197 results on '"Toyama K"'
Search Results
2. A Synthesis of Global Coastal Ocean Greenhouse Gas Fluxes
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Resplandy, L., primary, Hogikyan, A., additional, Müller, J. D., additional, Najjar, R. G., additional, Bange, H. W., additional, Bianchi, D., additional, Weber, T., additional, Cai, W.‐J., additional, Doney, S. C., additional, Fennel, K., additional, Gehlen, M., additional, Hauck, J., additional, Lacroix, F., additional, Landschützer, P., additional, Le Quéré, C., additional, Roobaert, A., additional, Schwinger, J., additional, Berthet, S., additional, Bopp, L., additional, Chau, T. T. T., additional, Dai, M., additional, Gruber, N., additional, Ilyina, T., additional, Kock, A., additional, Manizza, M., additional, Lachkar, Z., additional, Laruelle, G. G., additional, Liao, E., additional, Lima, I. D., additional, Nissen, C., additional, Rödenbeck, C., additional, Séférian, R., additional, Toyama, K., additional, Tsujino, H., additional, and Regnier, P., additional
- Published
- 2024
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3. Impact of Increased Horizontal Resolution of an Ocean Model on Carbon Circulation in the North Pacific Ocean
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Tsujino, H., primary, Nakano, H., additional, Sakamoto, K., additional, Urakawa, L. S., additional, Toyama, K., additional, Kosugi, N., additional, Kitamura, Y., additional, Ishii, M., additional, Nishikawa, S., additional, Nishikawa, H., additional, Sugiyama, T., additional, and Ishikawa, Y., additional
- Published
- 2024
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4. Materiais didáticos adaptados no ensino de Modelos Atômicos para alunos cegos
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TOYAMA, K. S. F., primary and PRAIS, J. L. S., additional
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- 2020
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5. Effect of an increase in dose of istradefylline, an A2A receptor antagonist, in levodopa-treated patients with Parkinson's Disease (PD)
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Hattori, N., primary, Nomura, T., additional, Salzman, P.M., additional, Kitabayashi, H., additional, Ishiuchi, M., additional, Toyama, K., additional, Ristuccia, R., additional, and Mori, A., additional
- Published
- 2020
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6. Efficacy of istradefylline, an A2A receptor antagonist, when added to levodopa and other medications for Parkinson's disease (PD)
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Le Witt, P., primary, Hattori, N., additional, Mori, A., additional, Toyama, K., additional, Salzman, P.M., additional, Parno, J., additional, Ristuccia, R., additional, and Isaacson, S.H., additional
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- 2020
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7. Effect of baseline dyskinesia on safety and efficacy of istradefylline, an A2A receptor antagonist, in Parkinson's disease: 8-study pooled analysis
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Truong, D., primary, Hattori, N., additional, Isaacson, S.H., additional, Rascol, O., additional, Mori, A., additional, Toyama, K., additional, Parno, J., additional, Salzman, P.M., additional, Ristuccia, R., additional, and Stocchi, F., additional
- Published
- 2020
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8. Reemergence of Anthropogenic Carbon Into the Ocean's Mixed Layer Strongly Amplifies Transient Climate Sensitivity
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Rodgers, K. B., primary, Schlunegger, S., additional, Slater, R. D., additional, Ishii, M., additional, Frölicher, T. L., additional, Toyama, K., additional, Plancherel, Y., additional, Aumont, O., additional, and Fassbender, A. J., additional
- Published
- 2020
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9. Extranodal natural killer/T‐cell lymphoma, nasal type with CCR3 and CXCR3 expression
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Omori, I., primary, Kamijo, H., additional, Suga, H., additional, Miyagaki, T., additional, Taoka, K., additional, Toyama, K., additional, Kurokawa, M., additional, and Sato, S., additional
- Published
- 2020
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10. Clinical Significance of Serum CEA and CA19-9 Levels before Surgery and during Postoperative Follow-up in Colorectal Cancer
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Sato, H., primary, Toyama, K., additional, Koide, Y., additional, Morise, Z., additional, and Uyama, I., additional
- Published
- 2019
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11. The effect of fast eating on the thermic effect of food in young Japanese women
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Yutaka Yoshitake, Yasuo Oguri, Nakamura T, Toyama K, Sachi Kuranuki, Kashiwa Kato E, and Zhao X
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Adult ,Sympathetic nervous system ,medicine.medical_specialty ,Autonomic Nervous System ,Eating ,Young Adult ,Animal science ,Japan ,Internal medicine ,Humans ,Medicine ,Ingestion ,Meals ,Mastication ,Meal ,business.industry ,digestive, oral, and skin physiology ,Calorimetry, Indirect ,Thermogenesis ,Feeding Behavior ,Autonomic nervous system ,medicine.anatomical_structure ,Endocrinology ,Energy expenditure ,Food ,embryonic structures ,Female ,Specific dynamic action ,Energy Intake ,Energy Metabolism ,business ,Food Science - Abstract
The relationship between eating speed and the thermic effect of food (TEF) remains unclear. We investigated the difference in the TEF when meals containing the same amount of energy were eaten in 5 min (fast eating) or 15 min (regular eating). Subjects were nine non-obese young women. Following a 350 kcal (1464 kJ) meal, energy expenditure and autonomic nervous system activity were measured. The frequency of mastication was also calculated. The TEF for the 15-min period after the start of eating with fast eating was significantly lower than with regular eating (p < 0.01). There was a significant positive correlation between the low-frequency/high-frequency ratio and TEF at 5-min intervals up to 20 min after the start of eating and between total mastication frequency and TEF during ingestion. Fast eating may reduce the TEF, potentially because a decrease in mastication frequency decreases sympathetic nervous system activity.
- Published
- 2015
12. Large reemergence of anthropogenic carbon into the ocean's surface mixed layer sustained by the ocean's overturning circulation
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Toyama, K., Rodgers, K. B., Blanke, B., Iudicone, D., Ishii, M., Aumont, Olivier, and Sarmiento, J. L.
- Abstract
We evaluate the output from a widely used ocean carbon cycle model to identify the subduction and obduction (reemergence) rates of anthropogenic carbon (Cant) for climatological conditions during the World Ocean Circulation Experiment (WOCE) era in 1995 using a new set of Lagrangian diagnostic tools. The principal scientific value of the Lagrangian diagnostics is in providing a new means to connect Cant reemergence pathways to the relatively rapid renewal time scales of mode waters through the overturning circulation. Our main finding is that for this model with 2.04 PgC yr(-1) of uptake of Cant via gas exchange, the subduction and obduction rates across the base of the mixed layer (MLbase) are 4.96 and 4.50 PgC yr(-1), respectively, which are twice as large as the gas exchange at the surface. Given that there is net accumulation of 0.17 PgC yr(-1) in the mixed layer itself, this implies the residual downward C-ant transport of 1.40 PgC yr(-1) across the MLbase is associated with diffusion. Importantly, the net patterns for subduction and obduction transports of Cant mirror the large-scale patterns for transport of water volume, thereby illustrating the processes controlling Cant uptake. Although the net transfer across the MLbase by compensating subduction and obduction is relatively smaller than the diffusion, the localized pattern of Cant subduction and obduction implies significant regional impacts. The median time scale for reemergence of obducting particles is short (
- Published
- 2017
13. Efficacy and safety of istradefylline in moderate to severe Parkinson’s disease: A phase 3, multinational, randomized, double-blind, placebo-controlled trial (i-step study)
- Author
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Isaacson, S., primary, Eggert, K., additional, Kumar, R., additional, Stocchi, F., additional, Mori, A., additional, Ohta, E., additional, Toyama, K., additional, Spence, G., additional, Clark, G., additional, and Cantillon, M., additional
- Published
- 2017
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14. Intrapulmonary Pharmacokinetics of Laninamivir, A Neuraminidase Inhibitor After A Single Nebulized Administration of Laninamivir Octanoate In Healthy Subjects
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Ishizuka, H., primary, Furuie, H., additional, and Toyama, K., additional
- Published
- 2017
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15. Safety and Pharmacokinetics of Nebulized Laninamivir Octanoate, A Long Acting Neuraminidase Inhibitor, In Healthy Subjects
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Toyama, K., primary, Furuie, H., additional, and Ishizuka, H., additional
- Published
- 2017
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16. Clinical significance of spleen stiffness in patients with acute decompensated heart failure
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Yuki Saito, Naoki Matsumoto, Yoshihiro Aizawa, Daisuke Fukamachi, Daisuke Kitano, Toyama Kazuto, Takehiro Tamaki, Hidesato Fujito, Akira Sezai, and Yasuo Okumura
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Congestive splenomegaly ,Shear wave elastography ,Acute decompensated heart failure ,Cardio‐splenic axis ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
Abstract Aims Congestive splenomegaly is a classic sign of organ congestion in acute decompensated heart failure (ADHF). Shear wave elastography (SWE) allows the measurement of spleen stiffness (SS). We hypothesized that SS could quantify the severity of splenic congestion and predict adverse events in ADHF. Methods and Results This study included two cohorts: a haemodynamic cohort (62 HF patients) and an outcome cohort (115 ADHF patients). SS was measured by two‐dimensional SWE on the same day of right heart catheterization in the haemodynamic cohort. Right atrial pressure (RAP) independently correlated with SS (β = 0.32, P = 0.002). SS was measured in the outcome cohort before discharge. The 115 patients were divided into three groups on the basis of the tertile value of SS. The third tertile SS group had a higher prevalence of severe tricuspid regurgitation, higher N‐terminal B‐type natriuretic peptide (NT pro‐BNP), and larger right ventricular diastolic diameter, than had the first tertile group and the second tertile group. During a median follow‐up period of 105 (77–135) days, adverse events occurred in 25 patients (one death and 24 rehospitalizations for HF). The third tertile SS group had a significantly higher rate of adverse events (P
- Published
- 2020
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17. The Co-Expression Pattern of p63 and HDAC1: A Potential Way to Disclose Stem Cells in Interfollicular Epidermis
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Jung-Won Shin, Hye-Ryung Choi, Kyung-Mi Nam, Hyun-Sun Lee, Sung-Ae Kim, Hyun-Jae Joe, Toyama Kazumi, and Kyoung-Chan Park
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epidermal stem cell ,HDAC1 ,interfollicular epidermis ,stem cell niche ,p63 ,suberoylanilohydroxamic acid (SAHA) ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Stem cell markers of interfollicular epidermis (IEF) have not been established thus far. The aim of this study is to suggest a new way to disclose IFE-stem cells by combining the expression of histone deacetylases (HDAC) 1 and p63. Immunohistochemical staining of HDAC1 and p63 was performed in six normal human samples. Moreover, a skin equivalent (SE) model was treated with suberoylanilohydroxamic acid (SAHA, an HDAC inhibitor) to elucidate the role of HDAC1. Finally, rapidly adhering (RA) keratinocytes to a type IV collagen, which have been identified to represent epidermal stem cells, were subjected to Western blot analysis with antibodies against HDAC1. In normal samples, there was a minor subpopulation comprised of p63-positive and HDAC1-negative cells in the basal layers. The proportion of this subpopulation was decreased with age. In the SE model, SAHA treatment increased the epidermal thickness and number of p63-positive cells in a dose dependent manner. After SAHA treatment, the expression of differentiation markers was decreased, while that of basement membrane markers was increased. In a Western blot analysis, HDAC1 was not expressed in RA cells. In conclusion, the combination of p63-positive and HDAC1-negative expressions can be a potential new way for distinguishing epidermal stem cells.
