Publications by authors named "Makoto Kodama"

200 Publications

Oral granuloma in a pediatric patient with chronic graft-versus-host disease: A case report.

World J Clin Cases 2020 Nov;8(22):5663-5669

Department of Oral Restitution, Graduate School, Tokyo Medical and Dental University, Tokyo 113-8549, Japan.

Background: Oral mucositis is often observed with graft-versus-host disease (GVHD); however, the occurrence of oral granuloma is rare. The rapid increase in granulomatous lesions should be distinguished from malignant tumors in patients with GVHD because malignant diseases can develop in those patients. This case is the youngest pediatric patient with granuloma associated with GVHD.

Case Summary: The patient was a 1-year and 5-mo-old girl who presented to our department for the management of oral nodules. At the age of 5 mo, she was diagnosed with primary immunodeficiency disease, cord blood transplant was performed at 11 mo and bone marrow transplant at 1 year of age. After transplantation, GVHD and oral mucositis developed, and tacrolimus was administered. Interestingly, nodules appeared on the lower lip and buccal mucosa, which spontaneously disappeared. Then, a new nodule appeared on the left lateral border of the tongue. Resection was performed and the histopathological diagnosis was granuloma. The origin of these nodules were considered to be the fibroblasts activated under inflammation caused by GVHD because the calcineurin inhibitor tacrolimus acted on their proliferation.

Conclusion: It is very important to distinguish oral granulomatous lesions from malignancies if GVHD is present at the base and if immunosuppressive agents and steroids are being administered.
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http://dx.doi.org/10.12998/wjcc.v8.i22.5663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716312PMC
November 2020

[Multiple Minute Pulmonary Meningothelial-like Nodules;Report of a Case].

Kyobu Geka 2020 Oct;73(11):968-971

Department of Thoracic Surgery, Tokyo Yamate Medical Center, Tokyo, Japan.

A 57-year-old woman was referred to our hospital for investigation of multiple tiny nodules in the lung fields bilaterally on computed tomography (CT). Video-assisted thoracoscopic lung biopsy was performed to diagnose the pulmonary lesions. Histological analysis showed nodular lesions with interstitial proliferation of uniform, round to oval cells with variable widening of the alveolar septa. Immunohistochemically, the cells were positive for EMA, CD56 and the progesterone receptor, but negative for chromogranin and synaptophysin. The diagnosis was "diffuse pulmonary meningotheliomatosis", with multiple diffuse "minute pulmonary meningothelial-like nodules". Diffuse pulmonary meningotheliomatosis should be kept in mind when we encounter small nodular shadows on a CT scan.
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October 2020

Epithelioid Cell Granulomas in Crohn's Disease Are Differentially Associated With Blood Vessels and Lymphatic Vessels: A Sequential Double Immunostaining Study.

J Histochem Cytochem 2020 08 26;68(8):553-560. Epub 2020 Jun 26.

Department of Human Pathology, Juntendo University Graduate School of Medicine, Bunkyo-Ku, Tokyo, Japan.

Crohn's disease (CD) is a gastrointestinal disorder of unknown etiology. CD-specific longitudinal ulcers show an association between disease pathogenesis and vasculature dysfunction. Granulomatous lymphangitis may also contribute to CD pathogenesis; meanwhile, vasculitis is the primary CD lesion. We investigated the association between granulomas and lymphatic and blood vessels to assess the role of vasculature in CD pathogenesis. Two small and large intestine specimens were obtained from four CD patients. From each specimen, 160 sequential sections were obtained and double immunohistochemical stained to label lymphatic and blood vessels in association with granulomas. We found that 289 of 342 granulomas (85%) were associated with a lymphatic vessel and 313 of 364 granulomas (86%) were associated with a blood vessel. Although intrablood vessel granulomas were not detected, intralymphatic vessel granulomas were. In the internal region of the granuloma, we found more blood vessels than lymphatic vessels. Hence, these results cumulatively demonstrate that CD epithelioid cell granulomas are differentially associated with lymphatic and blood vessels, suggesting both as essential for the formation and maintenance of these granulomas. Moreover, both lymphatic and blood vessels may participate in granulomatous inflammation in the primary CD lesions; however, additional studies with larger numbers of participants are required to validate our findings.
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http://dx.doi.org/10.1369/0022155420939535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400665PMC
August 2020

[Pancreatic Pleural Effusion;Report of a Case].

Kyobu Geka 2020 Jun;73(6):476-479

Department of Thoracic Surgery, Tokyo Yamate Medical Center, Tokyo, Japan.

A 50-year-old man was admitted with respiratory failure. Chest X-ray and computed tomography revealed massive left pleural effusion and mediastinal shift. Pleural effusion showed abnormally high amylase levels of 42,600 IU/l and a high protein level of 3.2 g/dl. The serum amylase level was also 42,100 IU/l, and the proportion of pancreatic-type amylase was 88%. We diagnosed the patient with pancreatic effusion. Chest and abdominal enhanced computed tomography and magnetic resonance cholangiopancreatography revealed no pancreaticopleural fistula. He underwent a thoracoscopic examination that revealed brown pleural effusion as well as fibrin clots and thickness of the pleura. Histologically, there was no malignancy and the cause of pleural effusion was considered to be chronic pancreatitis.
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June 2020

A case of immunoglobulin G4-related inflammatory pseudotumor mimicking renal cell carcinoma.

Abdom Radiol (NY) 2019 04;44(4):1230-1236

Department of Diagnostic Radiology, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo, Tokyo, 113-8519, Japan.

