRK inhibitors, and discussed the long-term efficacy of these inhibitors, and their optimal order of use. Notably, larotrectinib has demonstrated a high response rate in infantile fibrosarcoma, and its efficacy has been confirmed even in advanced cases. However, further research is warranted to optimize treatment duration and subsequent management strategies. The accumulation of clinical cases worldwide will play a pivotal role in refining the treatment approaches for tumors associated with NTRK fusion genes. No potential conflict of interest relevant to this article was reported.

Bioscientifica Acta Medica Okayama 2052-0573 2025 1 2025 Adult hypophosphatasia presenting with recurrent acute joint pain e240121 EN Hayao Yoshida Department of Diabetes and Endocrinology, Shiga General Hospital Takaaki Murakami Department of Diabetes and Endocrinology, Shiga General Hospital Atsubumi Ogawa Department of Rheumatology and Clinical Immunology, Kyoto University Graduate School of Medicine Takashi Sunouchi Division of Nephrology and Endocrinology, The University of Tokyo Hospital Naoko Hidaka Division of Nephrology and Endocrinology, The University of Tokyo Hospital Nobuaki Ito Osteoporosis Center, The University of Tokyo Hospital Hiromi Murakami Department of Genomic Medicine, Kyoto University Graduate School of Medicine Hidenori Kawasaki Department of Genomic Medicine, Kyoto University Graduate School of Medicine Tomoyuki Akiyama Department of Child Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Katsumi Nakajima Department of Diabetes and Endocrinology, Shiga General Hospital Daisuke Yabe Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine Taizo Yamamoto Department of Diabetes and Endocrinology, Shiga General Hospital Hypophosphatasia (HPP) is a genetic disorder due to pathological variants in ALPL, the gene encoding tissue-nonspecific alkaline phosphatase (ALP). HPP is typically associated with bone-related symptoms, such as bone deformity, fractures and bone pain in children, but can appear in adults with symptoms resembling arthritis. A 22-year-old male experienced repeated and severe sudden attacks of joint pain in the elbows and knees. Magnetic resonance imaging and joint ultrasonography showed joint effusions indicating chronic inflammation. Blood biochemical tests revealed a remarkably low serum ALP level, and repeated examination confirmed a sustained low ALP level; urine phosphoethanolamine, plasma inorganic pyrophosphate and plasma pyridoxal-5′-phosphate levels were elevated, raising concern for HPP. While the patient had no history of premature loss of primary teeth, fragility fractures, muscle weakness or abnormalities in growth, genetic testing revealed a likely pathogenic and a pathogenic heterozygous variant in the ALPL gene, i.e., c.979T>C (p.Phe327Leu) and c.1559del (p.Leu520Argfs), confirming HPP. Additional genetic testing of his parents showed a heterozygous c.1559del variant in his father and a heterozygous c.979T>C variant in his mother. A diagnosis of adult HPP due to compound heterozygous mutations was therefore confirmed. Enzyme replacement therapy with asfotase alfa was then introduced; no attacks of arthralgia occurred in the 1-year period since then. This case highlights the possibility of HPP in adults who present clinically with repeated joint symptoms and low serum ALP levels but without bone-related symptoms. No potential conflict of interest relevant to this article was reported.

Springer Science and Business Media LLC Acta Medica Okayama 1341-9625 2025 Japanese society for cancer of the colon and rectum (JSCCR) guidelines 2024 for the clinical practice of hereditary colorectal cancer EN Kohji Tanakaya Department of Surgery, National Hospital Organization Iwakuni Clinical Center Tatsuro Yamaguchi Department of Clinical Genetics, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital Keiji Hirata Department of Surgery 1, University of Occupational and Environmental Health Masayoshi Yamada Endoscopy Division, National Cancer Center Hospital Kensuke Kumamoto Department of Genome Medical Science and Medical Genetics, Faculty of Medicine, Kagawa University Yasuki Akiyama Department of Surgery 1, University of Occupational and Environmental Health Kei Ishimaru Division of Gastrointestinal Surgery and Surgical Oncology, Graduate School of Medicine, Ehime University Koichi Okamoto Department of Gastroenterology and Oncology, Tokushima University Graduate School of Medical Science Yuko Kawasaki College of Nursing, University of Hyogo Keigo Komine Department of Medical Oncology, Tohoku University Hospital Akira Sakamoto Department of Surgery, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital Kunitoshi Shigeyasu Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Yoshiko Shibata Himawari-No-Kai (Sunflower Association), a Patient Advocacy Group for Individuals and Families Affected By Lynch Syndrome Yusaku Shimamoto Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine Hideki Shimodaira Division of Medical Oncology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University Shigeki Sekine Department of Pathology, Keio University School of Medicine Akinari Takao Department of Gastroenterology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital Misato Takao Department of Surgery, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital Yasuyuki Takamizawa Department of Colorectal Surgery, National Cancer Center Hospital Yoji Takeuchi Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine Noriko Tanabe Department of Clinical Genetics, Saitama Medical Center, Saitama Medical University Fumitaka Taniguchi Department of Surgery, Hiroshima City Hospital Organization Hiroshima City Hiroshima Citizens Hospital Akiko Chino Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research Hourin Cho Endoscopy Center, Tokyo Medical University Hospital Satoru Doi Harmony Line (Association for Patients and Families With Familial Adenomatous Polyposis) Takeshi Nakajima Division of Hereditary Tumors, Department of Genetic Oncology, Osaka International Cancer Institute Sakiko Nakamori Department of Surgery, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital Yoshiko Nakayama Department of Pediatrics, Shinshu University School of Medicine Toshiya Nagasaki Department of Gastroenterological Surgery, Saitama Cancer Center Hisashi Hasumi Department of Urology, Yokohama City University Kouji Banno Center of Maternal -Fetal/Neonatal Medicine, Hiroshima University Hospital Takao Hinoi Department of Clinical and Molecular Genetics, Hiroshima University Hospital Kenji Fujiyoshi Department of Surgery, Kurume University School of Medicine Takahiro Horimatsu Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital Kenta Masuda Department of Obstetrics and Gynecology, Keio University School of Medicine Masashi Miguchi Department of Gastroenterological Surgery, Hiroshima Prefectural Hospital Yusuke Mizuuchi Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University Yasuyuki Miyakura Department of Colon and Pelvic Surgery, Cancer Prevention and Genetic Counseling, Tochigi Cancer Center Michihiro Mutoh Department of Molecular-Targeting Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine Takahiro Yoshioka Department of Gastroenterological Surgery, Kochi Health Sciences Center Shinji Tanaka JA Onomichi General Hospital Kazuhiro Sakamoto Koshigaya Municipal Hospital Kentaro Sakamaki Faculty of Health Data Science, Juntendo University Michio Itabashi Saiseikai Kazo Hospital Hideyuki Ishida Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University Naohiro Tomita Division of Cancer Treatment , Toyonaka Municipal Hospital Kenichi Sugihara Institute of Science Tokyo Yoichi Ajioka Division of Molecular and Diagnostic Pathology, Graduate School of Medical and Dental Sciences, Niigata University Approximately 5% of all colorectal cancers have a strong genetic component and are classified as hereditary colorectal cancer (HCRC). Some of the unique features commonly seen in HCRC cases include early age of onset, synchronous/metachronous cancer occurrence, and multiple cancers in other organs. These characteristics require different management approaches, including diagnosis, treatment or surveillance, from those used in the management of sporadic colorectal cancer. Accurate diagnosis of HCRC is essential because it enables targeted surveillance and risk reduction strategies that improve patient outcomes. Recent genetic advances revealed several causative genes for polyposis and non-polyposis syndromes. The Japanese Society for Cancer of the Colon and Rectum (JSCCR) first published guidelines for the management of HCRC in 2012, with subsequent revisions every 4 years. The 2024 update to the JSCCR guidelines for HCRC was developed by meticulously reviewing evidence from systematic reviews and the consensus of the JSCCR HCRC Guidelines Committee, which includes representatives from patient advocacy groups for FAP and Lynch syndrome. These guidelines provide an up-to-date summary of HCRC, along with clinical recommendations for managing FAP and Lynch syndrome. No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 1347-9032 2025 Comparative Analysis of a Dual DNA–RNA Panel and a DNA-Only Panel for Sarcoma: Real-World Data From a Nationwide Genomic Database EN Eiji Nakata Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Kiichiro Ninomiya Center for Comprehensive Genomic Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Tatsunori Osone Department of Regenerative Science, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Daisuke Ennishi Center for Comprehensive Genomic Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Shuta Tomida Center for Comprehensive Genomic Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Tomohiro Fujiwara Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Toshiyuki Kunisada Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Mashu Futagawa Department of Clinical Genomic Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Akira Hirasawa Department of Clinical Genomic Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Shinichi Toyooka Center for Comprehensive Genomic Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Toshifumi Ozaki Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Next-generation sequencing-based comprehensive cancer genomic profiling is promising in cancer management; however, most studies rely on tumor-only DNA panels from single institutions. In 2023, Japan introduced an insurance-covered cancer genomic profiling test—the GenMine TOP Cancer Genome Profiling System—a dual DNA–RNA panel with matched tumor–normal testing. This study evaluated its utility compared to a conventional DNA-only test (FoundationOne CDx) in managing sarcoma patients using a nationwide genetic profiling database provided by the Center for Cancer Genomics and Advanced Therapeutics. This study included 1046 patients registered between August 2023 and October 2024. The dual DNA–RNA test identified significantly more fusion genes (20.3% vs. 7.4%, p < 0.001) and therapeutically targetable kinase fusions (3.5% vs. 1.2%, p = 0.019) than the DNA-only test. Among patients with translocation-related sarcomas, histology-specific fusion genes were identified in 77.5% using the dual panel, compared to 40.0% with the DNA-only panel (p < 0.001). In non-gastrointestinal stromal tumor sarcomas, the dual test showed a trend toward higher rates of genotype-matched therapy (4.3% vs. 2.6%, p = 0.25) and a significantly higher rate of molecular targeted therapy (4.3% vs. 1.5%, p = 0.03). Additionally, 5.7% of patients had pathogenic germline variants identified through tumor–normal matched analysis. These findings suggest that a dual DNA–RNA panel with matched tumor–normal testing may improve diagnostic accuracy and inform treatment decisions in the routine clinical management of sarcoma. No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 0385-2407 2025 A Case of Netherton Syndrome/SPINK5-Syndromic Epidermal Differentiation Disorder Evaluated by Serial Tape-Stripping: Persistent Elevation of Serine Protease Activities Despite Clinical Improvement EN Shin Morizane Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Anri Morita Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ko Sunagawa Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hayato Nomura Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ken‐Ichi Hasui Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hiroyuki Honda Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Fumio Otsuka Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Mamoru Ouchida Department of Molecular Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences No potential conflict of interest relevant to this article was reported.

MDPI AG Acta Medica Okayama 2075-1729 15 11 2025 Kidney Organoids: Current Advances and Applications 1680 EN Hiroyuki Nakanoh Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kenji Tsuji Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kazuhiko Fukushima Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Naruhiko Uchida Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Soichiro Haraguchi Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Shinji Kitamura Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Jun Wada Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kidney organoids, derived from stem cells, including pluripotent stem cells and adult progenitor cells, have been reported as three-dimensional in vitro models that reflect key aspects of kidney development, structure, and function. Advances in differentiation protocols and tissue engineering have enabled the generation of organoids that exhibit nephron-like structures, including glomerular and tubular structures. Kidney organoids have been widely applied in several directions, including disease modeling and therapeutic screening, drug nephrotoxicity evaluation, and regenerative medicine. In particular, kidney organoids offer a promising platform for studying genetic kidney diseases, such as polycystic kidney disease and congenital anomalies of the kidney and urinary tract (CAKUT), by allowing patient-specific modeling for the analysis of pathophysiology and therapeutic screening. Despite several current limitations, such as incomplete maturation, lack of full nephron segmentation, and variability between protocols and cell conditions, further technological innovations such as microfluidics and bioengineering may refine kidney organoid systems. This review highlights recent advances in kidney organoid research, outlines major applications, and discusses future directions to enhance their physiological relevance, functional maturity, and translational integration into preclinical and clinical nephrology. No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 0385-2407 52 10 2025 Biologics and Small‐Molecule Therapies in Netherton Syndrome: A Comprehensive Review 1483 1493 EN Shin Morizane Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tomoyuki Mukai Department of Immunology and Molecular Genetics, Kawasaki Medical School Ko Sunagawa Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ken‐ichi Hasui Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Anri Morita Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hayato Nomura Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Mamoru Ouchida Department of Molecular Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Netherton syndrome (NS) is a rare congenital ichthyosis caused by loss-of-function mutations in the SPINK5 gene, leading to defective expression of the serine protease inhibitor LEKTI. Dysregulated epidermal protease activity results in impaired skin barrier function and chronic inflammation, accompanied by complex immune profiles. NS patients commonly show activation of the inflammatory axis, centered on IL-17 and IL-36, in the skin and blood, and show a psoriasis-like shift to Th17. Conversely, the immune profile differs depending on the clinical type, with ichthyosis linearis circumflexa type characterized by complement activation and Th2-type allergic responses, and scaly erythroderma type characterized by a type I IFN signature and Th9-type allergic responses. While symptomatic treatments such as emollients and topical corticosteroids have been the mainstay of care, recent advances have opened new therapeutic avenues involving biologic agents and oral small-molecule immunomodulators. This review provides a comprehensive overview of the current clinical landscape and future directions of biologics (e.g., dupilumab, secukinumab, ustekinumab) and small-molecule therapies (e.g., JAK inhibitors such as tofacitinib, baricitinib, and upadacitinib) in the treatment of NS. Though evidence remains limited to case reports and small series, preliminary data suggest that cytokine-targeted interventions—particularly those inhibiting IL-4, IL-13, IL-17, IL-36, and JAK pathways—may offer tangible clinical benefits. Well-designed clinical trials and mechanistic investigations are crucial to establishing their place in NS management. No potential conflict of interest relevant to this article was reported.

Ovid Technologies (Wolters Kluwer Health) Acta Medica Okayama 2376-7839 11 5 2025 Vanishing White Matter Disease With EIF2B2 c.254T >A Variant e200293 EN Toshiyuki Kakumoto Department of Neurology, Graduate School of Medicine, The University of Tokyo Takashi Matsukawa Department of Neurology, Graduate School of Medicine, The University of Tokyo Ryo Tokimura Department of Neurology, Graduate School of Medicine, The University of Tokyo Yoko Tsuboyama Department of Neurology, Graduate School of Medicine, The University of Tokyo Yasufumi Hayashi Department of Neurology, Graduate School of Medicine, The University of Tokyo Akihiko Mitsutake Department of Neurology, Graduate School of Medicine, The University of Tokyo Atsushi Iwata Department of Neurology, Graduate School of Medicine, The University of Tokyo Meiko Hashimoto Maeda Department of Neurology, Graduate School of Medicine, The University of Tokyo Jun Shimizu Department of Neurology, Graduate School of Medicine, The University of Tokyo Wataru Gonoi Department of Radiology, Graduate School of Medicine, The University of Tokyo Hiroyuki Ishiura Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Jun Mitsui Department of Neurology, Graduate School of Medicine, The University of Tokyo Shoji Tsuji Department of Molecular Neurology, Graduate School of Medicine, The University of Tokyo Tatsushi Toda Department of Neurology, Graduate School of Medicine, The University of Tokyo Objectives Typical MRI findings of vanishing white matter disease (VWM) include diffuse white matter lesions with cystic degeneration. However, mild cases may lack these typical features, posing diagnostic challenges. Methods We describe 2 of 3 individuals carrying the homozygous c.254T >A variant in EIF2B2 identified at our hospital, excluding 1 previously reported case.1 Genetic analyses were performed using whole-genome sequence or whole-exome sequence analysis, and detected variants were confirmed by direct nucleotide sequence analysis. Brain MRI findings and clinical features were reviewed for the 2 individuals along with other cases in the literature with the same variant. Results A 69-year-old woman presented with recurrent transient dizziness and secondary amenorrhea. MRI of the brain revealed small T2-hyperintense lesions confined to the subcortical white matter with hyperintensities on diffusion-weighted images and mildly elevated apparent diffusion coefficient values. A 28-year-old woman presented with transient dizziness and secondary amenorrhea. MRI of the brain showed mild T2-hyperintense lesions in the cerebral white matter with frontal predominance. Discussion This report highlights the clinically mild cases of VWM with subtle abnormalities on brain MRI who had the homozygous c.254T >A in EIF2B2, further expanding the clinical spectrum of VWM and underscoring the importance of genetic assessments in the diagnosis of individuals with mild clinical and MRI findings. No potential conflict of interest relevant to this article was reported.

Elsevier BV Acta Medica Okayama 0022-510X 478 2025 Two Japanese families with adult-onset leukoencephalopathy caused by pathogenic variants in CST3 123708 EN Kenta Orimo Department of Precision Medicine Neurology, Graduate School of Medicine, The University of Tokyo Takashi Matsukawa Department of Neurology, Graduate School of Medicine, The University of Tokyo Kazutaka Shiomi Division of Respirology, Rheumatology, Infectious Diseases, and Neurology, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki Ryoji Goto Department of Neurology, Graduate School of Medicine, The University of Tokyo Akihiko Mitsutake Department of Neurology, Graduate School of Medicine, The University of Tokyo Yumiko Kuromi Department of Neurology, Fukushima Medical University Nozomu Matsuda Department of Neurology, Fukushima Medical University Kazuaki Kanai Department of Neurology, Fukushima Medical University Ryo Kurokawa Department of Radiology, Graduate School of Medicine, The University of Tokyo Hiroyuki Ishiura Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Jun Mitsui Department of Precision Medicine Neurology, Graduate School of Medicine, The University of Tokyo Junko Nomoto Institute of Medical Genomics, International University of Health and Welfare Masaki Tanaka Institute of Medical Genomics, International University of Health and Welfare Yosuke Omae Genome Medical Science Project, National Institute of Global Health and Medicine Yosuke Kawai Genome Medical Science Project, National Institute of Global Health and Medicine Katsushi Tokunaga Genome Medical Science Project, National Institute of Global Health and Medicine Shoji Tsuji Department of Neurology, Graduate School of Medicine, The University of Tokyo Tatsushi Toda Department of Neurology, Graduate School of Medicine, The University of Tokyo CST3 (NM_000099.4) encodes cystatin C, whose C-terminal truncating variants in this gene have recently been reported to cause adult-onset leukoencephalopathy, characterized by headaches, transient neurological symptoms, and distinct imaging findings. We present four patients from two Japanese families, including one with a novel variant (c.358-2_395del). Three patients from one family developed chronic headaches around the age of 20, whereas the patient from the other family remained asymptomatic until his fifties. mRNA analysis of the patient with c.358-2_395del revealed a splicing alteration leading to an in-frame deletion (p.Lys120_Gln133del), representing the first CST3 variant that does not result in a truncated protein. These findings broaden our understanding of the clinical and genetic spectra of CST3-related leukoencephalopathy (114 words). No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 2328-9503 2025 INF2-Related Charcot–Marie–Tooth Disease in a Japanese Cohort: Genetic and Clinical Insights EN Chikashi Yano Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences Masahiro Ando Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences Yujiro Higuchi Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences Jun‐Hui Yuan Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences Akiko Yoshimura Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences Takahiro Hobara Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences Risa Nagatomo Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences Fumikazu Kojima Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences Yu Hiramatsu Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences Satoshi Nozuma Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences Tomonori Nakamura Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences Yusuke Sakiyama Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences Chika Matsuoka Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Toru Yamashita Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takashi Kimura Department of Neurology, Hyogo Medical University Ayako Miyazaki Department of Clinical Genetics, Hyogo Medical University Chinatsu Kinjo Department of Clinical Genetics, Hyogo Medical University Kenji Yokochi Department of Pediatrics, Toyohashi Municipal Hospital Nanami Yamanaka Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine Nozomu Matsuda Department of Neurology, Fukushima Medical University School of Medicine Tomoki Suichi Department of Neurology, Graduate School of Medicine, Chiba University Yoshiyuki Hanaoka Department of Pediatrics, Kurashiki Central Hospital Haruka Kojima Department of Neurology, Tokyo Women's Medical University Kenichi Todo Department of Neurology, Tokyo Women's Medical University Hiroyuki Ishiura Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Jun Mitsui Department of Precision Medicine Neurology, Graduate School of Medicine, The University of Tokyo Shoji Tsuji Department of Neurology, The University of Tokyo Hospital Hiroshi Takashima Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences Background: INF2 mutations cause focal segmental glomerulosclerosis (FSGS) and Charcot–Marie–Tooth disease (CMT). Accurate genetic diagnosis is critical, as INF2-related FSGS is typically resistant to immunotherapy yet rarely recurs after transplantation, and its associated neuropathy can mimic treatable immune-mediated disorders such as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Methods: We performed a multicenter study investigating 3329 Japanese patients with inherited peripheral neuropathies/CMT who underwent gene panel sequencing or whole-exome analysis between 2007 and 2024. Clinical data, including electrophysiological assessments, were obtained from the patients' medical records. Results: We identified six pathogenic INF2 variants in eight patients, all of which were located within the diaphanous inhibitory domain. Structural modeling revealed clustering of variants near the diaphanous autoregulatory domain-binding pocket, which is critical for INF2 autoinhibition. Clinically, all cases were sporadic, with a median age at neurological onset of 9 years. All patients exhibited lower limb weakness, and 6/8 (75%) had sensory disturbances. All patients also developed kidney dysfunction, with 7/8 (88%) progressing to end-stage renal disease at a median age of 15 years. Furthermore, all patients showed demyelinating neuropathy, and 2/8 (25%) received immunotherapy due to suspected immune-mediated neuropathy. Conclusion: Although INF2 variants are a rare cause of CMT in Japan, they should be considered in pediatric patients with demyelinating neuropathy and early-onset proteinuria, even in the absence of a family history. Blood and urine tests assessing renal dysfunction can provide guidance for appropriate genetic testing. No potential conflict of interest relevant to this article was reported.

Elsevier BV Acta Medica Okayama 2213-1779 13 11 2025 Pathophysiology and Therapeutic Needs in Nonobstructive Hypertrophic Cardiomyopathy 102658 EN Milind Y. Desai HCM Center, Department of Cardiovascular Medicine, Cleveland Clinic Niccolo Maurizi Cardiomyopathy Unit, Careggi University Hospital Elena Biagini Cardiology Unit, Cardiac Thoracic and Vascular Department, IRCCS Azienda Ospedaliero-Universitaria di Bologna Philippe Charron European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart (ERN GUARD-Heart) Fabio Fernandes InCor, Faculdade de Medicina da Universidade de São Paulo Esther González-López Puerta de Hierro Majadahonda University Hospital, Health Research Institute of the Puerta de Hierro Majadahonda-Segovia de Arana University Hospital (IDIPHISA) Paul L. van Haelst Cardiovascular Division, Department of Medicine, University of Virginia Health Kristina Hermann Haugaa Cardiovascular Division, Department of Medicine, University of Virginia Health Christopher M. Kramer Cardiovascular Division, Department of Medicine, University of Virginia Health Benjamin Meder Department of Internal Medicine III, Institute for Cardiomyopathies, University of Heidelberg Michelle Michels European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart (ERN GUARD-Heart) Anjali Owens Center for Inherited Cardiovascular Disease, Division of Cardiovascular Medicine, Department of Medicine, Perelman School of Medicine, University of Pennsylvania Shinsuke Yuasa Department of Cardiovascular Medicine, Academic Field, Dentistry and Pharmaceutical Sciences, Okayama University Perry Elliott UCL Institute of Cardiovascular Science and St Bartholomew’s Hospital Hypertrophic cardiomyopathy (HCM) affects individuals worldwide with an estimated prevalence of over 1 in 500 individuals. Nonobstructive HCM accounts for approximately 30% to 70% of cases, is extremely heterogeneous, and is associated with a notable degree of morbidity, including daily life limitations, ventricular tachyarrhythmias, progression to heart failure, and atrial fibrillation. No approved pharmaceutical therapies target the pathophysiology of nonobstructive HCM, although several clinical trials are underway. This narrative review provides a comprehensive overview of nonobstructive HCM, focusing on epidemiology, natural history, genetics, pathophysiology, clinical manifestations, diagnosis, burden of disease, and current treatments and ongoing clinical trials. No potential conflict of interest relevant to this article was reported.

MDPI AG Acta Medica Okayama 1422-0067 26 19 2025 Cardiac Myosin Inhibitors in Hypertrophic Cardiomyopathy: From Sarcomere to Clinic 9347 EN Kazufumi Nakamura Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takahiro Okumura Department of Advanced Cardiovascular Therapeutics, Nagoya University Graduate School of Medicine Seiya Kato Division of Pathology, Saiseikai Fukuoka General Hospital Kenji Onoue Department of Cardiovascular Medicine, Nara Medical University Toru Kubo Department of Cardiology and Geriatrics, Kochi Medical School, Kochi University Hidemichi Kouzu Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine Toshiyuki Yano Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine Takayuki Inomata Department of Cardiovascular Medicine, Niigata University Graduate School of Medical and Dental Sciences Hypertrophic cardiomyopathy (HCM) is a primary myocardial disease characterized by unexplained left ventricular hypertrophy, often resulting from pathogenic variants of sarcomeric protein genes. Conventional treatments, such as the use of beta blockers or calcium channel blockers, focus on symptomatic control but do not address the underlying hypercontractility at the sarcomere level. Recent advances in molecular understanding have led to the development of cardiac myosin inhibitors that directly modulate sarcomeric function by reducing myosin–actin cross-bridge formation and adenosine triphosphatase (ATPase) activity. Mavacamten and aficamten have shown promising results in phase 2 and 3 clinical trials, improving symptoms, exercise capacity, and left ventricular outflow tract gradients in patients with obstructive HCM. This review summarizes the current understanding of HCM pathophysiology, diagnostic strategies, and conventional treatments with a focus on the mechanisms of action of myosin inhibitors, clinical evidence supporting their use, and future directions for improvement. We also discuss their potential applications in non-obstructive HCM and the importance of precision medicine guided by genetic profiling. No potential conflict of interest relevant to this article was reported.

JMIR Publications Inc. Acta Medica Okayama 1929-0748 14 2025 Optimization of Preemptive Therapy for Cytomegalovirus Infections With Valganciclovir Based on Therapeutic Drug Monitoring: Protocol for a Phase II, Single-Center, Single-Arm Trial e72549 EN Naoki Tamura Department of Pharmacy, Kobe University Hospital Kotaro Itohara Department of Pharmacy, Kobe University Hospital Yo Ueda Department of Rheumatology and Clinical Immunology, Kobe University Graduate School of Medicine Yumi Kitahiro Department of Pharmacy, Kobe University Hospital Kazuhiro Yamamoto Department of Integrated Clinical and Basic Pharmaceutical Sciences, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Tomohiro Omura Department of Pharmacy, Kobe University Hospital Toshiyasu Sakane Department of Pharmaceutical Technology, Kobe Pharmaceutical University Jun Saegusa Department of Rheumatology and Clinical Immunology, Kobe University Graduate School of Medicine Ikuko Yano Department of Pharmacy, Kobe University Hospital Background: Valganciclovir (VGCV) is the first-line drug for preemptive therapy of cytomegalovirus (CMV) infections. However, even when administered at the dose specified in the package insert, there is significant interindividual variability in the plasma concentrations of ganciclovir (GCV). In addition, correlations have been reported between the area under the concentration–time curve and therapeutic efficacy or adverse events. Therefore, therapeutic drug monitoring (TDM) can be used to improve the efficacy and safety of preemptive VGCV therapy. Objective: This study aims to evaluate whether the dosage adjustment of VGCV based on TDM in patients undergoing preemptive therapy for CMV infections is associated with the successful completion rate of treatment without severe hematological adverse effects. Methods: This phase II, single-center, single-arm trial aims to enroll 40 patients admitted at the Department of Rheumatology and Clinical Immunology, Kobe University Hospital, who will receive oral VGCV as preemptive therapy for CMV infections. Participants will begin treatment with VGCV at the dose recommended in the package insert, with subsequent dose adjustments based on weekly TDM results. The primary end point will be the proportion of patients who achieve CMV antigenemia negativity within 3 weeks without severe hematological adverse events. The secondary end points will include weekly changes in CMV antigen levels, total VGCV dose, and duration of preemptive therapy. For safety evaluation, the occurrence, type, and severity of VGCV-related adverse events will be analyzed. Additionally, this study will explore the correlations between the efficacy and safety of preemptive therapy and the pharmacokinetic parameters of GCV, CMV-polymerase chain reaction values, and nudix hydrolase 15 (NUDT15) genetic polymorphisms. The correlation between GCV plasma concentrations obtained from regular venous blood and blood concentrations will be examined using dried blood spots. Results: This study began with patient recruitment in September 2024, with 5 participants enrolled as of June 16, 2025. The target enrollment is 40 participants, and the anticipated study completion is set for July 2027. Conclusions: This is the first study to investigate the impact of TDM intervention in patients receiving VGCV as preemptive therapy. The findings are postulated to provide valuable evidence regarding the utility of TDM in patients receiving VGCV as preemptive therapy. Trial Registration: Japan Registry of Clinical Trials jRCTs051240080; https://jrct.mhlw.go.jp/latest-detail/jRCTs051240080 International Registered Report Identifier (IRRID): DERR1-10.2196/72549 No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 2692-4609 6 1 2025 Adequacy evaluation of 22‐gauge needle endoscopic ultrasound‐guided tissue acquisition samples and glass slides preparation for successful comprehensive genomic profiling testing: A single institute experience e70104 EN Tami Nagatani Clinical Genomic Medicine, Dentistry and Pharmaceutical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yoji Wani Department of Pathology, Japanese Red Cross Society, Himeji Red Cross Hospital Masahiro Takatani Department of Internal Medicine, Japanese Red Cross Society, Himeji Red Cross Hospital Soichiro Fushimi Department of Pathology, Japanese Red Cross Society, Himeji Red Cross Hospital Hirofumi Inoue Division of Medical Support, Dentistry and Pharmaceutical Science, Okayama University Graduate School of Medicine Shinichiro Hori Department of Internal Medicine, Japanese Red Cross Society, Himeji Red Cross Hospital Kyohei Kai Department of Genetic Medicine, Japanese Red Cross Society, Himeji Red Cross Hospital Hideki Yamamoto Clinical Genomic Medicine, Dentistry and Pharmaceutical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tetsuya Okazaki Clinical Genomic Medicine, Dentistry and Pharmaceutical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Maki Tanioka Clinical Genomic Medicine, Dentistry and Pharmaceutical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hiroyuki Okada Department of Internal Medicine, Japanese Red Cross Society, Himeji Red Cross Hospital Akira Hirasawa Clinical Genomic Medicine, Dentistry and Pharmaceutical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Objectives: This study aimed to evaluate the successful sequencing rate of Foundation One CDx (F1CDx) using small tissue samples obtained with a 22-gauge needle (22G) through endoscopic ultrasound-guided fine needle acquisition (EUS-TA) and to propose guidelines for tissue quantity evaluation criteria and proper slide preparation in clinical practice. Methods: Between June 2019 and April 2024, 119 samples of 22G EUS-TA collected for F1CDx testing at Himeji Red Cross Hospital were retrospectively reviewed. Tissue adequacy was only assessed based on tumor cell percentage (≥20%). The procedure stopped when white tissue fragments reached 20 mm during macroscopic on-site evaluation. The specimens were prepared using both ‘tissue preserving sectioning’ to retain tissue within formalin-fixed paraffin-embedded blocks and the ‘thin sectioning matched needle gauge and tissue length’ method with calculation to ensure minimal unstained slides for the 1 mm3 sample volume criterion. Tissue area from HE slides and sample volume were measured, and F1CDx reports were analyzed. Results: Of 119 samples, 108 (90.8%) were suitable for F1CDx. Excluding the cases not submitted for testing, in the 45 cases where F1CDx was done using 22G EUS-TA samples, eight (17.8%) had a sum of tissue area tissue of 25 mm2 or greater in the HE-stained sample. However, all cases met the F1CDx 1 mm3 volume criterion by submitting > 30 unstained slides per sample. As a result, 43 of 45 cases (95.6%) were successfully analyzable. Conclusions: The 22G EUS-TA needle is an effective tool for providing the sufficient tissue volume required for F1CDx. No potential conflict of interest relevant to this article was reported.

Elsevier BV Acta Medica Okayama 0091-6749 156 2 2025 Dried blood spot proteome identifies subclinical interferon signature in neonates with type I interferonopathy 473 479.e1 EN Hiroshi Nihira Department of Pediatrics, Kyoto University Graduate School of Medicine Daisuke Nakajima Department of Applied Genomics, Kazusa DNA Research Institute Kazushi Izawa Department of Pediatrics, Kyoto University Graduate School of Medicine Yusuke Kawashima Department of Applied Genomics, Kazusa DNA Research Institute Hirofumi Shibata Department of Pediatrics, Kyoto University Graduate School of Medicine Ryo Konno Department of Applied Genomics, Kazusa DNA Research Institute Motoko Higashiguchi Department of Pediatrics, Kyoto University Graduate School of Medicine Takayuki Miyamoto Department of Pediatrics, Kyoto University Graduate School of Medicine Masahiko Nishitani-Isa Department of Pediatrics, Kyoto University Graduate School of Medicine Eitaro Hiejima Department of Pediatrics, Kyoto University Graduate School of Medicine Yoshitaka Honda Department of Pediatrics, Kyoto University Graduate School of Medicine Tadashi Matsubayashi Department of Pediatrics, Seirei Hamamatsu General Hospital Takashi Ishihara Department of Pediatrics, Nara Medical University Masato Yashiro Department of Pediatrics, Okayama University Naomi Iwata Department of Infection and Immunology, Aichi Children’s Health and Medical Center Yoko Ohwada Department of Pediatrics, Dokkyo Medical University School of Medicine Seiichi Tomotaki Department of Pediatrics, Kyoto University Graduate School of Medicine Masahiko Kawai Department of Neonatology, Kyoto University Graduate School of Medicine Kosaku Murakami Center for Cancer Immunotherapy and Immunobiology, Kyoto University Graduate School of Medicine Hidenori Ohnishi Department of Pediatrics, Gifu University Graduate School of Medicine Masataka Ishimura Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University Satoshi Okada Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences Motoi Yamashita Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo (SCIENCE TOKYO) Tomohiro Morio Laboratory of Immunology and Molecular Medicine, Advanced Research Initiative, Institute of Science Tokyo (SCIENCE TOKYO) Akihiro Hoshino Department of Child Health and Development, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo (SCIENCE TOKYO) Hirokazu Kanegane Department of Child Health and Development, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo (SCIENCE TOKYO) Kohsuke Imai Department of Pediatrics, National Defense Medical College Yasuko Nakamura Department of Pediatrics, National Defense Medical College Shigeaki Nonoyama Department of Pediatrics, National Defense Medical College Toru Uchiyama Department of Human Genetics, National Center for Child Health and Development Masafumi Onodera Department of Human Genetics, National Center for Child Health and Development Takashi Ishikawa Division of Immunology, National Center for Child Health and Development Toshinao Kawai Division of Immunology, National Center for Child Health and Development Junko Takita Department of Pediatrics, Kyoto University Graduate School of Medicine Ryuta Nishikomori Department of Pediatrics and Child Health, Kurume University School of Medicine Osamu Ohara Department of Applied Genomics, Kazusa DNA Research Institute Takahiro Yasumi Department of Pediatrics, Kyoto University Graduate School of Medicine Background: Type I interferonopathy is characterized by aberrant upregulation of type I interferon signaling. The mRNA interferon signature is a useful marker for activation of the interferon pathway and for diagnosis of type I interferonopathy; however, early diagnosis is challenging. Objective: This study sought to identify the proteomic interferon signature in dried blood spot (DBS) samples. The aim was to evaluate the usefulness of the interferon signature for neonatal screening and to gain insight into presymptomatic state of neonates with inborn errors of immunity (IEIs). Methods: DBS samples from healthy newborns/adults, patients with type I interferonopathy or other IEIs as well as from neonates with viral infections, including some samples obtained during the presymptomatic neonatal period, were examined by nontargeted proteome analyses. Expression of interferon-stimulated genes (ISGs) was evaluated and a DBS-interferon signature was defined. Differential expression/pathway analysis was also performed. Results: The ISG products IFIT5, ISG15, and OAS2 were detected. Expression of IFIT5 and ISG15 was upregulated significantly in individuals with type I interferonopathy. We defined the sum of the z scores for these as the DBS-interferon signature, and found that patients with IEIs other than type I interferonopathy, such as chronic granulomatous disease (CGD), also showed significant elevation. Additionally, neonatal samples of type I interferonopathy and CGD patients showed high interferon signatures. Pathway analysis of neonatal CGD samples revealed upregulation of systemic lupus erythematosus–like pathways. Conclusion: Upregulation of the interferon pathway exists already at birth—not only in neonates with type I interferonopathy but also in other IEIs, including CGD. No potential conflict of interest relevant to this article was reported.

Japanese Society of Internal Medicine Acta Medica Okayama 0918-2918 64 15 2025 Clinical and Genetic Analyses of SPG7 in Japanese Patients with Undiagnosed Ataxia 2290 2294 EN Akihiko Mitsutake Department of Neurology, Graduate School of Medicine, The University of Tokyo Takashi Matsukawa Department of Neurology, Graduate School of Medicine, The University of Tokyo Rimi Hino Department of Neurology, Graduate School of Medicine, The University of Tokyo Go Fujino Department of Neurology, Graduate School of Medicine, The University of Tokyo Yuto Sakai Department of Neurology, International University of Health and Welfare Mita Hospital Jun Mitsui Department of Precision Medicine Neurology, Graduate School of Medicine, The University of Tokyo Hiroyuki Ishiura Department of Neurology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Nobue K. Iwata Department of Neurology, International University of Health and Welfare Mita Hospital Shoji Tsuji Department of Precision Medicine Neurology, Graduate School of Medicine, The University of Tokyo Tatsushi Toda Department of Neurology, Graduate School of Medicine, The University of Tokyo Objective Spastic paraplegia 7 (SPG7) is an autosomal recessive neurodegenerative disorder caused by biallelic pathogenic variants in SPG7. It is predominantly characterized by adult-onset slowly progressive spastic paraparesis. While SPG7 presenting with ataxia with or without spasticity is relatively common in Europe and North America, it is considered rare in Japan. This study aimed to identify SPG7 patients among those with undiagnosed ataxia within the Japanese population. Methods We retrospectively selected 351 patients with undiagnosed ataxia, excluding those with secondary and common spinocerebellar ataxia. Whole-exome sequence analysis was conducted, and homozygosity of the identified variants was confirmed using droplet digital polymerase chain reaction (ddPCR). Results Among the 351 patients, 2 were diagnosed with SPG7, and homozygosity was confirmed by ddPCR. Both patients carried homozygous pathogenic variants in SPG7: c.1948G>A, p.Asp650Asn, and c.1192C>T, p.Arg398Ter (NM_003119.4). Clinically, both patients presented with progressive ataxia. In addition, Patient 1 exhibited partial ophthalmoplegia and spastic paraparesis, whereas Patient 2 demonstrated cerebellar ataxia without spasticity. Conclusion The rarity of SPG7 in Japan may be attributed to variation in the minor allele frequency of the c.1529C>T, p.Ala510Val variant, which is more prevalent in Europe and North America than in other areas. No potential conflict of interest relevant to this article was reported.

