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A recent clinical study indicated that an angiotensin II (Ang II) type 1 (AT 1 ) receptor-neprilysin inhibitor (ARNi) designated LCZ696 (sacubitril/valsartan, as combined sodium complex) was superior to enalapril at reducing the risks of death and hospitalization due to heart failure. Therefore, we investigated the possible mechanisms of the beneficial effect of LCZ696, in which the inhibition of neprilysin enhances atrial natriuretic peptide (NP) or brain NP (ANP or BNP)-evoked signals that can block Ang II/AT 1 receptor-induced aldosterone (Ald) synthesis in human adrenocortical cells. The binding affinity of valsartan+LBQ657 (active moiety of sacubitril) to the AT 1 receptor was greater than that of valsartan alone in an AT 1 receptor-expressing human embryonic kidney cell-based assay. There was no difference in the dissociation from the AT 1 receptor between valsartan+LBQ657 and valsartan alone. In Ang II-sensitized human adrenocortical cells, ANP or BNP alone, but not LBQ657 or valsartan alone, significantly decreased Ald synthesis. The level of suppression of Ald synthesis by ANP or BNP with LBQ657 was greater than that by ANP or BNP without LBQ657. The suppression of ANP was blocked by inhibitors of regulator of G-protein signaling proteins and cyclic GMP-dependent protein kinase. The inhibition of neprilysin did not change the mRNA levels of the AT 1 receptor, ANP receptor A, regulator of G-protein signaling protein, renin or 3β-hydroxysteroid dehydrogenases. In conclusion, the inhibition of neprilysin by LBQ657 enhances the NP-evoked signals that can block Ang II/AT 1 receptor-induced Ald synthesis in human adrenocortical cells.

Background: We compared the efficacy and safety of azilsartan to those of olmesartan in a prospective, randomized clinical trial., Methods: Forty-four hypertensive patients who had coronary artery disease (CAD) were enrolled. We randomly assigned patients to changeover from their prior angiotensin II receptor blockers (ARBs) to either azilsartan or olmesartan, and followed the patients for 12 weeks., Results: Office systolic blood pressure (SBP) in the azilsartan group was significantly decreased after 12 weeks. SBP and diastolic blood pressure (DBP) after 12 weeks in the azilsartan group were significantly lower than those in the olmesartan group. The percentage of patients who reached the target BP at 12 weeks (78%) in the azilsartan group was significantly higher than that at 12 weeks (45%) in the olmesartan group. There were no significant changes in pentraxin-3, high-sensitively C-reactive protein or adiponectin in blood after 12 weeks in either group. Although serum levels of creatinine (Cr) in the azilsartan group significantly increased, these changes were within the respective normal range., Conclusion: In conclusion, the ability of azilsartan to reduce BP may be superior to that of prior ARBs with equivalent safety in hypertensive patients with CAD.

Visit-to-visit variability (VVV) in blood pressure (BP) has been shown to be a predictor of cardiovascular events. It is unknown whether CR can improve VVV in BP as well as reducing BP. We enrolled 84 patients who had cardiovascular disease (CVD) and participated in a 3-month CR program. We measured systolic and diastolic BP (SBP and DBP), pulse pressure (PP), and heart rate (HR) before exercise training at each visit and determined VVV in BP or HR expressed as the standard deviation of the average BP or HR. Patients who had uncontrolled BP at baseline and who did not change their antihypertensive drugs throughout the study period showed a significant reduction of both SBP and DBP with a decrease in PP after 3 months. Patients who did not change their antihypertensive drugs were divided into larger (L-) and smaller (S-) VVV in the SBP groups and L- and S-VVV in the DBP groups according to the average value of VVV in SBP or DBP. In the L-VVV in the SBP and DBP groups, VVV in SBP and DBP in the 1st month was significantly decreased after the 3rd month in both groups. HR at baseline was significantly decreased after 3 months. In addition, CR induced a significant increase in the level of high-density lipoprotein cholesterol (HDL-C) in blood. In conclusion, CR improved VVV in BP in patients with L-VVV in BP and evoked a significant reduction in HR and an increase in HDL-C. These effects due to the CR program may be cardioprotective.

Cardiac rehabilitation (CR) improves cardiac function and exercise capacity in patients with cardiovascular disease (CVD). Simpler techniques are needed for use by physicians in the examination room to assess the usefulness of CR. We enrolled 46 consecutive CVD patients in a CR program (CR group) and prospectively followed them for 3 months. We compared them to 18 age-, gender- and body mass index-matched CVD patients without CR (non-CR group). Various parameters were measured at baseline and after 3 months using 3 simple non-invasive tests: severity of atherosclerosis [arterial velocity pulse index and arterial pressure volume index (API)] were determined using PASESA®, an autonomic nerve total activity amount index and a coefficient of variation of the R-R interval (CVRR) were determined using eHEART®, and peripheral resistance index, pressure rate product, stroke volume and cardiac index were determined using nico®]. There were no significant differences in patient characteristics including percentages (%) of ischemic heart disease and heart failure between the non-CR and CR groups. Systolic blood pressure (SBP), diastolic BP, heart rate and API at baseline significantly decreased and CVRR at baseline significantly increased after 3 months in the CR group, but not in the non-CR group. In addition, ΔAPI (Δ = the value after 3 months minus the value at baseline) was positively associated with ΔSBP in the CR group. In conclusion, CR significantly decreased BP and improved atherosclerosis and sympathetic nerve activity. These findings suggest that simple non-invasive tests may be useful for assessing the effects of CR.

Purpose: To evaluate the relationships between optic nerve head (ONH) blood flow by laser speckle flowgraphy (LSFG), and postmenstrual age and body weight in normal neonates., Methods: During their normal sleep, we studied 24 infants (postmenstrual age, 248-295 days) whose ocular blood flow could be measured three consecutive times. While the subjects slept in the supine position, three mean blur rate (MBR) values of the ONH were obtained: the MBR-A (mean of all values), MBR-V (vessel mean) and MBR-T (tissue mean) in the ONH. With regard to eye diseases, no retinopathy of prematurity (ROP) was observed, and no severe systemic diseases requiring treatment were noted in the subjects. Pearson's correlation coefficients were used to determine the relationship between the MBR-A, -V, -T and postmenstrual age (days) and body weight (g)., Results: Postmenstrual age was significantly correlated with MBR-A (r = 0.64, p = 0.0007), MBR-V (r = 0.62, p = 0.0012) and MBR-T (r = 0.62, p = 0.0012). However, the body weight was not correlated with the MBR (MBR-A: r = 0.37, p = 0.07, MBR-V: r = 0.31, p = 0.14, MBR-T: r = 0.38, p = 0.06)., Conclusions: Our results clarified that the values of ocular blood flow measured by LSFG correlate with the postmenstrual age of normal neonates.

We report the case of a 66 year-old woman with chronic atrial fibrillation, hypertrophic cardiomyopathy (HCM), and spinocerebellar atrophy (SCA). Her mother and first-born son had died of heart disease at the ages of 65 and 16 years, respectively. Four of her 8 siblings had died suddenly of unknown cause or of heart disease, and 2 others of cerebral infarction by the 7th decade. Genetic testing revealed that she had a novel mutation (c. 482C > A, p. Ala161Asp) in the troponin I gene (TNNI3), and no abnormality of the GAA repeat in the frataxin gene. Her older brother with SCA but without HCM was also analyzed, with no abnormality noted in either gene. The Ala161Asp mutation in TNNI3 was implicated in the pathogenesis of her HCM, though an association between HCM and SCA was not revealed.

