Publications by authors named "Takeshi Yamamoto"

391 Publications

Impact of the COVID-19 Pandemic on ST-elevation Myocardial Infarction from a Single-center Experience in Tokyo.

Intern Med 2021 Sep 25. Epub 2021 Sep 25.

Division of Cardiovascular Intensive Care, Nippon Medical School Hospital, Japan.

Objective The coronavirus disease 2019 (COVID-19) pandemic has had a significant impact on global healthcare systems. Some studies have reported the negative impact of COVID-19 on ST-elevation myocardial infarction (STEMI) patients; however, the impact in Japan remains unclear. This study investigated the impact of the COVID-19 pandemic on STEMI patients admitted to an academic tertiary-care center in Tokyo, Japan. Methods In this retrospective, observational, cohort study, we included 398 consecutive patients who were admitted to our institute from January 1, 2018, to March 10, 2021, and compared the incidence of hospitalization, clinical characteristics, time course, management, and outcomes before and after March 11, 2020, the date when the World Health Organization declared COVID-19 a pandemic. Results There was a 10.7% reduction in hospitalization of STEMI patients during the COVID-19 pandemic compared with that in the previous year (117 vs. 131 cases). During the COVID-19 pandemic, the incidence of late presentation was significantly higher (26.5% vs. 12.1%, p<0.001), and the onset-to-door (241 [IQR: 70-926] vs. 128 [IQR: 66-493] min, p=0.028) and door-to-balloon (72 [IQR: 61-128] vs. 60 [IQR: 43-90] min, p<0.001) times were significantly longer than in the previous year. Furthermore, the in-hospital mortality was higher, but the difference was not significant (9.4% vs. 5.0%, p=0.098). Conclusions The COVID-19 pandemic significantly impacted STEMI patients in Tokyo and resulted in a slight decrease in hospitalization, a significant increase in late presentation and treatment delays, and a slight but nonsignificant increase in mortality. In the COVID-19 era, the acute management system for STEMI in Japan must be reviewed.
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http://dx.doi.org/10.2169/internalmedicine.8220-21DOI Listing
September 2021

Human TRPV1 and TRPA1 are receptors for bacterial quorum sensing molecules.

J Biochem 2021 Sep 23. Epub 2021 Sep 23.

Tobacco Science Research Center, Japan Tobacco Inc., 6-2 Umegaoka, Aoba, Yokohama, Kanagawa, 227-8512, Japan.

In this study, we investigated the activation of TRPV1 and TRPA1 by N-acyl homoserine lactones, quorum sensing molecules produced by Gram-negative bacteria, and the inhibitory effect of TRPV1 and TRPA1 by autoinducing peptides, quorum sensing molecules produced by Gram-positive bacteria, using human embryonic kidney 293T cell lines stably expressing human TRPV1 and TRPA1, respectively. As a result, we found that some N-acyl homoserine lactones, such as N-octanoyl-L-homoserine lactone (C8-HSL), N-nonanoyl-L-homoserine lactone (C9-HSL) and N-decanoyl-L-homoserine lactone (C10-HSL) activated both TRPV1 and TRPA1. In addition, we clarified that some N-acyl homoserine lactones, for example, N-3-oxo-dodecanoyl-L-homoserine lactone (3-oxo-C12-HSL) only activated TRPV1, and N-acyl homoserine lactones having saturated short acyl chain, such as N-acetyl-L-homoserine lactone (C2-HSL) and N-butyryl-L-homoserine lactone (C4-HSL) only activated TRPA1, respectively. Furthermore, we found that an autoinducing peptide, simple linear peptide CHWPR, inhibited both TRPV1 and TRPA1, and peptide having thiolactone ring DICNAYF, thiolactone ring were formed between C3 to F7, strongly inhibited only the TRPV1. Although the specificity of TRPV1 and TRPA1 for quorum sensing molecules were different, these data suggest that both TRPV1 and TRPA1 would function as receptors for quorum sensing molecule produced by bacteria.
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http://dx.doi.org/10.1093/jb/mvab099DOI Listing
September 2021

Effect of Empagliflozin Versus Placebo on Body Fluid Balance in Patients With Acute Myocardial Infarction and Type 2 Diabetes Mellitus: Subgroup Analysis of the EMBODY Trial.

J Card Fail 2021 Aug 21. Epub 2021 Aug 21.

Department of Cardiovascular Medicine, Nippon Medical School, Tokyo, Japan.

Background: The development of heart failure is associated with fluid balance, including that of extracellular water (ECW) and intracellular water (ICW). This study determined whether sodium-glucose cotransporter 2 inhibitors affect fluid balance and improve heart failure in patients after acute myocardial infarction.

Methods And Results: EMBODY was a prospective, randomized, double-blinded, placebo-controlled trial of Japanese patients with acute myocardial infarction and type 2 diabetes. Overall, 55 patients who underwent bioelectrical impedance analysis were randomized to receive once daily 10 mg empagliflozin or placebo 2 weeks after acute myocardial infarction onset. We investigated the time course of body fluid balance measured using the bioelectrical impedance analysis device, InBody. The primary end points were changes in body fluid balance from weeks 0 to 24. Changes between baseline and week 24 in the empagliflozin and placebo groups were -0.21 L (P = .127) and +0.40 L (P = .001) in ECW (P = .001) and -0.23 L (P = .264) and +0.74 L (P < .001) in ICW (P < .001), respectively. In a stratified analysis, the rise in ECW and ICW was significantly attenuated in the empagliflozin group in contrast to the placebo group in participants with a body mass index of 25 or higher but not in those with a body mass index of less than 25.

Conclusions: Early sodium-glucose cotransporter 2 inhibitor administration may attenuate changes in ECW and ICW.
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http://dx.doi.org/10.1016/j.cardfail.2021.07.022DOI Listing
August 2021

Hemodynamic Collapse Caused by Cardiac Dysfunction and Abdominal Compartment Syndrome in a Patient with Mitochondrial Disease.

Intern Med 2021 Aug 13. Epub 2021 Aug 13.

Department of Cardiovascular Medicine, Nippon Medical School, Japan.

We herein report a case of mitochondrial disease with heart and intestinal tract involvement resulting in hemodynamic collapse. A 66-year-old woman was transferred to our hospital because of cardiogenic shock. Vasopressors were administered, and a circulatory support device was deployed. However, her hemodynamics did not improve sufficiently, and we detected abdominal compartment syndrome caused by the aggravation of chronic intestinal pseudo-obstruction as a complication. Insertion of a colorectal tube immediately decreased the intra-abdominal pressure, improving the hemodynamics. Finally, we diagnosed her with mitochondrial disease, concluding that the resulting combination of acute heart failure and abdominal compartment syndrome had aggravated the hemodynamics.
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http://dx.doi.org/10.2169/internalmedicine.7729-21DOI Listing
August 2021

Combined use of venoarterial extracorporeal membrane oxygenation and intra-aortic balloon pump after cardiac arrest.

