Published papers

Background: The aim of this study was to predict left ventricular (LV) dysfunction and the timing to perform echocardiography in patients with Duchenne muscular dystrophy (DMD). We developed a scoring system using clinical parameters and examined its efficacy. It is indispensable to utilize echocardiogram for evaluating myocardial damage of DMD patients, but there is no established guideline for determining the clinical conditions which require echocardiographic examination. Methods: We retrospectively analyzed 86 patients with DMD who were treated in Kobe University Hospital from 2007 to 2009. The multiple logistic regression analysis on routine clinical data was performed to identify parameters that can find abnormal LV contraction, and to develop a weighted scoring system. Echocardiogram was performed as the gold standard for detecting LV dysfunction. Results: Four parameters were associated with abnormal LV contraction: (i) brain natriuretic peptide (BNP); (ii) creatine kinase; (iii) scoliosis; and (iv) body surface area. When BNP was used as the only predictor to evaluate LV systolic dysfunction, sensitivity and specificity were 36.4% and 92.1%, respectively. In contrast, abnormal LV contraction was detected in high accuracy (sensitivity: 95.5%; specificity: 68.3%) when we used a two-step scoring system in which BNP was combined with the other three factors, raising the sensitivity compared to using BNP levels as the single parameter (P= 0.008). Conclusion: Our scoring system detects the early heart dysfunction of DMD patients, especially when BNP level is not elevated. This system is useful to determine the timing for echocardiographic examination and consulting cardiologists. © 2012 Japan Pediatric Society.

Serum 1,3-β-D-glucan (BG) assay may be helpful as a marker for the diagnosis of Pneumocystis jiroveci pneumonia (PJP) and invasive fungal infection (IFI). We conducted a systematic review to assess the diagnostic accuracy of this assay. We searched MEDLINE, Web of Science, Cochrane Collaboration databases, Ichushi-Web, reference lists of retrieved studies, and review articles. Our search included studies of serum BG assay that used (i) positive cytological or direct microscopic examination of sputum or bronchoalveolar lavage fluid for PJP and (ii) European Organization for Research and Treatment of Cancer or similar criteria for IFI as a reference standard and provided data to calculate sensitivity and specificity. Only major fungal infections such as invasive candidiasis and invasive aspergillosis were included in the IFI group. Twelve studies for PJP and 31 studies for IFI were included from January 1966 to November 2010. The pooled sensitivity, specificity, diagnostic odds ratio (DOR), and area under the summary receiver operating characteristic curve (AUC-SROC) for PJP were 96% (95% confidence interval [95% CI], 92% to 98%), 84% (95% CI, 83% to 86%), 102.3 (95% CI, 59.2 to 176.6) and 0.96 (95% CI, 0.94 to 0.99), respectively. No heterogeneity was found. For IFI, the values were 80% (95% CI, 77% to 82%), 82% (95% CI, 81% to 83%), 25.7 (95% CI, 15.0 to 44.1), and 0.88 (95% CI, 0.82 to 0.93). Heterogeneity was significant. The diagnostic accuracy of the BG assay is high for PJP and moderate for IFI. Because the sensitivity for PJP is particularly high, the BG assay can be used as a screening tool for PJP. Copyright © 2012, American Society for Microbiology. All Rights Reserved.

SS-A/Ro52 (Ro52), an autoantigen in systemic autoimmune diseases such as systemic lupus erythematosus and Sjögren's syndrome, has E3 ligase activity to ubiquitinate proteins that protect against viral infection. To investigate Ro52's role during stress, we transiently knocked it down in HeLa cells by siRo52 transfection. We found that Ro52 low HeLa cells were significantly more resistant to apoptosis than wild-type HeLa cells when stimulated by H 2O 2- or diamide-induced oxidative stress, IFN-α, IFN-γ and anti-Fas antibody, etoposide, or γ-irradiation. Furthermore, Ro52-mediated apoptosis was not influenced by p53 protein level in HeLa cells. Depleting Ro52 in HeLa cells caused Bcl-2, but not other Bcl-2 family molecules, to be upregulated. Taken together, our data showed that Ro52 is a universal proapoptotic molecule, and that its proapoptotic effect does not depend on p53, but is exerted through negative regulation of the anti-apoptotic protein Bcl-2. These findings shed light on a new physiological role for Ro52 that is important to intracellular immunity. © 2011 Elsevier Inc.

