Publications by authors named "Hiroshi Takeda"

330 Publications

Effects of Gadolinium Deposition in the Brain on Motor or Behavioral Function: A Mouse Model.

Radiology 2021 Aug 31:210892. Epub 2021 Aug 31.

From the Department of Radiology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan (H.A., H.S., K.Y., A.K.); Department of Pharmacology, and School of Pharmacy (K.M., K.T., A.M.S., K.K., M.T.), and International University of Health and Welfare (K.O.), Ohtawara, Tochigi, Japan; Department of Pharmacology, School of Pharmacy at Fukuoka, International University of Health and Welfare, Okawa, Fukuoka, Japan (H.T.); Department of Diagnostic Radiology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan (Y.I.); Department of Radiology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan (O.A.); and Department of Radiology, International University of Health and Welfare, Narita, Chiba, Japan (S.K.).

Background Recent studies showing gadolinium deposition in multiple organs have raised concerns about the safety of gadolinium-based contrast agents (GBCAs). Purpose To explore whether gadolinium deposition in brain structures will cause any motor or behavioral alterations. Materials and Methods This study was performed from July 2019 to December 2020. Groups of 17 female BALB/c mice were each repeatedly injected with phosphate-buffered saline (control group, group A), a macrocyclic GBCA (group B), or a linear GBCA (group C) for 8 weeks (5 mmol per kilogram of bodyweight per week for GBCAs). Brain MRI studies were performed every other week to observe the signal intensity change caused by the gadolinium deposition. After the injection period, rotarod performance test, open field test, elevated plus-maze test, light-dark anxiety test, locomotor activity assessment test, passive avoidance memory test, Y-maze test, and forced swimming test were performed to assess the locomotor abilities, anxiety level, and memory. Among-group differences were compared by using one-way or two-way factorial analysis of variance with Tukey post hoc testing or Dunnett post hoc testing. Results Gadolinium deposition in the bilateral deep cerebellar nuclei was confirmed with MRI only in mice injected with a linear GBCA. At 8 weeks, contrast ratio of group C (0.11; 95% CI: 0.10, 0.12) was higher than that of group A (-2.1 × 10; 95% CI: -0.011, 7.5 × 10; < .001) and group B (2.7 × 10; 95% CI: -8.2 × 10, 8.7 × 10; < .001). Behavioral analyses showed that locomotor abilities, anxiety level, and long-term or short-term memory were not different in mice injected with linear or macrocyclic GBCAs. Conclusion No motor or behavioral alterations were observed in mice with brain gadolinium deposition. Also, the findings support the safety of macrocyclic gadolinium-based contrast agents. © RSNA, 2021 See also the editorial by Chen in this issue.
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http://dx.doi.org/10.1148/radiol.2021210892DOI Listing
August 2021

Recent Insights into the Measurement of Carbon Dioxide Concentrations for Clinical Practice in Respiratory Medicine.

Sensors (Basel) 2021 Aug 21;21(16). Epub 2021 Aug 21.

Department of Child Health and the Child Health Research Institute, MU Women's and Children's Hospital, University of Missouri, Columbia, MO 65201, USA.

In the field of respiratory clinical practice, the importance of measuring carbon dioxide (CO) concentrations cannot be overemphasized. Within the body, assessment of the arterial partial pressure of CO (PaCO) has been the gold standard for many decades. Non-invasive assessments are usually predicated on the measurement of CO concentrations in the air, usually using an infrared analyzer, and these data are clearly important regarding climate changes as well as regulations of air quality in buildings to ascertain adequate ventilation. Measurements of CO production with oxygen consumption yield important indices such as the respiratory quotient and estimates of energy expenditure, which may be used for further investigation in the various fields of metabolism, obesity, sleep disorders, and lifestyle-related issues. Measures of PaCO are nowadays performed using the Severinghaus electrode in arterial blood or in arterialized capillary blood, while the same electrode system has been modified to enable relatively accurate non-invasive monitoring of the transcutaneous partial pressure of CO (PtcCO). PtcCO monitoring during sleep can be helpful for evaluating sleep apnea syndrome, particularly in children. End-tidal PCO is inferior to PtcCO as far as accuracy, but it provides breath-by-breath estimates of respiratory gas exchange, while PtcCO reflects temporal trends in alveolar ventilation. The frequency of monitoring end-tidal PCO has markedly increased in light of its multiple applications (e.g., verify endotracheal intubation, anesthesia or mechanical ventilation, exercise testing, respiratory patterning during sleep, etc.).
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http://dx.doi.org/10.3390/s21165636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8402333PMC
August 2021

Effects of 1-year treatment with canagliflozin on body composition and total body water in patients with type 2 diabetes.

Diabetes Obes Metab 2021 Aug 2. Epub 2021 Aug 2.

The Study Group of the Diabetes Committee, Kanagawa Physicians Association, Yokohama, Japan.

Aim: To characterize the long-term changes in body composition associated with sodium-glucose cotransporter-2 (SGLT2) inhibitors.

Materials And Methods: In this multicentre, single-arm, open-label study, 107 patients with type 2 diabetes were treated with canagliflozin 100 mg, as add-on therapy, for 12 months. Body composition was measured with a body composition analyser (T-SCAN PLUS) using the impedance method to prospectively analyse changes in body components, including percentage of body fat, body fat mass, total body water, muscle mass and mineral mass. Estimated plasma volume (PV) was calculated using the Kaplan formula.

Results: Body weight showed a significant decrease from 1 month to 12 months of treatment with canagliflozin, with a higher rate of decrease in body fat in body composition. A significant decrease in mineral mass was also observed, but its rate was low. Following treatment with canagliflozin, changes in total body water did not affect intracellular water, and a significant decrease in extracellular water, including plasma components, was observed early and was sustained up to 12 months. Protein mass, a component of muscle mass, was not affected, with only a slight decrease in water volume observed.

Conclusions: Canagliflozin decreased extracellular fluid and PV in addition to decreasing fat in the body via calorie loss resulting from urinary glucose excretion. This study suggested that SGLT2 inhibitors might reduce body weight by regulating fat mass or water distribution in the body and might have cardiac and renal protective effects by resetting the homeostasis of fluid balance.
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http://dx.doi.org/10.1111/dom.14508DOI Listing
August 2021

The Combined Usage of the Global Leadership Initiative on Malnutrition Criteria and Controlling Nutrition Status Score in Acute Care Hospitals.

Ann Nutr Metab 2021 16;77(3):178-184. Epub 2021 Jul 16.

Division of Laboratory and Transfusion Medicine, Hokkaido University Hospital, Sapporo, Japan.

