Publications by authors named "Takashi Oka"

112 Publications

Systematic analysis of exonic germline and postzygotic de novo mutations in bipolar disorder.

Nat Commun 2021 06 18;12(1):3750. Epub 2021 Jun 18.

Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Center for Brain Science, Wako, Saitama, Japan.

Bipolar disorder is a severe mental illness characterized by recurrent manic and depressive episodes. To better understand its genetic architecture, we analyze ultra-rare de novo mutations in 354 trios with bipolar disorder. For germline de novo mutations, we find significant enrichment of loss-of-function mutations in constrained genes (corrected-P = 0.0410) and deleterious mutations in presynaptic active zone genes (FDR = 0.0415). An analysis integrating single-cell RNA-sequencing data identifies a subset of excitatory neurons preferentially expressing the genes hit by deleterious mutations, which are also characterized by high expression of developmental disorder genes. In the analysis of postzygotic mutations, we observe significant enrichment of deleterious ones in developmental disorder genes (P = 0.00135), including the SRCAP gene mutated in two unrelated probands. These data collectively indicate the contributions of both germline and postzygotic mutations to the risk of bipolar disorder, supporting the hypothesis that postzygotic mutations of developmental disorder genes may contribute to bipolar disorder.
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http://dx.doi.org/10.1038/s41467-021-23453-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213845PMC
June 2021

Scanning Tunneling Microscopy as a Single Majorana Detector of Kitaev's Chiral Spin Liquid.

Phys Rev Lett 2021 Mar;126(12):127201

Max-Planck-Institut für Physik komplexer Systeme, 01187 Dresden, Germany.

We propose a local detection scheme for the Majorana zero mode (MZM) carried by a vison in Kitaev's chiral spin liquid (CSL) using scanning tunneling microscopy (STM). The STM introduces a single Majorana into the system through hole-charge injection and the Majorana interacts with the MZM to form a stable composite object. We derive the exact analytical expression of single-hole Green's function in the Mott insulating limit of Kitaev's model, and show that the differential conductance has split peaks, as a consequence of resonant tunneling through the vison-hole composite. The peak splitting turns out comparable to the Majorana gap in CSL, well within the reach of experimental observation.
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http://dx.doi.org/10.1103/PhysRevLett.126.127201DOI Listing
March 2021

Efficacy and Safety of Ivabradine in an Elderly Patient with Heart Failure with Reduced Ejection Fraction.

Clin Drug Investig 2021 Feb 27;41(2):193-196. Epub 2021 Jan 27.

Department of Cardiovascular Medicine, Toho University Graduate School of Medicine, 6-11-1 Omori-nishi, Ota-ku, Tokyo, 143-8541, Japan.

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http://dx.doi.org/10.1007/s40261-021-01004-xDOI Listing
February 2021

5-aminolevulinic acid-mediated photodynamic therapy can target aggressive adult T cell leukemia/lymphoma resistant to conventional chemotherapy.

Sci Rep 2020 10 14;10(1):17237. Epub 2020 Oct 14.

Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, Okayama, 700-8558, Japan.

Photodynamic therapy (PDT) is an emerging treatment for various solid cancers. We recently reported that tumor cell lines and patient specimens from adult T cell leukemia/lymphoma (ATL) are susceptible to specific cell death by visible light exposure after a short-term culture with 5-aminolevulinic acid, indicating that extracorporeal photopheresis could eradicate hematological tumor cells circulating in peripheral blood. As a bridge from basic research to clinical trial of PDT for hematological malignancies, we here examined the efficacy of ALA-PDT on various lymphoid malignancies with circulating tumor cells in peripheral blood. We also examined the effects of ALA-PDT on tumor cells before and after conventional chemotherapy. With 16 primary blood samples from 13 patients, we demonstrated that PDT efficiently killed tumor cells without influencing normal lymphocytes in aggressive diseases such as acute ATL. Importantly, PDT could eradicate acute ATL cells remaining after standard chemotherapy or anti-CCR4 antibody, suggesting that PDT could work together with other conventional therapies in a complementary manner. The responses of PDT on indolent tumor cells were various but were clearly depending on accumulation of protoporphyrin IX, which indicates the possibility of biomarker-guided application of PDT. These findings provide important information for developing novel therapeutic strategy for hematological malignancies.
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http://dx.doi.org/10.1038/s41598-020-74174-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7558012PMC
October 2020

Paddy fields located in water storage zones could take over the wetland plant community.

Sci Rep 2020 09 9;10(1):14806. Epub 2020 Sep 9.

Mitsubishi UFJ Research and Consulting Co. Ltd., 2-5-25, Umeda, Kita-ku, Osaka, 530-8213, Japan.

Land use change could affect not only local species richness but also community assemblies. Essentially, the possible patterns of plant community assemblies are nonrandom species loss (nestedness) and species turnover. Plant community assemblies in human-mediated land use have a combination of both nestedness and turnover. This is because of historical effects that cause nonrandom species loss due to previous and/or original habitat quality and because of direct effects of human activities that cause species turnover. We investigated the complexity of the process of plant community assemblage in a paddy field, which is a typical agricultural land use in the monsoon season in central Japan. Using multi-temporal plant monitoring records, we tested the relationship between the ratio of species nestedness/turnover through multi-temporal and both the original habitat conditions and the extent of human modification. The findings revealed that paddy fields that originated from wetland habitat had a high nestedness ratio, whereas paddy fields that were largely consolidated had a high turnover ratio. Thus, we could divide the community assembly processes in human-mediated land use based on original habitat conditions and human activities. This concept could help land managers establish conservation and/or restoration plans that take into account community assembly.
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http://dx.doi.org/10.1038/s41598-020-71958-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481222PMC
September 2020

/ oscillations in interlayer transport of delafossites.