- Published
- 2017
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18. Erdheim-Chester disease: consensus recommendations for evaluation, diagnosis, and treatment in the molecular era
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Xin Xin Cao, Benjamin H. Durham, Paul C. Hendrie, Aaron M. Goodman, Jennifer Picarsic, Eric D. Jacobsen, Juvianee Estrada-Veras, Andre Abdo, Michael Girschikofsky, Matthew Collin, Kenneth L. McClain, Mineo Kurokawa, Ronald S. Go, Augusto Vaglio, Mark L. Heaney, Kazuhiro Toyama, Lorenzo Dagna, Julien Haroche, Oshrat Hershkovitz-Rokah, Eli L. Diamond, Ofer Shpilberg, Roei D Mazor, Filip Janku, Fleur Cohen-Aubart, Gaurav Goyal, Goyal, G., Heaney, M. L., Collin, M., Cohen-Aubart, F., Vaglio, A., Durham, B. H., Hershkovitz-Rokah, O., Girschikofsky, M., Jacobsen, E. D., Toyama, K., Goodman, A. M., Hendrie, P., Cao, X. -X., Estrada-Veras, J. I., Shpilberg, O., Abdo, A., Kurokawa, M., Dagna, L., Mcclain, K. L., Mazor, R. D., Picarsic, J., Janku, F., Go, R. S., Haroche, J., and Diamond, E. L.
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Male ,Proto-Oncogene Proteins B-raf ,Erdheim-Chester Disease ,medicine.medical_specialty ,genetic structures ,MAP Kinase Signaling System ,medicine.medical_treatment ,Immunology ,MEDLINE ,Disease ,Biochemistry ,Targeted therapy ,Pericarditis ,Fibrosis ,medicine ,Humans ,Molecular Targeted Therapy ,Vemurafenib ,Clinical Trials as Topic ,business.industry ,Cell Biology ,Hematology ,Prognosis ,medicine.disease ,Dermatology ,Histiocytosis, Langerhans-Cell ,Histiocytosis ,Mutation ,Erdheim–Chester disease ,Female ,business ,medicine.drug - Abstract
Erdheim-Chester disease (ECD) is a rare histiocytosis that was recently recognized as a neoplastic disorder owing to the discovery of recurrent activating MAPK (RAS-RAF-MEK-ERK) pathway mutations. Typical findings of ECD include central diabetes insipidus, restrictive pericarditis, perinephric fibrosis, and sclerotic bone lesions. The histopathologic diagnosis of ECD is often challenging due to nonspecific inflammatory and fibrotic findings on histopathologic review of tissue specimens. Additionally, the association of ECD with unusual tissue tropism and an insidious onset often results in diagnostic errors and delays. Most patients with ECD require treatment, except for a minority of patients with minimally symptomatic single-organ disease. The first ECD consensus guidelines were published in 2014 on behalf of the physicians and researchers within the Erdheim-Chester Disease Global Alliance. With the recent molecular discoveries and the approval of the first targeted therapy (vemurafenib) for BRAF-V600–mutant ECD, there is a need for updated clinical practice guidelines to optimize the diagnosis and treatment of this disease. This document presents consensus recommendations that resulted from the International Medical Symposia on ECD in 2017 and 2019. Herein, we include the guidelines for the clinical, laboratory, histologic, and radiographic evaluation of ECD patients along with treatment recommendations based on our clinical experience and review of literature in the molecular era.
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- 2020
19. Fast and Selective Main-Chain Scission of Vinyl Polymers Using the Domino Reaction in the Alternating Sequence for Transesterification.
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Kohsaka Y, Toyama K, Kawauchi M, and Naganuma K
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This communication reports on vinyl polymers capable of selective and fast main-chain scission (MCS). The trick is the domino reaction in an alternating sequence of methyl 2-(trimethylsiloxymethyl)acrylate and 5,6-benzo-2-methylene-1,3-dioxepane, a cyclic ketene acetal for radical ring-opening polymerization. Removal of the trimethylsilyl group using Bu
4 N+ ·F- readily led to MCS via irreversible transesterification of the ester backbone, affording a five-membered lactone fragment. The molar mass decreased drastically within 5 min, and no side reactions were observed. Control experiments suggest that the formation of a five-membered ring via a domino reaction is critical for fast and selective MCS. The terpolymers with methyl methacrylate and styrene also exhibited a large decrease in molar mass within 5 min. In addition, MCS was also observed for the heterogeneous reaction system in acidic aqueous media; treatment of the binary copolymer in a 50 wt % acetic acid solution resulted in a significant decrease in molar mass after 30 min. These results suggest efficient construction of degradable sites using a binary monomer system corresponding to the pendant trigger and ester backbone. Because this molecular design using a binary monomer system provides selective and fast MCS for terpolymers containing other vinyl monomers, it can provide various degradable vinyl polymers.- Published
- 2024
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20. Optimal timing of electrical cardioversion for acute decompensated heart failure caused by atrial arrhythmias: The earlier, the better?
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Fujito H, Nagashima K, Saito Y, Mizobuchi S, Fukumoto K, Wakamatsu Y, Arai R, Watanabe R, Murata N, Toyama K, Kitano D, Fukamachi D, Yoda S, and Okumura Y
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- Humans, Male, Female, Retrospective Studies, Aged, Treatment Outcome, Time Factors, Acute Disease, Middle Aged, Atrial Flutter therapy, Atrial Flutter physiopathology, Atrial Flutter diagnosis, Time-to-Treatment, Echocardiography, Stroke Volume physiology, Heart Failure therapy, Heart Failure physiopathology, Heart Failure diagnosis, Heart Failure complications, Electric Countershock adverse effects, Electric Countershock methods, Atrial Fibrillation therapy, Atrial Fibrillation physiopathology, Atrial Fibrillation complications, Atrial Fibrillation diagnosis
- Abstract
The optimal timing for electrical cardioversion (ECV) in acute decompensated heart failure (ADHF) with atrial arrhythmias (AAs) is unknown. Here, we retrospectively evaluated the impact of ECV timing on SR maintenance, hospitalization duration, and cardiac function in patients with ADHF and AAs. Between October 2017 and December 2022, ECV was attempted in 73 patients (62 with atrial fibrillation and 11 with atrial flutter). Patients were classified into two groups based on the median number of days from hospitalization to ECV, as follows: early ECV (within 8 days, n = 38) and delayed ECV (9 days or more, n = 35). The primary endpoint was very short-term and short-term ECV failure (unsuccessful cardioversion and AA recurrence during hospitalization and within one month after ECV). Secondary endpoints included (1) acute ECV success, (2) ECVs attempted, (3) periprocedural complications, (4) transthoracic echocardiographic parameter changes within two months following successful ECV, and (5) hospitalization duration. ECV successfully restored SR in 62 of 73 patients (85%), with 10 (14%) requiring multiple ECV attempts (≥ 3), and periprocedural complications occurring in six (8%). Very short-term and short-term ECV failure occurred without between-group differences (51% vs. 63%, P = 0.87 and 61% vs. 72%, P = 0.43, respectively). Among 37 patients who underwent echocardiography before and after ECV success, the left ventricular ejection fraction (LVEF) significantly increased (38% [31-52] to 51% [39-63], P = 0.008) between admission and follow-up. Additionally, hospital stay length was shorter in the early ECV group than in the delayed ECV group (14 days [12-21] vs. 17 days [15-26], P < 0.001). Hospital stay duration was also correlated with days from admission to ECV (Spearman's ρ = 0.47, P < 0.001). In clinical practice, early ECV was associated with a shortened hospitalization duration and significantly increased LVEF in patients with ADHF and AAs., (© 2024. Springer Nature Japan KK, part of Springer Nature.)