In a 69-year-old woman with a history of Mikulicz's disease, a hypoechoic solitary renal mass was identified on routine ultrasound examination. Based on the findings of computed tomography (CT) and magnetic resonance imaging (MRI), renal cell carcinoma was a possible diagnosis. Subsequent partial nephrectomy revealed a mass characterized by an increased number of blood vessels, internal hemorrhage, and a thick fibrous capsule. Immunohistochemically, the mass comprised of tubulointerstitial nephritis with increased immunoglobulin (Ig)G4-positive plasma cells and fibrosis. Generally, diagnosis of IgG4-related kidney disease (IgG4-RKD) is not difficult when the kidney is involved together with other systemic involvements. However, diagnosis becomes harder when a solitary renal mass appears as a single-organ involvement. On precise review of our imaging findings, MRI signals were markedly affected by hemorrhage, so the mass showed hypointensity on both T1- and T2-weighted imaging, and the signal of in-phase images decreased. Dynamic MRI showed no apparent enhancement of the mass, while CT showed an apparent enhancement effect. Capsule formation was another key finding for IgG4-RKD and was recognized as a gradually enhancing boundary zone surrounding the mass on both CT and MRI. When a solitary renal mass is associated with hemorrhage and thick capsule formation, inflammatory pseudotumor should be considered as differential diagnosis.
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http://dx.doi.org/10.1007/s00261-018-01885-1DOI Listing
April 2019

Adenocarcinoma within anorectal fistulae: different clinicopathological characteristics between Crohn's disease-associated type and the usual type.

Mod Pathol 2019 02 11;32(2):314-325. Epub 2018 Sep 11.

Department of Human Pathology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, Japan.

Adenocarcinoma within anorectal fistulae is rare and is sometimes associated with Crohn's disease. Crohn's disease-associated adenocarcinoma within anorectal fistulae has a poor prognosis; however, little is known about the clinicopathological differences between Crohn's disease-associated adenocarcinoma within anorectal fistulae and usual adenocarcinoma within anorectal fistulae. We retrospectively searched patients' charts and pathology archives at Tokyo Yamate Medical Center and Tokyo Medical and Dental University Hospital for adenocarcinoma within anorectal fistulae. Clinical and pathological data were collected and immunohistochemical examinations were conducted. Overall survival rate was estimated using the Kaplan-Meier method. Prognostic factors of overall survival were assessed using univariate and multivariate Cox regression analyses. We examined 82 cases of adenocarcinoma within anorectal fistulae. Fifty-nine of 82 cases (72%) had usual adenocarcinoma within anorectal fistulae, while the remaining 23 cases (28%) had Crohn's disease-associated adenocarcinoma within anorectal fistulae. Patients with Crohn's disease-associated adenocarcinoma within anorectal fistulae were diagnosed at a younger age and at a more advanced stage than those with usual adenocarcinoma within anorectal fistulae. Macroscopic and histological types were also different between usual adenocarcinoma within anorectal fistulae and Crohn's disease-associated adenocarcinoma within anorectal fistulae. Crohn's disease-associated adenocarcinoma within anorectal fistulae included more ulcerative types and high-grade adenocarcinomas. The rate of lymphovascular invasion was higher in Crohn's disease-associated adenocarcinoma within anorectal fistulae. Immunohistochemically, the expression of E-cadherin, p53, and MUC5AC differed between usual adenocarcinoma within anorectal fistulae and Crohn's disease-associated adenocarcinoma within anorectal fistulae. Patients with Crohn's disease-associated adenocarcinoma within anorectal fistulae exhibited worse overall survival than those with usual adenocarcinoma within anorectal fistulae, and vascular invasion was the strongest significant independent predictor of overall survival in patients with adenocarcinoma within anorectal fistulae. In conclusion, usual adenocarcinoma within anorectal fistulae and Crohn's disease-associated adenocarcinoma within anorectal fistulae have different clinicopathological characteristics and should be considered separate clinical entities.
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http://dx.doi.org/10.1038/s41379-018-0105-8DOI Listing
February 2019

Glutamic Acid Decarboxylase Autoantibody-negative Slowly Progressive Type 1 Diabetes Mellitus: A Case Report and Literature Review.

Intern Med 2018 Dec 10;57(24):3581-3587. Epub 2018 Aug 10.

Department of Hematology, Endocrinology and Metabolism, Niigata University Faculty of Medicine, Japan.

A 59-year-old non-obese Japanese woman developed diabetes mellitus with a negative glutamic acid decarboxylase autoantibody (GADA) test result. Her hyperglycemia was initially well controlled by oral hypoglycemic agents; however, despite continued treatment the hyperglycemia gradually worsened. As she had endogenous insulin deficiency and tested positive for insulin autoantibody (IAA), insulin therapy was initiated. Few studies have investigated GADA-negative patients with slowly progressive type 1 diabetes mellitus (SPT1D). Our IAA-positive SPT1D patient progressed from the clinical onset of diabetes mellitus to starting insulin therapy relatively quickly (1.5 years), similarly to other previously reported non-obese patients with GADA-positive SPT1D.
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http://dx.doi.org/10.2169/internalmedicine.1008-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355411PMC
December 2018

Macroscopic Localized Subicular Thinning as a Potential Indicator of Amyotrophic Lateral Sclerosis.

Eur Neurol 2018 23;79(3-4):200-205. Epub 2018 Mar 23.

Department of Neurology, Nitobe Memorial Nakano General Hospital (NMNGH), Tokyo, Japan.