Science 2020 06;368(6496):1234-1238

Laboratory of Quantum Materials (QMAT), Institute of Materials, École Polytechnique Fédéral de Lausanne (EPFL), 1015 Lausanne, Switzerland.

Microstructures can be carefully designed to reveal the quantum phase of the wave-like nature of electrons in a metal. Here, we report phase-coherent oscillations of out-of-plane magnetoresistance in the layered delafossites PdCoO and PtCoO The oscillation period is equivalent to that determined by the magnetic flux quantum, , threading an area defined by the atomic interlayer separation and the sample width, where is Planck's constant and is the charge of an electron. The phase of the electron wave function appears robust over length scales exceeding 10 micrometers and persisting up to temperatures of T > 50 kelvin. We show that the experimental signal stems from a periodic field modulation of the out-of-plane hopping. These results demonstrate extraordinary single-particle quantum coherence lengths in delafossites.
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http://dx.doi.org/10.1126/science.aay8413DOI Listing
June 2020

The serum angiotensin-converting enzyme 2 and angiotensin-(1-7) concentrations after optimal therapy for acute decompensated heart failure with reduced ejection fraction.

Biosci Rep 2020 06;40(6)

Department of Cardiovascular Medicine, Toho University Graduate School of Medicine, Tokyo, Japan.

Objective: Elucidation of the role of angiotensin-converting enzyme (ACE) 2 (ACE2)/angiotensin (Ang)-(1-7)/Mas receptor axis in heart failure is necessary. No previous study has reported serial changes in ACE2 and Ang-(1-7) concentrations after optimal therapy (OT) in acute heart failure (AHF) patients. We aimed to investigate serial changes in serum ACE2 and Ang-(1-7) concentrations after OT in AHF patients with reduced ejection fraction (EF).

Methods: ACE2 and Ang-(1-7) concentrations were measured in 68 AHF patients with reduced EF immediately after admission and 1 and 3 months after OT. These parameters were compared with the healthy individuals at three time points.

Results: In the acute phase, Ang-(1-7) and ACE2 concentrations was statistically significantly lower and higher in AHF patients than the healthy individuals (2.40 ± 1.11 vs. 3.1 ± 1.1 ng/ml, P<0.005 and 7.45 ± 3.13 vs. 4.84 ± 2.25 ng/ml, P<0.005), respectively. At 1 month after OT, Ang-(1-7) concentration remained lower in AHF patients than the healthy individuals (2.37 ± 1.63 vs. 3.1 ± 1.1 ng/ml, P<0.05); however, there was no statistically significant difference in ACE2 concentration between AHF patients and the healthy individuals. At 3 months after OT, there were no statistically significant differences in Ang-(1-7) and ACE2 concentrations between AHF patients and the healthy individuals.

Conclusion: ACE2 concentration was equivalent between AHF patients and the healthy individuals at 1 and 3 months after OT, and Ang-(1-7) concentration was equivalent at 3 months after OT.
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http://dx.doi.org/10.1042/BSR20192701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295637PMC
June 2020

Cardio-ankle vascular index predicts the 1-year prognosis of heart failure patients categorized in clinical scenario 1.

Heart Vessels 2020 Nov 26;35(11):1537-1544. Epub 2020 May 26.

Department of Cardiovascular Medicine, Toho University Graduate School of Medicine, 6-11-1 Omori-nishi, Ota-ku, Tokyo, 143-8541, Japan.

The sudden increase in blood pressure by vascular dysfunction is associated with the development of acute decompensated heart failure (ADHF) categorized in clinical scenario (CS) 1. However, the relationship between vascular function and prognosis in ADHF patients with CS1 is unclear. 3239 consecutive ADHF patients between January 2012 and June 2018 were enrolled. ADHF patients with CS1 undergoing ankle brachial index/cardio-ankle vascular index (CAVI) were included and patients with peripheral artery disease were excluded. Finally, 113 patients were analyzed. The primary endpoint of the present study was composite endpoint at 1 year (the cardiac death or re-hospitalization by ADHF). Cox proportional hazard analysis was conducted to identify independent predictors of composite endpoint. 25 patients (22.1%) were developed composite endpoint. CAVI in patients who have composite endpoint were significantly higher than without non-composite endpoint (composite endpoint group: 9.9 ± 1.3 non-composite endpoint group 8.7 ± 1.7, P = 0.001). The composite endpoint group was elderly and had higher ejection fraction, lower hemoglobin, and less used beta blockers, and renin angiotensin aldosterone system inhibitors. After adjustment by these confounding factors, CAVI was independently associated with the occurrence of composite endpoint (hazard ratio 1.69, 95% CI 1.05-2.73, P = 0.032). A cut-off value of CAVI for predicting composite endpoint was 8.65 (sensitivity 0.444, specificity 0.920, area under the curve 0.724, 95% CI 0.614-0.834). High CAVI was associated with the occurrence of composite endpoint after CS1 ADHF.
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http://dx.doi.org/10.1007/s00380-020-01633-wDOI Listing
November 2020

Non-perturbative terahertz high-harmonic generation in the three-dimensional Dirac semimetal CdAs.

Nat Commun 2020 May 15;11(1):2451. Epub 2020 May 15.

Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany.

Harmonic generation is a general characteristic of driven nonlinear systems, and serves as an efficient tool for investigating the fundamental principles that govern the ultrafast nonlinear dynamics. Here, we report on terahertz-field driven high-harmonic generation in the three-dimensional Dirac semimetal CdAs at room temperature. Excited by linearly-polarized multi-cycle terahertz pulses, the third-, fifth-, and seventh-order harmonic generation is very efficient and detected via time-resolved spectroscopic techniques. The observed harmonic radiation is further studied as a function of pump-pulse fluence. Their fluence dependence is found to deviate evidently from the expected power-law dependence in the perturbative regime. The observed highly non-perturbative behavior is reproduced based on our analysis of the intraband kinetics of the terahertz-field driven nonequilibrium state using the Boltzmann transport theory. Our results indicate that the driven nonlinear kinetics of the Dirac electrons plays the central role for the observed highly nonlinear response.
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http://dx.doi.org/10.1038/s41467-020-16133-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229177PMC
May 2020

Retraction.