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- 2024
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21. Low-latitude mesopelagic nutrient recycling controls productivity and export.
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Rodgers KB, Aumont O, Toyama K, Resplandy L, Ishii M, Nakano T, Sasano D, Bianchi D, and Yamaguchi R
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- Global Warming, Phytoplankton metabolism, Temperature, Tropical Climate, Motion, Ecosystem, Nutrients metabolism, Oceans and Seas, Seawater chemistry, Aquatic Organisms metabolism, Water Movements
- Abstract
Low-latitude (LL) oceans account for up to half of global net primary production and export
1-5 . It has been argued that the Southern Ocean dominates LL primary production and export6 , with implications for the response of global primary production and export to climate change7 . Here we applied observational analyses and sensitivity studies to an individual model to show, instead, that 72% of LL primary production and 55% of export is controlled by local mesopelagic macronutrient cycling. A total of 34% of the LL export is sustained by preformed macronutrients supplied from the Southern Ocean via a deeper overturning cell, with a shallow preformed northward supply, crossing 30° S through subpolar and thermocline water masses, sustaining only 7% of the LL export. Analyses of five Coupled Model Intercomparison Project Phase 6 (CMIP6) models, run under both high-emissions low-mitigation (shared socioeconomic pathway (SSP5-8.5)) and low-emissions high-mitigation (SSP1-2.6) climate scenarios for 1850-2300, revealed significant across-model disparities in their projections of not only the amplitude, but also the sign, of LL primary production. Under the stronger SSP5-8.5 forcing, with more substantial upper-ocean warming, the CMIP6 models that account for temperature-dependent remineralization promoted enhanced LL mesopelagic nutrient retention under warming, with this providing a first-order contribution to stabilizing or increasing, rather than decreasing, LL production under high emissions and low mitigation. This underscores the importance of a mechanistic understanding of mesopelagic remineralization and its sensitivity to ocean warming for predicting future ecosystem changes., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2024
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22. Room temperature is a key factor for modeling human lower extremity artery disease with surgical murine hind limb ischemia.
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Abe Y, Javkhlant A, Spin JM, and Toyama K
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- Animals, Mice, Humans, Peripheral Arterial Disease physiopathology, Hindlimb blood supply, Disease Models, Animal, Ischemia, Lower Extremity blood supply, Temperature
- Abstract
Competing Interests: Declaration of competing interest None.
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- 2024
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23. Diagnostic efficacy of contrast-enhanced fluid-attenuated inversion recovery (FLAIR) imaging in idiopathic cerebrospinal fluid rhinorrhea.
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Watanabe H, Arai H, Ogihara K, Morisaka H, Saito A, Moriyama M, Nakano S, Aonuma K, Aoyagi K, Matsumoto K, Toyama K, and Onishi H
- Abstract
We report a case of a 50-year-old woman in which contrast-enhanced fluid-attenuated inversion recovery (FLAIR) was used for the diagnosis of idiopathic cerebrospinal fluid rhinorrhea. The pre- and postcontrast FLAIR subtraction images showed a contrasted protrusion of the right olfactory cleft canal, highlighting the potential practicality and effectiveness of using pre- and postcontrast FLAIR subtraction images in diagnosing idiopathic cerebrospinal fluid rhinorrhea, in conjunction with conventional high-resolution computed tomography and magnetic resonance cisternography. The successful diagnosis of cerebrospinal fluid rhinorrhea allowed for treatment through endoscopic nasal surgery to close the fistula with a positive clinical outcome., (© 2024 The Authors. Published by Elsevier Inc. on behalf of University of Washington.)
- Published
- 2024
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24. Primary analysis of a prospective cohort study of Japanese patients with plasma cell neoplasms in the novel drug era (2016-2021).
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Shibayama H, Itagaki M, Handa H, Yokoyama A, Saito A, Kosugi S, Ota S, Yoshimitsu M, Tanaka Y, Kurahashi S, Fuchida SI, Iino M, Shimizu T, Moriuchi Y, Toyama K, Mitani K, Tsukune Y, Kada A, Tamura H, Abe M, Iwasaki H, Kuroda J, Takamatsu H, Sunami K, Kizaki M, Ishida T, Saito T, Matsumura I, Akashi K, and Iida S
- Subjects
- Humans, Prospective Studies, Aged, Female, Middle Aged, Male, Japan, Transplantation, Autologous, Prognosis, Survival Rate, Adult, Hematopoietic Stem Cell Transplantation, Aged, 80 and over, Antineoplastic Agents therapeutic use, Multiple Myeloma therapy, Multiple Myeloma mortality, Multiple Myeloma drug therapy, East Asian People, Neoplasms, Plasma Cell therapy
- Abstract
The emergence of novel drugs has significantly improved outcomes of patients with plasma cell neoplasms (PCN). The Japanese Society of Hematology conducted a prospective observational study in newly diagnosed PCN patients between 2016 and 2021. The analysis focused on 1385 patients diagnosed with symptomatic PCN between 2016 and 2018. The primary endpoint was the 3-year overall survival (OS) rate among patients requiring treatment (n = 1284), which was 70.0% (95%CI 67.4-72.6%). Approximately 94% of these patients received novel drugs as frontline therapy. The 3-year OS rate was 90.3% (95%CI 86.6-93.1%) in the 25% of patients who received upfront autologous stem cell transplantation (ASCT), versus just 61.4% (95%CI 58.0-64.6%) in those who did not receive upfront ASCT. The only unfavorable prognostic factor that affected OS in ASCT recipients was an age of 65 or higher. For patients who did not receive ASCT, independent unfavorable prognostic factors included frontline treatment with conventional chemotherapies, international staging system score of 2/3, extramedullary tumors, and Freiberg comorbidity index of 2/3. This study unequivocally demonstrates that use of novel drugs improved OS in Japanese myeloma patients, and underscores the continued importance of upfront ASCT as the standard of care in the era of novel drugs., (© 2024. The Author(s).)
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- 2024
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25. Prognostic factors of idiopathic hypereosinophilic syndrome: A nationwide survey in Japan.
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Honda A, Masuda Y, Oyama Y, Matsuda K, Mizuno H, Saito AM, Katayama Y, Komatsu N, Toyama K, and Kurokawa M
- Abstract
Idiopathic hypereosinophilic syndrome (iHES) is a condition wherein persistent hypereosinophilia associated with end-organ damage occurs without any known causes. Due to the rarity of the disease, insufficient knowledge has been accumulated. We therefore conducted a retrospective, multicentre, nationwide survey on iHES in Japan. A total of 57 patients were identified. For 43 patients who received any treatment, all cases were first treated with corticosteroids. An eosinophil percentage of less than 30% in the bone marrow and the absence of oedema were identified as factors associated with steroid dependency. The 5-year overall survival was 88.2%, and five patients died during follow-up; factors associated with worse overall survival were age >50, haemoglobin <12 g/dL, activated partial thromboplastin time >34 s, the presence of dyspnoea, the presence of thrombotic tendency and the presence of renal failure. Given the rarity of fatalities in our cohort, time-to-next-treatment (TTNT) was further analysed; the presence of renal failure, splenomegaly and lung abnormalities were associated with worse TTNT. Our nationwide study not only demonstrated clinical characteristics and the outcome of patients with iHES but also for the first time revealed clinical factors associated with steroid dependency and duration of first-line corticosteroid efficacy., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)
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- 2024
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26. Triglyceride-Glucose Index Associated with Future Renal Function Decline in the General Population.
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Yoshida D, Ikeda S, Shinohara K, Kazurayama M, Tanaka S, Yamaizumi M, Nagayoshi H, Toyama K, and Kinugawa S
- Abstract
Background: The triglyceride-glucose index (TyG index), calculated as the logarithmic product of fasting triglyceride and glucose concentrations, is recognized as a simple marker of insulin resistance. However, the association between the TyG index and future decline of renal function remains unclear in the general population., Objective: To investigate whether the TyG index was associated with future decline of renal function in the general population who had not progressed to chronic kidney disease stage G2., Design: Retrospective longitudinal observational cohort study., Participants: Individuals who received a population-based health checkup at JA Ehime Kouseiren Checkup Center from 2010 to 2019 (n = 134,007). Individuals without data of baseline fasting triglyceride or glucose levels, or baseline and follow-up data of estimated glomerular filtration rate (eGFR), or those with baseline eGFR < 60 mL/min/1.73 m
2 were excluded., Main Measures: Future renal function decline, defined as a ≥ 25% decrease in eGFR from baseline., Key Results: Of 10,758 participants, 8,076 were classified into the low TyG index group (TyG index < 8.76, 1st to 3rd quartiles) and 2,682 into the high TyG index group (TyG index ≥ 8.76, 4th quartile). The mean follow-up period was 37.8 ± 23.6 months. The incidence rates of renal function decline were 0.31 and 0.69 per 100 person-years in the low and high TyG index groups, respectively. In multivariate Cox proportional hazard models, high TyG index was significantly associated with future renal function decline (hazard ratio 2.25, 95% CI 1.40-3.60). This association was consistent across subgroups stratified by age, sex, body mass index, baseline eGFR, and diagnosed hypertension, diabetes, or dyslipidemia., Conclusion: In the general population, high TyG index was associated with future renal function decline. The TyG index may be useful in identifying individuals at high risk for future renal function decline in the setting of health checkups., (© 2024. The Author(s), under exclusive licence to Society of General Internal Medicine.)- Published
- 2024
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27. α2-Antiplasmin is associated with macrophage activation and fibrin deposition in a macrophage activation syndrome mouse model.