Aim: Ventricular fibrillation (VF), the main cause of sudden cardiac death (SCD), occurs most frequently in the acute phase of myocardial infarction: a certain fraction of VF, however, develops in an apparently healthy heart, referred as idiopathic VF. The contribution of perturbation in the fast conduction system in the ventricle, the His-Purkinje system, for idiopathic VF has been implicated, but the underlying mechanism remains unknown. Irx3/IRX3 encodes a transcription factor specifically expressed in the His-Purkinje system in the heart. Genetic deletion of Irx3 provides a mouse model of ventricular fast conduction disturbance without anatomical or contraction abnormalities. The aim of this study was to examine the link between perturbed His-Purkinje system and idiopathic VF in Irx3-null mice, and to search for IRX3 genetic defects in idiopathic VF patients in human., Methods and Results: Telemetry electrocardiogram recording showed that Irx3-deleted mice developed frequent ventricular tachyarrhythmias mostly at night. Ventricular tachyarrhythmias were enhanced by exercise and sympathetic nerve activation. In human, the sequence analysis of IRX3 exons in 130 probands of idiopathic VF without SCN5A mutations revealed two novel IRX3 mutations, 1262G>C (R421P) and 1453C>A (P485T). Ventricular fibrillation associated with physical activities in both probands with IRX3 mutations. In HL-1 cells and neonatal mouse ventricular myocytes, IRX3 transfection up-regulated SCN5A and connexin-40 mRNA, which was attenuated by IRX3 mutations., Conclusion: IRX3 genetic defects and resultant functional perturbation in the His-Purkinje system are novel genetic risk factors of idiopathic VF, and would improve risk stratification and preventive therapy for SCD in otherwise healthy hearts., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Purpose: Acute radiation dermatitis (ARD) is one of the most common adverse events of proton beam therapy (PBT), and there is currently no effective method to manage ARD. The purpose of this study was to examine the prophylactic effect of a film dressing using Airwall on PBT-induced ARD compared with standard skin managements., Methods and Materials: A total of 271 patients with prostate cancer who were scheduled for PBT at our center were divided into 2 groups based on their own requests: 145 patients (53%) chose Airwall (group A) and 126 patients (47%) received standard treatments (group B). We evaluated irradiated skin every other day during PBT and followed up once a week for a month after completion of PBT., Results: Grade 0, 1, 2, and 3 dermatitis were seen in 2, 122, 21, and 0 and 0, 65, 57, and 4 patients in groups A and B, respectively (P<.001). Numbers of days to grades 1 and 2 ARD development were 34.9 ± 14.3 and 54.7 ± 10.3 and 31.8 ± 11.3 and 54.4 ± 11.6 in groups A and B, respectively. There were no significant differences between the 2 groups. Eighteen patients (12%) in group A who experienced problems in the region covered with Airwall switched to standard skin care after peeling the film off., Conclusions: Film dressing using Airwall reduced the severity of ARD without delaying the response time of the skin to proton beam irradiation compared with standard skin management. Hence, film dressing is considered a promising measure for preventing ARD secondary to PBT., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Left ventricular assist device (LVAD) mechanically unloads the left ventricle (LV). Theoretical analysis indicates that partial LVAD support (p-LVAD), where LV remains ejecting, reduces LV preload while increases afterload resulting from the elevation of total cardiac output and mean aortic pressure, and consequently does not markedly decrease myocardial oxygen consumption (MVO2). In contrast, total LVAD support (t-LVAD), where LV no longer ejects, markedly decreases LV preload volume and afterload pressure, thereby strikingly reduces MVO2. Since an imbalance in oxygen supply and demand is the fundamental pathophysiology of myocardial infarction (MI), we hypothesized that t-LVAD minimizes MVO2 and reduces infarct size in MI. The purpose of this study was to evaluate the differential impact of the support level of LVAD on MVO2 and infarct size in a canine model of ischemia-reperfusion., Methods: In 5 normal mongrel dogs, we examined the impact of LVAD on MVO2 at 3 support levels: Control (no LVAD support), p-LVAD and t-LVAD. In another 16 dogs, ischemia was induced by occluding major branches of the left anterior descending coronary artery (90 min) followed by reperfusion (300 min). We activated LVAD from the beginning of ischemia until 300 min of reperfusion, and compared the infarct size among 3 different levels of LVAD support., Results: t-LVAD markedly reduced MVO2 (% reduction against, Control: -56 ± 9%, p<0.01) whereas p-LVAD did less (-21 ± 14%, p<0.05). t-LVAD markedly reduced infarct size compared to p-LVAD (infarct area/area at risk: CONTROL; 41.8 ± 6.4, p-LVAD; 29.1 ± 5.6 and t-LVAD; 5.0 ± 3.1%, p<0.01). Changes in creatine kinase-MB paralleled those in infarct size., Conclusions: Total LVAD support that minimizes metabolic demand maximizes the benefit of LVAD in the treatment of acute myocardial infarction.

Aims: Angiotensin receptor-neprilysin inhibitors (ARNis) acts an ARB and neprilysin inhibitor. Diabetes mellitus significantly increases the risk of cardiovascular disease and heart failure (HF). Therefore, we evaluated the effects and mechanisms of ARNi in HF with reduced ejection fraction (HFrEF) in streptozotocin-induced diabetic mice., Methods and Results: Male C57BL/6J mice were injected with streptozotocin to produce diabetic mice. After myocardial reperfusion injury, diabetic mice were randomized to treatment for 4 weeks with LCZ696 (60 mg/kg), valsartan (30 mg/kg), or no treatment (n = 26-28 in each group). Cardiac function was assessed by a pressure-volume Millar catheter. The ratios of heart weight to body weight in the valsartan (P = 0.02) and LCZ696 (P = 0.005) groups were significantly less than that in the control group. Treatment with LCZ696 improved LVEF (43 ± 3.4%) with a significantly reduction of atrial natriuretic peptide mRNA in the left ventricle compared with that in the control group (29 ± 3.2%) (P = 0.006). The fibrotic area in the LCZ696 group was significantly suppressed compared with those in the control (P = 0.003) and valsartan (P = 0.04) groups. Moreover, the mRNA level of transforming growth factor-β (TGF-β) in the left ventricle was suppressed in the LCZ696 group compared with that in the control (P = 0.002) group., Conclusion: The ARNi LCZ696 improved cardiac function with the reduction of fibrosis in an HF-rEF model in diabetic mice, by suppressing TGF-β. This effect may be due to the specific inhibition of neprilysin, beyond the ARB effect of LCZ696., (© 2016 The Authors European Journal of Heart Failure © 2016 European Society of Cardiology.)