Elsevier BV Acta Medica Okayama 0022-510X 472 2025 Clinical, neuroimaging and genetic findings in the Japanese case series of CLCN2-related leukoencephalopathy 123486 EN Kenta Orimo Department of Neurology, Graduate School of Medicine, The University of Tokyo Takashi Matsukawa Department of Neurology, Graduate School of Medicine, The University of Tokyo Akihiko Mitsutake Department of Neurology, Graduate School of Medicine, The University of Tokyo Takusei Cho Department of Neurology, Graduate School of Medicine, The University of Tokyo Hiroya Naruse Department of Neurology, Graduate School of Medicine, The University of Tokyo Yoshio Sakiyama Division of Neurology, First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University Kensho Sumi Department of Neurology, Mitsui Memorial Hospital Naohiro Uchio Department of Neurology, Mitsui Memorial Hospital Akane Satake Department of Neurology, Fuefuki Central Hospital Yoshihisa Takiyama Department of Neurology, Fuefuki Central Hospital Takuya Matsushita Department of Neurology, Kochi Medical School, Kochi University Yosuke Omae Genome Medical Science Project, National Center for Global Health and Medicine Yosuke Kawai Genome Medical Science Project, National Center for Global Health and Medicine Katsushi Tokunaga Genome Medical Science Project, National Center for Global Health and Medicine Jun Mitsui Department of Precision Medicine Neurology, Graduate School of Medicine, The University of Tokyo Hiroyuki Ishiura Department of Neurology, Graduate School of Medicine, The University of Tokyo Shoji Tsuji Department of Neurology, Graduate School of Medicine, The University of Tokyo Tatsushi Toda Department of Neurology, Graduate School of Medicine, The University of Tokyo Biallelic loss-of-function variants in CLCN2 lead to CLCN2-related leukoencephalopathy (CC2L), also called leukoencephalopathy with ataxia (LKPAT). CC2L is characterized clinically by a spectrum of clinical presentations including childhood- to adult-onset mild ataxia, spasticity, cognitive decline, and vision loss as well as typical MRI findings of symmetrical high signal intensities on the DWIs/T2WIs of the middle cerebellar peduncles (MCPs). We searched for pathogenic variants of CLCN2 in a case series of undiagnosed leukoencephalopathy accompanied by MCP signs, which led to the identification of four Japanese patients with CC2L. All the patients carried at least one allele of c.61dupC (p.Leu21Profs*27) in CLCN2, including compound heterozygosity with either the novel pathogenic variant c.983 + 2 T > A or the previously reported pathogenic variant c.1828C > T (p.Arg610*). Of note, all the four previously reported cases from Japan also harbored c.61dupC, and no reports of this variant have been documented from outside Japan. The allele frequency of c.61dupC in the Japanese population is 0.002152, raising the possibility of a relatively high prevalence of CC2L in Japan. Patients in this study developed symptoms after the age of 30, and demonstrated neurological signs including cerebellar ataxia, pyramidal signs, and mild cognitive impairment, consistent with previous reports. One male patient had two children, supporting preserved fertility, and another patient had calcifications in the cerebral and cerebellar surfaces. These findings provide valuable insights into the broader clinical and genetic spectra of CC2L in the Japanese population, and emphasize the importance of considering this disease in the differential diagnoses of leukoencephalopathy with MCP signs. No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 2692-4609 4 1 2023 Alcohol consumption, multiple Lugol‐voiding lesions, and field cancerization e261 EN Chikatoshi Katada Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University Tetsuji Yokoyama Department of Health and Promotion, National Institute of Public Health Tomonori Yano Department of Gastroenterology and Endoscopy, National Cancer Center Hospital East Haruhisa Suzuki Endoscopy Division, National Cancer Center Hospital Yasuaki Furue Department of Gastroenterology, Kitasato University School of Medicine Keiko Yamamoto Division of Endoscopy, Hokkaido University Hospital Hisashi Doyama Department of Gastroenterology, Ishikawa Prefectural Central Hospital Tomoyuki Koike Division of Gastroenterology, Tohoku University Graduate School of Medicine Masashi Tamaoki Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University Noboru Kawata Division of Endoscopy, Shizuoka Cancer Center Motohiro Hirao Department of Surgery, National Hospital Organization Osaka National Hospital Yoshiro Kawahara Department of Practical Gastrointestinal Endoscopy, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Takashi Ogata Department of Gastroenterology, Kanagawa Cancer Center Atsushi Katagiri Department of Medicine, Division of Gastroenterology, Showa University Hospital Takenori Yamanouchi Department of Gastroenterology, Kumamoto Regional Medical Center Hirofumi Kiyokawa Division of Gastroenterology, Department of Internal Medicine, St. Marianna University School of Medicine Hirofumi Kawakubo Department of Surgery, Kawasaki Municipal Kawasaki Hospital Maki Konno Department of Gastroenterology, Tochigi Cancer Center Akira Yokoyama Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University Shinya Ohashi Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University Yuki Kondo Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University Yo Kishimoto Department of Otolaryngology-Head and Neck Surgery, Kyoto University Hospital Koichi Kano Department of Otorhinolaryngology-Head and Neck Surgery, Kitasato University School of Medicine Kanae Mure Department of Public Health, Wakayama Medical University School of Medicine Ryuichi Hayashi Department of Head and Neck Surgery, National Cancer Center Hospital East Hideki Ishikawa Department of Molecular-Targeting Prevention, Kyoto Prefectural University of Medicine Akira Yokoyama Clinical Research Unit, National Hospital Organization Kurihama Medical and Addiction Center Manabu Muto Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University The development of multiple squamous cell carcinomas (SCC) in the upper aerodigestive tract, which includes the oral cavity, pharynx, larynx, and esophagus, is explained by field cancerization and is associated with alcohol consumption and cigarette smoking. We reviewed the association between alcohol consumption, multiple Lugol-voiding lesions, and field cancerization, mainly based on the Japan Esophageal Cohort study. The Japan Esophageal Cohort study is a prospective cohort study that enrolled patients with esophageal SCC after endoscopic resection. Enrolled patients received surveillance by gastrointestinal endoscopy every 6 months and surveillance by an otolaryngologist every 12 months. The Japan Esophageal Cohort study showed that esophageal SCC and head and neck SCC that developed after endoscopic resection for esophageal SCC were associated with genetic polymorphisms related to alcohol metabolism. They were also associated with Lugol-voiding lesions grade in the background esophageal mucosa, the score of the health risk appraisal model for predicting the risk of esophageal SCC, macrocytosis, and score on alcohol use disorders identification test. The standardized incidence ratio of head and neck SCC in patients with esophageal SCC after endoscopic resection was extremely high compared to the general population. Drinking and smoking cessation is strongly recommended to reduce the risk of metachronous esophageal SCC after treatment of esophageal SCC. Risk factors for field cancerization provide opportunities for early diagnosis and minimally invasive treatment. Lifestyle guidance of alcohol consumption and cigarette smoking for esophageal precancerous conditions, which are endoscopically visualized as multiple Lugol-voiding lesions, may play a pivotal role in decreasing the incidence and mortality of esophageal SCC. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 79 4 2025 Effectiveness of Pallidal Stimulation for Dystonic Storm and Subsequent Ssevere Posterior Reversible Encephalopathy Syndrome in a Patient with GNAO1 Variant 293 297 EN Koji Kawai Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tatsuya Sasaki Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shun Tanimoto Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tomoya Saijo Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Susumu Sasada Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tomoyuki Akiyama Department of Pediatric Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takuya Hiraide Department of Biochemistry, Hamamatsu University School of Medicine Hirotomo Saitsu Department of Biochemistry, Hamamatsu University School of Medicine Shota Tanaka Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Case Report 10.18926/AMO/69156 GNAO1 variant affects primarily the brain and neurodevelopment, leading to a range of motor disorders including seizures beginning in infancy and involuntary movements such as dyskinesia and dystonia. Our patient, a 15-year-old Japanese female, began exhibiting involuntary movements at age 4. A de novo missense mutation (NM_020988.3: c.228C>G, NP_066268.1: p.(Asn76Lys)) in the GNAO1 gene was identified when the patient was 15, and during the same year she developed influenza pneumonia, accompanied by dystonic storm. She required intensive care with mechanical ventilation and underwent a tracheostomy. She also developed posterior reversible encephalopathy syndrome. Globus pallidal stimulation was administered, leading to an improvement in the dystonic storm. Early consideration of globus pallidal stimulation is recommended when treating difficult-to-manage dystonic storms. No potential conflict of interest relevant to this article was reported.

Elsevier BV Acta Medica Okayama 0387-7604 47 1 2025 Hypotheses of pathophysiological mechanisms in epileptic encephalopathies: A review 104318 EN Katsuhiro Kobayashi Department of Pediatrics, Asahigawaso Rehabilitation and Medical Center Takashi Shibata Department of Pediatric Neurology, Okayama University Hospital and Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Hiroki Tsuchiya Department of Pediatric Neurology, Okayama University Hospital and Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Mari Akiyama Department of Pediatric Neurology, Okayama University Hospital and Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Tomoyuki Akiyama Department of Pediatric Neurology, Okayama University Hospital and Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Introduction: Epileptic encephalopathy (EE) is a serious clinical issue that manifests as part of developmental and epileptic encephalopathy (DEE), particularly in childhood epilepsy. In EE, neurocognitive functions and behavior are impaired by intense epileptiform electroencephalogram (EEG) activity. Hypotheses of pathophysiological mechanisms behind EE are reviewed to contribute to an effective solution for EE. Review: Current hypotheses are as follows: 1) neuronal dysfunction based on genetic abnormalities that may affect neurocognitive functions and epilepsy separately; 2) impairment of synaptic homeostasis during sleep that may be responsible for DEE/EE with spike-and-wave activation in sleep; 3) abnormal subcortical regulation of the cerebral cortex; 4) abnormal cortical metabolism and hemodynamics with impairment of the neural network including default mode network; 5) neurotransmitter imbalance and disordered neural excitability; 6) the effects of neuroinflammation that may be caused by epileptic seizures and in turn aggravate epileptogenesis; 7) the interaction between physiological and pathological high-frequency EEG activity; etc. The causal relationship between epileptiform EEG activity and neurocognitive dysfunctions is small in DEE based on genetic abnormalities and it is largely unestablished in the other hypothetical mechanisms. Conclusion: We have not yet found answers to the question of whether the single-central or multiple derangements are present and what seizures and intense epileptiform EEG abnormalities mean in EE. We need to continue our best efforts in both aspects to elucidate the pathophysiological mechanisms of DEE/EE and further develop epilepsy treatment and precision medicine. No potential conflict of interest relevant to this article was reported.

Springer Science and Business Media LLC Acta Medica Okayama 0340-5354 272 1 2024 Genetic and functional analyses of SPTLC1 in juvenile amyotrophic lateral sclerosis 36 EN So Okubo Department of Neurology, Graduate School of Medicine, The University of Tokyo Hiroya Naruse Department of Neurology, Graduate School of Medicine, The University of Tokyo Hiroyuki Ishiura Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Atsushi Sudo Department of Neurology, Graduate School of Medicine, The University of Tokyo Kayoko Esaki Department of Biotechnology and Life Sciences, Faculty of Biotechnology and Life Sciences, Sojo University Jun Mitsui Department of Neurology, Graduate School of Medicine, The University of Tokyo Takashi Matsukawa Department of Neurology, Graduate School of Medicine, The University of Tokyo Wataru Satake Department of Neurology, Graduate School of Medicine, The University of Tokyo Peter Greimel Laboratory for Cell Function Dynamics, RIKEN Centre for Brain Sciences Nanoka Shingai Division of Applied Life Science, Graduate School of Engineering, Sojo University Yasushi Oya Department of Neurology, National Center of Neurology and Psychiatry Takeo Yoshikawa Laboratory of Molecular Psychiatry, RIKEN Center for Brain Science Shoji Tsuji Department of Neurology, Graduate School of Medicine, The University of Tokyo Tatsushi Toda Department of Neurology, Graduate School of Medicine, The University of Tokyo Introduction Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder of the motor system. Pathogenic variants in SPTLC1, encoding a subunit of serine palmitoyltransferase, cause hereditary sensory and autonomic neuropathy type 1 (HSAN1), and have recently been associated with juvenile ALS. SPTLC1 variants associated with ALS cause elevated levels of sphinganines and ceramides. Reports on ALS associated with SPTLC1 remain limited. This study aimed to investigate the frequency of SPTLC1 variants in ALS and relevant clinical characteristics. Methods We analyzed whole-exome and whole-genome sequence data from 40 probands with familial ALS and 413 patients with sporadic ALS without previously identified causative variants. Reverse transcription polymerase chain reaction (RT-PCR) analysis and droplet digital PCR (ddPCR) were used to assess splicing and mosaicism, respectively. Plasma sphingolipid levels were quantified to analyze biochemical consequences. Results The heterozygous c.58G>A, p.Ala20Thr variant was identified in a 21-year-old Japanese female patient presenting with symmetric weakness which slowly progressed over 15 years. RT-PCR analysis showed no splice defects. Plasma sphingolipid levels in the patient were significantly increased compared to her asymptomatic parents. ddPCR revealed that the asymptomatic father harbored a mosaic variant with 17% relative mutant allele abundance in peripheral blood leukocytes. Conclusions We identified a pathogenic c.58G>A, p.Ala20Thr SPTLC1 variant in a patient with juvenile ALS, likely inherited from an asymptomatic parent with mosaicism. Lipid analysis results are consistent with previous findings on SPTLC1-associated ALS. Further studies are necessary to determine the clinical effect of mosaic variants of SPTLC1. No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 2475-0328 8 6 2024 High risk of multiple gastric cancers in Japanese individuals with Lynch syndrome 1008 1016 EN Nobuhiko Kanaya Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Thijs A. van Schaik Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School Hideki Aoki Department of Surgery, National Hospital Organization Iwakuni Clinical Center Yumiko Sato Department of Pathology, National Hospital Organization Iwakuni Clinical Center Fumitaka Taniguchi Department of Surgery, National Hospital Organization Iwakuni Clinical Center Kunitoshi Shigeyasu Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kokichi Sugano Department of Genetic Medicine, Kyoundo Hospital, SSasaki Foundation Kiwamu Akagi Division of Molecular Diagnosis and Cancer Prevention, Saitama Cancer Center Hideyuki Ishida Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University Kohji Tanakaya Department of Surgery, National Hospital Organization Iwakuni Clinical Center Aim: Lynch syndrome (LS) is a dominantly inherited syndrome characterized by an increased risk for LS associated tumors such as colorectal cancer (CRC) and gastric cancer (GC). However, the clinical benefit of surveillance for GC remains unclear while it has already been recommended for CRC. This study aimed to elucidate the clinical features of GC in Japanese individuals with LS, and the risk of developing multiple GCs to build regional-tailored surveillance programs in LS patients with GC. Methods: Data on Japanese individuals with LS were retrospectively collected from a single institution. The clinical features of GC, including the cumulative risk of multiple GCs, were analyzed. Results: Among 96 individuals with LS (MLH1/MSH2/MSH6, 75:20:1), 32 GC lesions were detected in 15 individuals with LS (male/female, 11:4). The median age at initial GC diagnosis was 52.7 y (range: 28–71). Histological examination revealed a predominance of intestinal type (19/24: 87.5%). Moreover, the majority of the GC lesions (82%) were determined to have high-frequency of microsatellite instability. The cumulative risk of individuals with LS developing GC at 70 y was 31.3% (MLH1 36.1%, MSH2 18.0%). Notably, the cumulative risk of individuals with LS developing metachronous and/or synchronous GCs at 0, 10 and 20 y after initial diagnosis of GC was 26.7%, 40.7%, and 59.4%, respectively. Conclusion: Due to a higher risk of developing multiple GCs, intensive surveillance might be especially recommended for Japanese individuals with LS associated initial GC. No potential conflict of interest relevant to this article was reported.

Microbiology Society Acta Medica Okayama 0022-1317 106 7 2025 Summary of taxonomy changes ratified by the International Committee on Taxonomy of Viruses (ICTV) from the Animal dsRNA and ssRNA(−) Viruses Subcommittee, 2025 002112 EN Holly R. Hughes Centers for Disease Control and Prevention Matthew J. Ballinger Biological Sciences, Mississippi State University Yiming Bao National Genomics Data Center, China National Center for Bioinformation; Beijing Institute of Genomics, Chinese Academy of Sciences; University of Chinese Academy of Sciences Nicolas Bejerman Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) and Instituto Nacional de Tecnología Agropecuaria (INTA) Kim R. Blasdell CSIRO Health and Biosecurity Thomas Briese Center for Infection and Immunity, and Department of Epidemiology, Mailman School of Public Health, Columbia University Julia Brignone Instituto Nacional de Enfermedades Virales Humanas Dr. Julio I. Maiztegui. INEVH -ANLIS Jean Paul Carrera Instituto Conmemorativo Gorgas de Estudios de la Salud Lander De Coninck Division of Clinical and Epidemiological Virology, KU Leuven William Marciel de Souza Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky Humberto Debat Instituto Nacional de Tecnología Agropecuaria (INTA) Ralf G. Dietzgen QAAFI, The University of Queensland Ralf Dürrwald Robert Koch Institut Mert Erdin Department of Virology, University of Helsinki Anthony R. Fooks Animal and Plant Health Agency (APHA) Kristian M. Forbes Department of Biological Sciences, University of Arkansas Juliana Freitas-Astúa Embrapa Cassava and Fruits Jorge B. Garcia Instituto Nacional de Enfermedades Virales Humanas Dr. Julio I. Maiztegui. INEVH -ANLIS Jemma L. Geoghegan Department of Microbiology and Immunology, University of Otago Rebecca M. Grimwood Department of Microbiology and Immunology, University of Otago Masayuki Horie Osaka International Research Center for Infectious Diseases, Osaka Metropolitan University Timothy H. Hyndman School of Veterinary Medicine, Murdoch University Reimar Johne German Federal Institute for Risk Assessment John D. Klena Viral Special Pathogens Branch, The Centers for Disease Control and Prevention Hideki Kondo Institute of Plant Science and Resources, Okayama University Eugene V. Koonin Computational Biology Branch, Division of Intramural Research National Library of Medicine, National Institutes of Health Alexei Y. Kostygov University of Ostrava Mart Krupovic Institut Pasteur, Université Paris Cité, CNRS UMR6047, Archaeal Virology Unit Jens H. Kuhn Integrated Research Facility at Fort Detrick, National Institute of Allergy and Infectious Diseases, National Institutes of Health Michael Letko Paul G. Allen School for Global Health, Washington State University Jun-Min Li Institute of Plant Virology, Ningbo University Yiyun Liu National Genomics Data Center, China National Center for Bioinformation; Beijing Institute of Genomics, Chinese Academy of Sciences; University of Chinese Academy of Sciences Maria Laura Martin Instituto Nacional de Enfermedades Virales Humanas Dr. Julio I. Maiztegui. INEVH -ANLIS Nathaniel Mull Department of Natural Sciences, Shawnee State University Yael Nazar Instituto Nacional de Enfermedades Virales Humanas Dr. Julio I. Maiztegui. INEVH -ANLIS Norbert Nowotny College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai Health Márcio Roberto Teixeira Nunes Universidade Federal do Pará Arnfinn Lodden Økland Pharmaq Analytiq Dennis Rubbenstroth Institute of Diagnostic Virology, Friedrich-Loeffler-Institut Brandy J. Russell Centers for Disease Control and Prevention Eric Schott Institute of Marine and Environmental Technology, University of Maryland Center for Environmental Science Stephanie Seifert Paul G. Allen School for Global Health, Washington State University Carina Sen Instituto Nacional de Enfermedades Virales Humanas Dr. Julio I. Maiztegui. INEVH -ANLIS Elizabeth Shedroff Viral Special Pathogens Branch, The Centers for Disease Control and Prevention Tarja Sironen Department of Virology, University of Helsinki Teemu Smura Department of Virology, University of Helsinki Camila Prestes Dos Santos Tavares Integrated Group of Aquaculture and Environmental Studies, Federal University of Paraná Robert B. Tesh Department of Pathology, The University of Texas Medical Branch Natasha L. Tilston Department of Microbiology and Immunology, Indiana University School of Medicine Noël Tordo Institut Pasteur Nikos Vasilakis Department of Pathology, The University of Texas Medical Branch Peter J. Walker University of Queensland Fei Wang Wuhan Institute of Virology, Chinese Academy of Sciences Anna E. Whitfield North Carolina State University Shannon L.M. Whitmer Viral Special Pathogens Branch, The Centers for Disease Control and Prevention Yuri I. Wolf Computational Biology Branch, Division of Intramural Research National Library of Medicine, National Institutes of Health Han Xia Wuhan Institute of Virology, Chinese Academy of Sciences Gong-Yin Ye Institute of Insect Sciences, Zhejiang University Zhuangxin Ye Institute of Plant Virology, Ningbo University Vyacheslav Yurchenko University of Ostrava Mingli Zhao Department of Pathobiology and Population Sciences, Royal Veterinary College RNA viruses are ubiquitous in the environment and are important pathogens of humans, animals and plants. In 2024, the International Committee on Taxonomy of Viruses Animal dsRNA and ssRNA(−) Viruses Subcommittee submitted 18 taxonomic proposals for consideration. These proposals expanded the known virosphere by classifying 9 new genera and 88 species for newly detected virus genomes. Of note, newly established species expand the large family of Rhabdoviridae to 580 species. A new species in the family Arenaviridae includes a virus detected in Antarctic fish with a unique split nucleoprotein ORF. Additionally, four new species were established for historically isolated viruses with previously unsequenced genomes. Furthermore, three species were abolished due to incomplete genome sequence information, and one family was moved from being unassigned in the phylum Negarnaviricota into a subphylum and order. Herein, we summarize the 18 ratified taxonomic proposals and the general features of the current taxonomy, thereby supporting public and animal health responses. No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 0361-8609 2025 International Consensus Histopathological Criteria for Subtyping Idiopathic Multicentric Castleman Disease Based on Machine Learning Analysis EN Midori Filiz Nishimura Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Tomoka Haratake Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Yoshito Nishimura Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Asami Nishikori Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Remi Sumiyoshi The Research Program for Intractable Disease by Ministry of Health, Labor and Welfare, Castleman Disease, TAFRO and Related Ddisease Research Group Hideki Ujiie Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Yuri Kawahara Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Tomohiro Koga The Research Program for Intractable Disease by Ministry of Health, Labor and Welfare, Castleman Disease, TAFRO and Related Ddisease Research Group Masao Ueki School of Information and Data Sciences, Nagasaki University Dorottya Laczko Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania Eric Oksenhendler Department of Clinical Immunology, Hôpital Saint-Louis David C. Fajgenbaum Center for Cytokine Storm Treatment and Laboratory, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania Frits van Rhee Myeloma Center, University of Arkansas for Medical Sciences Atsushi Kawakami The Research Program for Intractable Disease by Ministry of Health, Labor and Welfare, Castleman Disease, TAFRO and Related Ddisease Research Group Yasuharu Sato Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Idiopathic multicentric Castleman disease (iMCD) is a rare lymphoproliferative disorder classified into three recognized clinical subtypes—idiopathic plasmacytic lymphadenopathy (IPL), TAFRO, and NOS. Although clinical criteria are available for subtyping, diagnostically challenging cases with overlapping histopathological features highlight the need for an improved classification system integrating clinical and histopathological findings. We aimed to develop an objective histopathological subtyping system for iMCD that closely correlates with the clinical subtypes. Excisional lymph node specimens from 94 Japanese iMCD patients (54 IPL, 28 TAFRO, 12 NOS) were analyzed for five key histopathological parameters: germinal center (GC) status, plasmacytosis, vascularity, hemosiderin deposition, and “whirlpool” vessel formation in GC. Using hierarchical clustering, we visualized subgroups and developed a machine learning-based decision tree to differentiate the clinical subtypes and validated it in an external cohort of 12 patients with iMCD. Hierarchical cluster analysis separated the IPL and TAFRO cases into mutually exclusive clusters, whereas the NOS cases were interspersed between them. Decision tree modeling identified plasmacytosis, vascularity, and whirlpool vessel formation as key features distinguishing IPL from TAFRO, achieving 91% and 92% accuracy in the training and test sets, respectively. External validation correctly classified all IPL and TAFRO cases, confirming the reproducibility of the system. Our histopathological classification system closely aligns with the clinical subtypes, offering a more precise approach to iMCD subtyping. It may enhance diagnostic accuracy, guide clinical decision-making for predicting treatment response in challenging cases, and improve patient selection for future research. Further validation of its versatility and clinical utility is required. No potential conflict of interest relevant to this article was reported.

SAGE Publications Acta Medica Okayama 2214-3599 2025 Recent progress in oculopharyngodistal myopathy research from clinical and genetic viewpoints EN Hiroyuki Ishiura Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Oculopharyngodistal myopathy (OPDM) is a rare muscular disorder characterized by ocular symptoms, pharyngeal symptoms, facial weakness, and distal predominant limb muscle weakness. The cause of the disease was unknown for a long time. Recently, however, it has been reported that expansions of CGG or CCG repeats in LRP12, LOC642361/NUTM2B-AS1, GIPC1, NOTCH2NLC, RILPL1, and ABCD3 are the causes of the disease. Cases sometimes present with neurological symptoms, and the clinical spectrum of diseases caused by expansions of CGG or CCG repeats has been proposed to be called FNOP-spectrum disorder after the names of fragile X-associated tremor/ataxia syndrome, neuronal intranuclear inclusion disease, oculopharyngeal myopathy with leukoencephalopathy, and OPDM. In this article, the recent progress in the field of OPDM is reviewed, and remaining issues in OPDM are discussed. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 79 3 2025 Immunometabolic Regulation of Innate Immunity in Systemic Lupus Erythematosus 147 155 EN Haruki Watanabe Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences Yoshinori Matsumoto Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences Jun Wada Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences Review 10.18926/AMO/68722 Pathogens or their components can induce long-lasting changes in the behavior of innate immune cells, a process analogous to “training” for future threats or environmental adaptation. However, such training can sometimes have unintended consequences, such as the development of autoimmunity. Systemic lupus erythematosus (SLE) is a chronic and heterogeneous autoimmune disease characterized by the production of autoantibodies and progressive organ damage. Innate immunity plays a central role in its pathogenesis, contributing through impaired clearance of apoptotic cells, excessive type I interferon production, and dysregulated formation of neutrophil extracellular traps. Recent studies have revealed that metabolites and nucleic acids derived from mitochondria, a crucial energy production site, directly regulate type I interferon and anti-inflammatory cytokine production. These insights have fueled interest in targeting metabolic pathways as a novel therapeutic approach for SLE, offering promise for improving long-term patient outcomes. No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 2045-7634 14 8 2025 Genomic Differences and Distinct TP53 Mutation Site-Linked Chemosensitivity in Early- and Late-Onset Gastric Cancer e70793 EN Tomohiro Kamio Department of Gastroenterology and Hepatology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Yoshiyasu Kono Department of Gastroenterology and Hepatology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kensuke Hirosuna Department of Regenerative Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Toshiki Ozato Department of Gastroenterology, Okayama University Hospital Hideki Yamamoto Department of Clinical Genomic Medicine, Okayama University Hospital Akira Hirasawa Department of Clinical Genomic Medicine, Okayama University Hospital Daisuke Ennishi Center for Comprehensive Genomic Medicine, Okayama University Hospital Shuta Tomida Center for Comprehensive Genomic Medicine, Okayama University Hospital Shinichi Toyooka Center for Comprehensive Genomic Medicine, Okayama University Hospital Motoyuki Otsuka Department of Gastroenterology and Hepatology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Background: Gastric cancer (GC) in younger patients often exhibits aggressive behavior and a poorer prognosis than that in older patients. Although the clinical differences may stem from oncogenic gene variations, it is unclear whether genetic differences exist between these groups. This study compared the genetic profiles of early- and late-onset GC and evaluated their impact on treatment outcomes. Methods: We analyzed genetic data from 1284 patients with GC in the Japanese nationwide Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database, comparing early-onset (<= 39 years; n = 143) and late-onset (>= 65 years; n = 1141) groups. The influence of TP53 mutations on the time to treatment failure (TTF) with platinum-based chemotherapy and the sensitivity of cancer cells with different TP53 mutation sites to oxaliplatin were assessed in vitro. Results: Early- and late-onset GC showed distinct genetic profiles, with fewer neoantigen-associated genetic changes observed in early-onset cases. In particular, TP53 has distinct mutation sites; R175H and R273 mutations are more frequent in early- and late-onset GC, respectively. The R175H mutation showed higher sensitivity to oxaliplatin in vitro, consistent with the longer TTF in early-onset patients (17.3 vs. 7.0 months, p = 0.013) when focusing on the patients with TP53 mutations. Conclusion: Genomic differences, particularly in TP53 mutation sites, between early- and late-onset GC support the need for age-specific treatment strategies. No potential conflict of interest relevant to this article was reported.

MDPI Acta Medica Okayama 1661-6596 26 6 2025 Involvement of a Novel Variant of FGFR1 Detected in an Adult Patient with Kallmann Syndrome in Regulation of Gonadal Steroidogenesis 2713 EN Yoshiaki Soejima Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yuki Otsuka Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Marina Kawaguchi Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kohei Oguni Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Koichiro Yamamoto Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yasuhiro Nakano Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Miho Yasuda Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kazuki Tokumasu Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Keigo Ueda Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kosei Hasegawa Department of Pediatrics, Okayama University Hospital Nahoko Iwata Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Fumio Otsuka Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Fibroblast growth factor receptor 1 (FGFR1), also known as KAL2, is a tyrosine kinase receptor, and variants of FGFR1 have been detected in patients with Kallmann syndrome (KS), which is a congenital developmental disorder characterized by central hypogonadism and anosmia. Herein, we report an adult case of KS with a novel variant of FGFR1. A middle-aged male was referred for a compression fracture of a lumbar vertebra. It was shown that he had severe osteoporosis, anosmia, gynecomastia, and a past history of operations for cryptorchidism. Endocrine workup using pituitary and gonadal stimulation tests revealed the presence of both primary and central hypogonadism. Genetic testing revealed a novel variant of FGFR1 (c.2197_2199dup, p.Met733dup). To identify the pathogenicity of the novel variant and the clinical significance for the gonads, we investigated the effects of the FGFR1 variant on the downstream signaling of FGFR1 and gonadal steroidogenesis by using human steroidogenic granulosa cells. It was revealed that the transfection of the variant gene significantly impaired FGFR1 signaling, detected through the downregulation of SPRY2, compared with that of the case of the forced expression of wild-type FGFR1, and that the existence of the variant gene apparently altered the expression of key steroidogenic factors, including StAR and aromatase, in the gonad. The results suggested that the novel variant of FGFR1 detected in the patient with KS was linked to the impairment of FGFR1 signaling, as well as the alteration of gonadal steroidogenesis, leading to the pathogenesis of latent primary hypogonadism. No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 0361-8609 96 10 2021 Validated international definition of the thrombocytopenia, anasarca, fever, reticulin fibrosis, renal insufficiency, and organomegaly clinical subtype (TAFRO) of idiopathic multicentric Castleman disease 1241 1252 EN Yoshito Nishimura Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences David C. Fajgenbaum Center for Cytokine Storm Treatment & Laboratory, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania Sheila K. Pierson Center for Cytokine Storm Treatment & Laboratory, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania Noriko Iwaki Hematology/Respiratory Medicine, Kanazawa University Graduate School of Medical Science Asami Nishikori Division of Pathophysiology, Okayama University Graduate School of Health Sciences Mitsuhiro Kawano Department of Rheumatology, Kanazawa University Graduate School of Medical Science Naoya Nakamura Department of Pathology, Tokai University School of Medicine Koji Izutsu Department of Hematology, National Cancer Center Hospital Kengo Takeuchi Department of Pathology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research Midori Filiz Nishimura Department of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Yoshinobu Maeda Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Fumio Otsuka Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Kazuyuki Yoshizaki Department of Organic Fine Chemicals, Institute of Scientific and Industrial Research, Osaka University Eric Oksenhendler Department of Clinical Immunology, Hôpital Saint-Louis Frits van Rhee Myeloma Center, University of Arkansas for Medical Sciences Yasuharu Sato Division of Pathophysiology, Okayama University Graduate School of Health Sciences Thrombocytopenia, anasarca, fever, reticulin fibrosis, renal insufficiency, and organomegaly (TAFRO) syndrome is a heterogeneous entity manifesting with a constellation of symptoms described above that can occur in the context of idiopathic multicentric Castleman disease (iMCD) as well as infectious diseases, malignancies, and rheumatologic disorders. So, iMCD-TAFRO is an aggressive subtype of iMCD with TAFRO syndrome and often hyper-vascularized lymph nodes. Since we proposed diagnostic criteria of iMCD-TAFRO in 2016, we have accumulated new insights on the disorder and additional cases have been reported worldwide. In this systematic review and cohort analysis, we established and validated a definition for iMCD-TAFRO. First, we searched PubMed and Japan Medical Abstracts Society databases using the keyword “TAFRO” to extract cases. Patients with possible systemic autoimmune diseases and hematologic malignancies were excluded. Our search identified 54 cases from 50 articles. We classified cases into three categories: (1) iMCD-TAFRO (TAFRO syndrome with lymph node histopathology consistent with iMCD), (2) possible iMCD-TAFRO (TAFRO syndrome with no lymph node biopsy performed and no other co-morbidities), and (3) TAFRO without iMCD or other co-morbidities (TAFRO syndrome with lymph node histopathology not consistent with iMCD or other comorbidities). Based on the findings, we propose an international definition requiring four clinical criteria (thrombocytopenia, anasarca, fever/hyperinflammatory status, organomegaly), renal dysfunction or characteristic bone marrow findings, and lymph node features consistent with iMCD. The definition was validated with an external cohort (the ACCELERATE Natural History Registry). The present international definition will facilitate a more precise and comprehensive approach to the diagnosis of iMCD-TAFRO. No potential conflict of interest relevant to this article was reported.

Springer Science and Business Media LLC Acta Medica Okayama 1865-7257 18 2 2025 A case of pancreatic ductal adenocarcinoma growing within the pancreatic duct mimicking an intraductal tubulopapillary neoplasm 376 382 EN Ryosuke Sato Department of Gastroenterology and Hepatology, Okayama University Hospital Kazuyuki Matsumoto Department of Gastroenterology and Hepatology, Okayama University Hospital Mayu Uka Department of Radiology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Kosei Takagi Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Kenji Nishida Department of Pathology, Dentistry and Pharmaceutical Science, Okayama University Graduate School of Medicine Takehiro Tanaka Department of Pathology, Dentistry and Pharmaceutical Science, Okayama University Graduate School of Medicine Yuki Fujii Department of Gastroenterology and Hepatology, Okayama University Hospital Koichiro Tsutsumi Department of Gastroenterology and Hepatology, Okayama University Hospital Shigeru Horiguchi Department of Gastroenterology and Hepatology, Okayama University Hospital Motoyuki Otsuka Department of Gastroenterology and Hepatology, Okayama University Hospital We herein report a case of pancreatic ductal adenocarcinoma (PDAC) that developed within the pancreatic duct and was initially diagnosed as an intraductal tubulopapillary neoplasm (ITPN). A 76-year-old man presented with weight loss and main pancreatic duct dilation. The imaging studies revealed a 30-mm hypovascular tumor within the main duct of the pancreatic head. An endoscopic examination with a biopsy revealed high-grade atypical epithelial cells with immunostaining patterns suggestive of ITPN. Following robot-assisted pancreaticoduodenectomy, postoperative pathology revealed conflicting features: nodular/cribriform infiltrations typical of ITPN and non-lobular replacement with scattered infiltrations characteristic of PDAC. A comprehensive genomic profiling test detected KRAS and TP53 mutations, leading to the final diagnosis of PDAC (fT3N1aM0, stage IIB). The patient received adjuvant S-1 chemotherapy and remained recurrence-free for 15 months post-surgery. This case highlights the diagnostic challenges of differentiating intraductal pancreatic tumors and demonstrates the utility of integrating genetic testing with conventional diagnostic modalities for an accurate diagnosis and appropriate treatment selection. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 79 1 2025 Endothelial Cell Polarity in Health and Disease 1 7 EN Moe Thiha Department of Pathophysiology and Drug Discovery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takao Hikita Department of Pathophysiology and Drug Discovery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Masanori Nakayama Department of Pathophysiology and Drug Discovery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Review 10.18926/AMO/68353 Endothelial cell polarity is fundamental to the organization and function of blood vessels, influencing processes such as angiogenesis, vascular stability, and response to shear stress. This review elaborates on the molecular mechanisms that regulate endothelial cell polarity, focusing on key players like the PAR polarity complex and Rho family GTPases. These pathways coordinate the front–rear, apical–basal and planar polarity of endothelial cells, which are essential for the proper formation and maintenance of vascular structures. In health, endothelial polarity ensures not only the orderly development of blood vessels, with tip cells adopting distinct polarities during angiogenesis, but also ensures proper vascular integrity and function. In disease states, however, disruptions in polarity contribute to pathologies such as coronary artery disease, where altered planar polarity exacerbates atherosclerosis, and cancer, where disrupted polarity in tumor vasculature leads to abnormal vessel growth and function. Understanding cell polarity and its disruption is fundamental not only to comprehending how cells interact with their microenvironment and organize themselves into complex, organ-specific tissues but also to developing novel, targeted, and therapeutic strategies for a range of diseases, from cardiovascular disorders to malignancies, ultimately improving patient outcomes. No potential conflict of interest relevant to this article was reported.

MDPI Acta Medica Okayama 1661-6596 26 2 2025 Pathophysiology of Group 3 Pulmonary Hypertension Associated with Lung Diseases and/or Hypoxia 835 EN Kazufumi Nakamura Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Satoshi Akagi Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kentaro Ejiri Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Satoshi Taya Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yukihiro Saito Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kazuhiro Kuroda Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yoichi Takaya Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Norihisa Toh Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Rie Nakayama Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yuki Katanosaka Department of Pharmacy, Kinjo Gakuin University Shinsuke Yuasa Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Pulmonary hypertension associated with lung diseases and/or hypoxia is classified as group 3 in the clinical classification of pulmonary hypertension. The efficacy of existing selective pulmonary vasodilators for group 3 pulmonary hypertension is still unknown, and it is currently associated with a poor prognosis. The mechanisms by which pulmonary hypertension occurs include hypoxic pulmonary vasoconstriction, pulmonary vascular remodeling, a decrease in pulmonary vascular beds, endothelial dysfunction, endothelial-to-mesenchymal transition, mitochondrial dysfunction, oxidative stress, hypoxia-inducible factors (HIFs), inflammation, microRNA, and genetic predisposition. Among these, hypoxic pulmonary vasoconstriction and subsequent pulmonary vascular remodeling are characteristic factors involving the pulmonary vasculature and are the focus of this review. Several factors have been reported to mediate vascular remodeling induced by hypoxic pulmonary vasoconstriction, such as HIF-1 alpha and mechanosensors, including TRP channels. New therapies that target novel molecules, such as mechanoreceptors, to inhibit vascular remodeling are awaited. No potential conflict of interest relevant to this article was reported.

Elsevier Acta Medica Okayama 1341-321X 31 2 2024 Clinical and microbiological characteristics of high-level daptomycin-resistant Corynebacterium species: A systematic scoping review 102575 EN Shinnosuke Fukushima Department of Bacteriology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hideharu Hagiya Department of Infectious Diseases, Okayama University Hospital Kazuyoshi Gotoh Department of Medical Laboratory Science, Okayama University Graduate School of Health Sciences Shuma Tsuji Department of Medical Laboratory Science, Okayama University Graduate School of Health Sciences Koji Iio Microbiology Division, Clinical Laboratory, Okayama University Hospital Hidemasa Akazawa Department of Infectious Diseases, Okayama University Hospital Osamu Matsushita Department of Bacteriology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Fumio Otsuka Department of Infectious Diseases, Okayama University Hospital Introduction: Corynebacterium species potentially develop high-level daptomycin resistance (HLDR) shortly after daptomycin (DAP) administration. We aimed to investigate the clinical and microbiological characteristics of HLDR Corynebacterium infections. Methods: We first presented a clinical case accompanied by the results of a comprehensive genetic analysis of the isolate, and then performed a systematic scoping review. Based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews, we searched for articles with related keywords, including “Corynebacterium”, “Daptomycin", and "Resistance”, in the MEDLINE and Web of Science databases from the database inception to October 25, 2024. Clinical case reports and research articles documenting the isolation of HLDR Corynebacterium species, defined by a minimum inhibitory concentration of DAP at ≥256 μg/mL, were deemed eligible for this review. Results: Of 80 articles screened, seven case reports detailing eight cases of HLDR Corynebacterium infections, as well as five research articles, were included. C. striatum was the most common species (7/9 cases, 77.8 %), and prosthetic device-associated infections accounted for 66.7 % of the cases. Duration of DAP administration before the emergence of HLDR isolates ranged from 5 days to 3 months; three-quarters of the cases developed within 17 days. Three HLDR isolates were genetically confirmed to have an alteration in pgsA2. The majority of the patients were treated with either glycopeptides or linezolid, with favorable outcomes. In vitro experiments confirmed that C. striatum strains acquire the HLDR phenotype at higher rates (71 %–100 %) within 24 h of incubation, compared to other Corynebacterium strains. Conclusion: DAP monotherapy, especially for prosthetic device-associated infections, can result in the development of HLDR Corynebacterium. Additional research is warranted to investigate the clinical implications of this potentially proliferating antimicrobial resistant pathogen. No potential conflict of interest relevant to this article was reported.