Aims: Cardiac resynchronization therapy (CRT) can stop the vicious cycle resulting from dyssynchrony and generates left ventricular (LV) reverse remodelling. Our objective was to assess the time course and the relationship between improvement in LV dyssynchrony and reverse remodelling after CRT. Methods and results: Sixty-four consecutive patients were evaluated before, immediately after, and 3- and 6 months after CRT. We measured LV volumes, ejection fraction (EF), and sphericity index, and dyssynchrony was assessed using speckletracking radial strain. Response was defined as a >15% decrease in end-systolic volume (ESV) 6 months after CRT, and event-free survival was followed for 24 months. Responders and non-responders had similar baseline LV volumes and EF. During the first and the following 3 months after CRT, LV volumes gradually decreased (enddiastolic volume: 195±73 to 164+60* to 129±51 mL†, ESV: 141±70 to 110±47* to 82±40 mL†), and sphericity index and EF progressively increased (sphericity index: 1.52±0.20 to 1.75±0.31* to 1.94±0.34†, EF: 28±7 to 34±7* to 38±8%†, *†P < 0.001) in responders. No such changes were observed in non-responders. Furthermore, dyssynchrony diminished progressively during the first and the following 3 months after CRT and patients with progressive resynchronization experienced fewer major cardiovascular events than those without (P < 0.001). Conclusion: CRT can stop the vicious cycle of remodelling and dyssynchrony, and actually, turn it into the virtuous cycle of reverse remodelling and further resynchronization. All rights reserved. © The Author 2011.

Background: The objectives of this study were to test the utility of right ventricular (RV) speckle-tracking strain as an assessment tool for RV function in patients with pulmonary hypertension (PH) compared with conventional echocardiographic parameters and to investigate the relationship of the findings obtained with RV speckle-tracking strain with the hemodynamic parameters of RV performance. Methods: Forty-five prospective consecutive patients with PH were studied. RV free wall longitudinal speckle-tracking strain (RV-free) and RV septal wall longitudinal speckle-tracking strain (RV-septal) were calculated by averaging each of three regional peak systolic strains along the entire right ventricle. The conventional echocardiographic parameters - RV fractional area change, RV myocardial performance index, tricuspid annular plane systolic excursion, and tricuspid annular peak systolic velocity - were also studied. For comparison, 22 age-matched volunteers with normal ejection fractions were studied. Results: RV-free in patients with PH was significantly lower than that in normal controls, but RV-septal in the two groups was similar. Importantly, multivariate analysis revealed that RV-free was an independent echocardiographic predictor of hemodynamic RV performance items, including mean pulmonary artery pressure (β = -0.844, P =.001) and pulmonary vascular resistance (β = -0.045, P <.001). RV-free was also correlated with RV ejection fraction and RV end-systolic volume measured by cardiac magnetic resonance imaging and with 6-min walking distance (r = 0.60, r = 0.56, and r = 0.49, respectively, P <.05). Furthermore, the improvement in RV-free 5 ± 3 months after adding medical treatment was significantly correlated with that in 6-min walking distance (r = 0.68, P <.0001). Conclusions: RV-free has the potential to allow for noninvasive follow-up of patients with PH. Copyright 2011 by the American Society of Echocardiography.

