Updated on 2022/11/25

写真a

 
KAWADA Junichi
 
Organization
Graduate School of Medicine Program in Integrated Medicine Medicine in Growth and Aging Associate professor
Graduate School
Graduate School of Medicine
Undergraduate School
School of Medicine Department of Medicine
Title
Associate professor
Contact information
メールアドレス

Degree 1

  1. 博士(医学) ( 2005.3   名古屋大学 ) 

Education 2

  1. Nagoya University

    - 1997.3

  2. Nagoya University   Graduate School, Division of Medical Sciences

    - 2005.3

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    Country: Japan

Professional Memberships 8

  1. 日本小児科学会

  2. 日本感染症学会

  3. 日本小児科学会

  4. 日本小児感染症学会

  5. 日本小児リウマチ学会

  6. 日本ワクチン学会

  7. 日本リウマチ学会

  8. 日本ウイルス学会

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Papers 92

  1. Post-exposure prophylaxis to prevent varicella in immunocompromised children.

    Yamaguchi M, Tetsuka N, Okumura T, Haruta K, Suzuki T, Torii Y, Kawada JI, Ito Y

    Infection prevention in practice   Vol. 4 ( 4 ) page: 100242   2022.12

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    Language:English  

    DOI: 10.1016/j.infpip.2022.100242

    PubMed

  2. Impact of the Coronavirus Disease 2019 Pandemic on the Clinical Features of Pediatric Respiratory Syncytial Virus Infection in Japan.

    Ozeki S, Kawada JI, Yamashita D, Yasufuku C, Akano T, Kato M, Suzuki K, Tano C, Matsumoto K, Mizutani SH, Mori A, Nishio N, Kidokoro H, Yasui Y, Takahashi Y, Sato Y, Nagoya Collaborative Clinical Research Team .

    Open forum infectious diseases   Vol. 9 ( 11 ) page: ofac562   2022.11

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    Language:English  

    DOI: 10.1093/ofid/ofac562

    PubMed

  3. Performance of Nanopore and Illumina Metagenomic Sequencing for Pathogen Detection and Transcriptome Analysis in Infantile Central Nervous System Infections

    Horiba Kazuhiro, Torii Yuka, Aizawa Yuta, Yamaguchi Makoto, Haruta Kazunori, Okumura Toshihiko, Suzuki Takako, Kawano Yoshihiko, Kawada Jun-ichi, Hara Shinya, Saitoh Akihiko, Giske Christian G., Ogi Tomoo, Ito Yoshinori

    OPEN FORUM INFECTIOUS DISEASES   Vol. 9 ( 10 ) page: ofac504   2022.10

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  4. Quantitative assessment of viral load in the blood and urine of patients with congenital cytomegalovirus infection using droplet digital PCR International journal

    Makoto Yamaguchi, Jun‐ichi Kawada, Yuka Torii, Kazunori Haruta, Takako Suzuki, Kazuhiro Horiba, Yoshiyuki Takahashi, Yoshinori Ito

    Journal of Medical Virology   Vol. 94 ( 9 ) page: 4559 - 4564   2022.9

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:Wiley  

    Congenital cytomegalovirus infection (cCMV) is a common cause of congenital infections, leading to neurodevelopmental sequelae. Real-time quantitative polymerase chain reaction (qPCR) has been widely used for the diagnosis and assessment of cCMV; however, the correlation between CMV DNA load and the severity of cCMV symptoms has been inconclusive. Droplet digital PCR (ddPCR) offers an improvement over the current qPCR methods through the absolute quantification of viral loads. We compared ddPCR and qPCR results for the quantification of CMV DNA in blood and urine specimens from 39 neonates with cCMV (21 symptomatic and 18 asymptomatic). There was no significant difference in blood CMV DNA loads measured by ddPCR and qPCR, with or without any clinical findings. However, developmental delays at 36 months were significantly more frequently observed in patients with high CMV DNA loads (≥2950 copies/ml), as measured by ddPCR at diagnosis, than in those with lower CMV DNA loads. The association of urine CMV DNA load with symptoms and developmental delay was not observed. CMV DNA loads in the blood might be used as a predictor of developmental outcomes in cCMV patients, and absolute quantitation of viral loads by ddPCR assay could contribute to the standardization of CMV load measurement.

    DOI: 10.1002/jmv.27844

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    PubMed

    Other Link: https://onlinelibrary.wiley.com/doi/full-xml/10.1002/jmv.27844

  5. Detection of antiviral drug resistance in patients with congenital cytomegalovirus infection using long-read sequencing: a retrospective observational study

    Yuka Torii, Kazuhiro Horiba, Jun-ichi Kawada, Kazunori Haruta, Makoto Yamaguchi, Takako Suzuki, Hideko Uryu, Naoyuki Kashiwa, Keiji Goishi, Tomoo Ogi, Yoshinori Ito

    BMC Infectious Diseases   Vol. 22 ( 1 ) page: 568   2022.6

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:Springer Science and Business Media LLC  

    Abstract

    Background

    Congenital human cytomegalovirus (cCMV) infection can cause sensorineural hearing loss and neurodevelopmental disabilities in children. Ganciclovir and valganciclovir (GCV/VGCV) improve long-term audiologic and neurodevelopmental outcomes for patients with cCMV infection; however, antiviral drug resistance has been documented in some cases. Long-read sequencing can be used for the detection of drug resistance mutations. The objective of this study was to develop full-length analysis of UL97 and UL54, target genes with mutations that confer GCV/VGCV resistance using long-read sequencing, and investigate drug resistance mutation in patients with cCMV infection.

    Methods

    Drug resistance mutation analysis was retrospectively performed in 11 patients with cCMV infection treated with GCV/VGCV. UL97 and UL54 genes were amplified using blood DNA. The amplicons were sequenced using a long-read sequencer and aligned with the reference gene. Single nucleotide variants were detected and replaced with the reference sequence. The replaced sequence was submitted to a mutation resistance analyzer, which is an open platform for drug resistance mutations.

    Results

    Two drug resistance mutations (UL54 V823A and UL97 A594V) were found in one patient. Both mutations emerged after 6 months of therapy, where viral load increased. Mutation rates subsided after cessation of GCV/VGCV treatment.

    Conclusions

    Antiviral drug resistance can emerge in patients with cCMV receiving long-term therapy. Full-length analysis of UL97 and UL54 via long-read sequencing enabled the rapid and comprehensive detection of drug resistance mutations.

    DOI: 10.1186/s12879-022-07537-6

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    Other Link: https://link.springer.com/article/10.1186/s12879-022-07537-6/fulltext.html

  6. MicroRNA expression profiling of cerebrospinal fluid/serum exosomes in children with human herpesvirus 6-associated encephalitis/encephalopathy by high-throughput sequencing

    Yuka Torii, Jun-ichi Kawada, Kazuhiro Horiba, Toshihiko Okumura, Takako Suzuki, Yoshinori Ito

    Journal of NeuroVirology   Vol. 28 ( 1 ) page: 151 - 157   2022.2

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:Springer Science and Business Media LLC  

    DOI: 10.1007/s13365-022-01058-3

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    Other Link: https://link.springer.com/article/10.1007/s13365-022-01058-3/fulltext.html

  7. Diagnosis of Peripheral Facial Palsy Associated with Parvovirus B19 Infection by Polymerase Chain Reaction.

    Fukuta T, Kawano Y, Ikeda M, Kawada JI, Ito Y, Hara S

    Case reports in pediatrics   Vol. 2022   page: 4574640   2022

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    Language:English  

    DOI: 10.1155/2022/4574640

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  8. A STING inhibitor suppresses EBV-induced B cell transformation and lymphomagenesis. International journal

    Shouhei Miyagi, Takahiro Watanabe, Yuya Hara, Masataka Arata, Md Kamal Uddin, Keisuke Mantoku, Ken Sago, Yusuke Yanagi, Takeshi Suzuki, H M Abdullah Al Masud, Jun-Ichi Kawada, Shigeo Nakamura, Yasuyuki Miyake, Yoshitaka Sato, Takayuki Murata, Hiroshi Kimura

    Cancer science   Vol. 112 ( 12 ) page: 5088 - 5099   2021.12

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

    Epstein-Barr virus-associated lymphoproliferative disease (EBV-LPD) is frequently fatal. Innate immunity plays a key role in protecting against pathogens and cancers. The stimulator of interferon genes (STING) is regarded as a key adaptor protein allowing DNA sensors recognizing exogenous cytosolic DNA to activate the type I interferon signaling cascade. In terms of EBV tumorigenicity, the role of STING remains elusive. Herein we showed that treatment with the STING inhibitor, C-176, suppressed EBV-induced transformation in peripheral blood mononuclear cells. In an EBV-LPD mouse model, C-176 treatment also inhibited tumor formation and prolonged survival. Treatment with B cells alone did not affect EBV transformation, but suppression of EBV-induced transformation was observed in the presence of T cells. Even without direct B cell-T cell contact in a Transwell system, the inhibitor reduced the transformation activity, indicating that intercellular communication by humoral factors was critical to prevent EBV-induced transformation. These findings suggest that inhibition of STING signaling pathway with C-176 could be a new therapeutic target of EBV-LPD.

    DOI: 10.1111/cas.15152

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  9. Next-Generation Sequencing to Detect Pathogens in Pediatric Febrile Neutropenia: A Single-Center Retrospective Study of 112 Cases

    Kazuhiro Horiba, Yuka Torii, Toshihiko Okumura, Suguru Takeuchi, Takako Suzuki, Jun-ichi Kawada, Hideki Muramatsu, Yoshiyuki Takahashi, Tomoo Ogi, Yoshinori Ito

    Open Forum Infectious Diseases   Vol. 8 ( 11 ) page: ofab223   2021.11

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:Oxford University Press (OUP)  

    <title>Abstract</title>
    <sec>
    <title>Background</title>
    Febrile neutropenia (FN) is a frequent complication in immunocompromised patients. However, causative microorganisms are detected in only 10% of patients. This study aimed to detect the microorganisms that cause FN using next-generation sequencing (NGS) to idenjpgy the genome derived from pathogenic microorganisms in the bloodstream. Here, we implemented a metagenomic approach to comprehensively analyze microorganisms present in clinical samples from patients with FN.


    </sec>
    <sec>
    <title>Methods</title>
    FN is defined as 1) a neutrophil count &amp;lt; 500/µL, and 2) fever ≥ 37.5 °C. Plasma/serum samples of 112 pediatric patients with FN, 10 patients with neutropenia without fever (NE), were sequenced by NGS and analyzed by a metagenomic pipeline PATHDET.


    </sec>
    <sec>
    <title>Results</title>
    The putative pathogens were detected by NGS in 5 of 10 patients with FN with positive for blood culture results, 15 of 87 patients (17%) with negative for blood culture results, and 3 of 8 patients with NE. Several bacteria that were common in the oral, skin, and gut flora were commonly detected in blood samples, suggesting translocation of the human microbiota to the bloodstream in the setting of neutropenia. The cluster analysis of the microbiota in blood samples using NGS demonstrated that the representative bacteria of each cluster was mostly consistent with the pathogens in each patient.


    </sec>
    <sec>
    <title>Conclusions</title>
    NGS technique has a great potential for detecting causative pathogens in patients with FN. Cluster analysis, which extracts characteristic microorganisms from a complex microbial population, may be effective to detect pathogens in minute quantities of microbiota, such as those from the bloodstream.