Elsevier Acta Medica Okayama 0006-4971 145 8 2025 Oral Inflammation and Microbiome Dysbiosis Exacerbate Chronic Graft-versus-host Disease 881 896 EN Yui Kambara Department of Hematology, Oncology and Respiratory Medicine, Okayama University Medical School Hideaki Fujiwara Department of Hematology and Oncology, Okayama University Hospital Akira Yamamoto Department of Hematology and Oncology, Okayama University Hospital Kazuyoshi Gotoh Department of Medical Laboratory Science, Okayama University Graduate School of Health Sciences Shuma Tsuji Department of Microbiology and Genetics, Okayama University Graduate School of Health Sciences Mari Kunihiro Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tadashi Oyama Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Toshiki Terao Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ayame Sato Division of Hospital Dentistry, Okayama University Hospital Takehiro Tanaka Department of Pathology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Daniel Peltier Division of Pediatric Hematology, Oncology, and Stem Cell Transplantation, Department of Pediatrics, Herman B Wells Center for Pediatric Research, Simon Cancer Center, Indiana University School of Medicine Keisuke Seike Department of Hematology and Oncology, Okayama University Hospital Hisakazu Nishimori Department of Hematology and Oncology, Okayama University Hospital Noboru Asada Department of Hematology and Oncology, Okayama University Hospital Daisuke Ennishi Center for Comprehensive Genomic Medicine, Okayama University Hospital Keiko Fujii Department of Clinical Laboratory, Okayama University Hospital Nobuharu Fujii Division of Blood Transfusion, Okayama University Hospital Ken-ichi Matsuoka Department of Hematology and Oncology, Okayama University Hospital Yoshihiko Soga Division of Hospital Dentistry, Okayama University Hospital Pavan Reddy Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine Maeda Yoshinobu Department of Hematology and Oncology, Okayama University Hospital The oral microbiota, second in abundance to the gut, is implicated in chronic systemic diseases, but its specific role in graft-versus-host disease (GVHD) pathogenesis has been unclear. Our study finds that mucositis-induced oral dysbiosis in patients after hematopoietic cell transplantation (HCT) associated with increased chronic GVHD (cGVHD), even in patients receiving posttransplant cyclophosphamide. In murine HCT models, oral dysbiosis caused by bilateral molar ligatures exacerbated cGVHD and increased bacterial load in the oral cavity and gut, with Enterococcaceae significantly increasing in both organs. In this model, the migration of Enterococcaceae to cervical lymph nodes both before and after transplantation activated antigen-presenting cells, thereby promoting the expansion of donor-derived inflammatory T cells. Based on these results, we hypothesize that pathogenic bacteria increase in the oral cavity might not only exacerbate local inflammation but also enhance systemic inflammation throughout the HCT course. Additionally, these bacteria translocated to the gut and formed ectopic colonies, further amplifying systemic inflammation. Furthermore, interventions targeting the oral microbiome mitigated murine cGVHD. Collectively, our findings highlight the importance of oral dysbiosis in cGVHD and suggest that modulation of the oral microbiome during transplantation may be an effective approach for preventing or treating cGVHD. No potential conflict of interest relevant to this article was reported.

Springer Science and Business Media LLC Acta Medica Okayama 2054-345X 11 1 2024 Genotypes and phenotypes of neurofibromatosis type 1 patients in Japan: A Hereditary Tumor Cohort Study 42 EN Mashu Futagawa Department of Clinical Genomic Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tetsuya Okazaki Department of Clinical Genomic Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Eiji Nakata Department of Orthopedic Surgery, Okayama University Hospital Chika Fukano Department of Clinical Genomic Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Risa Osumi Department of Clinical Genetics and Genomic Medicine, Okayama University Hospital Fumino Kato Department of Clinical Genetics and Genomic Medicine, Okayama University Hospital Yusaku Urakawa Department of Genetic Medicine, School of Medicine, Fujita Health University Hideki Yamamoto Department of Clinical Genomic Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Toshifumi Ozaki Department of Orthopedic Surgery, Okayama University Hospital Akira Hirasawa Department of Clinical Genomic Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Neurofibromatosis type 1 (NF1) presents with a broad spectrum of clinical manifestations, including an increased risk of tumor development and hypertension. Comprehensive data on genotype‒phenotype correlations in patients with NF1 are limited. Therefore, in this study, we aimed to elucidate the detailed genetic and clinical characteristics of NF1 in a hereditary tumor cohort. We performed sequencing and copy number assays in a clinical laboratory and analyzed the clinical data of 44 patients with suspected NF1. Germline pathogenic variants were detected in 36 patients (81.8%), and 20.7% of the variants were novel. Notably, 40.0% of adult patients presented with malignancies; female breast cancer occurred in 20.0% of patients, which was a higher rate than that previously reported. Hypertension was observed in 30.6% of the adult patients, with one patient experiencing sudden death and another developing pheochromocytoma. Three patients with large deletions in NF1 exhibited prominent cutaneous, skeletal, and neurological manifestations. These results highlight the importance of regular surveillance, particularly for patients with malignancies and hypertension. Our findings provide valuable insights for genetic counseling and clinical management, highlighting the multiple health risks associated with NF1 and the need for comprehensive and multidisciplinary care. No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 2045-7634 13 20 2024 New Anti-Angiogenic Therapy for Glioblastoma With the Anti-Depressant Sertraline e70288 EN Nobushige Tsuboi Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Yoshihiro Otani Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Atsuhito Uneda Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Joji Ishida Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Yasuki Suruga Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Yuji Matsumoto Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Atsushi Fujimura Neutron Therapy Research Center, Okayama University Kentaro Fujii Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Hideki Matsui Neutron Therapy Research Center, Okayama University Kazuhiko Kurozumi Department of Neurosurgery, Hamamatsu University School of Medicine Isao Date Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Hiroyuki Michiue Neutron Therapy Research Center, Okayama University Background and Aims: Anti-angiogenic therapies prolong patient survival in some malignancies but not glioblastoma. We focused on the relationship between the differentiation of glioma stem like cells (GSCs) into tumor derived endothelial cells (TDECs) and, anti-angiogenic therapy resistance. Especially we aimed to elucidate the mechanisms of drug resistance of TDECs to anti-angiogenic inhibitors and identify novel anti-angiogenic drugs with clinical applications. Results: The mouse GSCs, 005, were differentiated into TDECs under hypoxic conditions, and TDECs had endothelial cell characteristics independent of the vascular endothelial growth factor (VEGF) pathway. In vivo, inhibition of the VEGF pathway had no anti-tumor effect and increased the percentage of TDECs in the 005 mouse model. Novel anti-angiogenic drugs for glioblastoma were evaluated using a tube formation assay and a drug repositioning strategy with existing blood-brain barrier permeable drugs. Drug screening revealed that the antidepressant sertraline inhibited tube formation of TDECs. Sertraline was administered to differentiated TDECs in vitro and 005 mouse models in vivo to evaluate genetic changes by RNA-Seq and tumor regression effects by immunohistochemistry and MRI. Sertraline reduced Lama4 and Ang2 expressions of TDEC, which play an important role in non-VEGF-mediated angiogenesis in tumors. The combination of a VEGF receptor inhibitor axitinib, and sertraline improved survival and reduced tumor growth in the 005 mouse model. Conclusion: Collectively, our findings showed the diversity of tumor vascular endothelial cells across VEGF and non-VEGF pathways led to anti-angiogenic resistance. The combination of axitinib and sertraline can represent an effective anti-angiogenic therapy for glioblastoma with safe, low cost, and fast availability. No potential conflict of interest relevant to this article was reported.

Springer Science and Business Media LLC Acta Medica Okayama 1433-7398 42 1 2024 Tectal glioma: clinical, radiological, and pathological features, and the importance of molecular analysis 1 11 EN Ryoji Imoto Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yoshihiro Otani Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kentaro Fujii Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Joji Ishida Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shuichiro Hirano Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Naoya Kemmotsu Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yasuki Suruga Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ryo Mizuta Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yasuhito Kegoya Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yohei Inoue Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tsuyoshi Umeda Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Madoka Hokama Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kana Washio Department of Pediatrics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hiroyuki Yanai Department of Pathology, Okayama University Hospital Shota Tanaka Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kaishi Satomi Department of Pathology, Kyorin University Faculty of Medicine Koichi Ichimura Department of Brain Disease Translational Research, Juntendo University Graduate School of Medicine Isao Date Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tectal glioma (TG) is a rare lower grade glioma (LrGG) that occurs in the tectum, mainly affecting children. TG shares pathological similarities with pilocytic astrocytoma (PA), but recent genetic analyses have revealed distinct features, such as alterations in KRAS and BRAF. We conducted a retrospective review of cases clinically diagnosed as TG and treated at our institute between January 2005 and March 2023. Six cases were identified and the median age was 30.5 years. Four patients underwent biopsy and two patients underwent tumor resection. Histological diagnoses included three cases of PA, one case of astrocytoma, and two cases of high-grade glioma. The integrated diagnosis, according to the fifth edition of the World Health Organization Classification of Tumours of the central nervous system, included two cases of PA and one case each of diffuse high-grade glioma; diffuse midline glioma H3 K27-altered; glioblastoma; and circumscribed astrocytic glioma. Among the three patients who underwent molecular evaluation, two had KRAS mutation and one had H3-3A K27M mutation. Our results demonstrate the diverse histological and molecular characteristics of TG distinct from other LrGGs. Given the heterogeneous pathological background and the risk of pathological progression in TG, we emphasize the importance of comprehensive diagnosis, including molecular evaluation. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 78 5 2024 Prognostic Efficacy of the Albumin Grade in Patients with Hepatocellular Carcinoma 377 386 EN Yuichi Hirano Department of Gastroenterology, Okayama City Hospital Kazuhiro Nouso Department of Gastroenterology, Okayama City Hospital Kazuya Kariyama Department of Gastroenterology, Okayama City Hospital Atsushi Hiraoka Gastroenterology Center, Ehime Prefectural Central Hospital Shohei Shiota Department of Gastroenterology, Okayama City Hospital Akiko Wakuta Department of Gastroenterology, Okayama City Hospital Satoshi Yasuda Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital Hidenori Toyoda Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital Kunihiko Tsuji Center of Gastroenterology, Teine Keijinkai Hospital Takeshi Hatanaka Department of Gastroenterology, Saiseikai Maebashi Hospital Satoru Kakizaki Department of Clinical Research, NHO Takasaki General Medical Center Atsushi Naganuma Department of Gastroenterology, NHO Takasaki General Medical Center Toshifumi Tada Department of Internal Medicine, Japanese Red Cross Society Himeji Hospital Ei Itobayashi Department of Gastroenterology, Asahi General Hospital Toru Ishikawa Department of Gastroenterology, Saiseikai Niigata Hospital Noritomo Shimada Division of Gastroenterology and Hepatology, Otakanomori Hospital Koichi Takaguchi Department of Hepatology, Kagawa Prefectural Central Hospital Akemi Tsutsui Department of Hepatology, Kagawa Prefectural Central Hospital Takuya Nagano Department of Hepatology, Kagawa Prefectural Central Hospital Michitaka Imai Department of Gastroenterology, Niigata Cancer Center Hospital Shinichiro Nakamura Department of Internal Medicine, Japanese Red Cross Society Himeji Hospital Takashi Kumada Department of Nursing, Gifu Kyoritsu University Real-Life Practice Experts for HCC (RELPEC) Study Group in Japan Original Article 10.18926/AMO/67662 We previously found that “albumin grade”, formerly called the “ALBS grade,” demonstrated significant capability for prognostic stratification in hepatocellular carcinoma (HCC) patients treated with lenvatinib. The purpose of the present study was to compare the performance of the albumin grade with that of the modified albumin-bilirubin (mALBI) grade in predicting overall survival of HCC patients with different BCLC stages and treatment types. We enrolled 7,645 Japanese patients newly diagnosed with HCC using the Akaike information criteria (AIC), likelihood ratio, and C-index in different Barcelona Clinic Liver Cancer (BCLC) stages and treatments. The albumin grade showed similar and slightly better performance than the mALBI grade for BCLC stage 0 and A and especially for patients who underwent curative surgery and ablation. In patients treated with transcatheter arterial chemoembolization, molecular targeted agents, and the best supportive care, the mALBI grade had better performance than the albumin grade. However, the differences of the indices were very small in all scenarios. Overall, the albumin grade was comparable in efficacy to the mALBI grade, showing particular benefit for patients with early-stage HCC. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 78 5 2024 Phenotypic and Genetic Characteristics of Carbapenemase-Producing Enterobacterales Isolates at Okayama University Hospital 371 376 EN Kazuyoshi Gotoh Department of Bacteriology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Makoto Miyoshi Department of Medical Laboratory Science, Graduate School of Health Sciences, Okayama University I Putu Bayu Mayura Department of Clinical Microbiology, Faculty of Medicine, Udayana University Shuma Tsuji Department of Medical Laboratory Science, Graduate School of Health Sciences, Okayama University Koji Iio Microbiology Division, Clinical Laboratory, Okayama University Hospital Shinnosuke Fukushima Department of Bacteriology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Osamu Matsushita Department of Bacteriology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hideharu Hagiya Department of Infectious Diseases, Okayama University Hospital Original Article 10.18926/AMO/67657 Spread of carbapenemase-producing Enterobacterales (CPE) is an ongoing public health issue worldwide, including in Japan. In this study, we investigated the phenotypic and genetic characteristics of CPE isolates at Okayama University Hospital over the 5 years (2013-2018) prior to the outbreak of the 2019 coronavirus pandemic. Of 24 carbapenem-resistant Enterobacterales isolated during the study period, we identified 8 CPE isolates harboring blaIMP-1 (5 isolates) and blaIMP-6 genes (3 isolates). Bacterial species and carbapenem susceptibility patterns exhibited diversity. Minimum inhibitory concentrations (MICs) of meropenem were generally higher than those of imipenem and biapenem. Results of pulsed-field gel electrophoresis demonstrated that neither clonal nor plasmid-mediated outbreaks of blaIMP-harboring CPE isolates have developed at our hospital. One Klebsiella oxytoca isolate showed a high MIC (128 μg/mL) of meropenem, which could be explained by the high plasmid copy number. Subsequent analysis of this isolate may elucidate the intricacies of carbapenem resistance profiles among CPE isolates. Collectively, our findings underscore the necessity for ongoing genetic surveillance of CPE, complemented by tailored approaches for infection prevention and control. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 78 3 2024 Effect of Humidified High-Flow Nasal Cannula Oxygen Therapy with a Pulmonary Infection Control Window as a Ventilation Switching Indication in Combination with Atomizing Inhalation of Terbutaline on the Lung Function of Patients with Acute Exacerbation of COPD 271 279 EN Mengjiao Ye Department of Respiratory and Critical Care Medicine, Tiantai Hospital of Traditional Chinese Medicine Renwei Zhang Department of Respiratory and Critical Care Medicine, Tiantai Hospital of Traditional Chinese Medicine Original Article 10.18926/AMO/67202 We investigated how humidified high-flow nasal cannula oxygen therapy (HFNC) with a pulmonary infection control (PIC) window as a ventilation switching indication in combination with atomizing inhalation of terbutaline affects the lung function of patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). We examined 140 hospitalized AECOPD patients randomized to control and observation groups. Conventional supportive therapy and invasive mechanical ventilation with tracheal intubation were conducted in both groups, with a PIC window as the indication for ventilation switching. Noninvasive positive pressure ventilation (NIPPV) plus atomizing inhalation of terbutaline was used in the control group. In the observation group, HFNC combined with atomizing inhalation of terbutaline was used. Compared to the control group, after 48-hr treatment and treatment completion, the observation group had significantly increased levels of lung function indicators (maximal voluntary ventilation [MVV] plus forced vital capacity [FVC], p<0.05) and oxygen metabolism indicators (arterial oxygen partial pressure [PaO2], arterial oxygen content [CaO2], and oxygenation index, p<0.05). The comparison of the groups revealed that the levels of airway remodeling indicators (matrix metalloproteinase-2 [MMP-2], tissue inhibitor of metalloproteinase 2 [TIMP-2] plus MMP-9) and inflammatory indicators (interferon gamma [IFN-γ] together with interleukin-17 [IL-17], IL-10 and IL-4) were significantly lower after 48 h of treatment as well as after treatment completion (both p<0.05). These results demonstrate that HFNC with a PIC window as the indication for ventilation switching combined with atomizing inhalation of terbutaline can relieve the disorder of oxygen metabolism and correct airway hyper-reactivity. No potential conflict of interest relevant to this article was reported.

Public Library of Science Acta Medica Okayama 1932-6203 19 5 2024 The use of artificial intelligence in induced pluripotent stem cell-based technology over 10-year period: A systematic scoping review e0302537 EN Quan Duy Vo Faculty of Medicine, Department of Cardiovascular Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Yukihiro Saito Department of Cardiovascular Medicine, Okayama University Hospital Toshihiro Ida Faculty of Medicine, Department of Cardiovascular Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kazufumi Nakamura Faculty of Medicine, Department of Cardiovascular Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Shinsuke Yuasa Faculty of Medicine, Department of Cardiovascular Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Background Stem cell research, particularly in the domain of induced pluripotent stem cell (iPSC) technology, has shown significant progress. The integration of artificial intelligence (AI), especially machine learning (ML) and deep learning (DL), has played a pivotal role in refining iPSC classification, monitoring cell functionality, and conducting genetic analysis. These enhancements are broadening the applications of iPSC technology in disease modelling, drug screening, and regenerative medicine. This review aims to explore the role of AI in the advancement of iPSC research. Methods In December 2023, data were collected from three electronic databases (PubMed, Web of Science, and Science Direct) to investigate the application of AI technology in iPSC processing. Results This systematic scoping review encompassed 79 studies that met the inclusion criteria. The number of research studies in this area has increased over time, with the United States emerging as a leading contributor in this field. AI technologies have been diversely applied in iPSC technology, encompassing the classification of cell types, assessment of disease-specific phenotypes in iPSC-derived cells, and the facilitation of drug screening using iPSC. The precision of AI methodologies has improved significantly in recent years, creating a foundation for future advancements in iPSC-based technologies. Conclusions Our review offers insights into the role of AI in regenerative and personalized medicine, highlighting both challenges and opportunities. Although still in its early stages, AI technologies show significant promise in advancing our understanding of disease progression and development, paving the way for future clinical applications. No potential conflict of interest relevant to this article was reported.

American Society for Clinical Investigation Acta Medica Okayama 2379-3708 9 10 2024 Double-faced CX3CL1 enhances lymphangiogenesis-dependent metastasis in an aggressive subclone of oral squamous cell carcinoma e174618 EN Htoo Shwe Eain Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Hotaka Kawai Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Masaaki Nakayama Department of Oral Microbiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University May Wathone Oo Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Toshiaki Ohara Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama Universit Yoko Fukuhara Department of Oral Morphology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kiyofumi Takabatake Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Quisheng Shan Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Yamin Soe Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kisho Ono Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Keisuke Nakano Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Nobuyoshi Mizukawa Department of Oral and Maxillofacial Reconstructive Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Seiji Iida Department of Oral and Maxillofacial Reconstructive Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Hitoshi Nagatsuka Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Because cancer cells have a genetically unstable nature, they give rise to genetically different variant subclones inside a single tumor. Understanding cancer heterogeneity and subclone characteristics is crucial for developing more efficacious therapies. Oral squamous cell carcinoma (OSCC) is characterized by high heterogeneity and plasticity. On the other hand, CX3C motif ligand 1 (CX3CL1) is a double-faced chemokine with anti- and pro -tumor functions. Our study reported that CX3CL1 functioned differently in tumors with different cancer phenotypes, both in vivo and in vitro. Mouse OSCC 1 (MOC1) and MOC2 cells responded similarly to CX3CL1 in vitro. However, in vivo, CX3CL1 increased keratinization in indolent MOC1 cancer, while CX3CL1 promoted cervical lymphatic metastasis in aggressive MOC2 cancer. These outcomes were due to double-faced CX3CL1 effects on different immune microenvironments indolent and aggressive cancer created. Furthermore, we established that CX3CL1 promoted cancer metastasis via the lymphatic pathway by stimulating lymphangiogenesis and transendothelial migration of lymph -circulating tumor cells. CX3CL1 enrichment in lymphatic metastasis tissues was observed in aggressive murine and human cell lines. OSCC patient samples with CX3CL1 enrichment exhibited a strong correlation with lower overall survival rates and higher recurrence and distant metastasis rates. In conclusion, CX3CL1 is a pivotal factor that stimulates the metastasis of aggressive cancer subclones within the heterogeneous tumors to metastasize, and our study demonstrates the prognostic value of CX3CL1 enrichment in long-term monitoring in OSCC. No potential conflict of interest relevant to this article was reported.

Springer Science and Business Media LLC Acta Medica Okayama 1434-5161 68 3 2023 Recent advances in CGG repeat diseases and a proposal of fragile X-associated tremor/ataxia syndrome, neuronal intranuclear inclusion disease, and oculophryngodistal myopathy (FNOP) spectrum disorder 169 174 EN Hiroyuki Ishiura Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shoji Tsuji Department of Neurology, Graduate School of Medicine, The University of Tokyo Tatsushi Toda Department of Neurology, Graduate School of Medicine, The University of Tokyo While whole genome sequencing and long-read sequencing have become widely available, more and more focuses are on noncoding expanded repeats. Indeed, more than half of noncoding repeat expansions related to diseases have been identified in the five years. An exciting aspect of the progress in this field is an identification of a phenomenon called repeat motif–phenotype correlation. Repeat motif–phenotype correlation in noncoding repeat expansion diseases is first found in benign adult familial myoclonus epilepsy. The concept is extended in the research of CGG repeat expansion diseases. In this review, we focus on newly identified CGG repeat expansion diseases, update the concept of repeat motif–phenotype correlation in CGG repeat expansion diseases, and propose a clinical concept of FNOP (fragile X-associated tremor/ataxia syndrome, neuronal intranuclear inclusion disease, and oculopharyngodistal myopathy)-spectrum disorder, which shares clinical features and thus probably share some common disease pathophysiology, to further facilitate discussion and progress in this field. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 78 2 2024 p53-Armed Oncolytic Virotherapy Improves Radiosensitivity in Soft-Tissue Sarcoma by Suppressing BCL-xL Expression 151 161 EN Tadashi Komatsubara Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hiroshi Tazawa Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Joe Hasei Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Toshinori Omori Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kazuhisa Sugiu Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yusuke Mochizuki Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Koji Demiya Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Aki Yoshida Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tomohiro Fujiwara Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Toshiyuki Kunisada Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yasuo Urata Oncolys BioPharma, Inc. Shunsuke Kagawa Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Toshifumi Ozaki Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Toshiyoshi Fujiwara Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Original Article 10.18926/AMO/66924 Soft-tissue sarcoma (STS) is a heterogeneous group of rare tumors originating predominantly from the embryonic mesoderm. Despite the development of combined modalities including radiotherapy, STSs are often refractory to antitumor modalities, and novel strategies that improve the prognosis of STS patients are needed. We previously demonstrated the therapeutic potential of two telomerase-specific replication-competent oncolytic adenoviruses, OBP-301 and tumor suppressor p53-armed OBP-702, in human STS cells. Here, we demonstrate in vitro and in vivo antitumor effects of OBP-702 in combination with ionizing radiation against human STS cells (HT1080, NMS-2, SYO-1). OBP-702 synergistically promoted the antitumor effect of ionizing radiation in the STS cells by suppressing the expression of B-cell lymphoma-X large (BCL-xL) and enhancing ionizing radiation-induced apoptosis. The in vivo experiments demonstrated that this combination therapy significantly suppressed STS tumors’ growth. Our results suggest that OBP-702 is a promising antitumor reagent for promoting the radiosensitivity of STS tumors. No potential conflict of interest relevant to this article was reported.

MDPI Acta Medica Okayama 2072-6694 16 7 2024 Copy Number Analysis of 9p24.1 in Classic Hodgkin Lymphoma Arising in Immune Deficiency/Dysregulation 1298 EN Kumiko Ohsawa Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Shuji Momose Department of Pathology, Saitama Medical Center, Saitama Medical University Asami Nishikori Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Midori Filiz Nishimura Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Yuka Gion Department of Medical Technology, Faculty of Health Sciences, Ehime Prefectural University of Health Sciences Keisuke Sawada Department of Pathology, Saitama Medical Center, Saitama Medical University Morihiro Higashi Department of Pathology, Saitama Medical Center, Saitama Medical University Michihide Tokuhira Department of Hematology, Japan Community Health Care Organization Saitama Medical Center Jun-Ichi Tamaru Department of Pathology, Saitama Medical Center, Saitama Medical University Yasuharu Sato Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences A subset of patients with rheumatoid arthritis receiving methotrexate develop immune deficiencies and dysregulation-associated lymphoproliferative disorders. Patients with these disorders often exhibit spontaneous regression after MTX withdrawal; however, chemotherapeutic intervention is frequently required in patients with classic Hodgkin lymphoma arising in immune deficiency/dysregulation. In this study, we examined PD-L1 expression levels and 9p24.1 copy number alterations in 27 patients with classic Hodgkin lymphoma arising from immune deficiency/dysregulation. All patients demonstrated PD-L1 protein expression and harbored 9p24.1 copy number alterations on the tumor cells. When comparing clinicopathological data and associations with 9p24.1 copy number features, the copy gain group showed a significantly higher incidence of extranodal lesions and clinical stages than the amplification group. Notably, all cases in the amplification group had latency type II, while 6/8 (75%) in the copy gain group had latency type II, and 2/8 (25%) had latency type I. Thus, a subset of the copy-gain group demonstrated more extensive extranodal lesions and higher clinical stages. This finding speculates the presence of a genetically distinct subgroup within the group of patients who develop immune deficiencies and dysregulation-associated lymphoproliferative disorders, which may explain certain characteristic features. No potential conflict of interest relevant to this article was reported.

Springer Science and Business Media LLC Acta Medica Okayama 0167-594X 167 1 2024 Midline invasion predicts poor prognosis in diffuse hemispheric glioma, H3 G34-mutant: an individual participant data review 201 210 EN Yasuhito Kegoya Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Yoshihiro Otani Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Yohei Inoue Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Ryo Mizuta Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Fumiyo Higaki Department of Radiology, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences Kana Washio Department of Pediatrics, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Shinichiro Koizumi Department of Neurosurgery, Hamamatsu University School of Medicine Kazuhiko Kurozumi Department of Neurosurgery, Hamamatsu University School of Medicine Joji Ishida Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Kentaro Fujii Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Norio Yamamoto Department of Epidemiology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Yoshihiro Tanaka Division of Epidemiology, Graduate School of Public Health, Shizuoka Graduate University of Public Health Isao Date Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Introduction Diffuse hemispheric glioma, H3 G34-mutant (DHGs), is a newly categorized tumor in pediatric-type diffuse high-grade gliomas, World Health Organization grade 4, with a poor prognosis. Although prognostic factors associated with genetic abnormalities have been reported, few reports have examined the clinical presentation of DHGs, especially from the viewpoint of imaging findings. In this study, we investigated the relationship between clinical factors, including imaging findings, and prognosis in patients with DHGs. Methods We searched Medline through the PubMed database using two search terms: “G34” and “glioma”, between 1 April 2012 and 1 July 2023. We retrieved articles that described imaging findings and overall survival (OS), and added one DHG case from our institution. We defined midline invasion (MI) as invasion to the contralateral cerebrum, brainstem, corpus callosum, thalamus, and basal ganglia on magnetic resonance imaging. The primary outcome was 12-month survival, estimated using Kaplan–Meier curves and logistic regression. Results A total of 96 patients were included in this study. The median age was 22 years, and the proportion of male patients was 48.4%. Lesions were most frequently located in the frontal lobe (52.6%). MI was positive in 39.6% of all patients. The median OS was 14.4 months. Univariate logistic regression analysis revealed that OS was significantly worse in the MI-positive group compared with the MI-negative group. Multivariate logistic regression analysis revealed that MI was an independent prognostic factor in DHGs. Conclusions In this study, MI-positive cases had a worse prognosis compared with MI-negative cases. No potential conflict of interest relevant to this article was reported.

Japanese Society for Lymphoreticular Tissue Research Acta Medica Okayama 1346-4280 64 1 2024 Analysis of Notch1 protein expression in methotrexate-associated lymphoproliferative disorders 1 9 EN Takeshi Okatani Department of Pathology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Midori Filiz Nishimura Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Yuria Egusa Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Sayako Yoshida Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Yoshito Nishimura Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Asami Nishikori Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Tadashi Yoshino Department of Pathology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Hidetaka Yamamoto Department of Pathology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Yasuharu Sato Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Methotrexate (MTX)-associated lymphoproliferative disorder (MTX-LPD) is a lymphoproliferative disorder in patients treated with MTX. The mechanism of pathogenesis is still elusive, but it is thought to be a complex interplay of factors, such as underlying autoimmune disease activity, MTX use, Epstein-Barr virus infection, and aging. The NOTCH genes encode receptors for a signaling pathway that regulates various fundamental cellular processes, such as proliferation and differentiation during embryonic development. Mutations of NOTCH1 have been reported in B-cell tumors, including chronic lymphocytic leukemia/ lymphoma, mantle cell lymphoma, and diffuse large B-cell lymphoma (DLBCL). Recently, it has also been reported that NOTCH1 mutations are found in post-transplant lymphoproliferative disorders, and in CD20-positive cells in angioimmunoblastic T-cell lymphoma, which might be associated with lymphomagenesis in immunodeficiency. In this study, to investigate the association of NOTCH1 in the pathogenesis of MTX-LPD, we evaluated protein expression of Notch1 in nuclei immunohistochemically in MTX-LPD cases [histologically DLBCL-type (n = 24) and classical Hodgkin lymphoma (CHL)-type (n = 24)] and de novo lymphoma cases [DLBCL (n = 19) and CHL (n = 15)]. The results showed that among MTX-LPD cases, the expression of Notch1 protein was significantly higher in the DLBCL type than in the CHL type (P < 0.001). In addition, among DLBCL morphology cases, expression of Notch1 tended to be higher in MTX-LPD than in the de novo group; however this difference was not significant (P = 0.0605). The results showed that NOTCH1 may be involved in the proliferation and tumorigenesis of B cells under the use of MTX. Further research, including genetic studies, is necessary. No potential conflict of interest relevant to this article was reported.

Elsevier Acta Medica Okayama 0092-8674 186 2023 Structure of the thrombopoietin-MPL receptor complex is a blueprint for biasing hematopoiesis 4189 4203.e22 EN Naotaka Tsutsumi Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Zahra Masoumi York Biomedical Research Institute, Department of Biology, University of York Sophie C. James York Biomedical Research Institute, Department of Biology, University of York Julie A. Tucker York Biomedical Research Institute, Department of Biology, University of York Hauke Winkelmann Department of Biology/Chemistry and Center of Cellular Nanoanalytics, Osnabrück University William Grey York Biomedical Research Institute, Department of Biology, University of York Lora K. Picton Department of Molecular and Cellular Physiology, Stanford University School of Medicine Lucie Moss York Biomedical Research Institute, Department of Biology, University of York Steven C. Wilson Department of Molecular and Cellular Physiology, Stanford University School of Medicine Nathanael A. Caveney Department of Molecular and Cellular Physiology, Stanford University School of Medicine Kevin M. Jude Department of Molecular and Cellular Physiology, Stanford University School of Medicine Cornelius Gati Department of Structural Biology, Stanford University School of Medicine Jacob Piehler Department of Biology/Chemistry and Center of Cellular Nanoanalytics, Osnabrück University Ian S. Hitchcock York Biomedical Research Institute, Department of Biology, University of York K. Christopher Garcia Department of Molecular and Cellular Physiology, Stanford University School of Medicine Thrombopoietin (THPO or TPO) is an essential cytokine for hematopoietic stem cell (HSC) maintenance and megakaryocyte differentiation. Here, we report the 3.4 Å resolution cryoelectron microscopy structure of the extracellular TPO-TPO receptor (TpoR or MPL) signaling complex, revealing the basis for homodimeric MPL activation and providing a structural rationalization for genetic loss-of-function thrombocytopenia mutations. The structure guided the engineering of TPO variants (TPOmod) with a spectrum of signaling activities, from neutral antagonists to partial- and super-agonists. Partial agonist TPOmod decoupled JAK/STAT from ERK/AKT/CREB activation, driving a bias for megakaryopoiesis and platelet production without causing significant HSC expansion in mice and showing superior maintenance of human HSCs in vitro. These data demonstrate the functional uncoupling of the two primary roles of TPO, highlighting the potential utility of TPOmod in hematology research and clinical HSC transplantation. No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 1552-4825 194 5 2023 Radiological characteristics of skeletal growth in neonates and infants with achondroplasia e63525 EN Daisuke Miyahara Department of Pediatrics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kosei Hasegawa Department of Pediatrics, Okayama University Hospital Yuko Ago Department of Pediatrics, Okayama University Hospital Natsuko Futagawa Department of Pediatrics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hiroyuki Miyahara Department of Pediatrics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yousuke Higuchi Department of Pediatrics, Okayama University Hospital Kazuki Yamada Department of Orthopedics, Okayama University Hospital Tomonori Tetsunaga Department of Orthopedics, Okayama University Hospital Tadashi Moriwake Department of Pediatrics, Iwakuni Clinical Center, National Hospital Organization Hiroyuki Tanaka Department of Pediatrics, Okayama Saiseikai General Hospital Hirokazu Tsukahara Department of Pediatrics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Achondroplasia (ACH) is the most common form of skeletal dysplasia characterized by a rhizomelic short stature. Radiological skeletal findings in pediatric and adult patients with ACH include short long bones, a relatively longer fibula compared to the tibia, a narrow lumbar interpedicular distance, and a hypoplastic iliac wing. Nonetheless, the characteristics of skeletal growth during the neonatal and infantile periods have scarcely been explored. Therefore, this retrospective study aimed to analyze the radiological skeletal growth during the neonatal and infantile periods in 41 Japanese patients with genetically confirmed ACH. The length of long bones in the upper and lower limbs and the lumbar interpedicular distances at L1 and L4 were measured. These parameters showed significant positive correlations with age. The upper segment-to-lower segment ratio in the lower limbs resembled the data of healthy controls from previous reports. The L1/L4 and fibula/tibia ratios increased with age, suggesting that some representative skeletal phenotypes of ACH were less distinct during the neonatal and infantile periods. In conclusion, for the first time, this study radiologically characterized skeletal growth during the neonatal and infantile periods of patients with genetically confirmed ACH. No potential conflict of interest relevant to this article was reported.

BMC Acta Medica Okayama 1472-6831 23 1 2023 Ligneous periodontitis exacerbated by Behçet’s disease in a patient with plasminogen deficiency and a stop-gained variant PLG c.1468C > T: a case report 843 EN Yuki Shinoda-Ito Department of Pathophysiology‑Periodontal Science, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Anna Hirai Department of Periodontics and Endodontics, Division of Dentistry, Okayama University Hospital Kazuhiro Omori Department of Pathophysiology‑Periodontal Science, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Hidetaka Ideguchi Department of Periodontics and Endodontics, Division of Dentistry, Okayama University Hospital Hideki Yamamoto Department of Clinical Genomic Medicine, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Fumino Kato Department of Clinical Genomic Medicine, Okayama University Hospital Kyoichi Obata Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Tatsuo Ogawa Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Keisuke Nakano Department of Oral Pathology and Medicine, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Takato Nakadoi The Center for Graduate Medical Education (Dental Division), Okayama University Hospital Eri Katsuyama Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Soichiro Ibaragi Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Tadashi Yamamoto The Center for Graduate Medical Education (Dental Division), Okayama University Hospital Hitoshi Nagatsuka Department of Oral Pathology and Medicine, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Akira Hirasawa Department of Clinical Genomic Medicine, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Shogo Takashiba Department of Pathophysiology‑Periodontal Science, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Background Plasminogen serves as the precursor to plasmin, an essential element in the fibrinolytic process, and is synthesized primarily in the liver. Plasminogen activation occurs through the action of plasminogen activator, converting it into plasmin. This conversion greatly enhances the fibrinolytic system within tissues and blood vessels, facilitating the dissolution of fibrin clots. Consequently, congenital deficiency of plasminogen results in impaired fibrin degradation. Patients with plasminogen deficiency typically exhibit fibrin deposits in various mucosal sites throughout the body, including the oral cavity, eyes, vagina, and digestive organs. Behcet's disease is a chronic recurrent systemic inflammatory disease with four main symptoms: aphthous ulcers of the oral mucosa, vulvar ulcers, skin symptoms, and eye symptoms, and has been reported worldwide. This disease is highly prevalent around the Silk Road from the Mediterranean to East Asia. We report a case of periodontitis in a patient with these two rare diseases that worsened quickly, leading to alveolar bone destruction. Genetic testing revealed a novel variant characterized by a stop-gain mutation, which may be a previously unidentified etiologic gene associated with decreased plasminogen activity. Case presentation This case report depicts a patient diagnosed with ligneous gingivitis during childhood, originating from plasminogen deficiency and progressing to periodontitis. Genetic testing revealed a suspected association with the PLG c.1468C > T (p.Arg490*) stop-gain mutation. The patient's periodontal condition remained stable with brief intervals of supportive periodontal therapy. However, the emergence of Behçet's disease induced acute systemic inflammation, necessitating hospitalization and treatment with steroids. During hospitalization, the dental approach focused on maintaining oral hygiene and alleviating contact-related pain. The patient's overall health improved with inpatient care and the periodontal tissues deteriorated. Conclusions Collaborative efforts between medical and dental professionals are paramount in comprehensively evaluating and treating patients with intricate complications from rare diseases. Furthermore, the PLG c.1468C > T (p.Arg490*) stop-gain mutation could contribute to the association between plasminogen deficiency and related conditions. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 77 6 2023 Cochlear Implantation in the Poorer-Hearing Ear Is a Reasonable Choice 589 593 EN Ryotaro Omichi Department of Otolaryngology-Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shin Kariya Department of Otolaryngology-Head and Neck Surgery, Kawasaki Medial University Yukihide Maeda Department of Otolaryngology-Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kunihiro Fukushima Hayashima Clinic of Otolaryngology and Dermatology Yuko Kataoka Department of Otolaryngology-Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Akiko Sugaya Department of Otolaryngology-Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kazunori Nishizaki Department of Otolaryngology-Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Mizuo Ando Department of Otolaryngology-Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Original Article 10.18926/AMO/66150 Choosing the optimal side for cochlear implantation (CI) remains a major challenge because of the lack of evidence. We investigated the choice of the surgery side for CI (i.e., the better- or poorer-hearing ear) in patients with asymmetric hearing. Audiological records of 74 adults with a unilateral hearing aid who had undergone surgery at Okayama University Hospital were reviewed. The definition of ‘better-hearing ear’ was the aided ear, and the unaided ear was considered the poorer-hearing ear. We performed a multiple regression analysis to identify potential predictors of speech recognition performance after unilateral CI in the patients. Fifty-two patients underwent CI in the poorer-hearing ear. The post-Ci bimodal hearing rate was far higher in the poorer-ear group (77.8% vs. 22.2%). A multivariate analysis revealed that prelingual hearing loss and the patient’s age at CI significantly affected the speech recognition outcome (beta coefficients: 24.6 and −0.33, 95% confidence intervals [11.75-37.45] and [−0.58 to −0.09], respectively), but the CI surgery side did not (−6.76, [−14.92-1.39]). Unilateral CI in the poorer-hearing ear may therefore be a reasonable choice for adult patients with postlingual severe hearing loss, providing a greater opportunity for postoperative bimodal hearing. No potential conflict of interest relevant to this article was reported.

MDPI Acta Medica Okayama 1661-6596 24 20 2023 Roles of Oxidative Injury and Nitric Oxide System Derangements in Kawasaki Disease Pathogenesis: A Systematic Review 15450 EN Mitsuru Tsuge Department of Pediatrics, Okayama University Academic Field of Medicine, Dentistry, and Pharmaceutical Sciences Kazuhiro Uda Department of Pediatrics, Okayama University Academic Field of Medicine, Dentistry, and Pharmaceutical Sciences Takahiro Eitoku Department of Pediatrics, Kawasaki Medical School Naomi Matsumoto Department of Epidemiology, Okayama University Academic Field of Medicine, Dentistry, and Pharmaceutical Sciences Takashi Yorifuji Department of Epidemiology, Okayama University Academic Field of Medicine, Dentistry, and Pharmaceutical Sciences Hirokazu Tsukahara Department of Pediatrics, Okayama University Academic Field of Medicine, Dentistry, and Pharmaceutical Sciences Kawasaki disease (KD) is an acute febrile vasculitis that occurs mostly in children younger than five years. KD involves multiple intricately connected inflammatory reactions activated by a cytokine cascade. Despite therapeutic advances, coronary artery damage may develop in some patients, who will be at risk of clinical cardiovascular events and even sudden death. The etiology of KD remains unclear; however, it may involve both genetic and environmental factors leading to aberrant inflammatory responses. Given the young age of onset, prenatal or perinatal exposure may be etiologically relevant. Multisystem inflammatory syndrome in children, a post-infectious hyper-inflammatory disorder associated with severe acute respiratory syndrome coronavirus 2, has features that overlap with those of KD. Available evidence indicates that vascular endothelial dysfunction is a critical step in the sequence of events leading to the development of cardiovascular lesions in KD. Oxidative stress and the dysregulation of the nitric oxide (NO) system contribute to the pathogenesis of inflammatory responses related to this disease. This review provides current evidence and concepts highlighting the adverse effects of oxidative injury and NO system derangements on the initiation and progression of KD and potential therapeutic strategies for cardiovascular pathologies in affected children. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 77 5 2023 Association between BRCA Gene Variants and the Response to Modified FOLFIRINOX in Patients with Unresectable Pancreatic Cancer 517 525 EN Shigeru Horiguchi Department of Gastroenterology and Hepatology, Okayama University Hospital Kazuyuki Matsumoto Department of Gastroenterology and Hepatology, Okayama University Hospital Kosaku Morimoto Department of Gastroenterology and Hepatology, Okayama University Hospital Akihiro Matsumi Department of Gastroenterology and Hepatology, Okayama University Hospital Hiroyuki Terasawa Department of Gastroenterology and Hepatology, Okayama University Hospital Yuki Fujii Department of Gastroenterology and Hepatology, Okayama University Hospital Tatsuhiro Yamazaki Department of Gastroenterology and Hepatology, Okayama University Hospital Koichiro Tsutsumi Department of Gastroenterology and Hepatology, Okayama University Hospital Hironari Kato Department of Gastroenterology and Hepatology, Okayama University Hospital Original Article 10.18926/AMO/65974 We investigated the effect of modified FOLFIRINOX (mFFX) in unresectable pancreatic cancer by retrospectively analyzing the cases of 43 patients who underwent BRCA testing (germline, n=11; somatic, n=26; both germline and somatic, n=6). The association between BRCA mutations and therapeutic effect was clarified. Six patients tested positive for germline pathogenic variants. Familial pancreatic cancer (33% vs. 3%, p=0.006) and peritoneal disseminated lesions (66% vs. 8%, p<0.001) were significantly more common in patients with germline pathogenic variants. The partial response (PR) rate was 100% in the germline BRCA-positive patients, and 27% in the germline BRCA-negative patients (p<0.001). The median progression-free survival (PFS) was not reached for any germline BRCA-positive patients but was 9.0 months for the germline BRCA-negative patients (p=0.042). Patients with stage IV BRCA-associated pancreatic cancer had better overall survival than those with non-BRCA-associated pancreatic cancer, although the difference was nonsignificant (not reached vs. 655 days, p=0.061). Our results demonstrate that a PR and prolonged PFS can be expected in germline BRCA-positive patients after treatment with mFFX. Our findings also suggest that germline BRCA pathogenic variants may be useful as biomarkers for the therapeutic effect of mFFX in patients with pancreatic cancer. No potential conflict of interest relevant to this article was reported.