Introduction: The Global Leadership Initiative on Malnutrition (GLIM) lacks reliable blood tests for evaluating the nutrition status. We retrospectively compared the GLIM criteria, Controlling Nutrition Status (CONUT) score, and Subjective Global Assessment (SGA) to establish effective malnutrition screening and provide appropriate nutritional interventions according to severity.

Methods: We classified 177 patients into 3 malnutrition categories (normal/mild, moderate, and severe) according to the GLIM criteria, CONUT score, and SGA. We investigated the malnutrition prevalence, concordance of malnutrition severity, predictability of clinical outcome, concordance by etiology, and clinical outcome by inflammation.

Results: The highest prevalence of malnutrition was found using the GLIM criteria (87.6%). Concordance of malnutrition severity was low between the GLIM criteria and CONUT score. Concordance by etiology was low in all groups but was the highest in the "acute disease" group. The area under the curve of clinical outcome and that of the "with inflammation group" were significantly higher when using the CONUT score versus using the other tools (0.679 and 0.683, respectively).

Conclusion: The GLIM criteria have high sensitivity, while the CONUT score can effectively predict the clinical outcome of malnutrition. Their combined use can efficiently screen for malnutrition and patient severity in acute care hospitals.
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http://dx.doi.org/10.1159/000516994DOI Listing
July 2021

FGFR2 maintains cancer cell differentiation via AKT signaling in esophageal squamous cell carcinoma.

Cancer Biol Ther 2021 Jun 5;22(5-6):372-380. Epub 2021 Jul 5.

Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.

Fibroblast growth factors (FGFs) and their receptors (FGFRs) are important for signaling to maintain cancer stem-like cells (CSCs) in esophageal squamous cell carcinoma (ESCC). However, which FGF receptor, 1, 2, 3, 4, and L1, is essential or whether FGFRs have distinct different roles in ESCC-CSCs is still in question. This study shows that FGFR2, particularly the IIIb isoform, is highly expressed in non-CSCs. Non-CSCs have an epithelial phenotype, and such cells are more differentiated in ESCC. Further, FGFR2 induces keratinocyte differentiation through AKT but not MAPK signaling and diminishes CSC populations. Conversely, knockdown of FGFR2 induces epithelial-mesenchymal transition (EMT) and enriches CSC populations in ESCC. Finally, data analysis using The Cancer Genome Atlas (TCGA) dataset shows that expression of FGFR2 significantly correlated with cancer cell differentiation in clinical ESCC samples. The present study shows that each FGFR has a distinct role and FGFR2-AKT signaling is a key driver of keratinocyte differentiation in ESCC. Activation of FGFR2-AKT signaling could be a future therapeutic option targeting CSC in ESCC.
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http://dx.doi.org/10.1080/15384047.2021.1939638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8386746PMC
June 2021

Bcl-2-dependent autophagy disruption during aging impairs amino acid utilization that is restored by hochuekkito.

NPJ Aging Mech Dis 2021 Jul 1;7(1):13. Epub 2021 Jul 1.

Pathophysiology and Therapeutics, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido, Japan.

Chronic undernutrition contributes to the increase in frailty observed among elderly adults, which is a pressing issue in the sector of health care for older people worldwide. Autophagy, an intracellular recycling system, is closely associated with age-related pathologies. Therefore, decreased autophagy in aging could be involved in the disruption of energy homeostasis that occurs during undernutrition; however, the physiological mechanisms underlying this process remain unknown. Here, we showed that 70% daily food restriction (FR) induced fatal hypoglycemia in 23-26-month-old (aged) mice, which exhibited significantly lower hepatic autophagy than 9-week-old (young) mice. The liver expressions of Bcl-2, an autophagy-negative regulator, and Beclin1-Bcl-2 binding, were increased in aged mice compared with young mice. The autophagy inducer Tat-Beclin1 D11, not the mTOR inhibitor rapamycin, decreased the plasma levels of the glucogenic amino acid and restored the blood glucose levels in aged FR mice. Decreased liver gluconeogenesis, body temperature, physical activity, amino acid metabolism, and hepatic mitochondrial dynamics were observed in the aged FR mice. These changes were restored by treatment with hochuekkito that is a herbal formula containing several autophagy-activating ingredients. Our results indicate that Bcl-2 upregulation in the liver during the aging process disturbs autophagy activation, which increases the vulnerability to undernutrition. The promotion of liver autophagy may offer clinical therapeutic benefits to frail elderly patients.
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http://dx.doi.org/10.1038/s41514-021-00065-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249599PMC
July 2021

Disturbance of prefrontal cortical myelination in olfactory bulbectomized mice is associated with depressive-like behavior.

Neurochem Int 2021 09 23;148:105112. Epub 2021 Jun 23.

Department of Pharmacology, School of Pharmacy, International University of Health and Welfare, 2600-1 Kitakanemaru, Ohtawara, Tochigi, 324-8501, Japan. Electronic address:

Recent studies have reported that demyelination is associated with the development of depression. Olfactory bulbectomized (OBX) rodents are a useful experimental animal model for depressive disorder. However, little is known about the change in myelination in the brain of OBX mice. To address this question, we observed depressive-like behavior of OBX mice in the tail-suspension test, and determined the quantity of myelin proteins in the prefrontal cortex (PFC), striatum and hippocampus on day 14 or 21 after surgery. The number of nodes of Ranvier paired with the paranodal marker contactin-associated protein (Caspr), as well as the numbers of immature and mature oligodendrocytes in the PFC, were also measured on day 21 after surgery. We examined whether these behavioral and neurochemical changes observed in OBX mice were reversed by chronic administration of imipramine. OBX mice showed depressive-like behavior in the tail-suspension test together with a decrease in the levels of myelin proteins such as myelin basic protein, myelin-associated glycoprotein and cyclicnucleotide phosphodiesterase in the PFC on day 21 after surgery. The number of nodes of Ranvier and mature oligodendrocytes were also decreased in the PFC of OBX mice, while the number of immature oligodendrocytes was increased on day 21 after surgery. However, the number of immature oligodendrocytes in the PFC of OBX mice was decreased on day 35 after surgery. Administration of imipramine (20 mg/kg) for 2 weeks from day 21 after surgery improved OBX-induced depressive-like behavior and abnormal myelination in the PFC. The present findings suggest that the disturbance of myelin function in the PFC may contribute to the pathophysiology of depression, and further support the notion that it plays an important role in the psychological state.
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http://dx.doi.org/10.1016/j.neuint.2021.105112DOI Listing
September 2021

Error Evaluation for Automated Diameter Measurements of Cerebral Capillaries Captured with Two-Photon Laser Scanning Fluorescence Microscopy.

Adv Exp Med Biol 2021 ;1269:241-245

Department of Functional Brain Imaging Research, National Institute of Radiological Sciences, Chiba, Japan.