Resuscitation 2021 Jul 24. Epub 2021 Jul 24.

Tokyo CCU Network, Scientific Committee, Tokyo, Japan.

Objectives: We investigated whether intra-aortic balloon pump (IABP) combined with venoarterial extracorporeal membrane oxygenation (VA-ECMO) was associated with favourable neurological outcomes for patients after the return of spontaneous circulation (ROSC). Moreover, we evaluated the aetiology of cardiac arrest on the effectiveness of this therapy in a sub-study.

Background: There is insufficient research on the optimal combination of machines for patients after ROSC is not established.

Methods: This is a large-scale, multicentre, 30-day cohort study. Among 80,716 patients who delivered to the emergency room, 935 patients treated with VA-ECMO after ROSC were included using the data from the Tokyo Cardiovascular Care Unit Network Registry between 2010 and 2017. The study patients were stratified according to the use of IABP [the ECMO + IABP group (n = 762) vs. the ECMO-alone group (n = 173)]. We also evaluated the cause of cardiac arrest [acute coronary syndrome (ACS) and non-ACS] in the sub-study. To adjust the patients' backgrounds, we used the propensity score matching for additional analyses. The endpoint was 30-day favourable neurological outcome.

Results: The ECMO + IABP group showed significantly better neurological outcomes than the ECMO-alone group (crude; 35% vs. 25%; log-lank P < 0.001). In the ACS subgroup, the ECMO + IABP group showed significantly better neurological outcome (crude; 34% vs. 18%; log-lank P < 0.001), but not in the non-ACS subgroup (crude; 38% vs. 32%; log-lank P = 0.11). These results are similar after adjustments to their backgrounds using propensity matching.

Conclusions: Compared to VA-ECMO alone, the combined use of VA-ECMO and IABP is associated with better neurological outcomes after ROSC, especially in complicated ACS.
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http://dx.doi.org/10.1016/j.resuscitation.2021.07.019DOI Listing
July 2021

Suppression of plasmacytoid dendritic cell migration to colonic isolated lymphoid follicles abrogates the development of colitis.

Biomed Pharmacother 2021 Sep 7;141:111881. Epub 2021 Jul 7.

Division of Gastrointestinal Pathophysiology, Institute of Natural Medicine, University of Toyama, Japan.

Background: Dendritic cells (DCs) play a pivotal role in maintaining immunological homeostasis by orchestrating innate and adaptive immune responses via migration to inflamed sites and the lymph nodes (LNs). Plasmacytoid DCs (pDCs) have been reported to accumulate in the colon of inflammatory bowel disease (IBD) patients and dextran sulfate sodium (DSS)-induced colitis mice. However, the role of pDCs in the progression of colonic inflammation remains unclear.

Methods: 80 compounds in natural medicines were searched for inhibitors of pDC migration using bone marrow-derived pDCs (BMpDCs) and conventional DCs (BMcDCs). BALB/c mice were given 3% DSS in the drinking water to induce acute colitis. Compounds, which specifically inhibited pDC migration, were administrated into DSS-induced colitis mice.

Findings: Astragaloside IV (As-IV) and oxymatrine (Oxy) suppressed BMpDC migration but not BMcDC migration. In DSS-induced colitis mice, the number of pDCs was markedly increased in the colonic lamina propria (LP), and the expression of CCL21 was obviously observed in colonic isolated lymphoid follicles (ILFs). As-IV and Oxy reduced symptoms of colitis and the accumulation of pDCs in colonic ILFs but not in the colonic LP. Moreover, in a BMpDC adoptive transfer model, BMpDC migration to colonic ILFs was significantly decreased by treatment with As-IV or Oxy.

Interpretation: pDCs accumulated in the colon of colitis mice, and As-IV and Oxy ameliorated colitis by suppressing pDC migration to colonic ILFs. Accordingly, the selective inhibition of pDC migration may be a potential therapeutic approach for treating colonic inflammatory diseases.
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http://dx.doi.org/10.1016/j.biopha.2021.111881DOI Listing
September 2021

Effect of Empagliflozin Versus Placebo on Plasma Volume Status in Patients with Acute Myocardial Infarction and Type 2 Diabetes Mellitus.

Diabetes Ther 2021 Aug 8;12(8):2241-2248. Epub 2021 Jul 8.

Department of Cardiovascular Medicine, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo, 113-0022, Japan.

Introduction: Plasma volume status (PVS), a parameter of the discrepancy between actual plasma volume (PV) and ideal PV, has been recently evaluated as a prognostic marker in patients with heart failure. This subgroup analysis of the EMBODY trial was designed to determine whether a sodium-glucose cotransporter 2 (SGLT2) inhibitor affects the alleviation of heart failure and improvement of PVS in patients after acute myocardial infarction (AMI) with congestive heart failure (CHF).

Methods: The EMBODY trial was a prospective, multicenter, randomized, double-blind, placebo-controlled trial to identify the effect of an SGLT2 inhibitor on cardiac sympathetic hyperactivity in patients with AMI and type 2 diabetes mellitus (T2DM) in Japan. In total, 105 patients were randomized (1:1) to receive 10 mg empagliflozin or a placebo (once daily), 2 weeks after the onset of AMI. In this subanalysis, we investigated the time-course of PVS at baseline and weeks 4, 12, and 24.

Results: Overall, 96 patients were included in the subgroup analysis set (age 64.3 ± 10.9 years, 80.2% men; 46 in the empagliflozin group and 50 in the placebo group). Body weight and PVS decreased in the empagliflozin group compared with the placebo group at 24 weeks (- 2.2 vs. + 0.1 kg, P < 0.001, and - 5.1 vs. - 0.3%, P < 0.001, respectively). Decreased PVS, defined as a change in PVS of < - 4.5%, was associated with the administration of empagliflozin (odds ratio 2.61, 95% confidence interval 1.11-6.15, P = 0.028). N-terminal pro b-type natriuretic peptide levels decreased in both the empagliflozin and placebo groups (1028.7-370.3 pg/mL, P < 0.001, and 1270.6-673.7 pg/mL, P < 0.01, respectively).

Conclusion: Empagliflozin reduced the body weight and PVS. Early SGLT2 inhibitor administration in patients with AMI, CHF, and T2DM can therefore be effective in reducing the body weight and PVS.

Trial Registration: UMIN 000030158.
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http://dx.doi.org/10.1007/s13300-021-01103-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8342682PMC
August 2021

Empagliflozin confers reno-protection in acute myocardial infarction and type 2 diabetes mellitus.

ESC Heart Fail 2021 Oct 7;8(5):4161-4173. Epub 2021 Jul 7.

Department of Cardiovascular Medicine, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo, 113-0022, Japan.

Aims: Although the reno-protective effects of sodium-glucose cotransporter 2 inhibitors are known in patients with heart failure or type 2 diabetes mellitus (T2DM), this effect has not been confirmed in patients with acute myocardial infarction (AMI).