American Association for Cancer Research Acta Medica Okayama 2767-9764 2 7 2022 Mixed Response to Cancer Immunotherapy is Driven by Intratumor Heterogeneity and Differential Interlesion Immune Infiltration 739 753 EN Takao Morinaga Chiba Cancer Center, Research Institute Takashi Inozume Chiba Cancer Center, Research Institute Masahito Kawazu Chiba Cancer Center, Research Institute Youki Ueda Department of Tumor Microenvironment, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences Nicolas Sax KOTAI Biotechnologies Inc Kazuo Yamashita KOTAI Biotechnologies Inc Shusuke Kawashima Chiba Cancer Center, Research Institute Joji Nagasaki Department of Tumor Microenvironment, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences Toshihide Ueno Division of Cellular Signaling, National Cancer Center Research Institute Jason Lin Chiba Cancer Center, Research Institute Yuuki Ohara Department of Pathology, National Cancer Center Hospital East Takeshi Kuwata Department of Genetic Medicineand Services, National Cancer Center Hospital East Hiroki Yukami Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East Akihito Kawazoe Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East Kohei Shitara Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East Akiko Honobe-Tabuchi Department of Dermatology, University of Yamanashi Takehiro Ohnuma Department of Dermatology, University of Yamanashi Tatsuyoshi Kawamura Department of Dermatology, University of Yamanashi Yoshiyasu Umeda Department of Skin Oncology/Dermatology, Saitama Medical University International Medical Center Yu Kawahara Department of Skin Oncology/Dermatology, Saitama Medical University International Medical Center Yasuhiro Nakamura Department of Skin Oncology/Dermatology, Saitama Medical University International Medical Center Yukiko Kiniwa Department of Dermatology, Shinshu University School of Medicine Ayako Morita Department of Allergy and Respiratory Medicine, Okayama University Hospital Eiki Ichihara Department of Allergy and Respiratory Medicine, Okayama University Hospital Katsuyuki Kiura Department of Allergy and Respiratory Medicine, Okayama University Hospital Tomohiro Enokida Department of Head and Neck Medical Oncology, National Cancer Center Hospital East Makoto Tahara Department of Head and Neck Medical Oncology, National Cancer Center Hospital East Yoshinori Hasegawa Department of Applied Genomics, Kazusa DNA Research Institute Hiroyuki Mano Division of Cellular Signaling, National Cancer Center Research Institute Yutaka Suzuki Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo Hiroyoshi Nishikawa Division of Cancer Immunology, Research Institute/Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center Yosuke Togashi Department of Tumor Microenvironment, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences Some patients experience mixed response to immunotherapy, whose biological mechanisms and clinical impact have been obscure. We obtained two tumor samples from lymph node (LN) metastatic lesions in a same patient. Whole exome sequencing for the both tumors and single-cell sequencing for the both tumor-infiltrating lymphocytes (TIL) demonstrated a significant difference in tumor clonality and TILs' characteristics, especially exhausted T-cell clonotypes, although a close relationship between the tumor cell and T-cell clones were observed as a response of an overlapped exhausted T-cell clone to an overlapped neoantigen. To mimic the clinical setting, we generated a mouse model of several clones from a same tumor cell line. Similarly, differential tumor clones harbored distinct TILs, and one responded to programmed cell death protein 1 (PD-1) blockade but the other did not in this model. We further conducted cohort study (n = 503) treated with PD-1 blockade monotherapies to investigate the outcome of mixed response. Patients with mixed responses to PD-1 blockade had a poor prognosis in our cohort. Particularly, there were significant differences in both tumor and T-cell clones between the primary and LN lesions in a patient who experienced tumor response to anti-PD-1 mAb followed by disease progression in only LN metastasis. Our results underscore that intertumoral heterogeneity alters characteristics of TILs even in the same patient, leading to mixed response to immunotherapy and significant difference in the outcome. Significance: Several patients experience mixed responses to immunotherapies, but the biological mechanisms and clinical significance remain unclear. Our results from clinical and mouse studies underscore that intertumoral heterogeneity alters characteristics of TILs even in the same patient, leading to mixed response to immunotherapy and significant difference in the outcome. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 77 4 2023 Association of Tumor Necrosis Factor-Alpha with Psychopathology in Patients with Schizophrenia 395 405 EN Marko Pavlovic University Hospital Center Mostar, University of Mostar Dragan Babic University Hospital Center Mostar, University of Mostar Pejana Rastovic University Hospital Center Mostar, University of Mostar Jurica Arapovic University Hospital Center Mostar, University of Mostar Marko Martinac Health Care Center Mostar, University of Mostar Sanja Jakovac University Hospital Center Mostar, University of Mostar Romana Barbaric University Hospital Center Mostar, University of Mostar Original Article 10.18926/AMO/65750 We investigated the relationship between serum tumor necrosis factor-alpha (TNF-α) levels and psychopathological symptoms, clinical and socio-demographic characteristics and antipsychotic therapy in individuals with schizophrenia. TNF-α levels were measured in 90 patients with schizophrenia and 90 healthy controls matched by age, gender, smoking status, and body mass index. The Positive and Negative Syndrome Scale (PANSS) was used to assess the severity of psychopathology in patients. No significant differences in TNF-α levels were detected between the patients and controls (p=0.736). TNF-α levels were not correlated with total, positive, negative, general, or composite PANSS scores (all p>0.05). A significant negative correlation was observed between TNF-α levels and the PANSS cognitive factor (ρ=−0.222, p=0.035). A hierarchical regression analysis identified the cognitive factor as a significant predictor of the TNF-α level (beta=−0.258, t=−2.257, p=0.027). There were no significant differences in TNF-α levels among patients treated with different types of antipsychotics (p=0.596). TNF-α levels correlated positively with the age of onset (ρ=0.233, p=0.027) and negatively with illness duration (ρ=−0.247, p=0.019) and antipsychotic treatment duration (ρ=−0.256, p=0.015). These results indicate that TNF-α may be involved in cognitive impairment in schizophrenia, and would be a potential clinical-state marker in schizophrenia. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 77 4 2023 GATA4 rs61277615, rs73203482, and rs35813172 in Newborns with Transposition of the Great Arteries 365 370 EN Elena Moldovan Pediatric Intensive Care Unit, Cardiovascular and Transplant Emergency Institute of Târgu Mureș Claudia Bănescu George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Târgu Mureș Manuela Cucerea George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Târgu Mureș Valeriu Moldovan Târgu Mureș County Emergency Clinical Hospital Liliana Gozar George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Târgu Mureș Lucian Pușcașiu George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Târgu Mureș Original Article 10.18926/AMO/65745 Congenital heart disease is the most common malformative pathology in newborns, with a worldwide incidence at 0.4-5%. We investigated the possible relationship between variations in nucleotide sequences and specific cardiac malformations in the GATA-binding factor 4 (GATA4) exon 1 region by using Sanger sequencing. Forty-four newborns from a third-level neonatal intensive care unit who were diagnosed with nonsyndromic, ductal-dependent congenital heart disease (i.e., transposition of the great arteries or ductal-dependent coarctation of the aorta) were enrolled. Their DNA was extracted using commercial methods and tested using the multiplex ligation-dependent probe amplification (MLPA) technique. The Sanger sequencing for GATA4 exon 1 in the newborns’ DNA identified rs61277615, rs73203482, and rs35813172 variants not reported in the ClinVar archive of human variations in newborns previously diagnosed with transposition of the great arteries (n=5) and coarctation of the aorta (n=1). The identification of these novel variants in newborns with transposition of the great arteries or ductal-dependent coarctation of the aorta may be the first step in determining the variants’ contribution to the occurrence of congenital heart disease. However, these results may be inconclusive, since the observed variants within GATA4 gene were not previously reported. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 77 3 2023 Utility of Comprehensive Genomic Profiling for Precise Diagnosis of Pediatric-Type Diffuse High-Grade Glioma 323 330 EN Keigo Makino Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yoshihiro Otani Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kentaro Fujii Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Joji Ishida Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shuichiro Hirano Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yasuki Suruga Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kana Washio Departments of Pediatrics, Okayama University Hospital Kenji Nishida Departments of Pathology, Okayama University Hospital Hiroyuki Yanai Departments of Pathology, Okayama University Hospital Shuta Tomida Center for Comprehensive Genomic Medicine, Okayama University Hospital Daisuke Ennishi Center for Comprehensive Genomic Medicine, Okayama University Hospital Isao Date Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Case Report 10.18926/AMO/65502 In the current World Health Organization classification of central nervous system tumors, comprehensive genetic and epigenetic analyses are considered essential for precise diagnosis. A 14-year-old male patient who presented with a cerebellar tumor was initially diagnosed with glioblastoma and treated with radiation and concomitant temozolomide chemotherapy after resection. During maintenance temozolomide therapy, a new contrast-enhanced lesion developed in the bottom of the cavity formed by the resection. A second surgery was performed, but the histological findings in specimens from the second surgery were different from those of the first surgery. Although genome-wide DNA methylation profiling was conducted using frozen tissue for a precise diagnosis, the proportion of tumor cells was insufficient and only normal cerebellum was observed. We then performed comprehensive genetic analysis using formalin-fixed paraffin-embedded sections, which revealed MYCN amplification without alteration of IDH1, IDH2, or Histone H3. Finally, the patient was diagnosed with pediatric-type diffuse high-grade glioma, H3-wildtype and IDH-wildtype. In conclusion, comprehensive genetic and epigenetic analysis should be considered in pediatric brain tumor cases. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 77 3 2023 Current Prevalence of Antimicrobial Resistance in Okayama from a National Database between 2018 and 2021 255 262 EN Shinnosuke Fukushima Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hideharu Hagiya Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kazuhiro Uda Department of Pediatrics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kazuyoshi Gotoh Department of Bacteriology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Fumio Otsuka Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Original Article 10.18926/AMO/65490 Antimicrobial resistance is an emerging global threat that must be addressed using a multidisciplinary approach. This study aimed to raise awareness of high-level antimicrobial-resistant (AMR) pathogens in Japan by comparing their recent prevalences among prefectures, particularly Okayama. Data for the isolation proportions of meropenem-resistant Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecium, cefotaxime-resistant Escherichia coli and Klebsiella pneumoniae, and levofloxacin-resistant E. coli and K. pneumoniae were collected from the Japan Nosocomial Infections Surveillance, a national database sponsored by the Japanese Ministry of Health, Labour, and Welfare, between 2018 and 2021. The average isolated proportions of the seven AMR pathogens were higher in Okayama compared to other prefectures: the worst (19.9%) was meropenem-resistant P. aeruginosa, the sixth worst (57.2%) was methicillin-resistant S. aureus, the eighth worst (3.3%) was vancomycin-resistant E. faecium, the second (37.8%) and fifth worst (17.6%) were cefotaxime-resistant E. coli and K. pneumoniae, respectively, and the fourth (49.9%) and third worst (8.7%) were levofloxacin-resistant E. coli and K. pneumoniae, respectively. Our study highlights the notably high prevalences of representative AMR pathogens in Okayama, suggesting the need for fundamental infection prevention and control by healthcare professionals, promoting antimicrobial stewardship, and educating undergraduates and postgraduates in Okayama. No potential conflict of interest relevant to this article was reported.

Elsevier BV Acta Medica Okayama 0169-5002 178 2023 PD-1 blockade augments CD8+ T cell dependent antitumor immunity triggered by Ad-SGE-REIC in Egfr-mutant lung cancer 1 10 EN Takamasa Nakasuka Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kadoaki Ohashi Department of Respiratory Medicine, Okayama University Hospital Kazuya Nishii Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Atsuko Hirabae Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Sachi Okawa Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Nahoko Tomonobu Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kenji Takada Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Chihiro Ando Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hiromi Watanabe Department of Respiratory Medicine, Okayama University Hospital Go Makimoto Department of Respiratory Medicine, Okayama University Hospital Kiichiro Ninomiya Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine Masanori Fujii Department of Respiratory Medicine, Okayama University Hospital Toshio Kubo Center for Clinical Oncology, Okayama University Hospital Eiki Ichihara Department of Respiratory Medicine, Okayama University Hospital Katsuyuki Hotta Center for Innovative Clinical Medicine, Okayama University Hospital Masahiro Tabata Center for Clinical Oncology, Okayama University Hospital Hiromi Kumon Innovation Center Okayama for Nanobio-targeted Therapy, Okayama University Yoshinobu Maeda Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Katsuyuki Kiura Department of Respiratory Medicine, Okayama University Hospital Objectives: No immunotherapeutic protocol has yet been established in never-smoking patients with lung cancer harboring driver oncogenic mutations, such as epidermal growth factor receptor (EGFR) mutations. The immunostimulatory effect of Ad-REIC, a genetically engineered adenovirus vector expressing a tumor suppressor gene, reduced expression in immortalized cells (REIC), has been investigated in clinical trials for various solid tumors. However, the immunostimulatory effect of the Ad-REIC in EGFR-mutant lung cancer with a non-inflamed tumor microenvironment (TME) has not been explored. Materials and methods: We used a syngeneic mouse model developed by transplanting Egfr-mutant lung cancer cells into single or double flanks of C57BL/6J mice. Ad-SGE-REIC, a 2nd-generation vector with an enhancer sequence, was injected only into the tumors from one flank, and its antitumor effects were assessed. Tumor-infiltrating cells were evaluated using immunohistochemistry or flow cytometry. The synergistic effects of Ad-SGE-REIC and PD-1 blockade were also examined. Results: Injection of Ad-SGE-REIC into one side of the tumor induced not only a local antitumor effect but also a bystander abscopal effect in the non-injected tumor, located on the other flank. The number of PD-1+CD8+ T cells increased in both injected and non-injected tumors. PD-1 blockade augmented the local and abscopal antitumor effects of Ad-SGE-REIC by increasing the number of CD8+ T cells in the TME of Egfr-mutant tumors. Depletion of CD8+ cells reverted the antitumor effect, suggesting they contribute to antitumor immunity. Conclusion: Ad-SGE-REIC induced systemic antitumor immunity by modifying the TME status from non-inflamed to inflamed, with infiltration of CD8+ T cells. Additionally, in Egfr-mutant lung cancer, this effect was enhanced by PD-1 blockade. These findings pave the way to establish a novel combined immunotherapy strategy with Ad-SGE-REIC and anti-PD-1 antibody for lung cancer with a non-inflamed TME. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 77 1 2023 Development, Disappearance, and Clinical Course of Melanosis Coli: Sex Differences in the Progression of Severity 57 64 EN Ryo Katsumata Department of General Internal Medicine 2, Kawasaki Medical School General Medical Center Noriaki Manabe Division of Endoscopy and Ultrasonography, Department of Clinical Pathology and Laboratory Medicine, Kawasaki Medical School General Medical Center Yasumasa Monobe Pathology, Kawasaki Medical School General Medical Center Maki Ayaki Division of Endoscopy and Ultrasonography, Department of Clinical Pathology and Laboratory Medicine, Kawasaki Medical School General Medical Center Mitsuhiko Suehiro Department of General Internal Medicine 2, Kawasaki Medical School General Medical Center Minoru Fujita Division of Endoscopy and Ultrasonography, Department of Clinical Pathology and Laboratory Medicine, Kawasaki Medical School General Medical Center Tomoari Kamada Health Care Medicine, Kawasaki Medical School General Medical Center Hirofumi Kawamoto Department of General Internal Medicine 2, Kawasaki Medical School General Medical Center Ken Haruma Department of General Internal Medicine 2, Kawasaki Medical School General Medical Center Original Article 10.18926/AMO/64362 Melanosis coli (MC) is an acquired colorectal disorder visualized as colonic mucosa pigmentation. Disease severity is confirmed based on MC depth, shape, and coloration, although the clinical course is not fully understood. This study sought to clarify characteristics of MC development and disappearance and to investigate its clinical course and severity. Contributors to MC grade progression were explored. This study reviewed MC cases discovered via colonoscopy at a single institution over a 10-year period. Of all 216 MC cases, 17 developing and 10 disappearing cases were detected. Anthranoid laxative use was a key factor: 29.4% of the developing cases had used such agents before the initial MC diagnosis, whereas 40% of disappearing cases had discontinued anthranoids prior to detection of MC disappearance. Among 70 grade I cases, progression to grade II occurred in 16 cases during a mean follow-up of 3.67±2.1 years (rate of progression=22.8%). Males more commonly showed progressive than stable grade I cases, and the probability of progression was higher for male than for female cases. An association between anthranoid administration and MC presence was presumed, and grade I MC was found to progress in severity over 5 years. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 77 1 2023 Prevalence of Inducible Macrolide, Lincosamide, and Streptogramin B (inducible MLSB) Resistance in Clindamycin-Susceptible Staphylococcus aureus at Okayama University Hospital 1 9 EN Lutfun Nahar Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hideharu Hagiya Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takahiro Nada Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Koji Iio Microbiology Division, Clinical Laboratory, Okayama University Hospital Kazuyoshi Gotoh Department of Bacteriology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Osamu Matsushita Department of Bacteriology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Fumio Otsuka Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Original Article 10.18926/AMO/64355 Inducible resistance to the macrolide, lincosamide, and streptogramin B (iMLSB) antibiotic family is a latent mechanism for antimicrobial resistance in Staphylococcus aureus. We here investigated the frequency and genotypic profiles of iMLSB resistance in clindamycin (CLDM)-susceptible S. aureus isolated in Okayama University Hospital from June 2020 to June 2021. We phenotypically screened the iMLSB resistance via D-zone test and performed PCR testing for the erythromycin ribosomal methylase (erm) genes: ermA and ermC. Among 432 CLDM-susceptible S. aureus isolates, 138 (31.9%) exhibited an iMLSB-resistance phenotype, with methicillinresistant S. aureus isolates (MRSA; 61 isolates: 58.6%) exhibiting higher positivity than methicillin-sensitive S. aureus isolates (MSSA; 77 isolates: 23.5%) (p<0.001). Male patients had a higher frequency of iMLSB resistance than females (OR [95%CI]: 1.8 [1.2-2.8]; p=0.007). Genotypically, ermA predominated in both MSSA (70.1%) and MRSA (86.9%) compared to ermC (14.3% in MSSA and 11.5% in MRSA). A single strain of MRSA possessed both ermA and ermC, while 12 (15.6%) MSSA isolates were negative for both ermA and ermC, suggesting the presence of other genetic mechanisms. Collectively, these results show that approximately 33% of CLDM-susceptible S. aureus isolates at our university hospital exhibited iMLSB resistance, predominantly caused by ermA in both MSSA and MRSA. No potential conflict of interest relevant to this article was reported.

Springer Science and Business Media LLC Acta Medica Okayama 0300-8177 478 8 2022 Significance of UGT1A6, UGT1A9, and UGT2B7 genetic variants and their mRNA expression in the clinical outcome of renal cell carcinoma 1779 1790 EN Jun Matsumoto Department of Personalized Medicine and Preventive Healthcare Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Anzu Nishimoto Department of Personalized Medicine and Preventive Healthcare Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Shogo Watari Department of Urology, National Hospital Organization Okayama Medical Center Hideo Ueki Department of Urology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University Shoya Shiromizu Department of Pharmacy, Okayama University Hospital Naohiro Iwata Department of Pharmacy, Okayama University Hospital Tatsuaki Takeda Department of Pharmacy, Okayama University Hospital Soichiro Ushio Department of Pharmacy, Okayama University Hospital Makoto Kajizono Department of Pharmacy, Okayama University Hospital Masachika Fujiyoshi Department of Pharmacy, Tottori University Hospital Toshihiro Koyama Department of Pharmaceuticals Biomedicine, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University Motoo Araki Department of Urology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University Koichiro Wada Department of Urology, Faculty of Medicine, Shimane University Yoshito Zamami Department of Pharmacy, Okayama University Hospital Yasutomo Nasu Department of Urology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University Noritaka Ariyoshi Department of Personalized Medicine and Preventive Healthcare Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University UDP-glucuronosyltransferase (UGT) metabolizes a number of endogenous and exogenous substrates. Renal cells express high amounts of UGT; however, the significance of UGT in patients with renal cell carcinoma (RCC) remains unknown. In this study, we profile the mRNA expression of UGT subtypes (UGT1A6, UGT1A9, and UGT2B7) and their genetic variants in the kidney tissue of 125 Japanese patients with RCC (Okayama University Hospital, Japan). In addition, we elucidate the association between the UGT variants and UGT mRNA expression levels and clinical outcomes in these patients. The three representative genetic variants, namely, UGT1A6 541A > G, UGT1A9 i399C > T, and UGT2B7-161C > T, were genotyped, and their mRNA expression levels in each tissue were determined. We found that the mRNA expression of the three UGTs (UGT1A6, UGT1A9, and UGT2B7) are significantly downregulated in RCC tissues. Moreover, in patients with RCC, the UGT2B7-161C > T variant and high UGT2B7 mRNA expression are significantly correlated with preferable cancer-specific survival (CSS) and overall survival (OS), respectively. As such, the UGT2B7-161C > T variant and UGT2B7 mRNA expression level were identified as significant independent prognostic factors of CSS and CSS/OS, respectively. Taken together, these findings indicate that UGT2B7 has a role in RCC progression and may, therefore, represent a potential prognostic biomarker for patients with RCC. No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 2049-4173 11 1 2022 Novel ABCD1 mutation detected in a symptomatic female carrier of adrenoleukodystrophy 58 60 EN Yumiko Nakano Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yuki Taira Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ryo Sasaki Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Koh Tadokoro Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Taijun Yunoki Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Emi Nomura Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yusuke Fukui Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Mami Takemoto Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ryuta Morihara Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Nobuyuki Shimozawa Division of Genomics Research, Life Science Research Center, Gifu university Toru Yamashita Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences X-linked adrenoleukodystrophy (ALD) is a major peroxisomal disorder, in which abnormal accumulation of very long-chain fatty acids (VLCFA) caused by ABCD1 gene mutation results in damage to the peripheral and central nervous system and adrenal gland. While affected male patients with ALD present severe neurological symptoms, some female carriers slowly develop spastic gait and urinary incontinence. We report a case of a symptomatic female ALD carrier with a novel ABCD1 gene mutation. She has developed progressive gait disturbance since age 40, and her father and sister had similar symptoms. When admitted to our hospital at age 66, blood analysis showed slight increase of VLCFA, and DNA analysis of ABCD1 gene revealed a novel heterozygous missense mutation (c.1700 A>C, p.Gln567Pro). The genetic testing for ABCD1 gene can be considered in female patients over middle age presenting spastic gait, because female ALD carriers tend to be symptomatic beyond age 60. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 76 6 2022 Handling of Germline Findings in Clinical Comprehensive Cancer Genomic Profiling 673 678 EN Mika Okazawa-Sakai Department of Clinical Genomic Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yasuko Yamamoto Department of Cancer Genomic Medicine, National Hospital Organization Shikoku Cancer Center Mashu Futagawa Department of Clinical Genomic Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Miki Okamura Department of Hereditary Tumors, National Hospital Organization Shikoku Cancer Center Satoko Miyawaki Department of Cancer Genomic Medicine, National Hospital Organization Shikoku Cancer Center Tomohiro Nishina Department of Cancer Genomic Medicine, National Hospital Organization Shikoku Cancer Center Kazuhiro Takehara Department of Gynecologic Oncology, National Hospital Organization Shikoku Cancer Center Toshiyuki Kozuki Department of Clinical Research Center, National Hospital Organization Shikoku Cancer Center Shuta Tomida Center for Comprehensive Genomic Medicine, Okayama University Hospital Ichinosuke Hyodo Department of Cancer Genomic Medicine, National Hospital Organization Shikoku Cancer Center Shozo Ohsumi Department of Hereditary Tumors, National Hospital Organization Shikoku Cancer Center Akira Hirasawa Department of Clinical Genomic Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Original Article 10.18926/AMO/64117 Patients found to have presumed germline pathogenic variants (PGPVs) during comprehensive genomic profiling (CGP) require genetic counseling (GC) referrals. We retrospectively investigated the outcomes of patients with PGPVs. Among 159 patients who underwent CGP, we recommended GC for the 16 patients with PGPVs (3 with [FG group] and 13 without [G Group] a family/personal history of hereditary cancer) as well as for the 8 patients with no PGPVs, but a history (F group); 2 (67%), 5 (38%), and 3 (38%) patients received GC in the FG, G, and F groups, respectively. Germline testing results were positive in 1 and 2 patients of the FG and G groups, respectively. Among the patients recommended for GC, 58% did not receive GC due to lack of interest, poor performance status, or death. CGP contributes to the identification of germline variants in patients without a history of hereditary cancer. However, the proportion of patients who undergo GC should be improved. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 76 6 2022 Association of Genetic Polymorphism with Taxane-induced Peripheral Neuropathy: Sub-analysis of a Randomized Phase II Study to Determine the Optimal Dose of 3-week Cycle Nab-Paclitaxel in Metastatic Breast Cancer Patients 661 671 EN Yuko Abe Department of Thoracic, Breast, and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Naruto Taira Department of Breast and Endocrine surgery, Kawasaki Medical School Hospital Kosuke Kashiwabara Clinical Research Promotion Center, University of Tokyo Hospital Junji Tsurutani Advanced Cancer Translational Research Institute, Showa University Masahiro Kitada Breast Disease Center, Asahikawa Medical University Hospital Masato Takahashi Department of Breast Surgery, National Hospital Organization Hokkaido Cancer Center Hiroaki Kato Department of Breast Surgery, Teine Keijinkai Hospital Yuichiro Kikawa Department of Breast Surgery, Kansai Medical University Hospital Eiko Sakata Department of Breast Surgery, Niigata City General Hospital Yoichi Naito Department of Medical Oncology, National Cancer Center Hospital East Yoshie Hasegawa Department of Breast Surgery, Hachinohe City Hospital Tsuyoshi Saito Department of Breast Surgery, Japanese Red Cross Saitama Hospital Tsutomu Iwasa Department of Medical Oncology, Kindai University Faculty of Medicine Tsutomu Takashima Department of Breast and Endocrine Surgery, Osaka City University Graduate School of Medicine Tomohiko Aihara Breast Center, Aihara Hospital Hirofumi Mukai Department of Medical Oncology, National Cancer Center Hospital East Fumikata Hara Breast Oncology Center, Cancer Institute Hospital of Japanese Foundation for Cancer Research Tadahiko Shien Department of Breast and Endocrine surgery, Okayama University Hospital Hiroyoshi Doihara Department of Breast surgery, Kawasaki Medical School General Medical Center Shinichi Toyooka Department of Thoracic, Breast, and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Original Article 10.18926/AMO/64116 Chemotherapy-induced peripheral neuropathy (CIPN) is an important clinical challenge that threatens patients’ quality of life. This sub-study of the ABROAD trial investigated the influence of single nucleotide polymorphisms (SNPs) on CIPN, using genotype data from a randomized study to determine the optimal dose of a 3-week-cycle regimen of nab-paclitaxel (q3w nab-PTX) in patients with metastatic breast cancer (MBC). Patients with HER2-negative MBC were randomly assigned to three doses of q3w nab-PTX (SD: 260 mg/m2 vs. MD: 220 mg/m2 vs. LD: 180 mg/m2). Five SNPs (EPHA4-rs17348202, EPHA5-rs7349683, EPHA6-rs301927, LIMK2-rs5749248, and XKR4-rs4737264) were analyzed based on the results of a previous genome-wide association study. Per-allele SNP associations were assessed by a Cox regression to model the cumulative dose of nab-PTX up to the onset of severe or worsening sensory neuropathy. A total of 141 patients were enrolled in the parent study; 91(65%) were included in this sub-study. Worsening of CIPN was significantly greater in the cases with XKR4 AC compared to those with a homozygote AA (HR 1.86, 95%CI: 1.00001−3.46, p=0.049). There was no significant correlation of CIPN with any other SNP. A multivariate analysis showed that the cumulative dose of nab-PTX was most strongly correlated with CIPN (p<0.01). No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 76 5 2022 Current Insights into Mesenchymal Signatures in Glioblastoma 489 502 EN Yuji Matsumoto Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Tomotsugu Ichikawa Department of Neurological Surgery, Kagawa Prefectural Central Hospital Kazuhiko Kurozumi Department of Neurosurgery, Hamamatsu University Hospital Isao Date Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Review 10.18926/AMO/64024 Glioblastoma (GBM) is a fatal primary malignant brain tumor in adults. Despite decades of research, the prognosis for GBM patients is still disappointing. One major reason for the intense therapeutic resistance of GBM is inter- and intra-tumor heterogeneity. GBM-intrinsic transcriptional profiling has suggested the presence of at least three subtypes of GBM: the proneural, classic, and mesenchymal subtypes. The mesenchymal subtype is the most aggressive, and patients with the mesenchymal subtype of primary and recurrent tumors tend to have a worse prognosis compared with patients with the other subtypes. Furthermore, GBM can shift from other subtypes to the mesenchymal subtype over the course of disease progression or recurrence. This phenotypic transition is driven by diverse tumor-intrinsic molecular mechanisms or microenvironmental factors. Thus, better understanding of the plastic nature of mesenchymal transition in GBM is pivotal to developing new therapeutic strategies. In this review, we provide a comprehensive overview of the current understanding of the elements involved in the mesenchymal transition of GBM and discuss future perspectives. No potential conflict of interest relevant to this article was reported.

Elsevier BV Acta Medica Okayama 1341-321X 28 11 2022 High frequency of extended-spectrum beta-lactamase-producing Enterobacteriaceae carriers at a Japanese long-term care hospital 1578 1581 EN Hideharu Hagiya Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yuji Onishi Clinical Laboratory, Marugame Medical Center Natsumi Shinohara Clinical Laboratory, Marugame Medical Center Mayumi Tokuyasu Department of Nursing, Marugame Medical Center Aki Imanishi Department of Nursing, Marugame Medical Center Shinnosuke Fukushima Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Lutfun Nahar Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Koji Iio Microbiology Division, Clinical Laboratory, Okayama University Hospital Fumio Otsuka Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Introduction: Long-term care hospitals (LTCHs) are at a high risk for the inflow and spread of antimicrobial resistance (AMR) pathogens. However, owing to limited laboratory resources, little is known about the extent to which AMR organisms are endemic. Methods: We performed active surveillance for carbapenem-resistant Enterobacteriaceae (CRE) and extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-E) in newly admitted patients at Marugame Medical Center, a nearly 200-bedded LTCH located in Kagawa, Japan. From August to December 2021, we tested stool samples from patients wearing diapers and confirmed the genetic variants using specific PCR assays. We also collected clinical variables and compared them between AMR carriers and non-carriers. Results: Stool samples were collected from 75 patients, with a median age of 84 years. CRE strain was not detected, but 37 strains of ESBL-E were isolated from 32 patients (42.7%). During the study period, 4.9% of in-hospital patients (37 per 756 patients) were identified to be ESBL-E carriers in the routine microbiological processing, suggesting that active surveillance detected approximately 9-fold more ESBL-E carriers. The bla(CTM-M-9) group was the most common (38.5%), followed by the bla(TEM) (26.9%). The clinical backgrounds of the ESBL-E non-carriers and carriers were not significantly different. Conclusion: Our active screening demonstrated that nearly half of the patients hospitalized or transferred to a Japanese LTCH were colonized with ESBL-E. We highlight the enforcement of universal basic infection prevention techniques at LTCHs where patients carrying AMR pathogens gather. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 76 4 2022 Liquid Biopsy Revealed HBOC Pedigree and Led to Medical Management Among the Relatives 479 483 EN Chikako Ogawa Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Akira Hirasawa Department of Clinical Genomic Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Reimi Sogawa Department of Clinical Genetics and Genomic Medicine, Okayama University Hospital Kayoko Hasuoka Department of Nursing, Okayama University Hospital Shuta Tomida Department of Center for Comprehensive Genomic Medicine, Okayama University Hospital Biobank, Okayama University Hospital Mashu Futagawa Department of Clinical Genetics and Genomic Medicine, Okayama University Hospital Yusaku Urakawa Department of Clinical Genomic Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Mariko Kochi Department of Clinical Genetics and Genomic Medicine, Okayama University Hospital Hideki Yamamoto Department of Clinical Genomic Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Keiichiro Nakamura Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hisashi Masuyama Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Case Report 10.18926/AMO/63908 A hereditary breast and ovarian cancer (HBOC) pedigree was detected via liquid biopsy, and cancer prevention was initiated for the patient’s daughter, after receiving a definitive result from BRCA genetic testing. A 48-yearold woman with ovarian cancer was administered precision medicine, which used cell-free DNA from plasma. The results revealed a pathogenic variant of BRCA1 as a presumed germline pathogenic mutation. We confirmed the germline pathological variant BRCA1 c.81-1G> A and suggested treatment with a PARP inhibitor. One of her three children had the variant, was diagnosed as an unaffected pathogenic variant carrier, and was advised to initiate surveillance. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 76 4 2022 Gene Expression Profiling between Patient Groups with High and Low Ki67 Levels after Short-term Preoperative Aromatase Inhibitor Treatment for Breast Cancer 399 408 EN Yukiko Kajiwara Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takayuki Iwamoto Departments of Breast and Endocrine Surgery, Okayama University Hospital Yidan Zhu Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Mariko Kochi Departments of Breast and Endocrine Surgery, Okayama University Hospital Tadahiko Shien Departments of Breast and Endocrine Surgery, Okayama University Hospital Naruto Taira Departments of Breast and Endocrine Surgery, Okayama University Hospital Hiroyoshi Doihara Departments of Breast and Endocrine Surgery, Okayama University Hospital Shinichi Toyooka Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Original Article 10.18926/AMO/63894 According to a recent report, a low Ki67 level after short-term preoperative hormone therapy (post-Ki67) might suggest a more favorable prognosis compared with a high post-Ki67 level in patients with hormone receptorpositive/human epidermal growth factor 2-negative (HR+/HER2−) breast cancer with high levels of Ki67. This study aimed to evaluate the pre-treatment genetic differences between these two patient groups. Forty-five luminal B-like patients were stratified into two groups, namely, a group with high (H→H) and one with low (H→L) Ki67 levels after short-term preoperative aromatase inhibitor (AI) treatment. We compared pre-treatmentgene expression profiles between the two groups. In gene level analysis, there was no significant difference between the two groups by the class comparison test. In pathway analysis, five metabolism-related gene sets were significantly upregulated in the H→L group (p≤0.05). In the search for novel targets, five genes (PARP, BRCA2, FLT4, CDK6, and PDCD1LG2) showed significantly higher expression in the H→H group (p≤0.05). Several metabolism-related pathways were associated with sensitivity to AI. In the future, it will be necessary to seek out new therapeutic strategies for the poor prognostic group with high post-Ki67. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 76 4 2022 Therapeutic Approaches Targeting miRNA in Systemic Lupus Erythematosus 359 371 EN Sumie Hiramatsu-Asano Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Jun Wada Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Review 10.18926/AMO/63887 Systemic lupus erythematosus (SLE) is a potentially fatal systemic autoimmune disease, and its etiology involves both genetic and environmental factors such as sex hormone imbalance, genetic predisposition, epigenetic regulation, and immunological factors. Dysregulation of microRNA (miRNA) is suggested to be one of the epigenetic factors in SLE. miRNA is a 22-nucleotide single-stranded noncoding RNA that contributes to post-transcriptional modulation of gene expression. miRNA targeting therapy has been suggested to be useful for the treatment of cancers and other diseases. Gene knockout and miRNA targeting therapy have been demonstrated to improve SLE disease activity in mice. However, these approaches have not yet reached the level of clinical application. miRNA targeting therapy is limited by the fact that each miRNA has multiple targets. In addition, the expression of certain miRNAs may differ among cell tissues within a single SLE patient. This limitation can be overcome by targeted delivery and chemical modifications. In the future, further research into miRNA chemical modifications and delivery systems will help us develop novel therapeutic agents for SLE. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 76 3 2022 A Case of a Solitary Cortical Tuber with No Other Manifestations of Tuberous Sclerosis Complex Mimicking Focal Cortical Dysplasia Type II with Calcification 323 328 EN Kakeru Hosomoto Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tatsuya Sasaki Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Koji Kawai Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yosuke Okazaki Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yuki Hyodo Department of Child Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takashi Shibata Department of Child Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Susumu Sasada Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takao Yasuhara Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Katsuhiro Kobayashi Department of Child Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hiroyuki Yanai Department of Diagnostic Pathology,Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Isao Date Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Case Report 10.18926/AMO/63742 Cortical tubers are one of the typical intracranial manifestations of tuberous sclerosis complex (TSC). Multiple cortical tubers are easy to diagnose as TSC; however, a solitary cortical tuber without any other cutaneous or visceral organ manifestations can be confused with other conditions, particularly focal cortical dysplasia. We report a surgical case of refractory epilepsy caused by a solitary cortical tuber mimicking focal cortical dysplasia type II, and describe the radiological, electrophysiological, and histopathological findings of our case. No potential conflict of interest relevant to this article was reported.

BMC Acta Medica Okayama 1752-1947 16 1 2022 Adenomatoid mesothelioma arising from the diaphragm: a case report and review of the literature 228 EN Kenta Kawabe Center for Graduate Medical Education, Okayama University Hospital Hiroki Sato Department of Gastroenterological Surgery, Okayama University Hospital Akiko Kitano Department of Pathology, Okayama University Hospital Ryuichi Yoshida Department of Gastroenterological Surgery, Okayama University Hospital Kazuya Yasui Department of Gastroenterological Surgery, Okayama University Hospital Yuzo Umeda Department of Gastroenterological Surgery, Okayama University Hospital Kazuhiro Yoshida Department of Gastroenterological Surgery, Okayama University Hospital Tomokazu Fuji Department of Gastroenterological Surgery, Okayama University Hospital Kenjiro Kumano Department of Gastroenterological Surgery, Okayama University Hospital Kosei Takagi Department of Gastroenterological Surgery, Okayama University Hospital Masaaki Kagoura Department of Gastroenterological Surgery, Okayama University Hospital Takahito Yagi Department of Gastroenterological Surgery, Okayama University Hospital Toshiyoshi Fujiwara Department of Gastroenterological Surgery, Okayama University Hospital Background Adenomatoid mesothelioma is a rare subtype of malignant mesothelioma that can be confused with adenomatoid tumors, which are classified as benign. The clinical features and optimal management of adenomatoid mesothelioma have not been elucidated in the literature. In this report, we present an extremely rare case of adenomatoid mesothelioma that developed on the peritoneal surface of the diaphragm as well as a literature review of adenomatoid mesothelioma in the abdominal cavity. Case presentation The patient was a 61-year-old Japanese woman who had undergone resection of a malignant peripheral nerve sheath tumor of the hand 18 years prior. She was diagnosed with clinical stage I lung adenocarcinoma on follow-up chest radiography. Simultaneously, a 20-mm enhancing nodule with slow growth on the right diaphragm was detected on contrast-enhanced computed tomography. She presented no specific clinical symptoms. At this point, the lesion was suspected to be a hypervascular tumor of borderline malignancy, such as a solitary fibrous tumor. After a left upper lobectomy for lung adenocarcinoma, she was referred to our department, and laparoscopic tumor resection was performed. Adenomatoid tumors were also considered based on the histopathological and immunohistochemical analyses, but we made the final diagnosis of adenomatoid mesothelioma using the results of the genetic profile. The patient remains alive, with no recurrence noted 6 months after surgery. Conclusion We encountered a valuable case of adenomatoid mesothelioma of peritoneal origin. There are some previously reported cases of adenomatoid mesothelioma and adenomatoid tumors that may need to be recategorized according to the current classification. It is important to accumulate and share new findings to clarify the clinicopathological characteristics and genetic status of adenomatoid mesothelioma. No potential conflict of interest relevant to this article was reported.