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Kanno Y, Toyama K, Shibata H, Matsuo O, and Ozaki KI
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- Animals, Male, Mice, Disease Models, Animal, Galactosamine, Interferon-gamma metabolism, Liver immunology, Liver metabolism, Liver pathology, Mice, Inbred C57BL, Mice, Knockout, Tumor Necrosis Factor-alpha metabolism, alpha-2-Antiplasmin metabolism, Fibrin metabolism, Macrophage Activation immunology, Macrophage Activation Syndrome immunology, Macrophages immunology, Macrophages metabolism
- Abstract
Macrophage activation syndrome (MAS) is a life-threatening condition, characterized by cytopenia, multi-organ dysfunction, and coagulopathy associated with excessive activation of macrophages. In this study, we investigated the roles of alpha2-antiplasmin (α2AP) in the progression of MAS using fulminant MAS mouse model induced by toll-like receptor-9 agonist (CpG) and D-(+)-galactosamine hydrochloride (DG). α2AP deficiency attenuated macrophage accumulation, liver injury, and fibrin deposition in the MAS model mice. Interferon-γ (IFN-γ) is associated with macrophage activation, including migration, and plays a pivotal role in MAS progression. α2AP enhanced the IFN-γ-induced migration, and tissue factor production. Additionally, we showed that fibrin-induced macrophage activation and tumor necrosis factor-α production. Moreover, the blockade of α2AP by neutralizing antibodies attenuated macrophage accumulation, liver injury, and fibrin deposition in the MAS model mice. These data suggest that α2AP may regulate IFN-γ-induced responses and be associated with macrophage activation and fibrin deposition in the MAS progression., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Immunology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
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- 2024
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28. Tuning Electrocatalytic Activities of Dealloyed Nanoporous Catalysts by Macroscopic Strain Engineering.
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Li Q, Kudo A, Ma J, Kawashima R, Toyama K, Xu W, Gao Z, Liang Y, Jiang H, Li Z, Cui Z, Zhu S, and Chen M
- Abstract
It is technically challenging to quantitatively apply strains to tune catalysis because most heterogeneous catalysts are nanoparticles, and lattice strains can only be applied indirectly via core-shell structures or crystal defects. Herein, we report quantitative relations between macroscopic strains and hydrogen evolution reaction (HER) activities of dealloyed nanoporous gold (NPG) by directly applying macroscopic strains upon bulk NPG. It was found that macroscopic compressive strains lead to a decrease, while macroscopic tensile strains improve the HER activity of NPG, which is in line with the d -band center model. The overpotential and onset potential of HER display approximately a linear relation with applied macroscopic strains, revealing an ∼2.9 meV decrease of the binding energy per 0.1% lattice strains from compressive to tensile. The methodology with the high strain sensitivity of electrocatalysis, developed in this study, paves a new way to investigate the insights of strain-dependent electrocatalysis with high precision.
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- 2024
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29. Lack of ATP2B1 in CD4+ T Cells Causes Colitis.
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Javkhlant A, Toyama K, Abe Y, Spin JM, and Mogi M
- Abstract
Background: The ATP2B1 gene encodes for a calcium pump, which plays a role in removing Ca2+ from cells and maintaining intracellular Ca2+ homeostasis. Reduction of the intracellular Ca2+ concentration in CD4+ T cells is thought to reduce the severity of colitis, while elevation of Ca2+ in CD4+ T cells induces T cell hyperactivity. Our aim was to clarify the role of ATP2B1 in CD4+ T cells and in inflammatory bowel disease development., Methods: A murine CD4+ T cell-specific knockout (KO) of ATP2B1 was created using a Cre-loxP system. CD4+ T cells were isolated from thymus, spleen, and blood using fluorescence-activated cell sorting. To quantify messenger RNA levels, quantitative real-time polymerase chain reaction was performed., Results: Although the percentages of CD4+ T cells in both KO mouse spleen and blood decreased compared with those of the control samples, both T-bet (a T helper 1 [Th1] activity marker) and GATA3 (a Th2 activity marker) expression levels were further increased in KO mouse blood CD4+ T cells (vs control blood). Diarrhea and colonic wall thickening (with mucosal changes, including crypt distortion) were seen in KO mice but not in control mice. Prior to diarrhea onset, the KO mouse colon length was already noted to be shorter, and the KO mouse stool water and lipid content were higher than that of the control mice. Tumor necrosis factor α and gp91 expressions were increased in KO mouse colon., Conclusions: Lack of ATP2B1 in CD4+ T cells leads to Th1 and Th2 activation, which contributes to colitis via elevation of tumor necrosis factor α and oxidative stress., (© The Author(s) 2024. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
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- 2024
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30. Differences in collateral vessel formation after experimental retinal vein occlusion in spontaneously hypertensive rats and wild-type rats.
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Omi M, Yamada H, Takahashi H, Mori H, Oba S, Hattori Y, Yokota K, Toyama K, and Takahashi K
- Abstract
Objective: Retinal vein occlusion (RVO) can lead to visual impairment, but the development of collateral vessels can sometimes mitigate significant damage. This study aimed to investigate the relationship between collateral vessels and hypertension, the most common underlying condition associated with RVO, by comparing spontaneously hypertensive rats (SHRs) and wild-type Wister rats (WWRs). We also examined the differences between WWRs and SHRs in terms of sphingosine 1-phosphate receptor 1 (S1PR1) expression and its product nitric oxide synthase 3 (NOS3) expression, which are involved in the formation of collateral vessels after vascular occlusion., Methods: Laser photocoagulation (PC) was used to occlude one randomly selected retinal vein in WWRs and SHRs, and the area surrounding the occluded vessel was examined using optical coherence tomography angiography. If reperfusion of the occluded vessel occurred within 2 weeks, the vessel was re-occluded repeatedly by PC. The number of eyes with successfully occluded vessels accompanied by collateral vessels was recorded. Then, WWRs and SHRs were divided into the following four groups: 1) control (no treatment), 2) vehicle (20% DMSO), 3) S1PR1 agonist (2 mg/mL SEW2871), and 4) S1PR1 antagonist (0.25 mg/mL VPC 23019) groups. The drugs were administered intravitreally in all groups except the control. The number of laser shots required for successful RVO was recorded. Histological evaluation and quantitative real-time PCR of S1PR1 and NOS3 were performed to elucidate the mechanisms underlying collateral vessel formation., Results: The proportion of eyes achieving successful vein occlusion was lower in SHRs (4/12 eyes, 33.3%) than in WWRs (8/10 eyes, 80%, p = 0.043). NOS3 expression at 6 h after PC was significantly higher in WWRs than in SHRs (p = 0.021). In WWRs treated with SEW2871, vein occlusion failed in 7 of 10 eyes (70%). The expression of NOS3 was significantly higher in the SEW2871 treatment group than in the untreated group (p < 0.001). Furthermore, NOS3 expression was significantly higher after SEW2871 treatment in WWRs than in SHRs (p = 0.011)., Conclusion: In hypertensive environments, collateral vessels are less likely to develop, and S1PR1 may be involved in this phenomenon., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Masatoshi Omi reports financial support was provided by KAKENHI Grant in-Aid for Scientific Research C. Masatoshi Omi reports financial support was provided by Jhonson & Jhonson Surgical Vision. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)
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- 2024
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31. Rare Co-occurrence of Spinal Cord Hemorrhage from Radiation-induced Cavernous Hemangioma and Classical Hodgkin Lymphoma Post-transplant Lymphoproliferative Disorder.
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Shimizu T, Nagashima Y, Matsukawa T, Mitsutake A, Kawai M, Horiuchi Y, Yokoyama K, Takaoka K, Kurihara Y, Toyama K, Sakuishi K, Kurokawa M, and Toda T
- Abstract
Post-transplant lymphoproliferative disorders (PTLDs) are lymphoproliferative diseases that occur after solid organ transplantation or hematopoietic stem cell transplantation (HSCT). The development of PTLD is often associated with reactivation of Epstein-Barr virus (EBV). A 26-year-old woman with a history of HSCT and total-body irradiation developed spinal cord hemorrhage from a radiation-induced cavernous hemangioma (RICH) shortly after the development of classical Hodgkin lymphoma PTLD with EBV reactivation. Although little is known about the factors leading to hemorrhagic events from spinal cord RICH, we suspect that EBV reactivation may have been a factor contributing to the hemorrhage in the present case.
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- 2024
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32. Sodium-glucose co-transporter 2 inhibitors in acute heart failure: real-world prescription trends and outcomes analysis.
