Publications by authors named "Takuma Sato"

102 Publications

Polymer-Supported-Cobalt-Catalyzed Regioselective Cyclotrimerization of Aryl Alkynes.

JACS Au 2021 Nov 1;1(11):2080-2087. Epub 2021 Oct 1.

Center for Sustainable Resource Science, RIKEN, Wako, Saitama 351-0198, Japan.

A convoluted poly(4-vinylpyridine) cobalt(II) (P4VP-CoCl) system was developed as a stable and reusable heterogeneous catalyst. The local structure near the Co atom was determined on the basis of experimental data and theoretical calculations. This immobilized cobalt catalyst showed high selectivity and catalytic activity in the [2 + 2 + 2] cyclotrimerization of terminal aryl alkynes. With 0.033 mol % P4VP-CoCl, the regioselective formation of 1,3,5-triarylbenzene was realized without 1,2,4-triarylbenzene formation. Further, a multigram-scale (11 g) reaction proceeded efficiently. In addition, the polymer-supported catalyst was successfully recovered and used three times. X-ray photoelectron spectroscopy analysis of the recovered catalyst suggested that cobalt was in the +2 oxidation state. The 1,3,5-triarylbenzene derivatives were applied to the synthesis of a molecular beam electron resist and a polycyclic aromatic hydrocarbon.
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http://dx.doi.org/10.1021/jacsau.1c00360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8611791PMC
November 2021

A case of laparoscopically treated broad ligament ectopic pregnancy followed by spontaneous gestation.

J Obstet Gynaecol Res 2021 Nov 18. Epub 2021 Nov 18.

Department of Obstetrics and Gynecology, The Jikei University School of Medicine, Tokyo, Japan.

We present a case of spontaneous pregnancy after laparoscopic surgery for a broad ligament pregnancy. A 34-year-old nulliparous woman presented with 6 weeks of amenorrhea. Due to the presence of an empty uterus with a 10 mm right adnexal mass on transvaginal ultrasonography and elevated serum human chorionic gonadotropin (hCG), ectopic pregnancy was suspected. Upon diagnostic laparoscopy, the presence of a 2 cm broad ligament ectopic pregnancy was confirmed. Laparoscopic removal of the gestational tissues was performed. Six months after surgery, a spontaneous pregnancy was established. At the 40th week of gestation, a cesarean section was performed due to arrested labor, resulting in live birth. To the best of our knowledge, there have been no reports of a spontaneous pregnancy occurring after laparoscopic surgery for broad ligament pregnancy. Laparoscopic surgery as a treatment option for broad ligament pregnancy may be useful in early gestational age because it can be completed without complications.
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http://dx.doi.org/10.1111/jog.15099DOI Listing
November 2021

Contribution of Glucosylceramide Synthase to the Proliferation of Mouse Osteoblasts.

In Vivo 2021 Nov-Dec;35(6):3111-3123

Department of Pharmacology, School of Dentistry, Aichi Gakuin University, Nagoya, Japan.

Background/aim: Glycosphingolipids are known to be involved in bone metabolism. However, their roles and regulatory mechanisms in osteoblast proliferation are largely unknown. In this study, we examined the effects of inhibitors of glucosylceramide synthase (GCS), which is responsible for the generation of all glycosphingolipids, on osteoblast proliferation.

Materials And Methods: We analyzed the expression of glycosphingolipids and cell growth in MC3T3-E1 mouse osteoblast cells treated with the GCS inhibitors miglustat, D-PDMP and D-PPMP. We also conducted microarray analysis and RNA interference to identify genes involved in cell growth regulated by GCS.

Results: Glycosphingolipids GD1a and Gb4 expressed in MC3T3-E1 cells, were suppressed by GCS inhibitors. Furthermore, the proliferation of MC3T3-E1 cells was suppressed by the inhibitors. Using microarray analysis, we predicted nine genes (Fndc1, Acta2, Igfbp5, Cox6a2, Cth, Mymk, Angptl6, Mab21l2, and Igsf10) suppressed by all three inhibitors. Furthermore, partial silencing of Angptl6 by RNA interference reduced MC3T3-E1 cell growth.

Conclusion: These results show that GCS regulates proliferation through Angptl6 in osteoblasts.
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http://dx.doi.org/10.21873/invivo.12606DOI Listing
October 2021

Orthodontic tooth movement-activated sensory neurons contribute to enhancing osteoclast activity and tooth movement through sympathetic nervous signalling.

Eur J Orthod 2021 Oct 13. Epub 2021 Oct 13.

Department of Pharmacology, School of Dentistry, Aichi-Gakuin University, Nagoya, Japan.

Objectives: Orthodontic tooth movement (OTM) increases sympathetic and sensory neurological markers in periodontal tissue. However, the relationship between the sympathetic and sensory nervous systems during OTM remains unclear. Therefore, the present study investigated the relationship between the sympathetic and sensory nervous systems activated by OTM using pharmacological methods.

Materials And Methods: We compared the effects of sympathectomy and sensory nerve injury during OTM in C57BL6/J mice. Capsaicin (CAP) was used to induce sensory nerve injury. Sympathectomy was performed using 6-hydroxydopamine. To investigate the effects of a β-agonist on sensory nerve injury, isoproterenol (ISO) was administered to CAP-treated mice. Furthermore, to examine the role of the central nervous system in OTM, the ventromedial hypothalamic nucleus (VMH) was ablated using gold thioglucose.