Cerebral capillaries respond to changes in neural activity to maintain regional balances between energy demand and supply. However, the quantitative aspects of the capillary diameter responses and their contribution to oxygen supply to tissue remain incompletely understood. The purpose of the present study is to check if the diameters measured from large-scale angiographic image data of two-photon laser scanning fluorescent microscopy (2PLSM) are correctly determined with a custom-written MATLAB software and to investigate how the measurement errors can be reduced, such as at the junction areas of capillaries. As a result, nearly 17% of the measured locations appeared to be outliers of the automated diameter measurements, in particular arising from the junction areas where three capillary segments merged. We observed that about two-thirds of the outliers originated from the measured locations within 6 μm from the branching point. The results indicate that the capillary locations in the junction areas cause non-negligible errors in the automated diameter measurements. Considering the common site of the outliers, the present study identified that the areas within 6 μm from the branch point could be separately measured from the diameter analysis, and careful manual inspection with reference to the original images for these transition areas around the branch point is further recommended.
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http://dx.doi.org/10.1007/978-3-030-48238-1_38DOI Listing
May 2021

Sarcopenia in a patient with most serious complications after highly invasive surgeries treated with nutrition, rehabilitation, and pharmacotherapy: a case report.

J Pharm Health Care Sci 2021 Apr 6;7(1):16. Epub 2021 Apr 6.

Department of Pharmacy, Hokkaido University Hospital, Kita 14, Nishi 5, Kita-Ku, Sapporo, Hokkaido, 060-8648, Japan.

Background: Several studies have reported the implementation of nutrition therapy and rehabilitation for acute and critical illnesses. However, rehabilitation nutrition for elderly sarcopenia patients with extremely severe postoperative complications during hospitalization has not yet been established.

Case Presentation: We report the case of a 70-year-old man with sarcopenia that developed as a postoperative complication of the surgical resection of perihilar cholangiocarcinoma and left the patient bedridden from prolonged malnutrition and muscle weakness. The patient's general condition improved after a nearly 6-month intervention by our Nutrition Support Team (NST) that combined nutrition, exercise, and pharmacotherapy.

Conclusions: The appropriate timing and order of pharmacotherapy, nutrient administration, exercise therapy, and team collaboration may enable elderly patients with severe (secondary) sarcopenia and postoperative complications to regain self-sustained walking.
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http://dx.doi.org/10.1186/s40780-021-00197-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8022529PMC
April 2021

Activation of cholinergic system partially rescues olfactory dysfunction-induced learning and memory deficit in mice.

Behav Brain Res 2021 06 2;408:113283. Epub 2021 Apr 2.

Department of Pharmacology, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, Miyagi 981-8558, Japan; Complementary and Alternative Medicine Clinical Research and Development, Graduate School of Medicine Sciences, Kanazawa University, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8640, Japan.

Deficits in olfaction are associated with neurodegenerative disorders such as Alzheimer's disease. A recent study reported that intranasal zinc sulfate (ZnSO)-treated mice show olfaction and memory deficits. However, it remains unknown whether olfaction deficit-induced learning and memory impairment is associated with the cholinergic system in the brain. In this study, we evaluated olfactory function by the buried food find test, and learning and memory function by the Y-maze and passive avoidance tests in ZnSO-treated mice. The expression of choline acetyltransferase (ChAT) protein in the olfactory bulb (OB), prefrontal cortex, hippocampus, and amygdala was assessed by western blotting. Moreover, we observed the effect of the acetylcholinesterase inhibitor physostigmine on ZnSO-induced learning and memory deficits. We found that intranasal ZnSO-treated mice exhibited olfactory dysfunction, while this change was recovered on day 14 after treatment. Both short-term and long-term learning and memory were impaired on days 4 and 7 after treatment with ZnSO, whereas the former, but not the latter, was recovered on day 14 after treatment. A significant correlation was observed between olfactory function and short-term memory, but not long-term memory. Treatment with ZnSO decreased the ChAT level in the OB on day 4, and increased and decreased the ChAT levels in the OB and hippocampus on day 7, respectively. Physostigmine improved the ZnSO-induced deficit in short-term, but not long-term, memory. Taken together, the present results suggest that short-term memory may be closely associated with olfactory function via the cholinergic system.
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http://dx.doi.org/10.1016/j.bbr.2021.113283DOI Listing
June 2021

Protective effect of ISO-1 with inhibition of RIPK3 up-regulation and neutrophilic accumulation on acetaminophen-induced liver injury in mice.

Toxicol Lett 2021 Mar 25;339:51-59. Epub 2020 Dec 25.

Pathophysiology and Therapeutics, Hokkaido University Faculty of Pharmaceutical Sciences, kita-12, nishi-6, kita-ku Sapporo, 060-8638, Japan.

Overdose use of acetaminophen (APAP) often occurs a severe liver injury, and its liver injury is lethal in some cases. Macrophage migration inhibitory factor (MIF) is expressed in a variety of cells and has multifunctional roles. However, the role of MIF in APAP-induced liver injury has not been fully investigated. In this study, we investigated whether treatment with (S,R)-3-(4-hydroxyphenil)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1), a MIF inhibitor, protected mice from acute APAP-induced liver injury. Acute liver injury was induced by injection of APAP (300 mg/kg body weight). Mice were treated with a single injection of ISO-1(15 mg/kg body weight) 1 h (h) before APAP administration. Histological, biochemical and molecular analyses were performed in liver of mice 12 h after APAP administration. ISO-1 remarkably improved the histological findings of APAP-induced liver injury in mice. The increases in serum levels of alanine aminotransferase (ALT), and macrophage inflammatory protein-2 (MIP-2) by APAP were inhibited by ISO-1. In addition, ISO-1 reduced the increased number of the myeloperoxidase-staining cells and that of TUNEL-positive staining cells in the liver of mice with APAP-induced liver injury. Up-regulation of hepatic receptor interacting protein kinase (RIPK)3 and heat shock protein70 by APAP was suppressed in the liver of mice given ISO-1. These results provide the additional evidence that inhibition of MIF activity may be clinically effective for treatment of acute APAP-induced liver injury.
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http://dx.doi.org/10.1016/j.toxlet.2020.12.015DOI Listing
March 2021

Effects of Normoxic Recovery on Intima-Media Thickness of Aorta and Pulmonary Artery Following Intermittent Hypoxia in Mice.

Front Physiol 2020 22;11:583735. Epub 2020 Oct 22.

Department of Child Health and the Child Health Research Institute, MU Women's and Children's Hospital, University of Missouri, Columbia, MO, United States.