Methods And Results: The prospective, multicentre, randomized, double-blind, placebo-controlled EMBODY trial investigated patients with AMI and T2DM in Japan. The eligible patients included adults aged 20 years or older, diagnosed with AMI and T2DM, and who could be discharged within 2-12 weeks after the onset of AMI. One hundred and five patients were randomized (1:1) to receive once daily 10 mg empagliflozin or placebo within 2 weeks of AMI onset. In this sub-analysis, we investigated the time course of renal functional parameters such as serum creatinine levels and estimated glomerular filtration rate (eGFR) from baseline to Weeks 4, 12, and 24. Ninety-six patients (64 ± 11 years, 78 male) were included in the full analysis (n = 46 and 50 in the empagliflozin and placebo groups, respectively). We used serum creatinine and eGFR as indicators of renal function. In the placebo group, eGFR decreased from 66.14 mL/min/1.73 m at baseline to 62.77 mL/min/1.73 m by Week 24 (P = 0.023) but remained unchanged in the empagliflozin group (from 64.60 to 64.36 mL/min/1.73 m , P = 0.843). In the latter group, uric acid improved from 5.8 mg/dL at baseline to 4.9 mg/dL at Week 24 (P < 0.001). In the earlier analysis of 56 patients with eGFR ≥ 60 mL/min/1.73 m , the eGFR decreased and the serum creatinine increased from baseline to 24 weeks in the placebo group, significantly different to the empagliflozin group (-6.61 vs. +0.22 mL/min/1.73 m , P = 0.008 and +0.063 vs. -0.001 mg/dL, P = 0.030, respectively). The changes in serum creatinine and eGFR from baseline to Week 24 were significantly correlated with those in uric acid in the placebo group (r = 0.664, P < 0.001 and r = -0.675, P < 0.001, respectively) but not in the empagliflozin group.

Conclusions: Empagliflozin prevented the kidney functional decline in patients with AMI and T2DM, especially those with baseline eGFR ≥ 60 mL/min/1.73 m . Early administration of sodium-glucose cotransporter 2 inhibitors in these patients is considered desirable for renal protection.
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http://dx.doi.org/10.1002/ehf2.13509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8497324PMC
October 2021

Pathophysiological Roles of Neuro-Immune Interactions between Enteric Neurons and Mucosal Mast Cells in the Gut of Food Allergy Mice.

Cells 2021 06 23;10(7). Epub 2021 Jun 23.

Division of Gastrointestinal Pathophysiology, Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.

Recently, the involvement of the nervous system in the pathology of allergic diseases has attracted increasing interest. However, the precise pathophysiological role of enteric neurons in food allergies has not been elucidated. We report the presence of functional high-affinity IgE receptors (FcεRIs) in enteric neurons. FcεRI immunoreactivities were observed in approximately 70% of cholinergic myenteric neurons from choline acetyltransferase-eGFP mice. Furthermore, stimulation by IgE-antigen elevated intracellular Ca concentration in isolated myenteric neurons from normal mice, suggesting that FcεRIs are capable of activating myenteric neurons. Additionally, the morphological investigation revealed that the majority of mucosal mast cells were in close proximity to enteric nerve fibers in the colonic mucosa of food allergy mice. Next, using a newly developed coculture system of isolated myenteric neurons and mucosal-type bone-marrow-derived mast cells (mBMMCs) with a calcium imaging system, we demonstrated that the stimulation of isolated myenteric neurons by veratridine caused the activation of mBMMCs, which was suppressed by the adenosine A3 receptor antagonist MRE 3008F20. Moreover, the expression of the adenosine A3 receptor gene was detected in mBMMCs. Therefore, in conclusion, it is suggested that, through interaction with mucosal mast cells, IgE-antigen-activated myenteric neurons play a pathological role in further exacerbating the pathology of food allergy.
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http://dx.doi.org/10.3390/cells10071586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8305700PMC
June 2021

Exploring Barriers and Benefits of Implementing Interprofessional Education at Higher Health Professions Education Institutions in Japan.

J Allied Health 2021 ;50(2):97-103

Dep. of Nursing, School of Health Sciences, Sapporo Medical University, W-17, S-1, Chuo-ku, Sapporo, Hokkaido 060-8556, Japan. Tel +81-11-688-5188.

In the 1990s, interprofessional education (IPE) was introduced to health professionals in higher education; it has come to be regarded as a standard learning method. However, major barriers remain regarding its introduction and smooth operation. This study conducted a questionnaire survey at educational facilities for health professionals in Japan; it developed scales to measure the recognition of barriers to and benefits of IPE implementation. We surveyed chairpersons responsible for 2,690 courses in Japanese health education facilities. We used for analysis the responses related to 767 courses (valid response rate, 28.5%). In all, 216 courses (28.7%) implemented IPE. We conducted exploratory factor analysis and developed scales for measuring the recognition of barriers to IPE implementation (15 items) and its benefits (11 items). We observed a significant relationship between the state of IPE implementation and recognition of barriers to and benefits of IPE. Using information and communication technology and faculty development for faculty members would be effective in removing the barriers to IPE implementation.
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January 2021

Hospital performance in a large urban acute myocardial infarction emergency care system: Tokyo Cardiovascular Care Unit network.

J Cardiol 2021 Sep 30;78(3):177-182. Epub 2021 Apr 30.

Tokyo Cardiovascular Care Unit Network Council, Tokyo, Japan.

Background: An ideal urban network system for improving regional acute myocardial infarction (AMI) outcomes should be geographically balanced and uniform according to regional population in performance of participating hospitals. The objective of our study is to evaluate whether there is a major difference in risk-adjusted in-hospital mortality between the Tokyo Cardiovascular Care Unit (CCU) network hospitals, which cover the whole population of large cities.

Methods: The study subjects were all AMI patients without cardiac arrest on arrival admitted to the Tokyo CCU network hospitals from 2009 to 2017. Risk-adjusted in-hospital mortality rates (RAMRs) were compared between the categories of each hospital-level factor. A hospital-level multivariable linear regression was modeled to analyze the association between RAMRs and hospital-level factors. A funnel plot was constructed by plotting RAMRs against hospital volumes.

Results: From 2009 to 2017, there were 42,123 hospitalizations for AMI in Tokyo CCU network hospitals (n=72, as of December, 2017). There were no significant differences in RAMRs in the comparison of hospital backgrounds. Each hospital background was not significantly associated with the RAMR. Considering the 99% CI in funnel plots, only five hospitals (7.2%) were located outside the control limits.

Conclusions: There was no major difference in the RAMRs between the participating hospitals within the Tokyo CCU network, despite the different hospital backgrounds.
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http://dx.doi.org/10.1016/j.jjcc.2021.04.002DOI Listing
September 2021

Relationship Between Procedural Right Bundle Branch Block and 1-Year Outcome After Alcohol Septal Ablation for Hypertrophic Obstructive Cardiomyopathy - A Retrospective Study.

Circ J 2021 Aug 24;85(9):1481-1491. Epub 2021 Apr 24.

Division of Cardiovascular Intensive Care, Nippon Medical School Hospital.

Background: Alcohol septal ablation (ASA) is a treatment option in patients with drug-refractory symptomatic hypertrophic obstructive cardiomyopathy (HOCM). In many patients, right bundle branch block (RBBB) develops during ASA because septal branches supply the right bundle branch. However, the clinical significance of procedural RBBB is uncertain.Methods and Results:We retrospectively reviewed 184 consecutive patients with HOCM who underwent ASA. We excluded 40 patients with pre-existing RBBB (n=10), prior pacemaker implantation (n=15), mid-ventricular obstruction type (n=10), and those lost to follow-up (n=5), leaving 144 patients for analysis. Patients were divided into 2 groups according to the development (n=95) or not (n=49) of procedural RBBB. ASA conferred significant decreases in the left ventricular pressure gradient (LVPG) in both the RBBB and no-RBBB group (from 74±48 to 27±27 mmHg [P<0.001] and from 75±45 to 31±33 mmHg [P<0.001], respectively). None of the RBBB patients developed further conduction system disturbances. The percentage reduction in LVPG at 1 year after the procedure was significantly greater in the RBBB than no-RBBB group (66±24% vs. 49±45%; P=0.035). Procedural RBBB was not associated with pacemaker implantation after ASA, but was associated with reduction in repeat ASA (odds ratio 0.34; 95% confidence interval 0.13-0.92; P=0.045).

Conclusions: Although RBBB frequently occurs during the ASA procedure, it does not adversely affect clinical outcomes.
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http://dx.doi.org/10.1253/circj.CJ-20-1191DOI Listing
August 2021

Risk analysis for early mortality in emergency acute type A aortic dissection surgery: experience of Tokyo Acute Aortic Super-network.

Eur J Cardiothorac Surg 2021 Apr 8. Epub 2021 Apr 8.

Tokyo CCU Network Scientific Committee, Tokyo, Japan.

Objectives: We investigated the various pre- and postoperative complications related to early (30-day) mortality after open surgery for acute type A aortic dissection.

Methods: Data from the Tokyo Acute Aortic Super-network database spanning January 2015 to December 2017 were retrospectively reviewed. Pre- and postoperative factors related to early postoperative mortality were assessed in 1504 of 2058 (73.0%) consecutive patients [age: 66.6 (SD: 13.5) years, male: 52.9%] who underwent acute type A aortic dissection repair.

Results: The early mortality rate following surgical repair was 8.9%. According to multivariable analysis, male sex [odds ratio (OR) 1.670, 95% confidence interval (CI) 1.063-2.624, P = 0.026], use of percutaneous circulatory assist devices (n = 116, 7.7%) including extracorporeal membrane oxygenators or intra-aortic balloon pumps (OR 4.857, 95% CI 2.867-8.228, P < 0.001), shock (n = 162, 10.8%) (OR 3.06, 95% CI 1.741-5.387, P < 0.001), cardiopulmonary arrest (n = 41, 2.7%) (OR 7.534, 95% CI 3.407-16.661, P < 0.001), coronary ischaemia (n = 36, 2.3%) (OR 2.583, 95% CI 1.042-6.404, P = 0.041) and cerebral ischaemia (n = 59, 3.9%) (OR 2.904, 95% CI 1.347-6.261, P = 0.007) were independent preoperative risk factors for early mortality, while cardiac tamponade (n = 34, 2.3%) (OR 10.282, 95% CI 4.640-22.785, P < 0.001), cerebral ischaemia (n = 80, 5.3%) (OR 2.409, 95% CI 1.179-4.923, P = 0.016) and mesenteric ischaemia (n = 15, 1.0%) (OR 44.763, 95% CI 13.027-153.808, P < 0.001) were independent postoperative risk factors.

Conclusions: Not only critical preoperative conditions but also postoperative cardiac tamponade and vital organ ischaemia are risk factors for early mortality after acute type A aortic dissection repair.
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http://dx.doi.org/10.1093/ejcts/ezab146DOI Listing
April 2021

Non-cardiovascular disorders in a contemporary cardiovascular intensive care unit in Japan.

J Cardiol 2021 Aug 2;78(2):166-171. Epub 2021 Apr 2.

Division of Cardiovascular Intensive Care, Nippon Medical School Hospital, Tokyo, Japan; Department of Cardiovascular Medicine, Nippon Medical School, Tokyo, Japan.

Background: In the modern US cardiovascular intensive care unit (CICU), the incidence of non-cardiovascular disorders has increased and non-cardiovascular disorders are associated with an increase in morbidity and mortality. In Japan, however, data regarding the association between non-cardiovascular disorders and outcomes in the CICU are limited.

Methods: This study examined 490 consecutive admissions to a closed CICU at the Nippon Medical School Hospital from January to December 2017. Characteristics, diagnoses, treatments, and outcomes of admitted patients were identified.

Results: The most common primary diagnosis was acute coronary syndrome (50.4%), followed by acute heart failure (20.0%), arrhythmia (6.7%), and non-cardiovascular diseases (3.7%). The mortality rate and median length of stay (LOS) in the CICU were 4.7% and 4 (interquartile range, 2-8) days, respectively. Of all patients, 42.2% (n = 207) developed non-cardiovascular complications such as acute respiratory failure, acute kidney injury, or sepsis during CICU stay. Multivariate logistic regression analysis revealed that acute respiratory failure and sepsis were significantly associated with mortality in the CICU (odds ratio, 11.014 and 25.678, respectively; both p<0.05). The multiple linear regression analysis showed that acute kidney injury was significantly associated with LOS in the CICU (β=0.144, p = 0.002).

Conclusions: Approximately half of patients admitted to the CICU had non-cardiovascular disorders including non-cardiovascular disease and non-cardiovascular complications, which were significantly associated with mortality and LOS in the CICU.
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http://dx.doi.org/10.1016/j.jjcc.2021.03.002DOI Listing
August 2021

Enhancing calmodulin binding to ryanodine receptor is crucial to limit neuronal cell loss in Alzheimer disease.

Sci Rep 2021 03 31;11(1):7289. Epub 2021 Mar 31.

Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minamikogushi, Ube, Yamaguchi, 755-8505, Japan.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive neuronal cell loss. Recently, dysregulation of intracellular Ca homeostasis has been suggested as a common proximal cause of neural dysfunction in AD. Here, we investigated (1) the pathogenic role of destabilization of ryanodine receptor (RyR2) in endoplasmic reticulum (ER) upon development of AD phenotypes in App mice, which harbor three familial AD mutations (Swedish, Beyreuther/Iberian, and Arctic), and (2) the therapeutic effect of enhanced calmodulin (CaM) binding to RyR2. In the neuronal cells from App mice, CaM dissociation from RyR2 was associated with AD-related phenotypes, i.e. Aβ accumulation, TAU phosphorylation, ER stress, neuronal cell loss, and cognitive dysfunction. Surprisingly, either genetic (by V3599K substitution in RyR2) or pharmacological (by dantrolene) enhancement of CaM binding to RyR2 reversed almost completely the aforementioned AD-related phenotypes, except for Aβ accumulation. Thus, destabilization of RyR2 due to CaM dissociation is most likely an early and fundamental pathogenic mechanism involved in the development of AD. The discovery that neuronal cell loss can be fully prevented simply by stabilizing RyR2 sheds new light on the treatment of AD.
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http://dx.doi.org/10.1038/s41598-021-86822-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012710PMC
March 2021

[Two Cases in Which Simultaneous Laparoscopic Surgery and Breast Cancer Surgery Using a Head-Mounted Monitor Were Useful].

