〈Originals〉Relationship between clinical manifestations and CMR findings in cardiac sarcoidosis

[Abstract] Background : Different cardiac manifestations/events have been reported in patients with sarcoidosis ; however, factors related to the onsetof manifestations in cardiac sarcoidosis (CS) remain unclear. Late gadolinium-enhancement cardiac magnetic resonance (LGE-CMR) has been used to detect myocardial damage/fibrosis. Therefore, we examined the characteristics of clinical manifestations in CS patients using LGE-CMR. Methods : Thirty-three consecutive CS patients underwent CMR. According to the mural location of LGE ; mid-wall, epicardial, or transmural, the LGE pattern was classified into three groups : A : LGE existing at one location only, B: LGE at any two locations, C : LGE at all locations. CMR findings were also analyzed in relation to each clinical manifestation. Results : Myocardial damage was detected by LGE imaging in 91% of the patients and was most frequently observed in the basal septal myocardium. %LGE area was negatively correlated with LV ejection fraction (EF) (P <0.01). Significantly decreased LV EF and increased %LGE area were observed in Group B and C. In addition, all patients in group C exhibited a clinical manifestation. The patients with high-grade atrioventricular block showed the increased %LGE area (P < 0.01). Although occurrence of ventricular tachycardia was not associated with any changes in LV EF, mass, and %LGE area, hospitalization for heart failure was associated with reduced LV EF, and increased mass and %LGE area (P<0.05 for all).Conclusions : Different clinical manifestations in CS have been associated with the development of myocardial fibrosis/damage and resultant myocardial dysfunction shown by CMR. CMR may be useful for characterizing the pathophysiology of respective clinical manifestations/events

MicroRNA-133 regulates the expression of GLUT4 by targeting KLF15 and is involved in metabolic control in cardiac myocytes

GLUT4 shows decreased levels in failing human adult hearts. We speculated that GLUT4 expression in cardiac muscle may be fine-tuned by microRNAs. Forced expression of miR-133 decreased GLUT4 expression and reduced insulin-mediated glucose uptake in cardiomyocytes. A computational miRNA target prediction algorithm showed that KLF15 is one of the targets of miR-133. It was confirmed that over-expression of miR-133 reduced the protein level of KLF15, which reduced the level of the downstream target GLUT4. Cardiac myocytes infected with lenti-decoy, in which the 3′UTR with tandem sequences complementary to miR-133 was linked to the luciferase reporter gene, had decreased miR-133 levels and increased levels of GLUT4. The expression levels of KLF15 and GLUT4 were decreased at the left ventricular hypertrophy and congestive heart failure stage in a rat model. The present results indicated that miR-133 regulates the expression of GLUT4 by targeting KLF15 and is involved in metabolic control in cardiomyocytes

Erratum to: Expression of myeloperoxidase and gene mutations in AML patients with normal karyotype: double CEBPA mutations are associated with high percentage of MPO positivity in leukemic blasts

Erratum to: International Journal of Hematology, 94(1), pp.81-89: 2011DOI 10.1007/s12185-011-0883-yThe original version of this article unfortunately contained some errors in Table 2 in the column headed ‘‘Amino acid changes’’. The corrected table is given here

〈Originals〉Relation between low take-off of the left atrial appendage and thromboembolic events in patients with atrial fibrillation : evaluation with multi-detector CT

[Abstract] The left atrial appendage (LA-Ap) is one of the major sources of cardiac thrombus formation responsible for thromboembolism inpatients with atrial fibrillation (AF). We hypothesized that the particular anatomical characteristics of the LA-Ap may facilitate thrombus formation. Methods : Seventy-four AF patients underwent transesophageal echocardiography (TEE) and multi-detector CT (MDCT) examinations. These patients were divided into two groups, with and without systemic embolism (Emb) [Emb (+) group, 10 patients, male/female =7/3 ; Emb (—) group, 64 patients, male/female = 51/13]. To evaluate the location of the LA-Ap in relation to the left atrium (LA), we determined four distinctive points on MDCT images using two carefully defined orthogonal sections : the superior summit of the mitral annulus (point-A), the anterior and posterior sites of the LA-Ap orifice (point-B and C), and the posterior LA (point-D). Next, we evaluated the relation of the geometrical intervals (A-B, B-C, C-D) to the prior thromboembolism. Results : Using multivariate analysis, a shorter A-B interval was recognized as an independent factor positively associated witha history of thromboembolism. Conclusion : The position of the LA-Ap orifice may affect the hemodynamic state of the LA-Ap, and anterior deviation of the LA-Ap orifice (low take-off of the LA-Ap) may be a risk factor for thrombus formation in LA-Ap and systemic embolism

Relationship between monoclonal gammopathy of undetermined significance and radiation exposure in Nagasaki atomic bomb survivors.