Obstructive sleep apnea (OSA) patients are at risk for increased blood pressure and carotid intima-media thickness (IMT), with pulmonary hypertension and right-sided heart failure potentially developing as well. Chronic intermittent hypoxia (IH) has been used as an OSA model in animals, but its effects on vascular beds have not been evaluated using objective unbiased tools. Previously published and current experimental data in mice exposed to IH were evaluated for IMT in aorta and pulmonary artery (PA) after IH with or without normoxic recovery using software for meta-analysis, Review Manager 5. Because IMT data reports on PA were extremely scarce, atherosclerotic area percentage from lumen data was also evaluated. IH significantly increased IMT parameters in both aorta and PA as illustrated by Forest plots ( < 0.01), which also confirmed that IMT values after normoxic recovery were within the normal range in both vascular beds. One-sided scarce lower areas in Funnel Plots were seen for both aorta and PA indicating the likelihood of significant publication bias. Forest and Funnel plots, which provide unbiased assessments of published and current data, suggest that IH exposures may induce IMT thickening that may be reversed by normoxic recovery in both aorta and PA. In light of the potential likelihood of publication bias, future studies are needed to confirm or refute the findings. In conclusion, OSA may induce IMT thickening (e.g., aorta and/or PA), but the treatment (e.g., nasal continuous positive airway pressure) will likely lead to improvements in such findings.
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http://dx.doi.org/10.3389/fphys.2020.583735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645053PMC
October 2020

Impact of emphysema on sputum culture conversion in male patients with pulmonary tuberculosis: a retrospective analysis.

BMC Pulm Med 2020 Nov 7;20(1):287. Epub 2020 Nov 7.

Department of Internal Medicine, Division of Respiratory Diseases, The Jikei University School of Medicine, Tokyo, Japan.

Background: Although cigarette smoking may have a negative impact on the clinical outcome of pulmonary tuberculosis (PTB), few studies have investigated the impact of smoking-associated lung diseases. Emphysema is a major pathological finding of smoking-related lung damage. We aimed to clarify the effect of emphysema on sputum culture conversion rate for Mycobacterium tuberculosis (MTB).

Methods: We retrospectively studied 79 male patients with PTB confirmed by acid-fast bacillus smear and culture at Jikei University Daisan Hospital between January 2015 and December 2018. We investigated the sputum culture conversion rates for MTB after starting standard anti-TB treatment in patients with or without emphysema. Emphysema was defined as Goddard score ≥ 1 based on low attenuation area < - 950 Hounsfield Unit (HU) using computed tomography (CT). We also evaluated the effect on PTB-related CT findings prior to anti-TB treatment.

Results: Mycobacterial median time to culture conversion (TCC) in 38 PTB patients with emphysema was 52.0 days [interquartile range (IQR) 29.0-66.0 days], which was significantly delayed compared with that in 41 patients without emphysema (28.0 days, IQR 14.0-42.0 days) (p < 0.001, log-rank test). Multivariate Cox proportional hazards analysis showed that the following were associated with delayed TCC: emphysema [hazard ratio (HR): 2.43; 95% confidence interval (CI): 1.18-4.97; p = 0.015), cavities (HR: 2.15; 95% CI: 1.83-3.89; p = 0.012) and baseline time to TB detection within 2 weeks (HR: 2.95; 95% CI: 1.64-5.31; p < 0.0001). Cavities and consolidation were more often identified by CT in PTB patients with than without emphysema (71.05% vs 43.90%; p = 0.015, and 84.21% vs 60.98%; p = 0.021, respectively).

Conclusions: This study suggests that emphysema poses an increased risk of delayed TCC in PTB. Emphysema detection by CT might be a useful method for prediction of the duration of PTB treatment required for sputum negative conversion.
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http://dx.doi.org/10.1186/s12890-020-01325-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648401PMC
November 2020

Effects of feeding condition on the myocardial and hepatic accumulation of radioiodine-labeled BMIPP in mice.

Ann Nucl Med 2021 Jan 8;35(1):59-64. Epub 2020 Oct 8.

Graduate School of Medicine, Hokkaido University, Sapporo, Japan.

Objective: I-15-(p-iodophenyl)-3(R,S)-methylpentadecanoic acid ([I]BMIPP), a fatty acid analog, is widely used for the diagnosis of cardiac diseases. Feeding condition is one of the important factors in the myocardial fatty acid uptake, which may also affect myocardial accumulation of [I]BMIPP and image quality of [I]BMIPP scintigraphy. However, the relationship between the myocardial accumulation of [I]BMIPP and the feeding condition is not entirely clear. Therefore, we determined the myocardial accumulation of [I]BMIPP in mice at various metabolic statuses induced by fasting in comparison with the hepatic accumulation.

Methods: Fed or fasted (6-, 12-, and 24-h fasted) mice were intravenously injected with [I]BMIPP (35.2-75.0 kBq, 4 nmol). Radioactivities in the heart and liver were measured at 1, 5, 10, 30, 60, and 120 min after the injection (n = 5-15/time point for each group), and then, the heart-to-liver (H/L) ratios were calculated.

Results: The myocardial accumulation level of [I]BMIPP in the fed group was almost the same as that in the 6-h-fasted group at each time point, although it was decreased by 12- and 24-h fasting. The H/L ratios of [I]BMIPP accumulation level were significantly decreased by fasting (1.92 ± 0.22, 1.45 ± 0.13, 1.12 ± 0.13, and 0.91 ± 0.15 at 10 min, and 3.30 ± 0.62, 2.09 ± 0.35, 1.79 ± 0.34, and 1.27 ± 0.06 at 30 min after the injection, respectively, for the fed group and the 6-, 12-, and 24-h-fasted groups; p < 0.0001), largely owing to the increase in the hepatic accumulation level in the fasting groups.

Conclusion: Although short-period (6 h) fasting did not affect the myocardial accumulation level of [I]BMIPP, the hepatic accumulation level was increased. The present results indicate that the fed condition may provide higher-contrast images in myocardial [I]BMIPP scintigraphy.
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http://dx.doi.org/10.1007/s12149-020-01535-xDOI Listing
January 2021

Leukemia Inhibitory Factor Participates in the Formation of Stress Adaptation via Hippocampal Myelination in Mice.

Neuroscience 2020 10 29;446:1-13. Epub 2020 Aug 29.

Department of Pharmacology, School of Pharmacy, International University of Health and Welfare, 2600-1 Kitakanemaru, Ohtawara, Tochigi 324-8501, Japan.