Gan To Kagaku Ryoho 2021 Mar;48(3):403-406

Division of Gastroenterological Surgery, Clinical Oncology Center, Aomori Prefectural Central Hospital.

Herein, we report on how we were able to reduce the operation time by simultaneously performing laparoscopic surgery and breast cancer surgery using a head-mounted monitor(HMS-3000MT, Sony corporation). Case 1: 60s, female. A 5.5 cm leiomyoma was found in the central thoracic esophagus, and a 1 cm breast cancer was found in the C region of the left mammary gland. Subtotal esophagectomy with right thoracotomy and laparoscopy and a left partial mastectomy were performed. For the abdominal surgery, HMS-3000MT was used under hand-assisted laparoscopy, and a left partial mastectomy was performed concurrently. Operation time was 367 minutes(simultaneous surgery for 56 minutes). Esophagus: leiomyoma, 50×45 mm; and mammary gland: 16×15 mm, pTis(DCIS), pN0(sn), cM0, and pStage 0. Case 2: 70s, female. A 3 cm sized GIST was found on the posterior wall of the middle gastric body, and a breast cancer of 1.3 cm was also found in the B region of the right mammary gland. Using HMS-3000MT, laparoscopic local resection of the stomach and right total glandectomy were performed concurrently. Operation time was 114 minutes(simultaneous surgery for 58 minutes). Stomach: GIST, 25×22 mm, and modified Flecher classification low risk; and mammary gland: invasive ductal carcinoma, 15×15 mm, pT1c, pN0(sn), cM0, and pStage Ⅰ. Conclusion: In 2 fields of surgery, simultaneous surgery using HMS-3000MT was considered to be a useful method to shorten the operation time.
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March 2021

Characteristics of the Inter-arm Difference in Blood Pressure in Acute Aortic Dissection.

J Nippon Med Sch 2021 Mar 9. Epub 2021 Mar 9.

Department of Cardiovascular Medicine, Nippon Medical School.

Background: An inter-arm difference in blood pressure (IADBP) is characteristic of acute aortic dissection (AAD), but which arm shows lower blood pressure (BP) and the mechanism of IADBP has not been fully elucidatedMethods: We identified consecutive patients with chest and/or back pain and suspected acute cardiovascular disease whose BP had been measured in both arms. We retrospectively compared the characteristics of such patients with AAD (n=93) to those without (non-AAD group, n=122). Additionally, we separately compared patients with type A AAD (TAAD group, n=58) or type B AAD (TBAD group, n=35) to non-AAD group. Characteristics included in these comparisons were patients' backgrounds and IADBP-related factors such as systolic BP (SBP) in the right arm (R) and left arm (L), R-L or L-R as the IADBP. Computed tomography (CT) findings of AD extending to the brachiocephalic artery (BCA) and/or left subclavian artery (LSCA) were examined in patients having IADBP.

Results: In the TAAD group, the prevalence of R<130mmHg (38%-vs.-19%, p=0.009), L-R>15mmHg (19%-vs.-8%, p=0.047), L-R>20mmHg (14%-vs.-4%, p=0.029) was higher than in the non-AAD group. Multivariate analysis showed L-R>15mmHg with R<130mmHg was independently associated with TAAD (OR 25.97, 95% CI 2.45-275.67, p=0.007). However, IADBP-related factors were not associated with TBAD. AAD patients with L-R>20mmHg were all TAAD, and all aortic dissection extended to BCA just before the right common carotid artery on CT.

Conclusions: IADBP was characterized by R
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http://dx.doi.org/10.1272/jnms.JNMS.2021_88-605DOI Listing
March 2021

Clinical characteristics, secondary prevention goal attainment, and outcomes of patients with recurrent acute coronary syndrome.

J Nippon Med Sch 2021 Mar 9. Epub 2021 Mar 9.

Division of Cardiovascular Intensive Care, Nippon Medical School Hospital.

Background: Because acute coronary syndrome (ACS) development worsens the prognosis of patients with coronary artery disease, preventing recurrent ACS is crucial. However, the degree to which secondary prevention treatment goals in recurrent ACS patients are achieved is unknown.

Methods: Consecutive 214 ACS patients were divided into two groups; First ACS (n=182) and Recurrent ACS (n=32), and compared clinical characteristics between the groups. Fifteen patients developed death or cardiovascular (CV) events during hospitalization, and remained 199 patients were followed from the date of hospital discharge to evaluate subsequent CV events.

Results: Patients in the Recurrent ACS group were older (76.8±10.8 years vs 68.8±13.4 years, p=0.002) and had a higher rate of diabetes mellitus (DM) (65.6% vs 36.8%, p=0.003) than those in the First ACS group. The attainment rate of low-density lipoprotein cholesterol (LDL-C) < 70mg/dl in the Recurrent ACS group was only 28.1%, despite 68.8% of these patients receiving statin. HbA1c < 7.0% was achieved in 66.7% of recurrent ACS patients who had been diagnosed with DM. Overall, 12.5% of recurrent ACS patients had received optimal treatment for secondary prevention. CV events after hospital discharge were identified in 37.9% of the Recurrent ACS group and 21.2% of the First ACS group (log-rank: p=0.004). However, recurrent ACS was not an independent risk factor for CV events (adjusted hazard ratio: 2.09, 95% confidence interval: 0.95 to 4.63, p=0.068).

Conclusion: Optimal treatment for secondary prevention in recurrent ACS patients was insufficient. Attainment of the guideline-recommended LDL-C goal for secondary prevention was especially low in recurrent ACS patients.
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http://dx.doi.org/10.1272/jnms.JNMS.2021_88-601DOI Listing
March 2021

Gastrointestinal bleeding increases the risk of subsequent cardiovascular events in patients with acute cardiovascular diseases requiring intensive care.

Heart Vessels 2021 Sep 8;36(9):1327-1335. Epub 2021 Mar 8.

Division of Cardiovascular Intensive Care, Nippon Medical School Hospital, 1-1-5, Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan.