Background: To improve the clinical outcome of heart failure (HF), it is important to evaluate the etiology and comorbidities of HF. We previously reported the baseline clinical characteristics and medications in hospitalized patients with HF in years 2000 - 2002 (group 2000) and 2007 - 2009 (group 2008)., Methods: We conducted a retrospective study of 158 patients who were hospitalized due to HF between 2012 and 2014 (group 2013) in the Department of Cardiology, Fukuoka University Hospital. We analyzed the clinical characteristics and medications at admission and discharge, and compared the findings in group 2013 to those in group 2000 and group 2008., Results: The major causes of HF were ischemic heart disease, hypertensive cardiomyopathy, valvular heart disease, and dilated cardiomyopathy. The New York Heart Association classification in group 2013 was significantly higher than those in group 2000 and group 2008. There was no difference in the level of brain natriuretic peptide at admission between group 2008 and group 2013. Tolvaptan began to be administered in group 2013. The median dose of furosemide just before the use of tolvaptan was 40 mg/day. At discharge, group 2013 showed higher rates of β-blocker and aldosterone antagonist. There was no difference in the frequency of loop diuretics. The dose of carvedilol at discharge was only 6.2 ± 4.0 mg/day. Antiarrhythmic drugs and β-blocker were used more frequently in HF with reduced ejection fraction (EF) than in HF with preserved EF., Conclusions: We may be able to improve the clinical outcome of HF by examining the differences in the clinical characteristics and medications at admission and discharge in hospitalized patients with HF.

Nanomedicine allows achievement of tumor-selective drug delivery because of the enhanced permeability and retention (EPR) effect of solid tumors. We report here the first clinical application of a new agent-HPMA copolymer-conjugated pirarubicin (P-THP)-with a molecular size of about 8 nm, or 38.5 kDa. A patient had advanced prostate cancer with multiple metastases in the lung, pelvis, femur, and perhaps the sacrum. In April 2013, this 60-year-old patient started treatment with leuprorelin and estradiol, which continued until July 2014, but the patient became refractory to this treatment. So the patient underwent proton beam radiotherapy targeted to the primary prostate cancer, and P-THP was administered for numerous metastatic tumor nodules concomitantly with radiotherapy. This combination therapy had remarkable results, with complete remission of multiple metastases in the lung and bone. The prostate-specific antigen (PSA) value was decreased from about 1000 ng/mL on April 30, 2013, to about 100 ng/mL on June 24, 2013, with hormone therapy, but rose again to 964.2 ng/mL and then to 1472 ng/mL in July 2013, during leuprorelin administration. P-THP treatment administered concomitantly with proton beam irradiation was started in August 2013. The PSA value was decreased to 102 ng/mL on August 26, 2013, and then to 0.971 ng/mL on October 8, 2013, and 0.277 ng/mL on January 15, 2015. The P-THP doses ranged from 30 to 75 mg of free THP equivalent/patient every 2-3 weeks without signs of serious toxicity, such as cardiovascular side effects or a reduction in quality of life. No evidence of relapse was found more than 20 months after P-THP administration. This case demonstrates the value of hydrazone-bonded polymeric drugs in multimodal therapy.

Background: Exercise training may improve renal function in patients with chronic kidney disease (CKD). The effect of cardiac rehabilitation (CR) with exercise training on renal function has not yet been established. We evaluated the effects of CR on renal function in patients with cardiovascular disease (CVD)., Methods: Twenty-three CVD patients in a 1-year CR program (CR group) who had ischemic heart disease (IHD) and/or heart failure were compared with 26 age- and gender-matched CVD patients without CR (non-CR group, standard pharmacological care alone). At baseline and after 1 year, urea nitrogen (UN), creatinine (Cr), potassium (K), estimated glomerular filtration rate (eGFR) and hematocrit (Hct) in blood were assessed., Results: There were no differences in the patient characteristics at baseline between the CR and non-CR groups except for the percentages of heart failure and the use of calcium channel blocker. After 1 year, there were no significant changes in UN, Cr, K, eGFR or Hct in either the CR or non-CR groups. The patients in the CR group were divided into two groups according to the eGFR level at baseline: low (n = 12, eGFR < 51 mL/minute/1.73 m 2 , indicating mild-to-moderate CKD) and high (n = 11, eGFR ≥ 51 mL/minute/1.73 m 2 ) eGFR groups. Although there were no differences in the patient characteristics at baseline between the low and high eGFR groups, the low eGFR group showed a significant increase in eGFR after the 1-year CR program., Conclusions: CR may improve renal function in patients with mild-to-moderate CKD.

There is an overlap between the physiological cardiac remodeling associated with training in athletes, the so-called athlete's heart, and mild forms of hypertrophic cardiomyopathy (HCM), the most common hereditary cardiac disease. HCM is often accompanied by unfavorable outcomes including a sudden cardiac death in the adolescents. Because one of the initial signs of HCM is abnormality in electrocardiogram (ECG), athletes may need to monitor for ECG findings to prevent any unfavorable outcomes. HCM is caused by mutations in genes for sarcomere proteins, but there is no report on the systematic screening of gene mutations in athletes. One hundred and two genetically unrelated young Japanese athletes with abnormal ECG findings were the subjects for the analysis of four sarcomere genes, MYH7, MYBPC3, TNNT2 and TNNI3. We found that 5 out of 102 (4.9%) athletes carried mutations: a heterozygous MYH7 Glu935Lys mutation, a heterozygous MYBPC3 Arg160Trp mutation and another heterozygous MYBPC3 Thr1046Met mutation, all of which had been reported as HCM-associated mutations, in 1, 2 and 2 subjects, respectively. This is the first study of systematic screening of sarcomere gene mutations in a cohort of athletes with abnormal ECG, demonstrating the presence of sarcomere gene mutations in the athlete's heart.

Proton beam radiotherapy mainly has been used in the gynecological field in patients with cervical cancer. The efficacy of proton beam therapy in patients with recurrent endometrial cancer has not yet been determined. A 77-year-old endometrial cancer patient presented with recurrence in the vagina without distant metastasis following hysterectomy. A hard mass measuring 6 cm originated from the apex of the vagina, surrounded the vaginal cavity, and infiltrated the proximal and distal vagina. The patient received proton beam radiotherapy using a less invasive particle treatment system while minimizing the dose to the surrounding normal tissues. The dose to the planning target volume was 74 Gy (relative biological effectiveness) with 37 fractions. The patient was treated with 150-210-MeV proton beams for 53 days. Proton beam therapy led to the disappearance of tumors without any complications except for grade 1 cystitis although evidence of further complications is not available past our 6-month follow-up period. Proton beam therapy may become a useful treatment modality for recurrent endometrial cancer as well as cervical uterine cancer., (© 2014 The Authors. Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology.)

Background: Recent genome-wide association studies have demonstrated an association between MYH6, the gene encoding α-myosin heavy chain (α-MHC), and sinus node function in the general population. Moreover, a rare MYH6 variant, R721W, predisposing susceptibility to sick sinus syndrome has been identified. However, the existence of disease-causing MYH6 mutations for familial sick sinus syndrome and their underlying mechanisms remain unknown., Methods and Results: We screened 9 genotype-negative probands with sick sinus syndrome families for mutations in MYH6 and identified an in-frame 3-bp deletion predicted to delete one residue (delE933) at the highly conserved coiled-coil structure within the binding motif to myosin-binding protein C in one patient. Co-immunoprecipitation analysis revealed enhanced binding of delE933 α-MHC to myosin-binding protein C. Irregular fluorescent speckles retained in the cytoplasm with substantially disrupted sarcomere striation were observed in neonatal rat cardiomyocytes transfected with α-MHC mutants carrying delE933 or R721W. In addition to the sarcomere impairments, delE933 α-MHC exhibited electrophysiological abnormalities both in vitro and in vivo. The atrial cardiomyocyte cell line HL-1 stably expressing delE933 α-MHC showed a significantly slower conduction velocity on multielectrode array than those of wild-type α-MHC or control plasmid transfected cells. Furthermore, targeted morpholino knockdown of MYH6 in zebrafish significantly reduced the heart rate, which was rescued by coexpressed wild-type human α-MHC but not by delE933 α-MHC., Conclusions: The novel MYH6 mutation delE933 causes both structural damage of the sarcomere and functional impairments on atrial action propagation. This report reinforces the relevance of MYH6 for sinus node function and identifies a novel pathophysiology underlying familial sick sinus syndrome., (© 2015 American Heart Association, Inc.)

The purpose of this study was to investigate the factor structure of the Body Image Concern Inventory (BICI) using a Japanese population as a web-based survey. Two thousand and sixty individuals (1030 women, 1030 men) ranging from 20 to 69 years of age (M=40, SD=16) took part in the present research. A confirmatory factor analysis showed that the second-order factor model of the BICI, which had three first-order factors and one second-order factor of dysmorphic appearance concern was an adequate fit to the data. Additionally, the Cronbach's alpha values of the overall and three subscales of the BICI were adequate. Furthermore, measurement invariance tests revealed that the second-order factor model of the BICI had acceptable measurement invariance at the scale and factor-loading levels between genders. These findings suggested that the BICI was reliable, and able to compare its mean scores between women and men in Japan., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

We report a case involving a 43-year-old Japanese woman with steroid-resistant focal segmental glomerular sclerosis (FSGS) and severe renal dysfunction, which was ameliorated by low-density lipoprotein apheresis (LDL-A). She had been treated with steroid therapy, but had experienced anuria for over 10 weeks and required hemodialysis. She was then treated with LDL-A, which resulted in improved urinary protein excretion and renal function. Her renal function recovered after 97 days of hemodialysis therapy. This case suggests that LDL-A may represent an effective rescue treatment in patients with FSGS and long-term anuria.

While physiological levels of nitric oxide (NO) protect the endothelium and have vasodilatory effects, excessive NO has adverse effects on the cardiovascular system. Recently, new NO-releasing pharmacodynamic hybrids of angiotensin II (Ang II) type 1 (AT1) receptor blockers (ARBs) have been developed.We analyzed whether olmesartan with NO-donor side chains (Olm-NO) was superior to olmesartan (Olm) for the control of blood pressure (BP). Although there was no significant difference in binding affinity to AT1 wild-type (WT) receptor between Olm and Olm-NO in a cell-based binding assay, the suppressive effect of Olm-NO on Ang II-induced inositol phosphate (IP) production was significantly weaker than that of Olm in AT1 WT receptor-expressing cells. While Olm had a strong inverse agonistic effect on IP production, Olm-NO did not. Next, we divided 18 C57BL mice into 3 groups: Ang II (infusion using an osmotic mini-pump) as a control group, Ang II (n = 6) + Olm, and Ang II (n = 6) + Olm-NO groups (n = 6). Olm-NO did not block Ang II-induced high BP after 10 days, whereas Olm significantly decreased BP. In addition, Olm, but not Olm-NO, significantly reduced the ratio of heart weight to body weight (HW/BW) with downregulation of the mRNA levels of atrial natriuretic peptide.An ARB with a NO-donor may cancel BP-lowering effects probably due to excessive NO and a weak blocking effect by Olm-NO toward AT1 receptor activation.

Measuring the ocular blood flow in neonates may clarify the relationships between eye diseases and ocular circulation abnormalities. However, no method for noninvasively measuring ocular circulation in neonates is established. We used laser speckle flowgraphy (LSFG) modified for neonates to measure their ocular circulation and investigated whether this method is reproducible. During their normal sleep, we studied 16 subjects (adjusted age of 34-48 weeks) whose blood flow could be measured three consecutive times. While the subjects slept in the supine position, three mean blur rate (MBR) values of the optic nerve head (ONH) were obtained: the MBR-A (mean of all values), MBR-V (vessel mean), and MBR-T (tissue mean), and nine blood flow pulse waveform parameters in the ONH were examined. We analyzed the coefficient of variation (COV) and the intraclass correlation coefficient (ICC) for each parameter. The COVs of the MBR values were all ≤ 10%. The ICCs of the MBR values were all >0.8. Good COVs were observed for the blowout score, blowout time, rising rate, falling rate, and acceleration time index. Although the measurement of ocular circulation in the neonates was difficult, our results exhibited reproducibility, suggesting that this method could be used in clinical research.

Background: Despite the accumulating genetic and molecular investigations into hypertrophic cardiomyopathy (HCM), it remains unclear how this condition develops and worsens pathologically and clinically in terms of the genetic-environmental interactions. Establishing a human disease model for HCM would help to elucidate these disease mechanisms; however, cardiomyocytes from patients are not easily obtained for basic research. Patient-specific induced pluripotent stem cells (iPSCs) potentially hold much promise for deciphering the pathogenesis of HCM. The purpose of this study is to elucidate the interactions between genetic backgrounds and environmental factors involved in the disease progression of HCM., Methods and Results: We generated iPSCs from 3 patients with HCM and 3 healthy control subjects, and cardiomyocytes were differentiated. The HCM pathological phenotypes were characterized based on morphological properties and high-speed video imaging. The differences between control and HCM iPSC-derived cardiomyocytes were mild under baseline conditions in pathological features. To identify candidate disease-promoting environmental factors, the cardiomyocytes were stimulated by several cardiomyocyte hypertrophy-promoting factors. Interestingly, endothelin-1 strongly induced pathological phenotypes such as cardiomyocyte hypertrophy and intracellular myofibrillar disarray in the HCM iPSC-derived cardiomyocytes. We then reproduced these phenotypes in neonatal cardiomyocytes from the heterozygous Mybpc3-targeted knock in mice. High-speed video imaging with motion vector prediction depicted physiological contractile dynamics in the iPSC-derived cardiomyocytes, which revealed that self-beating HCM iPSC-derived single cardiomyocytes stimulated by endothelin-1 showed variable contractile directions., Conclusions: Interactions between the patient's genetic backgrounds and the environmental factor endothelin-1 promote the HCM pathological phenotype and contractile variability in the HCM iPSC-derived cardiomyocytes., (© 2014 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

In the wake of the Belousov-Zhabotinsky reaction catalyzed by ferroin, the swelling-deswelling oscillating soft actuator exhibits 7 min period of self-oscillation for the first time.