Leukemia inhibitory factor (LIF) has been shown to be involved in myelination. The present study investigated whether LIF plays a significant role in the formation of stress adaptation using stress-adaptive and -maladaptive mice, and also attempted to confirm whether there was any difference in myelination between these animal models. A single exposure to restraint stress for 1 h induced a decrease in head-dipping behavior in the hole-board test. This stress response was not seen in mice that had been exposed to restraint stress for 1 h/day for 14 days, which is referred to as stress adaptation. In contrast, repeated exposure to restraint stress for 4 h/day for 14 days did not lead to the development of stress adaptation, and was still associated with a decrease in head-dipping behaviors. Under these conditions, LIF protein was found to be increased with astrocyte activation in the hippocampus of stress-adaptive mice, whereas no change was observed in stress-maladaptive mice. On the other hand, major myelin proteins including myelin-associated glycoprotein and myelin basic protein, as well as mature oligodendrocytes, were decreased in the hippocampus of stress-maladaptive, but not stress-adaptive, mice. Furthermore, while the levels of phosphorylated-extracellular signal-regulated kinase (p-ERK) were increased in the hippocampus of stress-adaptive, this change did not occur in stress-maladaptive mice. Taken together, the present findings suggest that LIF, which may be derived from activated astrocytes, plays a critical role in the maintenance of hippocampal myelination via an ERK signaling pathway, and contributes to the development of stress adaptation.
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http://dx.doi.org/10.1016/j.neuroscience.2020.08.030DOI Listing
October 2020

Clinical utility of thoracoscopy in elderly tuberculous pleurisy patients under local anesthesia.

J Infect Chemother 2021 Jan 23;27(1):40-44. Epub 2020 Aug 23.

Division of Respiratory Medicine, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.

Introduction: Diagnosing tuberculous pleurisy is important in Japan because it currently has a moderate tuberculosis prevalence. However, physicians often have difficulty making a diagnosis. It was reported that thoracoscopy under local anesthesia is useful for the diagnosis of tuberculous pleurisy, but there are no reports focusing on elderly patients.

Methods: In this study, the usefulness of thoracoscopy under local anesthesia was evaluated in elderly patients. Among 170 patients who underwent thoracoscopy under local anesthesia at our hospital during 11 years from January 2008 to December 2018, those aged 75 years or older (n = 75) were investigated retrospectively.

Results: A total of 55 patients underwent thoracoscopy under local anesthesia for detailed examination of pleural effusion of unknown cause. Of these, 18 were diagnosed as tuberculous pleurisy. The median age was 82 years (range: 75-92 years). The diagnosis of tuberculous pleurisy was made in 11 patients in whom Mycobacterium tuberculosis was detected and in four patients whose pathological findings indicated epithelioid granuloma accompanied by caseous necrosis. Clinical diagnosis was made in the remaining three patients based on thoracoscopic findings of the pleural cavity and a high level of adenosine deaminase in pleural fluid. No serious complications attributable to the examination were observed in any patient.

Conclusions: Thoracoscopy under local anesthesia was useful for the diagnosis of tuberculous pleurisy in elderly patients, with useful information being also obtained for the treatment of tuberculosis.
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http://dx.doi.org/10.1016/j.jiac.2020.08.008DOI Listing
January 2021

Vulnerability to psychological stress-induced anorexia in female mice depends on blockade of ghrelin signal in nucleus tractus solitarius.

Br J Pharmacol 2020 10 2;177(20):4666-4682. Epub 2020 Sep 2.

Pathophysiology and Therapeutics, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido, Japan.

Background And Purpose: Women have a higher incidence of eating disorders than men. We investigated whether the effects of ghrelin on feeding are affected by sex and stress, and to elucidate the mechanisms that may cause sex differences in stress-mediated anorexia, focusing on ghrelin.

Experimental Approach: Acylated ghrelin was administered to naïve and psychologically stressed male and female C57BL/6J mice, followed by measurements of food intake and plasma hormone levels. Ovariectomy was performed to determine the effects of ovary-derived oestrogen on stress-induced eating disorders in female mice. The numbers of Agrp or c-Fos mRNA-positive cells and estrogen receptor α/c-Fos protein-double-positive cells were assessed.

Key Results: Ghrelin administration to naïve female mice caused a higher increase in food intake, growth hormone secretion, Agrp mRNA expression in the arcuate nucleus and c-Fos expression in the nucleus tractus solitarius (NTS) than in male mice. In contrast, psychological stress caused a more sustained reduction in food intake in females than males. The high sensitivity of naïve females to exogenous ghrelin was attenuated by stress exposure. The stress-induced decline in food intake was not abolished by ovariectomy. Estrogen receptor-α but not -β antagonism prevented the decrease in food intake under stress. Estrogen receptor-α/c-Fos-double-positive cells in the NTS were significantly increased by stress only in females.

Conclusion And Implications: Stress-mediated eating disorders in females may be due to blockade of ghrelin signalling via estrogen receptor-α activation in the NTS. Targeting the ghrelin signal in the brain could be a new treatment strategy to prevent these disorders.
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http://dx.doi.org/10.1111/bph.15219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7520439PMC
October 2020

Retrospective Analysis of the Renoprotective Effects of Long-Term Use of Six Types of Sodium-Glucose Cotransporter 2 Inhibitors in Japanese Patients with Type 2 Diabetes Mellitus and Chronic Kidney Disease.

Diabetes Technol Ther 2021 02 13;23(2):110-119. Epub 2020 Aug 13.

Committee of Hypertension and Kidney Disease, Kanagawa Physicians Association, Yokohama, Japan.

Sodium-glucose cotransporter 2 inhibitors (SGLT2is) provide renal protection in patients with type 2 diabetes mellitus (T2DM). The aim of this study was to elucidate the renal effects of long-term use of six types of SGLT2is in Japanese patients with T2DM and chronic kidney disease (CKD). The Kanagawa Physicians Association maintains a registry of patients who visit their 31 clinics. We retrieved clinical data of patients with T2DM and CKD who were prescribed with SGLT2is for >1 year. A total of 763 patients with a median treatment duration of 33 months were included. The logarithmic value of urine albumin-creatinine ratio (LNACR) decreased significantly from 1.60 ± 0.65 to 1.51 ± 0.67. The multiple linear regression analysis revealed that the LNACR at the initiation of treatment, change in (Δ) diastolic blood pressure, and Δ hemoglobin A1c were independently correlated with ΔLNACR ( < 0.001). The decrease in the LNACR was significantly smaller in the patients with estimated glomerular filtration rate (eGFR) [mL/(min ·1.73 m)] of <60 ( < 0.05). The eGFR decreased from 77.4 ± 22.3 to 72.7 ± 22.5 mL/(min ·1.73 m) ( < 0.001). The multiple linear regression analysis showed that the LNACR at the initiation of treatment, Δbody weight at the previous survey, ΔeGFR at the previous survey, and the eGFR at the initiation of treatment correlated independently with ΔeGFR during the maintenance period ( < 0.001). Greater changes in the eGFR during the maintenance period were observed in the patients with macroalbuminuria or eGFR of <60 ( < 0.01). The study confirmed that the long-term use of six types of SGLT2i improved the albumin-creatinine ratio (ACR), although the eGFR gradually decreased during the treatment. The change in the ACR was significantly smaller in the patients with eGFR of <60 mL/(min ·1.73 m) than in those with eGFR of >60 mL/(min ·1.73 m). However, this was a retrospective observational study; further studies are needed to formulate final conclusions.
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http://dx.doi.org/10.1089/dia.2020.0165DOI Listing
February 2021

Dopamine D receptor supersensitivity in the hypothalamus of olfactory bulbectomized mice.

