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Yoshinaga M.,National Hospital Organization Kagoshima Medical Center | Kucho Y.,National Hospital Organization Kagoshima Medical Center | Sarantuya J.,Ulaanbaatar University | Ninomiya Y.,National Hospital Organization Kagoshima Medical Center | And 4 more authors.
Circulation: Arrhythmia and Electrophysiology | Year: 2014

Background-A school-based electrocardiographic screening program has been developed in Japan. However, few data are available on the genetic characteristics of pediatric patients with long-QT syndrome who were diagnosed by this program. Methods and Results-A total of 117 unrelated probands aged =18 years were the subjects who were referred to our centers for genetic testing. Of these, 69 subjects diagnosed by the program formed the screened group. A total of 48 subjects were included in the clinical group and were diagnosed with long-QT syndrome-related symptoms, familial study, or by chance. Mutations were classified as radical, of high probability of pathogenicity, or of uncertain significance. Two subjects in the clinical group died. Genotypes were identified in 50 (72%) and 23 (48%) of subjects in the screened and clinical groups, respectively. Of the KCNQ1 or KCNH2 mutations, 31 of 33 (94%) in the screened group and 15 of 16 (94%) in the clinical group were radical and of high probability of pathogenicity. Prevalence of symptoms before (9/69 versus 31/48; P<0.0001) and after (12/69 versus 17/48; P=0.03) diagnosis was significantly lower in the screened group when compared with that in the clinical group although the QTc values, family history of long-QT syndrome, sudden death, and follow-up periods were not different between the groups. Conclusions-These data suggest that the screening program may be effective for early diagnosis of long-QT syndrome that may allow intervention before symptoms. In addition, screened patients should have follow-up equivalent to clinically identified patients. © 2013 American Heart Association, Inc.


Horigome H.,University of Tsukuba | Ishikawa Y.,Toyohashi University of Technology | Shiono J.,Ibaraki Childrens Hospital | Iwamoto M.,Yokohama City University | And 2 more authors.
Circulation: Arrhythmia and Electrophysiology | Year: 2011

Background-The main ECG criteria for the diagnosis of long-QT syndrome (LQTS) include abnormal T-wave morphology as well as prolonged QT interval. The T wave in LQTS probably includes additional components of the myocardial repolarization process, which are derived from aberrant ion currents. We investigated whether independent component analysis (ICA) can extract such abnormal repolarization components. Methods and Results-Digital ECG data were obtained as a time series from 10 channels using 20 surface electrodes in 22 patients with genetically confirmed LQTS type 1 (LQT1) and 30 normal subjects. In each case, T-wave area was analyzed by radical ICA after noise reduction by the wavelet thresholding method. Furthermore, inverse ICA was applied to determine the origin of each independent component (IC). Radical ICA revealed that a T-wave consisted of 4 basic ICs in all control subjects, whereas ≥5 (mostly 6) ICs were identified in all 22 patients with LQT1. The extra ICs, which were not evident in normal subjects, were assumed to contribute to the formation of abnormal T-wave morphology. The extra ICs were identified even in patients with normal QTc values and in those taking β-blockers. Inverse ICA indicated that the additional ICs originate predominantly from the late phase of the T wave of the left ventricle. Conclusions-Extra ICs appear during repolarization in all patients with LQT1 but not in normal subjects. ICA is a potentially useful multivariate statistical method to differentiate patients with LQT1 from normal subjects. © 2011 American Heart Association, Inc.


