Faculty Profiles - TSUKAHARA Hirokazu

Papers - TSUKAHARA Hirokazu

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Trajectory of body mass index and height changes from childhood to adolescence: a nationwide birth cohort in Japan. Reviewed International journal

Naomi Matsumoto, Toshihide Kubo, Kazue Nakamura, Toshiharu Mitsuhashi, Akihito Takeuchi, Hirokazu Tsukahara, Takashi Yorifuji

Scientific reports 11 ( 1 ) 23004 - 23004 2021.11

Language：English Publishing type：Research paper (scientific journal)

To investigate the dynamics of body mass index (BMI) and height changes in childhood leading to obesity in adolescents. BMI Z-scores were calculated using the LMS (lambda-mu-sigma) method based on yearly height and weight information (age 1.5-15 years) from a nationwide Japanese birth cohort that started in 2001 (n = 26,711). We delineated the trajectories of BMI and height changes leading to obesity at age 15 years using mixed effect models. Children who became obese at the age of 15 years kept relatively high BMI z-scores through childhood for both genders, and had an increasing trend over time as opposed to the normal weight group, with an increasing slope during puberty. Early adiposity rebound was associated with overweight or obesity at the age of 15 years. Age at peak height velocity (APHV) occurred earlier in the obese/overweight group at age 15 years than in the normal weight group, and occurred later in the underweight group. Obese adolescents experienced early adiposity rebound timing and maintained a serial BMI z-score increase throughout childhood, with a greater slope at puberty. An earlier peak in height gain during puberty may have contributed to the observed patterns of BMI change.

DOI： 10.1038/s41598-021-02464-z

Current Insights into Atopic March. Reviewed International journal

Mitsuru Tsuge, Masanori Ikeda, Naomi Matsumoto, Takashi Yorifuji, Hirokazu Tsukahara

Children (Basel, Switzerland) 8 ( 11 ) 2021.11

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

The incidence of allergic diseases is increasing, and research on their epidemiology, pathophysiology, and the prevention of onset is urgently needed. The onset of allergic disease begins in infancy with atopic dermatitis and food allergy and develops into allergic asthma and allergic rhinitis in childhood; the process is defined as "atopic march". Atopic march is caused by multiple immunological pathways, including allergen exposure, environmental pollutants, skin barrier dysfunction, type 2 inflammation, and oxidative stress, which promote the progression of atopic march. Using recent evidence, herein, we explain the involvement of allergic inflammatory conditions and oxidative stress in the process of atopic march, its epidemiology, and methods for prevention of onset.

DOI： 10.3390/children8111067

Head circumference in infants with nonopiate-induced neonatal abstinence syndrome. Reviewed International journal

Daisaku Morimoto, Yosuke Washio, Kazuki Hatayama, Tomoka Okamura, Hirokazu Watanabe, Junko Yoshimoto, Hirokazu Tsukahara

CNS spectrums 26 ( 5 ) 509 - 512 2021.10

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: No relationship has been reported between nonopiate neonatal abstinence syndrome (NAS) and anthropometric indices, including head circumference (HC). The purpose of this study was to determine the relationship between maternal nonopioid drug use and HC at birth in neonates with NAS. METHODS: This retrospective observational study included neonates born between January 1, 2010 and March 31, 2019, whose mothers had been taking antipsychotic, antidepressant, sedative, or anticonvulsant medications. The outcome measures were HCs of NAS infants and controls. RESULTS: Of 159 infants, 33 (21%) were diagnosed with NAS. There was no maternal opioid use among mothers during pregnancy. The HCs in the NAS group were significantly smaller than those in the control group. The median z-scores for HC at birth were -0.20 and 0.29 in the NAS group and the control group, respectively (P = .011). The median HCs at birth were 33.0 and 33.5 cm in the NAS group and the control group, respectively. Multivariate analysis revealed that maternal antipsychotic drug use and selective serotonin reuptake inhibitors were independently associated with NAS (P < .001 and P = .004, respectively). Notably, benzodiazepine use and smoking were not independent risk factors. CONCLUSIONS: The results suggest an association between maternal antipsychotic drug use and NAS, which was further associated with decreased HC. Careful monitoring of maternal drug use should be considered to improve fetal outcomes.