Radiation exposure is a possible predisposing factor for monoclonal gammopathy of undetermined significance (MGUS), but the association has been uncertain. We investigated the relationship between radiation exposure and MGUS prevalence by using data from the M-protein screening for Nagasaki atomic bomb survivors between 1988 and 2004. Radiation exposure was assessed by exposure distance from the hypocenter and exposure radiation dose. We computed prevalence ratios (PRs) and the 95% confidence intervals (CIs) adjusting for exposure age and sex. A total of 1082 cases of MGUS were identified from 52 525 participants. MGUS prevalence was significantly higher in people exposed at distance within 1.5 km than beyond 3.0 km (PR, 1.4; 95% CI, 1.1-1.9) among those exposed at age 20 years or younger, but it was not found among those exposed at age 20 years or older. MGUS prevalence was also significantly higher in people exposed to more than 0.1 Gy than those exposed to less than 0.01 Gy (PR, 1.7; 95% CI, 1.0-2.8) among those exposed at age 20 years or younger. Thus, people exposed at younger age exhibited a significantly high risk of MGUS when exposed to a high radiation dose. There was no clear association between radiation exposure and the malignant progression of MGUS. Further detailed analysis is needed

Topical application of 5-fluorouracil on attic cholesteatoma results in downregulation of keratinocyte growth factor and reduction of proliferative activity.

To investigate the cell-biological effect of topically applied 5-fluorouracil (5-FU) on middle ear cholesteatoma, 12 attic cholesteatomas were treated with topical application of 5-FU cream, two to five times with an interval of 2 weeks (5-FU group). The control group comprised 65 cholesteatoma that were not treated with 5-FU. All lesions were later excised surgically and processed for immunohistochemical analyses of Ki-67, keratinocyte growth factor (KGF) and its receptor (KGFR). 5-FU significantly reduced the expression of KGF, did not change KGFR expression, and significantly reduced the Ki-67 labeling index, relative to the control group. The effect of 5-FU on cholesteatoma seems to be mediated, at least in part, through downregulation of KGF in stromal cells and reduction of the proliferative activity of epithelial cells

Long-term outcome of immunosuppressive therapy for Japanese patients with lower-risk myelodysplastic syndromes

To investigate the long-term usefulness of immunosuppressive therapy (IST) for Japanese patients with lower-risk myelodysplastic syndromes, we retrospectively analyzed 29 MDS patients who were treated with cyclosporine A alone or with anti-thymocyte globulin at a single institute in Japan. A total of 58.6 % of patients showed hematological response to IST. Overall survival of all patients was 74.5 % at 5 years and 48.3 % at 10 years. The major adverse event was the elevation of creatinine level (grade 1 and 2). Eleven patients were still on IST at the time of analysis with, at least, some clinical benefits. Pneumonia was the most frequent cause of death (eight of 12 deaths), followed by bleeding (three of 12); most of the patients who died were non-responders. The presence of paroxysmal nocturnal hemoglobinuria-type cells was significantly associated with both response to IST and long-term survival by univariate analysis. The 10-year overall survival of responders (72.2 %) was significantly superior to that of non-responders (15.6 %, P < 0.0001). These results suggest that IST using cyclosporine A provides long-term benefit for Japanese patients with lower-risk MDS

Expression of myeloperoxidase and gene mutations in AML patients with normal karyotype: double CEBPA mutations are associated with high percentage of MPO positivity in leukemic blasts.

The percentage of myeloperoxidase (MPO)-positive blast cells is a simple and highly significant prognostic factor in AML patients. It has been reported that the high MPO group (MPO-H), in which >50% of blasts are MPO activity positive, is associated with favorable karyotypes, while the low MPO group (≤50% of blasts are MPO activity positive, MPO-L) is associated with adverse karyotypes. The MPO-H group shows better survival even when restricted to patients belonging to the intermediate chromosomal risk group or those with a normal karyotype. It has recently been shown that genotypes defined by the mutational status of NPM1, FLT3, and CEBPA are associated with treatment outcome in patients with cytogenetically normal AML. In this study, we aimed to evaluate the relationship between MPO positivity and gene mutations found in normal karyotypes. Sixty AML patients with normal karyotypes were included in this study. Blast cell MPO positivity was assessed in bone marrow smears stained for MPO. Associated genetic lesions (the NPM1, FLT3-ITD, and CEBPA mutations) were studied using nucleotide sequencing. Thirty-two patients were in the MPO-L group, and 28 patients in the MPO-H group. FLT3-ITD was found in 11 patients (18.3%), NPM1 mutations were found in 19 patients (31.7%), and CEBPA mutations were found in 11 patients (18.3%). In patients with CEBPA mutations, the carrying two simultaneous mutations (CEBPA (double-mut)) was associated with high MPO expression, while the mutant NPM1 without FLT3-ITD genotype was not associated with MPO activity. Both higher MPO expression and the CEBPA (double-mut) genotype appeared to be associated with improved overall survival after intensive chemotherapy. Further studies are required to determine the importance of blast MPO activity as a prognostic factor, especially in CEBPA wild-type patients with a normal karyotype

心筋エンドセリン-1は食塩感受性高血圧ラットにおける代償性心肥大から心不全への移行に際する左室機能不全進行に重要な役割を果たしている

京都大学0048新制・課程博士博士(医学)甲第7737号医博第2090号新制||医||709(附属図書館)UT51-99-G331京都大学大学院医学研究科内科系専攻(主査)教授 野間 昭典, 教授 中尾 一和, 教授 篠山 重威学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDA