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The aim of the study was to elucidate the aggressive reduction of both low-density lipoprotein cholesterol (LDL-C) and blood pressure (BP) reduced coronary atherosclerotic plaque volume compared with a standard treatment of LDL-C and BP in Japanese patients with coronary artery disease (CAD). This study is a prospective, randomized, and open-labelled with a blind-endpoint evaluation study. A total of 97 patients (81 men, mean age 62.09.6) with CAD undergoing intravascular ultrasonography (IVUS)-guided percutaneous coronary intervention (PCI) were randomized, and 68 patients had IVUS examinations at baseline and at 18-24months follow-up. Patients were randomly assigned to standard or aggressive strategies targeting LDL-C and a BP of 100mg/dL and 140/90mmHg vs. 70mg/dL and 120/70mmHg, respectively. The primary endpoint was the percent change in coronary plaque volume. Both standard and aggressive strategies succeeded to achieve target levels of LDL-C and BP; 74.914.7 vs. 63.711.9mg/dL (NS) and 124.19.4/75.87.7 vs. 113.69.6/65.89.4mmHg (systolic BP; NS, diastolic BP; p<0.05), respectively. Both groups showed a significant reduction in the coronary plaque volume of -9.410.7% and -8.78.6% (NS) in standard and aggressive therapies, respectively. Both standard and aggressive intervention significantly regressed coronary plaque volume by the same degree, suggesting the importance of simultaneous reductions of LDL-C and BP for prevention of CAD.

PubMed | Komatsu Municipal Hospital, Wakayama Medical University, Tokyo Metropolitan Childrens Medical Center and Kobe University
Type: | Journal: Clinical and experimental nephrology | Year: 2016

X-linked Alport syndrome (XLAS) is a progressive, hereditary nephropathy. Although males with XLAS usually develop end-stage renal disease before 30years of age, some men show a milder phenotype and possess somatic mosaic variants of the type IV collagen 5 gene (COL4A5), with severity depending on variant frequencies. In females, somatic mosaic variants are rarely reported in XLAS, and it is not clear what determines severity.Two females with somatic mosaic mutations in COL4A5 with variant frequencies of 17.9 and 22.1% were detected using the next-generation sequencing. One patient only had hematuria. The other, however, had moderate proteinuria, which is a severe phenotype for a female XLAS patient of her age. The molecular mechanisms for the severe phenotype were investigated by examining variant frequencies in urinary sediment cells and X chromosome inactivation patterns, and by looking for modifier variants in podocyte-related genes using the next-generation sequencing.The severe phenotype patient had a variant frequency of 36.6% in urinary sediment cells, which is not markedly high, nor did she show skewed X chromosome inactivation. However, she did have the heterozygous variant in COL4A3, which can affect severity.Factors determining severity in female XLAS patients remain unclear. One studied patient with the somatic variant in COL4A5 showed a severe phenotype without skewed X chromosome inactivation, which might be derived from digenic variants in COL4A3 and COL4A5. Further studies are required to determine molecular mechanisms behind female XLAS resulting in the severe phenotype.

PubMed | Saitama Prefectural Cardiovascular and Respiratory Center, Saga University, The Mutual, Komatsu Municipal Hospital and 4 more.
Type: Journal Article | Journal: Respiratory investigation | Year: 2015

Pleuroparenchymal fibroelastosis (PPFE) is a rare idiopathic interstitial pneumonia defined by pleural and subpleural parenchymal fibrosis predominantly in the upper lobes. Although the radiological and pathological characteristics of PPFE have become increasingly recognized, its pulmonary physiological features are not well understood.We reviewed nine patients with radiologically and histologically proven PPFE, and evaluated pulmonary physiological data.Of the nine patients, six were male and three were female. The median age at presentation was 61 years. Common symptoms were dyspnea on exertion, weight loss, and nonproductive cough. Recurrent pneumothorax was found in eight patients and pneumonia in four. Median pulmonary function test results were as follows: forced vital capacity, 55.4% predicted; total lung capacity (TLC), 67.1% predicted; residual volume (RV), 102.3% predicted; and RV/TLC, 143.6% predicted. RV/TLC was increased without evidence of small airway disease according to clinico-radiologic-pathologic evaluation. The median partial pressure of oxygen in arterial blood and the alveolar-arterial gradient of oxygen were within normal limits, although there was a slightly elevated partial pressure of carbon dioxide in arterial blood (PaCO2). PPFE progressed in all patients despite treatment with pirfenidone, corticosteroids, and immunosuppressive agents. Seven patients died during the follow-up, five because of hypercapnic respiratory failure.PPFE is characterized by severe mechanical restriction with high RV/TLC, causing increased PaCO2 and eventual hypercapnic respiratory failure. These physiological findings may be useful as an adjunct in the diagnosis of PPFE.