Brain Res 2020 11 13;1746:147015. Epub 2020 Jul 13.

Department of Pharmacology, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, Miyagi 981-8558, Japan.

Olfactory bulbectomy (OBX) in rodents induces neurochemical and behavioral changes similar to those observed in individuals with depressive disorders. Our previous study suggested that OBX alters dopaminergic function in the striatum of mice; however, the effects on dopaminergic function in the hypothalamus is unknown. Therefore, in this study we examined dopaminergic system changes in the hypothalamus after OBX. Mice were administrated either the nonselective dopamine (DA) agonist apomorphine or the selective D agonist quinelorane, or pretreated with the selective D antagonist SCH23390 in combination with the selective D antagonist sulpiride or D antagonist SB277011A. Body temperature, which is regulated by the hypothalamic dopaminergic system, was monitored to evaluate changes in the dopaminergic system of the hypothalamus. DA D receptor (D2DR), tyrosine hydroxylase (TH), and phosphorylated (p)- DA- and cAMP-regulated phosphoprotein-32 (DARPP-32) levels in the hypothalamus were evaluated by western blotting. OBX mice exhibited significantly enhanced apomorphine-induced or quinelorane-induced hypothermia. The apomorphine-induced hypothermic response was reversed by the administration of sulpiride, but not SCH23390 or SB277011A. Moreover, TH and p-DARPP-32 levels were reduced and D2DR increased in the hypothalamus of OBX mice. These findings revealed that the OBX mice display enhanced DA receptor responsiveness associated with the hypothalamus, which may relate to some of the behavioral and neurochemical alterations reported in this animal model. Identification of changes in the hypothalamic dopaminergic system of OBX mice may provide useful information for the development of novel antidepressant treatments.
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http://dx.doi.org/10.1016/j.brainres.2020.147015DOI Listing
November 2020

Blood pressure after treatment with sodium-glucose cotransporter 2 inhibitors influences renal composite outcome: Analysis using propensity score-matched models.

J Diabetes Investig 2021 Jan 10;12(1):74-81. Epub 2020 Jul 10.

Committee of Hypertension and Kidney Disease, Kanagawa Physicians Association, Yokohama, Japan.

Aims/introduction: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve renal outcome in patients with type 2 diabetes mellitus, but the mechanism is not fully understood. The aim of this retrospective study was to assess the association of achieved blood pressure with renal outcomes in Japanese type 2 diabetes mellitus patients with chronic kidney disease.

Materials And Methods: We assessed 624 Japanese type 2 diabetes mellitus patients with chronic kidney disease taking SGLT2i for >1 year. The patients were classified as those with post-treatment mean arterial pressure (MAP) of ≥92 mmHg (n = 344) and those with MAP of <92 mmHg (n = 280) for propensity score matching (1:1 nearest neighbor match with 0.04 of caliper value and no replacement). The end-point was a composite of progression of albuminuria or a decrease in the estimated glomerular filtration rate by ≥15% per year.

Results: By propensity score matching, a matched cohort model was constructed, including 201 patients in each group. The incidence of renal composite outcome was significantly lower among patients with MAP of <92 mmHg than among patients with MAP of ≥92 mmHg (n = 11 [6%] vs n = 26 [13%], respectively, P = 0.001). The change in estimated glomerular filtration rate was similar in the two groups; however, the change in the albumin-to-creatinine ratio was significantly larger in patients with MAP of <92 mmHg.

Conclusions: In Japanese type 2 diabetes mellitus patients with chronic kidney disease, blood pressure after SGLT2i administration influences the renal composite outcome. Blood pressure management is important, even during treatment with SGLT2i.
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http://dx.doi.org/10.1111/jdi.13318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7779270PMC
January 2021

Antidementia effects of Enterococcus faecalis 2001 are associated with enhancement of hippocampal neurogenesis via the ERK-CREB-BDNF pathway in olfactory bulbectomized mice.

Physiol Behav 2020 09 3;223:112997. Epub 2020 Jun 3.

Department of Pharmacology, School of Pharmacy, International University of Health and Welfare, 2600-1 Kitakanemaru, Ohtawara, Tochigi 324-8501, Japan.. Electronic address:

Our previous study showed that Enterococcus faecalis 2001 (EF-2001) suppresses colitis-induced depressive-like behavior through the enhancement of hippocampal neurogenesis in mice. In the present study, we investigated the effect of EF-2001 on the cognitive behavior of olfactory bulbectomized (OBX) mice and its molecular mechanisms. The OBX-induced cognitive dysfunction was significantly suppressed by EF-2001. Moreover, EF-2001 also recovered the reductions in p-ERK1/2, p-CREB, BDNF and DCX levels and in neurogenesis observed in the hippocampus of OBX mice. These results suggest that EF-2001-induced antidementia effects are associated with enhanced hippocampal neurogenesis through the ERK-CREB-BDNF pathway.
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http://dx.doi.org/10.1016/j.physbeh.2020.112997DOI Listing
September 2020

Characterization of 5-HT receptor and transport protein KIF13A expression in the hippocampus of stress-adaptive and -maladaptive mice.

Neurosci Lett 2020 08 24;733:135082. Epub 2020 May 24.

Department of Pharmacology, School of Pharmacy, International University of Health and Welfare, 2600-1 Kitakanemaru, Ohtawara, Tochigi 324-8501, Japan.