HLA locus contains immune-related genes and genetically regulates immune responses against both foreign- and self-antigens in humans. Inhibitor of κB-like protein (IκBL), encoded by HLA-linked NFKBIL1, is a protein of unknown function, while genetic variations in NFKBIL1 are known to associate with the susceptibility to inflammatory and/or autoimmune diseases. In this study, we found that IκBL suppressed exon exclusion in alternative splicing of human immune-related genes such as CD45. Yeast-two-hybrid screening and immunoprecipitation assay revealed molecular association of IκBL with CLK1, a serine/threonine and tyrosine kinase, which plays a role in the alternative splicing. Unexpectedly, we found that the regulation of alternative splicing in CD45 by IκBL was independent from the kinase activity of CLK1. On the other hand, it was demonstrated that an SR protein, ASF/SF2, bound both IκBL and CLK1 at the RNA-recognition motifs of ASF/SF2, implying a competition of IκBL and CLK1 on SR protein. In addition, IκBL was found to regulate the CLK1-dependent synthesis of M2 RNA, a splice variant of influenza A virus M gene. These observations suggest a functional involvement of IκBL in the regulation of alternative splicing in both human and viral genes, which is a novel link of HLA locus to the regulation of immunity and infection in humans., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Aims: Dilated cardiomyopathy (DCM) is characterized by ventricular dilation associated with systolic dysfunction, which could be caused by mutations in lamina/C gene (LMNA). LMNA-linked DCM is severe in males in both human patients and a knock-in mouse model carrying a homozygous p.H222P mutation (LmnaH222P/H222P). The aim of this study was to investigate the molecular mechanisms underlying the gender difference of LMNA-linked DCM., Methods and Results: A whole-exome analysis of a multiplex family with DCM exhibiting the gender difference revealed a DCM-linked LMNA mutation, p.R225X. Immunohistochemical analyses of neonatal rat cardiomyocytes expressing mutant LMNA constructs and heart samples from the LMNA-linked DCM patients and LmnaH222P/H222P mice demonstrated a nuclear accumulation of androgen receptor (AR) and its co-activators, serum response factor, and four-and-a-half LIM protein-2. Role of sex hormones in the gender difference was investigated in vivo using the LmnaH222P/H222P mice, where male and female mice were castrated and ovariectomized, respectively, or treated with testosterone or an antagonist of AR. Examination of the mice by echocardiography, followed by the analyses of histological changes and gene/protein expression profiles in the hearts, confirmed the involvement of testicular hormone in the disease progression and enhanced cardiac remodelling in the LmnaH222P/H222P mice., Conclusion: These observations indicated that nuclear accumulation of AR was associated with the gender difference in LMNA-linked DCM.

Objectives: The use of staplers for thoracic surgery has been widely accepted and regarded as a safe procedure. However, adverse events (AEs) of stapling are occasionally experienced. The aim of this retrospective study was to analyse the AEs of stapling in pulmonary vascular surgery., Methods: A retrospective multi-institutional review was conducted by the 29 institutions of the Central Japan Lung Cancer Surgery Study Group. All staplings of the pulmonary artery (PA) and vein in thoracic surgery were reviewed during the research period., Results: Stapling of the PA and vein was performed 3393 times. The total number of AEs related to stapling was nine (0.27%). Eight events occurred intraoperatively and one occurred immediately after the operation. Intraoperative AE occurred more frequently than postoperative AE. AE in the PA occurred more frequently than in the pulmonary vein. The intraoperative AEs were oozing (n=3), stapling failure (n=2), laceration of the peripheral vasculature at compression (n=2) and technical injury of the vasculature at insertion (n=1). The causes of AEs were reported to be tissue fragility (n=3), stapler rocking during stapling (n=2), stapler-tissue thickness mismatch (n=2) and technical failure (n=1). The only postoperative AE was staple line rupture of the PV stump. No relationship was seen between the incidence of AE and cartridge colours, compression types of staplers or numbers of staple lines., Conclusions: Generally, stapling of the pulmonary vasculatures in recent thoracic surgery has been safe. Furthermore, the knowledge of the possible risks of pulmonary vascular stapling may help to decrease the AEs of stapling.

Hypertrophic cardiomyopathy (HCM) is a myocardial disease associated with mutations in sarcomeric genes. Three mutations were found in ANKRD1, encoding ankyrin repeat domain 1 (ANKRD1), a transcriptional co-factor located in the sarcomere. In the present study, we investigated whether expression of HCM-associated ANKRD1 mutations affects contraction parameters after gene transfer in engineered heart tissues (EHTs). EHTs were generated from neonatal rat heart cells and were transduced with adeno-associated virus encoding GFP or myc-tagged wild-type (WT) or mutant (P52A, T123M, or I280V) ANKRD1. Contraction parameters were analyzed from day 8 to day 16 of culture, and evaluated in the absence or presence of the proteasome inhibitor epoxomicin for 24 h. Under standard conditions, only WT- and T123M-ANKRD1 were correctly incorporated in the sarcomere. T123M-ANKRD1-transduced EHTs exhibited higher force and velocities of contraction and relaxation than WT- P52A- and I280V-ANKRD1 were highly unstable, not incorporated into the sarcomere, and did not induce contractile alterations. After epoxomicin treatment, P52A and I280V were both stabilized and incorporated into the sarcomere. I280V-transduced EHTs showed prolonged relaxation. These data suggest different impacts of ANKRD1 mutations on cardiomyocyte function: gain-of-function for T123M mutation under all conditions and dominant-negative effect for the I280V mutation which may come into play only when the proteasome is impaired.

Objectives: Alexithymia has been shown to be associated with key pain-related variables in persons with chronic pain from western countries, but the generalizability of these findings across cultures has not been examined adequately. Also, there remain questions regarding the importance of alexithymia to patient functioning over and above the effects of the general negative affectivity., Methods: Alexithymia, pain intensity, pain interference, depression, anxiety, and pain catastrophizing were measured in 128 Japanese patients with chronic pain. Because of the low internal consistency coefficients for 2 of the alexithymia scales (measuring difficulty describing feelings and externally oriented feelings) in our sample, we limited our analyses to a scale assessing difficulty identifying feelings and the total alexithymia scale score., Results: Although the 20-item Toronto Alexithymia Scale total and the Difficulty Identifying Feelings scale scores were not significantly associated with pain intensity, these scales were associated with pain interference, catastrophizing, and negative affectivity in our sample. However, these associations became nonsignificant when measures of negative affectivity were controlled., Discussion: The findings support the cross-cultural generalizability of significant associations between alexithymia and both pain interference and catastrophizing. However, whether (1) alexithymia influences patient functioning indirectly by its effects on negative affect or (2) the univariate associations found between alexithymia and measures of patient functioning are a byproduct of both being influenced by negative affect needs to be tested using longitudinal and experimental research.

Background: Brugada syndrome (BrS) is characterized by specific alterations on ECG in the right precordial leads and associated with ventricular arrhythmia that may manifest as syncope or sudden cardiac death. The major causes of BrS are mutations in SCN5A for a large subunit of the sodium channel, Nav1.5, but a mutation in SCN3B for a small subunit of sodium channel, Navβ3, has been recently reported in an American patient., Methods and Results: A total of 181 unrelated BrS patients, 178 Japanese and 3 Koreans, who had no mutations in SCN5A, were examined for mutations in SCN3B by direct sequencing of all exons and adjacent introns. A mutation, Val110Ile, was identified in 3 of 178 (1.7%) Japanese patients, but was not found in 480 Japanese controls. The SCN3B mutation impaired the cytoplasmic trafficking of Nav1.5, the cell surface expression of which was decreased in transfected cells. Whole-cell patch clamp recordings of the transfected cells revealed that the sodium currents were significantly reduced by the SCN3B mutation., Conclusions: The Val110Ile mutation of SCN3B is a relatively common cause of SCN5A-negative BrS in Japan, which has a reduced sodium current because of the loss of cell surface expression of Nav1.5.

Background: Dilated cardiomyopathy (DCM) is characterized by a dilated left ventricular cavity with systolic dysfunction manifested by heart failure. It has been revealed that mutations in genes for cytoskeleton or sarcomere proteins cause DCM. However, the disease-causing mutations can be found only in far less than half of patients with a family history, indicating that there should be other disease genes for DCM. Formin homology 2 domain containing 3 (FHOD3) is a sarcomeric protein expressed in the heart that plays an essential role in sarcomere organization during myofibrillogenesis. The purpose of this study was to explore a possible novel disease gene for DCM., Methods and Results: We analyzed 48 Japanese familial DCM patients for mutations in FHOD3, and a missense variant, Tyr1249Asn, which was predicted to modify the 3D structure and damage protein function, was found in a case with adult-onset DCM. Functional studies revealed that the DCM-associated mutation significantly reduced the ability to induce actin dynamics-dependent activation of serum response factor, although no remarkable change in the cellular localization was induced in neonatal rat cardiomyocytes transfected with a mutant construct of FHOD3., Conclusions: The DCM-associated FHOD3 variant may cause DCM by interfering with actin filament assembly.

Background: Mutations in genes including SCN5A encoding the α-subunit of the cardiac sodium channel (hNav1.5) cause Brugada syndrome via altered function of cardiac ion channels, but more than two-thirds of Brugada syndrome remains pathogenetically elusive. T-tubules and sarcoplasmic reticulum are essential in excitation of cardiomyocytes, and sarcolemmal membrane-associated protein (SLMAP) is a protein of unknown function localizing at T-tubules and sarcoplasmic reticulum., Methods and Results: We analyzed 190 unrelated Brugada syndrome patients for mutations in SLMAP. Two missense mutations, Val269Ile and Glu710Ala, were found in heterozygous state in 2 patients but were not found in healthy individuals. Membrane surface expression of hNav1.5 in the transfected cells was affected by the mutations, and silencing of mutant SLMAP by small interfering RNA rescued the surface expression of hNav1.5. Whole-cell patch-clamp recordings of hNav1.5-expressing cells transfected with mutant SLMAP confirmed the reduced hNav1.5 current., Conclusions: The mutations in SLMAP may cause Brugada syndrome via modulating the intracellular trafficking of hNav1.5 channel.

In this study, we performed the self-assembly of the amylose-grafted carboxymethyl cellulose sodium salt (NaCMC) for the formation of nanofiber films under aqueous conditions. The introduction of amylose graft chains was conducted by the chemoenzymatic approach including phosphorylase-catalyzed enzymatic polymerization. The product had the rigid NaCMC main chain, which further assembled leading to nanofibers by the formation of double helix between the long amylose graft chains in the intermolecular NaCMC chains of the products. The lengths of the fibers were depended on degrees of polymerization of amylose chains. The nanofiber films were constructed by drying the alkaline solutions of the amylose-grafted NaCMC. The lengths of the nanofibers strongly affected their arrangements in the films. The nanofibers were merged further by washing out alkali to produce the robust nanofiber films., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Currently, there are no detailed reports on the effects of vitamin E-bonded polysulfone (PS) membrane dialyzers on intradialytic hypotension (IDH) in diabetic hemodialysis (HD) patients. This study was designed to evaluate changes in intradialytic systolic blood pressure (SBP) using "VPS-HA" vitamin E-bonded super high-flux PS membrane dialyzers. The subjects were 62 diabetic HD patients whose intradialytic SBP fell by more than 20%. Group A comprised patients who required vasopressors to be able to continue treatment or who had to discontinue therapy due to their lowest intradialytic SBP being observed at 210 min (28 patients). Group B comprised patients who showed no symptoms and required no vasopressors but showed a gradual reduction in blood pressure, with the lowest intradialytic SBP seen at the end of dialysis (34 patients). The primary outcome was defined as the lowest intradialytic SBP after 3 months using VPS-HA. Secondary outcomes included changes in the following: lowest intradialytic diastolic blood pressure, pulse pressure, pulse rate, plasma nitric oxide and peroxynitrite, serum albumin, and hemoglobin A1c. Group A's lowest intradialytic SBP had significantly improved at 3 months (128.0 ±  25.1 mm Hg vs. 117.1 ± 29.2 mm Hg; P = 0.017). Group B's lowest intradialytic SBP had significantly improved at 1 month (134.4 ± 13.2 mm Hg vs. 121.5 ± 25.8 mm Hg; P =  0.047) and 3 months (139.1 ± 20.9 mm Hg vs. 121.5 ±  25.8 mm Hg; P = 0.011). We conclude that VPS-HA may improve IDH in diabetic HD patients., (© 2012, Copyright the Authors. Artificial Organs © 2012, International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.)

Objective: Many patients still have high blood pressure (BP) after treatment with high-dose angiotensin II type 1 receptor blockers (ARBs) or Preminent® (medium-dose of losartan (50 mg/day)/hydrochlorothiazide (HCTZ) (12.5 mg/day)). Therefore, we analyzed whether Micombi®BP (high-dose telmisartan (80 mg/day)/HCTZ (12.5 mg/day)) could provide better results with regard to efficacy and safety for patients with uncontrolled hypertension., Methods: In total, 44 hypertensive patients (22 males, age 71±14 years) who showed uncontrolled BP despite the use of high-dose ARBs or Preminent® were enrolled in this study. We used a changeover design in which the patients were switched from high-dose ARBs or Preminent® to Micombi®BP. We analyzed BP, heart rate (HR), and biochemical parameters before and after treatment for 3 months., Results: Systolic BP and diastolic BP significantly decreased (125±15/69±11 mmHg) and 85% of the patients achieved their target BP at 3 months after changeover. Patients who switched from ARBs and those who switched from Preminent® showed similar BP-lowering effects. In addition, the reductions in BP after 3 months in patients with or without chronic kidney disease and in those with or without metabolic syndrome (MetS) were also similar. There were no significant changes in HR during the study period. Although blood levels of potassium, hemoglobin A1c and uric acid (UA) significantly increased after 3 months for all of the patients, none of the patients showed serious adverse effects., Conclusion: High-dose telmisartan/HCTZ therapy was associated with a significant reduction in BP and helped patients achieve their target BP.

Purpose: Although the content of thoughts has received a considerable amount of attention in pain research, the importance of thought processes (metacognitions) has received less attention., Method: One hundred twenty-nine individuals with muscular dystrophy and chronic pain completed measures assessing metacognitions and frequency of both catastrophizing and pain control beliefs., Results: Greater use of reappraisal and distraction metacognitions were associated with more perceived control over pain, whereas greater use of worry and punishment metacognitions were associated with more catastrophizing., Conclusions/implications: The current findings indicate that metacognitions are associated with both pain control beliefs and catastrophizing and therefore may play an important role in the development or maintenance of pain-related cognitive content thought to influence patient functioning. Research is needed to determine whether treatments that encourage changes in both metacognitions and cognitive content are more effective than treatments that focus on cognitive content alone.

Little is known about the efficacy and safety of intensive lowering of low-density lipoprotein cholesterol (LDL-C) with statin/ezetimibe therapy after coronary stent implantation in patients with stable angina. Fifty patients with stable angina were randomly divided into an atorvastatin (10 mg/day) (A) group and an atorvastatin (10 mg/day)/ezetimibe (10 mg/day) (A+E) group after stent implantation. Follow-up coronary angiography was performed at 6-9 months after stenting. The A and A+E groups showed significant reductions in LDL-C. The levels of LDL-C in the A+E group were significantly lower than those in the A group at follow-up, whereas there were no differences in major adverse cardiac events, in-stent restenosis, or in-stent % diameter stenosis (DS) between the groups. Only the A+E group showed a significant decrease in the levels of highly sensitive C-reactive protein. In a sub-analysis, %DS in the non-target vessel significantly decreased in both groups. Moreover, Δ%DS (Δ=the value at baseline minus that at follow-up) in the A+E group was more closely associated with LDL-C levels at follow-up than that in the A group. There were no significant differences in adverse effects between the A and A+E groups. In conclusion, although statin/ezetimibe therapy was effective and safe for intensive lipid-lowering in patients with stable angina after successful coronary stent implantation, improvement in clinical outcomes with the combination therapy remains unclear., (Copyright © 2012 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Objectives: The pleural invasion (PL) score is a useful prognostic indicator in lung cancer. However, in many cases, the cancer may exfoliate itself into the pleural cavity and may progress to a malignant pleural effusion without invading the parietal pleura. This stage is not currently evaluated, but it is detectable by means of the pleural lavage cytology (PLC). However, PLC's contribution to TNM staging has not yet been clarified. The purpose of this investigation was to demonstrate the usefulness of PLC in the precise staging of patients with such an occult pleural dissemination., Methods: A total of 3231 patients who were included in a multi-institutional database were studied retrospectively. PLC was performed by washing the thoracic cavity with a small amount of physiological saline immediately after opening the thoracic cavity during lung cancer surgery., Results: The incidence of positive PLC findings was 4.58%. In comparison with the negative group, the survival curves were significantly worse (P < 0.001) and the incidence of recurrence with pleuritis carcinomatosa was significantly higher (P < 0.001). According to the subset analysis, the survival difference was prominent in earlier stage groups and lower PL score groups. The positive findings were confirmed to be a significantly poor prognostic indicator (P = 0.016) by multivariate analysis using the Cox proportional hazard model (Cox analysis). However, integration of the positive findings with the PL score was attempted for the convenience of TNM staging. To find the accurate PL score for positive PLC findings, the Cox analysis was re-estimated using the PL score upgraded stepwise. The most reliable model with the highest score for the likelihood ratio χ(2) statistic was obtained by scoring positive findings as PL3. So, it was considered to be the most reliable conversion., Conclusions: Examining PLC in clinical practice is useful for detecting occult pleural dissemination before the appearance of a malignant pleural effusion. Evidence of positive findings should be treated as supplemental information to the precise diagnosis of TNM staging. Scoring positive PLC findings as PL3 (=T3) was appropriate.

Abnormalities in Z-disc proteins cause hypertrophic (HCM), dilated (DCM) and/or restrictive cardiomyopathy (RCM), but disease-causing mechanisms are not fully understood. Myopalladin (MYPN) is a Z-disc protein expressed in striated muscle and functions as a structural, signaling and gene expression regulating molecule in response to muscle stress. MYPN was genetically screened in 900 patients with HCM, DCM and RCM, and disease-causing mechanisms were investigated using comparative immunohistochemical analysis of the patient myocardium and neonatal rat cardiomyocytes expressing mutant MYPN. Cardiac-restricted transgenic (Tg) mice were generated and protein-protein interactions were evaluated. Two nonsense and 13 missense MYPN variants were identified in subjects with DCM, HCM and RCM with the average cardiomyopathy prevalence of 1.66%. Functional studies were performed on two variants (Q529X and Y20C) associated with variable clinical phenotypes. Humans carrying the Y20C-MYPN variant developed HCM or DCM, whereas Q529X-MYPN was found in familial RCM. Disturbed myofibrillogenesis with disruption of α-actinin2, desmin and cardiac ankyrin repeat protein (CARP) was evident in rat cardiomyocytes expressing MYPN(Q529X). Cardiac-restricted MYPN(Y20C) Tg mice developed HCM and disrupted intercalated discs, with disturbed expression of desmin, desmoplakin, connexin43 and vinculin being evident. Failed nuclear translocation and reduced binding of Y20C-MYPN to CARP were demonstrated using in vitro and in vivo systems. MYPN mutations cause various forms of cardiomyopathy via different protein-protein interactions. Q529X-MYPN causes RCM via disturbed myofibrillogenesis, whereas Y20C-MYPN perturbs MYPN nuclear shuttling and leads to abnormal assembly of terminal Z-disc within the cardiac transitional junction and intercalated disc.

Objective: The primary objectives of the current study were to 1) confirm the three-factor model of the Pain Catastrophizing Scale (PCS) items in a Japanese sample and 2) identify the catastrophizing subdomain(s) most closely associated with measures of pain and functioning in a sample of individuals with chronic pain., Design: This was based on a cross-sectional observational study., Setting: This study was conducted in a university-based clinic., Patients: One hundred and sixty outpatients with chronic pain participated in this study., Outcome Measures: Patients completed the PCS, the Brief Pain Inventory, and the Hospital Anxiety and Depression Scale; 30 patients completed the PCS again between 1 and 4 weeks later., Results: Confirmatory factor analysis supported a three-factor structure of the Japanese version of the PCS, and univariate and multivariate associations with validity criterion supported the validity of the measure. Catastrophic helplessness was shown to make a unique contribution to the prediction of pain intensity, pain interference and depression, and catastrophic magnification made a unique contribution to the prediction of anxiety., Conclusions: The findings support the cross-cultural generalizability of the three-factor structure of the PCS and indicate that the PCS-assessed catastrophizing subdomains provide greater explanatory power than the PCS total score for understanding pain-related functioning., (Wiley Periodicals, Inc.)

Objectives: The present study aimed to develop a Japanese version of the Short-Form McGill Pain Questionnaire (SF-MPQ-J) that focuses on cross-culturally equivalence to the original English version and to test its reliability and validity., Design: Cross-sectional design., Method: In study 1, SF-MPQ was translated and adapted into Japanese. It included construction of response scales equivalent to the original using a variation of the Thurstone method of equal-appearing intervals. A total of 147 undergraduate students and 44 pain patients participated in the development of the Japanese response scales. To measure the equivalence of pain descriptors, 62 pain patients in four diagnostic groups were asked to choose pain descriptors that described their pain. In study 2, chronic pain patients (N=126) completed the SF-MPQ-J, the Long-Form McGill Pain Questionnaire Japanese version (LF-MPQ-J), and the 11-point numerical rating scale of pain intensity. Correlation analysis examined the construct validity of the SF-MPQ-J., Results: The results from study 1 were used to develop SF-MPQ-J, which is linguistically equivalent to the original questionnaire. Response scales from SF-MPQ-J represented the original scale values. All pain descriptors, except one, were used by >33% in at least one of the four diagnostic groups. Study 2 exhibited adequate internal consistency and test-retest reliability, with the construct validity of SF-MPQ-J comparable to the original., Conclusion: These findings suggested that SF-MPQ-J is reliable, valid, and cross-culturally equivalent to the original questionnaire. Researchers might consider using this scale in multicenter, multi-ethnical trials or cross-cultural studies that include Japanese-speaking patients., (Wiley Periodicals, Inc.)

The LMNA gene encodes lamin A/C intermediate filaments that polymerize beneath the nuclear membrane, and are also found in the nucleoplasm in an uncharacterized assembly state. They are thought to have structural functions and regulatory roles in signaling pathways via interaction with transcription factors. Mutations in LMNA have been involved in numerous inherited human diseases, including severe congenital muscular dystrophy (L-CMD). We created the Lmna(ΔK32) knock-in mouse harboring a L-CMD mutation. Lmna(ΔK32/ΔK32) mice exhibited striated muscle maturation delay and metabolic defects, including reduced adipose tissue and hypoglycemia leading to premature death. The level of mutant proteins was markedly lower in Lmna(ΔK32/ΔK32), and while wild-type lamin A/C proteins were progressively relocated from nucleoplasmic foci to the nuclear rim during embryonic development, mutant proteins were maintained in nucleoplasmic foci. In the liver and during adipocyte differentiation, expression of ΔK32-lamin A/C altered sterol regulatory element binding protein 1 (SREBP-1) transcriptional activities. Taken together, our results suggest that lamin A/C relocation at the nuclear lamina seems important for tissue maturation potentially by releasing its inhibitory function on transcriptional factors, including but not restricted to SREBP-1. And importantly, L-CMD patients should be investigated for putative metabolic disorders.