    </sec>

    DOI: 10.1093/ofid/ofab223

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  10. A Case of Descending Necrotizing Mediastinitis in a Previously Healthy Child

    Okumura Toshihiko, Tetsuka Nobuyuki, Yamaguchi Makoto, Suzuki Takako, Torii Yuka, Kawada Jun-ichi, Ito Yoshinori

    CASE REPORTS IN PEDIATRICS   Vol. 2021   page: 3159092   2021.9

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  11. Pediatric sepsis cases diagnosed with group B streptococcal meningitis using next-generation sequencing: a report of two cases

    Kazuhiro Horiba, Michio Suzuki, Nobuyuki Tetsuka, Yoshihiko Kawano, Makoto Yamaguchi, Toshihiko Okumura, Takako Suzuki, Yuka Torii, Jun-ichi Kawada, Makoto Morita, Shinya Hara, Tomoo Ogi, Yoshinori Ito

    BMC Infectious Diseases   Vol. 21 ( 1 ) page: 531   2021.6

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:Springer Science and Business Media LLC  

    <title>Abstract</title><sec>
    <title>Background</title>
    Group B Streptococcus (GBS) is an important cause of invasive infection in neonates and infants. Cerebrospinal fluid (CSF) findings and culture may not show evidence of infection early in GBS meningitis. Next-generation sequencing (NGS) has the potential to detect microbial genetic material in patients with infectious diseases. We report two cases of infantile sepsis of GBS meningitis with negative results for CSF culture tests, but positive results for NGS analysis.


    </sec><sec>
    <title>Case presentation</title>
    Patient 1 was a 22-day-old male infant diagnosed with sepsis and meningitis. His CSF findings showed pleocytosis, decreased glucose, and increased protein levels. However, CSF and blood culture results at admission were negative. He received a total of 3 weeks of treatment with ampicillin and cefotaxime, and showed clinical improvement. GBS was detected through NGS analysis of CSF collected at admission. Patient 2 was a 51-day-old male infant with sepsis. CSF findings on admission were normal, and blood and CSF cultures were also negative. Intravenous ampicillin and cefotaxime treatment were initiated. Treatment was de-escalated to ampicillin alone because <italic>Enterococcus faecalis</italic> was cultured from urine. He was discharged after a total of 1 week of antibiotic treatment. Six days after discharge, he was re-hospitalized for sepsis. Blood and CSF cultures were negative, and <italic>E. faecalis</italic> was again cultured from urine. He received a total of 3 weeks of ampicillin treatment for enterococcal-induced nephritis and did not relapse thereafter. NGS pathogen searches were retrospectively performed on both blood and CSF collected at the first and second admission. GBS was detected in the CSF collected at the first admission, but no significant pathogen was detected in the other samples. Inadequate treatment for GBS meningitis at the first admission may have caused the recurrence of the disease.


    </sec><sec>
    <title>Conclusion</title>
    Infantile sepsis may present bacterial meningitis that is not diagnosed by either culture testing or CSF findings. NGS analysis for CSF may be useful for confirming the diagnosis of bacterial meningitis.


    </sec>

    DOI: 10.1186/s12879-021-06231-3

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    Other Link: https://link.springer.com/article/10.1186/s12879-021-06231-3/fulltext.html

  12. Temporal dynamics of the plasma microbiome in recipients at early post-liver transplantation: a retrospective study. International journal

    Toshihiko Okumura, Kazuhiro Horiba, Hideya Kamei, Suguru Takeuchi, Takako Suzuki, Yuka Torii, Jun-Ichi Kawada, Yoshiyuki Takahashi, Yasuhiro Ogura, Tomoo Ogi, Yoshinori Ito

    BMC microbiology   Vol. 21 ( 1 ) page: 104 - 104   2021.4

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    BACKGROUND: Immunosuppression during liver transplantation (LT) enables the prevention and treatment of organ rejection but poses a risk for severe infectious diseases. Immune modulation and antimicrobials affect the plasma microbiome. Thus, determining the impact of immunosuppression on the microbiome may be important to understand immunocompetence, elucidate the source of infection, and predict the risk of infection in LT recipients. We characterized the plasma microbiome of LT recipients at early post-LT and assessed the association between the microbiome and clinical events. RESULTS: In this study, 51 patients who received LT at Nagoya University Hospital from 2016 to 2018 were enrolled. Plasma samples were retrospectively collected at the following time points: 1) within a week after LT; 2) 4 ± 1 weeks after LT; 3) 8 ± 1 weeks after LT; and 4) within 2 days after a positive blood culture. A total of 111 plasma samples were analyzed using shotgun next-generation sequencing (NGS) with the PATHDET pipeline. Relative abundance of Anelloviridae, Nocardiaceae, Microbacteriaceae, and Enterobacteriaceae significantly changed during the postoperative period. Microbiome diversity was higher within a week after LT than that at 8 weeks after LT. Antimicrobials were significantly associated with the microbiome of LT recipients. In addition, the proportion of Enterobacteriaceae was significantly increased and the plasma microbiome diversity was significantly lower in patients with acute cellular rejection (ACR) than non-ACR patients. Sequencing reads of bacteria isolated from blood cultures were predominantly identified by NGS in 8 of 16 samples, and human herpesvirus 6 was detected as a causative pathogen in one recipient with severe clinical condition. CONCLUSIONS: The metagenomic NGS technique has great potential in revealing the plasma microbiome and is useful as a comprehensive diagnostic procedure in clinical settings. Temporal dynamics of specific microorganisms may be used as indirect markers for the determination of immunocompetence and ACR in LT recipients.

    DOI: 10.1186/s12866-021-02154-w

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  13. Immune cell infiltration landscapes in pediatric acute myocarditis analyzed by CIBERSORT Reviewed

    Jun-ichi Kawada, Suguru Takeuchi, Hiroshi Imai, Toshihiko Okumura, Kazuhiro Horiba, Takako Suzuki, Yuka Torii, Kazushi Yasuda, Kyoko Imanaka-Yoshida, Yoshinori Ito

    Journal of Cardiology   Vol. 77 ( 2 ) page: 174 - 178   2021.2

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    Authorship:Lead author, Corresponding author   Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:Elsevier BV  

    DOI: 10.1016/j.jjcc.2020.08.004

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  14. Comprehensive Detection of Candidate Pathogens in the Lower Respiratory Tract of Pediatric Patients With Unexpected Cardiopulmonary Deterioration Using Next-Generation Sequencing Reviewed International journal

    Suguru Takeuchi, Jun-ichi Kawada, Kazuhiro Horiba, Makoto Yamaguchi, Toshihiko Okumura, Takako Suzuki, Yuka Torii, Shinji Kawabe, Sho Wada, Takanari Ikeyama, Yoshinori Ito

    Pediatric Critical Care Medicine   Vol. 21 ( 11 ) page: E1026 - E1030   2020.11

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    Authorship:Corresponding author   Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:Ovid Technologies (Wolters Kluwer Health)  

    OBJECTIVES: Next-generation sequencing has been applied to the investigation of microorganisms in several clinical settings. We investigated the infectious etiologies in respiratory specimens from pediatric patients with unexpected cardiopulmonary deterioration using next-generation sequencing. DESIGN: Retrospective, single-center, observational study. SETTING: Tertiary care, a children's hospital. SUBJECTS: The study enrolled a total of 16 pediatric patients with unexpected cardiopulmonary deterioration who were admitted to the PICU. Ten bronchoalveolar lavage fluid and six transtracheal aspirate samples were analyzed. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: RNA libraries were prepared from specimens and analyzed using next-generation sequencing. One or more bacterial/viral pathogens were detected in the bronchoalveolar lavage fluid or transtracheal aspirate specimens from 10 patients. Bacterial and viral coinfection was considered in four cases. Compared with the conventional culture and viral antigen test results, an additional six bacterial and four viral pathogens were identified by next-generation sequencing. Conversely, among 18 pathogens identified by the conventional methods, nine pathogens were detected by next-generation sequencing. Candidate pathogens (e.g., coxsackievirus A6 and Chlamydia trachomatis) were detected by next-generation sequencing in four of 10 patients in whom no causative pathogen had been identified by conventional methods. CONCLUSIONS: Our results suggest that viral and bacterial infections are common triggers in unexpected cardiopulmonary deterioration in pediatric patients. Next-generation sequencing has the potential to contribute to clarification of the etiology of pediatric critical illness.

    DOI: 10.1097/PCC.0000000000002558

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  15. Comprehensive pathogen detection in sera of Kawasaki disease patients by high-throughput sequencing: a retrospective exploratory study. International journal

    Yuka Torii, Kazuhiro Horiba, Satoshi Hayano, Taichi Kato, Takako Suzuki, Jun-Ichi Kawada, Yoshiyuki Takahashi, Seiji Kojima, Yusuke Okuno, Tomoo Ogi, Yoshinori Ito

    BMC pediatrics   Vol. 20 ( 1 ) page: 482 - 482   2020.10

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    BACKGROUND: Kawasaki disease (KD) is an idiopathic systemic vasculitis that predominantly damages coronary arteries in children. Various pathogens have been investigated as triggers for KD, but no definitive causative pathogen has been determined. As KD is diagnosed by symptoms, several days are needed for diagnosis. Therefore, at the time of diagnosis of KD, the pathogen of the trigger may already be diminished. The aim of this study was to explore comprehensive pathogens in the sera at the acute stage of KD using high-throughput sequencing (HTS). METHODS: Sera of 12 patients at an extremely early stage of KD and 12 controls were investigated. DNA and RNA sequences were read separately using HTS. Sequence data were imported into the home-brew meta-genomic analysis pipeline, PATHDET, to identify the pathogen sequences. RESULTS: No RNA virus reads were detected in any KD case except for that of equine infectious anemia, which is known as a contaminant of commercial reverse transcriptase. Concerning DNA viruses, human herpesvirus 6B (HHV-6B, two cases) and Anelloviridae (eight cases) were detected among KD cases as well as controls. Multiple bacterial reads were obtained from KD and controls. Bacteria of the genera Acinetobacter, Pseudomonas, Delfita, Roseomonas, and Rhodocyclaceae appeared to be more common in KD sera than in the controls. CONCLUSION: No single pathogen was identified in serum samples of patients at the acute phase of KD. With multiple bacteria detected in the serum samples, it is difficult to exclude the possibility of contamination; however, it is possible that these bacteria might stimulate the immune system and induce KD.

    DOI: 10.1186/s12887-020-02380-7

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  16. Association between graft source and response to live-attenuated vaccination in pediatric hematopoietic stem cell transplantation recipients: a single-center retrospective study. Reviewed International journal

    Takako Suzuki, Jun-Ichi Kawada, Eri Nishikawa, Yuka Torii, Kazuhiro Horiba, Suguru Takeuchi, Toshihiko Okumura, Hideki Muramatsu, Yoshiyuki Takahashi, Yoshinori Ito

    Bone marrow transplantation   Vol. 55 ( 9 ) page: 1872 - 1874   2020.9

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  17. Viral DNA Loads in Various Blood Components of Patients With Epstein-Barr Virus–Positive T-Cell/Natural Killer Cell Lymphoproliferative Diseases Reviewed

    Jun-ichi Kawada, Yasuko Kamiya, Akihisa Sawada, Keiji Iwatsuki, Koji Izutsu, Yuka Torii, Hiroshi Kimura, Yoshinori Ito

    The Journal of Infectious Diseases   Vol. 220 ( 8 ) page: 1307 - 1311   2019.10

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    Authorship:Lead author   Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:Oxford University Press (OUP)  

    <title>Abstract</title>
    To evaluate diagnostic values for Epstein-Barr virus (EBV) DNA loads in different blood components of patients with EBV-positive T-cell/natural killer cell lymphoproliferative diseases, EBV DNA loads were compared among disease categories in each blood component from 59 patients. Plasma viral loads were significantly higher in “active” disease in chronic active EBV infection. EBV DNA was not detected in the plasma from 7 patients in whom EBV DNA was detected in peripheral blood mononuclear cells and whole blood. Diagnostic cutoff values for whole blood EBV DNA loads of patients with chronic active EBV infection compared with those of infectious mononucleosis was 104.2 (15 800) IU/mL.