Results: Sensory nerve injury and sympathectomy both suppressed OTM and decreased the percent of the alveolar socket covered with osteoclasts (Oc.S/AS) in periodontal tissue. Sensory nerve injury inhibited increases in OTM-induced calcitonin gene-related peptide (CGRP) immunoreactivity (IR), a marker of sensory neurons, and tyrosine hydroxylase (TH) IR, a marker of sympathetic neurons, in periodontal tissue. Although sympathectomy did not decrease the number of CGRP-IR neurons in periodontal tissue, OTM-induced increases in the number of TH-IR neurons were suppressed. The ISO treatment restored sensory nerve injury-inhibited tooth movement and Oc.S/AS. Furthermore, the ablation of VMH, the centre of the sympathetic nervous system, suppressed OTM-induced increases in tooth movement and Oc.S/AS.

Conclusions: The present results suggest that OTM-activated sensory neurons contribute to enhancements in osteoclast activity and tooth movement through sympathetic nervous signalling.
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http://dx.doi.org/10.1093/ejo/cjab072DOI Listing
October 2021

Association of high serum soluble interleukin 2 receptor levels with risk of adverse events in cardiac sarcoidosis.

ESC Heart Fail 2021 Sep 12. Epub 2021 Sep 12.

Department of Cardiovascular Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita 15, Nishi 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan.

Aims: Although soluble interleukin 2 receptor (sIL-2R) is a potentially useful biomarker in the diagnosis and evaluation of disease severity in patients with sarcoidosis, its prognostic implication in patients with cardiac sarcoidosis (CS) is unclear. We sought to investigate whether sIL-2R was associated with clinical outcomes and to clarify the relationship between sIL-2R levels and disease activity in patients with CS.

Methods And Results: We examined 83 consecutive patients with CS in our hospital who had available serum sIL-2R data between May 2003 and February 2020. The primary outcome was a composite of advanced atrioventricular block, ventricular tachycardia or ventricular fibrillation, heart failure hospitalization, and all-cause death. Inflammatory activity in the myocardium and lymph nodes was assessed by F-fluorideoxyglucose positron emission tomography/computed tomography. During a median follow-up period of 2.96 (IQR 2.24-4.27) years, the primary outcome occurred in 24 patients (29%). Higher serum sIL-2R levels (>538 U/mL, the median) were significantly related to increased incidence of primary outcome (P = 0.037). Multivariable Cox regression analysis showed that a higher sIL-2R was independently associated with an increased subsequent risk of adverse events (HR 3.71, 95% CI 1.63-8.44, P = 0.002), even after adjustment for significant covariates. sIL-2R levels were significantly correlated to inflammatory activity in lymph nodes (r = 0.346, P = 0.003) but not the myocardium (r = 0.131, P = 0.27).

Conclusions: Increased sIL-2R is associated with worse long-term clinical outcomes accompanied by increased systemic inflammatory activity in CS patients.
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http://dx.doi.org/10.1002/ehf2.13614DOI Listing
September 2021

Guanabenz inhibits alveolar bone resorption in a rat model of periodontitis.

J Pharmacol Sci 2021 Nov 14;147(3):294-304. Epub 2021 Aug 14.

Department of Orthodontics, School of Dentistry, Aichi Gakuin University, Nagoya, Japan.

Increase of sympathetic activity has been known to exacerbate osteoporosis through promotion of bone resorption. However, it is largely unknown about involvement of sympathetic activity in exacerbation of periodontitis. In this study, we investigated whether α-adrenergic receptor (α-AR) agonist guanabenz which decreases sympathetic activity, attenuates alveolar bone resorption in rats having high sympathetic activity with periodontitis. Volumes of residual alveolar bone and attachment levels in periodontium were examined using micro-computed tomography and hematoxylin-eosin staining, respectively. Furthermore, osteoclast numbers per bone surface and osteoclast surface per bone surface were measured using tartrate-resistant acid phosphatase staining. To examine the suppressive effects of guanabenz on pro-inflammatory cytokines, expression levels of tyrosine hydroxylase (TH), TNF-α, IL1-β, and IL-6 in periodontium were measured using immunohistostaining. Administration of guanabenz attenuated loss of alveolar bone and attachment levels in rats having high sympathetic activity. Furthermore, its administration suppressed osteoclast numbers in rats having high sympathetic activity. TH, TNF-α, IL-1β, and IL-6 positive cells in periodontium in rats treated with guanabenz for 12 weeks, were lower than those in control rats having high sympathetic activity. This study demonstrated administration of α-AR agonist guanabenz attenuates alveolar bone resorption through decrease of sympathetic activity in rats.
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http://dx.doi.org/10.1016/j.jphs.2021.08.003DOI Listing
November 2021

Suppression of alveolar bone resorption by salubrinal in a mouse model of periodontal disease.

Life Sci 2021 Nov 8;284:119938. Epub 2021 Sep 8.

Department of Orthodontics, School of Dentistry, Aichi Gakuin University, Nagoya, Japan.

Aims: The relationship between stress to endoplasmic reticulum (ER) and periodontitis has been known, and ER stress induced by Porphyromonas gingivalis results in the loss of alveolar bone. Salubrinal is a small synthetic compound and attenuates ER stress through inhibition of de-phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α). In this study, we examined whether salubrinal attenuates periodontitis in a mouse model of experimental periodontal disease.

Materials And Methods: We evaluated loss of alveolar bone and attachment levels in periodontium using micro-computed tomography (μCT) and hematoxylin-eosin (HE) staining, respectively. Furthermore, we measured osteoclast numbers using tartrate-resistant acid phosphatase (TRAP) staining and osteoblast numbers using HE staining for bone resorption and for bone formation, respectively. To examine the inhibitory effects of salubrinal against pro-inflammatory cytokines, we measured TNF-α and IL1-β score in periodontium using immunohistostaining.