Gastrointestinal (GI) bleeding worsens the outcomes of critically ill patients in the intensive care unit (ICU). Owing to a lack of corresponding data, we aimed to investigate whether GI bleeding during cardiovascular-ICU (C-ICU) admission in acute cardiovascular (CV) disease patients is a risk factor for subsequent CV events. Totally, 492 consecutive C-ICU patients (40.9% acute coronary syndrome, 22.8% heart failure) were grouped into GI bleeding (n = 27; 12 upper GI and 15 lower GI) and non-GI bleeding (n = 465) groups. Thirty-nine patients died or developed CV events during hospitalization, and 453 were followed up from the date of C-ICU discharge to evaluate subsequent major adverse CV events. The GI bleeding group had a higher Acute Physiology and Chronic Health Evaluation II score (20.2 ± 8.2 vs. 15.1 ± 6.8, p < 0.001), higher frequency of mechanical ventilator use (29.6% vs. 13.1%, p = 0.039), and longer C-ICU admission duration (8 [5-16] days vs. 5 [3-8] days, p < 0.001) than the non-GI bleeding group. The in-hospital mortality rate did not differ between the groups. Of those who were followed-up, CV events after C-ICU discharge were identified in 34.6% and 14.3% of patients in the GI and non-GI bleeding groups, respectively, during a median follow-up period of 228 days (log rank, p < 0.001). GI bleeding was an independent risk factor for subsequent CV events (adjusted hazard ratio: 2.23, 95% confidence interval: 1.06-4.71; p = 0.035). GI bleeding during C-ICU admission was independently associated with subsequent CV events in such settings.
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http://dx.doi.org/10.1007/s00380-021-01822-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937548PMC
September 2021

[A Case of Laparoscopic Distal Gastrectomy for Gastric Cancer with an Adachi Type Ⅵ Group 24 Vascular Anomaly].

Gan To Kagaku Ryoho 2020 Dec;47(13):2162-2164

Dept. of Surgery, Clinical Oncology Center, Aomori Prefectural Central Hospital.

We report a case of successful laparoscopic distal gastrectomy for gastric cancer with an Adachi type Ⅵ group 24 vascular anomaly. A male in his 60s exhibited a type 0-Ⅱa plus Ⅱc lesion at the lesser curvature of the gastric angle by esophagogastroduodenoscopy and was diagnosed with tub2. He was referred to us for surgical treatment. The clinical diagnosis was cT1bN0M0, and cStage Ⅰ. Preoperative multidetector-row computed tomography(MDCT)showed an Adachi type Ⅵ group 24 vascular anomaly. At laparoscopic surgery, we dissected No. 8a lymph nodes with exposure of the surface of the portal vein because the common hepatic artery was absent. The left gastric artery and splenic artery formed a common trunk. As there are various kinds of vascular anomalies of the celiac artery branch, we must understand the arterial running pattern prior to gastric surgery. This technique is more useful in laparoscopic surgeries where tactile sensation is limited. To prevent perioperative and postoperative complications, we must recognize the anomaly pattern prior to surgery using MDCT.
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December 2020

Urinary mulberry bodies as a potential biomarker for early diagnosis and efficacy assessment of enzyme replacement therapy in Fabry nephropathy.

Nephrol Dial Transplant 2020 Dec 24. Epub 2020 Dec 24.

Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan.

Background: The inability of enzyme replacement therapy (ERT) to prevent progression of Fabry nephropathy (FN) in the presence of >1 g/day proteinuria underscores the necessity of identifying effective biomarkers for early diagnosis of FN preceding proteinuria. Here we attempted to identify biomarkers for early detection of FN.

Methods: Fifty-one Fabry disease (FD) patients were enrolled. Urinary mulberry bodies (uMBs) were immunostained for globotriaosylceramide (Gb3) and renal cell markers to determine their origin. The association between semiquantitative uMB excretion and the histological severity of podocyte vacuolation was investigated in seven patients using the vacuolated podocyte:glomerular average area ratio. The association between the semiquantitative estimate of uMB excretion and duration of ERT was analyzed. A longitudinal study was conducted to assess the effect of ERT on uMB excretion.

Results: Thirty-two patients (63%) had uMBs, while only 31% showed proteinuria. The uMBs were positive for Gb3, lysosomal-associated membrane protein 1 and podocalyxin, suggesting they were derived from lysosomes with Gb3 accumulation in podocytes. We observed more severe podocyte vacuolation with increased uMB excretion (P = 0.03 for trend); however, the same was not observed with increased proteinuria. The percentage of patients with substantial uMB excretion increased with shorter ERT duration (P = 0.018). Eighteen-month-long ERT reduced uMB excretion (P = 0.03) without affecting proteinuria.

Conclusions: uMB excretion, implying ongoing podocyte injury, preceded proteinuria in most patients. Semiquantitative uMB estimates can serve as novel biomarkers for early FN diagnosis and for monitoring the efficacy of FD-specific therapies.
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http://dx.doi.org/10.1093/ndt/gfaa298DOI Listing
December 2020

Morphological elucidation of short-chain fatty acid receptor GPR41-positive enteric sensory neurons in the colon of mice with dextran sulfate sodium-induced colitis.

Heliyon 2020 Dec 9;6(12):e05647. Epub 2020 Dec 9.

Division of Gastrointestinal Pathophysiology, Institute of Natural Medicine, University of Toyama, Toyama, Japan.

Although the etiology of inflammatory bowel disease (IBD) remains unclear, it has generally been accepted that abnormalities in the intestinal immune system and dysbiosis of the gut microbiota are involved in the pathology of IBD. Recently, short-chain fatty acids (SCFAs) produced by gut microbiota were reported to maintain intestinal homeostasis through their receptors, such as GPR41. However, there are contradictory reports about the role of GPR41 in intestinal inflammation. Consequently, the roles of GPR41 in dysbiosis induced by intestinal inflammation remain unclear. Thus, we investigated the distribution of GPR41 in the colonic mucosa of mice with dextran sulfate sodium (DSS)-induced colitis. GPR41-immunoreactive fibrous structures were observed in the colonic lamina propria and muscularis layer of normal mice. In addition, GPR41-immunoreactive fibrous structures partly colocalized with calcitonin gene-related peptide (CGRP; a neurotransmitter of cholinergic enteric sensory neurons)-immunoreactive nerve fibers in the colonic lamina propria, indicating that GPR41 is expressed in cholinergic intrinsic sensory neurons. Furthermore, both GPR41-immunoreactivities and CGRP-immunoreactivities were significantly increased in the lamina propria of the colon in mice with DSS-induced colitis. Interestingly, GPR41-immunoreactivities were often found in close proximity to F4/80 macrophages in the colonic mucosa of normal mice, and their frequency was elevated in the colonic mucosa of mice with DSS-induced colitis. Therefore, the crosstalk between SCFA-sensing intrinsic sensory neurons and macrophages might be involved in the pathology of acute colitis.
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http://dx.doi.org/10.1016/j.heliyon.2020.e05647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726667PMC
December 2020

Isoflavones Suppress Cyp26b1 Expression in the Murine Colonic Lamina Propria.

Biol Pharm Bull 2020 ;43(12):1945-1949

Division of Gastrointestinal Pathophysiology, Institute of Natural Medicine, University of Toyama.