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Mizobuchi S, Saito Y, Kitano D, Toyama K, Miyagawa M, Koyama Y, Fujito H, Kojima K, Murata N, Fukamachi D, and Okumura Y
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- Aged, Female, Humans, Male, Aftercare, Glucose, Patient Discharge, Sodium, Stroke Volume, Ventricular Function, Left, Aged, 80 and over, Heart Failure, Sodium-Glucose Transporter 2 Inhibitors therapeutic use, Symporters therapeutic use
- Abstract
Aims: Sodium-glucose co-transporter 2 (SGLT2) inhibitors have shown potential therapeutic benefits in heart failure (HF). However, data on their real-world usage and benefits in acute decompensated heart failure (ADHF) are limited., Methods and Results: We conducted a post hoc analysis of real-world data from 1108 patients with ADHF admitted to Nihon University Itabashi Hospital (Tokyo, Japan) between 2018 and 2022. Patients were divided into two groups based on the prescription of SGLT2 inhibitors during hospitalization: an SGLT2 inhibitor group (SGLT2i group) (n = 289) and a non-SGLT2i group (n = 819). The primary endpoints were death and rehospitalization for HF after discharge. The median age was 76 [interquartile range (IQR): 66, 83] years, and 732 patients (66%) were male. Data showed an increasing trend in the prescription of SGLT2 inhibitors since 2021. During a median follow-up period of 366 days (IQR: 116, 614), 458 (41.3%) patients reached the primary endpoint. The Kaplan-Meier analysis showed that the SGLT2i group had a significantly lower rate of composite events than the non-SGLT2i group, both overall (log-rank test, P < 0.001) and in the following left ventricular ejection fraction (LVEF) subgroups: HF with reduced ejection fraction (EF) (n = 413), HF with mildly reduced EF (n = 226), and HF with preserved EF (n = 466) (log-rank test; P = 0.044, P = 0.013, and P = 0.001, respectively). Furthermore, patients starting SGLT2 inhibitors during hospitalization had a significantly lower rate of composite events than those not using SGLT2 inhibitors (log-rank test, P < 0.001). This association was also significant in the LVEF subgroups (P = 0.005, P = 0.032, and P = 0.004, respectively)., Conclusions: The prescription and initiation of SGLT2 inhibitors during hospitalization are associated with improved post-discharge outcomes in patients with ADHF, irrespective of LVEF., (© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)
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- 2024
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33. Association of baseline electrocardiographic left ventricular hypertrophy with future renal function decline in the general population.
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Ikeda S, Shinohara K, Tagawa K, Tohyama T, Kishimoto J, Kazurayama M, Tanaka S, Yamaizumi M, Nagayoshi H, Toyama K, Matsushima S, Tsutsui H, and Kinugawa S
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- Humans, Kidney, Blood Pressure, Incidence, Electrocardiography, Risk Factors, Hypertrophy, Left Ventricular diagnosis, Hypertension
- Abstract
Electrocardiographic left ventricular hypertrophy (LVH) could predict adverse renal outcomes in patients with hypertension. This study aimed to investigate the association between electrocardiographic LVH and future decline in renal function in the general population using a dataset of population-based health checkups from 2010 to 2019 including 19,825 participants. Electrocardiographic LVH was defined according to the Minnesota code. Renal function decline was defined as a decrease of ≥ 25% in the estimated glomerular filtration rate from baseline to < 60 mL/min/1.73 m
2 . Electrocardiographic LVH was found in 1263 participants at the baseline visit. The mean follow-up period was 3.4 ± 1.9 years. The incidence rates of renal function decline were 0.30 and 0.78 per 100 person-years in the non-LVH group and LVH groups, respectively. Electrocardiographic LVH was associated with the risk for renal function decline in the adjusted analysis (hazard ratio 1.69, 95% confidence interval 1.14-2.50, P = 0.009). This association was comparable across subgroups stratified by age, sex, body mass index, diagnosed hypertension, systolic blood pressure, hemoglobin A1c, and urinary protein. This study underscores the usefulness of electrocardiographic LVH to detect high-risk individuals for renal function decline in the setting of health checkups in the general population., (© 2024. The Author(s).)- Published
- 2024
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34. Safety, Tolerability, and Pharmacokinetics of Valemetostat Tablets and the Effect of Food on Valemetostat Pharmacokinetics in Healthy Subjects: Two Phase 1 Studies.
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Tachibana M, Matsuki S, Toyama K, Maekawa Y, Fukae M, Shimizu T, Tsutsumi J, Shinohara S, and Ishizuka H
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- Humans, Healthy Volunteers, Cross-Over Studies, Biological Availability, Tablets, Fasting, Enzyme Inhibitors
- Abstract
Valemetostat is an oral, selective inhibitor of enhancer of zeste homolog-2 (EZH2) and EZH1. In a first-in-human phase-1 trial, valemetostat capsules were well tolerated and clinically active in patients with relapsed/refractory non-Hodgkin lymphoma. Subsequently, a film-coated tablet formulation was developed for future clinical trials and commercialization. We report outcomes from 2 phase 1 trials in healthy Japanese participants, assessing the safety, tolerability, and pharmacokinetics (PK) of valemetostat tablets at single ascending doses (50, 100, and 200-mg), the relative bioavailability between capsules and tablets, and the effect of food (high-fat or low-fat meals) on the PK of valemetostat tablets. In the ascending-dose study, valemetostat maximum plasma concentration (C
max ) and area under the concentration-time curve (AUC) increased dose-proportionally. Valemetostat plasma PK parameters were similar between the capsule and tablet formulations following a single 200-mg dose. Administration of valemetostat, 200 mg after a meal, was associated with 50%-60% lower Cmax , 30%-50% lower AUC, and a median Tmax delay of 2.5-3 hours relative to fasted administration. Valemetostat was well tolerated in healthy subjects; treatment-emergent adverse events were mild (grade 1) in severity. Based on these trials, the tablet formulation of valemetostat is suitable for use in subsequent clinical trials and should be administered under fasted conditions to avoid a negative food effect., (© 2023 The Authors. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)- Published
- 2024
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35. Comprehensive metabolic profiling of Geotrichum candidum and comparison with Saccharomyces cerevisiae.
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Bamba T, Hori Y, Umebayashi K, Soh C, Hakozaki T, Toyama K, Osumi M, Kondo A, and Hasunuma T
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- Pantothenic Acid, Amino Acids, Saccharomyces cerevisiae, Cheese
- Abstract
Geotrichum candidum is a dimorphic yeast used in cheese processing. To our knowledge, no major metabolites have been identified to date in G. candidum except for some amino acid and fatty acid metabolites. This has limited research on the commercial use of G. candidum. In this study, we aimed to analyze temporal changes in the intra- and extra-cellular metabolites of G. candidum and Saccharomyces cerevisiae cultured in YM medium as reference. As a result of metabolite analysis, it was observed that G. candidum tends to accumulate pentose phosphate pathway compounds, which are involved in nucleic acid synthesis, after 48 h of cultivation when compared to S. cerevisiae. In addition, G. candidum accumulated higher amounts of the antioxidant glutathione in the medium than did S. cerevisiae. In addition, G. candidum accumulated large amounts of B vitamins such as pantothenic acid and nicotinic acid in the medium. Finally, we examined the potential of G. candidum as a host for the production of useful compounds such as pantothenic acid. When cultured in medium supplemented with the pantothenic acid precursor β-alanine, G. candidum produced 12-fold higher amounts of pantothenic acid (30 μM) than that by S. cerevisiae. This study indicates that G. candidum accumulates various useful compounds that are dissimilar to those produced by S. cerevisiae. Furthermore, G. candidum has the potential to produce useful chemicals under appropriate culture conditions., (Copyright © 2023 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.)
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- 2024
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36. Early Initiation of Dapagliflozin during Hospitalization for Acute Heart Failure Is Associated with a Shorter Hospital Stay.
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Mizobuchi S, Saito Y, Miyagawa M, Koyama Y, Fujito H, Kojima K, Iida K, Murata N, Yamada A, Kitano D, Toyama K, Fukamachi D, and Okumura Y
- Subjects
- Humans, Length of Stay, Prospective Studies, Hospitalization, Benzhydryl Compounds therapeutic use, Benzhydryl Compounds pharmacology, Hospitals, Stroke Volume, Heart Failure complications, Sodium-Glucose Transporter 2 Inhibitors therapeutic use
- Abstract
Objective Sodium-glucose co-transporter-2 inhibitors (SGLT2is), such as dapagliflozin, have a diuretic effect, and their early initiation to treat acute heart failure (AHF) may improve outcomes; however, the significance of the timing of starting dapagliflozin after hospital admission remains unclear. Methods We performed a post hoc analysis of a prospective, observational registry. Participants were divided into the early (E) group and late (L) group using the median time to the initiation of dapagliflozin (6 days) as the cut-off. We evaluated the relationship between the time to the initiation of dapagliflozin after hospital admission and patient characteristics and the length of the hospital stay. Patients Study subjects were 118 patients with AHF admitted between January 2021 and April 2022 who were started on dapagliflozin treatment (10 mg/day). Results Patients were divided into the E group (n=63) and L group (n=55). The HF severity as evaluated by the New York Heart Association class and the N-terminal pro-brain natriuretic peptide level was not significantly different between the groups. The time to the initiation of dapagliflozin and length of hospital stay showed a significant positive correlation (p<0.001, r=0.46). The hospital stay was significantly shorter in group E [median, 16.5 days; interquartile range (IQR): 13-22 days] than in group L (median, 22 days; IQR: 17-27 days; p=0.002). A multivariate logistic regression analysis showed that the early initiation of dapagliflozin was independently associated with a shorter hospital stay, even after multiple adjustments. Conclusion Early initiation of dapagliflozin after hospital admission is associated with a shorter hospital stay, suggesting it is a key factor for shortening hospital stays.
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- 2023
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37. The Association Between Dehydration and the Prognosis of Sudden Sensorineural Hearing Loss.