Subicular degeneration occurs in amyotrophic lateral sclerosis (ALS) patients. However, it was unknown whether microscopic subicular degeneration could be observed as macroscopic changes and whether these changes were associated with the transactive-response DNA binding protein 43 kDa (TDP-43) pathology. Topographic differences between subicular degeneration caused by ALS and Alzheimer disease (AD) had also not been characterized. Here we investigated the subiculum and related areas in autopsied brains from 3 ALS and 3 AD patients. Macroscopic subicular thinning and corresponding astrocytosis were pronounced in ALS compared to AD. This thinning was frequently accompanied by TDP-43 pathology in the transentorhinal cortex and nucleus accumbens. The preferential susceptibility of the perforant pathway to TDP-43 deposition may be an underlying cause of subicular thinning in ALS.
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http://dx.doi.org/10.1159/000487992DOI Listing
January 2019

Therapeutic efficacy of peramivir against H5N1 highly pathogenic avian influenza viruses harboring the neuraminidase H275Y mutation.

Antiviral Res 2017 Mar 22;139:41-48. Epub 2016 Dec 22.

Research Center for Zoonosis Control, Hokkaido University, Hokkaido, Japan; Global Station for Zoonosis Control, Global Institute for Collaborative Research and Education (GI-CoRE), Hokkaido University, Hokkaido, Japan.

High morbidity and mortality associated with human cases of highly pathogenic avian influenza (HPAI) viruses, including H5N1 influenza virus, have been reported. The purpose of the present study was to evaluate the antiviral effects of peramivir against HPAI viruses. In neuraminidase (NA) inhibition and virus replication inhibition assays, peramivir showed strong inhibitory activity against H5N1, H7N1 and H7N7 HPAI viruses with sub-nanomolar activity in enzyme assays. In H5N1 viruses containing the NA H275Y mutation, the antiviral activity of peramivir against the variant was lower than that against the wild-type. Evaluation of the in vivo antiviral activity showed that a single intravenous treatment of peramivir (10 mg/kg) prevented lethality in mice infected with wild-type H5N1 virus and also following infection with H5N1 virus with the H275Y mutation after a 5 day administration of peramivir (30 mg/kg). Furthermore, mice injected with peramivir showed low viral titers and low levels of proinflammatory cytokines in the lungs. These results suggest that peramivir has therapeutic activity against HPAI viruses even if the virus harbors the NA H275Y mutation.
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http://dx.doi.org/10.1016/j.antiviral.2016.12.011DOI Listing
March 2017

Failing Left Ventricles Have an Enhanced Post-Stimulation Potentiation Despite Their Impaired Force Frequency Relationship.

Int Heart J 2016 May 13;57(3):317-22. Epub 2016 May 13.

Department of Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences.

The left ventricular contractile force (LV dP/dtmax) of patients with left ventricular systolic dysfunction does not increase effectively with an increase in heart rate. In other words, their force-frequency relationship (FFR) is impaired. However, it is unknown whether a longer coupling interval subsequent to tachycardia causes a stronger contraction (poststimulation potentiation, PSP) in a rate-dependent manner.In 16 patients with idiopathic dilated cardiomyopathy (DCM) (48 ± 2 years old, LVEF 30 ± 10%) and 6 control patients (58 ± 4 years old, LVEF 70 ± 7%), FFR was assessed by right atrial pacing using a micro-manometer-tipped catheter. At each pacing rate, the increase of LV dP/dtmax over basal LV dP/dt (ΔFFR) and the increase of LV dP/dtmax of the first beat after pacing cessation over LV dP/dtmax during pacing (ΔPSP) were evaluated.Patients with DCM had smaller LV dP/dtmax at baseline (872 ± 251 versus 1370 ± 123 mmHg/second, P = 0.0002) and developed smaller ΔFFR (eg, at 120/minute, 77 ± 143 versus 331 ± 131 mmHg/second, P = 0.0011). In contrast, they showed a rate-dependent increase of LV dP/dtmax of PSP and had greater ΔPSP (eg, at 120/minute, 294 ± 173 versus -152 ± 131 mmHg/second, P < 0.0001).Failing left ventricles develop little contractile force during tachycardia despite their rate-dependent enhancement in post-stimulation potentiation, suggesting that refractoriness of contractile force underlies impaired FFR.
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http://dx.doi.org/10.1536/ihj.15-374DOI Listing
May 2016

Electrocardiographic abnormalities and risk of developing cardiac events in extracardiac sarcoidosis.

Int J Cardiol 2015 26;189:1-5. Epub 2015 Mar 26.

Division of Cardiology, Niigata University Hospital, Niigata, Japan.

Background: Cardiac involvement is a leading cause of death from sarcoidosis. Because the efficacy of corticosteroid treatment is limited in patients with cardiac manifestation, early diagnosis is important. However, cardiac involvement is difficult to identify at early stages and is often underdiagnosed. Therefore, this study aimed to identify electrocardiographic risk factors for cardiac events in patients with extracardiac sarcoidosis.

Methods: This prospective observational cohort study included 227 patients with extracardiac sarcoidosis who did not have any cardiac manifestation (age, 49 ± 17 years; women, 63%). We studied the association of electrocardiographic abnormalities with developing cardiac manifestations.

Results: During a follow-up of 6.3 ± 3.7 years, 11 patients developed cardiac events, including advanced atrioventricular block (4 patients), ventricular tachycardia (4 patients), and systolic dysfunction (3 patients). All patients had electrocardiographic abnormalities prior to the development of cardiac events. In multivariate analyses, the baseline heart rate and PR interval were associated with increased risk of developing cardiac events. The QRS duration and corrected QT interval were not associated with cardiac manifestations. The multivariate analyses also revealed that baseline conduction disorder, ST segment/T wave abnormalities, and fragmented QRS complexes were associated with cardiac events.

Conclusions: Electrocardiographic abnormalities occurred prior to cardiac events in extracardiac sarcoidosis. Patients with electrocardiographic abnormalities may require further evaluation for cardiac involvement and careful follow-up.
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http://dx.doi.org/10.1016/j.ijcard.2015.03.175DOI Listing
April 2016

Cutaneous paragonimiasis due to triploid Paragonimus westermani presenting as a non-migratory subcutaneous nodule: a case report.