DOI： 10.1017/S1092852920001522

Reactive Oxygen Species and Antioxidative Defense in Chronic Obstructive Pulmonary Disease. Reviewed International journal

Akihiko Taniguchi, Mitsuru Tsuge, Nobuaki Miyahara, Hirokazu Tsukahara

Antioxidants (Basel, Switzerland) 10 ( 10 ) 2021.9

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

The respiratory system is continuously exposed to endogenous and exogenous oxidants. Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation of the airways, leading to the destruction of lung parenchyma (emphysema) and declining pulmonary function. It is increasingly obvious that reactive oxygen species (ROS) and reactive nitrogen species (RNS) contribute to the progression and amplification of the inflammatory responses related to this disease. First, we described the association between cigarette smoking, the most representative exogenous oxidant, and COPD and then presented the multiple pathophysiological aspects of ROS and antioxidative defense systems in the development and progression of COPD. Second, the relationship between nitric oxide system (endothelial) dysfunction and oxidative stress has been discussed. Third, we have provided data on the use of these biomarkers in the pathogenetic mechanisms involved in COPD and its progression and presented an overview of oxidative stress biomarkers having clinical applications in respiratory medicine, including those in exhaled breath, as per recent observations. Finally, we explained the findings of recent clinical and experimental studies evaluating the efficacy of antioxidative interventions for COPD. Future breakthroughs in antioxidative therapy may provide a promising therapeutic strategy for the prevention and treatment of COPD.

DOI： 10.3390/antiox10101537

Anaphylaxis after jellyfish ingestion with no history of stings: a pediatric case report. Reviewed International journal

Mitsuru Tsuge, Masanori Ikeda, Osamu Mitani, Masato Yasui, Hirokazu Tsukahara

Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology 17 ( 1 ) 99 - 99 2021.9

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Jellyfish stings are known to induce allergic skin reactions; however, case reports of anaphylaxis after jellyfish ingestion have been increasing, especially in Asian countries. Some cases of anaphylaxis after jellyfish ingestion have been reported in patients with a previous history of frequent jellyfish stings. Herein, we report a pediatric patient with anaphylaxis after jellyfish ingestion with no history of jellyfish stings. CASE PRESENTATION: A 14-year-old girl developed two episodes of anaphylaxis, and her diet diaries revealed that edible jellyfish was common to the meals in both the anaphylaxis events. A skin prick test using five types of edible jellyfish products revealed a positive reaction to some jellyfish, and anaphylaxis was observed after the ingestion of jellyfish in an oral food challenge test. She had no history of jellyfish stings or frequent swimming in the ocean. The basophil activation test showed positive results on stimulation with extracts from various types of edible jellyfish. We observed serum immunoglobulin E (IgE) reactivity to purified jellyfish collagen and jellyfish acid-soluble extracts. Moreover, immunoblotting analysis showed IgE reactivity to two bands at approximately 40 and 70 kDa using purified jellyfish collagen, which may be a causative antigen. CONCLUSIONS: Edible salted jellyfish can be one of the causative foods of anaphylaxis. Clinicians should be aware of the possibility of anaphylactic reactions due to jellyfish ingestion even without a history of jellyfish stings.