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Abe Y, Okada M, Tanaka K, Toyama K, Miyamoto Y, and Hato N
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Background: There is an urgent need to identify undetermined risk factors for sudden sensorineural hearing loss (SSNHL) for the development of effective treatment strategies. SSNHL is likely associated with vascular insufficiency; however, no study has evaluated the relationship between dehydration and SSNHL., Objective: This study aimed to investigate the role of dehydration in the development and prognosis of sudden sensorineural hearing loss., Study Design: Retrospective case-control study., Setting: Secondary referral hospital., Patients and Interventions: This was a comparative study that compared dehydration parameters between healthy subjects without SSNHL (n = 94) and patients with SSNHL (n = 94). The study also evaluated the effect of dehydrated conditions on the prognosis of SSNHL., Main Outcome Measures: We compared dehydration parameters, such as the blood urea nitrogen-to-creatinine ratio (BUN/Cre) and plasma osmolality (Posm), between matched healthy subjects without SSNHL and patients with SSNHL. To evaluate the effect of dehydrated conditions on the SSNHL prognosis, the SSNHL patients were divided into 2 groups based on the cutoff value obtained from the receiver operating characteristic analysis: hydrated (n = 50; BUN/Cre <21.4) and dehydrated (n = 44; BUN/Cre ≥21.4) groups. Subsequently, the severity and prognosis of SSNHL were analyzed., Results: The dehydration parameters, BUN/Cre and Posm, were significantly higher in patients with SSNHL than in healthy subjects. The initial hearing levels and SSNHL grades were worse in the dehydrated group than in the hydrated group. Moreover, a dehydrated condition (BUN/Cre ≥21.4) was associated with a poor SSNHL prognosis in all models of the multiple logistic regression analysis., Conclusions: The dehydration parameters of BUN/Cre and Posm were higher in patients with SSNHL than in healthy subjects. Additionally, a dehydrated condition (BUN/Cre ≥21.4) was an independent prognostic factor for SSNHL. Level of evidence: Level 4., Competing Interests: None declared., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of Otology & Neurotology, Inc.)
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- 2023
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38. Pharmacokinetics and Bioequivalence of Mirogabalin Orally Disintegrating Tablets and Conventional Tablets in Healthy Japanese Participants.
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Toyama K, Eto T, Suzuki K, Shinohara S, Yoshiba S, Yoshihara K, and Ishizuka H
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- Humans, Male, Tablets administration & dosage, Tablets pharmacokinetics, Therapeutic Equivalency, Administration, Oral, Drug Liberation, Healthy Volunteers, Bridged Bicyclo Compounds administration & dosage, Bridged Bicyclo Compounds blood, Bridged Bicyclo Compounds pharmacokinetics, East Asian People
- Abstract
This single-center, randomized, open-label, single-dose, 2-group, 2-stage crossover trial evaluated the bioequivalence of 15 mg of mirogabalin as orally disintegrating tablets (ODTs) with conventional mirogabalin tablets in healthy Japanese men. The trial involved two studies: in Study 1, the ODT formulation was taken without water, and in Study 2, the ODT formulation was taken with water. The conventional tablet was taken with water in both studies. We investigated the pharmacokinetic parameters and bioequivalence of the 2 formulations, including the maximum plasma concentration and the area under the plasma concentration-time curve up to the last quantifiable time. The plasma concentrations of mirogabalin were determined by a validated liquid chromatography with tandem mass spectrometry method. A total of 72 participants were enrolled and completed the trial. The geometric least-squares mean ratios of maximum plasma concentration of the ODT formulation to the conventional formulation were within the prespecified bioequivalence range of 0.80-1.25 (Study 1, 0.995; Study 2, 1.009), as was the area under the plasma concentration-time curve up to the last quantifiable time (Study 1, 1.023; Study 2, 1.035). No serious adverse events were observed. In conclusion, mirogabalin 15-mg ODTs, either with or without water, were bioequivalent to conventional 15-mg tablets., (© 2023 The Authors. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)
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- 2023
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39. Dynamic organization of cerebellar climbing fiber response and synchrony in multiple functional components reduces dimensions for reinforcement learning.
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Hoang H, Tsutsumi S, Matsuzaki M, Kano M, Kawato M, Kitamura K, and Toyama K
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- Animals, Mice, Cerebellum, Axons, Purkinje Cells, Learning, Reinforcement, Psychology
- Abstract
Cerebellar climbing fibers convey diverse signals, but how they are organized in the compartmental structure of the cerebellar cortex during learning remains largely unclear. We analyzed a large amount of coordinate-localized two-photon imaging data from cerebellar Crus II in mice undergoing 'Go/No-go' reinforcement learning. Tensor component analysis revealed that a majority of climbing fiber inputs to Purkinje cells were reduced to only four functional components, corresponding to accurate timing control of motor initiation related to a Go cue, cognitive error-based learning, reward processing, and inhibition of erroneous behaviors after a No-go cue. Changes in neural activities during learning of the first two components were correlated with corresponding changes in timing control and error learning across animals, indirectly suggesting causal relationships. Spatial distribution of these components coincided well with boundaries of Aldolase-C/zebrin II expression in Purkinje cells, whereas several components are mixed in single neurons. Synchronization within individual components was bidirectionally regulated according to specific task contexts and learning stages. These findings suggest that, in close collaborations with other brain regions including the inferior olive nucleus, the cerebellum, based on anatomical compartments, reduces dimensions of the learning space by dynamically organizing multiple functional components, a feature that may inspire new-generation AI designs., Competing Interests: HH, ST, MM, MK, MK, KK, KT No competing interests declared, (© 2023, Hoang, Tsutsumi et al.)
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- 2023
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40. Treatment with Ligilactobacillus murinus lowers blood pressure and intestinal permeability in spontaneously hypertensive rats.
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Mukohda M, Yano T, Matsui T, Nakamura S, Miyamae J, Toyama K, Mitsui R, Mizuno R, and Ozaki H
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- Animals, Rats, Blood Pressure, Rats, Inbred SHR, Claudin-4, Intestines, Hypertension
- Abstract
One feature of hypertension is a microbial imbalance with increased intestinal permeability. In this study, we examined whether an alteration in the microbiota affects blood pressure and intestinal permeability in spontaneously hypertensive rats (SHRs). We performed a 16S metagenome analysis of feces from 10- to 15-week-old SHRs using a synthetic long-read sequencing approach, and found a candidate for the microbiome treatment, Ligilactobacillus murinus (L. murinus), that was robustly decreased. Oral administration of L. murinus to SHRs for 2 weeks significantly inhibited blood pressure elevation and improved endothelium-dependent vasodilation but did not attenuate enhanced vascular contraction in SHR mesenteric arteries. The proximal colon of SHRs exhibited increased intestinal permeability with decreased levels of the tight junction protein claudin 4, morphological changes such as decreased intestinal crypts and elevated TNF-α levels, which was reversed by treatment with L. murinus. Consistent with these intestinal phenotypes, plasma lipopolysaccharides levels were elevated in SHR but decreased following L. murinus administration. We concluded that oral administration of L. murinus to SHRs exerts protective effects on intestinal permeability via restoration of claudin 4 expression and reversal of morphologic disorder, which may improve low-grade endotoxemia and thus reduce development of hypertension via recovery of endothelial vasodilating functions., (© 2023. Springer Nature Limited.)
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- 2023
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41. A Redox-Responsive Ferrocene-Based Capsule Displaying Unusual Encapsulation-Induced Charge-Transfer Interactions.
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Toyama K, Tanaka Y, and Yoshizawa M
- Abstract
A ferrocene-based capsule is spontaneously and quantitatively formed in water by the assembly of bent amphiphiles carrying two ferrocene units. The disassembly and assembly of the new organometallic capsule, with a well-defined and highly condensed ferrocene core, are demonstrated by chemical redox stimuli in a fully reversible fashion under ambient conditions. In contrast to previously reported multiferrocene assemblies, only the present capsule efficiently encapsulates typical organic/inorganic dyes as well as electron-accepting molecules in water. As a result, unusual host-guest charge-transfer (CT) interactions, displaying relatively wide absorption bands in the visible to near-infrared region (λ=650-1350 nm), are observed upon the encapsulation of acceptors (i.e., chloranil and TCNQ). The resultant encapsulation-induced CT interactions can be released by a redox stimulus through the disassembly of the capsule., (© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)
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- 2023
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42. Mass Transfer from Mobile to Immobile Regions in Irregularly Shaped Micro-Channels at Low Reynolds Number.
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Toyama K, Togi F, and Harada S
- Abstract
Transient mass transfer in rough-walled micro-channels was investigated experimentally. We conducted experiments using rough-walled channels with various irregularities at small Reynolds number conditions. Mass transfer in the mainstream (mobile region) and dead water region (immobile region) were quantified using an image analysis technique based on absorption photometry. The experimental results showed that the solute dispersion in the mobile region was influenced by the irregular shape of the channel wall complicatedly. In contrast, mass transfer in the immobile region occurred by molecular diffusion independently on the wall roughness in our experimental conditions. The irregular shape of channel wall may enhance the mass transfer in mobile region by distorting the velocity distribution (Togi et al., 2020), while the solute redistribution to immobile region may suppress it in streamwise direction, just on a longer time scale. We developed a mass transfer model analogous to Mobile-Immobile model (MIM model) proposed by previous studies. The concept of the model is the same as the previous study (Zhou et al., 2019) and the coefficients of the model describing mass transfer in each region were quantified from the experimental results as functions of geometric characteristics of the rough-walled channel. In addition, mass transfer coefficient from mobile to immobile regions were derived mathematically based on the experimental results. The MIM model with the coefficients derived in this study well describes solute dispersion in variously shaped irregular channels quantitatively., (© 2022 National Ground Water Association.)