J Med Case Rep 2014 Oct 16;8:346. Epub 2014 Oct 16.

Section of Oncopathology and Regenerative Biology, Department of Pathology, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki, Miyazaki 889-1692, Japan.

Introduction: Paragonimiasis is a food-borne infection caused by Paragonimus parasites. The lungs and pleura are the primary sites for the infection; however, ectopic infection can occur in other organs such as skin, liver and brain. It is difficult to make a diagnosis of ectopic paragonimiasis due to an ignorance of, and unfamiliarity with the disease. We report the case of a patient with subcutaneous paragonimiasis diagnosed by histopathological analysis and serological testing.

Case Presentation: A 39-year-old Chinese immigrant woman presented with a subcutaneous nodule in her left lower back. The nodule was initially suspected of lipoma and she was followed up on without any treatment. However, it gradually indurated and the nodule was resected surgically. A magnetic resonance imaging scan revealed a polycystic lesion with inhomogeneous low or high intensity on T1- or T2-weighted images, respectively. The rim of the lesion was enhanced after contrast enhancement, but the inside did not show high-signal intensity. A histological analysis of the surgically resected specimen revealed variable-sized tubulo-cystic structures. The cyst wall showed a granulomatous change with scant eosinophilic infiltration. A number of parasite ova were observed in the necrotic tissue inside the cysts, and a parasite body with a presumed oral sucker and reproductive organ was also detected, suggesting a trematode infection. A subsequent serological examination showed a positive reaction of her serum to the Paragonimus westermani antigen. No abnormal findings were found on her chest computed tomography scan. The diagnosis of subcutaneous paragonimiasis caused by Paragonimus westermani was made.

Conclusions: We report a case presenting only as a non-migratory subcutaneous nodule without any pleuropulmonary lesion, which was initially suspected of lipoma but denied by magnetic resonance imaging scan results. The case was subsequently diagnosed as subcutaneous paragonimiasis from the results of histopathological analysis and serological testing.
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http://dx.doi.org/10.1186/1752-1947-8-346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4209769PMC
October 2014

The relationship between in vivo antiviral activity and pharmacokinetic parameters of peramivir in influenza virus infection model in mice.

Antiviral Res 2014 Sep 2;109:110-5. Epub 2014 Jul 2.

Medicinal Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.

The purpose of this study was to investigate the relationship between pharmacokinetic (PK) parameters of intravenous (IV) peramivir and in vivo antiviral activity pharmacodynamic (PD) outcomes in a mouse model of influenza virus infection. Peramivir was administrated to mice in three dosing schedules; once, twice and four times after infection of A/WS/33 (H1N1). The survival rate at day 14 after virus infection was employed as the antiviral activity outcome for analysis. The relationship between day 14 survival and PK parameters, including area under the concentration-time curve (AUC), maximum concentration (Cmax) and time that drug concentration exceeds IC95 (T(>IC95)), was estimated using a logistic regression model, and model fitness was evaluated by calculation of the Akaike information criterion (AIC) index. The AIC indices of AUC, Cmax and T(>IC95) were about 114, 151 and 124, respectively. The AIC of AUC and T(>IC95) were smaller than that of Cmax. Therefore, both AUC and T(>IC95) were the PK parameters that correlated best with the antiviral activity of peramivir IV against influenza virus infection in mice.
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http://dx.doi.org/10.1016/j.antiviral.2014.06.016DOI Listing
September 2014

Relative refractoriness of left ventricular contraction underlies human tachycardia-induced mechanical and electrical alternans.

Pacing Clin Electrophysiol 2014 Feb 11;37(2):197-206. Epub 2013 Sep 11.

Department of Cardiovascular Biology and Medicine, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.

Background: Mechanical alternans (MA) and electrical alternans (EA) are predictors of cardiac events. Experimental studies have suggested that refractoriness of calcium cycling underlies these cardiac alternans. However, refractoriness of left ventricular contraction has not been examined in patients with cardiac alternans.

Methods: In 51 patients with miscellaneous heart diseases, incremental right atrial pacing was performed to induce MA and EA. MA was quantified by alternans amplitude (AA: the difference between left ventricular dP/dt of a strong beat and that of a weak beat), and AA at 100/min (AA100) and maximal AA (AAmax) were measured. EA was defined as alternation of T wave morphology in 12-lead electrocardiogram. Relative refractoriness of left ventricular contraction was examined by drawing the mechanical restitution curve under a basal coupling interval (BCL) of 600 ms (100/min) and was assessed by the slope at BCL (Δmechanical restitution). Postextrasystolic potentiation (PESP) was also examined and the slope of PESP curve (ΔPESP) was assessed as a property to alternate strong and weak beats.

Results: MA and EA were induced in 19 patients and in none at 100/min or less, and at any heart rate in 32 and in 10, respectively. AA100 and AAmax correlated positively with Δmechanical restitution and negatively with ΔPESP. Patients with EA had a significantly larger Δmechanical restitution and a significantly larger absolute value of ΔPESP than those without.

Conclusions: In patients with MA and EA, the left ventricular contractile force during tachycardia is under relative refractoriness and prone to cause large fluctuation of contractile force.
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http://dx.doi.org/10.1111/pace.12230DOI Listing
February 2014

The time course of paroxysmal atrial fibrillation and its implications: an analysis from a snapshot.

Int J Cardiol 2013 Oct 28;168(3):2867-8. Epub 2013 Apr 28.

Niigata University Graduate School of Medical and Dental Science, Niigata, Japan; Tachikawa Medical Center, Nagaoka, Japan. Electronic address:

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http://dx.doi.org/10.1016/j.ijcard.2013.03.146DOI Listing
October 2013

A mutant mRNA expression in an endomyocardial biopsy sample obtained from a patient with a cardiac variant of Fabry disease caused by a novel acceptor splice site mutation in the invariant AG of intron 5 of the α-galactosidase A gene.