    DOI: 10.1093/infdis/jiz315

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    Other Link: http://academic.oup.com/jid/article-pdf/220/8/1307/30011073/jiz315.pdf

  18. Metagenomic analysis using next-generation sequencing of pathogens in bronchoalveolar lavage fluid from pediatric patients with respiratory failure Reviewed

    Suguru Takeuchi, Jun-ichi Kawada, Kazuhiro Horiba, Yusuke Okuno, Toshihiko Okumura, Takako Suzuki, Yuka Torii, Shinji Kawabe, Sho Wada, Takanari Ikeyama, Yoshinori Ito

    Scientific Reports   Vol. 9 ( 1 ) page: 12909   2019.9

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    Authorship:Corresponding author   Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:Springer Science and Business Media LLC  

    <title>Abstract</title>
    Next-generation sequencing (NGS) has been applied in the field of infectious diseases. Bronchoalveolar lavage fluid (BALF) is considered a sterile type of specimen that is suitable for detecting pathogens of respiratory infections. The aim of this study was to comprehensively identify causative pathogens using NGS in BALF samples from immunocompetent pediatric patients with respiratory failure. Ten patients hospitalized with respiratory failure were included. BALF samples obtained in the acute phase were used to prepare DNA- and RNA-sequencing libraries. The libraries were sequenced on MiSeq, and the sequence data were analyzed using metagenome analysis tools. A mean of 2,041,216 total reads were sequenced for each library. Significant bacterial or viral sequencing reads were detected in eight of the 10 patients. Furthermore, candidate pathogens were detected in three patients in whom etiologic agents were not identified by conventional methods. The complete genome of enterovirus D68 was identified in two patients, and phylogenetic analysis suggested that both strains belong to subclade B3, which is an epidemic strain that has spread worldwide in recent years. Our results suggest that NGS can be applied for comprehensive molecular diagnostics as well as surveillance of pathogens in BALF from patients with respiratory infection.

    DOI: 10.1038/s41598-019-49372-x

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    Other Link: http://www.nature.com/articles/s41598-019-49372-x

  19. Risk factors for absence of catch-up growth in small for gestational age very low-birthweight infants

    Arai Sakiko, Sato Yoshiaki, Muramatsu Hideki, Yamamoto Hidenori, Aoki Fumiko, Okai Yu, Kataoka Shinsuke, Hanada Yu, Hamada Motoharu, Morimoto Yoshihito, Kojima Seiji, Natsume Jun, Takahashi Yoshiyuki, Sugiyama Yuichiro, Hoshino Shin, Kawada Junichi, Kidokoro Hiroyuki, Hayakawa Masahiro, Hattori Tetsuo, Kato Yuichi, Yasuda Ayako, Oshiro Makoto, Takemoto Koji, Nishimura Naoko, Hayashi Seiji, Hyodo Reina, Ito Masatoki, Narahara Shou, Ieda Kuniko, Yamamoto Hikaru

    PEDIATRICS INTERNATIONAL   Vol. 61 ( 9 ) page: 889 - 894   2019.9

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    Language:Japanese  

    DOI: 10.1111/ped.13939

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  20. Reactivation of human herpesviruses 6 and 7 in Kawasaki disease Reviewed

    Yoshihiko Kawano, Jun-ichi Kawada, Noriko Nagai, Yoshinori Ito

    Modern Rheumatology   Vol. 29 ( 4 ) page: 651 - 655   2019.7

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    Authorship:Corresponding author   Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:Informa UK Limited  

    DOI: 10.1080/14397595.2018.1510758

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  21. Comparison of Clinical Characteristics of Human Metapneumovirus and Respiratory Syncytial Virus Infections in Hospitalized Young Children Reviewed

    Akinobu Taniguchi, Jun-ichi Kawada, Kiyotaka Go, Naozumi Fujishiro, Yosuke Hosokawa, Yuki Maki, Yuichiro Sugiyama, Michio Suzuki, Takeshi Tsuji, Shin Hoshino, Hideki Muramatsu, Hiroyuki Kidokoro, Fumie Kinoshita, Akihiro Hirakawa, Yoshiyuki Takahashi, Yoshiaki Sato, Jun Natsume

    Japanese Journal of Infectious Diseases   Vol. 72 ( 4 ) page: 237 - 242   2019.7

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    Authorship:Corresponding author   Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:Editorial Committee of Japanese Journal of Infectious Diseases, National Institute of Infectious Dis  

    Human metapneumovirus (HMPV) and respiratory syncytial virus (RSV) are the leading causes of acute respiratory tract infection in children, and clinical manifestations of these virus infections are considered similar. To investigate the differences in clinical characteristics between HMPV and RSV infections in young children, we prospectively enrolled children < 3 years old who required hospitalization with acute respiratory tract infection due to HMPV or RSV at 10 hospitals in Japan. We enrolled 48 children with HMPV infection and 141 with RSV infection. Patients with HMPV infection were older than those with RSV infection. High-grade fever was more frequently observed in patients with HMPV infection, whereas no significant differences in respiratory symptoms were apparent. Abnormal serum lactate dehydrogenase values and consolidation shadows on chest X-ray were more frequently observed in patients with HMPV infection. During hospitalization, nasal mucus suction was more frequently required in patients with RSV infection. On the other hand, β2-adrenergic agonists, corticosteroids, and leukotriene receptor antagonists were more frequently used in patients with HMPV infection. These findings suggest that HMPV and RSV infections show similar respiratory symptoms, but HMPV infection is more likely to lead to the development of pneumonia, at least among hospitalized young children.

    DOI: 10.7883/yoken.JJID.2018.480

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  22. Serological screening of immunoglobulin M and immunoglobulin G during pregnancy for predicting congenital cytomegalovirus infection Reviewed

    Yuka Torii, Shigeru Yoshida, Yoichiro Yanase, Takashi Mitsui, Kazuhiro Horiba, Toshihiko Okumura, Suguru Takeuchi, Takako Suzuki, Jun-ichi Kawada, Tomomi Kotani, Mamoru Yamashita, Yoshinori Ito

    BMC Pregnancy and Childbirth   Vol. 19 ( 1 ) page: 205   2019.6

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:Springer Science and Business Media LLC  

    DOI: 10.1186/s12884-019-2360-1

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    Other Link: http://link.springer.com/article/10.1186/s12884-019-2360-1/fulltext.html

  23. Design of a prospective multicenter randomized controlled trial evaluating the effects of gastric lavage on coffee-ground emesis in neonates: study protocol. Reviewed

    Takashi Maeda, Yoshiaki Sato, Akihiro Hirakawa, Masahiro Nakatochi, Fumie Kinoshita, Takeshi Suzuki, Shintaro Ichimura, Ryoichi Ito, Ryuji Kudo, Michio Suzuki, Shin Hoshino, Yuichiro Sugiyama, Hideki Muramatsu, Hiroyuki Kidokoro, Jun-Ichi Kawada, Yoshiyuki Takahashi

    Nagoya journal of medical science   Vol. 81 ( 2 ) page: 227 - 232   2019.5

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    Neonates who swallow a considerable amount of maternal blood may exhibit vomiting and suckling disorder during the first few days of the postnatal period. Some clinicians treat these neonates with gastric lavage (GL) to prevent vomiting and the establishment of enteral feeding empirically, but there was no study assessing the effect of GL for neonates with coffee-ground emesis. We designed a multicenter randomized controlled trial to evaluate the efficacy and safety of GL in neonates with coffee-ground emesis. Vigorous neonates with birth weight ranging from 2500 g to 3999 g and gestational age between 37w0d and 41w6d who presented with coffee-ground emesis on more than twice and diagnosed as false melena, were divided into two groups using computerized randomization. We defined feeding intolerance (FI) as (1) ≥2 vomiting episodes in 4h or ≥3 episodes in 24h and/or (2) feeding failure on at least two occasions because of retching or poor sucking. Primary outcome is percentage of infants who present FI within 24 hours from admission. We also assessed the residual volumes, number of vomiting episodes, percentage of weight reduction at postnatal day 4, rates of body weight gain at 1 month of age, and peak serum total bilirubin value before discharge. To our knowledge, this is the first study to evaluate the safety and efficacy of GL for neonates with coffee-ground emesis. This trial is registered at UMIN Clinical Trials Registry as UMIN000026483.

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  24. Comparison of high-dose and low-dose corticosteroid therapy for refractory Mycoplasma pneumoniae pneumonia in children Reviewed

    Toshihiko Okumura, Jun-ichi Kawada, Masaharu Tanaka, Kotaro Narita, Tomonori Ishiguro, Yuji Hirayama, Sho Narahara, Genki Tsuji, Yuichiro Sugiyama, Michio Suzuki, Takeshi Tsuji, Shin Hoshino, Masahiro Nakatochi, Hideki Muramatsu, Hiroyuki Kidokoro, Yoshiyuki Takahashi, Yoshiaki Sato, Yuji Miyajima, Nozomi Uno, Noriko Nagai, Shotaro Ando, Yuji Sudo, Kazuhisa Naruse, Yuma Takahashi, Ryosuke Suzui, Yoshihiro Nagata, Takashi Kawabe, Motohiro Shibata, Yusuke Shibata, Masashi Morishita, Mitsuharu Kajita, Takuto Ito, Shinji Kido, Shinji Hasegawa, Kei Ikeda, Noriko Tokumo, Maki Kato, Koji Kato, Daichi Fukumi, Satoru Doi, Marei Omori, Nobuhiro Watanabe, Hiroyuki Takada

    Journal of Infection and Chemotherapy   Vol. 25 ( 5 ) page: 346 - 350   2019.5

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    DOI: 10.1016/j.jiac.2019.01.003

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  25. Defective Epstein–Barr virus in chronic active infection and haematological malignancy Reviewed

    Yusuke Okuno, Takayuki Murata, Yoshitaka Sato, Hideki Muramatsu, Yoshinori Ito, Takahiro Watanabe, Tatsuya Okuno, Norihiro Murakami, Kenichi Yoshida, Akihisa Sawada, Masami Inoue, Keisei Kawa, Masao Seto, Koichi Ohshima, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Satoru Miyano, Yohei Narita, Masahiro Yoshida, Fumi Goshima, Jun-ichi Kawada, Tetsuya Nishida, Hitoshi Kiyoi, Seiichi Kato, Shigeo Nakamura, Satoko Morishima, Tetsushi Yoshikawa, Shigeyoshi Fujiwara, Norio Shimizu, Yasushi Isobe, Masaaki Noguchi, Atsushi Kikuta, Keiji Iwatsuki, Yoshiyuki Takahashi, Seiji Kojima, Seishi Ogawa, Hiroshi Kimura

    Nature Microbiology   Vol. 4 ( 3 ) page: 404 - 413   2019.3

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    DOI: 10.1038/s41564-018-0334-0

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  26. Ureteral dilatation detected in magnetic resonance imaging predicts vesicoureteral reflux in children with urinary tract infection Reviewed