Tanaka Y.,Kanazawa University | Tanaka Y.,Tsuruga Municipal Hospital | Nishi T.,Kanazawa University | Takase K.,Kanazawa University | And 5 more authors.
Circulation | Year: 2014

Background - : Dispatcher-assisted cardiopulmonary resuscitation (DA-CPR) attempts to improve the management of out-of-hospital cardiac arrest by laypersons who are unable to recognize cardiac arrest and are unfamiliar with CPR. Therefore, we investigated the sensitivity and specificity of our new DA-CPR protocol for achieving implementation of bystander CPR in out-of-hospital cardiac arrest victims not already receiving bystander CPR. METHODS AND RESULTS - : Since 2007, we have applied a new DA-CPR protocol that uses supplementary key words. Fire departments prospectively collected baseline data on DA-CPR from January 2009 to December 2011. DA-CPR was attempted in 2747 patients; of these, 417 (15.2%) did not experience cardiac arrest. The sensitivity and specificity of the 2007 protocol versus estimated values of the previous standard protocol were 72.9% versus 50.3% and 99.6% versus 99.8%, respectively. We identified key words that may be useful for detecting out-of-hospital cardiac arrest. Multiple logistic regression analysis revealed that the occurrence of cardiac arrest after an emergency call (odds ratio, 16.85) and placing an emergency call away from the scene of the arrest (odds ratio, 11.04) were potentially associated with failure to provide DA-CPR. Furthermore, at-home cardiac arrest (odds ratio, 1.61) and family members as bystanders (odds ratio, 1.55) were associated with bystander noncompliance with DA-CPR. No complications were reported in the 417 patients who received DA-CPR but did not have cardiac arrest. CONCLUSIONS - : Our 2007 protocol is safe and highly specific and may be more sensitive than the standard protocol. Understanding the factors associated with failure of bystanders to provide DA-CPR and implementing public education are necessary to increase the benefit of DA-CPR. © 2014 American Heart Association, Inc.

PubMed | Komatsu Municipal Hospital, Japan Community Health Care Organization Kanazawa Hospital and Kanazawa University
Type: Journal Article | Journal: Indian journal of palliative care | Year: 2016

Patients with end-stage interstitial lung disease (ILD) do not appear to receive adequate palliative care despite apparent suffering before death. The aim of this study was to evaluate their signs, symptoms, and treatment received before death.Patients with ILD and lung cancer (LC) who were hospitalized and died in our hospital were enrolled retrospectively. Signs and symptoms and treatments at 7 days, 3 days, and 1 day before death were evaluated and compared between the two groups of patients.A total of 23 patients with ILD and 59 patients with LC group were eligible for participation. Significantly more LC patients had loss of consciousness than ILD patients on 7 days (ILD: LC = 1 [5.6%]:24 [41%], P = 0.013), 3 days (1 [5.6%]:33 [56%], P < 0.001). Significantly more ILD patients had dyspnea than LC patients on 3 days (16 [89%]:38 [64%], P = 0.047) 1 day before death (21 [91%]:33 [56%], P = 0.001). On 1 day before death, significantly more LC patients received morphine than ILD patients (2 [8.7%]: 14 [24%], P = 0.015). More ILD patients received sedation (11 [48%]: 11 [19%], P = 0.007).End-stage ILD patients may experience dyspnea more frequently than terminal LC patients, and they need sedation. Morphine should be administered to ILD patients who have dyspnea. Additional prospective studies are needed.

Liu L.,Kanazawa University | Hayashi K.,Kanazawa University | Kaneda T.,Komatsu Municipal Hospital | Ino H.,Kanazawa University | And 11 more authors.
Heart Rhythm | Year: 2013

Background: Long QT syndrome (LQTS) is characterized by prolonged ventricular repolarization and variable clinical course with arrhythmia-related syncope and sudden death. Mutations in the nonpore region of the LQTS-associated KCNH2 gene (also known as hERG) are mostly associated with coassembly or trafficking abnormalities, resulting in haplotype insufficiency and milder clinical phenotypes compared with mutations in the pore domain. Objective: To investigate the effect of a nonpore mutation on the channel current, which was identified from an LQTS family with severe clinical phenotypes. Methods: Two members of a Japanese family with LQTS were searched for mutations in KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, and KCNJ2 genes by using automated DNA sequencing. We characterized the electrophysiological properties and glycosylation pattern of the mutant channels by using patch clamp recording and Western blot analysis. Results: In the LQTS patient with torsades de pointes and cardiopulmonary arrest, we identified the novel T473P mutation in the transmembrane nonpore region of KCNH2. The proband's father carried the same mutation and showed prolonged corrected QT interval and frequent torsades de pointes in the presence of hypokalemia following the administration of garenoxacin. Patch clamp analysis in heterologous cells showed that hERG T473P channels generated no current and exhibited a dominant negative effect when coexpressed with wild-type protein. Only incompletely glycosylated hERG T473P channels were observed by using Western blot analysis, suggesting impaired trafficking. CONCLUSIONS: These results demonstrated that a trafficking-deficient mutation in the transmembrane nonpore region of KCNH2 causes a dominant negative effect and a severe clinical course in affected patients. © 2013 Heart Rhythm Society.