Intern Med 2013 1;52(7):777-80. Epub 2013 Apr 1.

Department of Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences, Japan.

We herein describe the case of a 58-year-old man who presented with dilated-phase hypertrophic cardiomyopathy (HCM) and required an implantable cardioverter defibrillator implant. Subsequently, the patient was diagnosed with Fabry disease (FD), which was suspected based on the results of an endomyocardial biopsy and diagnosed following demonstration of deficient α-galactosidase A (GLA) activity. Molecular studies showed a novel point mutation in the 3' splice site consensus sequence of intron 5 in the gene encoding GLA that created a new splicing site, resulting in the expression of mutant mRNA. FD should be considered a cause of HCM in patients with severe tachyarrhythmia without other remarkable manifestations of FD.
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http://dx.doi.org/10.2169/internalmedicine.52.9213DOI Listing
January 2014

Efficacy of repeated intravenous injection of peramivir against influenza A (H1N1) 2009 virus infection in immunosuppressed mice.

Antimicrob Agents Chemother 2013 May 11;57(5):2286-94. Epub 2013 Mar 11.

Infectious Diseases, Medicinal Research Laboratories, Shionogi & Co, Ltd, Toyonaka, Osaka, Japan.

The efficacy of intravenous peramivir against influenza A (H1N1) 2009 virus infection was evaluated in mice in which the immune system was suppressed by cyclophosphamide (CP) treatment. The mortality rate of the vehicle control group was 100%, and the mice lost 20% of their body weight on average by day 13 postinfection (p.i.). Repeated administration of peramivir (40 mg/kg of body weight once a day, given intravenously for 20 days), starting at 1 h p.i., significantly reduced mortality, body weight loss, viral titers, and cytokine production in infected mice compared with results for administration of vehicle (P < 0.01). In addition, repeated administration of peramivir, starting at 24 h, 48 h, or 72 h p.i., also resulted in increases in survival rates and reduction of viral titers in the lungs (P < 0.01). The mean days to death (MDD) of the vehicle group was 14.5 days, while in the groups treated with peramivir starting at 24 h, 48 h, and 72 h p.i., the MDDs were >23.0, 20.9, and 21.8 days, respectively. In comparison, repeated administration of oseltamivir phosphate (5 mg/kg twice a day, given orally for 20 days), starting at 24 h, 48 h, and 72 h p.i., also significantly prevented body weight loss, whereas no significant differences in mortality rates and viral titers in the lungs were observed compared with results for the vehicle group. These data indicated that repeated administration of peramivir was effective in promoting the survival and reducing virus replication in immunosuppressed mice infected with influenza A (H1N1) 2009 virus.
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http://dx.doi.org/10.1128/AAC.02324-12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3632901PMC
May 2013

Acute heart failure syndrome associated with snow shoveling.

Int Heart J 2012 ;53(6):394-5

Division of Medical Education, Niigata University School of Medicine, Niigata, Japan.

There have been only a few reports regarding the relation between snow shoveling and acute heart failure syndromes (AHFS). We present a case series of 5 patients who presented with AHFS, all within 5 days after shoveling snow. Although all patients underwent examination at a regular out-patient clinic, no patient had prior signs or symptoms of heart failure. The condition of all patients had gradually deteriorated, with no abrupt onset of dyspnea after shoveling snow. Four of the 5 patients demonstrated a preserved ejection fraction on echocardiography. Snow shoveling may lead to AHFS in patients who are at risk for developing heart failure.
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http://dx.doi.org/10.1536/ihj.53.394DOI Listing
February 2013

Atrioventricular dissociation mimicking pulsus paradoxus and palsus alternans.

Intern Med 2012 15;51(24):3439-40. Epub 2012 Dec 15.

Division of Cardiology, Niigata University Graduate School of Medical and Dental Sciences, Japan.

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http://dx.doi.org/10.2169/internalmedicine.51.8832DOI Listing
May 2013

Estimation of paracrine signaling using quantitative RT-PCR from multiple patchy lesion samples.

Mol Cell Probes 2013 Apr 17;27(2):109-13. Epub 2012 Aug 17.

Division of Cardiology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.

We investigated whether correlations between mRNA levels of cytokines versus other proteins from patchy lesion could estimate cytokine paracrine signaling in vivo. Experiments with rat experimental autoimmune myocarditis (EAM), a patchy myocarditis model, indicated IL-1 and other protein levels were correlated, indicating paracrine signaling pathways in vivo.
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http://dx.doi.org/10.1016/j.mcp.2012.08.002DOI Listing
April 2013

Systemic transplantation of allogenic fetal membrane-derived mesenchymal stem cells suppresses Th1 and Th17 T cell responses in experimental autoimmune myocarditis.

J Mol Cell Cardiol 2012 Sep 13;53(3):420-8. Epub 2012 Jul 13.

Department of Regenerative Medicine and Tissue Engineering, National Cerebral and Cardiovascular Center, Osaka, Japan.