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- 2023
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43. Serum microRNA-501-3p is a potential diagnostic tool for detecting mild cognitive impairment: Ehime genome study.
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Toyama K, Spin JM, Tsao PS, Maruyama K, Osawa H, Mogi M, and Takata Y
- Subjects
- Humans, Male, Female, Mental Status and Dementia Tests, ROC Curve, Cognitive Dysfunction diagnosis, Cognitive Dysfunction genetics, Cognitive Dysfunction psychology, Dementia diagnosis, MicroRNAs metabolism
- Abstract
Tight junction disruption and dysfunction are involved in the progression of blood-brain barrier (BBB) breakdown. Recent investigations have revealed BBB disruption in patients with vascular cognitive decline. Our previous studies showed that miR-501-3p negatively regulates cerebral endothelial tight junction protein-1, resulting in the disruption of the BBB, and playing an important role in the development of vascular cognitive impairment. BBB breakdown in white matter lesions is often seen in the patients with vascular mild cognitive impairment (MCI). We therefore hypothesize that most early-phase MCI patients may demonstrate elevated expression of miR-501-3p and sought to investigate whether serum exosome miR-501-3p levels could be a clinical indicator for detecting mild cognitive impairment. One hundred and seventy-eight subjects (aged 73 [68-75] years, 53% male) were recruited for this study. The Japanese version of the Montreal Cognitive Assessment (MoCA-J) was used for detecting MCI. Serum exosome miR-501-3p expression levels were measured by qPCR methods. Patients were divided into two groups depending on whether their miR-501-3p ∆Ct values were above ("High"; n = 74) or below ("Low"; n = 104) cutoff levels determined by ROC curve. MCI was detected significantly more often in the miR-501-3p-High group (vs. -Low group, 63.5% vs. 47.1%, respectively; p < 0.05). Multivariate logistic regression analysis showed a significant association between MCI status and High miR-501-3p (odds ratio 2.662; p < 0.01), improved vs. known risk factors. In non-diabetic patients, High miR-501-3p was positively associated with MCI status (odds ratio 3.633; p < 0.01) and also positively associated with MCI status in those with atherosclerosis (odds ratio 3.219; p < 0.01). The present study demonstrates that elevated expression of blood exosomal miR-501-3p can indicate the presence of MCI in human patients. Early detection of vascular injuries may allow a reduction in progressive dementia through the management of vascular risk factors., (© 2023 International Society for Neurochemistry.)
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- 2023
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44. DS-5670a, a novel mRNA-encapsulated lipid nanoparticle vaccine against severe acute respiratory syndrome coronavirus 2: Results from a phase 2 clinical study.
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Toyama K, Eto T, Takazawa K, Shimizu S, Nakayama T, Furihata K, Sogawa Y, Kumazaki M, Jonai N, Matsunaga S, Takeshita F, Yoshihara K, and Ishizuka H
- Subjects
- Adult, Humans, COVID-19 Serotherapy, Immunoglobulin G, SARS-CoV-2, COVID-19 prevention & control
- Abstract
Background: DS-5670a is a vaccine candidate for coronavirus disease 2019 (COVID-19) harnessing a novel modality composed of messenger ribonucleic acid (mRNA) encoding the receptor-binding domain (RBD) from the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) encapsulated in lipid nanoparticles. Here, we report the safety, immunogenicity, and pharmacokinetic profile of DS-5670a from a phase 2 clinical trial in healthy adults who were immunologically naïve to SARS-CoV-2., Methods: The study consisted of an open-label, uncontrolled, dose-escalation part and a double-blind, randomized, uncontrolled, 2-arm, parallel-group part. A total of 80 Japanese participants were assigned to receive intramuscular DS-5670a, containing either 30 or 60 µg of mRNA, as two injections administered 4 weeks apart. Safety was assessed by characterization of treatment-emergent adverse events (TEAEs). Immunogenicity was assessed by neutralization titers against SARS-CoV-2, anti-RBD immunoglobulin (Ig)G levels, and SARS-CoV-2 spike-specific T cell responses. Plasma pharmacokinetic parameters of DS-5670a were also evaluated., Results: Most solicited TEAEs were mild or moderate with both the 30 and 60 µg mRNA doses. Four participants (10 %) in the 60 µg mRNA group developed severe redness at the injection site, but all cases resolved without treatment. There were no serious TEAEs and no TEAEs leading to discontinuation. Humoral immune responses in both dose groups were greater than those observed in human convalescent serum; the 60 µg mRNA dose produced better responses. Neutralization titers were found to be correlated with anti-RBD IgG levels (specifically IgG1). DS-5670a elicited antigen-specific T helper 1-polarized cellular immune responses., Conclusions: The novel mRNA-based vaccine candidate DS-5670a provided favorable immune responses against SARS-CoV-2 with a clinically acceptable safety profile. Confirmatory trials are currently ongoing to evaluate the safety and immunogenicity of DS-5670a as the primary vaccine and to assess the immunogenicity when administered as a heterologous or homologous booster., Trial Registry: https://jrct.niph.go.jp/latest-detail/jRCT2071210086., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Kaoru Toyama reports a relationship with Daiichi Sankyo Co Ltd that includes: employment. Shinji Shimizu reports a relationship with Daiichi Sankyo Co Ltd that includes: employment and equity or stocks. Kei Furihata reports a relationship with Daiichi Sankyo Co Ltd that includes: employment. Yoshitaka Sogawa reports a relationship with Daiichi Sankyo Co Ltd that includes: employment and equity or stocks. Masafumi Kumazaki reports a relationship with Daiichi Sankyo Co Ltd that includes: employment and equity or stocks. Nao Jonai reports a relationship with Daiichi Sankyo Co Ltd that includes: employment. Satoko Matsunaga reports a relationship with Daiichi Sankyo Co Ltd that includes: employment. Fumihiko Takeshita reports a relationship with Daiichi Sankyo Co Ltd that includes: employment and equity or stocks. Kazutaka Yoshihara reports a relationship with Daiichi Sankyo Co Ltd that includes: employment. Hitoshi Ishizuka reports a relationship with Daiichi Sankyo Co Ltd that includes: employment and equity or stocks., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)
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- 2023
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45. Clinical characteristics of Japanese patients with myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis.
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Edahiro Y, Ochiai T, Hashimoto Y, Morishita S, Shirane S, Inano T, Furuya C, Koike M, Noguchi M, Usuki K, Shiratsuchi M, Nakajima K, Ohtsuka E, Tanaka H, Kawata E, Nakamae M, Ueda Y, Aota Y, Sugita Y, Ohara S, Yamasaki S, Asagoe K, Yoshida S, Yamanouchi J, Suzuki S, Kondo T, Kanisawa Y, Toyama K, Omura H, Mizuchi D, Sakamaki S, Ando M, and Komatsu N
- Subjects
- Humans, Retrospective Studies, East Asian People, Mutation, RNA Splicing Factors genetics, Anemia, Sideroblastic genetics, Myelodysplastic Syndromes genetics, Myelodysplastic-Myeloproliferative Diseases genetics, Thrombocytosis genetics, Neoplasms complications
- Abstract
Myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) is a rare disease, which presents with features of myelodysplastic syndromes with ring sideroblasts and essential thrombocythemia, as well as anemia and marked thrombocytosis. SF3B1 and JAK2 mutations are often found in patients, and are associated with their specific clinical features. This study was a retrospective analysis of 34 Japanese patients with MDS/MPN-RS-T. Median age at diagnosis was 77 (range, 51-88) years, and patients had anemia (median hemoglobin: 9.0 g/dL) and thrombocytosis (median platelet count: 642 × 109/L). Median overall survival was 70 (95% confidence interval: 68-not applicable) months during the median follow-up period of 26 (range: 0-91) months. A JAK2V617F mutation was detected in 46.2% (n = 12) of analyzed patients (n = 26), while an SF3B1 mutation was detected in 87.5% (n = 7) of analyzed patients (n = 8). Like those with myelodysplastic syndromes or myeloproliferative neoplasms, patients often received erythropoiesis-stimulating agents and aspirin to improve anemia and prevent thrombosis. This study, which was the largest to describe the real-world characteristics of Japanese patients with MDS/MPN-RS-T, showed that the patients had similar characteristics to those in western countries., (© 2023. Japanese Society of Hematology.)
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- 2023
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46. Message to researchers: the characteristic absence of a posterior communicating artery is easily lost in the gerbil.