    Norihiro Murakami, Jun-ichi Kawada, Azumi Watanabe, Toshinao Arakawa, Takamasa Kano, Takako Suzuki, Ryo Tanaka, Daiei Kojima, Yoshihiko Kawano, Shin Hoshino, Hideki Muramatsu, Yoshiyuki Takahashi, Yoshiaki Sato, Masashi Koyama, Jun Natsume

    PLOS ONE   Vol. 13 ( 12 ) page: e0209595 - e0209595   2018.12

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  27. A case of refractory cytomegalovirus-related thrombocytopenia that achieved complete remission without antiviral therapy Reviewed

    Yosuke Nishio, Yoshihiko Kawano, Jun-ichi Kawada, Yoshinori Ito, Shinya Hara

    Journal of Infection and Chemotherapy   Vol. 24 ( 12 ) page: 995 - 997   2018.12

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    DOI: 10.1016/j.jiac.2018.06.004

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  28. Identification of potential pathogenic viruses in patients with acute myocarditis using next-generation sequencing Reviewed

    Suguru Takeuchi, Jun-ichi Kawada, Yusuke Okuno, Kazuhiro Horiba, Takako Suzuki, Yuka Torii, Kazushi Yasuda, Atsushi Numaguchi, Taichi Kato, Yoshiyuki Takahashi, Yoshinori Ito

    Journal of Medical Virology   Vol. 90 ( 12 ) page: 1814 - 1821   2018.12

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    DOI: 10.1002/jmv.25263

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  29. Risk factors and long-term outcomes of pediatric liver transplant recipients with chronic high Epstein-Barr virus loads Reviewed

    Hideya Kamei, Yoshinori Ito, Junichi Kawada, Satoshi Ogiso, Yasuharu Onishi, Masahiko Komagome, Nobuhiko Kurata, Yasuhiro Ogura

    Transplant Infectious Disease   Vol. 20 ( 4 ) page: e12911 - e12911   2018.8

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    DOI: 10.1111/tid.12911

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  30. Antitumor effects of duvelisib on Epstein-Barr virus-associated lymphoma cells Reviewed

    Jun-ichi Kawada, Shotaro Ando, Yuka Torii, Takahiro Watanabe, Yoshitaka Sato, Yoshinori Ito, Hiroshi Kimura

    Cancer Medicine   Vol. 7 ( 4 ) page: 1275 - 1284   2018.4

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    DOI: 10.1002/cam4.1311

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  31. Survey of rotavirus-associated severe complications in Aichi Prefecture Reviewed International journal

    Fumihiko Hattori, Yoshiki Kawamura, Jun-ichi Kawada, Seiji Kojima, Jun Natsume, Koichi Ito, Shinji Saito, Yoshiro Kitagawa, Akihisa Okumura, Tetsushi Yoshikawa

    Pediatrics International   Vol. 60 ( 3 ) page: 259 - 263   2018.3

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    BACKGROUND: Rotavirus can, rarely, cause severe complications such as encephalopathy/encephalitis, myocarditis, sudden death, urinary stone, and gastrointestinal (GI) bleeding; and the incidence of these severe complications remains unclear. Additionally, it has not been determined whether rotavirus (RV) vaccine could reduce cases of severe complications or not. METHODS: A two-part questionnaire was designed to determine the number and clinical features of severe complications between 1 September 2008 and 31 August 2015, including the observation periods before and after RV vaccine introduction in Aichi Prefecture. RESULTS: Twenty-four cases of encephalitis/encephalopathy, eight cases of sudden death, three cases of urinary tract stone, and three cases of GI bleeding were reported during the 2008/2009 season and the 2012/2013 seasons. Although five cases of encephalitis/encephalopathy were reported, no other cases of severe complications were reported during the 2013/2014 and 2014/2015 seasons. No age difference was noted according to type of complication. Although onset of encephalitis/encephalopathy and of sudden death was around day 2 of illness, that of urinary tract stone and GI bleeding was slightly later (day 6 and day 4). In addition to the eight sudden deaths, fatal outcome was also noted in four cases (13.8%) of encephalitis/encephalopathy, and in one case of GI bleeding. CONCLUSION: According to the questionnaire survey in Aichi Prefecture, the incidence of the four severe RV-associated complications appears to have declined as the vaccination rate has increased.

    DOI: 10.1111/ped.13506

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  32. Comprehensive detection of pathogens in immunocompromised children with bloodstream infections by next-generation sequencing Reviewed

    Kazuhiro Horiba, Jun-ichi Kawada, Yusuke Okuno, Nobuyuki Tetsuka, Takako Suzuki, Shotaro Ando, Yasuko Kamiya, Yuka Torii, Tetsuya Yagi, Yoshiyuki Takahashi, Yoshinori Ito

    Scientific Reports   Vol. 8 ( 1 ) page: 3784   2018.2

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    DOI: 10.1038/s41598-018-22133-y

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  33. Treatment with silver nitrate versus topical steroid treatment for umbilical granuloma: A non-inferiority randomized control trial Reviewed International journal

    Chikako Ogawa, Yoshiaki Sato, Chiyo Suzuki, Azusa Mano, Atsushi Tashiro, Takafumi Niwa, Sayako Hamazaki, Yoshihiro Tanahashi, Midori Suzumura, Satoshi Hayano, Masahiro Hayakawa, Takeshi Tsuji, Shin Hoshino, Yuichiro Sugiyama, Hiroyuki Kidokoro, Jun-ichi Kawada, Hideki Muramatsu, Akihiro Hirakawa, Masahiko Ando, Jun Natsume, Seiji Kojima

    PLOS ONE   Vol. 13 ( 2 ) page: e0192688 - e0192688   2018.2

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    OBJECTIVE: The aim of this prospective multicenter randomized controlled trial was to compare the efficacy of silver nitrate cauterization against that of topical steroid ointment in the treatment of neonatal umbilical granuloma. METHODS: An open-label, non-inferiority randomized controlled trial was conducted from January 2013 to January 2016. The primary endpoint for the silver nitrate cauterization and topical steroid ointment groups was the healing rate after 2 weeks of treatment, applying a non-inferiority margin of 10%. The healing rate was evaluated until completion of 3 weeks of treatment. RESULTS: Participants comprised 207 neonates with newly diagnosed umbilical granuloma, randomized to receive silver nitrate cauterization (n = 104) or topical steroid ointment (n = 103). Healing rates after 2 weeks of treatment were 87.5% (91/104) in the silver nitrate cauterization and 82% (82/100) in the topical steroid ointment group group. The difference between groups was -5.5% (95% confidence interval, -19.1%, 8.4%), indicating that the non-inferiority criterion was not met. After 3 weeks of treatment, the healing rate with topical steroid ointment treatment was almost identical to that of silver nitrate cauterization (94/104 [90.4%] vs. 91/100 [91.0%]; 0.6% [-13.2 to 14.3]). No major complications occurred in either group. CONCLUSIONS: This study did not establish non-inferiority of topical steroid ointment treatment relative to silver nitrate cauterization, presumably due to lower healing rates than expected leading to an underpowered trial. However, considering that silver nitrate cauterization carries a distinct risk of chemical burns and that the overall efficacy of topical steroid ointment treatment is similar to that of silver nitrate cauterization, topical steroid ointment might be considered as a good alternative in the treatment of neonatal umbilical granuloma due to its safety and simplicity. To clarify non-inferiority, a larger study is needed.

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  34. Neurological disorders associated with human alphaherpesviruses Invited

    Jun-ichi Kawada

    Advances in Experimental Medicine and Biology   Vol. 1045   page: 85 - 102   2018

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    Herpes simplex virus (HSV) encephalitis is the most common cause of sporadic fatal encephalitis worldwide, and central nervous system (CNS) involvement is observed in approximately one-third of neonatal HSV infections. In recent years, single-gene inborn errors of innate immunity have been shown to be associated with susceptibility to HSV encephalitis. Temporal lobe abnormalities revealed by magnetic resonance imaging—the most sensitive imaging method for HSV encephalitis—are considered strong evidence for the disease. Detection of HSV DNA in the cerebrospinal fluid by polymerase chain reaction (PCR) is the gold standard for the diagnosis of HSV encephalitis and neonatal meningoencephalitis. Intravenous acyclovir for 14−21 days is the standard treatment in HSV encephalitis. Neurological outcomes in neonates are improved by intravenous high-dose acyclovir for 21 days followed by oral acyclovir suppressive therapy for 6 months. Varicella-zoster virus (VZV) causes a wide range of CNS manifestations. VZV encephalitis typically occurs after primary infection, and reactivation of VZV may cause encephalitis. On the other hand, VZV infection of cerebral arteries produces vasculopathy, which can manifest as ischemic stroke. Vasculopathy can occur after primary infection or reactivation of VZV. PCR detection of VZV DNA in the cerebrospinal fluid can be used for the diagnosis of encephalitis or vasculopathy. Although there are no controlled treatment trials to assess VZV treatments of encephalitis or vasculopathy, intravenous acyclovir is a common treatment.

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  35. Comprehensive detection of viruses in pediatric patients with acute liver failure using next-generation sequencing. Reviewed International journal

    Takako Suzuki, Jun-Ichi Kawada, Yusuke Okuno, Satoshi Hayano, Kazuhiro Horiba, Yuka Torii, Yoshiyuki Takahashi, Syuichiro Umetsu, Tsuyoshi Sogo, Ayano Inui, Yoshinori Ito

    Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology   Vol. 96   page: 67 - 72   2017.11

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    BACKGROUND: Pediatric acute liver failure (PALF) is a rare and severe syndrome that frequently requires liver transplantation. Viruses are one of the most frequent causes of this disease, however, pathogenic viruses are not determined in many patients. Recently next-generation sequencing (NGS) has been applied to comprehensively detect pathogens of infectious diseases of unknown etiology. OBJECTIVES: To evaluate an NGS-based approach for detecting pathogenic viruses in patients with PALF or acute hepatitis of unknown etiology. STUDY DESIGN: To detect virus-derived DNA and RNA sequences existing in sera/plasma from patients, both DNA and RNA sequencing were performed. First, we validated the ability of NGS to detect viral pathogens in clinical serum/plasma samples, and compared different commercial RNA library preparation methods Then, serum/plasma of fourteen patients with PALF or acute hepatitis of unknown etiology were evaluated using NGS. RESULTS: Among three RNA library preparation methods, Ovation RNA-Seq System V2 had the highest sensitivity to detect RNA viral sequences. Among fourteen patients, sequence reads of torque teno virus, adeno-associated virus, and stealth virus were found in the sera of one patient each, however, the pathophysiological role of these three viruses was not clarified. Significant virus reads were not detected in the remaining 11 patients. CONCLUSIONS: This finding might be due to low virus titer in blood at the time of referral or a non-infectious cause might be more frequent. These results suggest an NGS-based approach has potential to detect viral pathogens in clinical samples and would contribute to clarification of the etiology of PALF.