American Society for Clinical Investigation Acta Medica Okayama 1558-8238 132 7 2022 Tankyrase represses autoinflammation through the attenuation of TLR2 signaling e140869 EN Yoshinori Matsumoto Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ioannis D. Dimitriou Princess Margaret Cancer Centre, University Health Network, University of Toronto Jose La Rose Princess Margaret Cancer Centre, University Health Network, University of Toronto Melissa Lim Princess Margaret Cancer Centre, University Health Network, University of Toronto Susan Camilleri Centre for Modeling Human Disease, Toronto Centre for Phenogenomics Napoleon Law Centre for Modeling Human Disease, Toronto Centre for Phenogenomics Hibret A. Adissu Labcorp Early Development Laboratories Inc. Jiefei Tong Program in Cell Biology, The Hospital for Sick Children, Department of Molecular Genetics Michael F. Moran Program in Cell Biology, The Hospital for Sick Children, Department of Molecular Genetics Andrzej Chruscinski Multi-Organ Transplant Program, University Health Network Fang He Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yosuke Asano Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takayuki Katsuyama Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ken-ei Sada Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Jun Wada Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Robert Rottapel Princess Margaret Cancer Centre, University Health Network, University of Toronto Dysregulation of Toll-like receptor (TLR) signaling contributes to the pathogenesis of autoimmune diseases. Here, we provide genetic evidence that tankyrase, a member of the poly(ADP-ribose) polymerase (PARP) family, negatively regulates TLR2 signaling. We show that mice lacking tankyrase in myeloid cells developed severe systemic inflammation with high serum inflammatory cytokine levels. We provide mechanistic evidence that tankyrase deficiency resulted in tyrosine phosphorylation and activation of TLR2 and show that phosphorylation of tyrosine 647 within the TIR domain by SRC and SYK kinases was critical for TLR2 stabilization and signaling. Last, we show that the elevated cytokine production and inflammation observed in mice lacking tankyrase in myeloid cells were dependent on the adaptor protein 3BP2, which is required for SRC and SYK activation. These data demonstrate that tankyrase provides a checkpoint on the TLR-mediated innate immune response. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 76 2 2022 Overexpression of Adenovirus E1A Reverses Transforming Growth Factor-β-induced Epithelial-mesenchymal Transition in Human Esophageal Cancer Cells 203 215 EN Tomoya Masuda Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hiroshi Tazawa Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yuuri Hashimoto Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takeshi Ieda Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Satoru Kikuchi Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shinji Kuroda Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kazuhiro Noma Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yasuo Urata Oncolys BioPharma Inc. Shunsuke Kagawa Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Toshiyoshi Fujiwara Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Original Article 10.18926/AMO/63425 The epithelial-mesenchymal transition (EMT), a normal biological process by which epithelial cells acquire a mesenchymal phenotype, is associated with migration, metastasis, and chemoresistance in cancer cells, and with poor prognosis in patients with esophageal cancer. However, therapeutic strategies to inhibit EMT in tumor environments remain elusive. Here, we show the therapeutic potential of telomerase-specific replication- competent oncolytic adenovirus OBP-301 in human esophageal cancer TE4 and TE6 cells with an EMT phenotype. Transforming growth factor-β (TGF-β) administration induced the EMT phenotype with spindleshaped morphology, upregulation of mesenchymal markers and EMT transcription factors, migration, and chemoresistance in TE4 and TE6 cells. OBP-301 significantly inhibited the EMT phenotype via E1 accumulation. EMT cancer cells were susceptible to OBP-301 via massive autophagy induction. OBP-301 suppressed tumor growth and lymph node metastasis of TE4 cells co-inoculated with TGF-β-secreting fibroblasts. Our results suggest that OBP-301 inhibits the TGF-β-induced EMT phenotype in human esophageal cancer cells. OBP-301-mediated E1A overexpression is a promising antitumor strategy to inhibit EMT-mediated esophageal cancer progression. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 76 2 2022 Changes in Plasma Clozapine Levels after Smoking Cessation in Japanese Inpatients with Schizophrenia: A Retrospective Cohort Study 137 143 EN Masaru Tsukahara Department of Psychiatry, Okayama Psychiatric Medical Center Ryuhei So Department of Psychiatry, Okayama Psychiatric Medical Center Yuji Yada Department of Psychiatry, Okayama Psychiatric Medical Center Masafumi Kodama Department of Psychiatry, Okayama Psychiatric Medical Center Yoshiki Kishi Department of Psychiatry, Okayama Psychiatric Medical Center Norihito Yamada Department of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Original Article 10.18926/AMO/63407 Although reported for Caucasians, changes in plasma clozapine levels after smoking cessation in East Asians remain unclear. We here investigated plasma clozapine levels before and after smoking cessation in Japanese inpatients with schizophrenia. We conducted a retrospective chart review of 14 inpatients with schizophrenia who were being treated with clozapine between June 1, 2019, and July 31, 2019 and who were smokers as of July 1, 2019, the day on which a smoking ban was instituted in the tertiary public psychiatric hospital. The primary outcome was individual differences in plasma clozapine levels between before and after the smoking ban, which were compared using paired t-tests. The mean plasma clozapine level was significantly increased, by 213.4 ng/mL (95% CI 119.9-306.8; p<0.01) or 53.2%. Four of the 14 inpatients experienced clinically significant side effects, such as myoclonus, drooling, and amnesia, due to the development of high plasma clozapine levels. Our findings indicated that close monitoring of plasma clozapine levels before and after smoking cessation and prior dose adjustment of clozapine may be necessary, to prevent a significant risk of developing high plasma clozapine levels, even in Japanese patients. No potential conflict of interest relevant to this article was reported.

Elsevier BV Acta Medica Okayama 0022-510X 387 15 2018 Familial and sporadic chronic progressive degenerative parietal ataxia 70 74 EN Ryuta Morihara Departments of Neurology, Dentistry and Pharmaceutical Sciences, Graduate School of Medicine, Okayama University Toru Yamashita Departments of Neurology, Dentistry and Pharmaceutical Sciences, Graduate School of Medicine, Okayama University Kentaro Deguchi Departments of Neurology, Dentistry and Pharmaceutical Sciences, Graduate School of Medicine, Okayama University Tomoko Kurata Departments of Neurology, Dentistry and Pharmaceutical Sciences, Graduate School of Medicine, Okayama University Emi Nomura Departments of Neurology, Dentistry and Pharmaceutical Sciences, Graduate School of Medicine, Okayama University Kota Sato Departments of Neurology, Dentistry and Pharmaceutical Sciences, Graduate School of Medicine, Okayama University Yumiko Nakano Departments of Neurology, Dentistry and Pharmaceutical Sciences, Graduate School of Medicine, Okayama University Yasuyuki Ohta Departments of Neurology, Dentistry and Pharmaceutical Sciences, Graduate School of Medicine, Okayama University Nozomi Hishikawa Departments of Neurology, Dentistry and Pharmaceutical Sciences, Graduate School of Medicine, Okayama University Takeshi Ikeuchi Department of Molecular Genetics, Bioresource Science Branch, Center of Bioresource, Brain Research Institute Niigata University Masataka Kitaguchi Department of Neurology, Baba Memorial Hospital Koji Abe Departments of Neurology, Dentistry and Pharmaceutical Sciences, Graduate School of Medicine, Okayama University Background & objective: Parietal ataxia has been mainly reported as a consequence of acute ischemic stroke, while degenerative parietal ataxia has not been reported. Methods: We investigated clinical characteristics, neuroimaging data, and genetic analysis of patients with cerebellar ataxia plus parietal atrophy. Results: We identified seven patients, including five patients from two families, with chronic progressive cerebellar ataxia due to degenerative parietal atrophy but not stroke. Age at onset of ataxia was 57.6 +/- 6.9 years. All patients showed chronic progressive cerebellar ataxia with severity of ataxic gait > limb ataxia > dysarthria. Patients showed no cognitive dysfunction, muscle weakness, or parkinsonism, and only two patients showed mild sensory disturbances. The seven patients showed lateralized limb ataxia with greater contralateral parietal lobe atrophy by magnetic resonance imaging, and hypoperfusion by single photon emission computed tomography, without any abnormal cerebellar pathology (i.e., crossed cerebellar diaschisis). Pathogenic mutations in the microtubule-associated protein tau gene were not found using two single nucleotide polymorphisms. Conclusions: This is the first description showing unique clinical features of familial and sporadic chronic progressive degenerative parietal ataxia. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 76 1 2022 Urinary Protein-to-creatinine Ratios Predict Recurrence in Pediatric and Young Adult Cases of Minimal Change Nephrotic Syndrome 41 49 EN Hiroyuki Miyahara Department of Pediatrics, Okayama University Hospital Takayuki Miyai Department of Pediatrics, Okayama University Hospital Kunihiko Aya Department of Pediatrics, Okayama University Hospital Hirokazu Tsukahara Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Original Article 10.18926/AMO/63207 High-dose steroids are required for the treatment of minimal change nephrotic syndrome (MCNS), especially for episodes of recurrence. Predicting and avoiding recurrence can help reduce the steroid dose, but prediction is currently difficult. We herein examined whether changes in laboratory data, especially the urinary protein- to-creatinine ratio (UTP/UCr), can predict clinical recurrence. We also assessed differences in clinical features between children and young adults. We included 36 patients with MCNS; for each case, we retrospectively studied laboratory data during stable remission and pre-recurrence, with the “stable” period defined as all but the 6 weeks before recurrence, and pre-recurrence defined as the 4±2 weeks before recurrence. UTP/UCr, serum albumin, etc. were measured every 5 years during stable periods. We divided patients into cohorts by age at recurrence, < 15 years and ≥ 15 years, and compared stable and pre-recurrence values for the two groups. UTP/UCr values during stable periods tended to be higher in younger patients. UTP/UCr and serum albumin showed statistically significant changes during pre-recurrence periods, but only in those aged ≥ 15 years. Thus, clinical features of recurrence differed depending on age. Signs of recurrence can be confirmed via UTP/UCr or serum albumin several weeks before recurrence in patients ≥ 15 years. No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 2049-4173 10 2022 A case of a heterozygous ABCC6 mutation showing recurrent ischemic strokes and intracranial hemorrhages 98 101 EN Emi Nomura Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Yuko Kawahara Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Yoshio Omote Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Yoshiaki Takahashi Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Namiko Matsumoto Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Ken Ikegami Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Mami Takemoto Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Nozomi Hishikawa Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Yumiko Nakano Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Taijun Yunoki Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Ryuta Morihara Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Masahiro Uemura Department of Neurology, Brain Research Institute, Niigata University Koji Abe Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Toru Yamashita Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Mutations in the ATP-binding cassette subfamily C member 6 (ABCC6) gene are responsible for pseudoxanthoma elasticum (PXE). PXE is a rare genetic metabolic disease with autosomal recessive inheritance that shows ectopic mineralization in skin, eyes and blood vessels, and causes cerebrovascular disease. There are few reports of intracranial hemorrhages in patients with the ABCC6 mutation. We report the first Japanese case with a heterozygous ABCC6 mutation displaying recurrent ischemic strokes and intracranial hemorrhages. We propose that the ABCC6 mutation may be one cause of neurovascular diseases with a family history. No potential conflict of interest relevant to this article was reported.

BMC Acta Medica Okayama 1756-9966 41 1 2022 Different pancreatic cancer microenvironments convert iPSCs into cancer stem cells exhibiting distinct plasticity with altered gene expression of metabolic pathways 29 EN Ghmkin Hassan Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University Toshiaki Ohara Department of Pathology and Experimental Medicine, Medical School, Okayama University Said M. Afify Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University Kazuki Kumon Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University Maram H. Zahra Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University Xiaoying Fu Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University Mohamad Al Kadi Department of Bacterial Infections, Research Institute for Microbial Diseases, Osaka University Akimasa Seno Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University David S. Salomon Mouse genetics program, Center for Cancer Research, National Cancer Institute Masaharu Seno Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University Background Cancer stem cells (CSCs) are generated under irregular microenvironment in vivo, of which mimic is quite difficult due to the lack of enough information of the factors responsible for cancer initiation. Here, we demonstrated that mouse induced pluripotent cells (miPSCs) reprogrammed from normal embryonic fibroblasts were susceptible to the microenvironment affected by cancer cells to convert into CSCs in vivo. Methods Three different pancreatic cancer line cells, BxPC3, PANC1, and PK8 cells were mixed with miPSCs and subcutaneously injected into immunodeficient mice. Tumors were evaluated by histological analysis and cells derived from iPSCs were isolated and selected from tumors. The isolated cells were characterized for cancer stem cell characters in vitro and in vivo as well as their responses to anticancer drugs. The impact of co-injection of iPSCs with cancer cells on transcriptome and signaling pathways of iPSCs was investigated. Results The injection of miPSCs mixed with human pancreatic cancer cells into immunodeficient mice maintained the stemness of miPSCs and changed their phenotype. The miPSCs acquired CSC characteristics of tumorigenicity and self-renewal. The drug responses and the metastatic ability of CSCs converted from miPSCs varied depending on the microenvironment of cancer cells. Interestingly, transcriptome profiles of these cells indicated that the pathways related with aggressiveness and energy production were upregulated from the levels of miPSCs. Conclusions Our result suggests that cancer-inducing microenvironment in vivo could rewire the cell signaling and metabolic pathways to convert normal stem cells into CSCs. No potential conflict of interest relevant to this article was reported.

MDPI Acta Medica Okayama 1422-0067 22 23 2021 Multifaceted Analysis of IL-23A-and/or EBI3-Including Cytokines Produced by Psoriatic Keratinocytes 12659 EN Kota Tachibana Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Science Nina Tang Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Science Hitoshi Urakami Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Science Ai Kajita Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Science Mina Kobashi Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Science Hayato Nomura Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Science Minori Sasakura Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Science Satoru Sugihara Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Science Fan Jiang Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Science Nahoko Tomonobu Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Science Masakiyo Sakaguchi Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Science Mamoru Ouchida Department of Molecular Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Science Shin Morizane Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Science Interleukin (IL) 23 (p19/p40) plays a critical role in the pathogenesis of psoriasis and is upregulated in psoriasis skin lesions. In clinical practice, anti-IL-23Ap19 antibodies are highly effective against psoriasis. IL-39 (p19/ Epstein-Barr virus-induced (EBI) 3), a newly discovered cytokine in 2015, shares the p19 subunit with IL-23. Anti-IL-23Ap19 antibodies may bind to IL-39; also, the cytokine may contribute to the pathogenesis of psoriasis. To investigate IL23Ap19- and/or EBI3-including cytokines in psoriatic keratinocytes, we analyzed IL-23Ap19 and EBI3 expressions in psoriasis skin lesions, using immunohistochemistry and normal human epidermal keratinocytes (NHEKs) stimulated with inflammatory cytokines, using quantitative real-time polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), and liquid chromatography-electrospray tandem mass spectrometry (LC-Ms/Ms). Immunohistochemical analysis showed that IL-23Ap19 and EBI3 expressions were upregulated in the psoriasis skin lesions. In vitro, these expressions were synergistically induced by the triple combination of tumor necrosis factor (TNF)-alpha, IL-17A, and interferon (IFN)-gamma, and suppressed by dexamethasone, vitamin D3, and acitretin. In ELISA and LC-Ms/Ms analyses, keratinocyte-derived IL-23Ap19 and EBI3, but not heterodimeric forms, were detected with humanized anti-IL-23Ap19 monoclonal antibodies, tildrakizumab, and anti-EBI3 antibodies, respectively. Psoriatic keratinocytes may express IL-23Ap19 and EBI3 proteins in a monomer or homopolymer, such as homodimer or homotrimer. No potential conflict of interest relevant to this article was reported.

BMC Acta Medica Okayama 1731-2302 19 1 2021 Retroperitoneal leiomyosarcoma in a female patient with a germline splicing variant RAD51D c.904-2A > T: a case report 48 EN Mashu Futagawa Department of Clinical Genomic Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Hideki Yamamoto Department of Clinical Genomic Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Mariko Kochi Department of Clinical Genomic Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Yusaku Urakawa Department of Clinical Genomic Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Reimi Sogawa Department of Clinical Genomic Medicine, Okayama University Hospital Fumino Kato Department of Clinical Genomic Medicine, Okayama University Hospital Mika Okazawa-Sakai Department of Clinical Genomic Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Daisuke Ennishi Center for Comprehensive Genomic Medicine, Okayama University Hospital Katsunori Shinozaki Division of Clinical Oncology, Hiroshima Prefecture Hospital Hirofumi Inoue Department of Pathology, Okayama University Hospital Hiroyuki Yanai Department of Pathology, Okayama University Hospital Akira Hirasawa Department of Clinical Genomic Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Background RAD51D (RAD51 paralog D) is an intermediate cancer susceptibility gene for primary ovarian cancer, including fallopian tube and peritoneal carcinomas and breast cancer. Although gynecological non-epithelial tumors such as uterine sarcomas are associated with genomic instability, including BRCA impairment, there is no clear evidence of the relationship between RAD51D variants and the risk of sarcoma development. Case presentation A Japanese woman in her 50s underwent multiple surgical resections and several regimens of chemotherapy for tumors that originated in the retroperitoneum and recurred in the peritoneum over a clinical course of approximately 4 years. The peritoneal tumor was histologically diagnosed as a leiomyosarcoma and was genetically identified to show a splice variant of RAD51D c.904-2A > T [NM_002878] through tumor profiling performed as a part of cancer precision medicine. The confirmatory genetic test performed after genetic counseling revealed that the RAD51D splicing variant detected in her tumor was of germline origin. In silico analyses supported the possible pathogenicity of the detected splice variant of RAD51D with a predicted attenuation in mRNA transcription and truncated protein production due to frameshifting, which was attributed to a single-nucleotide alteration in the splicing acceptor site at the 3 '-end of intron 9 of RAD51D. Considering her unfavorable clinical outcome, which showed a highly aggressive phenotype of leiomyosarcoma with altered RAD51D, this case provided novel evidence for the relationship of a RAD51D splicing variant with malignant tumor development or progression. We report the findings of this rare case with possible involvement of the germline variant of RAD51D c.904-2A > T as a potential predisposing factor for malignant tumors, including leiomyosarcoma. Conclusions We present the findings of a case of leiomyosarcoma in the peritoneum of a female patient with a novel germline splicing variant of RAD51D as potential evidence for the pathogenicity of the variant and its involvement in the risk of sarcoma etiology and/or development. To the best of our knowledge, this is the first case report describing a leiomyosarcoma carrying a germline RAD51D splicing variant and elucidating its pathogenicity on the basis of computational prediction of the impairment of normal transcription and the presumed loss of functional protein production. No potential conflict of interest relevant to this article was reported.

Lippincott Williams & Wilkins Acta Medica Okayama 2155-384X 12 11 2021 The Impact of KRAS Mutation in Patients With Sporadic Nonampullary Duodenal Epithelial Tumors e00424 EN Hideaki Kinugasa Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Hiromitsu Kanzaki Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Takehiro Tanaka Department of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Shumpei Yamamoto Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Yasushi Yamasaki Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Kazuhiro Nouso Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Kouichi Ichimura Department of Pathology, Hiroshima City Hiroshima Citizens Hospital Masahiro Nakagawa Department of Endoscopy, Hiroshima City Hiroshima Citizens Hospital Toshiharu Mitsuhashi Center for Innovative Clinical Medicine, OkayamaUniversity Hospital Hiroyuki Okada Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences INTRODUCTION: The genomic characterization of primary nonampullary duodenal adenocarcinoma indicates a genetic resemblance to gastric and colorectal cancers. However, a correlation between the clinical and molecular characteristics of these cancers has not been established. This study aimed to elucidate the clinicopathological features of sporadic nonampullary duodenal epithelial tumors, including their molecular characteristics and prognostic factors. METHODS: One hundred forty-eight patients with sporadic nonampullary duodenal epithelial tumors were examined in this study. Patient sex, age, TNM stage, tumor location, treatment methods, histology, KRAS mutation, BRAF mutation, Fusobacterium nucleatum, mucin phenotype, and programmed death-ligand 1 (PD-L1) status were evaluated. KRAS and BRAF mutations, Fusobacterium nucleatum, mucin phenotype, and PD-L1 status were analyzed by direct sequencing, quantitative polymerase chain reaction, and immunochemical staining. RESULTS: The median follow-up duration was 119.4 months. There were no deaths from duodenal adenoma (the primary disease). Kaplan-Meier analysis for duodenal adenocarcinoma showed a significant effect of TNM stage (P < 0.01). In univariate analysis of primary deaths from duodenal adenocarcinoma, TNM stage II or higher, undifferentiated, KRAS mutations, gastric phenotype, intestinal phenotype, and PD-L1 status were significant factors. In multivariate analysis, TNM stage II or higher (hazard ratio: 1.63 x 10(10), 95% confidence interval: 18.66-6.69 x 10(36)) and KRAS mutation (hazard ratio: 3.49, confidence interval: 1.52-7.91) were significant factors. DISCUSSION: Only KRAS mutation was a significant prognostic factor in primary sporadic nonampullary duodenal adenocarcinoma in cases in which TNM stage was considered. No potential conflict of interest relevant to this article was reported.

Future Science Ltd. Acta Medica Okayama 2056-5623 Concordance of acquired mutations between metastatic lesions and liquid biopsy in metastatic colorectal cancer FSO757 EN Fumitaka Taniguchi Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry & Pharmaceutical Sciences Akihiro Nyuya Department of Clinical Oncology, Kawasaki Medical School Toshiaki Toshima Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry & Pharmaceutical Sciences Kazuya Yasui Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry & Pharmaceutical Sciences Yoshiko Mori Department of Clinical Genetics & Digestive Tract & General Surgery, Saitama Medical Center, Saitama Medical University, Makoto Okawaki Department of Clinical Oncology, Kawasaki Medical School Hiroyuki Kishimoto Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry & Pharmaceutical Sciences Yuzo Umeda Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry & Pharmaceutical Sciences Toshiyoshi Fujiwara Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry & Pharmaceutical Sciences Hiroaki Tanioka Department of Clinical Oncology, Kawasaki Medical School Yoshiyuki Yamaguchi Department of Clinical Oncology, Kawasaki Medical School Ajay Goel Department of Molecular Diagnostics & Experimental Therapeutics, Beckman Research Institute of City of Hope Comprehensive Cancer Center Takeshi Nagasaka Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry & Pharmaceutical Sciences Aim: To evaluate whether PCR-reverse sequence-specific oligonucleotide can examine the concordance between liquid biopsy and metastatic lesions with acquired resistance. Materials & methods: We examined acquired mutations in chemoresistant lesions and blood obtained from four patients with RAS wildtype metastatic colorectal cancer who underwent treatment with anti-epidermal growth factor receptor antibodies. Results: In one patient, metastatic lesions harbored diverse acquired mutations in KRAS in all seven metastases; the two acquired mutations were detectable in blood collected after the patient acquired resistance. None of the other patients exhibited liquid biopsy mutations, except one, with a BRAF mutation confirmed in primary tumor and peritoneal dissemination. Conclusion: Liquid biopsy based on PCR-reverse sequence-specific oligonucleotide is a successful procedure for capturing acquired mutations with precise information on the RAS mutational spectrum. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 75 6 2021 Pulmonary Enteric Adenocarcinoma Harboring a BRAF G469V Mutation 759 762 EN Dai Shimizu Department of Thoracic Surgery, Okayama University Hospital Hiromasa Yamamoto Department of Thoracic Surgery, Okayama University Hospital Kazuhiko Shien Department of Thoracic Surgery, Okayama University Hospital Kohei Taniguchi Department of Diagnostic Pathology, Okayama University Hospital Kentaroh Miyoshi Department of Thoracic Surgery, Okayama University Hospital Kei Namba Department of Thoracic Surgery, Okayama University Hospital Kumi Mesaki Department of Thoracic Surgery, Okayama University Hospital Seiichiro Sugimoto Department of Thoracic Surgery, Okayama University Hospital Junichi Soh Department of Thoracic Surgery, Okayama University Hospital Masaomi Yamane Department of Thoracic Surgery, Okayama University Hospital Shinichi Toyooka Department of Thoracic Surgery, Okayama University Hospital Case Report 10.18926/AMO/62819 Pulmonary enteric adenocarcinoma (PEAC) is a rare subtype of lung cancer that should be differentiated from colorectal cancer metastasis. Little is known about its genetic background. An 84-year-old male with adenocarcinoma of the lung underwent left upper lobectomy. The histology of the surgical specimen was suggestive of PEAC. Gastrointestinal and colorectal fiberscopy revealed no evidence of colorectal cancer. Next-generation sequencing of the tumor identified a G469V substitution in serine/threonine-protein kinase B-raf (BRAF). Based on the higher prevalence of the G469 substitution in BRAF-mutant lung adenocarcinoma than in BRAFmutant colorectal cancer, the tumor likely originated from the lung. Identification of mutational genotype may be of some help in distinguishing PEAC from the lung metastasis of colorectal cancer. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 75 6 2021 Non-Invasive Prenatal Genetic Testing (NIPT) Leading to Prenatal Diagnosis of Trisomy 21 Mosaicism and 18q Deletion Syndrome: Two Cases 745 750 EN Kei Hayata Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science Sakurako Mishima Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science Akiko Ohira Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science Kazumasa Tani Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science Jota Maki Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science Eriko Eto Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science Chikako Ogawa Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science Hisashi Masuyama Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science Case Report 10.18926/AMO/62816 NIPT is non-definitive testing to estimate the possibility that fetuses have trisomy 21, trisomy 18, or trisomy 13. However, in NIPT-positive and indeterminate cases, rare chromosomal disease may become apparent, requiring advanced genetic considerations and counseling skills. We experienced two such cases, a trisomy 21 mosaicism case triggered by NIPT-positive status and 18q deletion syndrome triggered by NIPT-indeterminate status. These cases have two clinical implications for NIPT. First, it was revealed that trisomy mosaicism might be found in NIPT-positive cases that have lower Z-Scores than those inferred from the fraction of fetal cfDNA in the case of standard trisomy. Second, it is possible that microdeletion syndrome could be the reason for an indeterminate NIPT result. Today’s genetic counseling requires more expertise in ethics and communication as well as genetic science because NIPT can lead to totally unexpected results. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 75 5 2021 Glial Cells as Possible Targets of Neuroprotection through Neurotrophic and Antioxidative Molecules in the Central and Enteric Nervous Systems in Parkinson’s Disease 549 556 EN Nami Isooka Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ikuko Miyazaki Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Masato Asanuma Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Review 10.18926/AMO/62767 Parkinson’s disease (PD) is the second most common neurodegenerative disease worldwide. The loss of nigrostriatal dopaminergic neurons produces its characteristic motor symptoms, but PD patients also have non-motor symptoms such as constipation and orthostatic hypotension. The pathological hallmark of PD is the presence of α-synuclein-containing Lewy bodies and neurites in the brain. However, the PD pathology is observed in not only the central nervous system (CNS) but also in parts of the peripheral nervous system such as the enteric nervous system (ENS). Since constipation is a typical prodromal non-motor symptom in PD, often preceding motor symptoms by 10-20 years, it has been hypothesized that PD pathology propagates from the ENS to the CNS via the vagal nerve. Discovery of pharmacological and other methods to halt this progression of neurodegeneration in PD has the potential to improve millions of lives. Astrocytes protect neurons in the CNS by secretion of neurotrophic and antioxidative factors. Similarly, astrocyte-like enteric glial cells (EGCs) are known to secrete neuroprotective factors in the ENS. In this article, we summarize the neuroprotective function of astrocytes and EGCs and discuss therapeutic strategies for the prevention of neurodegeneration in PD targeting neurotrophic and antioxidative molecules in glial cells. No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 1320-5463 2021 2021 Investigation of the molecular causes underlying physical abnormalities in Diamond‐Blackfan anemia patients with RPL5 haploinsufficiency 1 11 EN Yuko Fukui Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Okayama University Satoru Hayano Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Okayama University Noriaki Kawanabe Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Okayama University Ziyi Wang Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Okayama University Akira Shimada Department of Pediatric Hematology/Oncology Okayama University Hospital Megumu K. Saito Department of Clinical Application, Center for iPS Cell Research and Application Kyoto University Isao Asaka Department of Fundamental Cell Technology, Center for iPS Cell Research and Application Kyoto University Hiroshi Kamioka Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Okayama University Diamond-Blackfan anemia (DBA) is a genetic disorder caused by mutations in genes encoding ribosomal proteins and characterized by erythroid aplasia and various physical abnormalities. Although accumulating evidence suggests that defective ribosome biogenesis leads to p53-mediated apoptosis in erythroid progenitor cells, little is known regarding the underlying causes of the physical abnormalities. In this study, we established induced pluripotent stem cells from a DBA patient with RPL5 haploinsufficiency. These cells retained the ability to differentiate into osteoblasts and chondrocytes. However, RPL5 haploinsufficiency impaired the production of mucins and increased apoptosis in differentiated chondrocytes. Increased expression of the pro-apoptotic genes BAX and CASP9 further indicated that RPL5 haploinsufficiency triggered p53-mediated apoptosis in chondrocytes. MDM2, the primary negative regulator of p53, plays a crucial role in erythroid aplasia in DBA patient. We found the phosphorylation level of MDM2 was significantly decreased in RPL5 haploinsufficient chondrocytes. In stark contrast, we found no evidence that RPL5 haploinsufficiency impaired osteogenesis. Collectively, our data support a model in which RPL5 haploinsufficiency specifically induces p53-mediated apoptosis in chondrocytes through MDM2 inhibition, which leads to physical abnormalities in DBA patients. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 75 4 2021 Arrhythmogenic Right Ventricular Cardiomyopathy Diagnosed during Hospitalization for Cardiac Arrest 517 521 EN Masahiko Ochi Department of Cardiology, Japan Red Cross Okayama Hospital Atsuyoshi Iida Department of Emergency Medicine, Japan Red Cross Okayama Hospital Yuka Takahashi Division of Pathology and Clinical Laboratories, National Cancer Center Hospital Masamichi Tanaka Department of Cardiology, Japan Red Cross Okayama Hospital Hironori Saito Department of Cardiology, Japan Red Cross Okayama Hospital Hiromichi Naito Department of Emergency, Critical Care, and Disaster Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takeshi Mikane Department of Emergency Medicine, Japan Red Cross Okayama Hospital Soichiro Fuke Department of Cardiology, Japan Red Cross Okayama Hospital Case Report 10.18926/AMO/62405 Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetically mediated cardiomyopathy charac-terized by progressive myocardial loss of the right ventricle and its replacement by fibrofatty tissue, causing dyskinesia, aneurysm, and/or arrhythmia. The prevalence of ARVC is estimated to be 1 in 2,000-5,000, with the condition accounting for up to 20% of sudden cardiac deaths in individuals < 35 years old. This report describes the case of 61-year-old Japanese who was diagnosed with ARVC after cardiac arrest (CA) and successful resusci-tation. After the sudden CA, the restoration of spontaneous circulation was achieved with appropriate resusci-tation, followed by the introduction of target temperature management in the intensive care unit. He was diag-nosed with ARVC based on angiography and histology results. An ICD (implantable cardioverter-defibrillator) was implanted, and he was discharged without neurological sequelae 1 month post-CA. ARVC is an important cause of sudden CA, and successfully resuscitated patients with right ventricular dilation should undergo testing to rule out ARVC. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 75 4 2021 Two Types of Polyp Shape Observed in the Stomach of Patients with Peutz-Jeghers Syndrome 471 477 EN Masaya Iwamuro Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tatsuya Toyokawa Department of Gastroenterology, Fukuyama Medical Center Kazuhiro Matsueda Department of Gastroenterology and Hepatology, Kurashiki Central Hospital Shinichiro Hori Department of Endoscopy, Shikoku Cancer Center Masao Yoshioka Department of Internal Medicine, Okayama Saiseikai General Hospital Yuki Moritou Department of Internal Medicine, Hiroshima City Hiroshima Citizens Hospital Takehiro Tanaka Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Motowo Mizuno Department of Gastroenterology and Hepatology, Kurashiki Central Hospital Hiroyuki Okada Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Original Article 10.18926/AMO/62399 The characteristics of gastric polyps in patients with Peutz-Jeghers (PJ) syndrome (PJS) have not been fully investigated. The objective of this study was to reveal the endoscopic and pathologic findings of gastric polyps in patients with PJS. We reviewed 11 patients with PJS treated at 6 institutions, and summarized the endo-scopic and pathologic features of their gastric polyps. The polyps were mainly classified into 2 types: (i) soli-tary or sporadic polyps > 5 mm, reddish in color with a sessile or semi-pedunculated morphology (n = 9); and (ii) multiple sessile polyps ≤ 5 mm with the same color tone as the peripheral mucosa (n = 9). Patients who underwent endoscopic mucosal resection for polyps > 5 mm were diagnosed with PJ polyps (n = 2), whereas those who underwent biopsy were diagnosed with hyperplastic polyps. Polyps ≤ 5 mm were pathologically diagnosed as fundic gland polyps or hyperplastic polyps. This study revealed that patients with PJS present with 2 types of polyps in the stomach. Endoscopic mucosal resection of polyps > 5 mm seems necessary for the pathologic diagnosis of PJ polyps. No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 1552-4825 188A 2021 A novel pathogenic variant p.Asp797Val in IFIH1 in a Japanese boy with overlapping Singleton-Merten syndrome and Aicardi-Goutieres syndrome 249 252 EN Kosei Hasegawa Department of Pediatrics, Okayama University Hospital Hiroyuki Tanaka Department of Pediatrics, Okayama University Hospital Natsuko Futagawa Department of Pediatrics, Okayama University Hospital Hiroyuki Miyahara Department of Pediatrics, Okayama University Hospital Yousuke Higuchi Department of Pediatrics, Okayama University Hospital Hirokazu Tsukahara Department of Pediatrics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Pathogenic-activating variants of interferon induced with Helicase C domain 1 (IFIH1) cause Singleton-Merten (S-M) syndrome, which accompanies acro-osteolysis, loss of permanent teeth, and aortic calcification, as well as causing Aicardi-Goutières (A-G) syndrome, which shows progressive encephalopathy, spastic paraplegia, and calcification of basal ganglia. Recently, patients with overlapping syndromes presenting with features of S-M syndrome and A-G syndrome were reported. However, progression of clinical features of this condition has not been fully understood. We report a Japanese boy with a novel pathogenic IFIH1 variant who presented with clinical features of S-M syndrome and A-G syndrome. No potential conflict of interest relevant to this article was reported.

Spandidos Publications Acta Medica Okayama 1792-1074 22 3 2021 Triple therapy with osimertinib, bevacizumab and cetuximab in EGFR‑mutant lung cancer with HIF‑1α/TGF‑α expression 639 EN Kazuya Nishii Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kadoaki Ohashi Department of Respiratory Medicine, Okayama University Hospital Hiromi Watanabe Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Go Makimoto Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takamasa Nakasuka Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hisao Higo Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kiichiro Ninomiya Department of Respiratory Medicine, Okayama University Hospital Yuka Kato Center for Innovative Clinical Medicine, Okayama University Hospital Toshio Kubo Center for Clinical Oncology, Okayama University Hospital Kammei Rai Department of Respiratory Medicine, Okayama University Hospital Eiki Ichihara Department of Respiratory Medicine, Okayama University Hospital Katsuyuki Hotta Center for Innovative Clinical Medicine, Okayama University Hospital Masahiro Tabata Center for Clinical Oncology, Okayama University Hospital Yoshinobu Maeda Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Katsuyuki Kiura Department of Respiratory Medicine, Okayama University Hospital Osimertinib, a third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is the standard treatment for patients with lung cancer harboring EGFR T790M; however, acquired resistance is inevitable due to genetic and epigenetic changes in cancer cells. In addition, a recent randomized clinical trial revealed that the combination of osimertinib and bevacizumab failed to exhibit superior progression‑free survival compared with osimertinib alone. The present study aimed to investigate the effect of triple therapy with osimertinib, bevacizumab and cetuximab in xenograft tumors with different initial tumor volumes (conventional model, 200 mm3 and large model, 500 mm3). The results demonstrated that osimertinib significantly inhibited tumor growth in both the conventional and large models; however, maximum tumor regression was attenuated in the large model in which hypoxia‑inducible factor‑1α (HIF‑1α) and transforming growth factor‑α (TGF‑α) expression levels increased. Although the combination of osimertinib and bevacizumab exerted a greater inhibitory effect on tumor growth compared with osimertinib in the conventional model, the effect of this combination therapy was attenuated in the large model. TGF‑α attenuated sensitivity to osimertinib in vitro; however, this negative effect was counteracted by the combination of osimertinib and cetuximab, but not osimertinib and bevacizumab. In the large xenograft tumor model, the triple therapy induced the greatest inhibitory effect on tumor growth compared with osimertinib alone and its combination with bevacizumab. Clinical trials of the triple therapy are required for patients with lung cancer with EGFR mutations and HIF‑1α/TGF‑α. No potential conflict of interest relevant to this article was reported.

LIPPINCOTT WILLIAMS & WILKINS Acta Medica Okayama 0025-7974 100 13 2021 Disseminated gonococcal infection in a Japanese man with complement 7 deficiency with compound heterozygous variants A case report e25265 EN Misaki Kageyama Department of General Medicine, Osaka University Hospital Hideharu Hagiya Department of General Medicine, Osaka University Hospital Yasutaka Ueda Department of Hematology and Oncology, Osaka University Hospital Katsuki Ohtani The Japanese Association for Complement Research Yasuo Fukumori Department of Molecular Genetics, Wakayama Medical University Norimitsu Inoue The Japanese Association for Complement Research Nobutaka Wakamiya The Japanese Association for Complement Research Nanoka Yoneda Laboratory for Clinical Investigation, Osaka University Hospital Keigo Kimura Laboratory for Clinical Investigation, Osaka University Hospital Motonori Nagasawa Department of General Medicine, Osaka University Hospital Futoshi Nakagami Department of General Medicine, Osaka University Hospital Isao Nishi Laboratory for Clinical Investigation, Osaka University Hospital Ken Sugimoto Department of General Medicine, Osaka University Hospital Hiromi Rakugi Department of General Medicine, Osaka University Hospital Rationale: Complement deficiency are known to be predisposed to disseminated gonococcal infection (DGI). We herein present a case of DGI involving a Japanese man who latently had a complement 7 deficiency with compound heterozygous variants. Patient concerns: A previously healthy 51-year-old Japanese man complained of sudden-onset high fever. Physical examination revealed various skin lesions including red papules on his trunk and extremities, an impetigo-like pustule on left forearm, and tendinitis of his right forefinger. Diagnosis: Blood culture testing detected gram-negative cocci, which was confirmed to be Neisseria gonorrhoeae based on mass spectrometry and a pathogen-specific PCR test. Interventions: Screening tests for underlying immunocompromised factors uncovered that complement activities (CH50) was undetectable. With a suspicion of a congenital complement deficiency, genetic analysis revealed rare single nucleotide variants in complement 7 (C7), including c.281-1G>T and a novel variant c.1454C>T (p.A485V). CH50 was normally recovered by adding purified human C7 to the patient's serum, supporting that the patient has C7 deficiency with compound heterozygous variants. Outcomes: Under a diagnosis of DGI, the patient underwent an antibiotic treatment with cefotaxime for a week and was discharged without any sequela. Lessons: DGI is a rare sexually-transmitted infection that potentially induces systemic complications. Complement immunity usually defeats N. gonorrhoeae and prevents the organism from causing DGI. This case highlighted the importance of suspecting a complement deficiency when a person develops DGI. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 75 3 2021 A Case of Metastatic Fumarate Hydratase-Deficient–like Renal Cell Carcinoma Successfully Managed by Ipilimumab plus Nivolumab 397 402 EN Takanori Sekito Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Atsushi Takamoto Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yasuyuki Kobayashi Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Masao Mitsui Department of Urology, Kurashiki Medical Center Shogo Watari Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Risa Kubota Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takuya Sadahira Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takehiro Iwata Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shingo Nishimura Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kohei Edamura Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tomoko Sako Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Motoo Araki Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Masami Watanabe Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Toyohiko Watanabe Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Rei Shibata Department of Pathology, Okayama University Hospital Daisuke Ennishi Department of Hematology and Oncology, Okayama University Hospital Yasutomo Nasu Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Case Report 10.18926/AMO/62237 We report a 62-year-old male with metastatic fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) without fumarate hydratase (FH) mutation (FH-deficient–like RCC). The International Metastatic RCC Database Consortium risk score was intermediate, and immunotherapy with nivolumab and ipilimumab (Ipi/ Nivo) was initiated. Four cycles of Ipi/Nivo and 5 cycles of nivolumab resulted in a complete response of the metastases. Hypophysitis occurred as an immune-related adverse event after four cycles of Ipi/Nivo. The prognosis of patients with FH-deficient RCC is generally poor. Few reports of FH-deficient RCC successfully treated with Ipi/Nivo have been published. Ipi/Nivo can be effective for treating FH-deficient RCC. No potential conflict of interest relevant to this article was reported.