Key Findings: The results revealed that salubrinal suppressed loss of alveolar bone and attachment levels in periodontium induced by periodontitis. It decreased osteoclast numbers and increased osteoblasts. It also suppressed the expression levels of TNF-α in periodontium.

Significance: These results show that salubrinal alleviates periodontitis through suppression of alveolar bone resorption and the pro-inflammatory cytokine, and promotion of the bone formation. Since salubrinal has been shown to have these beneficial effects for periodontal disease, it may provide a novel therapeutic possibility for the disease.
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http://dx.doi.org/10.1016/j.lfs.2021.119938DOI Listing
November 2021

Development and characterization of microsatellite markers in the small Indian mongoose (Urva auropunctata).

Mol Biol Rep 2021 Oct 24;48(10):7029-7034. Epub 2021 Aug 24.

Faculty of Law, Economics and Management, Okinawa University, Naha, 902-8521, Japan.

Background: The small Indian mongoose (Urva auropunctata) is one of the world's worst invasive alien species and eradication programs are ongoing worldwide. The development of individual and sex identification markers will improve their management.

Methods And Results: We searched for novel mongoose microsatellite markers using genome-wide screening and identified 115,265 tetra-nucleotide repeat loci. Of 96 loci tested, 17 were genotyped in 28 mongooses from the Okinawa population. The genetic diversity analysis showed that the average expected and observed heterozygosity and number of alleles were 0.55, 0.56, and 2.94, respectively. Of 17 loci, one deviated from Hardy-Weinberg equilibrium and six loci pairs were likely linked to each other. However, we succeed in identifying all individuals using all of the microsatellite loci. The novel sex identification markers worked successfully in a test using sex known samples.

Conclusion: Our novel microsatellite and sex identification markers should be useful in studies of individual identification and population genetics of the mongoose.
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http://dx.doi.org/10.1007/s11033-021-06655-9DOI Listing
October 2021

Acute Myocardial Infarction of the Left Main Coronary Artery Presenting with Cardiogenic Shock and Pulmonary Edema during Noncardiac Surgery.

Case Rep Cardiol 2021 13;2021:5460816. Epub 2021 Aug 13.

Department of Cardiovascular Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.

Acute myocardial infarction (AMI) caused by severe stenosis of left main coronary artery (LMCA) presenting with cardiogenic shock and pulmonary edema during noncardiac surgery is uncommon, but a catastrophic event. A 77-year-old male with cholangiocarcinoma underwent hepatectomy. During the surgery, he presented with cardiogenic shock, which did not respond to infusion administration or vasopressor. A transesophageal echocardiogram revealed anterior, septal, and lateral severe hypokinesia and impaired left ventricular function. Emergent coronary angiogram showed severe stenosis of LMCA. The patient underwent primary percutaneous coronary intervention (PCI) under the support of intra-aortic balloon pump, followed by extracorporeal membrane oxygenation. The chest roentgenogram showed pulmonary edema. Two days after PCI, he successfully underwent hepatectomy and bile duct resection. Early identification of the cause of hemodynamic instability during noncardiac surgery and invasive strategy are important for minimizing the myocardial injury and improving clinical outcomes in AMI of LMCA.
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http://dx.doi.org/10.1155/2021/5460816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8380411PMC
August 2021

Molecular Diagnosis of Rejection in Heart Transplantation.

Circ J 2021 Aug 21. Epub 2021 Aug 21.

Department of Cardiology, Cedars-Sinai Smidt Heart Institute.

Despite the overall success of heart transplantation as a definitive treatment for endstage heart failure, cardiac allograft rejection remains an important cause of morbidity and mortality. Endomyocardial biopsy has been the standard of care for rejection monitoring, but is associated with several diagnostic limitations and serious procedural complications. The use of molecular diagnostics has emerged over the past decade as a tool to potentially circumvent some of these limitations. We present an update on novel molecular approaches to detecting transplant rejection, focusing on 4 categories: microarray technology, gene expression profiling, cell-free DNA and microRNA.
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http://dx.doi.org/10.1253/circj.CJ-21-0591DOI Listing
August 2021

Performance of the HFPEF and the HFA-PEFF scores for the diagnosis of heart failure with preserved ejection fraction in Japanese patients: A report from the Japanese multicenter registry.

Int J Cardiol 2021 Nov 5;342:43-48. Epub 2021 Aug 5.

Department of Cardiovascular Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.

Background: Diagnosing heart failure with preserved ejection fraction (HFpEF) is challenging. Although the HFPEF score and HFA-PEFF algorithm have been proposed for diagnosing HFpEF, previous validation studies were conducted in stable chronic heart failure (HF). Moreover, information on their applicability in the Asian population is limited. We sought to investigate these scores' diagnostic performance for HFpEF in Japanese patients recently hospitalized due to acute decompensated HF.

Methods: We examined patients with HFpEF recently hospitalized with acute decompensated HF from a nationwide HFpEF-specific multicenter registry (HFpEF group) and control patients who underwent echocardiography to investigate the cause of dyspnea in our hospital (Non-HFpEF group).

Results: The studied population included 372 patients (194 HFpEF group and 178 Non-HFpEF group; HFpEF prevalence, 52%). A high HFPEF score (6-9 points) could diagnose HFpEF with a high specificity of 97% and a positive predictive value (PPV) of 94%, and a low HFPEF score (0-1 point) could rule out HFpEF with a high sensitivity of 97% and a negative predictive value (NPV) of 93%. HFpEF could be diagnosed with a high HFA-PEFF score (5-6 points) (specificity, 84%; PPV, 82%) or ruled out with a low HFA-PEFF score (0-1 point) (sensitivity, 99%; NPV, 89%). The HFPEF score was significantly superior to the HFA-PEFF score in diagnostic accuracy (area under the curve: 0.89 vs. 0.82, respectively, p = 0.004).

Conclusions: The HFPEF and the HFA-PEFF scores had acceptable diagnostic accuracy in diagnosing HFpEF in Japanese patients.
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http://dx.doi.org/10.1016/j.ijcard.2021.08.001DOI Listing
November 2021

Applicability of the AHA/ACC/HRS Guideline for Implantable Cardioverter Defibrillator Implantation in Japanese Patients With Cardiac Sarcoidosis.

JACC Clin Electrophysiol 2021 Nov 30;7(11):1410-1418. Epub 2021 Jun 30.

Department of Cardiovascular Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan; Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan.

Objectives: This study aimed to assess, among Japanese patients with cardiac sarcoidosis (CS), the implantable cardioverter-defibrillator (ICD) recommendations from the 2017 American Heart Association/American College of Cardiology/Heart Rhythm Society (AHA/ACC/HRS) guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death (SCD).

Background: Although ICDs are used to prevent SCD from ventricular tachycardia or ventricular fibrillation (VT/VF) in patients with CS, the generalizability of the AHA/ACC/HRS guidelines for Japanese patients with CS remains unclear.

Methods: This study examined 188 consecutive patients with CS in 2 tertiary hospitals between 1979 and 2020. Patients were followed for a primary outcome of VT/VF or SCD.

Results: During a median follow-up of 5.68 years, the primary outcome occurred in 44 patients (23%). Patients with a Class I recommendation for ICD implantation showed the highest incidence of the primary outcome among patients in whom the guideline recommendations for ICD implantation were used (log-rank test; p = 0.03). However, compared with patients with left ventricular ejection fractions (LVEFs) ≤35%, there was no significant difference in the incidence of the primary outcome among patients with LVEFs >35% and those who required a permanent pacemaker (p = 0.31); similar results were observed in those with LVEFs >35% and late gadolinium enhancement during cardiovascular magnetic resonance imaging (p = 0.22).

Conclusions: The American guideline recommendations for ICD implantation might be applicable to Japanese patients with CS. Implantation of an ICD may need to be considered in these patients if they require a permanent pacemaker or have late gadolinium enhancement, regardless of LVEF.
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http://dx.doi.org/10.1016/j.jacep.2021.04.009DOI Listing
November 2021

Blood flow dynamics with four-dimensional flow cardiovascular magnetic resonance in patients with aortic stenosis before and after transcatheter aortic valve replacement.

J Cardiovasc Magn Reson 2021 06 28;23(1):81. Epub 2021 Jun 28.

Department of Cardiovascular Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita 15, Nishi 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan.

Background: Pre- and post-procedural hemodynamic changes which could affect adverse outcomes in aortic stenosis (AS) patients who undergo transcatheter aortic valve replacement (TAVR) have not been well investigated. Four-dimensional (4D) flow cardiovascular magnetic resonance (CMR) enables accurate analysis of blood flow dynamics such as flow velocity, flow pattern, wall shear stress (WSS), and energy loss (EL). We sought to examine the changes in blood flow dynamics of patients with severe AS who underwent TAVR.

Methods: We examined 32 consecutive severe AS patients who underwent TAVR between May 2018 and June 2019 (17 men, 82 ± 5 years, median left ventricular ejection fraction 61%, 6 self-expanding valve), after excluding those without CMR because of a contraindication or inadequate imaging from the analyses. We analyzed blood flow patterns, WSS and EL in the ascending aorta (AAo), and those changes before and after TAVR using 4D flow CMR.

Results: After TAVR, semi-quantified helical flow in the AAo was significantly decreased (1.4 ± 0.6 vs. 1.9 ± 0.8, P = 0.002), whereas vortical flow and eccentricity showed no significant changes. WSS along the ascending aortic circumference was significantly decreased in the left (P = 0.038) and left anterior (P = 0.033) wall at the basal level, right posterior (P = 0.011) and left (P = 0.010) wall at the middle level, and right (P = 0.012), left posterior (P = 0.019) and left anterior (P = 0.028) wall at the upper level. EL in the AAo was significantly decreased (15.6 [10.8-25.1 vs. 25.8 [18.6-36.2]] mW, P = 0.012). Furthermore, a significant negative correlation was observed between EL and effective orifice area index after TAVR (r = - 0.38, P = 0.034).

Conclusions: In severe AS patients undergoing TAVR, 4D flow CMR demonstrates that TAVR improves blood flow dynamics, especially when a larger effective orifice area index is obtained.
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http://dx.doi.org/10.1186/s12968-021-00771-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237445PMC
June 2021

Long-Term Prognostic Significance of Ventricular Repolarization Dispersion in Patients with Cardiac Sarcoidosis.

Am J Cardiol 2021 08 11;152:125-131. Epub 2021 Jun 11.

Department of Cardiovascular Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan; Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan.

Cardiac sarcoidosis (CS) is frequently complicated by fatal ventricular arrhythmias. T-peak to T-end interval to QT interval ratio (TpTe/QT) on electrocardiograms (ECG) was proposed as a marker of ventricular repolarization dispersion. Although this ratio could be associated with the incidence of ventricular arrhythmias in cardiovascular diseases, its prognostic implication in patients with CS is unclear. We sought to investigate whether TpTe/QT was associated with long-term clinical outcomes in patients with CS. Ninety consecutive patients with CS in 2 tertiary hospitals who had ECG data before initiation of immunosuppressive therapy between November 1995 and March 2019 were examined. The primary outcome was a composite of advanced atrioventricular block, ventricular tachycardia or ventricular fibrillation (VT/VF), heart failure hospitalization, and all-cause death. During a median follow-up period of 4.70 (interquartile range 2.06-7.23) years, the primary outcome occurred in 21 patients (23.3%). Survival analyses revealed that the primary outcome (p < 0.001), especially VT/VF or sudden cardiac death (p = 0.002), occurred more frequently in patients with higher TpTe/QT (≥ 0.242, the median) than in those with lower TpTe/QT. Multivariable Cox regression analysis showed that a higher TpTe/QT was independently associated with increased subsequent risk of adverse events (hazard ratio1.11, 95% confidence interval 1.03-1.20, p = 0.008) even after adjustment for the significant covariates. In conclusion, a higher TpTe/QT was associated with worse long-term clinical outcomes, especially fatal ventricular arrhythmic events, in patients with cardiac sarcoidosis, suggesting the importance of assessing TpTe/QT as a surrogate for risk stratification in these patients.
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http://dx.doi.org/10.1016/j.amjcard.2021.04.039DOI Listing
August 2021

A multilocular thymic cyst associated with mediastinal seminoma: evidence for its medullary epithelial origin highlighted by POU2F3-positive thymic tuft cells and concomitant myoid cell proliferation.

Virchows Arch 2021 Jul 24;479(1):215-220. Epub 2021 May 24.

Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan.

Multilocular thymic cyst (MTC) and germ cell tumors are common diseases that impact the mediastinum. Correctly diagnosing these diseases can be difficult because several other conditions can mimic them. We report a male patient with MTC associated with mediastinal seminoma. A needle biopsy of the mediastinal tumor revealed numerous epithelioid cell granulomas that mimicked sarcoidosis or mycobacterial infection. However, large atypical cells positive for Oct3/4 and KIT were noted between the granulomas; thus, we diagnosed the patient with mediastinal seminoma. The resected tumor, after chemotherapy, consisted of multiple cystic lesions, and a residual germ cell tumor was first considered. However, thymic medulla-specific elements, namely, POU2F3-positive thymic tuft cells and rhabdomyomatous myoid cells accompanying the epithelium, led to the correct diagnosis of MTC. Our case underscores the importance of recognizing the histological features associated with mediastinal seminoma and provides novel findings for MTC pathogenesis, namely, the presence of thymic tuft cells.
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http://dx.doi.org/10.1007/s00428-021-03125-2DOI Listing
July 2021

Effects of a β2-adrenergic receptor blocker on experimental periodontitis in spontaneously hypertensive rats.

Life Sci 2021 Jul 9;277:119593. Epub 2021 May 9.

Department of Orthodontics, School of Dentistry, Aichi Gakuin University, 2-11 Suemoridori, Chikusa-ku, Nagoya, Aichi 464-8651, Japan.

Aims: Recent studies have reported a relationship between periodontal disease and hypertension, and previous evidence suggests that the sympathetic nervous system plays an important role in the control of bone metabolism. This study sought to evaluate the effect of the beta-2 adrenergic receptor (β2-AR) blocker butoxamine on experimental periodontitis in a rat model.

Materials And Methods: Wistar-Kyoto and spontaneously hypertensive rats (n = 6 per group) were orally administered butoxamine 1 mg/kg/day and experimental periodontitis was induced by applying an orthodontic ligature wire. The rats were sacrificed after 4 weeks and the residual alveolar bone was measured using micro-computed tomography (micro-CT) imaging analysis software for histological analysis.

Key Findings: Micro-CT imaging analysis showed a higher ratio of residual alveolar bone, BV/TV, and Tb.N in both Wistar-Kyoto and spontaneously hypertensive rats treated with butoxamine compared with the corresponding control rats. In histological analysis, compared with the Wistar-Kyoto and spontaneously hypertensive rat control groups, the corresponding butoxamine-treated groups showed a lower ratio of attachment level, lower values of osteoclast number and surface.

Significance: β2-AR blockers maintained the alveolar bone mass and attachment level by suppressing osteoclast activity. Thus, β2-AR blockers may be effective in preventing periodontitis.
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http://dx.doi.org/10.1016/j.lfs.2021.119593DOI Listing
July 2021

Follicular development during hormone replacement therapy in patients with premature ovarian insufficiency.

Reprod Med Biol 2021 Apr 19;20(2):234-240. Epub 2021 Mar 19.

Department of Obstetrics and Gynecology Jikei University School of Medicine Tokyo Japan.

Purpose: To provide information about the relationship between follow-up period and follicular development in patients with infertility due to premature ovarian insufficiency (POI) who are undergoing hormone replacement therapy (HRT). It is necessary to detect follicle development for artificial insemination or in vitro fertilization.

Methods: This retrospective cohort study was conducted at a university hospital in Tokyo, Japan, from April 2014 to February 2019 in 20 patients [follicular development group, 11 women (55%); non-follicular development group, 9 women (45%)] with POI; their follicular development was followed up weekly. Background characteristics, including age, follicle-stimulating hormone (FSH) and anti-Mullerian hormone levels (AMH), the period from the last spontaneous menstruation to hormone replacement therapy initiation, and follow-up period during HRT were investigated. The period without follicular development was tabulated, and the subsequent cumulative follicular development detection rate was calculated.