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  36. Metabolome analysis reveals the association between the kynurenine pathway and human herpesvirus 6 encephalopathy in immunocompetent children Reviewed

    Yuka Torii, Yoshihiko Kawano, Hajime Sato, Tamaki Fujimori, Kazunori Sasaki, Jun-ichi Kawada, Osamu Takikawa, Chai K. Lim, Gilles J. Guillemin, Yoshiaki Ohashi, Yoshinori Ito

    METABOLOMICS   Vol. 13 ( 11 )   2017.11

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    Introduction Human herpesvirus 6 (HHV-6) is the second most common causative pathogen of acute encephalopathy in immunocompetent children in Japan. Identification of biomarkers associated the pathophysiology is desirable to monitor disease severity, progression, and prognosis.
    Objectives To investigate potential biomarkers for HHV-6 encephalopathy, serum metabolome profiling was analyzed and candidate metabolites were investigated the function in the diseases.
    Methods Pediatric patients with HHV-6 encephalopathy (n = 8), febrile seizure (n = 20), and febrile infection without febrile seizure (n = 7) were enrolled in this study, and serum metabolites were identified and quantified. For further analysis, serum samples of HHV-6 infected patients were analyzed by absolute quantification assay for kynurenine (KYN) and quinolinic acid (QUIN) in a total of 38 patients with or without encephalopathy. An in vitro blood-brain barrier (BBB) model was used to evaluate the effect of KYN and QUIN on BBB integrity because BBB damage induces brain edema.
    Results Metabolome profiling identified 159 metabolites in serum samples. The levels of KYN and QUIN, which belong to the tryptophan-KYN pathway, were significantly higher in the HHV-6 encephalopathy group than the other two groups. When quantified in the larger patient group, remarkably high levels of KYN and QUIN were observed exclusively in the encephalopathy group. Trans-endothelial electrical resistance of the BBB model was significantly decreased after QUIN treatment in culture.
    Conclusion Metabolome analysis revealed that KYN and QUIN may be associated with the pathophysiology of HHV-6 encephalopathy. In particular, QUIN may damage BBB integrity.

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  37. Chronic High Epstein-Bar Virus Loads in Pediatric Liver Transplant Recipients - Risk Factors and Long-term Outcomes

    Kamei H., Ito Y., Ohnishi Y., Kawada J., Kurata N., Komagome M., Ogura Y.

    TRANSPLANTATION   Vol. 101 ( 5 ) page: 83 - 83   2017.5

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  38. Epstein-Barr virus infection-induced inflammasome activation in human monocytes Reviewed

    Yuka Torii, Jun-ichi Kawada, Takayuki Murata, Hironori Yoshiyama, Hiroshi Kimura, Yoshinori Ito

    PLOS ONE   Vol. 12 ( 4 ) page: e0175053   2017.4

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    Inflammasomes are cytoplasmic sensors that regulate the activity of caspase-1 and the secretion of interleukin-1 beta (IL-1 beta) or interleukin-18 (IL-18) in response to foreign molecules, including viral pathogens. They are considered to be an important link between the innate and adaptive immune responses. However, the mechanism by which inflammasome activation occurs during primary Epstein-Barr virus (EBV) infection remains unknown. Human B lymphocytes and epithelial cells are major targets of EBV, although it can also infect a variety of other cell types. In this study, we found that EBV could infect primary human monocytes and the monocyte cell line, THP-1, inducing inflammasome activation. We incubated cell-free EBV with THP-1 cells or primary human monocytes, then confirmed EBV infection using confocal microscopy and flow cytometry. Lytic and latent EBV genes were detected by real-time RT-PCR in EBV-infected monocytes. EBV infection of THP-1 cells and primary human monocytes induced caspase-dependent IL-1 beta production, while EBV infection of B-cell or T-cell lines did not induce IL-1 beta production. To identify the sensor molecule responsible for inflammasome activation during EBV infection, we examined the mRNA and the protein levels of NLR family pyrin domain-containing 3 (NLRP3), absent in melanoma 2 (AIM2), and interferon-inducible protein 16 (IFI16). Increased AIM2 levels were observed in EBV-infected THP-1 cells and primary human monocytes, whereas levels of IFI16 and NLRP3 did not show remarkable change. Furthermore, knockdown of AIM2 by small interfering RNA attenuated caspase-1 activation. Taken together, our results suggest that EBV infection of human monocytes induces caspase-1-dependent IL-1 beta production, and that AIM2, acting as an inflammasome, is involved in this response.

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  39. Analysis of circulating human and viral microRNAs in patients with congenital cytomegalovirus infection Reviewed

    Y. Kawano, J. Kawada, Y. Kamiya, M. Suzuki, Y. Torii, H. Kimura, Y. Ito

    JOURNAL OF PERINATOLOGY   Vol. 36 ( 12 ) page: 1101 - 1105   2016.12

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    OBJECTIVE: Cytomegalovirus (CMV) is the most common cause of congenital infection and can cause neurodevelopmental disabilities, although a majority of patients are asymptomatic. Biomarkers associated with disease severity would be desirable to distinguish asymptomatic from mildly symptomatic patients who may benefit from antiviral treatment. MicroRNAs (miRNAs) are noncoding RNAs that may have the potential to serve as biomarkers.
    STUDY DESIGN: Thirteen infants with congenital CMV infection were enrolled, and plasma levels of 11 human- and 3 CMV-encoded miRNAs were quantitated by real-time PCR. Plasma levels of miRNAs and their associations with clinical features were evaluated.
    RESULTS: The levels of miR-183-5p and miR-210-3p were significantly higher in patients with congenital CMV infection than in control infants, whereas no significant associations between levels of miRNAs and clinical features of congenital CMV infection were observed.
    CONCLUSION: Plasma miRNAs could be associated with the pathogenesis of congenital CMV infection and could be used as disease biomarkers.

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  40. Abnormal urinalysis on day 7 in patients with IgA vasculitis (Henoch-Schonlein purpura) Reviewed

    Nozomu Kawashima, Jun-ichi Kawada, Yuichi Nishikado, Yuma Kitase, Sanae Ito, Hideki Muramatsu, Yoshiaki Sato, Taichi Kato, Jun Natsume, Seiji Kojima

    Nagoya Journal of Medical Science   Vol. 78 ( 4 ) page: 359 - 367   2016.11

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    Rare progression to renal failure imposes a burden on children with IgA vasculitis (Henoch-Schonlein purpura, HSP). An abnormal urinalysis on day 7 (7d-UA) may be a surrogate marker for persistent nephritis, but this has not been established. We retrospectively analyzed the risk factors for persistent nephritis in a cohort of 138 children. Of 35 children with abnormal 7d-UA, 24 (69%) had an abnormal urinalysis 6 months after the diagnosis of HSP, which was significantly more than 6 of 103 children (6%) with normal 7d-UA (P &lt; 0.0001). The negative predictive values for normal urinalysis and negative proteinuria 6 months after diagnosis were 0.94 (95% confidence interval [CI], 0.90-0.97) and 0.98 (95% CI, 0.95-0.99), respectively. When children with abnormal urinalysis 6 months after diagnosis were compared with those without, the following factors were significantly associated: age at diagnosis, abnormal urinalysis at diagnosis, abnormal 7d-UA, complement C3, steroid treatment, and presence of abdominal pain. However, multivariate analysis revealed that abnormal 7d-UA was the only significant risk factor for abnormal urinalysis 6 months after diagnosis (odds ratio 54.3, 95% CI 15.3-275, P = 1.89 x 10(-6)). Abnormal 7d-UA may be an independent risk factor for persistent nephritis, but this should be confirmed in a prospective study.

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  41. Quantitative metabolome profiling reveals the involvement of the kynurenine pathway in influenza-associated encephalopathy Reviewed

    Yuka Torii, Yoshihiko Kawano, Hajime Sato, Kazunori Sasaki, Tamaki Fujimori, Jun-ichi Kawada, Osamu Takikawa, Chai K. Lim, Gilles J. Guillemin, Yoshiaki Ohashi, Yoshinori Ito

    METABOLOMICS   Vol. 12 ( 5 )   2016.5

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    Introduction Influenza-associated encephalopathy is a serious complication of influenza and is the most common form of acute encephalitis/encephalopathy in Japan. The number of reports from other countries is increasing, reflecting international recognition and concern.
    Objectives Identification of a specific biomarker could provide important clues about the pathophysiology of influenza-associated encephalopathy.
    Methods During the 2009-2011 flu seasons, 34 pediatric patients hospitalized with influenza complications, including influenza-associated encephalopathy, were enrolled in the study. Serum samples were collected during the acute and convalescent phases of disease. Patients were classified into encephalopathy (n = 12) and non-encephalopathy (n = 22) groups. Serum metabolites were identified and quantified by capillary electrophoresis coupled with time-of-flight mass spectrometry. Quantified data were evaluated for comparative analysis. Subsequently, a total of 55 patients with or without encephalopathy were enrolled for absolute quantification of serum kynurenine and quinolinic acid.
    Results Based on m/z values and migration times, 136 metabolites were identified in serum samples. During the acute phase of disease, three metabolites (succinic acid, undecanoic acid, and kynurenine) were significantly higher, and two other metabolites (decanoic acid and cystine) were significantly lower, in the encephalopathy group compared to the non-encephalopathy group (p = 0.012, 0.022, 0.044, 0.038, 0.046, respectively). In a larger patient group, serum kynurenine and its downstream product in tryptophan metabolism, quinolinic acid, a known neurotoxin, were significantly higher in the encephalopathy than the non-encephalopathy without febrile seizure group.
    Conclusion Comprehensive metabolite profiles revealed five metabolites as potential biomarkers for influenza-associated encephalopathy; the tryptophan-kynurenine metabolic process could be associated with its pathophysiology.

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  42. Tofacitinib induces G1 cell-cycle arrest and inhibits tumor growth in Epstein-Barr virus-associated T and natural killer cell lymphoma cells Reviewed

    Ando S, Kawada J, Watanabe T, Suzuki M, Sato Y, Torii Y, Asai M, Goshima F, Murata T, Shimizu N, Ito Y, Kimura H

    Oncotarget   Vol. 7 ( 47 ) page: 76793-76805   2016

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    DOI: 10.18632/oncotarget.12529.

  43. Abnormal urinalysis on day 7 in patients with IgA vasculitis Reviewed

    Kawashima N, Kawada J, Nishikado Y, Kitase Y, Ito S, Muramatsu M, Sato Y, Kato T, Natsume J, Kojima S

    Nagoya Journal of Medical Science   Vol. 78 ( 4 ) page: 359-368   2016

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    DOI: 10.18999/nagjms.78.4.359.

  44. Primary psoas abscess caused by group A streptococcus in a child: Case report with microbiologic findings Reviewed

    Kamiya Y, Hasegawa T, Takegami Y, Horiba K, Ando S, Torii Y, Kidokoro H, Kato K, Natsume J, Kawada J, Ito Y

    Journal of Infection and Chemotherapy   Vol. 22 ( 12 ) page: 811-814   2016

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    DOI: 10.1016/j.jiac.2016.06.011.

  45. Identification of Viruses in Cases of Pediatric Acute Encephalitis and Encephalopathy Using Next-Generation Sequencing

    Kawada J, Okuno Y, Torii Y, Okada R, Hayano S, Ando S, Kamiya Y, Kojima S, Ito Y

    Scientific Reports   Vol. 6   page: 33452   2016

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  46. Recurrent neonatal herpes simplex virus infection with central nervous system disease after completion of a 6-month course of suppressive therapy: Case report.

    Kato K, Hara S, Kawada J, Ito Y

    Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy   Vol. 21 ( 12 ) page: 879 - 81   2015.12

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    DOI: 10.1016/j.jiac.2015.08.005

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  47. Serum microRNAs as Potential Biomarkers of Juvenile Idiopathic Arthritis.