Science 2020 04;368(6489):376

Department of Physics, Graduate School of Science, Kyoto University, Kyoto 606-8502, Japan.

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http://dx.doi.org/10.1126/science.abc0469DOI Listing
April 2020

Sensitive Photodynamic Detection of Adult T-cell Leukemia/Lymphoma and Specific Leukemic Cell Death Induced by Photodynamic Therapy: Current Status in Hematopoietic Malignancies.

Cancers (Basel) 2020 Feb 2;12(2). Epub 2020 Feb 2.

Department of Hematology, Imamura General Hospital, Kagoshima 890-0064, Japan.

Adult T-cell leukemia/lymphoma (ATL), an aggressive type of T-cell malignancy, is caused by the human T-cell leukemia virus type I (HTLV-1) infections. The outcomes, following therapeutic interventions for ATL, have not been satisfactory. Photodynamic therapy (PDT) exerts selective cytotoxic activity against malignant cells, as it is considered a minimally invasive therapeutic procedure. In PDT, photosensitizing agent administration is followed by irradiation at an absorbance wavelength of the sensitizer in the presence of oxygen, with ultimate direct tumor cell death, microvasculature injury, and induced local inflammatory reaction. This review provides an overview of the present status and state-of-the-art ATL treatments. It also focuses on the photodynamic detection (PDD) of hematopoietic malignancies and the recent progress of 5-Aminolevulinic acid (ALA)-PDT/PDD, which can efficiently induce ATL leukemic cell-specific death with minor influence on normal lymphocytes. Further consideration of the ALA-PDT/PDD system along with the circulatory system regarding the clinical application in ATL and others will be discussed. ALA-PDT/PDD can be promising as a novel treatment modality that overcomes unmet medical needs with the optimization of PDT parameters to increase the effectiveness of the tumor-killing activity and enhance the innate and adaptive anti-tumor immune responses by the optimized immunogenic cell death.
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http://dx.doi.org/10.3390/cancers12020335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072618PMC
February 2020

Bisoprolol transdermal patch improves orthostatic hypotension in patients with chronic heart failure and hypertension.

Clin Exp Hypertens 2020 Aug 2;42(6):539-544. Epub 2020 Feb 2.

Department of Cardiovascular Medicine, Toho University Graduate School of Medicine , Tokyo, Japan.

β blockers (BBs) play an important role in heart failure (HF) treatment. However, orthostatic hypotension (OH) is sometimes caused by BBs. The bisoprolol transdermal patch works more slowly and is long acting compared with the bisoprolol fumarate tablet. The risk of OH may be reduced by using the bisoprolol transdermal patch. We evaluated 57 consecutive patients who were taking the bisoprolol fumarate tablet for chronic HF with hypertension from November 2016 to September 2017. We switched the patients to the bisoprolol transdermal patch. Because 12 of 57 subjects could not continue using the bisoprolol transdermal patch, we analyzed the remaining 45 patients. We investigated BP, blood tests, and changes in BP from supine to standing positions before and after 6 months of switching from tablet to patch. OH was diagnosed by observing a systolic/diastolic BP drop of at least 20/10 mmHg or an absolute systolic BP (sBP) of <90 mmHg from the standing position. No significant changes were observed in the BP and BPs from supine to standing positions, whereas log brain natriuretic peptide was significantly reduced after switching from patch to tablet (2.102 to 2.070pg/dl, = .039). OH, which occurred in originally 17 patients, showed improvement and eventually appeared in 4 patients. In these patients, changes in BP from supine to standing positions were also significantly improved (changes in sBP, -11 to -6mmHg, = .016). This study demonstrated that switching from the bisoprolol fumarate tablet to transdermal patch reduced the morbidity of OH in HF patients.
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http://dx.doi.org/10.1080/10641963.2020.1723616DOI Listing
August 2020

Comparing the effects of milrinone and olprinone in patients with congestive heart failure.

Heart Vessels 2020 Jun 21;35(6):776-785. Epub 2019 Dec 21.

Department of Cardiovascular Medicine, Toho University Graduate School of Medicine, 6-11-1 Omorinishi, Ota-ku, Tokyo, 143-8541, Japan.

Phosphodiesterase-3 (PDE3) inhibitors are widely used among patients with congestive heart failure (CHF). However, no studies have compared the cardiovascular outcomes between different PDE3 inhibitors in CHF management. In this report, we retrospectively compared the clinical benefits of two PDE3 inhibitors, milrinone and olprinone, to determine which better controls the progression of CHF. A total of 288 hospitalized patients who received PDE3 inhibitors [(milrinone; n = 77 and olprinone; n = 211, respectively)] for CHF were retrospectively enrolled. The primary endpoint was defined as having a major adverse cardiovascular and cerebrovascular event (MACCE) or cardiac death by day 60. Kaplan-Meier curves and multivariate Cox proportional models were used to compare the outcomes for patients treated with milrinone and olprinone. We found no significant differences in the baseline characteristics between the two groups. In patients treated with milrinone, a greater incidence of a MACCE or cardiac death was observed (log rank; P = 0.005 and P = 0.01, respectively). Milrinone-treated patients with ischemic heart disease and chronic kidney disease (CKD) at stage ≥ 4 presented with greater incidence of MACCE (log rank; P < 0.001 and P = 0.006, respectively). Similarly, these patients were significantly more likely to succumb to cardiac death (log rank; P < 0.001 and P = 0.02). Multivariate Cox proportional hazard models demonstrated that milrinone treatment was an independent predictor of MACCE [hazard ratio (HR) 3.17; 95% CI 1.64-6.10] and cardiac death (HR 2.64; 95% CI 1.42-4.91). Oral administration of a β-blocker at discharge occurred more often in the olprinone-treated patients than in the milrinone-treated patients (63% vs. 29%, P = 0.004). We compared the outcomes of milrinone and olprinone treatment in patients with CHF. Those treated with milrinone were more likely to succumb to a MACCE or cardiac death within 60 days of treatment, which was especially true for patients with ischemic heart disease or CKD.
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http://dx.doi.org/10.1007/s00380-019-01543-6DOI Listing
June 2020

Extraction of higher-order nonlinear electronic response in solids using high harmonic generation.