Results: At least 1-year follow-up, the cumulative follicular development rate was 70%; follicular development was observed with a probability of 49.1% at 3 months, 33.4% at 6 months, and 8.3% at 12 months in the follow-up period.

Conclusions: The results show that the longer the non-follicle development period, the lower the probability of subsequent follicular development in patients with POI during HRT.
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http://dx.doi.org/10.1002/rmb2.12375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8022089PMC
April 2021

Does local injection of reveromycin A inhibit tooth movement without causing systemic side effects?

Eur J Orthod 2021 Mar 19. Epub 2021 Mar 19.

Department of Orthodontics, School of Dentistry, Aichi Gakuin University, Chikusa-ku, Nagoya, Aichi, Japan.

Objective: To determine the feasibility of local inhibition of osteoclast activity and control of tooth movement with local intraoral reveromycin A (RMA) injection in model mice for experimental tooth movement.

Materials And Methods: Eight-week-old wild-type mice (n = 6 per group) were divided into four groups consisting of two non-RMA groups that received normal saline for 14 (14-day non-RMA group) or 21 consecutive days (21-day non-RMA group) and 2 RMA groups that received RMA (1.0 mg/kg of weight) for 14 (14-day RMA group) or 21 consecutive days (21-day RMA group). RMA was injected locally into the buccal mucosa of the left first maxillary molar twice daily starting 3 days before placement of the 10-gf Ni-Ti closed coil spring. Tooth movement distance was analysed using micro-computed tomography. The effects on surrounding alveolar bone were evaluated by measuring the ratio of bone surface area to tissue surface area with haematoxylin-eosin-stained sections and counting the number of osteoclasts in periodontal tissue with TRAP-stained sections. Blood tests were performed and bone volume and trabecular separation at the tibial neck were measured to analyse systemic side effects.

Results: Local RMA injection inhibited tooth movement by 40.6 per cent, promoted alveolar bone volume maintenance by 37.4 per cent, and inhibited osteoclast activity around the tooth root at 21 days by 40.8 per cent. Systemic effects on osteoclasts or osteoblasts were not observed.

Conclusion: Local injection of RMA enabled control of tooth movement without systemic side effects in a mouse model.
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http://dx.doi.org/10.1093/ejo/cjaa067DOI Listing
March 2021

Safety assessment of the prophylactic use of silicone gel sheets (Lady Care) for the prevention of hypertrophic scars following caesarean section.

J Obstet Gynaecol 2021 Apr 26;41(3):380-384. Epub 2021 Feb 26.

Department of Obstetrics and Gynecology, The Jikei University School of Medicine, Tokyo, Japan.

This study aimed to investigate the side effects of silicone gel sheet (Lady Care) and evaluate its prophylactic efficacy in preventing abnormal scarring. Sixty women who underwent caesarean section were recruited from September 2016 to September 2017 in this prospective study. Lady Care was applied from the 2nd to the 6th postoperative months. Side effects of Lady Care were evaluated through medical examinations and questionnaires. A plastic surgeon diagnosed abnormal scarring. Pruritus was diagnosed in 25 (47.2%) patients; folliculitis, four (7.5%); dry skin, four (7.5%); contact dermatitis, three (5.7%); wound infection, two (3.8%); and epidermolysis, one (1.9%), albeit with mild severity. Following Lady Care application, no abnormal scarring and mild hypertrophic scarring was observed in 32 (64.0%) and 18 (36.0%) patients respectively. Of seven patients with pre-existing hypertrophic scars, only two showed hypertrophic scarring after Lady Care application. Our findings support the safety and prophylactic efficacy of Lady Care.Impact Statement The incidence of abnormal scarring, i.e. keloid or hypertrophic scar formation after caesarean section (CS) is reported to be ∼41%. Abnormal or excessive scar formation can lead to functional limitations, pruritus, pain and cosmetic issues. Studies have also shown a prophylactic effect of the application of silicone materials against the development of hypertrophic and keloid scars, though prohibitive cost and lack of adhesiveness of such gel sheets are known factors limiting their usage. The new silicone gel sheet 'Lady Care' has strong adhesive properties and is consequently not easily peeled off. Furthermore, it is easy to use and economically efficient. This is the first clinical trial on the application of Lady Care silicone gel sheet for the prevention of CS scarring. Our findings support the safety and prophylactic efficacy of Lady Care.
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http://dx.doi.org/10.1080/01443615.2020.1852540DOI Listing
April 2021

BK Virus-Associated Urothelial Carcinoma in a Patient with Peripheral Blood Stem Cell Transplantation for Acute Lymphoblastic Leukemia: A Case Report.

Case Rep Oncol 2021 Jan-Apr;14(1):8-12. Epub 2021 Jan 11.

Department of Urology, Tohoku University Graduate School of Medicine, Sendai, Japan.