We have reported that systemic administration of autologous bone marrow or allogenic fetal membrane (FM)-derived mesenchymal stem cells (MSCs) similarly attenuated myocardial injury in rats with experimental autoimmune myocarditis (EAM). Since rat EAM is a T-helper (Th) cell-mediated autoimmune disease, and recent evidence has indicated that both autologous and allogenic MSCs exert an immunosuppressive effect on Th cell activity, we focused on Th cell differentiation in allogenic FM-MSC administered EAM rats. EAM was induced in Lewis rats by injecting porcine cardiac myosin (day 0). Allogenic FM-MSCs, obtained from major histocompatibility complex mismatched ACI rats, were intravenously injected (5 × 10(5)cells/rat) on days 7, 10, or 14 (MSCd7, MSCd10, or MSCd14 groups, respectively). At day 21, echocardiography confirmed that reduced ejection fraction in the untreated EAM group (63 ± 2%) was significantly improved in the MSCd10 and MSCd14 groups (74 ± 1 and 75 ± 2%, respectively, P<0.01). CD68 immunostaining revealed that prominent macrophage infiltration in the myocardium of the EAM group (1466 ± 93 cells/mm(2)) was significantly decreased in the MSCd10 group (958 ± 139 cells/mm(2), P<0.05). To evaluate Th cell differentiation, we used flow cytometry to determine the percentage of interferon (IFN)-γ positive Th1 and interleukin (IL)-17 positive Th17 cells in peripheral CD4-positive Th cells. The percentage of Th1 cells at day 16 was significantly lower in the MSCd10 (1.3 ± 0.2%) and MSCd14 (1.6 ± 0.3%) groups compared to the EAM group (2.4 ± 0.3%, P<0.05), as was the percentage of Th17 cells in the MSCd10 group (1.9 ± 0.5%) compared to the EAM group (2.2 ± 0.9%, P<0.05). At day 21, infiltrating Th17 cells in myocardium were significantly decreased in the MSCd10 group (501 ± 132 cells/mm(2), P<0.05) compared to EAM (921 ± 109 cells/mm(2)). In addition, human CD4+ Th cells co-cultured with human FM-MSCs exhibited reduced Th1 and Th17 cell-differentiation and proliferation, with increased expression of immunosuppressive molecules including indoleamine 2,3-dioxygenase 2 and IL-6 in co-cultured FM-MSCs. These results suggest that intravenous administration of allogenic FM-MSCs ameliorates EAM via the suppression of Th1/Th17 immunity.
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http://dx.doi.org/10.1016/j.yjmcc.2012.06.020DOI Listing
September 2012

Mechanical alternans in human idiopathic dilated cardiomyopathy is caused with impaired force-frequency relationship and enhanced poststimulation potentiation.

Heart Vessels 2013 May 10;28(3):336-44. Epub 2012 May 10.

Division of Cardiology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi, Niigata, 951-8510, Japan.

Mechanical alternans (MA) is frequently observed in patients with heart failure, and is a predictor of cardiac events. However, there have been controversies regarding the conditions and mechanisms of MA. To clarify heart rate-dependent contractile properties related to MA, we performed incremental right atrial pacing in 17 idiopathic dilated cardiomyopathy (DCM) patients and in six control patients. The maximal increase in left ventricular dP/dt during pacing-induced tachycardia was assessed as the force gain in the force-frequency relationship (FG-FFR), and the maximal increase in left ventricular dP/dt of the first post-pacing beats was examined as the force gain in poststimulation potentiation (FG-PSP). As a result, MA was induced in 9 DCM patients (DCM MA(+)) but not in the other 8 DCM patients (DCM MA(-)), and not in any of the control patients. DCM MA(+) had significantly lower FG-FFR (34.7 ± 40.9 vs 159.4 ± 103.9 mmHg/s, P = 0.0091) and higher FG-PSP (500.0 ± 96.8 vs 321.9 ± 94.9 mmHg/s, P = 0.0017), and accordingly a wider gap between FG-PSP and FG-FFR (465.3 ± 119.4 vs 162.5 ± 123.6 mmHg/s, P = 0.0001) than DCM MA(-) patients. These characteristics of DCM MA(+) showed clear contrasts to those of the control patients. In conclusion, MA is caused with an impaired force-frequency relationship despite significant poststimulation potentiation, suggesting that MA reflects ineffective utilization of the potentiated intrinsic force during tachycardia.
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http://dx.doi.org/10.1007/s00380-012-0251-8DOI Listing
May 2013

Involvement of AMPK and MAPK signaling during the progression of experimental autoimmune myocarditis in rats and its blockade using a novel antioxidant.

Exp Mol Pathol 2012 Oct 18;93(2):183-9. Epub 2012 Apr 18.

Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata City 956-8603, Japan.

There are various reports suggesting the role of angiotensin (Ang) receptor blockers, Ang converting enzyme inhibitors, calcium channel blockers, diuretics and antioxidants against the progression of experimental autoimmune myocarditis (EAM) to dilated cardiomyopathy (DCM). Most of them were reported to be effective during this adverse cardiac remodeling. Recently much attention has been paid to studying the involvement of AMP-activated protein kinase (AMPK) and mitogen activated protein kinase (MAPK) in various cardiovascular ailments. AMPK acts as a master sensor of cellular energy balance via maintenance of lipid and glucose metabolism. Evidences also suggest the relation between AMPK and oxidative stress during physiological and pathological myocardial cellular function. Since, it is of interest to identify the roles of AMPK and MAPK during the progression of EAM to DCM and also the effect of edaravone, a novel free radical scavenger, against its progression. For this, we have carried out western blotting, histopathological staining and immunohistochemical analyses to measure the myocardial expressions of AMPK signaling and oxidative stress related parameters in normal and vehicle or edaravone-treated EAM rats, respectively. We identified the myocardial levels of phospho Akt and phosphoinositide 3-kinase, which are the upstream proteins of AMPK and MAPK activation and both were up-regulated in the vehicle-treated rats, whereas candesartan treatment significantly reversed these changes. We have also measured the myocardial levels of p-AMPKα, different isoforms of protein kinase C and MAPK signaling proteins. All of these protein levels were significantly elevated in the hearts of DCM rats whereas edaravone treatment significantly reversed these changes. In viewing these results, we can suggest that along with MAPK, AMPK signaling also plays a crucial role in the progression of EAM and it can be effectively blocked by the treatment with a novel antioxidant, edaravone.
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http://dx.doi.org/10.1016/j.yexmp.2012.04.012DOI Listing
October 2012

Olmesartan medoxomil treatment potently improves cardiac myosin-induced dilated cardiomyopathy via the modulation of ACE-2 and ANG 1-7 mas receptor.