Nat Commun 2019 Jul 22;10(1):3272. Epub 2019 Jul 22.

Max Planck Institute for the Physics of Complex Systems, 01187, Dresden, Germany.

Nonlinear susceptibilities are key to ultrafast lightwave driven optoelectronics, allowing petahertz scaling manipulation of the signal. Recent experiments retrieved a 3rd order nonlinear susceptibility by comparing the nonlinear response induced by a strong laser field to a linear response induced by the otherwise identical weak field. The highly nonlinear nature of high harmonic generation (HHG) has the potential to extract even higher order nonlinear susceptibility terms. However, up till now, such characterization has been elusive due to a lack of direct correspondence between high harmonics and nonlinear susceptibilities. Here, we demonstrate a regime where such correspondence can be clearly made, extracting nonlinear susceptibilities (7th, 9th, and 11th) from sapphire of the same order as the measured high harmonics. The extracted high order susceptibilities show angular-resolved periodicities arising from variation in the band structure with crystal orientation. Our results open a door to multi-channel signal processing, controlled by laser polarization.
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http://dx.doi.org/10.1038/s41467-019-11096-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6646338PMC
July 2019

Recumbent cycling with integrated volitional control electrical stimulation improves gait speed during the recovery stage in stroke patients.

J Exerc Rehabil 2019 Feb 25;15(1):95-102. Epub 2019 Feb 25.

Department of Rehabilitation, Faculty of Health Science, Kumamoto Health Science University, Kumamoto, Japan.

The purpose of this study was to investigate the effect of recumbent cycling with integrated volitional control electrical stimulation (IVES) on gait ability in stroke patients. Six stroke patients (all male; average age, 55.7±8.3 years) participated. Recumbent cycling (R-cycling) was performed with and without IVES in the power assist (IVES-P) mode. The targeted muscle for electrostimulation was the tibialis anterior. Patients performed 10 min of IVES-P mode plus R-cycling (program A) or R-cycling alone (program B), once per day, 5 times per week. Patients completed two sets of each program, alternating between programs each week. Gait speed and the number of steps numbers on a 10-m walking test was assessed before and after each interventional session. Program A improved gait speed, but not the number of steps, to a greater extent than that in program B. Specifically, the combined intervention significantly improved gait speed in the first set, but not the second set of the intervention. R-cycling with IVES-P mode improved gait speed during the recovery stage in stroke patients to a greater extent than that achieved with R-cycling alone. Thus, this combined therapy has potential as a standardized treatment in the field of rehabilitation medicine.
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http://dx.doi.org/10.12965/jer.1836500.250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6416497PMC
February 2019

Comparable effect of tolvaptan in heart failure patients with preserved or reduced ejection fraction.

Clin Exp Hypertens 2020 22;42(2):110-117. Epub 2019 Feb 22.

Department of Cardiovascular Medicine, Toho University Graduate School of Medicine, Tokyo, Japan.

: It is unclear that the difference in efficacy of tolvaptan (TLV) on the length of hospital stay for both heart failure (HF) preserved ejection fraction (EF) (HFpEF) and reduced EF (HFrEF) patients.: We investigated 369 patients who were hospitalized with HF from February 2011 to June 2016 and initiated TLV. Patients who died in hospital, transferred hospital or clinical scenario 4 or 5 were excluded. Finally, we analyzed 108 patients with HFpEF and 96 patients with HFrEF. We evaluated the relationship between the length of hospital stay and the date of TLV initiation. Moreover, we compared the early use (within the median) and delayed use (the median or later) of TLV.: The date of TLV initiation was statistically associated with the length of hospital stay in both HFpEF and HFrEF (HFpEF: r = 0.625, P < 0.001, HFrEF: r = 0.618, P < 0.001). In HFpEF, the length of hospital stay in delayed use group was significantly longer than the early use group (22.2 ± 10.7 days and 38.1 ± 22.6 days, P < 0.001). The result was similar in HFrEF (22.0 ± 15.0 days and 32.1 ± 22.0 days, P = 0.008). On the other hand, there were no statistically significant differences in the length of hospital stay after initiation of TLV in both HFpEF and HFrEF. Other findings (including the severity of HF) were similar between the early use group and the delayed group in HFpEF and HFrEF.: The time until TLV initiation after hospitalization was related to the length of hospital stay in HFpEF and HFrEF patients.
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http://dx.doi.org/10.1080/10641963.2019.1583244DOI Listing
March 2020

Metabolic abnormalities in adult T-cell leukemia/lymphoma and induction of specific leukemic cell death using photodynamic therapy.

Sci Rep 2018 10 8;8(1):14979. Epub 2018 Oct 8.

Department of Hematology, Imamura General Hospital, Kagoshima, 890-0064, Japan.

Adult T-cell leukemia/lymphoma (ATL) is an aggressive T-cell neoplasm caused by human T-cell leukemia virus type I (HTLV-I). Therapeutic interventions have not been associated with satisfactory outcomes. We showed that the porphyrin metabolic pathway preferentially accumulates the endogenous photosensitive metabolite, protoporphyrin IX (PpIX) in ATL, after a short-term culture with 5-aminolevulinic acid (ALA). PpIX accumulated 10-100-fold more in ATL leukemic cells when compared to healthy peripheral blood mononuclear cells (PBMCs). Patient specimens showed dynamic changes in flow cytometry profiles during the onset and progression of ATL. Furthermore, 98.7% of ATL leukemic cell death in the ATL patient specimens could be induced with 10 min of visible light exposure, while 77.5% of normal PBMCs survived. Metabolomics analyses revealed that a specific stage of the metabolic pathway progressively deteriorated with HTLV-I infection and at the onset of ATL. Therefore, this method will be useful in diagnosing and identifying high-risk HTLV-I carriers with single cell resolutions. Photodynamic therapy in the circulatory system may be a potential treatment due to its highly-specific, non-invasive, safe, simultaneous, and repeatedly-treatable modalities.
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http://dx.doi.org/10.1038/s41598-018-33175-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6175925PMC
October 2018

Merkel cell polyomavirus and Langerhans cell neoplasm.

Cell Commun Signal 2018 08 22;16(1):49. Epub 2018 Aug 22.

AP-HP Hôpital Necker-Enfants Malades, University Paris Descartes (Paris 5), 75006, Paris, France.

Background: The relationship between various external agents such as pollen, food, and infectious agents and human sensitivity exists and is variable depending upon individual's health conditions. For example, we believe that the pathogenetic potential of the Merkel cell polyomavirus (MCPyV), the resident virus in skin, is variable and depends from the degree of individual's reactivity. MCPyV as well as Epstein-Barr virus, which are normally connected with humans under the form of subclinical infection, are thought to be involved at various degrees in several neoplastic and inflammatory diseases. In this review, we cover two types of Langerhans cell neoplasms, the Langerhans cell sarcoma (LCS) and Langerhans cell histiocytosis (LCH), represented as either neoplastic or inflammatory diseases caused by MCPyV.

Methods: We meta-analyzed both our previous analyses, composed of quantitative PCR for MCPyV-DNA, proteomics, immunohistochemistry which construct IL-17 endocrine model and interleukin-1 (IL-1) activation loop model, and other groups' data.

Results: We have shown that there were subgroups associated with the MCPyV as a causal agent in these two different neoplasms. Comparatively, LCS, distinct from the LCH, is a neoplastic lesion (or sarcoma) without presence of inflammatory granuloma frequently observed in the elderly. LCH is a proliferative disease of Langerhans-like abnormal cells which carry mutations of genes involved in the RAS/MAPK signaling pathway. We found that MCPyV may be involved in the development of LCH.

Conclusion: We hypothesized that a subgroup of LCS developed according the same mechanism involved in Merkel cell carcinoma pathogenesis. We proposed LCH developed from an inflammatory process that was sustained due to gene mutations. We hypothesized that MCPyV infection triggered an IL-1 activation loop that lies beneath the pathogenesis of LCH and propose a new triple-factor model.
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http://dx.doi.org/10.1186/s12964-018-0261-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6103986PMC
August 2018

Long-term use of ipragliflozin improved cardiac sympathetic nerve activity in a patient with heart failure: A case report.

Drug Discov Ther 2018 Mar 25;12(1):51-54. Epub 2018 Feb 25.

Department of Cardiovascular Medicine, Toho University Faculty of Medicine.

Ipragliflozin is the first SGLT2 inhibitor approved in Japan. Reported here is a case where long-term administration of ipragliflozin decreased the rate of re-hospitalization due to heart failure (HF). An 83-year-old man with chronic HF and diabetes mellitus (DM) was hospitalized four times in the last five years. He was discharged six months after his last hospitalization, but he continued to have class III HF according to the New York Heart Association classification (NYHA), and his DM was also not properly managed. Therefore, he received ipragliflozin. One year after initiation of ipragliflozin, he lost weight (body weight (BW): 79.0 to 76.2 kg), his levels of brain natriuretic peptide (BNP) decreased (191.4 to 122.5 mg/dL), and the class of his HF improved (class III to class II). The management of DM also improved (fasting blood glucose: 100 to 110 mg/dL; hemoglobin A1C: 6.8 to 6.6%). In addition, cardiac sympathetic nerve function evaluated with I-metaiodobenzylguanidine cardiac-scintigraphy (I-MIBG) also improved (the average of the heart-to-mediastinum ratio in early and delayed phases; 1.44 to 2.17 in the early phase, 1.41 to 1.92 in the delayed phase, washout rate; 43.3 to 35.6). The patient was not re-hospitalized due to HF two years after administration of ipragliflozin started. A reduction in cardiac sympathetic nerve hyperactivity by an SGLT2 inhibitor might be one of the mechanisms of its cardio-protective effect, but clinical studies need to be conducted to verify this finding.
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http://dx.doi.org/10.5582/ddt.2017.01069DOI Listing
March 2018

Effect of Switching from Cilnidipine to Azelnidipine on Cardiac Sympathetic Nerve Function in Patients with Heart Failure Preserved Ejection Fraction.

Int Heart J 2018 Jan 20;59(1):120-125. Epub 2017 Dec 20.

Department of Cardiovascular Medicine, Toho University Faculty of Medicine.

Cardiac sympathetic nerve activity is known to play a key role in the development and progression of heart failure (HF). Azelnidipine, an L-type calcium channel blocker (CCB), inhibits the sympathetic nerve activity of the central system. In contrast, cilnidipine, an N-type CCB, inhibits the sympathetic nerve activity of the peripheral system. CCBs are recommended as class IIa in patients with HF preserved ejection fraction (HFpEF); however, there are no comparative data on the difference in effect of cilnidipine and azelnidipine in patients with HFpEF and hypertension. We investigated the difference in effect of azelnidipine compared with cilnidipine in patients with HFpEF. Twenty-four consecutive HF patients who received angiotensin II type1a receptor blocker and beta blocker from April 2013 to January 2015 were enrolled. Cilnidipine was switched to azelnidipine during the follow-up period. Blood pressures, heart rate, blood tests, echocardiography, and I-metaiodobenzylguanidine (MIBG) cardiac-scintigraphy were measured before and after 6 months from azelnidipine administration. B-type natriuretic peptide tended to decrease after switching to azelnidipine; however, there were no significant differences between the pre-state and post-state (pre-state: 118.5 pg/mL and post-state: 78.4 pg/mL, P = 0.137). Other laboratory findings, including catecholamine, also did not change significantly. In echocardiography, there were no significant differences in systolic and diastolic functions at the pre-state and post-state. As for MIBG, there were no significant changes in heart/mediastinum ratio. However, washout rate was significantly reduced (pre-state: 42.9 and post-state: 39.6, P = 0.030). Azelnidipine improved the dysfunction of cardiac sympathetic nerve activity compared with cilnidipine in patients with HFpEF.
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http://dx.doi.org/10.1536/ihj.17-024DOI Listing
January 2018

Current-induced strong diamagnetism in the Mott insulator CaRuO.

Science 2017 11;358(6366):1084-1087

Department of Physics, Graduate School of Science, Kyoto University, Kyoto 606-8502, Japan.

Mott insulators can host a surprisingly diverse set of quantum phenomena when their frozen electrons are perturbed by various stimuli. Superconductivity, metal-insulator transition, and colossal magnetoresistance induced by element substitution, pressure, and magnetic field are prominent examples. Here we report strong diamagnetism in the Mott insulator calcium ruthenate (CaRuO) induced by dc electric current. The application of a current density of merely 1 ampere per centimeter squared induces diamagnetism stronger than that in other nonsuperconducting materials. This change is coincident with changes in the transport properties as the system becomes semimetallic. These findings suggest that dc current may be a means to control the properties of materials in the vicinity of a Mott insulating transition.
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http://dx.doi.org/10.1126/science.aah4297DOI Listing
November 2017

The relationship between the time until commencement of tolvaptan and the length of hospital stay in heart failure patients.

Heart Vessels 2018 Apr 11;33(4):367-373. Epub 2017 Nov 11.

Department of Cardiovascular Medicine, Toho University Faculty of Medicine, 6-11-1 Omori-nishi, Ota-ku, Tokyo, 143-8541, Japan.

The effect of early use of tolvaptan (TLV) for acute decompensated heart failure (ADHF) is unclear. We investigated the relationship between early use of TLV and the length of hospital stay. 369 consecutive ADHF patients who received TLV during hospitalization between February 2011 and June 2016 were initially enrolled. Patients who died in hospital, transferred hospital or clinical scenario 4 or 5 were excluded. We analyzed 247 ADHF patients. We evaluated the relationship between the length of hospital stay and the following findings: blood pressures, heart rate, New York Heart Association classification, and blood tests on admission. Moreover, we also evaluated treated agents and TLV initiated days from admission. TLV initiated days was statistically associated with the length of hospital stay (r = 0.625, P < 0.001). We compared the early use (within 4 days) vs delayed use of TLV (5 days or later), because the median of time until commencement of TLV from hospitalization was 4 days. The length of hospital stay in the delayed use group was significantly longer than early use group (31.9 ± 20.4 and 21.0 ± 12.9 days, P < 0.001). However, there was no difference in the length of hospital stay after initiation of TLV in both groups. Moreover, we investigated the factors related to the long-term hospitalization (hospital stay of median length or more). Multivariate analysis showed that TLV initiated days was independently related to the long-term hospitalization (odds ratio 1.32, 95% confidence interval 1.13-1.53, P < 0.001). Early use of TLV was related to the length of hospital stay for ADHF patients.
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http://dx.doi.org/10.1007/s00380-017-1067-3DOI Listing
April 2018

Experience with long-term administration of tolvaptan to patients with acute decompensated heart failure.

Drug Discov Ther 2017 Jul 19;11(3):133-139. Epub 2017 Jul 19.

Department of Cardiovascular Medicine, Toho University Graduate School of Medicine.

Tolvaptan (TLV) is an oral selective vasopressin type 2 receptor antagonist. Long-term use of TLV is not recommended in patients with heart failure (HF) if fluid retention disappears and/or body weight is within the target range. However, some patients require long-term use of TLV. The current study investigated the efficacy and safety of long-term use of TLV. Subjects were 258 consecutive patients with HF who received TLV during hospitalization from January 2011 to March 2015. The rate of continuing administration of TLV was evaluated. Moreover, the one-year mortality rate and rate of re-hospitalization either with or without TLV were investigated. Results at discharge and one year later were compared for patients who continued to receive TLV one year after discharge. Oral concomitant medications, blood pressures, heart rate, blood tests, chest X-ray and transthoracic echocardiography were investigated. In-hospital and one-year mortality rates were 15.9% and 27.8%, respectively. Moreover, the mortality rate and/or rate of re-hospitalization within one year was 54.4%. The rate of re-hospitalization for HF was significantly higher in patients who continued to receive TLV after discharge compared to patients who ceased receiving TLV after discharge (p < 0.001). However, the subjects who continued to receive TLV for up to one year after discharge tended to have a longer duration until re-hospitalization for HF and significantly decreased brain natriuretic peptide levels (577.6 ± 528.5 pg/mL to 397.3 ± 365.8 pg/mL, p = 0.015). Long-term use of TLV might delay re-hospitalization for HF in patients with severe HF. Large-scale clinical studies are necessary to verify these results.
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http://dx.doi.org/10.5582/ddt.2017.01018DOI Listing
July 2017

Azelnidipine is a useful medication for the treatment of heart failure preserved ejection fraction.