Elsevier BV Acta Medica Okayama 0006-291X 557 2021 Adrenergic signaling promotes the expansion of cancer stem-like cells of malignant peripheral nerve sheath tumors 199 205 EN Rongsheng Huang Department of Cellular Physiology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Atsushi Fujimura Department of Cellular Physiology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Eiji Nakata Department of Orthopedic Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Shota Takihira Department of Orthopedic Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Hirofumi Inoue Department of Clinical Genetics and Genomic Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Soichiro Yoshikawa Department of Cellular Physiology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Takeshi Hiyama Department of Cellular Physiology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Toshifumi Ozaki Department of Orthopedic Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Atsunori Kamiya Department of Cellular Physiology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Malignant peripheral nerve sheath tumor (MPNST), a highly malignant tumor that arises in peripheral nerve tissues, is known to be highly resistant to radiation and chemotherapy. Although there are several reports on genetic mutations and epigenetic changes that define the pathogenesis of MPNST, there is insufficient information regarding the microenvironment that contributes to the malignancy of MPNST. In the present study, we demonstrate that adrenaline increases the cancer stem cell population in MPNST. This effect is mediated by adrenaline stimulation of beta-2 adrenergic receptor (ADRB2), which activates the Hippo transducer, YAP/TAZ. Inhibition and RNAi experiments revealed that inhibition of ADRB2 attenuated the adrenaline-triggered activity of YAP/TAZ and subsequently attenuated MPNST cells stemness. Furthermore, ADRB2-YAP/TAZ axis was confirmed in the MPNST patients’ specimens. The prognosis of patients with high levels of ADRB2 was found to be significantly worse. These data show that adrenaline exacerbates MPNST prognosis and may aid the development of new treatment strategies for MPNST. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 75 2 2021 Long-term Survival with a Rare Advanced Primary Gastrointestinal Malignant Melanoma Treated with Laparoscopic Surgery/Immune Checkpoint Inhibitor 231 238 EN Motochika Endo Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shuya Yano Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hiroaki Asano Department of Surgery, Mitoyo general Hospital Sho Takeda Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yuki Hamada Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yoshitaka Kondo Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shinji Kuroda Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kunitoshi Shigeyasu Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Satoru Kikuchi Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takehiro Tanaka Department of Pathology, Okayama University Hospital Fuminori Teraishi Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Masahiko Nishizaki Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shunsuke Kagawa Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Toshiyoshi Fujiwara Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Case Report 10.18926/AMO/61906 Targeted therapies for malignant melanoma have improved patients’ prognoses. A primary gastrointestinal malignant melanoma is very rare, with no standard treatment strategy. We treated a 78-year-old Japanese female with advanced primary gastrointestinal melanoma of the descending colon and gallbladder. We administered a multidisciplinary treatment: surgical resection of the descending colon and gallbladder tumors, resection of the metastatic lymph nodes behind the pancreas head, and immune checkpoint antibody-blockade therapy (nivolumab) for ~4 years. PET/CT demonstrated no recurrent lesion for > 3 years. Multidisciplinary therapies (e.g., surgery, chemotherapy, radiotherapy, target therapy, and immune checkpoint antibody-blockade therapy) can successfully treat primary gastrointestinal malignant melanoma. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 75 2 2021 Camouflage Treatment for Skeletal Maxillary Protrusion and Lateral Deviation with Classic-Type Ehlers-Danlos Syndrome 205 212 EN Mitsuhiro Hoshijima Department of Orthodontics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Noriaki Kawanabe Department of Orthodontics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Seiji Iida Department of Oral and Maxillofacial Reconstructive Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takashi Yamashiro Department of Orthodontics and Dentofacial Orthopedics, Graduate School of Dentistry, Osaka University Hiroshi Kamioka Department of Orthodontics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Case Report 10.18926/AMO/61902 We herein report the case of a 19-year-old female with a transverse discrepancy, skeletal Class II malocclusion, severe crowding with concerns of classic-type Ehlers-Danlos syndrome (EDS), aesthetics problems and functional problems. The main characteristics of classic EDS are loose-jointedness and fragile, easily bruised skin that heals with peculiar “cigarette-paper” scars. The anteroposterior and transverse skeletal discrepancies can generally be resolved by maxilla repositioning and mandibular advancement surgery following pre-surgical orthodontic treatment. However, this patient was treated with orthodontic camouflage but not orthognathic surgery because of the risks of skin bruising, poor healing and a temporomandibular disorder. A satisfactory dental appearance and occlusion were achieved after camouflage treatment with orthodontic anchor screws and the use of Class II elastics, including the preservation of the stomatognathic functions. Acceptable occlusion and dentition were maintained after a two-year retention period. This treatment strategy of orthodontic camouflage using temporary anchorage, such as anchor screws and Class II elastics, may be a viable treatment option for skeletal malocclusion patients with EDS. No potential conflict of interest relevant to this article was reported.

Elsevier Acta Medica Okayama 24681245 2021 Profile of down syndrome–associated malignancies: Epidemiology, clinical features and therapeutic aspects EN Akira Shimada Department of Pediatric Hematology, Okayama University Hospital Down syndrome (DS) is a congenital chromosomal abnormality caused by the presence of all or part of a third copy of chromosome 21 (+21). DS is frequently complicated by congenital heart or digestive tract diseases at birth. DS patients are prone to infections and have mental retardation, with dementia such as Alzheimer's disease showing in later life. Furthermore, malignancies with specific characteristics are also highly reported in DS patients compared with non-DS patients. Therefore, DS is believed to be a cancer predisposition syndrome due to the chromosomal instability. Acute myeloid leukemia (AML) and especially acute megakaryoblastic leukemia (AMKL) by French-American-British (FAB) classification are the most frequent hematological malignancies in DS patients, occurring at a rate that is 500 times higher than that in non-DS patients. Interestingly, transient abnormal myelopoiesis (TAM) is observed in approximately 10% of DS neonates with GATA1 mutations, and most TAM patients are asymptomatic and show spontaneous regression; however, about 10%–20% of TAM cases are fatal because of complications such as fetal effusion, liver fibrosis, and other complications.Acute lymphoblastic leukemia (ALL) is also associated with DS, occurring at a rate that is 20 times higher than that in non-DS patients. Furthermore, the prognosis of DS-ALL patients is poorer than that of non-DS-ALL patients. A recent genetic analysis revealed that more than half of DS-ALL cases have a mutation in the CRLF2–JAK pathway, indicating that JAK inhibitors might have a limited effect for DS-ALL patients.Notably, solid tumors such as neuroblastoma, Wilms tumor, and brain tumor, which are frequently observed in non-DS children, are rarely reported in DS children. The reason remains unknown, but it may be because of the triplication of the Down syndrome critical region 1 (DSCR1) gene on chromosome 21. In adult patients with DS, the expected age-adjusted incidence rates of solid tumors are low compared with age-matched euploid cohorts for most cancers except for testicular cancer. Although the average life expectancy of patients with DS will increase with advances in healthcare, the detailed health problems including cancer rates in older DS patients remain unknown. Therefore, these issues will be needed to be addressed in future studies. No potential conflict of interest relevant to this article was reported.

Japanese Society of Internal Medicine Acta Medica Okayama 0918-2918 58 7 2019 Characteristic Clinical Features of Werner Syndrome with a Novel Compound Heterozygous WRN Mutation c.1720+1G>A Plus c.3139-1G>C 1033 1036 EN Namiko Matsumoto Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Yasuyuki Ohta Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kentaro Deguchi Department of Neurology, Okayama Citizen's Hospital Masayuki Kishida Department of General Internal Medicine, Okayama Citizen's Hospital Kota Sato Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Jingwei Shang Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Mami Takemoto Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Nozomi Hishikawa Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Toru Yamashita Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Aki Watanabe Department of Clinical Cell Biology and Medicine, Graduate School of Medicine, Chiba University Koutaro Yokote Department of Clinical Cell Biology and Medicine, Graduate School of Medicine, Chiba University Minoru Takemoto Department of Diabetes, Metabolism and Endocrinology, School of Medicine, International University of Health and Welfare Junko Oshima Department of Pathology, University of Washington Koji Abe Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Werner syndrome (WS) is an autosomal recessive progeroid disorder caused by mutations in the WRN gene (WRN). Most Japanese WS patients are born from a consanguineous marriage with homozygous WRN mutations. We herein report a rare WS patient born from non-consanguineous parents with compound heterozygous WRN mutations with a novel heterogeneous c.1720+1G>A substitution plus the most frequent heterogeneous c.3139-1G>C substitution among Japanese. Although the present case showed clinical characteristics common to previous Japanese WS patients, he had not developed any malignant tumors as of 43 years of age, suggesting that WS patients with this particular genetic mutation have a different phenotype than others. No potential conflict of interest relevant to this article was reported.

MDPI Acta Medica Okayama 1422-0067 22 3 2021 Epstein-Barr Virus-Positive Mucocutaneous Ulcer: A Unique and Curious Disease Entity 1053 EN Tomoka Ikeda Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yuka Gion Division of Pathophysiology, Okayama University Graduate School of Health Sciences Yoshito Nishimura Department of General Medicine, Okayama University Hospital Midori Filiz Nishimura Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tadashi Yoshino Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yasuharu Sato Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Epstein-Barr virus (EBV)-positive mucocutaneous ulcer (EBVMCU) was first described as a lymphoproliferative disorder in 2010. EBVMCU is a unifocal mucosal or cutaneous ulcer that often occurs after local trauma in patients with immunosuppression; the patients generally have a good prognosis. It is histologically characterized by proliferating EBV-positive atypical B cells accompanied by ulcers. On the basis of conventional pathologic criteria, EBVMCU may be misdiagnosed as EBV-positive diffuse large B-cell lymphoma or other lymphomas. However, its prognosis differs from that of EBV-associated lymphomas, in that patients with EBVMCU frequently show spontaneous regression or complete remission without chemotherapy. Therefore, EBVMCU is now recognized as a low-grade malignancy or a pseudo-malignant lesion. Avoiding unnecessary chemotherapy by distinguishing EBVMCU from other EBV-associated lymphomas will reduce the burden and unnecessary harm on patients. On the basis of these facts, EBVMCU was first described as a new clinicopathological entity by the World Health Organization in 2017. In this review, we discuss the clinicopathological characteristics of previously reported EBVMCU cases, while focusing on up-to-date clinical, pathological, and genetic aspects. No potential conflict of interest relevant to this article was reported.

Spandidos Publications Acta Medica Okayama 2049-9434 13 5 2020 Panel‑based next‑generation sequencing facilitates the characterization of childhood acute myeloid leukemia in clinical settings 46 EN Hisashi Ishida Department of Pediatrics/Pediatric Hematology and Oncology, Okayama University Hospital Akihiro Iguchi Department of Pediatrics, Hokkaido University Hospital Michinori Aoe Division of Medical Support, Okayama University Hospital Ritsuo Nishiuchi Department of Pediatrics, Kochi Health Sciences Center Takehiro Matsubara Division of Biobank, Center for Comprehensive Genomic Medicine, Okayama University Hospital Dai Keino Department of Pediatrics, St. Marianna University School of Medicine Hospital Masashi Sanada Clinical Research Center, National Hospital Organization Nagoya Medical Center Akira Shimada Department of Pediatrics/Pediatric Hematology and Oncology, Okayama University Hospital Acute myeloid leukemia (AML) accounts for ~20% of pediatric leukemia cases. The prognosis of pediatric AML has been improved in recent decades, but it trails that of most other types of pediatric cancer, with mortality rates of 30‑40%. Consequently, newer more targeted drugs are required for incorporation into treatment plans. These newer drugs selectively target AML cells with specific gene alterations. However, there are significant differences in genetic alterations between adult and pediatric patients with AML. In the present study, inexpensive and rapid next‑generation sequencing (NGS) of >150 cancer‑related genes was performed for matched diagnostic, remission and relapse (if any) samples from 27 pediatric patients with AML. In this analysis, seven genes were recurrently mutated. KRAS was mutated in seven patients, NRAS was mutated in three patients, and KIT, GATA1, WT1, PTPN11, JAK3 and FLT3 were each mutated in two patients. Among patients with relapsed AML, six harbored KRAS mutations at diagnosis; however, four of these patients lost these mutations at relapse. Additionally, two genetic alterations (FLT3‑ITD and TP53 alterations) were detected among patients who eventually relapsed, and these mutations are reported to be adverse prognostic factors for adult patients with AML. This panel‑based, targeted sequencing approach may be useful in determining the genetic background of pediatric AML and improving the prediction of treatment response and detection of potentially targetable gene alterations. RAS pathway mutations were highly unstable at relapse; therefore, these mutations should be chosen as a target with caution. Incorporating this panel‑based NGS approach into the clinical setting may allow for a patient‑oriented strategy of precision treatment for childhood AML. No potential conflict of interest relevant to this article was reported.

BMC Acta Medica Okayama 1897-4287 19 2021 Familial pancreatic cancer with PALB2 and NBN pathogenic variants: a case report 5 EN Kodai Abe Department of Surgery, Keio University School of Medicine Arisa Ueki Center for Medical Genetics, Keio University School of Medicine Yusaku Urakawa Department of Clinical Genomic Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Minoru Kitago Department of Surgery, Keio University School of Medicine Tomoko Yoshihama Department of Obstetrics and Gynecology, Keio University School of Medicine Yoshiko Nanki Department of Obstetrics and Gynecology, Keio University School of Medicine Yuko Kitagawa Department of Surgery, Keio University School of Medicine Daisuke Aoki Department of Obstetrics and Gynecology, Keio University School of Medicine Kenjiro Kosaki Center for Medical Genetics, Keio University School of Medicine Akira Hirasawa Department of Clinical Genomic Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Background Family history is one of the risk factors for pancreatic cancer. It is suggested that patients with pancreatic cancer who have a familial history harbor germline pathogenic variants of BRCA1 and/or BRCA2 (BRCA1/2), PALB2, or ATM. Recently, some germline variants of familial pancreatic cancers (FPCs), including PALB2, have been detected. Several countries, including Japan, perform screening workups and genetic analysis for pancreatic cancers. We have been carrying out active surveillance for FPC through epidemiological surveys, imaging analyses, and genetic analysis. Case presentation Here, we present the case of a female patient harboring pathogenic variants of PALB2 and NBN, with a family history of multiple pancreatic cancer in her younger brother, her aunt, and her father. Moreover, her father harbored a PALB2 pathogenic variant and her daughter harbored the same NBN pathogenic variant. Given the PALB2 and NBN variants, we designed surveillance strategies for the pancreas, breast, and ovary. Conclusions Further studies are required to develop strategies for managing FPCs to facilitate prompt diagnosis before their progression. No potential conflict of interest relevant to this article was reported.

MDPI Acta Medica Okayama 1422-0067 21 24 2020 Molecular Features and Clinical Management of Hereditary Gynecological Cancers 9504 EN Arisa Ueki Center for Medical Genetics, Keio Cancer Center, Keio University School of Medicine Akira Hirasawa Department of Clinical Genomic Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Hereditary gynecological cancers are caused by several inherited genes. Tumors that arise in the female reproductive system, such as ovaries and the uterus, overlap with hereditary cancers. Several hereditary cancer-related genes are important because they might lead to therapeutic targets. Treatment of hereditary cancers should be updated in line with the advent of various new methods of evaluation. Next-generation sequencing has led to rapid, economical genetic analyses that have prompted a concomitant and significant paradigm shift with respect to hereditary cancers. Molecular tumor profiling is an epochal method for determining therapeutic targets. Clinical treatment strategies are now being designed based on biomarkers based on tumor profiling. Furthermore, the National Comprehensive Cancer Network (NCCN) guidelines significantly changed the genetic testing process in 2020 to initially consider multi-gene panel (MGP) evaluation. Here, we reviewed the molecular features and clinical management of hereditary gynecological malignancies, such as hereditary breast and ovarian cancer (HBOC), and Lynch, Li-Fraumeni, Cowden, and Peutz-Jeghers syndromes. We also reviewed cancer-susceptible genes revealed by MGP tests. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 74 6 2020 Delayed Methotrexate Elimination after Administration of a Medium Dose of Methotrexate in a Patient with Genetic Variants Associated with Methotrexate Clearance 545 550 EN Yasuhisa Tatebe Department of Pharmacy, Okayama University Hospital Kiichiro Kanamitsu Department of pediatrics, Okayama University Hospital Hirotaka Kanzaki Department of Pharmacy, Okayama University Hospital Hisashi Ishida Department of pediatrics, Okayama University Hospital Kaori Fujiwara Department of pediatrics, Okayama University Hospital Kana Washio Department of pediatrics, Okayama University Hospital Yoshihisa Kitamura Department of Pharmacy, Okayama University Hospital Toshiaki Sendo Department of Pharmacy, Okayama University Hospital Akira Shimada Department of pediatrics, Okayama University Hospital Hirokazu Tsukahara Department of pediatrics, Okayama University Hospital Case Report 10.18926/AMO/61215 Polymorphisms in methotrexate transporter pathways have been associated with methotrexate toxicities and clearance. Recent genome-wide association studies have revealed that the SLCO1B1 T521C variant is associated with methotrexate elimination. We present a case of a pediatric patient with acute lymphoblastic leukemia who suffered from persistently high plasma methotrexate concentrations and acute kidney injuries after the admin-istration of a medium dose of methotrexate. Subsequent genetic analysis showed that he was a carrier of dys-functional genetic variants associated with methotrexate clearance. This case highlights that polymorphisms of methotrexate transporter pathways can adversely affect methotrexate elimination in a clinically significant manner. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 74 6 2020 Soft Tissue Myoepithelioma of the Shoulder 531 535 EN Kazuhiko Hashimoto Department of Orthopedic Surgery, Kindai University Hospital Shunji Nishimura Department of Orthopedic Surgery, Kindai University Hospital Takaaki Chikugo Department of Pathology, Kindai University Hospital Ryosuke Kakinoki Department of Orthopedic Surgery, Kindai University Hospital Masao Akagi Department of Orthopedic Surgery, Kindai University Hospital Case Report 10.18926/AMO/61213 Soft tissue myoepitheliomas are often misdiagnosed due to their rarity. Herein, we describe a case of soft tissue myoepithelioma of the shoulder. A 72-year-old woman had a suspected sarcoma on her shoulder and under-went open biopsy. She was referred to our hospital, where the tumor was widely resected and the diagnosis of myoepithelioma was histologically confirmed. No recurrence has been observed in the 3 years since the sur-gery. Careful and prompt planning is necessary for the effective treatment of myoepithelioma. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 74 6 2020 Antenatal Care Visits and Adverse Pregnancy Outcomes at a Hospital in Rural Western Province, Rwanda 495 503 EN Simba Akintije Calliope Department of International Health and Medical Anthropology, Institute of Tropical Medicine, Nagasaki University Takashi Yorifuji Department of Epidemiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takayuki Wada Graduate School of Human Life Science, Osaka City University Marie Goret Mukakarake Mibilizi District Hospital Leon Mutesa Center for Human Genetics, College of Medicine and Health Sciences, University of Rwanda Taro Yamamoto Department of International Health and Medical Anthropology, Institute of Tropical Medicine, Nagasaki University Original Article 10.18926/AMO/61209 In many economically developing countries, and especially in the rural regions of sub-Saharan African coun-tries, there have been only limited investigations into the association between antenatal care (ANC) and adverse pregnancy outcomes. We obtained information on ANC and pregnancy outcomes between 2011 and 2016 from hospital files of pregnant women (n = 4,960) served at a rural hospital in Rwanda, and we examined the associa-tions between their ANC visits and the adverse pregnancy and neonatal outcomes by using univariate and mul-tivariate logistic regression models to estimate the odds ratios (ORs) and 95% confidence intervals (CIs). Most of the pregnant women had ≥ 4 ANC visits, but 39% (n = 1,911) did not have ≥ 3 visits before delivery. The prev-alence of low birth weight (LBW) and that of preterm birth (PTB) were 12% and 9.9%, respectively. Compared to the women who attended only one ANC visit, those who attended ≥ 4 ANC visits had lower risks of LBW (OR 0.20; 95%CI: 0.11-0.36) and PTB (OR 0.28; 95%CI: 0.11-0.76). Frequent ANC visits were also associ-ated with better postnatal outcomes of the newborns. Encouraging women to attend ANC visits before delivery can markedly reduce PTB-related and LBW-related complications, especially in resource-limited settings. No potential conflict of interest relevant to this article was reported.

Elsevier Acta Medica Okayama 2214-4269 25 2020 Marked motor function improvement in a 32-year-old woman with childhood-onset hypophosphatasia by asfotase alfa therapy: Evaluation based on standardized testing batteries used in Duchenne muscular dystrophy clinical trials 100643 EN Hitomi Nishizawa Faculty of Health Sciences, Department of Medicine, Shinshu University Yoshihiko Sato Department of Diabetes, Endocrinology and Metabolism, Division of Internal Medicine, Shinshu University School of Medicine, Matsumoto Masumi Ishikawa Center for Medical Genetics, Shinshu University Hospital Yuko Arakawa Department of Dentistry and Oral Surgery, Shinshu University School of Medicine Mari Iijima Department of Clinical Nutrition, Shinshu University Hospital Tomoyuki Akiyama Department of Child Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science Kyoko Takano Center for Medical Genetics, Shinshu University Hospital Atsushi Watanabe Division of Clinical Genetics, Kanazawa University Hospital Tomoki Kosho Center for Medical Genetics, Shinshu University Hospital Hypophosphatasia (HPP) is a rare disorder resulting from biallelic loss-of-function variants or monoallelic dominant negative variants in the ALPL gene. We herein describe the clinical outcome of a 32-year-old woman with childhood-onset HPP caused by compound heterozygous variants in ALPL. Her chief complaints were severe musculoskeletal pain, muscle weakness, and impaired daily activities necessitating assistance in housework and child-rearing in addition to a history of early tooth loss and mildly short stature. Asfotase alfa therapy produced a remarkable increase in muscle strength and daily activities and markedly reduced musculoskeletal pain. Drug efficacy was clearly demonstrated through multiple test batteries (muscle strength test using microFET®2, six-minute walking test, Stair Climb Test, rising-from-floor-time test, and number-of-steps test using Actigraph®) currently adopted as standardized evaluations in Duchenne muscular dystrophy clinical trials since no test batteries for HPP have been established to date. These tests may also be promising for the assessment of HPP. No potential conflict of interest relevant to this article was reported.

Elsevier Acta Medica Okayama 2352-3964 62 2020 A detection method for latent circadian rhythm sleep-wake disorder 103080 EN Makoto Akashi The Research Institute for Time Studies, Yamaguchi University Reimi Sogawa Department of Clinical Genetics and Genomic Medicine, Okayama University Hospital Ritsuko Matsumura The Research Institute for Time Studies, Yamaguchi University Atsuhiro Nishida The Research Institute for Time Studies, Yamaguchi University Rino Nakamura The Research Institute for Time Studies, Yamaguchi University Isao T. Tokuda Department of Mechanical Engineering, Ritsumeikan University Koichi Node Department of Cardiovascular Medicine, Saga University Background Individuals with typical circadian rhythm sleep-wake disorders (CRSWDs) have a habitual sleep timing that is desynchronized from social time schedules. However, it is possible to willfully force synchronisation against circadian-driven sleepiness, which causes other sleep problems. This pathology is distinguishable from typical CRSWDs and is referred to here as latent CRSWD (LCRSWD). Conventional diagnostic methods for typical CRSWDs are insufficient for detecting LCRSWD because sufferers have an apparently normal habitual sleep timing. Methods We first evaluated the reliability of circadian phase estimation based on clock gene expression using hair follicles collected at three time points without sleep interruption. Next, to identify detection criteria for LCRSWD, we compared circadian and sleep parameters according to estimated circadian phases, at the group and individual level, between subjects with low and high Pittsburgh Sleep Quality Index (PSQI) scores. To validate the reliability of identified detection criteria, we investigated whether the same subjects could be reproducibly identified at a later date and whether circadian amelioration resulted in sleep improvement. Findings We successfully validated the reliability of circadian phase estimation at three time points and identified potential detection criteria for individuals with LCRSWD attributed to delayed circadian-driven sleepiness. In particular, a criterion based on the interval between the times of the estimated circadian phase of clock gene expression and getting out of bed on work or school days was promising. We also successfully confirmed the reproducibility of candidate screening and sleep improvement by circadian amelioration, supporting the reliability of the detection criteria. Interpretation Although several limitations remain, our present study demonstrates a promising prototype of a detection method for LCRSWD attributed to delayed circadian-driven sleepiness. More extensive trials are needed to further validate this method. No potential conflict of interest relevant to this article was reported.

Elsevier Acta Medica Okayama 0887-8994 113 2020 Pyridoxal in the Cerebrospinal Fluid May Be a Better Indicator of Vitamin B6–dependent Epilepsy Than Pyridoxal 5′-Phosphate 33 41 EN Tomoyuki Akiyama Department of Child Neurology, Okayama University Hospital Yuki Hyodo Department of Child Neurology, Okayama University Hospital Kosei Hasegawa Department of Pediatrics, Okayama University Hospital Taikan Oboshi Department of Pediatric Neurology, Osaka Women’s and Children’s Hospital Katsumi Imai Department of Pediatrics, NHO Shizuoka Institute of Epilepsy and Neurological Disorders Naoko Ishihara Department of Pediatrics, Fujita Health University School of Medicine Yuri Dowa Department of Neurology, Gunma Children’s Medical Center Takayoshi Koike Department of Pediatrics, NHO Shizuoka Institute of Epilepsy and Neurological Disorders Toshiyuki Yamamoto Institute of Clinical Genomics, Tokyo Women’s Medical University Jun Shibasaki Department of Neonatology, Kanagawa Children’s Medical Center Hiroko Shimbo Clinical Institute, Kanagawa Children’s Medical Center Tetsuhiro Fukuyama Department of Pediatrics, Shinshu University Kyoko Takano Center for Medical Genetics, Shinshu University Hospital Hiroshi Shiraku Department of Pediatrics, JA Toride Medical Center Saoko Takeshita Department of Pediatrics, Yokohama City University Medical Center Tohru Okanishi Department of Child Neurology, Comprehensive Epilepsy Center, Seirei Hamamatsu General Hospital Shimpei Baba Department of Child Neurology, Comprehensive Epilepsy Center, Seirei Hamamatsu General Hospital Masaya Kubota Division of Neurology, National Center for Child Health and Development Shin-ichiro Hamano Division of Neurology, Saitama Children’s Medical Center Katsuhiro Kobayashi Department of Child Neurology, Okayama University Hospital Background We aimed to demonstrate the biochemical characteristics of vitamin B6–dependent epilepsy, with a particular focus on pyridoxal 5′-phosphate and pyridoxal in the cerebrospinal fluid. Methods Using our laboratory database, we identified patients with vitamin B6–dependent epilepsy and extracted their data on the concentrations of pyridoxal 5′-phosphate, pyridoxal, pipecolic acid, α-aminoadipic semialdehyde, and monoamine neurotransmitters. We compared the biochemical characteristics of these patients with those of other epilepsy patients with low pyridoxal 5′-phosphate concentrations. Results We identified seven patients with pyridoxine-dependent epilepsy caused by an ALDH7A1 gene abnormality, two patients with pyridoxal 5′-phosphate homeostasis protein deficiency, and 28 patients with other epilepsies with low cerebrospinal fluid pyridoxal 5′-phosphate concentrations. Cerebrospinal fluid pyridoxal and pyridoxal 5′-phosphate concentrations were low in patients with vitamin B6–dependent epilepsy but cerebrospinal fluid pyridoxal concentrations were not reduced in most patients with other epilepsies with low cerebrospinal fluid pyridoxal 5′-phosphate concentrations. Increase in 3-O-methyldopa and 5-hydroxytryptophan was demonstrated in some patients with vitamin B6–dependent epilepsy, suggestive of pyridoxal 5′-phosphate deficiency in the brain. Conclusions Low cerebrospinal fluid pyridoxal concentrations may be a better indicator of pyridoxal 5′-phosphate deficiency in the brain in vitamin B6–dependent epilepsy than low cerebrospinal fluid pyridoxal 5′-phosphate concentrations. This finding is especially helpful in individuals with suspected pyridoxal 5′-phosphate homeostasis protein deficiency, which does not have known biomarkers. No potential conflict of interest relevant to this article was reported.

Springer Acta Medica Okayama 2192-3183 2020 Germline multigene panel testing revealed a BRCA2 pathogenic variant in a patient with suspected Lynch syndrome EN Tomoko Yoshihama Department of Obstetrics and Gynecology, Keio University School of Medicine Akira Hirasawa Department of Clinical Genomic Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kokichi Sugano Oncogene Research Unit/Cancer Prevention Unit, Tochigi Cancer Center Research Institute Teruhiko Yoshida Department of Genetic Medicine and Services, National Cancer Center Hospital Mineko Ushiama Department of Genetic Medicine and Services, National Cancer Center Hospital Arisa Ueki Center for Medical Genetics, Keio University School of Medicine Tomoko Akahane Department of Obstetrics and Gynecology, Keio University School of Medicine Yoshiko Nanki Department of Obstetrics and Gynecology, Keio University School of Medicine Kensuke Sakai Department of Obstetrics and Gynecology, Keio University School of Medicine Takeshi Makabe Department of Obstetrics and Gynecology, Keio University School of Medicine Wataru Yamagami Department of Obstetrics and Gynecology, Keio University School of Medicine Nobuyuki Susumu Department of Obstetrics and Gynecology, Keio University School of Medicine Kaori Kameyama Department of Pathology, Showa University Northern Yokohama Hospital Kenjiro Kosaki Center for Medical Genetics, Keio University School of Medicine Daisuke Aoki Department of Obstetrics and Gynecology, Keio University School of Medicine There has been a rapid advance in germline multigene panel testing by next-generation sequencing, and it is being widely used in clinical settings. A 56-year-old woman suspected of having Lynch syndrome was identified as a BRCA2 pathogenic variant carrier by multigene panel testing. The patient was diagnosed with endometrial cancer at the age of 39 years, and total laparoscopic hysterectomy and bilateral salpingectomy were performed at the age of 49 years; however, bilateral oophorectomy was not performed at that time. As she had a family history of colorectal cancer and a history of endometrial cancer, Lynch syndrome was suspected. However, germline multigene panel testing revealed a pathogenic BRCA2 variant rather than pathogenic variants in mismatch repair genes. In this case, with conventional genetic risk assessment, we were unable to determine whether the patient had a high risk of hereditary breast and ovarian cancer; thus, germline multigene panel testing may provide valuable information to improve disease management strategies for patients in clinical settings. Particularly, germline multigene panel testing may be useful for detecting hereditary tumor syndromes if a patient does not present with a typical family history of cancer. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 74 5 2020 Combined Laparoscopic and CT Monitoring of the Ice-Ball Margin during Cryoablation for Renal Cell Carcinoma Associated with von Hippel-Lindau Disease: First Case 443 448 EN Takanori Sekito Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Motoo Araki Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takao Hiraki Department of Radiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Mayu Uka Department of Radiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Toshiyuki Komaki Department of Radiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yusuke Matsui Department of Radiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Toshihiro Iguchi Department of Radiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Satoshi Katayama Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kasumi Yoshinaga Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shogo Watari Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yuki Maruyama Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yosuke Mitsui Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Risa Kubota Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takuya Sadahira Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shingo Nishimura Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Koichiro Wada Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Atsushi Takamoto Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kohei Edamura Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tomoko Sako Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yasuyuki Kobayashi Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Toyohiko Watanabe Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Susumu Kanazawa Department of Radiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yasutomo Nasu Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Case Report 10.18926/AMO/60806 We report a 47-year-old Japanese female with 10 previous treatments for multiple bilateral renal cell carcinoma (RCC) associated with von Hippel-Lindau disease. The 14-mm right lower pole renal tumor was in contact with the right ureter. Laparoscopic cryoablation was performed to protect the ureter wrapped with gauze. Computed tomography (CT) monitoring was used to confirm the precise ≥ 6 mm ice-ball margin. There was no local progression at 6-months post-surgery. The serum creatinine has been stable. This is apparently the first report of combined laparoscopic and CT monitoring of an ice-ball formation and its margin during cryoablation for RCC. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 74 5 2020 A Disseminated Fusarium fujikuroi Species Complex Infection Prior to Allogeneic Hematopoietic Stem Cell Transplantation 435 441 EN Keigo Fujishita Department of Hematology and Blood Transfusion, Kochi Health Sciences Center Satoshi Oka Department of Hematology and Blood Transfusion, Kochi Health Sciences Center Katsuhiko Kamei Medical Mycology Research Center, Chiba University Katsuma Tani Department of Hematology and Blood Transfusion, Kochi Health Sciences Center Yuka Fujisawa Department of Hematology and Blood Transfusion, Kochi Health Sciences Center Wataru Kitamura Department of Hematology and Blood Transfusion, Kochi Health Sciences Center Takuya Machida Department of Hematology and Blood Transfusion, Kochi Health Sciences Center Toshi Imai Department of Hematology and Blood Transfusion, Kochi Health Sciences Center Case Report 10.18926/AMO/60805 A 53-year-old man was diagnosed with acute myeloid leukemia, which was refractory to chemotherapies. Systemic papules appeared afterward. The skin biopsies revealed filamentous fungal infection including fusariosis. Despite antifungal therapy, the infection did not resolve, because neutropenia persisted with the leukemia. He underwent hematopoietic stem cell transplantation (HSCT) to overcome the leukemia and restore normal hematopoiesis but died from fusariosis just before engraftment. Fusarium fujikuroi species complex was detected in blood cultures with poor antifungal susceptibility. Because restoring normal hematopoiesis is important in the treatment of fusariosis, HSCT might be considered for patients with persistent pancytopenia. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 74 5 2020 Polydactyly of the Foot Diagnosed from a Minor Nail Problem 427 429 EN Tomohiro Hiraoka Department of Pediatrics, Ochiai Hospital Haruka Senoo Department of Dermatology, Ochiai Hospital Yuka Yamazaki Department of Pediatrics, Okayama University Hospital Kosaku Suenobu Department of Plastic Surgery, Okayama Medical Center Hirokazu Tsukahara Department of Pediatrics, Okayama University Hospital Case Report 10.18926/AMO/60803 Polydactyly is one of the most common foot congenital anomalies. It is often detected immediately after birth, but the diagnosis can sometimes be delayed if the symptoms are less evident. A 2-year-old girl with a complaint of recurrent bleeding from the right toenail was diagnosed with foot polydactyly. She underwent corrective surgery, and her family was satisfied with the outcome. Although the diagnosis of polydactyly may be difficult in cases with minor nail problems, further radiographic evaluation will be needed for the improvement of the patient’s quality of life. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 74 4 2020 Recurrence of Solitary Fibrous Tumor/Hemangiopericytoma Could Be Predicted by Ki-67 Regardless of Its Origin 335 343 EN Yumiko Yamamoto Department of Diagnostic Pathology, Kochi University Yoshihiro Hayashi Department of Equipment of Support Planning Office, Kochi University Ichiro Murakami Department of Diagnostic Pathology, Kochi University Original Article 10.18926/AMO/60372 Since the discovery of the NAB2-STAT6 gene fusion in 2013, solitary fibrous tumor (SFT) and hemangiopericytoma (HPC) have been considered the same disease. STAT6 nuclear stain is approved as a highly sensitive and specific marker to diagnose SFT/HPC from other tumors with similar histology. As the next step, detection of fusion variants that may predict clinical malignancy of SFT/HPC has been attempted. However, no fusion variants with a clear relation to malignancy have been identified. In this study, the clinical and histological backgrounds of 23 Japanese patients diagnosed with SFT/HPC from 2000 to 2019 at Kochi University Hospital were examined to identify factors potentially related to recurrence. A significant relationship to recurrence was detected for mitosis ≥ 1/10 HPF (400×), necrosis, and Ki-67>5%. These findings indicate that a deliberate investigation of histological features such as mitosis and necrosis is crucial for the clinical observation of SFT/ HPC patients. In addition, Ki-67 was revealed to be a useful parameter to predict recurrence in SFT/HPC patients. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 74 4 2020 Factors Predicting a Favorable Disease Course Without Anti-TNF Therapy in Crohn’s Disease Patients 265 274 EN Toshihiro Inokuchi Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Sakiko Hiraoka Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Eriko Yasutomi Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shohei Oka Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yasushi Yamasaki Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hideaki Kinugasa Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Masahiro Takahar Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Seiji Kawano Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Keita Harada Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hiroyuki Okada Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Jun Kato bDepartment of Gastroenterology, Mitsui Memorial Hospital Original Article 10.18926/AMO/60363 Determining factors that predict a favorable disease course without anti-tumor necrosis factor (TNF) agents would help establish a more cost-effective strategy for Crohn’s disease (CD). A retrospective chart review was performed for CD patients with disease durations > 10 years who had not received anti-TNF agents as first-line therapy. Patients were divided into 2 groups: those who received neither anti-TNF agents nor bowel resection (G1), and those who had received an anti-TNF agent and/or bowel resection (G2). The patient backgrounds, therapies and clinical courses were compared between the groups. A total of 62 CD patients met the inclusion criteria (males: 71%; median duration of follow-up: 19 years). Six patients were included in G1; they were significantly less likely to have upper gastrointestinal lesions than G2 (p=0.007). A multivariate analysis revealed that the significant factors for avoidance of bowel resection without anti-TNF treatment were non-stricturing and non-penetrating behaviors, and absence of upper gastrointestinal lesions at the diagnosis (hazard ratios 0.41 and 0.52; p=0.004 and 0.04, respectively). In consideration of the long treatment course of CD, patients with non-stricturing and non-penetrating behaviors and no upper gastrointestinal lesions should not be treated with anti-TNF agents as first-line therapy. No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 132 1 2020 岡山大学病院臨床遺伝子診療科の紹介 25 28 EN Akira Hirasawa Department of Clinical Cenomic Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences No potential conflict of interest relevant to this article was reported.

Springer Nature Acta Medica Okayama 0893-3952 33 12 2020 Clinicopathological analysis of 34 Japanese patients with EBV-positive mucocutaneous ulcer 2437 2448 EN Tomoka Ikeda Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yuka Gion Okayama University Graduate School of Health Sciences Misa Sakamoto Okayama University Graduate School of Health Sciences Tomoyasu Tachibana Department of Otolaryngology, Japanese Red Cross Society Himeji Hospital Asami Nishikori Okayama University Graduate School of Health Sciences Midori Filiz Nishimura Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tadashi Yoshino Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yasuharu Sato Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Epstein–Barr virus (EBV)-positive mucocutaneous ulcer (EBVMCU) is a unifocal mucosal or cutaneous ulcer that is histologically characterized by proliferating EBV-positive atypical B cells. While EBVMCU demonstrates a histology similar to that of EBV-positive diffuse large B-cell lymphoma (DLBCL), their clinical behavior differs. Thus, characterizing distinguishing features of EBVMCU and EBV-positive DLBCL is critical. To identify unique characteristics between EBVMCU and lymphoma, we analyzed the clinicopathological and genetic features of 34 Japanese patients with EBVMCU and compared them to those of 24 EBV-positive DLBCL patients and 25 EBV-negative DLBCL patients. All patients with EBVMCU had localized ulcerative lesions, and 31 patients (91%) were using immunosuppressants, such as methotrexate (MTX) or hydroxycarbamide. All patients that were followed up with exhibited good prognosis following immunosuppressant reduction or chemotherapy. In addition, 17 EBV-positive DLBCL patients, and 15 EBV-negative DLBCL patients, received chemotherapy (P < 0.001, P < 0.001, respectively). Our data showed that EBVMCU did not increase indicators associated with lymphoma prognosis, such as soluble interleukin 2 receptor (sIL-2R) and lactate dehydrogenase (LDH) compared to those in the EBV-positive DLBCL or EBV-negative DLBCL groups (sIL-2R, P < 0.001, P = 0.025; LDH, P = 0.018, P = 0.038, respectively). However, histologically, EBVMCU exhibited EBV-positive, variable-sized, atypical B-cell proliferation. Thus, EBVMCU was histologically classified as: (1) polymorphous; (2) large cell-rich; (3) classic Hodgkin lymphoma-like; and (4) mucosa-associated lymphoid tissue lymphoma-like. Moreover, genetic analysis showed that immunoglobin heavy chain (IGH) gene rearrangement did not differ significantly between EBVMCU and EBV-positive DLBCL (44% vs. 32%; P = 0.377), or between EBVMCU and EBV-negative DLBCL (44% vs. 58%; P = 0.280). Therefore, it is difficult to distinguish EBVMCU from EBV-positive DLBCL using only pathological and genetic findings, suggesting that clinical information is important in accurately distinguishing between EBVMCU and EBV-positive DLBCL. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 74 3 2020 Stem Cell Therapy in Heart Disease: Limitations and Future Possibilities 185 190 EN Toshikazu Sano Department of Surgery, Division of Pediatric Cardiothoracic Surgery, University of California San Francisco Shuta Ishigami Department of Surgery, Division of Pediatric Cardiothoracic Surgery, University of California San Francisco Tatsuo Ito Department of Hygiene, Kawasaki Medical University Shunji Sano Department of Surgery, Division of Pediatric Cardiothoracic Surgery, University of California San Francisco Review 10.18926/AMO/59948 Heart diseases are one of the major causes of morbidity and mortality worldwide. Despite major advances in drug and interventional therapies, surgical procedures, and organ transplantation, further research into new therapeutic options is still necessary. Stem cell therapy has emerged as one option for the treatment of a variety of heart diseases. Although a large number of clinical trials have shown stem cell therapy to be a promising therapeutic approach, the results obtained from these clinical studies are inconsistent, and stem cell-based improvements of heart performance and cardiac remodeling were found to be quite limited. Since the precise mechanisms underlying the therapeutic actions of stem cells are still under debate, researchers have developed a variety of strategies to improve and boost the potency of stem cells in repair. In this review, we summarize both the current therapeutic strategies using stem cells and future directions for enhancing stem cell potency. No potential conflict of interest relevant to this article was reported.