Free Radic Res 2012 Jul 14;46(7):850-60. Epub 2012 May 14.

Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata, Japan.

Angiotensin converting enzyme-2 (ACE-2) is a monocarboxypeptidase that metabolises angiotensin (ANG)-II into angiotensin 1-7 (ANG 1-7), thereby functioning as a negative regulator of the renin-angiotensin system. We investigated whether treatment with ANG-II type 1 receptor blocker, olmesartan medoxomil is associated with the attenuation of cardiac myosin-induced dilated cardiomyopathy (DCM) through recently established new axis of ACE-2/ANG 1-7 mas receptor. DCM was elicited in Lewis rats by immunisation with cardiac myosin, and 28 days after immunisation, the surviving Lewis rats were divided into two groups and treated with either olmesartan medoxomil (10 mg/kg/day) or vehicle. Myocardial protein and mRNA levels of ACE-2, ANG 1-7 mas receptor were upregulated in the olmesartan-treated group compared with those of vehicle-treated DCM rats. In contrast, Olmesartan treatment effectively suppressed the myocardial protein and mRNA expressions of inflammatory markers in comparison to the vehicle-treated DCM rats. Olmesartan treatment significantly reduced fibrosis, hypertrophy and their marker molecules (OPN, CTGF, ANP and GATA-4, respectively), as well as matrix metalloproteinases compared with those of vehicle-treated DCM rats. Enhanced myocardial protein levels of phospho-p38 MAPK, phospho-JNK and phospho MAPKAPK-2 in the vehicle-treated DCM rats were prevented by olmesartan treatment. In addition, olmesartan treatment significantly lowered the protein expressions (Nitrotyrosine, p47phox and p67phox) and superoxide radical production compared with those of vehicle-treated DCM rats. Our present study might serve as a new therapeutic target of DCM in cardiovascular diseases and cardiac myosin-induced DCM via the modulation of ACE-2/ANG 1-7 mas receptor axis in rats with DCM after myosin-immunisation.
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http://dx.doi.org/10.3109/10715762.2012.684878DOI Listing
July 2012

Modulation of endoplasmic reticulum stress and cardiomyocyte apoptosis by mulberry leaf diet in experimental autoimmune myocarditis rats.

J Clin Biochem Nutr 2012 Mar 18;50(2):139-44. Epub 2011 Nov 18.

Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, 265-1 Higashizima, Akiha-ku, Niigata 956-8603, Japan.

Mulberry is commonly used as silkworm diet and an alternative medicine in Japan and China, has recently reported to contain many antioxidative flavanoid compounds and having the free radical scavenging effects. Antioxidants reduce cardiac oxidative stress and attenuate cardiac dysfunction in animals with pacing-induced congestive heart failure. Hence we investigated the cardioprotective effect of mulberry leaf powder in rats with experimental autoimmune myocarditis. Eight-week-old Lewis rats immunized with cardiac myosin were fed with either normal chow or a diet containing 5% mulberry leaf powder and were examined on day 21. ML significantly decreased oxidative stress, myocyte apoptosis, cellular infiltration, cardiac fibrosis, mast cell density, myocardial levels of sarco/endo-plasmic reticulum Ca(2+) ATPase2, p22(phox), receptor for advanced glycation end products, phospho-p38 mitogen activated protein kinase, phospho-c-Jun NH(2)-terminal protein kinase, glucose regulated protein78, caspase12 and osteopontin levels in EAM rats. These results may suggest that mulberry diet can preserve the cardiac function in experimental autoimmune myocarditis by modulating oxidative stress induced MAPK activation and further afford protection against endoplasmic reticulum stress mediated apoptosis.
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http://dx.doi.org/10.3164/jcbn.11-44DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3303476PMC
March 2012

Beneficial effects of edaravone, a novel antioxidant, in rats with dilated cardiomyopathy.

J Cell Mol Med 2012 Sep;16(9):2176-85

Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata City, Japan.

Edaravone, a novel antioxidant, acts by trapping hydroxyl radicals, quenching active oxygen and so on. Its cardioprotective activity against experimental autoimmune myocarditis (EAM) was reported. Nevertheless, it remains to be determined whether edaravone protects against cardiac remodelling in dilated cardiomyopathy (DCM). The present study was undertaken to assess whether edaravone attenuates myocardial fibrosis, and examine the effect of edaravone on cardiac function in rats with DCM after EAM. Rat model of EAM was prepared by injection with porcine cardiac myosin 28 days after immunization, we administered edaravone intraperitoneally at 3 and 10 mg/kg/day to rats for 28 days. The results were compared with vehicle-treated rats with DCM. Cardiac function, by haemodynamic and echocardiographic study and histopathology were performed. Left ventricular (LV) expression of NADPH oxidase subunits (p47(phox), p67(phox), gp91(phox) and Nox4), fibrosis markers (TGF-β(1) and OPN), endoplasmic reticulum (ER) stress markers (GRP78 and GADD 153) and apoptosis markers (cytochrome C and caspase-3) were measured by Western blotting. Edaravone-treated DCM rats showed better cardiac function compared with those of the vehicle-treated rats. In addition, LV expressions of NADPH oxidase subunits levels were significantly down-regulated in edaravone-treated rats. Furthermore, the number of collagen-III positive cells in the myocardium of edaravone-treated rats was lower compared with those of the vehicle-treated rats. Our results suggest that edaravone ameliorated the progression of DCM by modulating oxidative and ER stress-mediated myocardial apoptosis and fibrosis.
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http://dx.doi.org/10.1111/j.1582-4934.2012.01526.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3822987PMC
September 2012

Telmisartan acts through the modulation of ACE-2/ANG 1-7/mas receptor in rats with dilated cardiomyopathy induced by experimental autoimmune myocarditis.