DOI： 10.1186/s13223-021-00601-x

Association between Dental Caries and Influenza Infection in Children: A Japanese Nationwide Population-Based Study. Reviewed International journal

Naomi Matsumoto, Tomoka Kadowaki, Hirokazu Tsukahara, Takashi Yorifuji

Children (Basel, Switzerland) 8 ( 9 ) 2021.9

Language：English Publishing type：Research paper (scientific journal)

Dental caries is the most common chronic childhood disease. Recent studies have suggested that dental caries harbor respiratory infections in adults. We investigated the association between dental caries and influenza in children. In this study, 42,812 children aged 2.5 years, 38,540 children aged 5.5 years, and 34,124 children aged 10 years were included in the analysis from the Longitudinal Survey of Newborns in the 21st Century in Japan, which targeted all children born during a certain period in 2001. We used information on dental caries treated at hospitals and clinics in the past year as exposure and influenza as outcome during the observation periods (1.5-2.5, 4.5-5.5, and 9-10 years of age). We performed a log-binomial regression analysis, adjusting for potential confounders, and stratified analysis according to previous dental caries status. The presence of dental caries increased the incidence of influenza in all three target ages compared with the absence of dental caries. The incidence of influenza increased with the presence of current dental caries, regardless of the presence of past dental caries. These associations were observed irrespective of household income. Early detection and treatment of dental caries may reduce the risk of influenza in children.

DOI： 10.3390/children8090780

医学部学生に対する予防接種記録判定方法の現状と問題点

茂原研司, 八代将登, 宇田和宏, 塚原宏一

日本環境感染学会総会プログラム・抄録集 36回 253 - 253 2021.9

医学部学生に対する予防接種記録の判定方法に関する検討

八代将登, 茂原研司, 宇田和宏, 塚原宏一

日本環境感染学会総会プログラム・抄録集 36回 253 - 253 2021.9

岡山大学病院における抗菌薬適正使用支援チーム(AST)の取り組みと評価

東恩納司, 森下陽介, 稲葉裕明, 草野展周, 塚原宏一

日本環境感染学会総会プログラム・抄録集 36回 245 - 245 2021.9

Association Between Eosinophilia and Late-onset Circulatory Collapse in Preterm Infants: A case-Control Study. Reviewed

Tomoka Okamura, Yosuke Washio, Hirokazu Watanabe, Hidehiko Nakanishi, Atsushi Uchiyama, Hirokazu Tsukahara, Satoshi Kusuda

Acta medica Okayama 75 ( 4 ) 505 - 509 2021.8

Language：English Publishing type：Research paper (scientific journal)

Late-onset circulatory collapse (LCC) in preterm infants is presumably caused by relative adrenal insufficiency. Because eosinophilia is known to be associated with adrenal insufficiency, we attempted to clarify the relation-ship between eosinophilia and LCC in preterm infants. We divided the cases of the infants (born at < 28 weeks' gestation) admitted to our neonatal intensive care unit in 2008-2010 into 2 groups: those diagnosed with LCC that received glucocorticoids (LCC group), and those who did not receive glucocorticoids (control group). We compared eosinophil counts between the 2 groups and between before and after glucocorticoid treatment in the LCC group. A total of 28 infants were examined: LCC group (n = 12); control group (n = 16). The peak eosin-ophil counts of the LCC group were significantly higher than those of the control group (median: 1.392 × 109/L vs. 1.033 × 109/L, respectively; p = 0.02). Additionally, in the LCC group, the eosinophil counts declined significantly after glucocorticoid treatment (0.877 × 109/L vs. 0.271 × 109/L, p = 0.003). Eosinophil counts in the LCC group were significantly higher than in the control group and decreased rapidly after gluco-corticoid treatment. These results indicate that eosinophilia may be a factor associated with LCC caused by adrenal insufficiency.