The ability to adapt to stress is an essential defensive function of a living body, and disturbance of this ability in the brain may contribute to the development of affective illness including major depression and anxiety disorders. A growing body of evidence suggests that brain serotonin (5-HT) receptors may be involved, at least in part, in the development of adaptation to stress. 5-HT receptor was reported to be transported by KIF13A, a motor protein and a member of the kinesin superfamily, from the golgi apparatus to the plasma membrane. The aim of the present study was to characterize the expression pattern of 5-HT receptor and KIF13A in the hippocampus of stress-adaptive and -maladaptive mice. Mice were either exposed to repeated adaptable (1 h/day) or unadaptable (4 h/day) restraint stress, or left in their home cage for 14 days. The levels of 5-HT receptor and KIF13A expression were assessed by western blot analysis. To confirm the formation of a 5-HT receptor and KIF13A complex, we performed blue native-sodium dodecyl sulfate-polyacrylamide gel electrophoresis (BN-SDS-PAGE). Western blotting showed that neither 5-HT receptor nor KIF13A expression changed significantly in the hippocampal total extract of stress-adaptive and -maladaptive mice. In contrast, expression of 5 H T receptor and KIF13A in the hippocampal membrane fraction was increased in stress-adaptive mice, but not in stress-maladaptive mice. BN-SDS-PAGE analysis revealed that the bands of 5-HT receptor and KIF13A were both observed at a molecular weight of approximately 70 kDa, which indicated that 5-HT receptor and KIF13A form a complex. The present findings suggest that translocation of 5-HT receptor in complex with KIF13A to the plasma membrane of the hippocampus may play an important role in the formation of stress adaptation.
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http://dx.doi.org/10.1016/j.neulet.2020.135082DOI Listing
August 2020

Lenvatinib suppresses cancer stem-like cells in HCC by inhibiting FGFR1-3 signaling, but not FGFR4 signaling.

Carcinogenesis 2021 02;42(1):58-69

Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.

In hepatocellular carcinoma (HCC), a subset of cells defined by high CD44 and CD133 expression has been reported to possess cancer stem-like cell (CSC) characteristics and to be associated with a poor prognosis. Since the approval of the multikinase inhibitor, lenvatinib, for patients with unresectable HCC, two such inhibitors (sorafenib and lenvatinib) have been employed as first-line systemic chemotherapeutics for these patients. Based on differences in the kinase-affinity profiles between these two drugs, evidence has suggested that both exert different effects on HCC, although these differences are not fully characterized. In this study, using in vitro and a preclinical in vivo xenograft mouse model, we showed that lenvatinib alone (not sorafenib or the cytotoxic agent, 5-fluorouracil) diminished CD44High/CD133High CSCs in HCC. Furthermore, western blotting and reverse transcriptase-polymerase chain reaction analysis revealed that the expression of fibroblast growth factor receptor (FGFR)-1-4 differed between CD44High/CD133High CSCs and control cells. Analysis of the effects of selective FGFR inhibitors and FGFR small interfering RNAs on CSCs in HCC revealed that lenvatinib diminished CSCs in HCC by inhibiting FGFR1-3 signaling, however, FGFR4 signaling was not impacted. Finally, we showed that FGF2 and FGF19 were involved in maintaining CD44High/CD133High CSCs in HCC, potentially, via FGFR1-3. The findings provide novel mechanistic insights into the effects of lenvatinib on CSCs in HCC and provide clues for developing effective targeted therapies against CSCs in HCC.
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http://dx.doi.org/10.1093/carcin/bgaa049DOI Listing
February 2021

Estimation of dietary C dose coefficient using C-labelled compound administration analysis.

Sci Rep 2020 05 18;10(1):8156. Epub 2020 May 18.

Institute for Environmental Sciences, Aomori, Japan.

Carbon-14 released from nuclear facilities has been assessed to contribute significantly to the radiation dose that people are exposed to through the food chain. However, the current dose coefficient for members of public, which is the ratio of the 50-year committed effective dose to ingested 1 Bq C, recommended by the International Commission on Radiological Protection (ICRP) is not based on experimental human metabolic data for C in nutrients and diet. Therefore, to validate the coefficient, we administered C-labelled nutrients consisting of four amino acids, three fatty acids, and one monosaccharide to volunteers as substitutes for C labelled nutrients and measured the C concentration in various excreta samples. Although metabolic models were constructed from the excretion data, a significant fraction of administered C was not recovered from some nutrients. The dose coefficients of C in uniformly labelled Japanese diet, which were estimated under several assumptions about the unrecoverable fraction, varied from (6.2 ± 0.9) × 10 to (8.9 ± 4.4) × 10 Sv Bq and were approximately comparable to the current value of 5.8 × 10 Sv Bq recommended by the ICRP. Further studies are necessary to elucidate the metabolism of C in various nutrients in the unrecoverable fraction.
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http://dx.doi.org/10.1038/s41598-020-64954-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235250PMC
May 2020

A Study of Seasonal Variation in the Effect of Add-On Sitagliptin on Blood Glucose Control in Insulin-Treated Patients With Type 2 Diabetes.

J Clin Med Res 2020 Mar 2;12(3):200-208. Epub 2020 Mar 2.

Diabetes Committee Study Group, Kanagawa Physicians Association, 1-3 Fujimichou, Nakaku, Yokohama, Kanagawa 231-0037, Japan.

Background: There are several reports of seasonal variation in hemoglobin A1c (HbA1c) in patients with type 2 diabetes (T2DM), but no reports of seasonal variation in the effect of add-on drugs on blood glucose control in insulin-treated patients.

Methods: Using data collected from 630 patients in a multicenter study, we compared the amount of change in HbA1c after 1, 3, 6, 9, and 12 months of add-on administration of sitagliptin in insulin-treated patients divided into four groups based on the month when sitagliptin was started.

Results: A significantly larger decrease in HbA1c at 6 months from baseline was observed in the group that started add-on sitagliptin in February to April than in the other three groups. However, the amount of change in HbA1c at 12 months did not differ among the groups.

Conclusions: The consideration of seasonal variation enables more accurate evaluation of a drug's short-term effect on blood glucose control.
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http://dx.doi.org/10.14740/jocmr4103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7092762PMC
March 2020

Effects of ipragliflozin on the development and progression of kidney disease in patients with type 2 diabetes: An analysis from a multicenter prospective intervention study.

J Diabetes Investig 2020 Sep 25;11(5):1248-1257. Epub 2020 Apr 25.

Division of Metabolism and Endocrinology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan.

Aims/introduction: Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available.

Methods: This was an investigator-initiated multicenter prospective intervention study in which ipragliflozin (50 mg) was administered once daily, and glycemic control, estimated glomerular filtration rate (eGFR) and adverse events were evaluated until 104 weeks after starting research.

Results: There were 407 patients analyzed. In the eGFR ≥90 group and eGFR ≥60 to <90 group, eGFR had significantly decreased compared with baseline at all time points from 4 to 104 weeks. There were significant increases in the eGFR ≥45 to <60 groups compared with baseline at 36 weeks (2.3 ± 1.0) and 52 weeks (2.6 ± 1.2). Comparison between the eGFR <60, urine albumin-to-creatinine ratio >300 group and the eGFR <60, urine albumin-to-creatinine ratio <300 group showed a greater reduction in eGFR in the former (-5.4 ± 2.4 vs 3.3 ± 1.1) at 12 weeks and was maintained to 104 weeks. In any group, eGFR did not significantly decrease until 104 weeks compared with 4 weeks. The urine albumin-to-creatinine ratio after 52 weeks and after 104 weeks was significantly decreased compared with baseline in the eGFR ≥90 group.