Cell Press Acta Medica Okayama 23290501 17 2020 Hair cell transduction efficiency of single- and dual-AAV serotypes in adult murine cochleae 1167 1177 EN Ryotaro Omichi Department of Otolaryngology–Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hidekane Yoshimura Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa Seiji B. Shibata Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa Luk H. Vandenberghe Grousbeck Gene Therapy Center, Ocular Genomics Institute, Schepens Eye Research Institute and Mass Eye and Ear Richard J.H. Smith Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa Gene delivery is a key component for the treatment of genetic hearing loss. To date, a myriad of adeno-associated virus (AAV) serotypes and surgical approaches have been employed to deliver transgenes to cochlear hair cells, but the efficacy of dual transduction remains unclear. Herein, we investigated cellular tropism of single injections of AAV serotype 1 (AAV1), AAV2, AAV8, AAV9, and Anc80L65, and quantitated dual-vector co-transduction rates following co-injection of AAV2 and AAV9 vectors in adult murine cochlea. We used the combined round window membrane and canal fenestration (RWM+CF) injection technique for vector delivery. Single AAV2 injections were most robust and transduced 96.7% ± 1.1% of inner hair cells (IHCs) and 83.9% ± 2.0% of outer hair cells (OHCs) throughout the cochlea without causing hearing impairment or hair cell loss. Dual AAV2 injection co-transduced 96.9% ± 1.7% of IHCs and 65.6% ± 8.95% of OHCs. Together, RWM+CF-injected single or dual AAV2 provides the highest auditory hair cell transduction efficiency of the AAV serotypes we studied. These findings broaden the application of cochlear gene therapy targeting hair cells. No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 03855600 64 6 2020 Genomic characterization of antibiotic resistance‐encoding genes in clinical isolates of Vibrio cholerae non‐O1/non‐O139 strains from Kolkata, India: generation of novel types of genomic islands containing plural antibiotic resistance genes 435 444 EN Daichi Morita Collaborative Research Center of Okayama University for Infectious Diseases in India, Okayama University Eizo Takahashi Collaborative Research Center of Okayama University for Infectious Diseases in India, Okayama University Masatomo Morita Department of Bacteriology I, National Institute of Infectious Diseases Makoto Ohnishi Department of Bacteriology I, National Institute of Infectious Diseases Tamaki Mizuno Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Shin‐ichi Miyoshi Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Devarati Dutta Division of Bacteriology, National Institute of Cholera and Enteric Diseases Thandavarayan Ramamurthy Center for Human Microbial Ecology, Translational Health Science and Technology Institute Goutam Chowdhury Division of Bacteriology, National Institute of Cholera and Enteric Diseases Asish K. Mukhopadhyay Division of Bacteriology, National Institute of Cholera and Enteric Diseases Keinosuke Okamoto Collaborative Research Center of Okayama University for Infectious Diseases in India, Okayama University Non‐O1/non‐O139 nontoxigenic Vibrio cholerae associated with cholera‐like diarrhea has been reported in Kolkata, India. However, the property involved in the pathogenicity of these strains has remained unclear. The character of 25 non‐O1/non‐O139 nontoxigenic V. cholerae isolated during 8 years from 2007 to 2014 in Kolkata was examined. Determination of the serogroup showed that the serogroups O6, O10, O35, O36, O39, and O70 were represented by two strains in each serogroup, and the remaining isolates belonged to different serogroups. To clarify the character of antibiotic resistance of these isolates, an antibiotic resistance test and the gene analysis were performed. According to antimicrobial drug susceptibility testing, 13 strains were classified as drug resistant. Among them, 10 strains were quinolone resistant and 6 of the 13 strains were resistant to more than three antibiotics. To define the genetic background of the antibiotic character of these strains, whole‐genome sequences of these strains were determined. From the analysis of these sequences, it becomes clear that all quinolone resistance isolates have mutations in quinolone resistance‐determining regions. Further research on the genome sequence showed that four strains possess Class 1 integrons in their genomes, and that three of the four integrons are found to be located in their genomic islands. These genomic islands are novel types. This indicates that various integrons containing drug resistance genes are spreading among V. cholerae non‐O1/non‐O139 strains through the action of newly generated genomic islands. No potential conflict of interest relevant to this article was reported.

Elsevier Acta Medica Okayama 10967192 125 1-2 2018 Pyridoxal 5′-phosphate and related metabolites in hypophosphatasia: Effects of enzyme replacement therapy 174 180 EN Tomoyuki Akiyama Department of Child Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takuo Kubota Department of Pediatrics, Osaka University Graduate School of Medicine Keiichi Ozono Department of Pediatrics, Osaka University Graduate School of Medicine Toshimi Michigami Department of Bone and Mineral Research, Osaka Women's and Children's Hospital Daisuke Kobayashi Department of Food and Chemical Toxicology, School of Pharmaceutical Sciences, Health Sciences University of Hokkaido Shinji Takeyari Department of Pediatrics, Osaka University Graduate School of Medicine Yuichiro Sugiyama Department of Pediatrics, Nagoya University Graduate School of Medicine Masahiro Noda Department of Pediatrics, Showa General Hospital Daisuke Harada Department of Pediatrics, Osaka Hospital, Japan Community Healthcare Organization Noriyuki Namba Department of Pediatrics, Osaka Hospital, Japan Community Healthcare Organization Atsushi Suzuki Department of Neonatology and Pediatrics, Nagoya City University Graduate School of Medical Sciences Maiko Utoyama Department of Pediatrics, Faculty of Medicine, University of Miyazaki Sachiko Kitanaka Department of Pediatrics, Graduate School of Medicine, University of Tokyo Mitsugu Uematsu Department of Pediatrics, Tohoku University Graduate School of Medicine Yusuke Mitani Department of Pediatrics, Kanazawa University Hospital Kunihiro Matsunami Department of Pediatrics, Gifu Prefectural General Medical Center Shigeru Takishima Department of Pediatrics, Soka Municipal Hospital Erika Ogawa Department of Pediatrics and Child Health, Nihon University School of Medicine Katsuhiro Kobayashi Department of Child Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Objective To investigate the utility of serum pyridoxal 5′-phosphate (PLP), pyridoxal (PL), and 4-pyridoxic acid (PA) as a diagnostic marker of hypophosphatasia (HPP) and an indicator of the effect of, and patient compliance with, enzyme replacement therapy (ERT), we measured PLP, PL, and PA concentrations in serum samples from HPP patients with and without ERT. Methods Blood samples were collected from HPP patients and serum was frozen as soon as possible (mostly within one hour). PLP, PL, and PA concentrations were analyzed using high-performance liquid chromatography with fluorescence detection after pre-column derivatization by semicarbazide. We investigated which metabolites are associated with clinical phenotypes and how these metabolites change with ERT. Results Serum samples from 20 HPP patients were analyzed. The PLP-to-PL ratio and PLP concentration were elevated in all HPP patients. They correlated negatively with serum alkaline phosphatase (ALP) activity and showed higher values in more severe phenotypes (perinatal severe and infantile HPP) compared with other phenotypes. PL concentration was reduced only in perinatal severe HPP. ERT reduced the PLP-to-PL ratio to mildly reduced or low-normal levels and the PLP concentration was reduced to normal or mildly elevated levels. Urine phosphoethanolamine (PEA) concentration did not return to normal levels with ERT in most patients. Conclusions The serum PLP-to-PL ratio is a better indicator of the effect of ERT for HPP than serum PLP and urine PEA concentrations, and a PLP-to-PL ratio of <4.0 is a good indicator of the effect of, and patient compliance with, ERT. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 74 2 2020 Identification of a Novel ACVRL1 Gene Mutation (c.100T>A, p.Cys34Ser) in a Japanese Patient with Possible Hereditary Hemorrhagic Telangiectasia (Osler-Weber-Rendu Disease) 165 169 EN Hiroshi Umemura Division of Laboratory Medicine, Department of Pathology and Microbiology, Nihon University School of Medicine Katsuhiro Miura Division of Hematology and Rheumatology, Department of Medicine, Nihon University School of Medicine Hiromu Naruse Division of Laboratory Medicine, Department of Pathology and Microbiology, Nihon University School of Medicine Yoshihiro Hatta Division of Hematology and Rheumatology, Department of Medicine, Nihon University School of Medicine Masami Takei Division of Hematology and Rheumatology, Department of Medicine, Nihon University School of Medicine Tomohiro Nakayama Division of Laboratory Medicine, Department of Pathology and Microbiology, Nihon University School of Medicine Case Report 10.18926/AMO/58276 Hereditary hemorrhagic telangiectasia (HHT; also known as Osler-Weber-Rendu disease) is an autosomal dominant genetic disorder that causes frequent epistaxis, mucocutaneous telangiectasia, and visceral arteriovenous malformations. Four genes (ENG, ACVRL1, SMAD4, and GDF2) have been identified as pathogenic in HHT. We describe the case of a 50-year-old Japanese man highly suspected of having HHT due to recurrent epistaxis, mucocutaneous telangiectasia, and a family history. Genomic analysis revealed a novel missense mutation of c.100T>A, p.Cys34Ser in the patient’s ACVRL1 gene. We used 6 freeware programs to perform an in silico analysis of this mutation. The results demonstrated the mutation’s high pathogenicity. No potential conflict of interest relevant to this article was reported.

MDPI Acta Medica Okayama 1422-0067 20 21 2019 Animal Models for Parkinson's Disease Research: Trends in the 2000s E5402 EN Kyohei Kin Department of Neurological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Takao Yasuhara Department of Neurological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Masahiro Kameda Department of Neurological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Isao Date Department of Neurological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Parkinson's disease (PD) is a chronic and progressive movement disorder and the second most common neurodegenerative disease. Although many studies have been conducted, there is an unmet clinical need to develop new treatments because, currently, only symptomatic therapies are available. To achieve this goal, clarification of the pathology is required. Attempts have been made to emulate human PD and various animal models have been developed over the decades. Neurotoxin models have been commonly used for PD research. Recently, advances in transgenic technology have enabled the development of genetic models that help to identify new approaches in PD research. However, PD animal model trends have not been investigated. Revealing the trends for PD research will be valuable for increasing our understanding of the positive and negative aspects of each model. In this article, we clarified the trends for animal models that were used to research PD in the 2000s, and we discussed each model based on these trends. No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 2049-4173 7 5 2019 Late presented congenital myasthenic syndrome with novel compound heterozygous CHRNE mutations mimicking seronegative myasthenia gravis 288 290 EN Yumiko Nakano Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Keiichiro Tsunoda Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Toru Yamashita Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Jun Mitsui Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kota Sato Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Mami Takemoto Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Nozomi Hishikawa Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yasuyuki Ohta Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tatsushi Toda Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shoji Tsuji Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Koji Abe Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences We found a late presented congenital myasthenic syndrome (CMS) patient with novel CHRNE gene mutations. Although our patient has shown blepharoptosis since youth, fatigable muscle weakness began at age 71. Genetic analysis revealed novel compound heterozygous CHRNE mutations (c.1032+2T>G, c.1306_1307 delGA). His myasthenic symptoms were well managed by oral anti‐cholinesterase drug until he died at 82‐year‐old. The present case showed mild myasthenic symptoms with very late presentation and slow progression. Late presented CMS is often underdiagnosed; therefore, genetic testing is important to distinguish it from other myasthenic disease. No potential conflict of interest relevant to this article was reported.

Elsevier Acta Medica Okayama 12019712 91 2019 Collagen adhesion gene is associated with blood stream infections caused by methicillin-resistant Staphylococcus aureus 22 31 EN Yasunori Iwata Division of Infection Control, Kanazawa University Kenji Satou Faculty of Electrical and Computer Engineering, Kanazawa University Kengo Furuichi Division of Nephrology, Kanazawa Medical University School of Medicine Ikuko Yoneda Division of Nephrology, Kanazawa University Takuhiro Matsumura Department of Bacteriology, Kanazawa University Masahiro Yutani Graduate School of Environmental and Life Science, Okayama University Yukako Fujinaga Graduate School of Environmental and Life Science, Okayama University Atsushi Hase Faculty of Electrical and Computer Engineering, Kanazawa University Hidetoshi Morita Graduate School of Environmental and Life Science, Okayama University Toshiko Ohta University of Tsukuba Yasuko Senda Division of Infection Control, Kanazawa University Yukiko Sakai-Takemori Division of Infection Control, Kanazawa University Taizo Wada Division of Infection Control, Kanazawa University Shinichi Fujita Division of Infection Control, Kanazawa University Taito Miyake Division of Nephrology, Kanazawa University, Kanazawa, Japan; Department of Disease Control and Homeostasis, Kanazawa University Haruka Yasuda Department of Nephrology and Laboratory Medicine, Kanazawa University Norihiko Sakai Division of Nephrology, Kanazawa University, Kanazawa, Japan; Division of Blood Purification, Kanazawa University Shinji Kitajima Division of Nephrology, Kanazawa University, Kanazawa, Japan; Department of Disease Control and Homeostasis, Kanazawa University Tadashi Toyama Division of Nephrology, Kanazawa University, Kanazawa, Japan; Department of Disease Control and Homeostasis, Kanazawa University Yasuyuki Shinozaki Division of Nephrology, Kanazawa University, Kanazawa, Japan; Department of Disease Control and Homeostasis, Kanazawa University Akihiro Sagara Division of Nephrology, Kanazawa University, Kanazawa, Japan; Department of Disease Control and Homeostasis, Kanazawa University Taro Miyagawa Division of Nephrology, Kanazawa University, Kanazawa, Japan; Department of Disease Control and Homeostasis, Kanazawa University Akinori Hara Division of Nephrology, Kanazawa University, Kanazawa, Japan; Department of Disease Control and Homeostasis, Kanazawa University Miho Shimizu Division of Nephrology, Kanazawa University, Kanazawa, Japan; Department of Disease Control and Homeostasis, Kanazawa University Yasutaka Kamikawa Division of Nephrology, Kanazawa University, Kanazawa, Japan; Department of Disease Control and Homeostasis, Kanazawa University Kazuho Ikeo Laboratory of DNA Data Analysis, National Institute of Genetics Shigeyuki Shichino Department of Molecular Preventive Medicine, University of Tokyo Satoshi Ueha Department of Molecular Preventive Medicine, University of Tokyo Takuya Nakajima Department of Molecular Preventive Medicine, University of Tokyo Kouji Matsushima Department of Molecular Preventive Medicine, University of Tokyo Shuichi Kaneko epartment of Disease Control and Homeostasis, Kanazawa University Takashi Wada Division of Nephrology, Kanazawa University, Kanazawa, Japan; Department of Nephrology and Laboratory Medicine, Kanazawa University Objectives: Methicillin-resistant Staphylococcus aureus (MRSA) causes hospital- and community-acquired infections. It is not clear whether genetic characteristics of the bacteria contribute to disease pathogenesis in MRSA infection. We hypothesized that whole genome analysis of MRSA strains could reveal the key gene loci and/or the gene mutations that affect clinical manifestations of MRSA infection. Methods: Whole genome sequences (WGS) of MRSA of 154 strains were analyzed with respect to clinical manifestations and data. Further, we evaluated the association between clinical manifestations in MRSA infection and genomic information. Results: WGS revealed gene mutations that correlated with clinical manifestations of MRSA infection. Moreover, 12 mutations were selected as important mutations by Random Forest analysis. Cluster analysis revealed strains associated with a high frequency of bloodstream infection (BSI). Twenty seven out of 34 strains in this cluster caused BSI. These strains were all positive for collagen adhesion gene (cna) and have mutations in the locus, those were selected by Random Forest analysis. Univariate and multivariate analysis revealed that these gene mutations were the predictor for the incidence of BSI. Interestingly, mutant CNA protein showed lower attachment ability to collagen, suggesting that the mutant protein might contribute to the dissemination of bacteria. Conclusions: These findings suggest that the bacterial genotype affects the clinical characteristics of MRSA infection. (c) 2019 The Author(s). Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. No potential conflict of interest relevant to this article was reported.

Elsevier Acta Medica Okayama 22144269 21 2019 Clinical and genetic aspects of mild hypophosphatasia in Japanese patients 100515 EN Katsuyuki Yokoi Department of Pediatrics, Fujita Health University School of Medicine Yoko Nakajima Department of Pediatrics, Fujita Health University School of Medicine Yasuko Shinkai Division of Molecular Genetics, Institute for Comprehensive Medical Science, Fujita Health University Yoshimi Sano Department of Plastic Surgery, Division of Pediatric Dentistry & Orthodontics, Fujita Health University of Medicine Mototaka Imamura Department of Plastic Surgery, Division of Pediatric Dentistry & Orthodontics, Fujita Health University of Medicine Tomoyuki Akiyama Department of Child Neurology, Okayama University Hospital Tetsushi Yoshikawa Department of Pediatrics, Fujita Health University School of Medicine Tetsuya Ito Department of Pediatrics, Fujita Health University School of Medicine Hiroki Kurahashi Division of Molecular Genetics, Institute for Comprehensive Medical Science, Fujita Health University Background: Hypophosphatasia (HPP) is a rare inborn error of metabolism that results from a dysfunctional tissue non-specific alkaline phosphatase enzyme (TNSALP). Although genotype-phenotype correlations have been described in HPP patients, only sparse information is currently available on the genetics of mild type HPP. Methods: We investigated 5 Japanese patients from 3 families with mild HPP (patients 1 and 2 are siblings; patient 4 is a daughter of patient 5) who were referred to Fujita Health University due to the premature loss of deciduous teeth. Physical and dental examinations, and blood, urine and bone density tests were conducted. Genetic analysis of the ALPL gene was performed in all patients with their informed consent. Results: After a detailed interview and examination, we found characteristic symptoms of HPP in some of the study cases. Mobile teeth or the loss of permanent teeth were observed in 2 patients, and 3 out of 5 patients had a history of asthma. The serum ALP levels of all patients were 30% below the lower limit of the age equivalent normal range. ALPL gene analysis revealed compound heterozygous mutations, including Ile395Val and Leu520Argfs in family 1, Val95Met and Gly491Arg in family 2, and a dominant missense mutation (Gly456Arg) in family 3. The 3D-modeling of human TNSALP revealed three mutations (Val95Met, Ile395Val and Gly456Arg) at the homodimer interface. Severe collisions between the side chains were predicted for the Gly456Arg variant. Discussion: One of the characteristic findings of this present study was a high prevalence of coexisting asthma and a high level serum IgE level. These characteristics may account for the fragility of tracheal tissues and a predisposition to asthma in patients with mild HPP. The genotypes of the five mild HPP patients in our present study series included 1) compound heterozygous for severe and hypomorphic mutations, and 2) dominant-negative mutations. All of these mutations were at the homodimer interface, but only the dominant-negative mutation was predicted to cause a severe collision effect between the side chains. This may account for varying mechanisms leading to different effects on TNSALP function. No potential conflict of interest relevant to this article was reported.

Cell Press Acta Medica Okayama 2329-0501 13 2019 Induction of Expandable Tissue-Specific Progenitor Cells from Human Pancreatic Tissue through Transient Expression of Defined Factors 243 252 EN Hirofumi Noguchi Department of Regenerative Medicine, Graduate School of Medicine, University of the Ryukyus Chika Miyagi-Shiohira Department of Regenerative Medicine, Graduate School of Medicine, University of the Ryukyus Yoshiki Nakashima Department of Regenerative Medicine, Graduate School of Medicine, University of the Ryukyus Takao Kinjo Department of Basic Laboratory Sciences, School of Health Sciences in Faculty of Medicine, University of the Ryukyus Naoya Kobayashi Okayama Saidaiji Hospital Issei Saitoh Division of Pediatric Dentistry, Graduate School of Medical and Dental Science, Niigata University Masami Watanabe Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences A. M. James Shapiro Clinical Islet Transplant Program and Department of Surgery, University of Alberta Tatsuya Kin Clinical Islet Transplant Program and Department of Surgery, University of Alberta We recently demonstrated the generation of mouse induced tissue-specific stem (iTS) cells through transient overexpression of reprogramming factors combined with tissue-specific selection. Here we induced expandable tissue-specific progenitor (iTP) cells from human pancreatic tissue through transient expression of genes encoding the reprogramming factors OCT4 (octamer-binding transcription factor 4), p53 small hairpin RNA (shRNA), SOX2 (sex-determining region Y-box 2), KLF4 (Kruppel-like factor 4), L-MYC, and LIN28. Transfection of episomal plasmid vectors into human pancreatic tissue efficiently generated iTP cells expressing genetic markers of endoderm and pancreatic progenitors. The iTP cells differentiated into insulin-producing cells more efficiently than human induced pluripotent stem cells (iPSCs). iTP cells continued to proliferate faster than pancreatic tissue cells until days 100–120 (passages 15–20). iTP cells subcutaneously inoculated into immunodeficient mice did not form teratomas. Genomic bisulfite nucleotide sequence analysis demonstrated that the OCT4 and NANOG promoters remained partially methylated in iTP cells. We compared the global gene expression profiles of iPSCs, iTP cells, and pancreatic cells (islets >80%). Microarray analyses revealed that the gene expression profiles of iTP cells were similar, but not identical, to those of iPSCs but different from those of pancreatic cells. The generation of human iTP cells may have important implications for the clinical application of stem/progenitor cells. No potential conflict of interest relevant to this article was reported.

Academic Press Acta Medica Okayama 09699961 50 2013 CACNA1A variants may modify the epileptic phenotype of Dravet syndrome 209 217 EN Iori Ohmori Department of Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Mamoru Ouchida Department of Molecular Genetics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Katsuhiro Kobayashi Yoshimi Jitsumori Akiko Mori Department of Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Hiroyuki Michiue Department of Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Teiichi Nishiki Department of Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Yoko Ohtsuka Hideki Matsui Department of Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Dravet syndrome is an intractable epileptic syndrome beginning in the first year of life. De novo mutations of SCN1A, which encode the Na(v)1.1 neuronal voltage-gated sodium channel, are considered the major cause of Dravet syndrome. In this study, we investigated genetic modifiers of this syndrome. We performed a mutational analysis of all coding exons of CACNA1A in 48 subjects with Dravet syndrome. To assess the effects of CACNA1A variants on the epileptic phenotypes of Dravet syndrome, we compared clinical features in two genotype groups: 1) subjects harboring SCN1A mutations but no CACNA1A variants (n=20) and 2) subjects with SCN1A mutations plus CACNA1A variants (n=20). CACNA1A variants detected in patients were studied using heterologous expression of recombinant human Ca(v)2.1 in HEK 293 cells and whole-cell patch-clamp recording. Nine CACNA1A variants, including six novel ones, were detected in 21 of the 48 subjects (43.8%). Based on the incidence of variants in healthy controls, most of the variants seemed to be common polymorphisms. However, the subjects harboring SCN1A mutations and CACNA1A variants had absence seizures more frequently than the patients with only SCN1A mutations (8/20 vs. 0/20, p=0.002). Moreover, the former group of subjects exhibited earlier onset of seizures and more frequent prolonged seizures before one year of age, compared to the latter group of subjects. The electrophysiological properties of four of the five novel Ca(v)2.1 variants exhibited biophysical changes consistent with gain-of-function. We conclude that CACNA1A variants in some persons with Dravet syndrome may modify the epileptic phenotypes. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 73 4 2019 A Patient with Type 3 Autoimmune Polyglandular Syndrome who Developed Systemic Lupus Erythematosus 8 years after the Diagnosis of Autoimmune Hepatitis 367 372 EN Tomoyo Mifune-Morioka Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Haruhito A. Uchida Department of Chronic Kidney Disease and Cardiovascular Disease, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kazuhiko Fukushima Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Mayu Watanabe Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Chihiro Ouchi Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Koki Mise Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Chieko Kawakita Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yuzuki Kano Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Akifumi Onishi Department of Human Resource Development of Dialysis Therapy for Kidney Disease, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kishio Toma Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Jun Eguchi Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Nozomu Wada Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Fusao Ikeda Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Erika Sasaki Department of General Internal Medicine and Endocrinology, Okayama City Hospital Yu Suganami Department of General Internal Medicine and Endocrinology, Okayama City Hospital Masayuki Kishida Department of General Internal Medicine and Endocrinology, Okayama City Hospital Hitoshi Sugiyama Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hiroyuki Okada Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Jun Wada Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Case Report 10.18926/AMO/56940 Eight years prior to her present admission, a 61-year-old Japanese woman was diagnosed with autoimmune hepatitis, slowly progressive insulin-dependent diabetes mellitus, and chronic thyroiditis; she had been treated with oral prednisolone (PSL). After she suddenly discontinued PSL, she newly developed systemic lupus erythematosus. A combination therapy of oral PSL and intravenous cyclophosphamide resulted in remission. She was finally diagnosed with autoimmune polyglandular syndrome (APS) type 3 (3A ,3B, 3D), complicated with four different autoimmune diseases. Since patients with type 3 APS may present many manifestations over a long period of time, they should be carefully monitored. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 73 4 2019 Construction and Characterization of a PGN_0297 Mutant of Porphyromonas gingivalis: Evidence of the Contribution of PGN_0297 to Gingipain Activity 315 323 EN Shintaro Ono Department of Periodontal Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Masaaki Nakayama Department of Oral Microbiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Masato Tachibana Department of Oral Microbiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Abu Saleh Muhammad Shahriar Department of Oral Microbiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Wang Heling Department of Oral Microbiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shogo Takashiba Department of Periodontal Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Naoya Ohara Department of Oral Microbiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Original Article 10.18926/AMO/56933 The periodontal pathogen Porphyromonas gingivalis shows colonial pigmentation on blood agar and produces gingipains (Kgp, RgpA, and RgpB), cysteine proteases involved in an organism’s virulence and pigmentation. We showed previously that deletion of the PGN_0300 gene abolished the pigmentation activity and reduced the proteolytic activity of gingipains. The role of the PGN_0297 gene, which consists of an operon with the PGN_0300 gene, is unclear. Herein we examined the effect of PGN_0297 gene deletion on the pigmentation and proteolytic activities and transcriptional levels of gingipains. A PGN_0297 gene deletion mutant (ΔPGN_0297) did not exhibit the pigmentation. The proteolytic activity of the gingipains was decreased in the culture supernatant and on the cell surface of ΔPGN_0297. The mutant ΔPGN_0297 failed to attenuate Akt phosphorylation at Thr308 and Ser473, but both phosphorylations were attenuated in the wild-type and its complementation strain. The deletion of PGN_0297 gene did not substantially affect the transcriptional levels of the gingipain genes kgp, rgpA, and rgpB. Taken together, these results indicate that PGN_0297 is closely involved in the secretion and maturation of gingipains. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 73 4 2019 Dynamic Reorganization of Microtubule and Glioma Invasion 285 297 EN Yoshihiro Otani Department of Neurosurgery, The University of Texas Health Science Center at Houston Tomotsugu Ichikawa Department of Neurosurgery, Kagawa Prefectural Central Hospital Kazuhiko Kurozumi Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Isao Date Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Review 10.18926/AMO/56930 Gliomas are characterized as highly diffuse infiltrating tumors, and currently available treatments such as surgery, radiation and chemotherapy are unfeasible or show limited efficacy against these tumors. Recent genetic and epigenetic analyses of glioma have revealed increasing evidence of the role of driver genetic alterations in glioma development and led to the identification of prognostic factors. Despite these findings, the survival rates of glioma patients remain low, and alternative treatments and novel targets are needed. Recent studies identified neural stem cells as the possible origin of gliomas, and some evidence has revealed shared functions and mechanisms between glioma cells and neurons, also supporting their similarity. The cytoskeleton plays important roles in the migration of normal cells as well as cancer cells. Recent reports have described a role for microtubules, a component of the cytoskeleton, in glioma invasion. Notably, several factors that regulate microtubule functions, such as microtubule-associated proteins, plus-end tracking proteins, or motor proteins, are upregulated in glioma tissues compared with normal tissue, and upregulation of these factors is associated with high invasiveness of glioma cells. In this review, we describe the mechanism of microtubules in glioma invasion and discuss the possibility of microtubule-targeted therapy to inhibit glioma invasion. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 73 3 2019 A Case of Nager Syndrome Diagnosed Before Birth 273 277 EN Kei Hayata Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hisashi Masuyama Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Eriko Eto Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takashi Mitsui Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shoko Tamada Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takeshi Eguchi Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Jota Maki Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kazumasa Tani Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Akiko Ohira Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yosuke Washio Department Pediatrics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Junko Yoshimoto Department Pediatrics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kosei Hasegawa Department Pediatrics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Case Report 10.18926/AMO/56872 Nager syndrome is a rare disease involving severe micrognathia and upper limb shortening. In this report, we describe a case in which micrognathia of the fetus was suspected based on the observation of upper limb shortening during detailed B mode and 3D/4D ultrasonographic observation, and combined fetal MRI and 3D-CT led to a prenatal diagnosis of Nager syndrome. Upon birth, because severe micrognathia caused airway obstruction and made it difficult to spread the larynx for intubation, effective ventilation could not be carried out and a tracheostomy was necessary. Since a differential diagnosis of Nager syndrome can be made based on the fact that micrognathia typically co-occurs with upper limb shortening, it is possible to diagnose the disease before birth and prepare for life-saving measures accordingly. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 73 3 2019 Sudden, Sharp Turn in an AIDS Patient’s Course Following the Onset of Fulminant Type 1 Diabetes 263 267 EN Yuichiro Shimoyama Department of Intensive Care Unit, Osaka Medical College Hospital Osamu Umegaki Department of Intensive Care Unit, Osaka Medical College Hospital Yukimasa Ooi Department of Internal Medicine, Osaka Medical College Hospital Sho Shigemoto Department of Internal Medicine, Osaka Medical College Hospital Tomoyuki Agui Department of Surgery, Osaka Medical College Hospital Noriko Kadono Department of Intensive Care Unit, Osaka Medical College Hospital Toshiaki Minami Department ofAnesthesiology, Osaka Medical College Hospital Case Report 10.18926/AMO/56870 A previously healthy 40-year-old Japanese male was urgently admitted with a 2-month history of dysphagia, 30-kg weight loss, and fever. Human immunodeficiency virus (HIV) antibodies and cytomegalovirus antigenemia were positive. Pneumocystis pneumonia and cytomegalovirus pneumonia were suspected. The patient was diagnosed with acquired immune deficiency syndrome (AIDS). Cytomegalovirus antigenemia became negative 20 days after the positive result. On hospital day 41, he experienced cardiopulmonary arrest. The clinical diagnosis was fulminant type 1 diabetes mellitus. He later developed hypoglycemia and was diagnosed with adrenal insufficiency accompanied by septic shock. He died of multiple organ failure 29 h post-admission to our ICU. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 73 3 2019 Improvement of Open Bite and Stomatognathic Function in an Axenfeld- Rieger Syndrome Patient by Orthodontic Sectional Arch Mechanics: Clinical Considerations and the Risk of Orthodontic Tooth Movement 255 262 EN Daisuke Seki Division of Orthodontics and Dentofacial Orthopedics, Tohoku University Graduate School of Dentistry Nobuo Takeshita Division of Orthodontics and Dentofacial Orthopedics, Tohoku University Graduate School of Dentistry Masahiro Seiryu Division of Orthodontics and Dentofacial Orthopedics, Tohoku University Graduate School of Dentistry Toru Deguchi Division of Orthodontics, The Ohio State University College of Dentistry Teruko Takano-Yamamoto Department of Biomaterials and Bioengineering, Faculty of Dental Medicine, Hokkaido University Case Report 10.18926/AMO/56869 Orthodontists need to understand the orthodontic risks associated with systemic disorders. Axenfeld-Rieger syndrome (ARS) is a rare autosomal dominant disorder with genetic and morphological variability. The risks of orthodontic treatment in ARS patients have been unclear. Here we describe the correction of an anterior open bite in a 15-year-old Japanese female ARS patient by molar intrusion using sectional archwires with miniscrew implants. An undesirable development of external apical root resorption (EARR) was observed in all intrusive force-applied posterior teeth during the patient’s orthodontic treatment, suggesting that ARS patients have a higher risk of EARR than the general population. No potential conflict of interest relevant to this article was reported.

American Society for Microbiology Acta Medica Okayama 00951137 51 3 2013 Molecular Characterization of High-Level-Cholera-Toxin-Producing El Tor Variant Vibrio cholerae Strains in the Zanzibar Archipelago of Tanzania 1040 1045 EN A. Naha 1National Institute of Cholera and Enteric Diseases G. Chowdhury 1National Institute of Cholera and Enteric Diseases J. Ghosh-Banerjee 1National Institute of Cholera and Enteric Diseases M. Senoh Collaborative Research Center of Okayama University for Infectious Diseases at NICED, T. Takahashi Collaborative Research Center of Okayama University for Infectious Diseases at NICED, B. Ley The International Vaccine Institute K. Thriemer The International Vaccine Institute J. Deen The International Vaccine Institute L. V. Seidlein Menzies School of Health Research S. M. Ali Ministry of Health and Social Welfare A. Khatib Ministry of Health and Social Welfare T. Ramamurthy 1National Institute of Cholera and Enteric Diseases R. K. Nandy 1National Institute of Cholera and Enteric Diseases G. B. Nair 1National Institute of Cholera and Enteric Diseases Y. Takeda Collaborative Research Center of Okayama University for Infectious Diseases at NICED, A. K. Mukhopadhyay 1National Institute of Cholera and Enteric Diseases Analysis of 1,180 diarrheal stool samples in Zanzibar detected 247 Vibrio cholerae O1, Ogawa strains in 2009. Phenotypic traits and PCR-based detection of rstR, rtxC, and tcpA alleles showed that they belonged to the El Tor biotype. Genetic analysis of ctxB of these strains revealed that they were classical type, and production of classical cholera toxin B (CTB) was confirmed by Western blotting. These strains produced more CT than the prototype El Tor and formed a separate cluster by pulsed-field gel electrophoresis (PFGE) analysis. No potential conflict of interest relevant to this article was reported.

Oxford University Press Acta Medica Okayama 03051048 44 12 2016 Physiological TLR5 expression in the intestine is regulated by differential DNA binding of Sp1/Sp3 through simultaneous Sp1 dephosphorylation and Sp3 phosphorylation by two different PKC isoforms 5658 5672 EN Bhupesh Kumar Thakur Division of Clinical Medicine, National Institute of Cholera and Enteric Diseases Nirmalya Dasgupta Division of Clinical Medicine, National Institute of Cholera and Enteric Diseases Atri Ta Division of Clinical Medicine, National Institute of Cholera and Enteric Diseases Santasabuj Das Division of Clinical Medicine, National Institute of Cholera and Enteric Diseases Toll-like receptor 5 (TLR5) expression in the intestinal epithelial cells (IECs) is critical to maintain health, as underscored by multiple intestinal and extra-intestinal diseases in mice genetically engineered for IEC-specific TLR5 knockout. A gradient of expression exists in the colonic epithelial cells from the cecum to the distal colon. Intriguingly, an identical gradient for the dietary metabolite, butyrate also exists in the luminal contents. However, both being critical for intestinal homeostasis and immune response, no studies examined the role of butyrate in the regulation of TLR5 expression. We showed that butyrate transcriptionally upregulates TLR5 in the IECs and augments flagellin-induced immune responses. Both basal and butyrate-induced transcription is regulated by differential binding of Sp-family transcription factors to the GC-box sequences over the TLR5 promoter. Butyrate activates two different protein kinase C isoforms to dephosphorylate/acetylate Sp1 by serine/threonine phosphatases and phosphorylate Sp3 by ERK-MAPK, respectively. This resulted in Sp1 displacement from the promoter and binding of Sp3 to it, leading to p300 recruitment and histone acetylation, activating transcription. This is the first study addressing the mechanisms of physiological TLR5 expression in the intestine. Additionally, a novel insight is gained into Sp1/Sp3-mediated gene regulation that may apply to other genes. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 73 2 2019 Exchange Transfusion and Cytarabine for Transient Abnormal Myelopoiesis in Hydrops Fetalis 181 188 EN Tomoka Okamura Department of Pediatrics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yousuke Washio Department of Pediatrics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Junko Yoshimoto Department of Pediatrics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kazumasa Tani Department of Obstetrics and Gynecology, Okayama University Hospital Hirokazu Tsukahara Department of Pediatrics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Akira Shimada Department of Pediatric Hematology/Oncology, Okayama University Hospital Case Report 10.18926/AMO/56655 Most cases of transient abnormal myelopoiesis (TAM) in neonates with Down syndrome (DS) resolve spontaneously; however, DS-TAM neonates with hydrops fetalis (HF) show poor clinical outcomes. We report three infants with DS-TAM and HF who were treated with exchange transfusion (ET) followed by low-dose cytarabine (LD-CA). All of them survived without developing liver failure, acute leukemia, or other serious adverse events. Our results suggest that this combination treatment with ET and LD-CA would be safe, tolerable and effective as an novel approach for DS-TAM patients with HF. No potential conflict of interest relevant to this article was reported.

Acta Medica Okayama 2018 Clinical impact of endometrial cancer stratified by genetic mutational profiles, POLE mutation, and microsatellite instability EN Tomoko Haruma Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 72 4 2018 Study Design of a Phase II Clinical Trial to Assess the Efficacy and Safety of Eperisone in Japanese Type 2 Diabetes Patients with Risk and Non-risk Alleles of CDKAL1 423 426 EN Kourin Sakakida Department of Molecular Physiology, Faculty of Life Sciences, Kumamoto University Fan-Yan Wei Department of Molecular Physiology, Faculty of Life Sciences, Kumamoto University Takafumi Senokuchi Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University Seiya Shimoda Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University Tatsuyuki Kakuma Biostatics Center, Medical School, Kurume University Eiichi Araki Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University Kazuhito Tomizawa Department of Molecular Physiology, Faculty of Life Sciences, Kumamoto University The Eperisone for Diabetes with Impaired tRNA (EDIT) Study Group Clinical Study Protocol 10.18926/AMO/56182 Genetic variation in Cdk5 Regulatory Associated Protein 1-Like 1 (CDKAL1) is associated with the development of type 2 diabetes (T2D). Dysfunction of CDKAL1 impairs the translation of proinsulin, which leads to glucose intolerance. Eperisone, an antispasmodic agent, has been shown to ameliorate glucose intolerance in Cdkal1-deficient mice. We have launched a phase II clinical study to investigate the potential anti-diabetic effect of eperisone in T2D patients carrying risk or non-risk alleles of CDKAL1. The primary endpoint is the change of hemoglobin A1c (HbA1c) levels. We also examined whether the efficacy of eperisone in T2D patients is associated with CDKAL1 activity. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 72 3 2018 Analysis of All 34 Exons of the SPINK5 Gene in Japanese Atopic Dermatitis Patients 275 282 EN Shin Morizane Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Mamoru Ouchida Department of Molecular Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ko Sunagawa Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Saeko Sugimoto Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Mina Kobashi Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Satoru Sugihara Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hayato Nomura Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kazuhide Tsuji Nishigawara Dermatology Clinic Atsushi Sato Sato Dermatology Clinic Yoshihiro Miura Miura Dermatology Clinic Hiroaki Hattori Hattori Dermatology and Allergy Clinic Kotaro Tada Tada Dermatology Clinic Wook-Kang Huh Dr. Huh's Dermatology Clinic Akemi Seno Department of Dermatology, Mitoyo General Hospital Keiji Iwatsuki Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Original Article 10.18926/AMO/56073 Lympho-epithelial Kazal-type-related inhibitor (LEKTI) is a large multidomain serine protease inhibitor that is expressed in epidermal keratinocytes. Nonsense mutations of the SPINK5 gene, which codes for LEKTI, cause Netherton syndrome, which is characterized by hair abnormality, ichthyosis, and atopy. A single nucleotide polymorphism (SNP) of SPINK5, p.K420E, is reported to be associated with the pathogenesis of atopic dermatitis (AD). We studied all 34 exons of the SPINK5 gene in Japanese 57 AD patients and 50 normal healthy controls. We detected nine nonsynonymous variants, including p.K420E; these variants had already been registered in the SNP database. Among them, p.R654H (n=1) was found as a heterozygous mutation in the AD patients, but not in the control. No new mutation was detected. We next compared the data of the AD patients with data from the Human Genetic Variation Database provided by Kyoto University; a significant difference was found in the frequency of the p.S368N genotype distribution. PolyPhen-2 and SIFT, two algorithms for predicting the functional effects of amino acid substitutions, showed significant scores for p.R654H. Therefore, R654H might be a risk factor for epidermal barrier dysfunction in some Japanese AD patients. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 71 5 2017 Genetic Factors of Low-responsiveness to Hepatitis B Virus Vaccine Confirms the Importance of Human Leukocyte Antigen Class II Types in a Japanese Young Adult Population 433 436 EN Nobuyasu Yukimasa Department of Medical Technology, Kagawa Prefectural University of Health Sciences Shota Kohama Graduate School of Health Sciences, Kagawa Prefectural University of Health Sciences Wataru Oboshi Department of Medical Technology, Kagawa Prefectural University of Health Sciences Shoichi Sato Clinical Laboratory, Chiba Emergency Medical Center Takehiro Nakamura Department of Medical Technology, Kagawa Prefectural University of Health Sciences Short Communication 10.18926/AMO/55442 We investigated the genetic mechanisms underlying the association between human leukocyte antigen (HLA) types and the immune response to hepatitis B virus (HBV) vaccination in 84 healthy Japanese adults, and found that the HLA-DRB1＊04 and HLA-DQB1＊03 frequencies were higher in the low responders (<10 mIU/ml; n=9, 10.7%) compared to the responders (≥10 mIU/ml, n=75, 89.3%). The combination of DRB1＊04 and DQB1＊03 was associated with a low response to vaccination. The DRB1＊04 and DQB1＊03 haplotypes’ frequencies were significantly higher in the low responders compared to responders. Novel candidate HLA types may be important in Japanese individuals. No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 129 2 2017 家族性大腸腺腫症術後20年後に小腸癌を発症した1例 111 114 EN Yuusaku Sugihara Department of Gastroenterology and Hepatology, Okayama University Hospital Seiji Kawano Department of Gastroenterology and Hepatology, Okayama University Hospital Keita Harada Department of Gastroenterological Surgery, Okayama University Hospital Shiho Takashima Department of Gastroenterology and Hepatology, Okayama University Hospital Daisuke Takei Department of Gastroenterological Surgery, Okayama University Hospital Toshihiro Inokuchi Department of Gastroenterology and Hepatology, Okayama University Hospital Masahiro Takahara Department of Gastroenterology and Hepatology, Okayama University Hospital Sakiko Hiraoka Department of Gastroenterology and Hepatology, Okayama University Hospital Yoshiko Mori Division of Endoscopy, Okayama University Hospital Hiroyuki Kishimoto Division of Endoscopy, Okayama University Hospital Takeshi Nagasaka Division of Endoscopy, Okayama University Hospital Hiroyuki Okada Department of Gastroenterology and Hepatology, Okayama University Hospital A 58-year-old Japanese man visited a local clinic for the evaluation of a stomachache. He was diagnosed with intestinal obstruction. His medical history included a proctocolectomy at the age of 38 years, due to familial adenomatous polyposis (FAP). He was referred to our institution, where he underwent a computed tomography examination and endoscopy of the small intestine. The pathological diagnosis was adenocarcinoma. No invasive or metastatic lesions were observed. Therefore, partial resection of the ileum with lymphadenectomy and reconstruction of the ileostomy were performed. Pathological examination revealed that the tumor was type 2, pT3 (SS) , pN1, pPM0, pDM0, pRM0, INFb, ly1, v1, pEX0, PN0. Twenty-nine days after the surgery, the patient was diagnosed with lung metastasis and he underwent lung radiofrequency ablation. We suggest that long-term follow-up is necessary for patients after surgery for FAP, because of the risk of malignant disease developing in other organs. No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 128 3 2016 バイオバンク 237 239 EN Mizuki Morita Department of Biorepository Research and Networking, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shinichi Toyooka Department of Clinical Genomic Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 128 3 2016 脳波：小児てんかんにおける古くて新しい検査 183 189 EN Katsuhiro Kobayashi Department of Child Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 128 3 2016 平成27年度岡山医学会賞総合研究奨励賞（結城賞） 165 169 EN Hideaki Fujiwara University of Michigan No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 70 4 2016 Moyamoya Disease: A Review of Clinical Research 229 236 EN Tomohito Hishikawa Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kenji Sugiu Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Isao Date Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Review 10.18926/AMO/54497 About 5 decades have passed since the concept of moyamoya disease (MMD) was established in Japan. In that time, many clinical MMD studies have been performed from several different points of view, such as epidemiology, pathophysiology, surgical procedures, and prognosis. In addition, rapid developments in MMD genetic analysis have occurred. In light of all this activity, clinicians must continually update their knowledge of MMD in order to improve the prognosis of MMD patients. In this review article, we summarize the clinical MMD studies and introduce cutting-edge findings regarding MMD. No potential conflict of interest relevant to this article was reported.

Acta Medica Okayama 2016 Individual risk alleles of susceptibility to schizophrenia are associated with poor clinical and social outcomes EN Shinji Sakamoto No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 128 1 2016 Helicobacter pylori 感染診療の現況と展望 13 19 EN Hiroyuki Okada No potential conflict of interest relevant to this article was reported.

Acta Medica Okayama 2015 Genetic and epigenetic alterations of netrin-1 receptors in gastric cancer with chromosomal instability EN Keisuke Toda No potential conflict of interest relevant to this article was reported.

PUBLIC LIBRARY SCIENCE Acta Medica Okayama 1932-6203 8 8 2013 Calpain-2 Compensation Promotes Angiotensin II-Induced Ascending and Abdominal Aortic Aneurysms in Calpain-1 Deficient Mice e72214 EN Venkateswaran Subramanian Jessica　J. Moorleghen Anju Balakrishnan Deborah　A. Howatt Athar H. Chishti Haruhito A. Uchida Background and Objective Recently, we demonstrated that angiotensin II (AngII)-infusion profoundly increased both aortic protein and activity of calpains, calcium-activated cysteine proteases, in mice. In addition, pharmacological inhibition of calpain attenuated AngII-induced abdominal aortic aneurysm (AA) in mice. Recent studies have shown that AngII infusion into mice leads to aneurysmal formation localized to the ascending aorta. However, the precise functional contribution of calpain isoforms (-1 or -2) in AngII-induced abdominal AA formation is not known. Similarly, a functional role of calpain in AngII-induced ascending AA remains to be defined. Using BDA-410, an inhibitor of calpains, and calpain-1 genetic deficient mice, we examined the relative contribution of calpain isoforms in AngII-induced ascending and abdominal AA development. Methodology/Results To investigate the relative contribution of calpain-1 and -2 in development of AngII-induced AAs, male LDLr −/− mice that were either calpain-1 +/+ or −/− were fed a saturated fat-enriched diet and infused with AngII (1,000 ng/kg/min) for 4 weeks. Calpain-1 deficiency had no significant effect on body weight or blood pressure during AngII infusion. Moreover, calpain-1 deficiency showed no discernible effects on AngII-induced ascending and abdominal AAs. Interestingly, AngII infusion induced increased expression of calpain-2 protein, thus compensating for total calpain activity in aortas of calpain-1 deficient mice. Oral administration of BDA-410, a calpain inhibitor, along with AngII-infusion significantly attenuated AngII-induced ascending and abdominal AA formation in both calpain-1 +/+ and −/− mice as compared to vehicle administered mice. Furthermore, BDA-410 administration attenuated AngII-induced aortic medial hypertrophy and macrophage accumulation. Western blot and immunostaining analyses revealed BDA-410 administration attenuated AngII-induced C-terminal fragmentation of filamin A, an actin binding cytoskeletal protein in aorta. Conclusion Calpain-2 compensates for loss of calpain-1, and both calpain isoforms are involved in AngII-induced aortic aneurysm formation in mice. No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 127 3 2015 術前内照射および化学療法が著効し,根治切除し得た巨大異所性褐色細胞腫の1例 213 218 EN Kazuya Yasui Yuzo Umeda Kenjiro Kumano Masahiro Tabata Fumio Otsuka Takahito Yagi Toshiyoshi Fujiwara A 46-year-old man was found to be positive for occult blood at a medical checkup and was revealed to have a 14-cm tumor on the right side of abdominal aorta by a subsequent abdominal CT scan. The endocrinology laboratory data showed elevations in the levels of serum noradrenaline, and ectopic pheochromocytoma was suspected. The tumor was compressing the inferior vena cava and portal vein, the superior mesenteric artery and the pancreas. Since it would be difficult to cure by operation, neoadjuvant therapy was started using radioisotope therapy by I-131 metaiodobenzylguanidine (131I-MIBG) and chemotherapy (CVD therapy ; cyclophosphamide, vincristine, dacarbazine). He was treated with three courses of radioisotope therapy and 16 courses of chemotherapy, which significantly reduced the tumor size. This made radical resection possible ; we were able to avoid the merger excision of great vessels and other organs. On pathological and immunopathological findings, the tumor was diagnosed as ectopic　pheochromocytoma. Regarding the safety and curability of the treatment, neoadjuvant therapy may be useful in treating very large tumors that show invasion of other organs. No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 127 3 2015 血管内皮機能を対象にした基礎および臨床医学研究 187 195 EN Hirokazu Tsukahara No potential conflict of interest relevant to this article was reported.

Acta Medica Okayama 0735-1097 63 20 2014 Electrocardiographic Parameters and Fatal Arrhythmic Events in Patients With Brugada Syndrome 2131 2138 EN Koji Tokioka Kengo F. Kusano Hiroshi Morita Daiji Miura Nobuhiro Nishii Satoshi Nagase Kazufumi Nakamura Kunihisa Kohno Hiroshi Ito Tohru Ohe Objectives This study aimed to determine the usefulness of the combination of several electrocardiographic markers on risk assessment of ventricular fibrillation (VF) in patients with Brugada syndrome (BrS). Background Detection of high-/low-risk BrS patients using a noninvasive method is an important issue in the clinical setting. Several electrocardiographic markers related to depolarization and repolarization abnormalities have been reported, but the relationship and usefulness of these parameters in VF events are unclear. Methods Baseline characteristics of 246 consecutive patients (236 men; mean age, 47.6 +/- 13.6 years) with a Brugada-type electrocardiogram, including 13 patients with a history of VF and 40 patients with a history of syncope episodes, were retrospectively analyzed. During the mean follow-up period of 45.1 months, VF in 23 patients and sudden cardiac death (SCD) in 1 patient were observed. Clinical/ genetic and electrocardiographic parameters were compared with VF/SCD events. Results On univariate analysis, a history of VF and syncope episodes, paroxysmal atrial fibrillation, spontaneous type 1 pattern in the precordial leads, and electrocardiographic markers of depolarization abnormalities (QRS duration >= 120 ms, and fragmented QRS [f-QRS]) and those of repolarization abnormalities (inferolateral early repolarization [ER] pattern and QT prolongation) were associated with later cardiac events. On multivariable analysis, a history of VF and syncope episodes, inferolateral ER pattern, and f-QRS were independent predictors of documented VF and SCD (odds ratios: 19.61, 28.57, 2.87, and 5.21, respectively; p < 0.05). Kaplan-Meier curves showed that the presence/ absence of inferolateral ER and f-QRS predicted a worse/better prognosis (log-rank test, p < 0.01). Conclusions The combination of depolarization and repolarization abnormalities in BrS is associated with later VF events. The combination of these abnormalities is useful for detecting high-and low-risk BrS patients. No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 126 3 2014 平成25年度岡山医学会賞総合研究奨励賞（結城賞） 187 190 EN Hiromasa Yamamoto 受賞対象論文: Yamamoto H, Higasa K, Sakaguchi M, Shien K, Soh J, Ichimura K, Furukawa M, Hashida S, Tsukuda K, Takigawa N, Matsuo K, Kiura K, Miyoshi S, Matsuda F, Toyooka S：Novel germline mutation in the transmembrane domain of HER2 in familial lung adenocarcinomas. J Natl Cancer Inst (2014) 106, djt338 No potential conflict of interest relevant to this article was reported.

Acta Medica Okayama 1078-0432 19 23 2013 A Genetically Engineered Oncolytic Adenovirus Decoys and Lethally Traps Quiescent Cancer Stem-like Cells in S/G(2)/M Phases 6495 6505 EN Shuya Yano Hiroshi Tazawa Yuuri Hashimoto Yasuhiro Shirakawa Shinji Kuroda Masahiko Nishizaki Hiroyuki Kishimoto Futoshi Uno Takeshi Nagasaka Yasuo Urata Shunsuke Kagawa Robert M. Hoffman Toshiyoshi Fujiwara Purpose: Because chemoradiotherapy selectively targets proliferating cancer cells, quiescent cancer stem-like cells are resistant. Mobilization of the cell cycle in quiescent leukemia stem cells sensitizes them to cell death signals. However, it is unclear that mobilization of the cell cycle can eliminate quiescent cancer stem-like cells in solid cancers. Thus, we explored the use of a genetically-engineered telomerase-specific oncolytic adenovirus, OBP-301, to mobilize the cell cycle and kill quiescent cancer stem-like cells. Experimental Design: We established CD133(+) cancer stem-like cells from human gastric cancer MKN45 and MKN7 cells. We investigated the efficacy of OBP-301 against quiescent cancer stem-like cells. We visualized the treatment dynamics of OBP-301 killing of quiescent cancer stem-like cells in dormant tumor spheres and xenografts using a fluorescent ubiquitination cell-cycle indicator (FUCCI). Results: CD133(+) gastric cancer cells had stemness properties. OBP-301 efficiently killed CD133(+) cancer stem-like cells resistant to chemoradiotherapy. OBP-301 induced cell-cycle mobilization from G(0)-G(1) to S/G(2)/M phases and subsequent cell death in quiescent CD133(+) cancer stem-like cells by mobilizing cell-cycle-related proteins. FUCCI enabled visualization of quiescent CD133(+) cancer stem-like cells and proliferating CD133(-) non-cancer stem-like cells. Three-dimensional visualization of the cell-cycle behavior in tumor spheres showed that CD133(+) cancer stem-like cells maintained stemness by remaining in G(0)-G(1) phase. We showed that OBP-301 mobilized quiescent cancer stem-like cells in tumor spheres and xenografts into S/G(2)/M phases where they lost viability and cancer stem-like cell properties and became chemosensitive. Conclusion: Oncolytic adenoviralinfection is an effective mechanism of cancer cell killing in solid cancer and can be a new therapeutic paradigm to eliminate quiescent cancer stem-like cells. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 68 3 2014 Biallelic Disruption of the PTCH1 Gene in Multiple Basal Cell Carcinomas in Japanese Patients with Nevoid Basal Cell Carcinoma Syndrome 163 170 EN Genshu Tate Koji Kishimoto Toshiyuki Mitsuya Original Article 10.18926/AMO/52657 The aim of the present study is to address whether the molecular pathogenesis is identical among multiple basal cell carcinomas (BCCs) present in the same nevoid basal cell carcinoma syndrome (NBCCS) patient. Patient 1 is a 61-year-old (yo) Japanese female whose clinical characteristics and findings of a genetic analysis of PTCH1 have been previously described. Patient 2 is patient 1ʼs 64-yo sister who also suffered from NBCCS with a single base deletion at nucleotide 2613 in exon 16 (c.2613delC) in one PTCH1 allele. Thirteen and 3 independent specimens of BCC were applied for a molecular analysis of loss of heterozygosity (LOH) in PTCH1 in patients 1 and 2, respectively. Of particular note is that all BCC specimens examined showed a loss of the wild-type allele of exon 16 in PTCH1, thus indicating that LOH results in the biallelic disruption of PTCH1 in multiple BCCs that develop in an age- and location-independent manner in the same patient. These results indicate that the germline single base deletion of PTCH1 (c.2613 delC) is a first hit and the LOH of the wild-type allele is a second hit, implying that all 16 BCCs detected in these NBCCS sisters fit the standard two-hit model. No potential conflict of interest relevant to this article was reported.

Acta Medica Okayama 2014 A Genetically Engineered Oncolytic Adenovirus Decoys and Lethally Traps Quiescent Cancer Stem-like Cells in S/G2/M Phases EN Shuya Yano No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 126 1 2014 重症熱性血小板減少症候群 65 67 EN Tokiko Watanabe Nobuchika Kusano Keiji Iwatsuki No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 126 1 2014 てんかん治療ガイドラインについて 55 58 EN Nobutoshi Morimoto Koji Abe No potential conflict of interest relevant to this article was reported.

Endocrine Soc Acta Medica Okayama 0021-972X 97 7 2012 Serum Vaspin Concentrations Are Closely Related to Insulin Resistance, and rs77060950 at SERPINA12 Genetically Defines Distinct Group with Higher Serum Levels in Japanese Population E1202 E1207 EN Sanae Teshigawara Jun Wada Kazuyuki Hida Atsuko Nakatsuka Jun Eguchi Kazutoshi Murakami Motoko Kanzaki Kentaro Inoue Takahiro Terami Akihiro Katayama Izumi Iseda Yuichi Matsushita Nobuyuki Miyatake John F. McDonald Kikuko Hotta Hirofumi Makino Context: Vaspin is an adipokine with insulin-sensitizing effects identified from visceral adipose tissues of genetically obese rats. Objective: We investigated genetic and nongenetic factors that define serum concentrations of vaspin. Design, Setting and Participants: Vaspin levels were measured with RIA in Japanese subjects with normal fasting plasma glucose (NFG; n = 259) and type 2 diabetes patients (T2D; n = 275). Single nucleotide polymorphisms (SNP) at SERPINA12 (vaspin) gene locus were discovered, and five SNP were genotyped in the subjects with varied body mass index (n = 1138). Results: The level of serum vaspin in 93% of the samples was found to vary from 0.2 to nearly 2 ng/ml in NFG subjects (n = 259) and from 0.2 to nearly 3 ng/ml in T2D patients (n = 275) (Vaspin(Low) group), whereas a significant subpopulation (7%) in both groups displayed much higher levels of 10-40 ng/ml (Vaspin(High) group). In the Vaspin(Low) group, serum vaspin levels in T2D were significantly higher than healthy subjects (0.99 +/- 0.04 vs. 0.86 +/- 0.02 ng/ml; P < 0.01). Both in T2D and genotyped Japanese population, serum vaspin levels closely correlated with homeostasis model of assessment for insulin resistance rather than anthropometric parameters. By genotyping, rs77060950 tightly linked to serum vaspin levels, i.e. CC (0.6 +/- 0.4 ng/ml), CA (18.4 +/- 9.6 ng/ml), and AA (30.5 +/- 5.1 ng/ml) (P < 2 x 10(-16)). Putative GATA-2 and GATA-3 binding consensus site was found at rs77060950. Conclusions: Serum vaspin levels were related to insulin resistance, and higher levels of serum vaspin in 7% of the Japanese population are closely linked to minor allele sequence (A) of rs77060950. (J Clin Endocrinol Metab 97: E1202-E1207, 2012) No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 125 1 2013 内陸地津山で発症した季節外れのVibrio vulnificus感染症 35 39 EN Hideharu Hagiya Sumiko Shiota Shin-ichi Miyoshi Yasutoshi Kuroe Hiroyoshi Nojima Shinkichi Otani Junichi Sugiyama Hiromichi Naito Susumu Kawanishi Shingo Hagioka Naoki Morimoto 　A 68-year-old man with alcohol addiction, who lived in the suburbs of Tsuyama, an inland city located in northeast Okayama prefecture, was transported to the emergency unit of the Tsuyama Central Hospital in a state of cardiopulmonary arrest (CPA). Despite rigorous systemic investigation and treatment, the patient died 2 hours after arrival. After his death, Vibrio vulnificus was isolated from his blood culture. 　Vibrio vulnificus causes fatal infection in humans, usually only in areas located close to the sea where appropriate temperature and suitable salt concentration for its growth are available. Therefore, its occurrence is epidemiologically restricted ; in Japan, the western coastal areas, especially in summers, are reported to be the high-risk regions. This is a rare case because it occurred in a city approximately 50 kilometers from both the Sea of Japan and the Pacific coast of Okayama, and at the end of October in 2011. Economic development and distribution systems have made it possible to transport various food products from coastal areas or abroad to any place in a short time, such that these infections can potentially develop in areas other than expected. We should be aware of the increasing risk of Vibrio vulnificus infection during any season and at any place, especially in patients with abnormal liver function. No potential conflict of interest relevant to this article was reported.

Acta Medica Okayama 2012 Serum Vaspin Concentrations Are Closely Related to Insulin Resistance, and rs77060950 at SERPINA12 Genetically Defines Distinct Group with Higher Serum Levels in Japanese Population EN Sanae Teshigawara No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 66 5 2012 Dravet Syndrome : A Genetic Epileptic Disorder 369 376 EN Mari Akiyama Katsuhiro Kobayashi Yoko Ohtsuka Review 10.18926/AMO/48961 Dravet syndrome (DS), or severe myoclonic epilepsy in infancy, is one of the most severe types of genetic epilepsy. It is characterized by the initial occurrence of febrile or afebrile seizures that often evolve into status epilepticus in infants with normal development, and by the subsequent appearance of myoclonic and/or atypical absence seizures as well as complex partial seizures. The key feature that characterizes DS is fever sensitivity, although photosensitivity and pattern-sensitivity are also often seen. The prognosis is unfavorable in most cases. Seizures become drug-resistant and persist, with many patients suffering from motor and cognitive impairment. Mutations of SCN1A, which encodes the voltage-gated sodium channel NaV1.1, are the most frequent genetic cause of this syndrome. SCN1A mutations and/or microchromosomal rearrangements involving SCN1A are detected in about 85% of patients. Mutations of PCDH19 have also been reported in female patients with clinical findings compatible with DS. PCDH19 mutations might account for 5% of overall DS cases. Thirty years after its first description, DS is considered as a model of channelopathy. This survey reviews recent developments in the research literature on DS, focusing on the clinical course, as well as its genetic causes. No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 124 2 2012 ボツリヌスＡ型菌変異株が産生するHA複合体の構造に関する研究 137 143 EN Shaobo Ma Clostridium botulinum produces seven neurotoxin (NTX) serotypes, classified from as A to G. In culture, NTX forms protein complexes by association with non-toxic components, such as nontoxic-nonhemagglutinin (NTNH) and hemagglutinins (HA1, HA2, HA3). C. botulinum serotype A produces three types of toxin complexes, M-toxin (NTX and NTNH), L-toxin (M-toxin and HAs) and LL-toxin (dimer of L-toxin). In this study, I found three HA complexes in the culture of a nontoxigenic mutant serotype A lacking ntx and ntnh expression. The HA complexes displayed similar banding patterns on SDS-PAGE, but the staining intensities of the HA1 and HA2 bands were different. In addition, their native-PAGE banding profiles exhibited different behaviors. The large-molecular-size HA complex showed the highest activity, similar to that of an L-toxin. Based on the combined results of the PAGE and gel-filtration profiles, the differences in molecular size among the three HA complexes were thought to be caused by different numbers of HA1 and HA2 molecules. This paper reports for the first time the purification and characterization of a native HA complex of serotype A, and suggests that the HA can form complex structures without NTX and NTNH. This may help in understanding the toxin complex assembly pathway. No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 124 2 2012 Scn1a遺伝子変異ラットを用いた抗てんかん薬の熱性けいれん抑制効果 115 117 EN Keiichiro Hayashi Iori Ohmori Hideki Matsui No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 66 2 2012 Different Responses to 5-fluoraouracil in Mutagenicity and Gene Expression between Two Human Lymphoblastoid Cell Lines with or without TP53 Mutation 119 129 EN Hiroaki Oka Mamoru Ouchida Takuya Kondo Fumio Morita Kenji Shimizu Original Article 10.18926/AMO/48262 Human lymphoblastoid TK6 and WTK-1 cells are widely used to detect mutagens in vitro. TK6 cells have wild-type TP53 alleles, while WTK-1 cells have one allele of mutated TP53. Both cells were treated with 5-fluorouracil (5-FU), and gene mutation assay and micronucleus assay were performed to clarify the differential response related to the TP53 gene status. The effects of 5-FU on gene expression were assessed by microarray and quantitative RT-PCR analyses. In WTK-1 cells, 5-FU increased the frequency of cells with micronucleus and mutation. In TK6 cells, frequency of cells with micronucleus was increased but the mutation frequency was not. The cytotoxicity induced by 5-FU was more prominent in TK6 cells than in WTK-1 cells. Analysis of gene expression showed that the genes involved in the TP53 pathway were up-regulated in TK6 cells but not in WTK-1 cells. The differential responses to 5-FU between these cell lines appeared to be due to the difference in the TP53 gene status, thus providing a molecular basis for the bioassays using these cell lines in the toxicology field. Our results indicate that the clinical efficacy of 5-FU chemotherapy may depend on the TP53 genotype. No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 124 1 2012 骨形成不全症の治療 67 70 EN Hiroyuki Tanaka No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 123 3 2011 軟部腫瘍診療ガイドライン 231 235 EN Yuki Morimoto Toshifumi Ozaki No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 65 5 2011 Single Nucleotide Polymorphism WRN Leu1074Phe Is Associated with Prostate Cancer Susceptibility in Chinese Subjects 315 323 EN Lei Wang Haruki Kaku Peng Huang Kexin Xu Kai Yang Jiheng Zhang Ming Li Liping Xie Xiaofeng Wang Akiko Sakai Masami Watanabe Yasutomo Nasu Kenji Shimizu Hiromi Kumon Yanqun Na Original Article 10.18926/AMO/47013 Deficiencies in the human DNA repair gene WRN are the cause of Werner syndrome, a rare autosomal recessive disorder characterized by premature aging and a predisposition to cancer. This study evaluated the association of WRN Leu1074Phe (rs1801195), a common missense single nucleotide polymorphism in WRN, with prostate cancer susceptibility in Chinese subjects. One hundred and forty-seven prostate cancer patients and 111 male cancer-free control subjects from 3 university hospitals in China were included. Blood samples were obtained from each subject, and the single nucleotide polymorphism WRN Leu1074Phe was genotyped by using a Snapshot assay. The results showed that WRN Leu1074Phe was associated with the risk of prostate cancer in Chinese men and that the TG/GG genotype displayed a decreased prevalence of prostate cancer compared with the TT genotype (OR＝0.58, 95%CI:0.35-0.97, p＝0.039). Through stratified analysis, more significant associations were revealed for the TG/GG genotype in the subgroup with diagnosis age <_ 72 yr (OR＝0.27, 95%CI:0.12-0.61, p＝0.002) and in patients with localized diseases (OR＝0.36, 95%CI:0.19-0.70, p＝0.003). However, no statistically significant difference was found in the subgroup with age ＞72 yr or in patients with advanced diseases. We concluded that the genetic variant Leu1074Phe in the DNA repair gene WRN might play a role in the risk of prostate cancer in Chinese subjects. No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 123 2 2011 成人期に達したDravet症候群の長期経過に関する研究 91 95 EN Mari Akiyama Katsuhiro Kobayashi Harumi Yoshinaga Yoko Ohtsuka No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 69 1 1957 結核菌のストレプトマイシン耐性に関する研究第2編ストレプトマイシン耐性結核菌の耐性持続性並びに緩解に就いて 37 91 EN Tatsuo Nozaki In 1887, Kossiakoff first described the phenomenon of drug-resistance of bacteria. Recently with the wide-spread use of streptomycin and other various antibiotics in the field of therapeutics, this phenomenon of drug-resistance has become very important in clinical medicine. As to streptomycin alone, which was discovered in 1944 by Waksmann and brought the epoch-making progress to the therapy ef tuberculosis, the acquisition of resistance is one of the problems which need great precautions at the execution of streptomycin-therapy. Since 1946 when Luria and Delbrück first reported about the mechanism of acquisition of resistance to sulfonamide, the mechanism of acquisition of resistance to streptomycin and other antibiotics and that of reversion from it have been hotly argued. No decidedly substantiating results, however, have yet been obtained, though two confronting theories, spotaneous mutation theory and adaptation theory, are now advocated. The former is the theory which asserts that the acquisition of resistance is originated in their spontaneous mutation happening during the process of proliferation and in the selective action of drugs; this theory has nowadays many sustaining scholars. In the latter theory, the direct action of drugs to the rise of resistance is considered as the mehanism of the acquisition of resistance. Now that this phenomenon of drug-resistance is demonstrated to be the genetic variation with heredity and its mode of transmission is also clarified by Lederberg and Newcombe, it is difficult to explain the mechanism of acquisition of resistance according to the adaptation theory only. In the adaptation theory, however, refering to the idea of “Dauermodifikation” described on paramecium by Jollos in 1921, they have become to consider that antibiotics have the mutagenicity which seems to be the direct cause of the acquisition of drug-resistance. Since 1952, the author has carried out many experiments to study the essential features of streptomycin-resistant tubercle bacilli in vitro and in vivo, according to the "theory of spontaneous mutation with selection" which is supported by many researchers. The results are as follows: 1) Wolinsky reported that mutants over 0.1% of the original streptomycin-sensitive tubercle bacilli were observed on the culture media containig 1000γ/cc of streptomycin. In the present reports, the author studied the development of resistance by succesive cultures of the strains newly isolated from the tnberculosis patients who had received no or little streptomycin-therapy, and observed the spontaneous mutants over 0.1% of 0.1 mg and 1 mg of the inoculated bacilli. 2) Akiba et al. reported that, besides the spontaneous mutation, streptomycin itself had some effect on the mutation of gene. In the present work, many facts were observed which were hardly explained by “spontaneous mutation with selection” only. For example, the author also isolated one strain which seemed to be caused by such cause as that Akiba et al. reported. 3) There are many reports that the resistance of streptomycin-resistant tubercle bacilli is stable and long-lasting. The author performed many experiments in vitro and in vivo to study the development of the resistance of highly resistant strain over 1000γ/cc, of middle grade-resistant one over 100γ/cc and of low grade-resistant one under 10γ/cc. As a result of these experiments, the falling tendency of resistance was clearly observed in not only low and middle grade-resistant but also in highly resistant strains. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 64 4 2010 Common Acute Lymphoblastic Leukemia Ph＋ Following Langerhans Cell Histiocytosis in a Multi-Malformed Child with INV (9) (p12;q13) (mat):Case Report 263 265 EN Jasminka Pavelić Srdjana Čulić Vida Čulić Case Report 10.18926/AMO/40135 The occurrence of Langerhans cell histiocytosis (LCH) and another malignancy in the same patient is infrequent but has been recognized. The genetic changes that could be responsible for LCH and/or concomitant leukemia development are obscure. To the best of our knowledge, this is the first description of constitutional maternally derived inv (9) (p12;q13) in an LCH patient, and also of the development of common ALL Ph after LCH diagnosis and therapy. The potential significance of these findings [inv (9)LCHALL Ph] and their mutual relationship are unknown. Therefore, cooperative studies of large numbers of patients are needed to identify the common risk factors, if any. No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 122 2 2010 精神腫瘍学概論 119 124 EN Yosuke Uchitomi No potential conflict of interest relevant to this article was reported.

Wiley-Liss, Inc. Acta Medica Okayama 1552-4841 135B 1 2005 A functional glutathione S-transferase P1 gene polymorphism is associated with methamphetamine-induced psychosis in Japanese population 5 9 EN Tasuku Hashimoto Kenji Hashimoto Daisuke Matsuzaka Eiji Shimizu Yoshimoto Sekine Inada Yoshiya Nakao Iwata Mutsuo Harano Tokutaro Komiyama Mitsuhiko Yamada Ichiro Sora Hiroshi Ujike Masaomi Iyo Several lines of evidence suggest that oxidative stress plays a role in the mechanisms of action of methamphetamine (MAP) in the human brain. Given the role of glutathione S-transferases (GSTs) in the protection against oxidative stress, genes encoding the GSTs have been considered as candidates for association studies of MAP abuse. This study was undertaken to investigate the role of the functional polymorphism of GSTP1 gene exon 5 (Ile105Val) in the pathogenesis of MAP abuse. Genotyping for GSTP1 gene polymorphism exon 5 (Ile105Val) in 189 MAP abusers and 199 normal controls was performed by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP). Association between GSTP1 gene polymorphism and clinical features (prognosis of psychosis (transient-type and prolonged-type), spontaneous relapse (positive and negative), and poly-substance abuse) of MAP abusers was evaluated. Significant differences in the frequency of both alleles (P = 0.026, odds ratio: 1.70, 95% confidence intervals (CI) 1.06-2.72) and genotypes (P = 0.029) between MAP abusers and controls were detected. In particular, a significant difference in both genotype frequency (P = 0.013) and allele frequency (P = 0.014, odds ratio: 1.84, 95% CI 1.13-2.97) between MAP abusers with psychosis (transient-type and prolonged-type) and controls was detected. Our findings suggest that the polymorphism (Ile 105Val) on exon 5 of the GSTP1 gene may contribute to a vulnerability to psychosis associated with MAP abuse in Japanese population. No potential conflict of interest relevant to this article was reported.

Wiley-Liss, Inc. Acta Medica Okayama 1552-4841 132B 1 2005 Association study between brain-derived neurotrophic factor gene polymorphisms and methamphetamine abusers in Japan 70 73 EN Kanako Itoh Kenji Hashimoto Eiji Shimizu Yoshimoto Sekine Norio Ozaki Toshiya Inada Mutsuo Harano Nakao Iwata Tokutaro Komiyama Mitsuhiko Yamada Ichiro Sora Kenji Nakata Hiroshi Ujike Masaomi Iyo Several lines of evidence suggest that genetic factors might contribute to drug abuse vulnerability. Recent genomic scans for association demonstrated that the brain-derived neurotrophic factor (BDNF) gene was associated with drug abuse vulnerability. In this study, we analyzed association of two BDNF gene single nucleotide polymorphisms (SNPs), 132C>T (C270T named formerly) in the noncoding region of exon V and 196G >A (val66met) in the coding region of exon XIIIA, with methamphetamine (MAP) abuse in Japan. No significant differences were found in the frequency of the genotype or allele in these two SNPs between MAP abusers and controls (132C>T in exon V: genotype, p = 0.586, allele, p = 0.594; 196G>A (val66met) in exon XIIIA: genotype, p = 0.889, allele, p = 0.713). Furthermore, there was no difference between clinical parameters (e.g. prognosis psychosis, spontaneous relapse, or poly-substance abuse) and the two SNPs of BDNF gene. These results suggest that the two SNPs (132C>T in exon V and 196G>A (val66met) in exon XIIIA) of the BDNF gene may not be associated with Japanese MAP abusers. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 46 6 1992 Detection of oncogene rearrangements in human non-Hodgkin's lymphomas. 407 415 EN Eisaku Kondo Tadashi Yoshino Tadaatsu Akagi Kazuhiko Hayashi Kiyoshi Takahashi Article 10.18926/AMO/32636 Southern blot hybridization was used to detect the rearrangement and amplification of five proto-oncogenes (bcl-2, bcl-1, c-myc, c-myb and c-Ha-ras) and one tumor suppressor gene (RB-1) in 55 Japanese patients with non-Hodgkin's lymphoma; 16 with T-cell lymphomas and 39 with B-cell lymphomas (7 follicular and 32 diffuse lymphomas). Genetic abnormalities of the proto-oncogenes were detected in 7 of the 55 (13%). Genetic abnormalities of bcl-2 plus other genes were detected in 5 of 7 cases of follicular lymphoma (71%), rearrangements of bcl-2 and c-myc, rearrangement of bcl-2 and amplification of c-myb. Genetic abnormalities were observed in only three cases of diffuse lymphoma. In each of 3 cases of B-cell lymphoma, one of the genes, blc-2 mbr, bcl-2 mcr and c-myc, was rearranged respectively. The incidence of genetic abnormalities in diffuse lymphomas (6.3%) was lower than that in follicular lymphomas. None of diffuse lymphomas had double oncogene abnormality. No abnormalities were found in RB-1, bcl-1, and Ha-ras. These findings suggest that follicular lymphomas are associated with some abnormalities of oncogenes not restricted to bcl-2 that facilitate growth which may be associated with their clinical features. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 46 4 1992 Anti-C100-3 antibody status, viral genomic sequences, and clinical features in chronic hepatitic patients with hepatitis C virus RNA in sera. 285 293 EN Kazuhiko Morii Hiroyuki Shimomura Hiroshi Nakagawa Toshimi Hasui Takao Tsuji Article 10.18926/AMO/32629 Since detection of hepatitis C virus RNA by the polymerase chain reaction (PCR) showed that there existed anti-C100-3 (anti-HCV) antibody negative patients infected with HCV, we attempted to find out whether there were any clinical or viral genomic differences between the anti-HCV antibody positive and negative groups. One hundred and fifty-nine patients with chronic liver diseases with hepatitis C virus RNA in their sera were selected. Anti-HCV antibody was tested for anti-C100-3 antibody by an enzyme linked immunosorbent assay. The incidence of anti-HCV antibody was 129/159. The concentration of serum gamma-globulin, the titier of ZTT, and the positive rate of the PCR with the primers of the NS3/4 region (NS3/4PCR) were significantly higher in the anti-HCV antibody positive group than in the negative group. However, the other data such as alanine aminotransferase activity or past history were not significantly different. Nucleotide sequence of the cDNA fragments of NS3/4 region amplified by the PCR did not differ significantly between isolates from anti-HCV antibody positive and negative sera. The sequences observed in the present study did not differ significantly from those reported previously. Although there remains the possibility that the variation of viral genomic sequences may cause the absence of anti-HCV antibody, these results suggested that the individual clinical backgrounds or immunoreactivity of the patients might influence the antibody development. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 45 4 1991 Genetic variation of putative core gene in hepatitis C virus. 241 248 EN Kozo Fujio Hiroyuki Shimomura Takao Tsuji Article 10.18926/AMO/32163 Genetic variation of hepatitis C virus was assessed. We prepared RNA fractions from 21 patients' sera which were positive for hepatitis C virus RNA, synthesized their cDNAs, and amplified fragments, 406 base pairs, encoding a putative core protein, by polymerase chain reaction. One of them, N 15, was cloned and sequenced. N 15 showed 92.4% homology at the nucleotide level and 97.0% homology at the amino acid level compared with HC-J 1 which is the first isolated clone in Japan and similar to that isolated in USA. By restriction fragment length polymorphisms analysis, 14 out of 21 patients (66.7%) showed the same pattern as N 15. No patients showed the pattern of HC-J 1. We could not find a correlation between the genetic variation and clinical features of hepatitis C virus infection. These results indicate that the region, which encodes the core protein and is believed to be relatively conserved in hepatitis C virus genome, has several variations at the nucleotide level, and the major part of hepatitis C virus in Okayama district is different from HC-J 1 and the USA clone. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 58 2 2004 Sneddon's syndrome: clinical and laboratory analysis of 10 cases. 59 65 EN Ertugrul Bolayir Abdulkerim Yilmaz Nesim Kugu Haydar Erdogan Melih Akyol Aytekin Akyuz Article 10.18926/AMO/32100 Sneddon's syndrome is characterized by livedo reticularis and cerebrovascular lesions. We report the cases of women (mean age, 36.2 +/- 8.1 years) diagnosed with Sneddon's syndrome based on the presence of livedo reticularis and characteristic cerebrovascular findings. Seven of these patients had cerebral infarcts on cranial computed tomography scan. Antiphospholipid antibodies were positive in 6 of these cases. Three cases had abnormal levels of antithrombin III. Analyses of chromosome 6 revealed no abnormalities. In 3 of the cases, investigation of the pedigrees revealed autosomal dominant traits. Two cases had epilepsy, and 3 had migraine. One case with migraine also had myasthenia gravis. In addition, we detected inferior altudinal hemianopia in 2 cases, cognitive functional disorder in 3 and depression in 2. Based on these findings, the entire vascular, haematologic, neurologic, and dermatologic systems should be evaluated in patients diagnosed with Sneddon's syndrome. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 58 6 2004 Brugada syndrome: 12 years of progression. 255 261 EN Kui Hong Charles Antzelevitch Pedro Brugada Josep Brugada Tohru Ohe Ramon Brugada Article 10.18926/AMO/32094 Brugada syndrome is increasingly being recognized in clinical medicine. What started as an electrocardiographic curiosity has become an important focus of attention for individuals working in the different disciplines related to sudden cardiac death, from basic scientists to clinical cardiac electrophysiologists. In just 12 years, since the description of the disease, clinically relevant information is continuously being provided to physicians to help protect the individuals with Brugada syndrome to the best of our ability. And this information has been gathered thanks to the effort of hundreds of basic scientists, physicians and patients who continue to give their time, effort and data to help understand how the electrocardiographic pattern may cause sudden cardiac death. There are still many unanswered questions, both at the clinical and basic field. However, with the further collection of data, the longer follow-up and the continued interest from the basic science world we will have the necessary tools to the successful unraveling of the disease. No potential conflict of interest relevant to this article was reported.