Bladder tamponade due to hemorrhagic cystitis caused by BK virus in immunocompetent patients is familiar to urologists. BK virus is an important cause of nephropathy and graft loss in kidney transplant recipients. Although urothelial carcinoma of the bladder in kidney transplant recipients with persistent BK viruria is known, BK virus-associated urothelial carcinoma (BKVUC) in peripheral blood stem cell transplantation recipients is not as well known. A 54-year-old man with acute lymphoblastic leukemia was treated in the Department of Hematology of our hospital. After recurrence 25 months later, he received chemotherapy for half a year and underwent peripheral blood stem cell transplantation. He achieved temporarily complete remission, but he developed hematuria with BK virus-positive result 1 month after peripheral blood stem cell transplantation. One month later, he developed bladder tamponade-diagnosed hemorrhagic cystitis due to BK virus in our Urological Department. We performed transurethral coagulation to manage hemorrhage and removed a bleeding lesion in the bladder wall. Pathological examination of the removed bladder wall revealed pT1 stage BKVUC. We found that bladder tamponade could have led to reactivation of BK virus in this immunocompetent patient. This could be the first report of BKVUC of the bladder found in a peripheral blood stem cell transplantation recipient with close urological follow-up for 24 months. Adequate removal of bleeding lesions from the bladder mucosa with appropriate timing during hemorrhagic cystitis due to BKVUC could be essential to achieve good outcomes.
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http://dx.doi.org/10.1159/000511053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879257PMC
January 2021

Prognostic value of admission serum magnesium in acute myocardial infarction complicated by malignant ventricular arrhythmias.

Am J Emerg Med 2021 06 5;44:100-105. Epub 2021 Feb 5.

Department of Cardiovascular Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.

Objectives: Although electrolyte abnormalities are related to worse clinical outcomes in patients with acute myocardial infarction (AMI), little is known about the association between admission serum magnesium level and adverse events in AMI patients complicated by out-of-hospital cardiac arrest presenting with malignant ventricular arrhythmias (OHCA-MVA). We investigated the prognostic value of serum magnesium level on admission in these patients.

Methods: We retrospectively analyzed the data of 165 consecutive reperfused AMI patients complicated with OHCA-MVA between April 2007 and February 2020 in our university hospital. Serum magnesium concentration was measured on admission. The primary outcome was in-hospital death.

Results: Fifty-four patients (33%) died during hospitalization. Higher serum magnesium level was significantly related to in-hospital death (Fine & Gray's test; p < 0.001). In multivariable logistic regression analyses, serum magnesium level on admission was independently associated with in-hospital death (hazard ratio 2.68, 95% confidence interval 1.24-5.80) even after adjustment for covariates. Furthermore, the incidences of cardiogenic shock necessitating an intra-aortic balloon pump (p = 0.005) or extracorporeal membrane oxygenation (p < 0.001), tracheal intubation (p < 0.001) and persistent vegetative state (p = 0.002) were significantly higher in patients with higher serum magnesium level than in those with lower serum magnesium level.

Conclusions: In reperfused AMI patients complicated by OHCA-MVA, admission serum magnesium level might be a potential surrogate marker for predicting in-hospital death.
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http://dx.doi.org/10.1016/j.ajem.2021.02.005DOI Listing
June 2021

RasGRP2 inhibits glyceraldehyde-derived toxic advanced glycation end-products from inducing permeability in vascular endothelial cells.

Sci Rep 2021 02 3;11(1):2959. Epub 2021 Feb 3.

Faculty of Pharmaceutical Sciences, Hiroshima International University, Hiroshima, Japan.

Advanced glycation end-products (AGEs) are formed by the non-enzymatic reaction of sugars and proteins. Among the AGEs, glyceraldehyde-derived toxic AGEs (TAGE) are associated with various diseases, including diabetic complications such as diabetic retinopathy (DR). The risk of developing DR is strongly associated with poor glycemic control, which causes AGE accumulation and increases AGE-induced vascular permeability. We previously reported that Ras guanyl nucleotide releasing protein 2 (RasGRP2), which activates small G proteins, may play an essential role in the cell response to toxicity when exposed to various factors. However, it is not known whether RasGRP2 prevents the adverse effects of TAGE in vascular endothelial cells. This study observed that TAGE enhanced vascular permeability by disrupting adherens junctions and tight junctions via complex signaling, such as ROS and non-ROS pathways. In particular, RasGRP2 protected adherens junction disruption, thereby suppressing vascular hyper-permeability. These results indicate that RasGRP2 is an essential protective factor of vascular permeability and may help develop novel therapeutic strategies for AGE-induced DR.
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http://dx.doi.org/10.1038/s41598-021-82619-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859393PMC
February 2021

Alterations in Glucose Metabolism Due to Decreased Expression of Heterogeneous Nuclear Ribonucleoprotein M in Pancreatic Ductal Adenocarcinoma.

Biology (Basel) 2021 Jan 14;10(1). Epub 2021 Jan 14.

Faculty of Pharmaceutical Sciences, Hiroshima International University, 5-1-1 Hirokoshingai, Kure, Hiroshima 737-0112, Japan.

The prognosis of pancreatic cancer is considerably worse than that of other cancers, as early detection of pancreatic cancer is difficult and due to its hypovascular environment, which involves low blood flow and a low supply of oxygen and nutrients. Moreover, pancreatic cancer demonstrates a mechanism that allows it to survive in a hypovascular environment. However, the detailed mechanism remains elusive. Recently, it has been reported that heterogeneous ribonuclear protein M (HNRNPM) is a splicing factor associated with malignant tumors. Thus, in this study, we investigated the expression and effects of HNRNPM in pancreatic ductal adenocarcinoma (PDA). We observed that HNRNPM expression, which is highly expressed in pancreatic tissues, was reduced in PDA tissues. Additionally, knockdown of HNRNPM under low-glucose conditions that mimic a hypovascular environment was shown to alter glucose metabolism and prolong cell survival by suppressing glucose consumption. These results suggest that the decreased expression of HNRNPM in PDA may be involved in its adaptation to a hypovascular environment.
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http://dx.doi.org/10.3390/biology10010057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830884PMC
January 2021

Suppression of Hepatic Stellate Cell Death by Toxic Advanced Glycation End-Products.