Isoflavones have many biological activities and are major bioactive components of kakkonto, a traditional Japanese herbal medicine. We previously reported that the combined therapy of oral immune therapy (OIT) and kakkonto downregulates the mRNA expression of Cyp26b1, a major retinoic acid (RA)-degrading enzyme, in the colon of food allergy mice and thereby ameliorates allergic symptoms. In this study, we evaluated the effects of various isoflavones on Cyp26b1 expression in primary cultured lamina propria (LP) cells isolated from the mouse colon. The mRNA expression of Cyp26b1 was extremely downregulated by all isoflavones tested in the LP cells except for puerarin. In particular, genistein and genistin markedly suppressed Cyp26b1 mRNA expression without affecting RA-synthesizing enzyme expression. Moreover, to evaluate the effects of isoflavones on allergic reactions, genistein and genistin were administered to ovalbumin (OVA)-induced food allergy mice. Oral administration of genistin suppressed the development of allergic symptoms. These results raise the possibility that isoflavones elevated the level of RA in the colon by inhibiting RA degradation and then the high concentration of RA in the colon might exert immunosuppressive and antiallergic effects on food allergy mice.
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http://dx.doi.org/10.1248/bpb.b20-00355DOI Listing
August 2021

Enhancing calmodulin binding to cardiac ryanodine receptor completely inhibits pressure-overload induced hypertrophic signaling.

Commun Biol 2020 11 26;3(1):714. Epub 2020 Nov 26.

Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minamikogushi, Ube, Yamaguchi, 755-8505, Japan.

Cardiac hypertrophy is a well-known major risk factor for poor prognosis in patients with cardiovascular diseases. Dysregulation of intracellular Ca is involved in the pathogenesis of cardiac hypertrophy. However, the precise mechanism underlying cardiac hypertrophy remains elusive. Here, we investigate whether pressure-overload induced hypertrophy can be induced by destabilization of cardiac ryanodine receptor (RyR2) through calmodulin (CaM) dissociation and subsequent Ca leakage, and whether it can be genetically rescued by enhancing the binding affinity of CaM to RyR2. In the very initial phase of pressure-overload induced cardiac hypertrophy, when cardiac contractile function is preserved, reactive oxygen species (ROS)-mediated RyR2 destabilization already occurs in association with relaxation dysfunction. Further, stabilizing RyR2 by enhancing the binding affinity of CaM to RyR2 completely inhibits hypertrophic signaling and improves survival. Our study uncovers a critical missing link between RyR2 destabilization and cardiac hypertrophy.
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http://dx.doi.org/10.1038/s42003-020-01443-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7691336PMC
November 2020

Sweet scent lactones activate hot capsaicin receptor, TRPV1.

Biochem Biophys Res Commun 2021 01 22;534:547-552. Epub 2020 Nov 22.

Tobacco Science Research Center, Japan Tobacco Inc, 6-2 Umegaoka, Aoba, Yokohama, Kanagawa, 227-8512, Japan. Electronic address:

In this study, we investigated the activation of Transient receptor potential vanilloid subtype 1, TRPV1, by lactones, a representative flavor ingredient currently used for foods and beverages. As a result, we found that some lactones having C4 acyl chain length, γ-octalactone, δ-nonalactone and β-methyl-γ-octalactone, γ-undecalactone with C7 acyl chain length and δ-undecalactone with C6 acyl chain length activated TRPV1. TRPV1 is known as a non-selective cation channels that respond to a wide range of physical and chemical stimuli such as high temperature, protons, capsaicin and so on. Furthermore, it has been also demonstrated that activation of TRPV1 induced energy expenditure enhancement and thermogenesis, suppressed accumulation of visceral fat in mice and prevented non-alcoholic fatty acid liver. Thus, lactones that function as TRPV1 agonists are thought to be important candidates for decreasing the risks of developing a metabolic syndrome.
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http://dx.doi.org/10.1016/j.bbrc.2020.11.046DOI Listing
January 2021

Interleukin-4 Receptor α Subunit Deficiency Alleviates Murine Intestinal Inflammation In Vivo Through the Enhancement of Intestinal Mucosal Barrier Function.

Front Pharmacol 2020 28;11:573470. Epub 2020 Oct 28.

Division of Gastrointestinal Pathophysiology, Institute of Natural Medicine, University of Toyama, Toyama, Japan.

Disturbance of epithelial barrier function causes chronic intestinal inflammation such as inflammatory bowel disease. Several studies have reported that Th2 cytokines such as interleukin (IL)-4 and IL-13 play an important role in the regulation of intestinal barrier function. However, the precise role of the IL-4 receptor α subunit (IL-4Rα) in intestinal inflammation remains unclear. Thus, we used an experimental colitis model to investigate the role of IL-4Rα in intestinal inflammation. IL-4Rα-deficient (IL-4Rα-/-) mice and their littermate wild-type (WT) mice were used. Experimental colitis was induced by administration of 3% dextran sulfate sodium (DSS) in the drinking water for seven days. Treatment with DSS caused body weight loss, an increase in the disease activity index and histological abnormalities in WT colitis mice, all of which were significantly attenuated in IL-4Rα-/- colitis mice. Neutrophil infiltration in the colonic mucosa was reduced in IL-4Rα-/- colitis mice compared with WT colitis mice. NADPH oxidase 1 expression and reactive oxygen species production were increased in the colons of IL-4Rα-/- mice. Furthermore, elevated intestinal permeability induced by DSS treatment was suppressed in IL-4Rα-/- colitis mice. These results demonstrate that IL-4Rα-/- mice exhibit reduced susceptibility to DSS-induced colitis. Our present findings suggest that IL-4Rα deficiency enhances intestinal mucosal barrier function through the upregulation of NADPH oxidase 1-dependent reactive oxygen species production, thereby suppressing the development of intestinal inflammation.
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http://dx.doi.org/10.3389/fphar.2020.573470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7656058PMC
October 2020

Therapeutic Benefit in Allergic Dermatitis Derived from the Inhibitory Effect of Byakkokaninjinto on the Migration of Plasmacytoid Dendritic Cells.

Evid Based Complement Alternat Med 2020 22;2020:9532475. Epub 2020 Oct 22.

Division of Gastrointestinal Pathophysiology, Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.