A 62-year-old woman complained of sudden chest pain and 64-multidetector row computed tomography (MDCT) was performed. The volume-rendered image showed severe stenosis of the left main coronary trunk artery (LMT). The mean density of the plaque was 32.4 hounsfield units (HU), which indicated soft plaque. Coronary angiography (CAG) showed significant focal stenosis of the LMT. Since the patient had experienced chest pain, and since focal stenosis of the LMT was demonstrated, lipid-lowering therapy using statin and coronary artery bypass graft (CABG, right internal mammary artery-left anterior descending branch, left internal mammary artery-obtuse marginal branch) were applied. Three years after treatment, 64-MDCT showed mild stenosis and a regression of plaque in the LMT. The mean density of the plaque was 73.1 HU (intermediate plaque). CAG showed a degradation of CABG flow, in addition to mild stenosis of the LMT. In conclusion, lipid-lowering therapy with statins may stabilize soft coronary plaque. In addition, non-invasive MDCT is a useful tool for diagnosing coronary artery disease, and for evaluating the size and properties of coronary plaque.

We herein report the case of a 61-year-old woman with dilated phase of hypertrophic cardiomyopathy (D-HCM) who had been diagnosed with HCM 17 years previously. On admission, her left ventricle (LV) had marked dilation, dyssynchrony with diffuse severe hypokinesis, and ventricular tachycardia. She had two mutations in the cardiac myosin binding protein-C gene, which were suspected to be the causes of the D-HCM. We performed LV reconstruction surgery and cardiac resynchronization therapy with a defibrillator for her drug-resistant severe heart failure. After surgery, her New York Heart Association class dramatically improved, and she has not been re-hospitalized since these treatments.

Background: Hypertrophic cardiomyopathy (HCM), which is inherited as an autosomal dominant trait, is the most prevalent hereditary cardiac disease. Although there are several reports on the systematic screening of mutations in the disease-causing genes in European and American populations, only limited information is available for Asian populations, including Japanese., Methods and Results: Genetic screening of disease-associated mutations in 8 genes for sarcomeric proteins, MYH7, MYBPC3, MYL2, MYL3, TNNT2, TNNI3, TPM1, and ACTC, was performed by direct sequencing in 112 unrelated Japanese proband patients with familial HCM; 37 different mutations, including 13 novel ones in 5 genes, MYH7, MYBPC3, TNNT2, TNNI3, and TPM1, were identified in 49 (43.8%) patients. Among them, 3 carried compound heterozygous mutations in MYBPC3 or TNNT2. The frequency of patients carrying the MYBPC3, MYH7, and TNNT2 mutations were 19.6%, 10.7%, and 8.9%, respectively, and the most frequently affected genes in the northeastern and southwestern parts of Japan were MYBPC3 and MYH7, respectively. Several mutations were found in multiple unrelated proband patients, for which the geographic distribution suggested founder effects of the mutations., Conclusions: This study demonstrated the frequency and distribution of mutations in a large cohort of familial HCM in Japan.

Fifty-four patients were randomly divided into irbesartan and olmesartan groups. Blood pressure (BP) was significantly decreased in all patients at 12 weeks. In particular, BP in patients who initially received irbesartan showed significant reductions. The equality of variance of BP in the irbesartan group was significantly smaller than that in the olmesartan group at 12 weeks. Blood concentrations of adiponectin were significantly increased in the irbesartan group at 12 weeks. Log [pentraxin-3] in the irbesartan group were significantly decreased. In conclusion, the ability of irbesartan to reduce BP is comparable to that of olmesartan with equivalent safety.

Dilated cardiomyopathy (DCM) is characterized by dilation of left ventricular cavity with systolic dysfunction. Clinical symptom of DCM is heart failure, often associated with cardiac sudden death. About 20-35% of DCM patients have apparent family histories and it has been revealed that mutations in genes for sarcomere proteins cause DCM. However, the disease-causing mutations can be found only in about 17% of Japanese patients with familial DCM. Bcl-2-associated athanogene 3 (BAG3) is a co-chaperone protein with antiapoptotic function, which localizes at Z-disc in the striated muscles. Recently, BAG3 gene mutations in DCM patients were reported, but the functional abnormalities caused by the mutations are not fully unraveled. In this study, we analyzed 72 Japanese familial DCM patients for mutations in BAG3 and found two mutations, p.Arg218Trp and p.Leu462Pro, in two cases of adult-onset DCM without skeletal myopathy, which were absent from 400 control subjects. Functional studies at the cellular level revealed that the DCM-associated BAG3 mutations impaired the Z-disc assembly and increased the sensitivities to stress-induced apoptosis. These observations suggested that BAG3 mutations present in 2.8% of Japanese familial DCM patients caused DCM possibly by interfering with Z-disc assembly and inducing apoptotic cell death under the metabolic stress., (© 2011 Wiley Periodicals, Inc.)

This paper reports the chemoenzymatic synthesis of an amylose-grafted xanthan gum. An amine-functionalized maltooligosaccharide was chemically introduced to xanthan gum by condensation with its carboxylates using a condensing agent to produce a maltooligosaccharide-grafted xanthan gum. Then, a phosphorylase-catalyzed enzymatic polymerization of glucose 1-phosphate from the graft chain ends on the xanthan gum derivative was performed, giving an amylose-grafted xanthan gum. Furthermore, the product formed a gel with an ionic liquid, which was converted into a hydrogel with high water content by replacement of the ionic liquid with water. The ionically cross-linked hydrogel was also provided by soaking the primary formed hydrogel in FeCl(3) aqueous solution. The mechanical properties of the resulting hydrogels were evaluated by compressive testing., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Pigment epithelium-derived factor (PEDF) and pentosidine have received growing attention as sensitive biomarkers of the progression of atherosclerosis. The present study was performed to evaluate the utility of these biomarkers for assessing the effects of angiotensin II type 1 receptor blockers (ARBs). Sixty-three patients with coronary artery disease (CAD) following successful stent implantation were divided into an ARB group (n = 50), who initially received valsartan or olmesartan immediately following stent implantation, and a non-ARB group (n = 13) according to their blood pressure (BP) at baseline. Measurement of BP and blood sampling was performed prior to (at baseline) and 6-8 months following stent implantation (at follow-up). There were no significant differences in the baseline characteristics between the groups. Although there were no differences in the percentage of diameter re-stenosis between the groups, the BP level in the ARB group at follow-up showed a significant reduction and reached the target BP. The levels of plasma PEDF were significantly increased at follow-up in the ARB group, but not in the non-ARB group, while there were no differences in the levels of pentosidine between the groups. Changes in BP (ΔBP = BP at follow-up minus BP at baseline) were not associated with ΔPEDF. In conclusion, PEDF may be a useful biomarker for assessing the effects of ARBs independent of a reduction in BP.