Clin Exp Hypertens 2017 17;39(4):350-354. Epub 2017 May 17.

a Department of Cardiovascular Medicine , Toho University Faculty of Medicine , Tokyo , Japan.

Background: The optimal therapy in patients with heart failure preserved ejection fraction (HFpEF) and hypertension (HT) has not been revealed. The beta blocker (BB) and the renin angiotensin aldosterone system inhibitor (RAAS-I) are recommend as class IIa in patients with HFpEF. The calcium channel blocker (CCB), a major anti-hypertensive drugs in Japan, is also recommend as class IIa in patients with HFpEF. However, the difference between azelnidipine, an L type CCB, and cilnidipine, an N type CCB, is unclear. We investigated the difference between azelnidipine and cilnidipine in patients with HFpEF and HT.

Methods: Twenty-five consecutive HFpEF patients treated with BB and RAAS-I from April 2013 to March 2015 were enrolled. Initially, cilnidipine was used, and then switched to azelnidipine. Age, gender, blood pressure (BP), heart rate (HR), blood tests, echocardiography, and cardiac-scintigraphy (I-metaiodobenzylguanidine: MIBG) were measured before and after six months from azelnidipine administration.

Results: There was no statistically significant difference in BP. B type natriuretic peptides were significantly reduced (pre-state: 195.4 ± 209.7 pg/ml and post-state: 140.7 ± 136.4 pg/ml, p = 0.050). In echocardiography, the TEI index tended to be decreased (pre-state: 0.47 ± 0.15 and post-state: 0.42 ± 0.08, p = 0.057). As for MIBG, there was no significant change in the heart/mediastinum ratio. However, the washout rate was significantly reduced (pre-state: 44.7 ± 12.2 and post-state: 40.7 ± 12.1, p = 0.011). In addition, there was no statistically significant change, although HR tended to decrease by switching to azelnidipine (pre-state: 62.7 ± 11.6 and post-state: 61.8 ± 16.5, p = 0.373).

Conclusions: In patients with HT and HFpEF, azelnidipine improved the severity of HF and cardiac sympathetic nerve activity compared with cilnidipine.
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http://dx.doi.org/10.1080/10641963.2016.1267198DOI Listing
February 2018

Cardio-Ankle Vascular Index and C-Reactive Protein Are Useful Parameters for Identification of Ischemic Heart Disease in Acute Heart Failure Patients.

J Clin Med Res 2017 May 1;9(5):439-445. Epub 2017 Apr 1.

Department of Cardiovascular Medicine, Toho University Graduate School of Medicine, Tokyo, Japan.

Background: The most common cause of heart failure (HF) is ischemic heart disease (IHD). Evaluation of IHD with non-invasive examinations is useful for the treatment of HF, and cardio-ankle vascular index (CAVI) is a good parameter for detecting systemic arteriosclerosis. However, the relationship between IHD and CAVI in acute HF (AHF) patients is still unclear. Therefore, we investigated the effect of non-invasive examinations, including CAVI to detect IHD.

Methods: We studied 53 consecutive patients (average age of 66.5 ± 10.9 years old, 36 males) with AHF from January 2009 to December 2012. These patients were classified into the IHD group (n = 19) and non-IHD group (n = 34) according to the coronary artery angiography results. We evaluated the vital signs, laboratory findings and CAVI.

Results: According to the laboratory findings, the C-reactive protein (CRP) in IHD group was significantly higher than non-IHD group (1.5 ± 2.1 mg/dL vs. 0.4 ± 0.4 mg/dL, P = 0.002). CAVI in IHD group was significantly higher than non-IHD group (9.58 ± 1.73 vs. 7.83 ± 1.86, P < 0.001). In the receiver operating characteristic (ROC) curve for discriminating the probability of IHD, the cut-off point of the CRP plus CAVI was 9.00. At that cut-off point, the sensitivity and the specificity were 69.7% and 89.5%, respectively. The mean area under the ROC curve (AUC) defined by the CRP plus CAVI was the greatest at all parameters.

Conclusion: The CRP and CAVI were useful parameters for the identification of IHD in patients with AHF.
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http://dx.doi.org/10.14740/jocmr2994wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5380178PMC
May 2017

Efficacy of Intravenous Administration of Landiolol in Patients With Acute Heart Failure and Supraventricular Tachyarrhythmia.

J Clin Med Res 2017 May 1;9(5):426-432. Epub 2017 Apr 1.

Department of Cardiovascular Medicine, Toho University Faculty of Medicine, Tokyo, Japan.

Background: Patients with acute heart failure (HF) complicated by supraventricular tachyarrhythmia (SVT) often receive continuous intravenous infusion of landiolol or diltiazem for rate control. It is unclear whether the interval from initiation of infusion to commencement of oral beta-blocker (BB) therapy differs for these two drugs.

Methods: From January 2013 to July 2015, 94 consecutive patients were hospitalized for acute HF complicated by SVT. After 35 patients were excluded, the remaining 59 were divided into groups treated with diltiazem or landiolol. We investigated the blood pressure, heart rate, New York Heart Association classification, brain natriuretic peptide, chest X-ray film, echocardiographic findings (ejection fraction (EF)), time until commencement of oral BB therapy, and hospital stay.

Results: There were no significant between-group differences of heart rate, blood pressure, or the severity of HF. The time until commencing oral BB therapy was significantly shorter in the landiolol group compared with the diltiazem group (median: 2 vs. 4 days, P = 0.002), but there was no significant difference in hospital stay. This interval was significantly shorter in patients with a reduced EF in the landiolol group (median: 2 days) compared with those with a reduced EF in the diltiazem group (median: 5 days, P = 0.008), and patients with a preserved EF in the landiolol group tended to have a shorter interval (median: 2 days) than those with a preserved EF in the diltiazem group (median: 4 days, P = 0.092).