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Abe Y, Toyama K, Shinohara A, Nagura-Kato GA, Ikai Y, Koshimoto C, Spin JM, and Hato N
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- Animals, Male, Female, Gerbillinae physiology, Hippocampus, Ischemia, Circle of Willis, Brain Ischemia
- Abstract
The Mongolian gerbil has historically been useful for brain ischemia experiments, owing to the gerbil's uniquely underdeveloped circle of Willis (CoW). This led to a gerbil model of cochlear ischemia being generated in our unit. However, we have found that the usual severe hearing loss seen in this model was not being induced consistently in recent experiments using the MON/Jms/GbsSlc gerbil (the sole commercially available gerbil in Japan). We set out to evaluate the posterior communicating artery (PcomA) in MON/Jms/GbsSlc, to re-establish whether this strain is appropriate for ischemia models. Having found that this unique feature is often lost, we then attempted to breed for the characteristic absent PcomA. India-ink perfusion revealed that the percentage of intact bilateral PcomA ("communicating type") in the MON/Jms/GbsSlc gerbil was 57%; unilateral only ("unilateral communicating type") was 39%; and completely absent PcomA ("non-communicating type") was 4%. We were able to obtain few examples of the indigenous old aged Japanese UNG/Mz gerbil strain (at University of Miyazaki). Unfortunately, the pure UNG/Mz female was too elderly for mating. Therefore, selective breeding crosses between MON/Jms/GbsSlc and male UNG/Mz were carried out. After five generations of selective breeding, the percentage of non-communicating type gerbils was significantly higher in the newly generated strain, MON/Jms/SlcMz (F6 generation; 63%) than in the MON/Jms/GbsSlc gerbil. Bilateral common carotid artery occlusion surgery demonstrated that the cerebral blood flow was significantly reduced in MON/Jms/SlcMz compared with MON/Jms/GbsSlc (p < 0.0001) and induced more hippocampal injuries in MON/Jms/SlcMz than in MON/Jms/GbsSlc (p < 0.01). In conclusion, the commercially available MON/Jms/GbsSlc gerbil can easily regain PcomA, and we established a new gerbil strain (MON/Jms/SlcMz) displaying non-PcomA., (© 2022. The Author(s), under exclusive licence to Japanese Association of Anatomists.)
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- 2023
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47. Impact of the coronavirus disease 2019 (COVID-19) pandemic on the operational efficiency of emergency medical services and its association with out-of-hospital cardiac arrest survival rates: A population-based cohort study in Kobe, Japan.
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Sugiyama J, Inoue S, Inada M, Miyazaki Y, Nakanishi N, Fujinami Y, Saito M, Ono Y, Toyama K, Toda F, Shirotsuki T, Shiotani S, and Kotani J
- Abstract
Aim: To identify whether the coronavirus disease 2019 (COVID-19) pandemic affects the operational efficiency of emergency medical services (EMS) and the survival rate of out-of-hospital cardiac arrest (OHCA) in prehospital settings., Methods: We conducted a population-based cohort study in Kobe, Japan, between March 1, 2020, and September 31, 2022. In study 1, the operational efficiency of EMS, such as the total out-of-service time for ambulances, the daily occupancy rate of EMS, and response time, was compared between the pandemic and nonpandemic periods. In study 2, the impacts of the changes in EMS operational efficiency were investigated among patients with OHCA, with 1-month survival as the primary outcome and return of spontaneous circulation, 24-h survival, 1-week survival, and favorable neurological outcomes as the secondary outcomes. Logistic regression analysis was conducted to identify the factors associated with survival among patients with OHCA., Results: The total out-of-service time, occupancy rate, and response time significantly increased during the pandemic period ( p < 0.001). The response time during the pandemic period increased significantly per pandemic wave. Regarding OHCA outcomes, 1-month survival rates during the pandemic period significantly decreased compared with those during the nonpandemic period (pandemic 3.7% vs. nonpandemic 5.7%; p < 0.01). Similarly, 24-h survival (9.9% vs. 12.8%), and favorable neurological outcomes significantly decreased during the pandemic period. In the logistic regression analysis, response time was associated with lower OHCA survival in all outcomes ( p < 0.05)., Conclusion: The COVID-19 pandemic has been associated with reduced operational efficiency of EMS and decreased OHCA survival rates. Further research is required to improve the efficiency of EMS and OHCA survival rates., Competing Interests: The authors declare no conflicts of interest., (© 2023 The Authors. Acute Medicine & Surgery published by John Wiley & Sons Australia, Ltd on behalf of Japanese Association for Acute Medicine.)
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- 2023
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48. The behavior of sympatric sea urchin species across an ecosystem state gradient.
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Belleza DFC, Urae T, Tanimae SI, Toyama K, Isoda A, and Nishihara GN
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- Animals, Ecosystem, Sea Urchins physiology, Forests, Anthocidaris, Seaweed
- Abstract
Background: In temperate macroalgal forests, sea urchins are considered as a keystone species due to their grazing ability. Given their potential to shape benthic communities, we monitored the habitat use by three sympatric sea urchin species and compared their behaviors in a vegetated habitat (VH) and an adjacent isoyake habitat (IH)., Methods: We monitored the environmental conditions and sea urchin density along deep and shallow transects of the VH and IH for over a year. The benthic rugosity at both sites were also surveyed. A mark-recapture experiment was conducted on the two most abundant sea urchins, Diadema setosum and Heliocidaris crassispina , to elucidate sea urchin movement patterns and group dynamics., Results: We found that exposure to waves was highest at the VH while the IH was sheltered. The deep IH experienced the least amount of light due to high turbidity. Water temperature patterns were similar across sites. The VH benthic topography was more rugose compared to the smoother and silt-covered IH substate. Peak macroalgal bloom occurred three months earlier in IH, but macroalgae persisted longer at the shallow VH. Among the sympatric sea urchins, H. crassispina was most abundant at the shallow VH and was observed in pits and crevices. The most abundant across IH and in the deep VH was D. setosum , preferring either crevices or free-living, depending on hydrodynamic conditions. The least abundant species was D. savignyi , and most often observed in crevices. Small and medium sea urchins were most often observed at the IH site, whereas larger sea urchins were more likely observed at the VH. The mark-recapture study showed that D. setosum was found to displace further at the IH, and H. crassispina was more sedentary. Additionally, D. setosum was always observed in groups, whereas H. crassispina was always solitary., Discussion: The behaviors of sympatric urchins, Diadema savignyi, D. setosum and H. crassispina , differed in response to changes in the benthic environment and physical conditions. Sea urchin displacement increased when rugosity and wave action were low. Habitat preference shifted to crevices in seasons with high wave action. In general, the mark-recapture experiment showed that sea urchins displaced further at night., Competing Interests: The authors declare that they have no competing interests., (© 2023 Belleza et al.)
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- 2023
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49. Five-year follow-up of a phase II study of DA-EPOCH-R with high-dose MTX in CD5-positive DLBCL.
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Miyazaki K, Sakai R, Iwaki N, Yamamoto G, Murayama K, Nishikori M, Sunami K, Yoshida I, Yano H, Takahashi N, Okamoto A, Munemoto S, Sawazaki A, Suehiro Y, Fukuhara N, Wake A, Arai A, Masaki Y, Toyama K, Yokoyama A, Tsunemine H, Hasegawa Y, Matsumoto K, Yamada T, Nishimura Y, Tamaru S, Asano N, Miyawaki K, Izutsu K, Kinoshita T, Suzuki R, Ohshima K, Kato K, Katayama N, and Yamaguchi M
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- Humans, Follow-Up Studies, Rituximab therapeutic use, Cyclophosphamide therapeutic use, Etoposide therapeutic use, Doxorubicin therapeutic use, Prednisone adverse effects, Vincristine adverse effects, Antineoplastic Combined Chemotherapy Protocols adverse effects, Lymphoma, Large B-Cell, Diffuse drug therapy
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- 2023
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50. Steady-State Pharmacokinetics of Intravenous Hydromorphone in Japanese Patients With Renal Impairment and Cancer Pain.
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Nakatani T, Shiosakai K, Hashimoto T, Shionoya M, Akasaka T, Toyama K, Ishizuka H, and Saito Y
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- Humans, East Asian People, Prospective Studies, Pain drug therapy, Pain etiology, Cancer Pain drug therapy, Hydromorphone pharmacokinetics, Neoplasms complications, Renal Insufficiency
- Abstract
Background: The opioid analgesic hydromorphone has a low renal excretion ratio; however, exposure after oral administration is several times higher in those with moderate or severe renal impairment. Objectives: We evaluated the impact of renal impairment on the steady-state pharmacokinetics of intravenously administered hydromorphone in patients with cancer being treated for pain. Design: This was an open-label, prospective, parallel-comparison, interventional clinical pharmacology study. Setting/Subjects: This study was conducted at one hospital in Japan. Using creatinine clearance (CLcr) values, patients were grouped according to kidney function: CLcr ≥90 mL/min (normal), 60-<90 mL/min (mild impairment), 30-<60 mL/min (moderate impairment), or <30 mL/min (severe impairment). Measurements: Hydromorphone was administered by constant infusion to patients at the same constant dose rate as at the time of enrollment. Hydromorphone and its glucuronide metabolite concentrations in plasma and urine were measured by liquid chromatography-mass spectrometry. Pharmacokinetic parameters at steady state were assessed using noncompartmental analysis. Results: Thirty-two patients were enrolled (normal, n = 3; mild, n = 10; moderate, n = 15; and severe, n = 4). Adjusted geometric mean ratios for hydromorphone steady-state clearance (CLss) for patients with impaired versus normal renal function were 0.69 (90% confidence interval [CI], 0.41-1.14), 0.52 (90% CI, 0.31-0.84), and 0.55 (90% CI, 0.30-1.02) for mild, moderate, or severe impairment, respectively. Exposures to the metabolite hydromorphone-3-glucuronide generally increased with renal impairment. No adverse event was reported. Conclusion: Hydromorphone CLss in patients with impaired renal function (moderate and severe) was decreased ∼50% of that of normal renal function.
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- 2023
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