PubMed | Komatsu Municipal Hospital, Shinshu University, Cedars Sinai Medical Center and Kanazawa University
Type: Case Reports | Journal: Journal of immunology (Baltimore, Md. : 1950) | Year: 2015

Neutrophil-specific granule deficiency (SGD) is a rare autosomal recessive primary immunodeficiency characterized by neutrophil dysfunction, bilobed neutrophil nuclei and lack of neutrophil-specific granules. Defects in a myeloid-specific transcription factor, CCAAT/enhancer binding protein- (C/EBP), have been identified in two cases in which homozygous frameshift mutations led to loss of the leucine zipper domain. In this study, we report a 55-y-old woman affected with SGD caused by a novel homozygous 2-aa deletion (RS) in the leucine zipper domain of the C/EBP gene. The patient showed characteristic neutrophil abnormalities and recurrent skin infections; however, there was no history of deep organ infections. Biochemical analysis revealed that, in contrast to the two frameshift mutations, the RS mutant maintained normal cellular localization, DNA-binding activity, and dimerization, and all three mutants exhibited marked reduction in transcriptional activity. The RS mutant was defective in its association with Gata1 and PU.1, as well as aberrant cooperative transcriptional activation of eosinophil major basic protein. Thus, the RS likely impairs protein-protein interaction with other transcription factors, resulting in a loss of transcriptional activation. These results further support the importance of the leucine zipper domain of C/EBP for its essential function, and indicate that multiple molecular mechanisms lead to SGD.

Mabuchi H.,Kanazawa University | Nohara A.,Kanazawa University | Noguchi T.,Kanazawa University | Kobayashi J.,Kanazawa University | And 12 more authors.
Atherosclerosis | Year: 2014

Backgrounds: Familial hypercholesterolemia (FH) is an autosomal dominant disease characterized by hypercholesterolemia, tendon xanthomas, and premature coronary heart disease. FH is caused by mutations of "FH genes," which include the LDL-receptor (LDLR), apolipoprotein B-100 (APOB) or proprotein convertase subtilisin/kexin type 9 (PCSK9). We evaluated the usefulness of FH gene analysis for diagnosing homozygous FH (homo-FH), particularly in cases caused by gain-of-function (g-o-f) mutations in PCSK9 (PCSK9 E32K). Objectives: To evaluate the frequency of homo-FH caused by PCSK9 E32K compared with FH due to other genetic causes and to report the phenotypic features of homo-FH caused by PCSK9 E32K. Methods: Genomic DNA was prepared from white blood cells, and LDLR and PCSK9 mutations were identified using the Invader assay method. Results: Of the 1055 hetero-FH patients, 62 patients (5.9%) carried the PCSK9 E32K mutation, while in the 82 alleles of 41 homo-FH patients, 13 (15.9%) had double mutations of LDLR allele and PCSK9 E32K mutation. Mean plasma total cholesterol (TC) (9.93±2.95mmol/L, mean±SD) in true homo-FH cases with PCSK9 E32K or double hetero-FH cases with PCSK9 E32K and LDLR mutations were significantly lower than those in true homo-FH (18.06±4.96mmol/L) and compound heterozygous cases with LDLR mutations (14.84±1.62mmol/L). Mean plasma TC concentrations in the 59 hetero-FH cases with PCSK9 E32K (7.21±1.55mmol/L) were significantly lower than those (8.94±1.53mmol/L) in the hetero-FH by LDLR mutations. Conclusions: FH caused by PCSK9 g-o-f mutations is relatively common in Japan and causes a mild type of homo- and hetero-FH compared with FH caused by LDLR mutations. © 2014 Elsevier Ireland Ltd.

Hayashi K.,Kanazawa University | Konno T.,Kanazawa University | Tada H.,Kanazawa University | Tani S.,Kanazawa University | And 10 more authors.
Circulation: Arrhythmia and Electrophysiology | Year: 2015

Background - Few rare variants in atrial fibrillation (AF)-associated genes have been functionally characterized to identify a causal relationship between these variants and development of AF. We here sought to determine the clinical effect of rare variants in AF-associated genes in patients with lone AF and characterized these variants electrophysiologically and bioinformatically. Methods and Results - We screened all coding regions in 12 AF-associated genes in 90 patients with lone AF, with an onset of 47±11 years (66 men; mean age, 56±13 years) by high-resolution melting curve analysis and DNA sequencing. The potassium and sodium currents were analyzed using whole-cell patch clamping. In addition to using 4 individual in silico prediction tools, we extended those predictions to an integrated tool (Combined Annotation Dependent Depletion). We identified 7 rare variants in KCNA5, KCNQ1, KCNH2, SCN5A, and SCN1B genes in 8 patients: 2 of 8 probands had a family history of AF. Electrophysiological studies revealed that 2 variants showed a loss-of-function, and 4 variants showed a gain-of-function. Five of 6 variants with electrophysiological abnormalities were predicted as pathogenic by Combined Annotation Dependent Depletion scores. Conclusions - In our cohort of patients with lone AF, 7 rare variants in cardiac ion channels were identified in 8 probands. A combination of electrophysiological studies and in silico predictions showed that these variants could contribute to the development of lone AF, although further in vivo study is necessary to confirm these results. More than half of AF-associated rare variants showed gain-of-function behavior, which may be targeted using genotype-specific pharmacological therapy. © 2015 American Heart Association, Inc.

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