Objective. To clarify the role of platelet-derived microparticles (PDMP), which are small vesicles with thrombotic and immunological properties, in systemic lupus erythematosus (SLE), systemic sclerosis (SSc), dermatomyositis/polymyositis (PM/DM), and mixed connective tissue disease (MCTD). Methods. Plasma levels of PDMP were measured by ELISA, and compared among patients with one of the 4 diseases. Association of PDMP levels with clinical characteristics and medication of the patients was also examined. Results. PDMP levels were higher in patients with MCTD and SSc than in controls. Multiple linear regression analysis revealed that patients with Raynaud's phenomenon (RP) showed higher PDMP levels than those without. PDMP levels in individual patients did not fluctuate significantly over several months. Conclusion. PDMP level is associated with MCTD, SSc, and RP, and could be a novel marker for RP. The Journal of Rheumatology Copyright © 2011. All rights reserved.

To examine the association of PPP3CC (rs10108011 and rs2461491) and EGR3 (rs3750192) single-nucleotide polymorphisms (SNPs) with Japanese schizophrenia, we performed a case-control association study using 337 patients and 369 healthy controls. As a result, by our moderated cohort-size study, PPP3CC and EGR3 are not genetic risk factors for schizophrenia, whereas meta-analysis showed weak association of rs10108011 with schizophrenia in the Japanese population (odds ratio (OR) = 1.12, P= 0.01). © 2009 Elsevier Ireland Ltd.

Background: We have previously proposed the CAT classification system, a simple and clear-cut system for classifying segmental mandibular defects after oncological surgery: “C” refers to the loss of the condylar head of the mandible, “A” the mandibular angle and “T” the mental tubercle. Here, we report a statistical and mathematical taxonomical study on the validity and utility of the classification system. Methods: Data were collected from 17 medical institutions in Japan on 259 patients who had undergone surgical ablation and simultaneous microsurgical oromandibular reconstruction (osteocutaneous free flap or soft tissue free flap with reconstruction-plate) attributed to head and neck cancer. The mandibular defects were classified according to the CAT system and the two commonly used systems HCL and Urken, and the validity and utility of the CAT system were tested as follows: 1) the tendency among the numbers of the three reference points of the CAT system (C, A and T) and the esthetic outcome of each patient were analyzed by Jonckheere's trend test, 2) each of the classified patterns of the three systems was analyzed by cluster analysis based on the esthetic results using Ward's method. Results: 1) There was a statistically significant trend among the numbers of the three reference points in the CAT system and the esthetic outcome, 2) each of the grouped clusters in the CAT system was clinically explicable and demonstrated a significant difference in the esthetic outcome; the two other systems did not yield such information. Conclusion: The CAT classification system is valid and useful for oncological segmental mandibular defects.

Background: Rheumatoid factor (RF), anti-citrullinated peptide antibody (ACPA), C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) have been studied extensively as prognostic markers of rheumatoid arthritis (RA). However, despite the fact that matrix metalloproteinase-3 (MMP-3) is linked to RA activity, few studies have evaluated MMP-3 as prognostic marker. Objective: To evaluate the performance of MMP-3 as predictor of joint destruction in RA treated with non-biological disease modifying anti-rheumatic drugs. Methods: In a retrospective study of 58 early to moderate stage RA patients who consulted the Department of Clinical Pathology and Immunology, Kobe University Hospital between May 2002 and April 2009, we evaluated the performance of MMP-3 and other biomarkers as predictors of joint destruction, by comparing them between radiographically progressive and non-progressive group. Results: Serum levels of RF at entry and ACPA, but not MMP-3 at entry, were significantly higher for the progressive group. Ratios of patients with MMP-3 levels higher than healthy control were not significantly different for the two groups. However, cutoff values determined through receiver operating characteristic analysis showed that the ratio of patients with elevated RF was significantly higher in the progressive group (p=0.001), while MMP-3 (p=0.092), ACPA (p=0.052), CRP (p=0.056), and ESR (p=0.069) tended to be more elevated in the progressive group. Multiple logistic regression analysis using the cutoff value identified MMP-3 positive and RF positive, but not ACPA, CRP or ESR, as significant factors for radiographic progression (OR 16.79 [95% CI: 1.34-414.19]). Conclusion: MMP-3 can be a useful marker for prediction of joint destruction.

Background - Left ventricular (LV) remodeling can increase tethering force to mitral valve and functional mitral regurgitation (FMR). Because the relationship between FMR and regional myocardial function has not been quantitatively evaluated, we conducted a quantitative investigation of this association. Methods and Results-The effective regurgitant orifice (ERO) of FMR in 51 patients with depressed LV ejection fraction (32±9%) secondary to ischemic or nonischemic cardiomyopathy was compared with mitral deformation (valve and annulus), global LV remodeling (volume indices, function, and sphericity), and regional myocardial contractile function, as assessed by longitudinal peak systolic strain rate (Ssr) in LV anterior, anteroseptal, inferoseptal, inferior, inferolateral, and anterolateral segments at rest. Low-dose dobutamine (10 μg/kg per minute)-induced changes in ERO were compared with changes in the variables. Multivariable analysis identified the predictors of ERO at rest as mitral valvular tenting (β=0.062; P<0.001), Ssr in the inferior segment (inferior Ssr) (β=-0.178; P<';.001), and LV sphericity (β=0.414; P=0.001) and the predictors of valvular tenting at rest as inferior Ssr (β=1.680; P<;0.001), LV end-systolic volume index (β=0.022; P=0.001), and LV sphericity (β=3.886; P=0.012). Furthermore, dobutamineinduced reduction in ERO was predicted by reduction in valvular tenting (β=-0.087; P<;0.001) and increase in inferior Ssr (β=-0.082; P<;0.001), and dobutamine-induced reduction in valvular tenting was predicted by increase in inferior Ssr (β=-0.860; P<;0.001).Conclusions-Inferior regional myocardial dysfunction was quantitatively associated with mitral valvular tenting and FMR. Moreover, improvement with dobutamine of inferior myocardial contractile function attenuated valvular tenting and FMR. Inferior myocardial contractile function can affect the configuration of the mitral apparatus and predict FMR severity. © 2010 American Heart Association, Inc.

Objectives: We described the characteristics of congenital cholesteatoma in Japanese patients and assessed whether the staging system is useful for predicting the rate of residual disease, the need for reexploration, and surgical outcomes. Methods: We performed a retrospective chart analysis of 23 consecutive patients with congenital cholesteatoma. Results: The proportion of cases with anterior-superior quadrant involvement was significantly lower in the Asian group than in Western patients. The total residual rate was 26%, and there was a positive association between stage and residual rate, ranging from 0% in stage ? and ?? to 44% in stage IV. Canal wall-up tympanomastoidectomy was the most frequent procedure (57%), and 61% had reexploration. Conclusions: Congenital cholesteatoma in Asia is less likely to involve the anterior-superior quadrant than in Western patients. The 4-stage system was useful for predicting residual rates, even in patients in whom anterior-superior quadrant involvement was less common. Postoperative hearing was significantly related to the stages. A routine second-look procedure may be unnecessary in the early stages, whereas reexploration would be better performed in advanced stages. Endoscopy might reduce residual disease and the need for reexploration in the near future. © 2010 Annals Publishing Company. All rights reserved.