    Clinical rheumatology   Vol. 34 ( 10 ) page: 1705-1712   2015.10

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  48. Viral load in children with congenital cytomegalovirus infection identified on newborn hearing screening Reviewed

    Jun-ichi Kawada, Yuka Torii, Yoshihiko Kawano, Michio Suzuki, Yasuko Kamiya, Tomomi Kotani, Fumitaka Kikkawa, Hiroshi Kimura, Yoshinori Ito

    Journal of Clinical Virology   Vol. 65   page: 41 - 45   2015.4

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    Background: Congenital cytomegalovirus (CMV) infection is the most common non-genetic cause of sensorineural hearing loss (SNHL) in children. However, congenital SNHL without other clinical abnormalities is rarely diagnosed as CMV-related in early infancy.
    Objectives: The aim of this study was to identify and treat patients with congenital CMV-related SNHL or CMV-related clinical abnormalities other than SNHL. The association between CMV load and SNHL was also evaluated.
    Study design: Newborns who had abnormal hearing screening results or other clinical abnormalities were screened for congenital CMV infection by PCR of saliva or urine specimens, and identified infected patients were treated with valganciclovir (VGCV) for 6 weeks. The CMV load of patients with or without SNHL was compared at regular intervals during as well as after VGCV treatment.
    Results: Of 127 infants with abnormal hearing screening results, and 31 infants with other clinical abnormalities, CMV infection was identified in 6 and 3 infants, respectively. After VGCV treatment, 1 case had improved hearing but the other 5 SNHL cases had little or no improvement. Among these 9 patients with or without SNHL at 1 year of age, there was no significant difference in CMV blood or urine load at diagnosis, but both were significantly higher in patients with SNHL during VGCV treatment.
    Conclusions: Selective CMV screening of newborns having an abnormal hearing screening result would be a reasonable strategy for identification of symptomatic congenital CMV infection. Prolonged detection of CMV in blood could be a risk factor for SNHL. (C) 2015 Elsevier B.V. All rights reserved.

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  49. Effectiveness and safety of immunization with live-attenuated and inactivated vaccines for pediatric liver transplantation recipients

    Yoshihiko Kawano, Michio Suzuki, Jun-ichi Kawada, Hiroshi Kimura, Hideya Kamei, Yasuharu Ohnishi, Yasuyuki Ono, Hiroo Uchida, Yasuhiro Ogura, Yoshinori Ito

    VACCINE   Vol. 33 ( 12 ) page: 1440 - 1445   2015.3

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    Background: Liver transplantation recipients are at high risk for severe complications due to infections because of being treated with immunosuppressive drugs that affect the immune system. Vaccination for liver transplantation candidates is generally recommended before surgery, but the opportunities for vaccination prior to transplantation in pediatric candidates are often limited by severe disease conditions.
    Methods: The participants in this study comprised 39 pediatric recipients of living donor liver transplantation performed between 2005 and 2013. Criteria for administering live-attenuated (measles, rubella, mumps, and varicella) and inactivated (hepatitis B, pertussis, and Japanese encephalitis) vaccines were as follows; (1) &gt;1 year after transplantation; (2) no use of systemic steroids to treat acute rejection within the last 6 months; (3) serum trough concentration of tacrolimus &lt;5 ng/mL; (4) no severe immunosuppression according to blood examinations; and (5) provision of written informed consent. Median age at transplantation was 17 months, and median period from transplantation to the beginning of immunization was 18 months.
    Results: Seroprotection rates for measles, rubella, mumps, varicella, hepatitis B, pertussis, and Japanese encephalitis after post-transplant immunization were 44% (11/25), 70% (19/27), 48% (12/25), 32% (6/19), 83% (19/23), 87% (13/15), and 88% (7/8), respectively. Seroprotection rates for measles, rubella, mumps, and varicella after second vaccination for recipients with primary vaccine failure after first vaccination were 100% (8/8), 50% (1/2), 71% (5/7), and 50% (5/10), respectively. While four recipients contracted mumps and eight contracted varicella before immunization, one recipient developed varicella after immunization. No serious systemic adverse events were observed in vaccinated recipients.
    Conclusions: Seroprotection rates for measles, mumps, and varicella appeared low in children after the first post-transplantation vaccination. Immunizations with four live-attenuated and three inactivated vaccines were safe and effective for pediatric liver transplantation recipients who were not severely immunosuppressed. (C) 2015 Published by Elsevier Ltd.

    DOI: 10.1016/j.vaccine.2015.01.075

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  50. The heat shock protein 90 inhibitor BIIB021 suppresses the growth of T and natural killer cell lymphomas

    Suzuki M, Takeda T, Nakagawa H, Iwata S, Watanabe T, Siddiquey MN, Goshima F, Murata T, Kawada J, Ito Y, Kojima S, Kimura H

    Frontiers in microbiology   Vol. 6   page: 280   2015

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  51. Diagnostic values for the viral load in peripheral blood mononuclear cells of patients with chronic active Epstein-Barr virus disease Reviewed

    Ito Y, Suzuki M, Kawada J, Kimura H

    Journal of Infection and Chemotherapy   Vol. 22   page: 268-271   2015

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  52. Fulminant adenovirus hepatitis after hematopoietic stem cell transplant: Retrospective real-time PCR analysis for adenovirus DNA in two cases Reviewed

    Kawashima N, Muramatsu H, Okuno Y, Torii Y, Kawada J, Narita A, Nakanishi K, Hama A, Kitamura A, Asai N, Nakamura S, Takahashi Y, Ito Y, Kojima S

    Journal of Infection and Chemotherapy   Vol. 21   page: 857-863   2015

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  53. Recurrent neonatal herpes simplex virus infection with central nervous system disease after completion of a 6-month course of suppressive therapy Reviewed

    Kato K, Hara S, Kawada J, Ito Y

    Journal of Infection and Chemotherapy   Vol. 21   page: 879-881   2015

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  54. mTOR Inhibitors Induce Cell-Cycle Arrest and Inhibit Tumor Growth in Epstein-Barr Virus-Associated T and Natural Killer Cell Lymphoma Cells Reviewed

    Jun-ichi Kawada, Yoshinori Ito, Seiko Iwata, Michio Suzuki, Yoshihiko Kawano, Tetsuhiro Kanazawa, Mohammed Nure Alam Siddiquey, Hiroshi Kimura

    CLINICAL CANCER RESEARCH   Vol. 20 ( 21 ) page: 5412 - 5422   2014.11

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    Purpose: Epstein-Barr virus (EBV) infects B cells, as well as T cells and natural killer (NK) cells, and is associated with T or NK cell lymphoid malignancies. In various tumor cells, mTOR performs an essential function together with Akt with regard to cell growth. We investigated the effects of mTOR inhibitors on EBV-associated T-and NK-cell lymphomas.
    Experimental Design: We investigated the Akt/mTOR activation pathway in EBV-positive and -negative T-and NK-cell lines (SNT13, SNT16, Jurkat, SNK6, KAI3, and KHYG1). We evaluated the antitumor effects of mTOR inhibitors (rapamycin and its analogue, CCI-779) against these cell lines in culture and in a murine xenograft model that was established by subcutaneous injection of SNK6 cells into NOG mice.
    Results: All EBV-positive and -negative T- and NK-cell lines tested displayed activation of the Akt/mTOR pathway, and treatment with mTOR inhibitors suppressed mTOR activation. The inhibitors inducedG1 cell-cycle arrest and inhibited cell proliferation in T- and NK-cell lines. Overall, T cell lines were more sensitive to rapamycin, but there were no significant differences between EBV-positive and -negative cell lines. Treatment with rapamycin did not affect lytic or latent EBV gene expression. Intraperitoneal treatment with CCI-779 significantly inhibited the growth of established tumors in NOG mice and reduced the EBV load in peripheral blood.
    Conclusion: These results suggest that inhibition of mTOR signaling is a promising new strategy for improving treatment of EBV-associated T-and NK-cell lymphoma. (C) 2014 AACR.

    DOI: 10.1158/1078-0432.CCR-13-3172

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  55. Epstein-Barr virus microRNAs in plasma as potential biomarkers for chronic infections: reply to Makarewicz et al. Reviewed

    Kawano Y, Kawada J, Ito Y.

    J Infect Dis   Vol. 209 ( 8 ) page: 1298-300   2014.4

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  56. Hyperferritinemia in neonatal and infantile human parechovirus-3 infection in comparison with other infectious diseases

    Hara S, Kawada J, Kawano Y, Yamashita T, Minagawa H, Okumura N, Ito Y.

    J Infect Chemother   Vol. 20 ( 1 ) page: 15-19   2014.1

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  57. Identification of a novel HLA-A*24:02-restricted adenovirus serotype 11-specific CD8(+) T-cell epitope for adoptive immunotherapy. Reviewed

    Imahashi N, Nishida T, Ito Y, Kawada J, Nakazawa Y, Toji S, Suzuki S, Terakura S, Kato T, Murata M, Naoe T.

    Mol Immunol   Vol. 2013 ( 56 ) page: 399-405.   2013.12

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  58. Immunogenicity of inactivated seasonal influenza vaccine in adult and pediatric liver transplant recipients over two seasons Reviewed

    Suzuki M, Torii Y, Kawada J, Kimura H, Kamei H, Onishi Y, Kaneko K, Ando H, Kiuchi T, Ito Y.

    Microbiol Immunol   Vol. 57 ( 10 ) page: 715-722   2013.10

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  59. Plasma viral microRNA profiles reveal potential biomarkers for chronic active Epstein-Barr virus infection. Reviewed

    Kawano Y, Iwata S, Kawada J, Gotoh K, Suzuki M, Torii Y, Kojima S, Kimura H, Ito Y.

    The Journal of infectious diseases   Vol. 208 ( 5 ) page: 771-779   2013.9

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  60. Clinical characteristics of influenza virus infection in juvenile idiopathic arthritis patients treated with tocilizumab Reviewed

    Jun-ichi Kawada, Yoshiro Kitagawa, Naomi Iwata, Yoshinori Ito

    MODERN RHEUMATOLOGY   Vol. 23 ( 5 ) page: 972 - 6   2013.9

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    Inhibition of interleukin-6 (IL-6) signaling by tocilizumab is highly effective for treatment of refractory juvenile idiopathic arthritis (JIA). It appears that IL-6 plays an important role in the immune response to the influenza virus, but it is not clear whether treatment with tocilizumab affects the severity of influenza.
    We retrospectively collected clinical and laboratory data from JIA patients (n = 33) treated with tocilizumab. Ten patients who developed influenza (tocilizumab group; 10.1 %, 10/99 patient-years) were analyzed. Eleven JIA patients who experienced influenza during conventional treatments, without tocilizumab (control group), were compared with the tocilizumab group.
    Of the 10 patients in the tocilizumab group, 6 patients did not have high fever (&gt; 38 A degrees C), and the other 4 febrile patients recovered from fever in 1 day. White blood cell counts and lymphocyte counts were significantly lower at the acute phase of infection compared with data from before influenza infection. The degree of fever and level of C-reactive protein in the tocilizumab group were significantly reduced compared with the control group.
    IL-6 inhibition by tocilizumab reduced inflammation associated with infection and resulted in mild symptoms during influenza. Leukopenia might be a useful indicator of viral infection, including influenza, during tocilizumab treatment.

    DOI: 10.1007/s10165-012-0780-0

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  61. Epstein-Barr Virus-Associated Lymphoid Malignancies Reviewed

    Kimura H, Kawada J, Ito Y.

    Nagoya Journal of Medical Science   Vol. 75   page: 169-179   2013.8

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  62. Remission of juvenile idiopathic arthritis with primary Epstein-Barr virus infection Reviewed

    Jun-ichi Kawada, Yoshinori Ito, Yuka Torii, Hiroshi Kimura, Naomi Iwata

    RHEUMATOLOGY   Vol. 52 ( 5 ) page: 956 - 958   2013.5

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    DOI: 10.1093/rheumatology/kes299

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  63. Identification of an HLA-A*24:02-restricted adenovirus serotype 11 epitope recognized by cytotoxic T-cells

    Imahashi N., Nishida T., Terakura S., Ito Y., Kawada J., Nakazawa Y., Kato T., Murata M., Naoe T.