Life Sci 2012 Feb 19;90(7-8):289-300. Epub 2011 Dec 19.

Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata, Japan.

Aim: Recent findings have suggested that a therapeutic approach to amplify or stimulate the angiotensin-converting enzyme-2 [ACE-2]-angiotensin 1-7 [ANG 1-7] mas axis could provide protection against the development of cardiovascular diseases. We investigated the cardioprotective effects of telmisartan in rats with dilated cardiomyopathy [DCM] after experimental autoimmune myocarditis [EAM].

Main Methods: DCM was elicited in Lewis rats by immunization with cardiac myosin, and twenty-eight days after immunization, the surviving Lewis rats were divided into two groups and treated with either telmisartan (10mg/kg/day) or vehicle.

Key Findings: Telmisartan treatment effectively suppressed myocardial protein and mRNA expressions of inflammatory markers [CD68, iNOS, NF-kB, interleukin-1β, interferon-γ, monocyte chemotactic protein-1] in comparison to vehicle-treated rats. In contrast, myocardial protein levels of ACE-2 and ANG 1-7 mas receptor were upregulated in the telmisartan-treated group compared with vehicle-treated rats. Telmisartan treatment significantly reduced fibrosis and hypertrophy and their marker molecules [OPN, CTGF, TGF-β1 and collagens I and III and atrial natriuretic peptide and GATA-4, respectively] compared with those of vehicle-treated rats. In addition, telmisartan treatment significantly lowered the protein expressions of NADPH oxidase subunits p47phox, p67phox, and superoxide production when compared with vehicle-treated rats. Telmisartan treatment significantly decreased the expression levels of mitogen-activated protein kinase (MAPK) signaling molecules than with those of vehicle-treated rats. Also, telmisartan treatment significantly improved LV systolic and diastolic function.

Significance: These results indicate that telmisartan treatment significantly improved LV function and ameliorated the progression of cardiac remodeling through the modulation of ACE-2/ANG 1-7/Mas receptor axis in rats with DCM after EAM.
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http://dx.doi.org/10.1016/j.lfs.2011.11.018DOI Listing
February 2012

Olmesartan attenuates the development of heart failure after experimental autoimmune myocarditis in rats through the modulation of ANG 1-7 mas receptor.

Mol Cell Endocrinol 2012 Apr 19;351(2):208-19. Epub 2011 Dec 19.

Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata, Japan.

Angiotensin-converting enzyme 2 (ACE-2) is a membrane-associated carboxy-peptidase catalyzes the conversion of the vasoconstrictor angiotensin (ANG)-II to the vasodilatory peptide ANG 1-7. In view of the expanding axis of the renin angiotensin system, we have investigated the cardioprotective effects of olmesartan (10mg/kg/day) in experimental autoimmune myocarditis. Olmesartan treatment effectively suppressed the myocardial protein expressions of inflammatory markers in comparison to the vehicle-treated rats. However, the protein and mRNA levels of ACE-2 and ANG 1-7, and its receptor Mas were upregulated in olmesartan treated group compared to vehicle-treated rats. Olmesartan medoxomil treatment significantly decreased the expression levels of phospho-p38 mitogen-activated protein kinase (MAPK), phospho-JNK, phospho-ERK and phospho-(MAPK) activated protein kinase-2 than with those of vehicle-treated rats. Moreover, vehicle-treated rats were shown to be up-regulated protein expressions of NADPH oxidase subunits (p47phox, p67phox and Nox-4), myocardial apoptotic markers and endoplasmic reticulum stress markers in comparison to those of normal and all these effects are expectedly down-regulated by an olmesartan. In addition, attenuated protein levels of phosphatidylinositol-3-kinase (PI3K) and phospho-Akt in the vehicle-treated EAM rats were prevented by olmesartan treatment. Our results suggest that beneficial effects of olmesartan treatment was more effective therapy in combating the inflammation, oxidative stress, apoptosis and signaling pathways associated with heart failure at least in part via the modulation of ANG 1-7 mas receptor.
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http://dx.doi.org/10.1016/j.mce.2011.12.010DOI Listing
April 2012

Lymph nodes harbor viral reservoirs that cause rebound of plasma viremia in SIV-infected macaques upon cessation of combined antiretroviral therapy.

Virology 2012 Feb 21;423(2):107-18. Epub 2011 Dec 21.

Laboratory of Primate Model, Experimental Research Center for Infectious Diseases, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan.

Attempts to find a cure for HIV infection are hindered by the presence of viral reservoirs that resist highly active antiretroviral therapy. To identify the properties of these reservoirs, four SIV239-infected Rhesus macaques were treated with combined antiretroviral therapy (cART) for 1 year. While plasma viral RNA (vRNA) was effectively suppressed, a systemic analysis revealed that vRNA was distributed in the following order: lymphatic tissues>lungs and intestine>other tissues. Histochemistry yielded no cells with viral signals. To increase the chance of detection, two additional SIV-infected animals were treated and analyzed on Day 10 after the cessation of cART. These animals exhibited similar vRNA distribution patterns to the former animals, and immunohistochemistry revealed Nef-positive T lymphocytes predominantly in the follicles of mesenteric lymph nodes (MLNs). These data suggest that lymphatic tissues, including MLNs, contain major cellular reservoirs that cause rebound of plasma viremia upon cessation of therapy.
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http://dx.doi.org/10.1016/j.virol.2011.11.024DOI Listing
February 2012