Murakami T.,Chiba Cardiovascular Center | Niwa K.,Chiba Cardiovascular Center | Yoshinaga M.,National Hospital Organization Kagoshima Medical Center | Nakazawa M.,Southern Tohoku General Hospital
International Journal of Cardiology | Year: 2012

Background: Despite the recent progress of cardiac surgery, the indications for surgical intervention during the active phase of infective endocarditis have not yet been established in patients with congenital heart diseases due to the limited number of such patients. The present study aims to determine the surgical indications for active infective endocarditis in congenital heart diseases. Methods: A retrospective observational cohort multi-center study on infective endocarditis with congenital heart diseases was conducted from January 1997 to December 2001 in Japan and 239 patients were registered. Sixty-one (26%) of the 239 patients had undergone surgical therapy for active infective endocarditis, which was defined as cardiac surgery during administration of intravenous antibiotics. Results: There were 7 deaths (11%). A univariate regression analysis revealed that the factors significantly associated with the need for surgical intervention for active IE were the lack of diagnosis of cardiac disorders before the onset of infective endocarditis, aortic valve infective endocarditis, perivalvular abscess, presence of heart failure, and change of antibiotics. A stepwise logistic regression analysis revealed that the presence of a perivalvular abscess, heart failure and a change in the antibiotics were independent determinant factors for the need for surgical treatment of active infective endocarditis in patients with congenital heart diseases. Conclusions: Surgery should therefore be considered even during the active phase in patients with congenital heart diseases and infective endocarditis, when they develop associated with heart failure, a perivalvular abscess, or the need for a change in antibiotics. © 2010 Elsevier Ireland Ltd. All rights reserved.


Komori M.,Clinical Research Institute | Yasaka M.,Clinical Research Institute | Kokuba K.,Clinical Research Institute | Matsuoka H.,National Hospital Organization Kagoshima Medical Center | And 8 more authors.
Circulation Journal | Year: 2014

Background: The incidence of intracranial bleeding during dabigatran treatment is lower than that during warfarin treatment. The characteristics of intracranial hemorrhage during dabigatran therapy, however, remain unclear. Methods and Results: The clinical data and treatment summaries of 9 intracranial bleeds that developed during dabigatran treatment in 8 patients with non-valvular atrial fibrillation were retrospectively reviewed. Five patients had small-moderate subdural hematomas, 2 had intracerebral hemorrhage and 1 had traumatic subarachnoid and parenchymal hemorrhage associated with cerebral contusion. Activated partial thromboplastin time upon admission ranged from 31.6 to 72.4 s. After admission, systolic blood pressure in the 2 patients with intracerebral hemorrhage was maintained below 140 mmHg, and the subdural hematomas in 4 patients were surgically treated. None of the hematomas became enlarged and outcome was good in most cases. Conclusions: Hematomas that arise due to acute intracranial bleeding during dabigatran treatment seem to remain small to moderate, hard to expand, and manageable.


Nakajo M.,Kagoshima University | Nakajo M.,Nanpuh Hospital | Jinguji M.,Nanpuh Hospital | Tani A.,National Hospital Organization Kagoshima Medical Center | And 5 more authors.
Radiology | Year: 2013

Purpose: To compare positron emission tomography (PET)/computed tomography (CT) studies performed with the glucose analog fluorine 18 (18F) fluorodeoxyglucose (FDG) and the cell proliferation tracer 18F fluorothymidine (FLT) in the diagnosis of metastases from postoperative differentiated thyroid cancer. Materials and Methods: The institutional ethics review board approved this prospective study. From March 2010 to February 2012, 20 patients (mean age, 53 years; age range, 22-79 years) with postoperative differentiated thyroid cancer underwent both FDG and FLT PET/CT as a staging work-up before radioiodine therapy. In each patient, 28 anatomic areas were set and analyzed for lymph node and distant metastases. The McNemar exact or χ2 test was used to examine differences in diagnostic indexes in the detection of lymph node and distant metastases between both tracer PET/CT studies. Results: There were 34 lymph node metastases and/or 73 distant metastases (70 metastases in lung and one each in bone, nasopharynx, and brain) in 13 patients. At patient-based analysis, the sensitivity, specificity, and accuracy were 92% (12 of 13 patients), 86% (six of seven patients), and 90% (18 of 20 patients), respectively, for FDG PET/CT and 69% (nine of 13 patients), 29% (two of seven patients), and 55% (11 of 20 patients) for FLT PET/CT. The accuracy of FDG PET/CT was significantly better than that of FLT PET/CT (P = .023). At lesion-based analysis, the sensitivity, specificity, and accuracy for diagnosing lymph node metastases were 85% (29 of 34 lesions), 99.6% (245 of 246 lesions), and 97.9% (274 of 280 lesions), respectively, for FDG PET/CT and 50% (17 of 34 lesions), 90.7% (223 of 246 lesions), and 85.7% (240 of 280 lesions) for FLT PET/CT. The sensitivity, specificity, and accuracy for diagnosing distant metastases were 45% (33 of 73 lesions), 100% (207 of 207 lesions), and 85.7% (240 of 280 lesions), respectively, for FDG PET/CT and 6.8% (five of 73 lesions), 100% (207 of 207 lesions), and 75.7% (212 of 280 lesions) for FLT PET/CT. The sensitivity (P = .002), specificity (P < .001), and accuracy (P < .001) of FDG PET/CT in the diagnosis of lymph node metastases were superior to those of FLT PET, as were the sensitivity (P < .001) and accuracy (P < .001) in the diagnosis of distant metastases. Conclusion: FDG PET/CT is superior to FLT PET/CT in the diagnosis of postoperative differentiated thyroid cancer lymph node and distant metastases. Thus, FDG PET/CT is more suitable than FLT PET/CT for examining recurrence of postoperative differentiated thyroid cancer. © RSNA, 2013.