    BONE MARROW TRANSPLANTATION   Vol. 48   page: S303 - S303   2013.4

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  64. Demonstration of type II latency in T lymphocytes of Epstein-Barr Virus-associated hemophagocytic lymphohistiocytosis Reviewed

    Yoshinori Ito, Yoshiki Kawamura, Seiko Iwata, Jun-ichi Kawada, Tetsushi Yoshikawa, Hiroshi Kimura

    PEDIATRIC BLOOD & CANCER   Vol. 60 ( 2 ) page: 326 - 328   2013.2

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    EpsteinBarr virus (EBV) is the most common infectious cause of non-genetic hemophagocytic lymphohistiocytosis (HLH). To investigate EBV-infected lymphocytes and immune dysfunction in EBV-associated HLH, blood samples from a 6-year-old boy were longitudinally analyzed using molecular techniques. EBV-positive lymphocytes were detected as CD5+, CD8+, and/or HLA DR+ lymphocytes on Day 25 of the disease, mostly disappearing thereafter. CD8+ cells specific for lytic antigen BRLF1 were detected, but cells specific for latent antigens EBNA3 and LMP2 were not. EBV genes EBNA1, LMP1, LMP2, EBER1, BARTs were detected, suggesting a latency type II gene expression pattern in this case. Pediatr Blood Cancer 2013;60:326328. (c) 2012 Wiley Periodicals, Inc.

    DOI: 10.1002/pbc.24319

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  65. Causes of vertical transmission of hepatitis B virus under the at-risk prevention strategy in Japan Reviewed

    Torii Y, Kimura H, Hayashi K, Suzuki M, Kawada J, Kojima S, Katano Y, Goto H, Ito Y.

    Microbiol Immunol   Vol. 57 ( 2 ) page: 118-121   2013.2

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  66. Interleukin-17A-producing T lymphocytes in chronic active Epstein-Barr virus infection Reviewed

    Ohta R, Imai M, Kawada J, Kimura H, Ito Y.

    Microbiol Immunol   Vol. 57   page: 139-44   2013

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  67. Clinical characteristics of norovirus gastroenteritis among hospitalized children in Japan Reviewed

    Jun-Ichi Kawada, Naoko Arai, Naoko Nishimura, Michio Suzuki, Rieko Ohta, Takao Ozaki, Yoshinori Ito

    MICROBIOLOGY AND IMMUNOLOGY   Vol. 56 ( 11 ) page: 756 - 759   2012.11

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    Acute diarrhea is one of commonest pediatric illnesses worldwide. Although the importance of norovirus as a cause of gastroenteritis outbreaks is well documented, its role in sporadic acute gastroenteritis is not well characterized. The aim of this study was to clarify the prevalence and clinical characteristics of norovirus gastroenteritis among hospitalized children. Between November 2007 and April 2008, inpatients under 12 years of age with acute gastroenteritis in a single hospital in Japan were investigated. A stool sample from each patient was screened for enteropathogenic bacteria and tested by reverse transcription polymerase reaction for norovirus and by an immunochromatographic method for rotavirus and enteric adenoviruses. The clinical features of children with norovirus gastroenteritis were compared with those of children with rotavirus and children without noro- or rotovirus infections. Among 107 patients included in this study, norovirus and rotavirus were detected in 36 (34%) and 37 (35%) patients, respectively. Compared with rotavirus enteritis, the duration of vomiting and diarrhea was significantly longer, and serum C-reactive protein concentrations were higher, in patients with norovirus enteritis. Norovirus was detected as frequently as rotavirus in hospitalized pediatric gastroenteritis patients. Our results suggest that norovirus gastroenteritis among hospitalized young children is not less severe than rotavirus gastroenteritis.

    DOI: 10.1111/j.1348-0421.2012.00498.x

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  68. Prospective monitoring of Epstein-Barr virus and other herpesviruses in patients with juvenile idiopathic arthritis treated with methotrexate and tocilizumab. Reviewed

    Kawada J, Iwata N, Kitagawa Y, Kimura H, Ito Y

    Mod Rheumatol     page: 565-70   2012.8

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  69. Antitumor activities of valproic acid on Epstein-Barr virus-associated T and natural killer lymphoma cells Reviewed

    Seiko Iwata, Takashi Saito, Yoshinori Ito, Maki Kamakura, Kensei Gotoh, Jun-ichi Kawada, Yukihiro Nishiyama, Hiroshi Kimura

    CANCER SCIENCE   Vol. 103 ( 2 ) page: 375 - 381   2012.2

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    EpsteinBarr virus (EBV), which infects B cells, T cells, and natural killer (NK) cells, is associated with multiple lymphoid malignancies. Recently, histone deacetylase (HDAC) inhibitors have been reported to have anticancer effects against various tumor cells. In the present study, we evaluated the killing effect of valproic acid (VPA), which acts as an HDAC inhibitor, on EBV-positive and -negative T and NK lymphoma cells. Treatment of multiple T and NK cell lines (SNT13, SNT16, Jurkat, SNK6, KAI3 and KHYG1) with 0.1-5 mM of VPA inhibited HDAC, increased acetylated histone levels and reduced cell viability. No significant differences were seen between EBV-positive and -negative cell lines. Although VPA induced apoptosis in some T and NK cell lines (SNT16, Jurkat and KHYG1) and cell cycle arrest, it did not induce lytic infection in EBV-positive T or NK cell lines. Because the killing effect of VPA was modest (1 mM VPA reduced cell viability by between 22% and 56%), we tested the effects of the combination of 1 mM of VPA and 0.01 mu M of the proteasome inhibitor bortezomib. The combined treated of cells with VPA and bortezomib had an additive killing effect. Finally, we administered VPA to peripheral blood mononuclear cells from three patients with EBV-associated T or NK lymphoproliferative diseases. In these studies, VPA had a greater killing effect against EBV-infected cells than uninfected cells, and the effect was increased when VPA was combined with bortezomib. These results indicate that VPA has antitumor effects on T and NK lymphoma cells and that VPA and bortezomib may have synergistic effects, irrespective of the presence of EBV. (Cancer Sci 2012; 103: 375381)

    DOI: 10.1111/j.1349-7006.2011.02127.x

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  70. Bortezomib induces apoptosis in T lymphoma cells and natural killer lymphoma cells independent of Epstein-Barr virus infection

    Seiko Iwata, Shoko Yano, Yoshinori Ito, Yoko Ushijima, Kensei Gotoh, Jun-ichi Kawada, Shigeyoshi Fujiwara, Koichi Sugimoto, Yasushi Isobe, Yukihiro Nishiyama, Hiroshi Kimura

    INTERNATIONAL JOURNAL OF CANCER   Vol. 129 ( 9 ) page: 2263 - 2273   2011.11

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    Epstein-Barr virus (EBV), which infects not only B cells, but also T cells and natural killer (NK) cells, is associated with multiple lymphoid malignancies. Recently, the proteasome inhibitor bortezomib was reported to induce apoptosis of EBV-transformed B cells. We evaluated the killing effect of this proteasome inhibitor on EBV-associated T lymphoma cells and NK lymphoma cells. First, we found that bortezomib treatment decreased the viability of multiple T and NK cell lines. No significant difference was observed between EBV-positive and EBV-negative cell lines. The decreased viability in response to bortezomib treatment was abrogated by a pan-caspase inhibitor. The induction of apoptosis was confirmed by flow cytometric assessment of annexin V staining. Additionally, cleavage of caspases and polyadenosine diphosphate-ribose polymerase, increased expression of phosphorylated I kappa B, and decreased expression of inhibitor of apoptotic proteins were detected by immunoblotting in bortezomib-treated cell lines. We found that bortezomib induced lytic infection in EBV-positive T cell lines, although the existence of EBV did not modulate the killing effect of bortezomib. Finally, we administered bortezomib to peripheral blood mononuclear cells from five patients with EBV-associated lymphoproliferative diseases. Bortezomib had a greater killing effect on EBV-infected cells. These results indicate that bortezomib killed T or NK lymphoma cells by inducing apoptosis, regardless of the presence or absence of EBV.

    DOI: 10.1002/ijc.25873

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  71. Cytomegalovirus and Epstein-Barr virus coinfection in three toddlers with prolonged illnesses. Reviewed

    Ito Y, Shibata-Watanabe Y, Kawada J, Maruyama K, Yagasaki H, Kojima S, Kimura H

    J Med Virol   Vol. 81 ( 8 ) page: 1399-402   2009.8

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  72. Tubacin kills Epstein-Barr virus (EBV)-Burkitt lymphoma cells by inducing reactive oxygen species and EBV lymphoblastoid cells by inducing apoptosis. Reviewed

    Kawada J, Zou P, Mazitschek R, Bradner JE, Cohen JI

    Kawada J, Zou P, Mazitschek R, Bradner JE, Cohen JI   Vol. 284 ( 25 ) page: 17102-9   2009.6

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  73. Multiplex real-time PCR for the simultaneous detection of herpes simplex virus, human herpesvirus 6, and human herpesvirus 7. Reviewed

    Wada K, Mizoguchi S, Ito Y, Kawada J, Yamauchi Y, Morishima T, Nishiyama Y, Kimura H

    Microbiol Immunol   Vol. 53 ( 1 ) page: 22-9   2009.1

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  74. Oropharyngeal shedding of Epstein-Barr virus in the absence of circulating B cells. Reviewed

    Hoover SE, Kawada J, Wilson W, Cohen JI.

    J Infect Dis   Vol. 198 ( 3 ) page: 318-23   2008.8

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  75. Clinical and virological characteristics of 15 patients with chronic active Epstein-Barr virus infection treated with hematopoietic stem cell transplantation. Reviewed

    Gotoh K, Ito Y, Shibata-Watanabe Y, Kawada J, Takahashi Y, Yagasaki H, Kojima S, Nishiyama Y, Kimura H

    Clin Infect Dis   Vol. 46 ( 10 ) page: 1525-34   2008.5

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  76. Oligonucleotide microarray analysis of gene expression profiles followed by real-time reverse-transcriptase polymerase chain reaction assay in chronic active Epstein-Barr virus infection. Reviewed

    Ito Y, Shibata-Watanabe Y, Ushijima Y, Kawada J, Nishiyama Y, Kojima S, Kimura H

    J Infect Dis   Vol. 197 ( 5 ) page: 663-6   2008.5

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  77. Bortezomib induce aoptosis of Epstein-Barr virus (EBV)-transformed B cells and prolongs survival of mice inoculated with EBV-transformed B cells Reviewed

    Ping Zou, Junichi Kawada, Lesley Pesnicak, Jeffrey I. Cohen

    JOURNAL OF VIROLOGY   Vol. 81 ( 18 ) page: 10029 - 10036   2007.9

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    Bortezomib, an inhibitor of the 26S proteasome, is currently approved for treatment of multiple myeloma and is being studied for therapy of non-Hodgkin's lymphoma. We found that Epstein-Barr virus (EBV) -positive B cells with type III latency were more susceptible to killing by bortezomib than those with type I latency. Bortezomib induced apoptosis of EBV lymphoblastoid cell lines (LCLs) by inducing cleavage of caspases 8 and 9; apoptosis was inhibited by pretreatment with a pan-caspase inhibitor. Bortezomib reduced the levels of the p50 and p65 components of the canonical NF-kappa B pathway and reduced the level of p52 in the noncanonical NF-kappa B pathway, which is induced by EBV LMP1. Bortezomib inhibited expression of cIAP-1, cIAP-2, and XIAP, which are regulated by NF-kappa B and function as inhibitors of apoptosis. Bortezomib did not inhibit expression of several other antiapoptotic proteins, including Bcl-2 and Bcl-XL. Finally, bortezomib significantly prolonged the survival of severe combined immunodeficiency mice inoculated with LCLs. These findings suggest that bortezomib may represent a novel strategy for the treatment of certain EBV-associated lymphomas.