Conclusions: Switching to oral BBs was accomplished earlier with landiolol than with diltiazem.
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http://dx.doi.org/10.14740/jocmr2954wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5380176PMC
May 2017

Gene expression analysis of hypersensitivity to mosquito bite, chronic active EBV infection and NK/T-lymphoma/leukemia.

Leuk Lymphoma 2017 11 3;58(11):2683-2694. Epub 2017 Apr 3.

a Department of Pediatrics , Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama , Japan.

The human herpes virus, Epstein-Barr virus (EBV), is a known oncogenic virus and plays important roles in life-threatening T/NK-cell lymphoproliferative disorders (T/NK-cell LPD) such as hypersensitivity to mosquito bite (HMB), chronic active EBV infection (CAEBV), and NK/T-cell lymphoma/leukemia. During the clinical courses of HMB and CAEBV, patients frequently develop malignant lymphomas and the diseases passively progress sequentially. In the present study, gene expression of CD16CD56-, EBV HMB, CAEBV, NK-lymphoma, and NK-leukemia cell lines, which were established from patients, was analyzed using oligonucleotide microarrays and compared to that of CD56CD16 NK cells from healthy donors. Principal components analysis showed that CAEBV and NK-lymphoma cells were relatively closely located, indicating that they had similar expression profiles. Unsupervised hierarchal clustering analyses of microarray data and gene ontology analysis revealed specific gene clusters and identified several candidate genes responsible for disease that can be used to discriminate each category of NK-LPD and NK-cell lymphoma/leukemia.
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http://dx.doi.org/10.1080/10428194.2017.1304762DOI Listing
November 2017

Short-Term Subcutaneous Fondaparinux and Oral Edoxaban for Acute Venous Thromboembolism.

Circ J 2017 May 25;81(6):855-861. Epub 2017 Feb 25.

Department of Cardiovascular Medicine, Toho University Faculty of Medicine.

Background: No studies have compared treatment efficacy between subcutaneous (SC) fondaparinux and oral edoxaban, which are categorized as factor Xa inhibitors, for venous thromboembolism (VTE) in the acute phase, and only a limited number of imaging-based quantitative studies have evaluated treatment.Methods and Results:In this open-label, randomized study, 50 patients with acute non-massive pulmonary embolism (PE) and/or deep-vein thrombosis (DVT) were assigned to fondaparinux or edoxaban groups. Lower-limb venous ultrasonography (US), and chest computed tomography (CT) were compared before and 7 days after treatment. Thrombus volume in DVT was calculated using quantitative ultrasound thrombosis (QUT) score on US. For evaluation of PE thrombus volume, lung perfused blood volume (PBV) on CT was calculated. The measurements before and after treatment, respectively, were as follows: QUT score: fondaparinux, 8.1±7.3 to 4.1±4.5; edoxaban, 7.7±6.3 to 4.4±4.3, both significant decreases (P=0.001, P<0.001, respectively); lung PBV: fondaparinux, 32.0±7.8 to 32.1±8.2 HU; edoxaban, 34.2±8.6 to 38.5±11.8 HU (P=0.732, P=0.426, respectively). On subjective CT-based evaluation, all pulmonary artery-related filling defects decreased/disappeared after treatment in both groups (P=NS).

Conclusions: Both SC fondaparinux and oral edoxaban are effective in acute VTE. Effects on thrombus regression on imaging-based quantitative measurement did not differ between the 2 drugs.
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http://dx.doi.org/10.1253/circj.CJ-16-1012DOI Listing
May 2017

Pulse Pressure and Upstroke Time Are Useful Parameters for the Diagnosis of Peripheral Artery Disease in Patients With Normal Ankle Brachial Index.

Cardiol Res 2016 Oct 3;7(5):161-166. Epub 2016 Nov 3.

Department of Cardiovascular Medicine, Toho University Faculty of Medicine, Tokyo, Japan.

Background: Some peripheral artery disease (PAD) patients have normal ankle brachial index (ABI) (0.9 - 1.4), although ABI is a useful parameter for the diagnosis of PAD. We investigated whether other parameters of ABI report sheet are useful to detect these patients.

Methods: We initially enrolled 3,912 patients (7,824 limbs) who underwent ABI for the first time. Subjects who have normal ABI were divided into the PAD group (n = 136) and the non-PAD group (n = 240) by lower extremity ultrasonography. We investigated blood pressures (BP) (systolic (SBP), diastolic (DBP), mean (mBP) and pulse pressure (PP)), heart rate, upstroke time (UT), and %mean arterial pressure (%MAP).

Results: SBP, mBP, PP, UT, and %MAP in the PAD group were significantly higher. A multivariate analysis showed that mBP, DBP, PP, UT and %MAP were independently associated with the presence of PAD (mBP: odds ratio (OR) 2.30, 95% confidence interval (CI) 1.22 - 4.37, P = 0.010; DBP: OR 0.52, 95% CI 0.28 - 0.97, P = 0.039; PP: OR 1.30, 95% CI 0.69 - 2.46, P = 0.041; UT: OR 3.40, 95% CI 2.03 - 5.83, P < 0.001; %MAP: OR 1.77, 95% CI 1.05 - 2.98, P = 0.031). Maximal area under the curve (AUC) of BPs for associating PAD was PP. The cut-off value of PP was 53.0 mm Hg (sensitivity 0.500, specificity 0.721, AUC 0.628, 95% CI 0.569 - 0.687).

Conclusions: The present study demonstrated that BPs are associated with PAD in patients with normal ABI. The measurement of BPs could provide additional information for the diagnosis of PAD.
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http://dx.doi.org/10.14740/cr508eDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5295562PMC
October 2016
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