Biol Pharm Bull 2021 ;44(1):112-117

Faculty of Pharmaceutical Sciences, Hiroshima International University.

Advanced glycation end-products (AGEs) are produced by the non-enzymatic reaction of sugars with proteins. It has been revealed that glyceraldehyde-derived toxic AGEs (TAGE) are elevated in the serum of non-alcoholic steatohepatitis (NASH) patients. NASH causes liver fibrosis and progresses to cirrhosis and hepatocellular carcinoma. However, the impact of TAGE in liver fibrosis caused by extracellular matrix accumulation remains poorly understood. In this study, we examined the effect of TAGE on the activation of hepatic stellate cells that are involved in liver fibrosis. LX-2 cells treated with transforming growth factor-β1 (TGF-β1) significantly reduced cell viability by apoptosis. However, the decrease in cell viability with TGF-β1 treatment was significantly suppressed by TAGE co-treatment. The levels of α-smooth muscle actin (α-SMA) and platelet-derived growth factor (PDGF)-Rβ and its ligand PDGF-B were increased in LX-2 cells following TGF-β1 treatment, suggesting that these cells were activated; however, these increases were unaffected by TAGE co-treatment. Moreover, collagen I level was increased with TGF-β1 treatment, and this increase was further increased by TAGE co-treatment. These results suggested that the suppression of apoptosis in activated LX-2 cells by TGF-β1 and TAGE co-treatment is related to an increase in the production of the extracellular matrix such as collagen I. Therefore, it was suggested that TAGE might aggravate the liver fibrosis of chronic hepatitis, such as NASH.
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http://dx.doi.org/10.1248/bpb.b20-00708DOI Listing
August 2021

Night-Time Urinary Frequency Is Increased after the Great East Japan Earthquake along with Seasonal Variation: A Five-Year Longitudinal Study in Kesennuma City.

Tohoku J Exp Med 2020 12;252(4):329-337

Department of Urology, Tohoku University Graduate School of Medicine.

Disasters influence various health conditions; however, little has been reported about urinary symptoms. The objective of this study is to evaluate whether night-time urinary frequency was influenced by the Great East Japan Earthquake (GEJE) in March 2011. We also evaluated seasonal variation of night-time frequency, which may affect the primary objective. A retrospective chart review was conducted on 300 evaluable patients who resided in the impacted area: 263 men with benign prostatic hyperplasia and/or overactive bladder and 37 women with overactive bladder. Data concerning night-time frequency were collected repeatedly every three months from March 2009 until March 2014, then compared yearly and seasonally among same patients. In addition, night-time frequency was analyzed for potential relations to sex, age, comorbidities, and whether residences had been destroyed. There was a significant increase of night-time frequency during 2011-2013 when compared yearly with 2009 and 2010. In seasonal comparisons of the entire period, night-time frequency was greater during autumn and winter compared with summer. In quarterly comparisons, a sudden increase was not observed after the GEJE, but night-time frequency was increased significantly in spring, summer and autumn in 2011 when compared with the corresponding seasons in 2010. While hypertension was related to exacerbation of night-time frequency during winter, we did not find any factors associated with increase after the disaster out of sex, age, comorbidities or residential situations. In conclusion, night-time urinary frequency is increased shortly after the GEJE and remains elevated for the following three years along with seasonal variation.
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http://dx.doi.org/10.1620/tjem.252.329DOI Listing
December 2020

A novel deletion of the dystrophin gene in a patient without muscle-related symptoms.

Eur Heart J 2021 04;42(16):1638

Department of Cardiovascular Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, West 7, North 15, Kita-ku, Sapporo 060-8638, Japan.

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http://dx.doi.org/10.1093/eurheartj/ehaa928DOI Listing
April 2021

Impact of cancer therapy on post-treatment ejaculation disorder and sexual life in testicular cancer survivors.

Int J Urol 2021 01 31;28(1):69-74. Epub 2020 Oct 31.

Department of Urology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.

Objective: To evaluate the impact of cancer therapy on post-treatment ejaculation in patients with testicular cancer.

Methods: A total of 74 testicular cancer survivors provided completed International Index of Erectile Function-15 questionnaires before and after treatment between 2010 and 2017. Sexual function, particularly ejaculatory function, was evaluated before and after treatment. In this study, patients who answered "1 = almost never/never" or "2 = a few times" for questionnaire number 9 (ejaculation frequency) were defined as having "ejaculation disorder."

Results: Of 74 testicular cancer survivors, 50 (68%) had no ejaculation disorders before treatment. Four (44%) of nine survivors, who received chemotherapy and retroperitoneal lymph node dissection, developed ejaculation disorders after treatment. On multivariate analysis, retroperitoneal lymph node dissection was a significant predictor of post-treatment ejaculation disorder (P = 0.042). Of 60 survivors with evaluable ejaculation function after treatment, 24 (40%) did not attempt sexual intercourse, and multivariate analysis showed ejaculation disorder had a significant negative impact on having sexual intercourse (P = 0.035). Furthermore, the mean International Index of Erectile Function-15 scores in the groups with and without ejaculation disorders after treatment were 24.0 and 51.9, respectively (P < 0.001).

Conclusion: Ejaculation disorders occur at high rate after retroperitoneal lymph node dissection. Many testicular cancer survivors reporting no sexual intercourse have ejaculation disorders, suggesting an adverse impact on sexual life. Urologists should provide proper counselling regarding the risk of ejaculation disorder and its possible impact on sexual life.
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http://dx.doi.org/10.1111/iju.14403DOI Listing
January 2021
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