Dendritic cells (DCs) are well known to be essential immunocytes involved in innate and adaptive immunity. DCs are classified as conventional dendritic cells (cDCs) and plasmacytoid dendritic cells (pDCs). Recently, the accumulation of pDCs in inflamed tissues and lymphoid tissues has been considered to be a possible contributing factor in the development of immunological diseases, but little is known about the pathophysiological roles of pDCs in immunological diseases. To date, many studies have demonstrated that many kinds of Kampo formulas can regulate immunological reactions in human immune diseases. Thus, we screened Kampo formulas to identify an agent that inhibits pDC migration. Furthermore, we investigated the therapeutic effects of these formulas on a murine DNFB-induced allergic contact dermatitis model. Bone marrow-derived pDCs (BMpDCs) were derived from the bone marrow cells of BALB/c mice in a culture medium with Flt3 ligand. The effects of Kampo formulas on BMpDC migration were evaluated by assessing the number, velocity, and directionality of BMpDCs chemotaxing toward the more concentrated side of a chemokine (C-C motif) ligand 21 (CCL21) gradient. The Kampo formulas that exerted inhibitory effects on pDC migration were orally administered to DNFB-induced allergic contact dermatitis model mice. Byakkokaninjinto reduced the number of migrated BMpDCs and suppressed the velocity and directionality of BMpDC migration in a chemotaxis assay. Gypsum Fibrosum and Ginseng Radix, which are components of byakkokaninjinto, obviously suppressed the velocity of BMpDC migration. Furthermore, Gypsum Fibrosum significantly suppressed the directionality of BMpDC migration. In DNFB-induced allergic contact dermatitis model mice, byakkokaninjinto markedly abrogated ear swelling in late-phase allergic reactions. In conclusions, byakkokaninjinto, which has an inhibitory effect on pDC migration, was able to prevent the occurrence of allergic contact dermatitis, suggesting that pDCs were involved in the onset of allergic contact dermatitis in the mouse model. Therefore, byakkokaninjinto is anticipated to be a therapeutic agent for disorders related to pDC migration.
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http://dx.doi.org/10.1155/2020/9532475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603581PMC
October 2020

Ginger Increases ALDH1A1 Expression and Enhances Retinoic Acid Signaling in a Human Colonic Epithelial Cell Line.

J Nutr Sci Vitaminol (Tokyo) 2020 ;66(5):462-467

Division of Gastrointestinal Pathophysiology, Institute of Natural Medicine, University of Toyama.

Aldehyde dehydrogenase 1A1 (ALDH1A1) in intestinal epithelial cells (IECs) plays a critical role in regulating immune responses through the production of retinoic acid (RA). However, little is known about its regulation by dietary components. We previously demonstrated that kakkonto, a Japanese traditional herbal medicine, and its constituent puerarin induce the expression of ALDH1A1 mRNA in colonic IECs and thereby attenuate food allergy symptoms in mice. This study aims to investigate the cellular responses of IECs to ALDH1A1 expression as a result of natural food components. The seven medicinal herbs that compose kakkonto were used to treat cultured an IEC line: Caco-2 cells. Expressions levels of ALDH1A1 were analyzed in Caco-2 cells by quantitative RT-PCR, immunocytochemistry and western blotting. Ginger increased the expression levels of ALDH1A1 mRNA and protein in Caco-2 cells. In addition, ginger significantly upregulated the gene expression of retinoic acid receptor (RAR) alpha (RARA), thereby enhancing RA signaling. Furthermore, ginger downregulated the expression of histone deacetylase (HDAC)2 (HDAC2) and HDAC3 in Caco-2 cells. The present study suggests the possibility that food ingredients such as a ginger modulate vitamin A metabolism in the gut through the regulation of RA synthesis, which may contribute to RA-mediated regulation of immune responses and the regulation of allergic inflammation.
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http://dx.doi.org/10.3177/jnsv.66.462DOI Listing
August 2021

Enantioconvergent Cu-Catalyzed Intramolecular C-C Coupling at Boron-Bound C(sp) Atoms of α-Aminoalkylboronates Using a -Symmetrical 2,2'-Bipyridyl Ligand Attached to a Helically Chiral Macromolecular Scaffold.

J Am Chem Soc 2020 10 16;142(43):18317-18323. Epub 2020 Oct 16.

Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Katsura, Nishikyo-ku, Kyoto 615-8510, Japan.

Enantioconvergent intramolecular coupling of α-(2-bromobenzoylamino)benzylboronic esters was achieved using a copper catalyst having helically chiral macromolecular bipyridyl ligand, PQXbpy. Racemic α-(2-bromobenzoylamino)benzylboronic esters were converted into ()-configured 3-arylisoindolinones with high enantiopurity using right-handed helical PQXbpy as a chiral ligand in a toluene/CHCl mixed solvent. When enantiopure ()- and ()-configured boronates were separately reacted under the same reaction conditions, both afforded ()-configured products through formal stereoinvertive and stereoretentive processes, respectively. From these results, a mechanism involving deracemization of organocopper intermediates in the presence of PQXbpy is assumed. PQXbpy switched its helical sense to left-handed when a toluene/1,1,2-trichloroethane mixed solvent was used, resulting in the formation of the corresponding ()-products from the racemic starting material.
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http://dx.doi.org/10.1021/jacs.0c09080DOI Listing
October 2020

Effects of empagliflozin versus placebo on cardiac sympathetic activity in acute myocardial infarction patients with type 2 diabetes mellitus: the EMBODY trial.

Cardiovasc Diabetol 2020 09 25;19(1):148. Epub 2020 Sep 25.

Department of Cardiovascular Medicine, Shizuoka Medical Center, Shizuoka, Japan.

Background: Protection from lethal ventricular arrhythmias leading to sudden cardiac death (SCD) is a crucial challenge after acute myocardial infarction (AMI). Cardiac sympathetic and parasympathetic activity can be noninvasively assessed using heart rate variability (HRV) and heart rate turbulence (HRT). The EMBODY trial was designed to determine whether the Sodium-glucose cotransporter 2 (SGLT2) inhibitor improves cardiac nerve activity.

Methods: This prospective, multicenter, randomized, double-blind, placebo-controlled trial included patients with AMI and type 2 diabetes mellitus (T2DM) in Japan; 105 patients were randomized (1:1) to receive once-daily 10-mg empagliflozin or placebo. The primary endpoints were changes in HRV, e.g., the standard deviation of all 5-min mean normal RR intervals (SDANN) and the low-frequency-to-high-frequency (LF/HF) ratio from baseline to 24 weeks. Secondary endpoints were changes in other sudden cardiac death (SCD) surrogate markers such as HRT.

Results: Overall, 96 patients were included (46, empagliflozin group; 50, placebo group). The changes in SDANN were + 11.6 and + 9.1 ms in the empagliflozin (P = 0.02) and placebo groups (P = 0.06), respectively. Change in LF/HF ratio was - 0.57 and - 0.17 in the empagliflozin (P = 0.01) and placebo groups (P = 0.43), respectively. Significant improvement was noted in HRT only in the empagliflozin group (P = 0.01). Whereas intergroup comparison on HRV and HRT showed no significant difference between the empagliflozin and placebo groups. Compared with the placebo group, the empagliflozin group showed significant decreases in body weight, systolic blood pressure, and uric acid. In the empagliflozin group, no adverse events were observed.

Conclusions: This is the first randomized clinical data to evaluate the effect of empagliflozin on cardiac sympathetic and parasympathetic activity in patients with T2DM and AMI. Early SGLT2 inhibitor administration in AMI patients with T2DM might be effective in improving cardiac nerve activity without any adverse events.

Trial Registration: The EMBODY trial was registered by the UMIN in November 2017 (ID: 000030158). UMIN000030158; https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000034442 .
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http://dx.doi.org/10.1186/s12933-020-01127-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519555PMC
September 2020
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