    DOI: 10.1128/JVI.02241-06

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  78. Bortezomib induces apoptosis of Epstein-Barr virus (EBV)-transformed B cells and prolongs survival of mice inoculated with EBV-transformed B cells. Reviewed

    Zou P, Kawada J, Pesnicak L, Cohen JI

    J Virol   Vol. 81 ( 8 ) page: 10029-36   2007.9

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  79. Rapid detection of Epstein-Barr virus DNA by loop-mediated isothermal amplification method. Reviewed

    Iwata S, Shibata Y, Kawada J, Hara S, Nishiyama Y, Morishima T, Ihira M, Yoshikawa T, Asano Y, Kimura H

    J Clin Virol   Vol. 37 ( 2 ) page: 128-33   2006.10

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  80. Analysis of gene-expression profiles by oligonucleotide microarray in children with influenza. Reviewed

    Kawada J, Kimura H, Kamachi Y, Nishikawa K, Taniguchi M, Nagaoka K, Kurahashi H, Kojima S, Morishima T

    J Gen Virol   Vol. 87 ( 6 ) page: 1677-83   2006.6

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  81. Fatal varicella infection in a girl with systemic lupus erythematosus after oral acyclovir prophylaxis. Reviewed

    Hirose I, Ymamaguchi H, Inaguma D, Ono K, Shimada S, Kawada J, Shiraki K, Kimura H

    Eur J Pediatr   Vol. 165 ( 4 ) page: 280-1   2006.4

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  82. Evaluation of apoptosis in Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis. Reviewed

    Kawada J, Kimura H, Shibata Y, Hara S, Hoshino Y, Kojima S, Nishikawa K, Morishima T

    J Med Virol   Vol. 78 ( 3 ) page: 400-7   2006.3

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  83. Evaluation of Apoptosis in Epstein-Barr Virus-Associated Haemophagocytic Lymphohistiocytosis. Reviewed

    Kawada J, Kimura H, Shibata Y, Hara S, Hoshino Y, Kojima S, Nishikawa K, Morishima T

    J Mel Virol   Vol. 17 ( 78 ) page: 400-407   2006

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  84. Rapid detection of herpes simplex virus DNA in cerebrospinal fluid: comparison between loop-mediated isothermal amplification and real-time PCR. Reviewed

    Kimura H, Ihira M, Enomoto Y, Kawada J, Ito Y, Morishima T, Yoshikawa T, Asano Y

    Med Microbiol Immunol   Vol. 194 ( 4 ) page: 181-5   2005.8

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  85. Differences between T cell-type and natural killer cell-type chronic active Epstein-Barr virus infection. Reviewed

    Kimura H, Hoshino Y, Hara S, Sugaya N, Kawada J, Shibata Y, Kojima S, Nagasaka T, Kuzushima K, Morishima T

    J Infect Dis   Vol. 191 ( 4 ) page: 531-9   2005.2

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  86. Association of cytomegalovirus with infantile hepatitis. Reviewed

    Shibata Y, Kitajima N, Kawada J, Sugaya N, Nishikawa K, Morishima T, Kimura H

    Microbiol Immunol   Vol. 49 ( 8 ) page: 771-7   2005

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  87. Hemiconvulsion-hemiplegia syndrome and primary human herpesvirus 7 infection. Reviewed

    Kawada J, Kimura H, Yoshikawa T, Ihira M, Okumura A, Morishima T, Hayakawa F

    Brain Dev   Vol. 26 ( 6 ) page: 412-4   2004.9

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  88. Evaluation of systemic inflammatory responses in neonates with herpes simplex virus infection. Reviewed

    Kawada J, Kimura H, Ito Y, Ando Y, Tanaka-Kitajima N, Hayakawa M, Nunoi H, Endo F, Morishima T

    J Infect Dis   Vol. 190 ( 3 ) page: 494-8   2004.8

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  89. Influenza virus and febrile convulsions. Reviewed

    Kawada J, Kimura H, Morishima, T.

    J Infect Dis   Vol. 189 ( 3 ) page: 564-565   2004.2

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  90. Comparison of real-time and nested PCR assays for detection of herpes simplex virus DNA. Reviewed

    Kawada J, Kimura H, Ito Y, Hoshino Y, Tanaka-Kitajima N, Ando Y, Futamura M, Morishima T

    Microbiol Immunol   Vol. 48 ( 5 ) page: 411-5   2004

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  91. Systemic cytokine responses in patients with influenza-associated encephalopathy. Reviewed

    Kawada J, Kimura H, Ito Y, Hara S, Iriyama M, Yoshikawa T, Morishima T

    J Infect Dis   Vol. 188 ( 5 ) page: 690-8   2003.9

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  92. Absence of associations between influenza-associated encephalopathy and human herpesvirus 6 or human herpesvirus 7. Reviewed

    Kawada J, Kimura H, Hara S, Ito Y, Kawashima H, Okuno T, Morishima T

    Pediatr Infect Dis J   Vol. 22 ( 2 ) page: 115-9   2003.2

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Books 1

  1. Human Herpesviruses, Neurological Disorders Associated with Human Alphaherpesviruses

    Kawada J( Role: Contributor)

    Springer, Singapore  2018.6  ( ISBN:978-981-10-7229-1

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    Language:English Book type:Scholarly book

Research Project for Joint Research, Competitive Funding, etc. 3

  1. EBウイルス関連T/NKリンパ増殖性症に対する Jak阻害剤の治療効果の検討

    2015

    第40回がんその他の悪性新生物研究助成 

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    Grant type:Competitive

  2. EBウイルス関連T/NKリンパ増殖症 に対する新規分子標的薬剤の効果

    2014.4 - 2016.3

    武田科学振興財団 生命科学研究助成 

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    Grant type:Competitive

  3. 小児リウマチ性疾患におけるmiRNAの網羅的な解析

    2014

    森永奉仕会奨励金 

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    Grant type:Competitive

KAKENHI (Grants-in-Aid for Scientific Research) 5

  1. 微生物叢・シングルセル遺伝子解析によるウイルス性肺炎の重症化機序の解明

    Grant number:21K07748  2021.4 - 2024.3

    川田 潤一

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    Authorship:Principal investigator 

    Grant amount:\4160000 ( Direct Cost: \3200000 、 Indirect Cost:\960000 )

  2. 次世代シークエンスによる包括的な重症感染症リキッドバイオプシー

    Grant number:19K08298  2019.4 - 2022.3

    伊藤 嘉規

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    Authorship:Coinvestigator(s) 

    近年の分子生物学の進展を応用し、侵襲性の少ない、包括的(微生物と生体情報をともに含む)な重症診断法開発の基盤となる研究を行う。病原微生物である、細菌、ウイルス、真菌などは、培養や核酸検出など様々な方法で検出されるが、次世代シークエンスは網羅的な微生物検出が可能である。他方、血液などの体液中には、細胞から分泌されるエクソソーム、Cell-free DNA、マイクロRNAが存在する。これらの微小な細胞由来分子を分離・解析し、重症感染症患者の炎症反応、免疫応答や臓器障害に関する評価を行い、リキッドバイオプシー(体液による病態解析・診断)を可能とするアッセイシステムを構築する。
    小児期には急性脳炎・脳症、劇症肝炎・急性肝不全、心筋炎などの重篤な感染症が存在する。基礎疾患や免疫抑制剤の投与により易感染性を示す患者は、血流感染症などの重症感染症のリスクにさらされる。これら重症感染症では、病原微生物は幅広く、通常は複数の検査を平行して病原微生物の同定を試みる。重症感染症では、早期診断と適切な抗微生物薬の選択が予後を左右する。次世代シークエンス法は、一度のアッセイで、1,000万~10億程度のリード(DNA・RNA断片のシークエンス数)を得ることができ、臨床検体中の核酸断片を網羅的・定量的に解析できる。さらに薬剤耐性も同時に解析可能である。重症感染症における病原微生物診断は現状では不十分であり、多くの症例で診断できれば、抗微生物薬の効率的な使用が可能になり、感染症診療に大きな進展が予想される。生体内の微生物分布(マイクロバイオーム)を調べる方法は臨床診断法にそのまま応用できない。次世代シークエンス法を臨床応用できる基盤的研究を推進し、重症感染症の病原を早期に網羅的に診断できる方法を開発する。
    2019年度は、150bpの断片配列を読むショートリード法、網羅的な解析を念頭にショットガン法により、血液培養・核酸検出法に比べて、病原微生物検出における次世代シークエンスの位置づけを検討した。シークエンスデータの解析は、2019年12月にウェブ上で公開した解析パイプライン「PATHDET」(新規に開発)を使用した。発熱性好中球減少症の病原微生物確定診断例は10~20%であり、多くは原因不明である。次世代シークエンス法による病原微生物の診断は、血液培養陽性例では全例可能であり、血液培養陰性例では15%程度の症例で病原微生物が検出できた。
    2019年は主に発熱性好中球減少症の血漿検体を解析し、次世代シークエンス診断法の優位性を示唆する結果を得た。重症感染症の臨床検体中のcell-free DNAやmiRNAの分離・解析について、検討を進めている。
    発熱性好中球減少症以外の疾患のデータを蓄積する。
    次世代シークエンスを用いて、重症感染症の血液・髄液検体のcell-free DNAおよびmiRNAの分離・解析を進め、感染症の急性期に病態把握につながる結果が得られないか、引き続き検討する。重症感染症におけるリンパ球検体を用いた次世代シークエンス解析により、免疫応答を多面的に解析できないか、検討する。

  3. Comprehensive detection of viruses in pediatric patients with severe infectious diseases using next-generation sequencing

    Grant number:17K10107  2017.4 - 2020.3

    Kawada Jun-ichi

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    Authorship:Principal investigator 

    Grant amount:\4550000 ( Direct Cost: \3500000 、 Indirect Cost:\1050000 )

    Next-generation sequencing (NGS) has been applied to the diagnosis of infectious diseases. The present study aimed to comprehensively analyze potential pathogenic viruses using NGS in clinical samples obtained from pediatric patients with severe diseases including fulminant hepatitis, myocarditis, and pneumonia. DNA and RNA sequencing libraries were prepared using extracted nuclear acids from clinical samples and then analyzed by NGS. Viral sequence reads were detected in 2 and 6 serum samples obtained from 14 fulminant hepatitis patients and 17 myocarditis patients, respectively. On the other hand, bronchoalveolar lavage fluid samples were used to detect viral pathogens in severe pneumonia, and viral sequence reads were detected in 7 of the 10 patients. Among them, enterovirus D 68 was detected in 2 patients. These data indicate that comprehensive detection of virus-derived DNA and RNA using NGS can be useful for the identification of pathogenic viruses in infectious diseases.

  4. 若年性特発性関節炎における新規バイオマーカーとしてのmiRNAの同定

    2014.4 - 2017.3

    科学研究費補助金  基盤研究(C)

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    Authorship:Principal investigator 

  5. 新規薬剤治療中の小児リウマチ疾患における重症ウイルス感染症の発症予測・病態の解析

    2012.4 - 2014.3

    科学研究費補助金  若手研究(B)

    川田潤一

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    Authorship:Principal investigator