Tokito A.,National Hospital Organization Kagoshima Medical Center | Jougasaki M.,National Hospital Organization Kagoshima Medical Center | Ichiki T.,National Hospital Organization Kagoshima Medical Center | Ichiki T.,Cardiorenal Research Laboratory | Hamasaki S.,Kagoshima University
PLoS ONE | Year: 2013

Rupture of an atherosclerotic plaque is a key event in the development of cardiovascular disorders, in which matrix metalloproteinase-1 (MMP-1) plays a crucial role by degradation of extracellular matrix resulting in plaque instability. Cardiotrophin-1 (CT-1), a member of interleukin-6-type proinflammatory cytokines, has potent cardiovascular actions and is highly expressed in vascular endothelium, however its role in atherosclerosis has not been fully elucidated to date. The present study was designed to investigate whether CT-1 induces MMP-1 in human aortic endothelial cells (HAECs). Ribonuclease protection assay demonstrated that MMP-1 gene level in HAECs was enhanced by the treatment of CT-1 in a dose- and time-dependent manner. Immunocytochemical staining, Western immunoblot analysis and enzyme-linked immunosorbent assay revealed that CT-1 augmented MMP-1 protein synthesis and secretion. MMP-1 activity assay revealed that MMP-1 present in the supernatant of HAECs was exclusively precursor form. Casein zymography disclosed proteolytic activity in the supernatant of HAECs, which was enhanced by CT-1 treatment. Furthermore, pharmacological inhibitor study indicated the important roles of extracellular signal-regulated kinase (ERK) 1/2, p38 mitogen-activated protein (MAP) kinase, c-Jun N-terminal kinase (JNK) and Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathways in mediating CT-1-induced MMP-1 gene and protein expression. These data reveal for the first time that CT-1 induces the proteolytic potential in HAECs by upregulating MMP-1 expression through ERK1/2, p38 MAP kinase, JNK and JAK/STAT pathways, and suggest that CT-1 may play an important role in the pathophysiology of atherosclerosis and plaque instability. © 2013 Tokito et al.


PubMed | National Hospital Organization Kagoshima Medical Center and Kagoshima University
Type: | Journal: The neuroradiology journal | Year: 2017

We present three cases of anomalous origin of the left vertebral artery (LVA) detected during the evaluation of stroke. The VA usually enters the transverse foramen of the sixth cervical vertebra (C6), but an anomalous LVA originating from the aorta frequently enters at a higher level. In our series, ultrasound of the LVA showed entry at C4 in two patients and at C5 in one patient. These findings suggested anomalous LVA origin, and three-dimensional computed tomography demonstrated the LVA arising from the aorta proximal to the left subclavian arteries. Carotid duplex ultrasound is useful for the diagnosis of this anomaly.