DOI： 10.18926/AMO/62403

食物アレルゲン経口負荷試験で診断に至った食用クラゲアレルギーの1小児例

津下充, 茂原研司, 斎藤有希恵, 八代将登, 池田政憲, 塚原宏一

アレルギー 70 ( 6-7 ) 788 - 788 2021.8

研究者の最新動向インフルエンザ脳症における自然免疫を標的とした新規治療の探索

津下充, 西堀正洋, 森島恒雄, 塚原宏一

Precision Medicine 4 ( 6 ) 596 - 599 2021.6

Language：Japanese Publisher：(株)北隆館

インフルエンザ脳症はインフルエンザ感染を契機にけいれんや意識障害を伴う。その病態は高サイトカイン血症による血液脳関門の障害が起きることで結果的に脳浮腫に至る。インフルエンザ脳症児の血液では特に「自然免疫」に関連した反応が強く起き、自然免疫メディエーターであるHigh Mobility Group Box-1(HMGB-1)は、インフルエンザ脳症児の血液中で高値を示す。岡山大学小児科では、インフルエンザ脳症における宿主の過剰な自然免疫反応を制御し、脳障害を軽減する次世代の炎症抑制療法の一つとして、HMGB-1をターゲットとした抗体治療の研究開発に取り組んでいる。(著者抄録)

Genetic analysis in Japanese patients with osteogenesis imperfecta: Genotype and phenotype spectra in 96 probands. Reviewed International journal

Yousuke Higuchi, Kosei Hasegawa, Natsuko Futagawa, Miho Yamashita, Hiroyuki Tanaka, Hirokazu Tsukahara

Molecular genetics & genomic medicine 9 ( 6 ) e1675 2021.6

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Osteogenesis imperfecta (OI) is a rare connective-tissue disorder characterized by bone fragility. Approximately 90% of all OI cases are caused by variants in COL1A1 or COL1A2. Additionally, IFITM5 variants are responsible for the unique OI type 5. We previously analyzed COL1A1/2 variants in 22 Japanese families with OI through denaturing high-performance liquid chromatography screening, but our detection rate was low (41%). METHODS: To expand the genotype-phenotype correlations, we performed a genetic analysis of COL1A1/2 and IFITM5 in 96 non-consanguineous Japanese OI probands by Sanger sequencing. RESULTS: Of these individuals, 54, 41, and 1 had type 1 (mild), type 2-4 (moderate-to-severe), and type 5 phenotypes, respectively. In the mild group, COL1A1 nonsense and splice-site variants were prevalent (n = 30 and 20, respectively), but there were also COL1A1 and COL1A2 triple-helical glycine substitutions (n = 2 and 1, respectively). In the moderate-to-severe group, although COL1A1 and COL1A2 glycine substitutions were common (n = 14 and 18, respectively), other variants were also detected. The single case of type 5 had the characteristic c.-14C>T variant in IFITM5. CONCLUSION: These results increase our previous detection rate for COL1A1/2 variants to 99% and provide insight into the genotype-phenotype correlations in OI.

DOI： 10.1002/mgg3.1675

COVID-19 in Okayama Prefecture: Looking back and looking forward. Reviewed

Hirokazu Tsukahara, Tsukasa Higashionna, Mitsuru Tsuge, Junko Miyamura, Nobuchika Kusano

Global health & medicine 3 ( 2 ) 102 - 106 2021.4

Authorship：Lead author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

In Japan, clinical and experimental studies addressing COVID-19 have been increasing in number since early February 2020, with many case reports being published. Concurrently, many notifications and guidelines have been issued from the government and academic societies. Taking optimal measures at the prefectural level as well as the national level is necessary to prevent the spread of COVID-19. Surveying and analyzing details of the incidences of infected persons in each prefecture is extremely important. This report describes the epidemiological characteristics of COVID-19 observed in Okayama Prefecture, followed by discussion of the direction of public health actions to be taken in the future. We reiterate the crucial importance of reinforcing and maintaining current public health measures, including rapid and detailed compilation of information related to infected persons and their surroundings, appropriate blocking of viral transmission, and early containment of infected persons, to minimize the spread of infection especially during the overlapping epidemic period of influenza in Okayama Prefecture.

DOI： 10.35772/ghm.2020.01104

Outcomes of Right Ventricular Outflow Tract Reconstruction in Children: Retrospective Comparison Between Bovine Jugular Vein and Expanded Polytetrafluoroethylene Conduits. Reviewed International journal

Kenta Hirai, Kenji Baba, Takuya Goto, Daiki Ousaka, Maiko Kondo, Takahiro Eitoku, Yasuhiro Kotani, Shingo Kasahara, Shinichi Ohtsuki, Hirokazu Tsukahara

Pediatric cardiology 42 ( 1 ) 100 - 108 2021.1

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

Bovine jugular vein (BJV) and expanded polytetrafluoroethylene (ePTFE) conduits have been described as alternatives to the homograft for right ventricular outflow tract (RVOT) reconstruction. This study compared RVOT reconstructions using BJV and ePTFE conduits performed in a single institution. The valve functions and outcomes of patients aged < 18 years who underwent primary RVOT reconstruction with a BJV or ePTFE conduit between 2013 and 2017 were retrospectively investigated. 44 patients (20 and 24 with BJV and ePTFE conduits, respectively) met the inclusion criteria. The mean follow-up time was 4.5 ± 1.5 years. No significant differences in peak RVOT velocity (1.8 ± 0.9 m/s vs 2.1 ± 0.9 m/s, P = 0.27), branch pulmonary stenosis (P = 0.50), or pulmonary regurgitation (P = 0.44) were found between the BJV and ePTFE conduit groups, respectively. Aneurysmal dilatation of the conduit was observed in 25.0% of the patients in the BJV conduit group but not in the ePTFE conduit group (P = 0.011). All the cases with aneurysmal dilatation of the BJV conduit were complicated with branch pulmonary stenosis up to 3.0 m/s (P = 0.004). No conduit infections occurred during the follow-up period, and no significant difference in conduit replacement (20.0% vs 8.3%, P = 0.43) was found between the BJV and ePTFE conduit groups, respectively. The outcomes of the RVOT reconstructions with BJV and ePTFE conduits were clinically satisfactory. Aneurysmal dilatation was found in the BJV conduit cases, with branch pulmonary stenosis as the risk factor.

DOI： 10.1007/s00246-020-02458-0

Clinical Factors Affecting the Dose Conversion Ratio from Intravenous to Oral Tacrolimus Formulation among Pediatric Hematopoietic Stem Cell Transplantation Recipients. Reviewed International journal

Kiichiro Kanamitsu, Takashi Yorifuji, Hisashi Ishida, Kaori Fujiwara, Kana Washio, Akira Shimada, Hirokazu Tsukahara

Therapeutic drug monitoring 42 ( 6 ) 803 - 810 2020.12

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Tacrolimus is converted from intravenous to oral formulation for the prophylaxis of graft-versus-host disease when patients can tolerate oral intake and graft-versus-host disease is under control. Oral tacrolimus formulation presents poor bioavailability with intraindividual and interindividual variations; however, some factors affecting its blood concentration among pediatric hematopoietic stem cell transplantation (HCT) recipients are still unclear. This study aimed to identify the clinical factors affecting tacrolimus blood concentrations after switching its formulation. METHODS: Changes in the blood concentration/dose ratio (C/D) of tacrolimus in pediatric HCT recipients were analyzed after the switching of tacrolimus from intravenous to oral formulation. Clinical records of 57 pediatric patients who underwent allogenic HCT from January 2006 to April 2019 in our institute were retrospectively reviewed. The C/D of tacrolimus before discontinuation of intravenous infusion (C/Div) was compared with the tacrolimus trough level within 10 days after the initiation of oral administration (C/Dpo). Multiple linear regression analysis was performed to identify factors affecting (C/Dpo)/(C/Div). RESULTS: The constant coefficient of (C/Dpo)/(C/Div) was 0.1692 [95% confidence interval (CI), 0.137-0.2011]. The concomitant use of voriconazole or itraconazole and female sex were significant variables with a beta coefficient of 0.0974 (95% CI, 0.062-0.133) and -0.0373 (95% CI, -0.072 to -0.002), respectively. CONCLUSIONS: After switching of tacrolimus formulation, pediatric HCT recipients might need oral tacrolimus dose that is 5-6 and 3.5-4.5 times the intravenous dose to maintain tacrolimus blood concentrations and area under the concentration-time curve, respectively. With the concomitant use of voriconazole or itraconazole, an oral tacrolimus dose of 4-5 times the intravenous dose seemed appropriate to maintain blood tacrolimus concentration.

DOI： 10.1097/FTD.0000000000000793

Delayed Methotrexate Elimination after Administration of a Medium Dose of Methotrexate in a Patient with Genetic Variants Associated with Methotrexate Clearance. Reviewed

Yasuhisa Tatebe, Kiichiro Kanamitsu, Hirotaka Kanzaki, Hisashi Ishida, Kaori Fujiwara, Kana Washio, Yoshihisa Kitamura, Toshiaki Sendo, Akira Shimada, Hirokazu Tsukahara

Acta medica Okayama 74 ( 6 ) 545 - 550 2020.12

Authorship：Last author Language：English

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.

DOI： 10.18926/AMO/61215

Influenza Encephalopathy: What Is Encephalopathy? Invited Reviewed

Mitsuru Tsuge, Masato Yashiro, Naoki Ohno, Hirokazu Tsukahara

Respiratory Disease Series: Diagnostic Tools and Disease Managements 115 - 126 2020.11

Associations of Birth Weight for Gestational Age with Child Health and Neurodevelopment among Term Infants: A Nationwide Japanese Population-Based Study. Reviewed International journal

Kei Tamai, Takashi Yorifuji, Akihito Takeuchi, Yu Fukushima, Makoto Nakamura, Naomi Matsumoto, Yosuke Washio, Misao Kageyama, Hirokazu Tsukahara

The Journal of pediatrics 226 135 - 141 2020.11

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

OBJECTIVE: To examine the association of specific Z-score categories of birth weight for gestational age with child health and neurodevelopment using a large nationwide survey in Japan, focusing on term infants. STUDY DESIGN: We included 36 321 children born in 2010. Hospitalization up to 66 months of age was used as an indicator of health status, and responses to questions about age-appropriate behaviors at 30 and 66 months of age were used to indicate neurobehavioral development. We conducted binomial log-linear regression analyses, controlling for child and parental variables. A restricted cubic spline function was used to model the relationship. RESULTS: Compared with children with birth weight appropriate for gestational age (-1.28 to 1.28 SDs of expected birthweight for gestational age), children who were small for gestational age (SGA) (<-1.28 SD) had higher risks of hospitalization and unfavorable neurobehavioral development, and the risks increased as SGA status became more severe. Compared with the appropriate for gestational age group, the adjusted risk ratios for hospitalization for all causes were 2.5 (95% CI, 1.7-3.6), 1.3 (95% CI, 1.1-1.6), and 1.1 (95% CI, 1.0-1.2) for children who were severely, moderately, and mildly SGA and 1.0 (95% CI, 0.9-1.1), 1.1 (95% CI, 0.9-1.2), and 1.4 (95% CI, 0.9-2.1) for children who were mildly, moderately, and severely large for gestational age, respectively. Severely large for gestational age children also had higher risks of unfavorable neurobehavioral development. These results were supported by spline analyses. CONCLUSIONS: Among term infants, the risks of unfavorable child health and neurodevelopment increased with the severity of SGA.

DOI： 10.1016/j.jpeds.2020.06.075

Polydactyly of the Foot Diagnosed from a Minor Nail Problem.

Tomohiro Hiraoka, Haruka Senoo, Yuka Yamazaki, Kosaku Suenobu, Hirokazu Tsukahara

Acta medica Okayama 74 ( 5 ) 427 - 429 2020.10

Language：English

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.

DOI： 10.18926/AMO/60803

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