Background-The best predictor for postoperative left ventricular (LV) systolic dysfunction in patients with chronic aortic regurgitation is still a matter of debate. The aim of this study was to assess the clinical significance of preoperative systolic radial strain rate (Ssr) derived from tissue Doppler echocardiography as a predictor of postoperative LV systolic dysfunction in patients with chronic aortic regurgitation. Methods and Results-In 52 patients (mean age, 58 years; 13 women) with isolated chronic aortic regurgitation, we performed standard and tissue Doppler echocardiography before and after operation, obtained echocardiographic parameters such as LV dimensions and LV ejection fraction, and measured Ssr in 4 walls of the LV. Linear regression analysis determined correlations between preoperative parameters and postoperative LV ejection fraction. Receiver-operating characteristic curve analysis assessed the optimal cutoff values of parameters that predicted postoperative LV systolic dysfunction (ejection fraction <50%). The operation caused significant decreases in LV dimensions and volumes and significant increases in Ssr (1.94±0.64 to 2.39±0.83 per second; P<0.001) and ejection fraction (53.0±8.7 to 59.0±8.8%; P<0.001). Multiple regression analysis demonstrated that averaged Ssr was the only independent predictor of postoperative LV systolic dysfunction among the covariates examined (P<0.001). Using receiver-operating characteristic curve analysis, averaged Ssr yielded the greatest area under the curve among preoperative parameters (0.80) and was indicated to be a good predictor of postoperative LV dysfunction, with 90.9% sensitivity and 73.2% specificity (cutoff value, 1.82 per second). Conclusions-Measurement of preoperative averaged Ssr is useful in predicting postoperative LV systolic dysfunction and optimizing surgical timing in patients with isolated chronic aortic regurgitation.

Harvesting the radial forearm flap may cause circulatory problems in the donor arm. To investigate the influence on donor hands after radial forearm flap harvesting, we assessed the process of circulatory changes prospectively by measuring skin perfusion pressure (SPP) that is clinically useful in detecting vascular lesions. The records of 17 patients (14 men and 3 women aged 59.7 ± 11.8 years) who had undergone free radial forearm flap transfer for head and neck reconstruction, between December 2005 and April 2007, were analysed. SPP in the thumb (finger I), the middle finger (III) and the little finger (V) was measured in the 17 patients preoperatively and 1 month and 3, 6, 9 and 12 months postoperatively. All statistical tests were two sided, with a significance level defined as p < 0.05. Preoperatively, baseline SPP was more dominant in finger I than in finger V. Postoperatively, SPP changed significantly in both fingers, while it showed no change in finger III and tended to be higher in finger I than in the other two. Harvesting the free radial forearm flap reduces skin perfusion in the fingers of the donor arm and, we assume, leads to a re-distribution of blood flow to the fingers, with the residual ulnar artery still supplying more blood flow to finger I than to finger V. This suggests the presence of an autoregulating mechanism whereby blood perfusion to the fingers is controlled by the physiological demands of individual fingers. © 2010 British Association of Plastic, Reconstructive and Aesthetic Surgeons.

Objectives: To assess whether smoking is a risk factor for developing rheumatoid arthritis (RA). Design: Meta-analysis. Method: Data sources were observational studies that examined the association between smoking history and the risk of developing RA identified through Medline and EMBASE (from 1966 to December 2006), relevant books and a reference search. Two authors independently extracted the following: authors' names, publication year, sample size, participant characteristics, odds ratios (OR) or relative risks, adjustment factors, study design and area where the study was conducted. Data syntheses were based upon random effects model. Summarised syntheses effects were expressed by OR. Results: Sixteen studies were selected from among 433 articles. For men, summary OR for ever, current and past smokers were 1.89 (95% CI 1.56 to 2.28), 1.87 (1.49 to 2.34) and 1.76 (1.33 to 2.31), respectively. For rheumatoid factor-positive (RF+) RA, summary OR for ever, current and past smokers were 3.02 (2.35 to 3.88), 3.91 (2.78 to 5.50) and 2.46 (1.74 to 3.47), respectively. Summary OR for 20 or more pack-years of smoking was 2.31 (1.55 to 3.41). For women, summary OR for ever, current and past smokers were 1.27 (1.12 to 1.44), 1.31 (1.12 to 1.54) and 1.22 (1.06 to 1.40), respectively. For RF+ RA, summary OR for ever, current and past smokers were 1.34 (0.99 to 1.80), 1.29 (0.94 to 1.77) and 1.21 (0.83 to 1.77). Summary OR for 20 or more pack-years of smoking was 1.75 (1.52 to 2.02). Conclusion: Smoking is a risk factor for RA, especially RF+ RA men and heavy smokers.