Conclusions: Ipragliflozin lowers eGFR and corrects hyperfiltration in patients with high eGFR (eGFR ≥60). In patients with low eGFR (eGFR ≥30 to <60), ipragliflozin has the possibility of increasing eGFR and exerting a renoprotective effect.
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http://dx.doi.org/10.1111/jdi.13248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477528PMC
September 2020

Canagliflozin Increases Calorie Intake in Type 2 Diabetes Without Changing the Energy Ratio of the Three Macronutrients: CANA-K Study.

Diabetes Technol Ther 2020 03 3;22(3):228-234. Epub 2020 Feb 3.

Division of Metabolism and Endocrinology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki City, Japan.

Sodium/glucose cotransporter-2 (SGLT2) inhibitors improve glycemic control and reduce body weight by increasing glycosuria. Although a compensatory increase of food intake has been reported, the long-term effect of SGLT2 inhibitors on food intake remains unclear. This study investigated the influence of canagliflozin on calorie and nutrient intake over 1 year. Patients with type 2 diabetes ( = 107) were enrolled and followed prospectively while receiving canagliflozin at 100 mg/day for 12 months. Intake of nutrients was investigated by using the food frequency questionnaire. Hemoglobin A1c, body weight, and satisfaction with diabetes treatment (assessed by the Diabetes Treatment Satisfaction Questionnaire: DTSQ) were also investigated. The baseline total energy intake was 1723 ± 525 kcal/day and it showed a persistent increase during treatment with canagliflozin, being 132 kcal higher at 6 months ( = 0.0058) and 113 kcal higher at 12 months ( = 0.0516). Intake of all three macronutrients (carbohydrate, protein, and fat) was significantly increased after 6 months of canagliflozin treatment ( = 0.0129,  = 0.0160, and  = 0.0314, respectively), but their ratio was unchanged. The DTSQ score improved significantly and both hemoglobin A1c and body weight showed a significant decrease throughout treatment (all  < 0.0001). After patients with type 2 diabetes commenced canagliflozin, their calorie intake increased without changing the ratio of the three macronutrients. Despite elevation of the calorie intake, glycemic control improved and weight loss was achieved. Satisfaction with treatment of diabetes also increased.
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http://dx.doi.org/10.1089/dia.2019.0372DOI Listing
March 2020

Preclinical investigation of potential use of thymidine phosphorylase-targeting tracer for diagnosis of nonalcoholic steatohepatitis.

Nucl Med Biol 2020 Mar - Apr;82-83:25-32. Epub 2019 Dec 16.

Central Institute of Isotope Science, Hokkaido University, Hokkaido 060-0815, Japan; Graduate School of Biomedical Science and Engineering, Hokkaido University, Hokkaido 060-0815, Japan.

Introduction: Although liver biopsy is the gold standard for the diagnosis of nonalcoholic steatohepatitis (NASH), it has several problems including high invasiveness and sampling errors. Therefore, the development of alternative methods to overcome these disadvantages is strongly required. In this study, we evaluated the potential use of our tracer targeting thymidine phosphorylase (TYMP), 5-[I]iodo-6-[(2-iminoimidazolidinyl)methyl]uracil ([I]IIMU) for the diagnosis of NASH.

Methods: The mice used as the NASH model (hereafter, NASH mice) were prepared by feeding a methionine- and choline-deficient diet for 4 weeks. A control group was similarly given a control diet. The expression levels of the TYMP gene and protein in the liver were examined by real-time reverse-transcription polymerase chain reaction and western blot analyses. The localizations of [I]IIMU and the TYMP protein in the liver were examined by autoradiography and immunohistochemical staining, respectively. Finally, the mice were injected with [I]IIMU and single-photon emission tomography (SPECT) imaging was conducted.

Results: The hepatic expression levels of TYMP were significantly lower in the NASH mice than in the control mice at both mRNA and protein levels, suggesting that a decrease in TYMP level could be an indicator of NASH. [I]IIMU was uniformly distributed in the liver of the control mice, whereas it showed a patchy distribution in that of the NASH mice. The localization of [I]IIMU was visually consistent with that of the TYMP protein in the liver of the control and NASH mice. SPECT analysis indicated that the hepatic accumulation of [I]IIMU in the NASH mice was significantly lower than that in the control mice [SUV (g/ml): 4.14 ± 0.87 (Control) vs 2.31 ± 0.29 (NASH)].

Conclusions: [I]IIMU may provide a noninvasive means for imaging TYMP expression in the liver and may be applicable to the diagnosis of NASH.
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http://dx.doi.org/10.1016/j.nucmedbio.2019.12.006DOI Listing
May 2021

Relation between Blood Pressure Management and Renal Effects of Sodium-Glucose Cotransporter 2 Inhibitors in Diabetic Patients with Chronic Kidney Disease.

J Diabetes Res 2019 3;2019:9415313. Epub 2019 Nov 3.

Committee of Hypertension and Kidney Disease, Kanagawa Physicians Association, Yokohama, Kanagawa Prefecture, Japan.

Aim: The renoprotective effect of sodium-glucose cotransporter 2 inhibitors is thought to be due, at least in part, to a decrease in blood pressure. The aim of this study was to determine the renal effects of these inhibitors in low blood pressure patients and the dependence of such effect on blood pressure management status.

Methods: The subjects of this retrospective study were 740 patients with type 2 diabetes mellitus and chronic kidney disease who had been managed at the clinical facilities of the Kanagawa Physicians Association. Data on blood pressure management status and urinary albumin-creatinine ratio were analyzed before and after treatment.

Results: Changes in the logarithmic value of urinary albumin-creatinine ratio in 327 patients with blood pressure < 130/80 mmHg at the initiation of treatment and in 413 patients with BP above 130/80 mmHg were -0.13 ± 1.05 and -0.24 ± 0.97, respectively. However, there was no significant difference between the two groups by analysis of covariance models after adjustment of the logarithmic value of urinary albumin-creatinine ratio at initiation of treatment. Changes in the logarithmic value of urinary albumin-creatinine ratio in patients with mean blood pressure of <102 mmHg ( = 537) and those with ≥102 mmHg ( = 203) at the time of the survey were -0.25 ± 1.02 and -0.03 ± 0.97, respectively, and the difference was significant in analysis of covariance models even after adjustment for the logarithmic value of urinary albumin-creatinine ratio at initiation of treatment ( < 0.001).

Conclusion: Our results confirmed that blood pressure management status after treatment with SGLT2 inhibitors influences the extent of change in urinary albumin-creatinine ratio. Stricter blood pressure management is needed to allow the renoprotective effects of sodium-glucose cotransporter 2 inhibitors.
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http://dx.doi.org/10.1155/2019/9415313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6875192PMC
April 2020
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