Otsuka M.,National Hospital Organization Kagoshima Medical Center | Hanada S.,National Hospital Organization Kagoshima Medical Center | Arita K.,National Hospital Organization Nagoya Medical Center | Ohashi H.,National Hospital Organization Nagoya Medical Center
International Journal of Hematology | Year: 2014

Essential thrombocythemia (ET) is a subtype of myeloproliferative neoplasms. Approximately half of the patients with ET harbor a gain-of-function mutation in the JAK2 gene (JAK2-V617F), a small percentage have mutations in codon 515 of MPL (thrombopoietin receptor) gene, and the rest have neither mutation. Pregnancy is a rare complication of ET, and it has been reported that the number of blood platelets falls with pregnancy in ET patients and the number of blood platelets increases again after a delivery and this phenomenon is observed in JAK2-V617F-positive and JAK2-V617F-negative patients. We report the first case of an ET patient with MPL mutations, whose platelet count improved with the onset of menopause, not pregnancy, and the MPL mutation also simultaneously disappeared. © 2014 The Japanese Society of Hematology.


Tokito A.,National Hospital Organization Kagoshima Medical Center | Jougasaki M.,National Hospital Organization Kagoshima Medical Center
International Journal of Molecular Sciences | Year: 2016

The matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases belonging to the metzincin superfamily. There are at least 23 members of MMPs ever reported in human, and they and their substrates are widely expressed in many tissues. Recent growing evidence has established that MMP not only can degrade a variety of components of extracellular matrix, but also can cleave and activate various non-matrix proteins, including cytokines, chemokines and growth factors, contributing to both physiological and pathological processes. In normal conditions, MMP expression and activity are tightly regulated via interactions between their activators and inhibitors. Imbalance among these factors, however, results in dysregulated MMP activity, which causes tissue destruction and functional alteration or local inflammation, leading to the development of diverse diseases, such as cardiovascular disease, arthritis, neurodegenerative disease, as well as cancer. This article focuses on the accumulated evidence supporting a wide range of roles of MMPs in various non-neoplastic diseases and provides an outlook on the therapeutic potential of inhibiting MMP action. © 2016 by the authors; licensee MDPI, Basel, Switzerland.


Otsuka A.,University of Zürich | Dreier J.,University of Zürich | Cheng P.F.,University of Zürich | Nageli M.,University of Zürich | And 7 more authors.
Clinical Cancer Research | Year: 2015

Purpose: Basal cell carcinomas (BCCs) are tumors ignored by immune surveillance. Activated Hedgehog (Hh) signaling within primary cilia is a key driver in the pathogenesis of BCCs. We examined immune alterations during treatment with systemic Hh inhibitors. Experimental Design: We investigated biopsies from patients with BCC before (23 patients) and after 4 weeks of treatment (5 patients) with Hh signaling inhibitor. Ber-Ep4, BCL-2, Ki-67, CD4, CD8, MHC class I, HLA-DR-class II, and SOX9 were analyzed by immunohistochemistry. Primary cilia were analyzed by double immunofluorescence of acetylated tubulin and SOX9. Differential gene expression for 84 cytokines and chemokines was analyzed in 3 patients. Results: After 4 weeks of treatment, we found reduction of Ki-67, SOX9, Ber-EP4, and BCL-2 expression in tumors associated with morphologic signs of squamous differentiation. In addition, the number of cilia-positive BCC cells was significantly decreased. An upregulation of MHC I expression on the cell membranes of residual tumor cells and an influx of CD4+, HLA-DR-class II+, and CD8+ cells with invasion into the tumor cell nests were found. Finally, qPCR arrays showed the differential expression of genes involved in modulating immune responses. Conclusions: We show that Hh pathway inhibitor-induced tumor regression is accompanied by a dynamic change of the microenvironment with a disruption of immune privilege involving an influx of cytotoxic T cells, activation of the adaptive immune functions, and a profound alteration of the local chemokine/cytokine network. ©2015 American Association for Cancer Research.

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