In cardiac myocytes Calmodulin (CaM) bound to the ryanodine receptor (RyR2) constitutes a large pool of total myocyte CaM, but the CaM-RyR2 affinity is reduced in pathological conditions. Knock-in ...mice expressing RyR2 unable to bind CaM also developed hypertrophy and early death. However, it is unknown whether CaM released from this RyR2-bound pool participates in pathological cardiac hypertrophy.
We found that angiotensin II (AngII) or phenylephrine (PE) both cause CaM to dissociate from the RyR2 and translocate to the nucleus. To test whether this nuclear CaM accumulation depends on CaM released from RyR2, we enhanced CaM-RyR2 binding affinity (with dantrolene), or caused CaM dissociation from RyR2 (using suramin). Dantrolene dramatically reduced AngII- and PE-induced nuclear CaM accumulation. Conversely, suramin enhanced nuclear CaM accumulation. This is consistent with nuclear CaM accumulation coming largely from the CaM-RyR2 pool. CaM lacks a nuclear localization signal (NLS), but G-protein coupled receptor kinase 5 (GRK5) binds CaM, has a NLS and translocates like CaM in response to AngII or PE. Suramin also promoted GRK5 nuclear import, and caused nuclear export of histone deacetylase 5 (HDAC5). Dantrolene prevented these effects. After 2–8 weeks of pressure overload (TAC) CaM binding to RyR2 was reduced, nuclear CaM and GRK5 were both elevated and there was enhanced nuclear export of HDAC5.
Stress (acute AngII or TAC) causes CaM dissociation from RyR2 and translocation to the nucleus with GRK5 with parallel HDAC5 nuclear export. Thus CaM dissociation from RyR2 may be an important step in driving pathological hypertrophic gene transcription.
•Calmodulin (CaM), which dissociated from RyR2, translocated to the nucleus.•Movement of RyR2-CaM to the nucleus along with GRK5 promotes pathological cardiac hypertrophy.•Dantrolene prevents RyR2-CaM movement and HDAC5 nuclear export.•Amlexanox, a pharmacological inhibitor of GRK5 kinase activity, suppressed HDAC5 nuclear export.•Pressure overload causes CaM movement from RyR2 to nucleus with GRK5 and promotes the nuclear export of class IIa HDAC.
Scavenging Free Radicals by Low-Dose Carvedilol Prevents Redox-Dependent Calcium Sulfate Hemihydrate Leak Via Stabilization of Ryanodine Receptor in Heart Failure Mamoru Mochizuki, Masafumi Yano, ...Tetsuro Oda, Hiroki Tateishi, Shigeki Kobayashi, Takeshi Yamamoto, Yasuhiro Ikeda, Tomoko Ohkusa, Noriaki Ikemoto, Masunori Matsuzaki Although the clinical benefits of widely used carvedilol (CV) for the treatment of heart failure have been established in several clinical trials, the molecular mechanism by which CV improves cardiac function in heart failure is unclear. We investigated whether the defectiveness is corrected by CV, which is an antioxidant as well as a beta-blocker. Low-dose CV, via its antioxidant effect, corrected ryanodine receptor defects in failing hearts, thereby improving failing cardiomyocyte function. Carvedilol, at a concentration that is sufficient to produce antioxidant effect, improved the intracellular calcium sulfate hemihydrate handling and contractile dysfunction, by correcting defective inter-domain interaction within the ryanodine receptor 2 in the failing heart.
Amino acid positron emission tomography (PET) may provide additional information to computed tomography and magnetic resonance imaging for detecting the pretreatment diagnosis of intracranial ...lesions. The purpose of this study was to investigate the role of cutoff values of 11C-METPET, an amino acid PET tracer, in the differentiation of pretreatment brain tumors from non-neoplastic lesions.
This retrospective cohort study analyzed 101 pretreatment patients with a definitive diagnosis out of a total of 425 consecutive 11C-METPET imaging studies. The standardized uptake values (SUV) and the ratios of lesion to contralateral normal frontal-lobe gray matter uptake (L/N ratios) were measured. Cutoff values for the differential diagnosis of brain tumors from non-neoplastic lesions were determined using receiver operating characteristics curve (ROC) analysis.
Based on the ROC analyses, the cutoffs were 3.33 for maximum SUV, 2.54 for mean SUV, 2.33 for peak SUV, 2.04 for Lmax/Nmean, and 2.23 for Lmax/Nmax. The sensitivity and specificity of these cutoffs were 69.2% and 82.6%, respectively, for maximum SUV, 64.1% and 91.3% for mean SUV, 69.2% and 91.3% for peak SUV, 70.5% and 91.3% for Lmax/Nmax and 75.6% and 82.6% for Lmax/Nmean.
In differentiating intracranial brain tumor from non-neoplastic lesion with 11C-METPET, the use of optimal cutoff values indicates the high specificity, which means that positive result indicates the high likelihood of brain tumor. Considering the high specificity of 11C-METPET, more invasive examinations such as biopsy may be considered in positive cases.
•The role of optimal cutoff for pretreatment 11C-METPET differentiation of intracranial brain tumors from non-neoplastic lesions is debatable.•Considering the high specificity using optimal cutoffs, 11C-METPET is useful for definitive diagnosis.•In positive cases, additional intrusive procedures such as biopsy may be undertaken based on 11C-METPET imaging.
Increasing the switching frequency of direct current–direct current converters is effective in reducing the size of magnetic components used in converters. However, as the switching frequency ...increases, the loss and heat generated by the magnetic components increase. Therefore, in this study, a magnetic tape that bypasses the magnetic flux in the windings of magnetic components is proposed to reduce the loss and heat generation of these components. The effect of suppressing the temperature rise of magnetic components with a magnetic tape during the converter drive was investigated. The temperature rise of a 1-MHz 100-V/200-V 800-W boost inductor was reduced by 16.8 K by applying the magnetic tape. Additionally, applying the magnetic tape to the inductor reduced the heat generation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A new Symplocos trumpet leafminer, Coptotriche yanbarensis Kim & Yagi sp. nov., feeding on S. stellaris and S. okinawensis (Symplocaceae) is described from Okinawa Island, Japan. The new species is ...distinguishable from the Japanese Symplocos feeding described species, C. symplocosella Kobayashi & Hirowatari, 2016 by the forewing coloration, the shape of genitalia, and also DNA barcodes.
Calmodulin (CaM) is a key modulator of the channel gating function of the ryanodine receptor (RyR).
The purpose of this study was to investigate the pathogenic role of RyR-bound CaM in diastolic Ca
...leakage from the sarcoplasmic reticulum and arrhythmogenesis in pressure-overloaded heart failure.
Pressure overload was induced in 12-week-old mice by transverse aortic constriction (TAC) using a 27-gauge needle.
TAC operation for 8 weeks produced a significant increase in left ventricular end-diastolic diameter and frequent occurrence of lethal arrhythmias after infusion of epinephrine and caffeine in TAC mice. The amount of RyR-bound CaM decreased significantly in TAC mice compared with sham mice. The apparent affinity of CaM binding to RyR decreased in pressure-overloaded cells compared with sham cells and untreated cells. High-affinity calmodulin (HA-CaM; ie, CaM whose binding affinity to RyR was significantly increased) restored a normal level of CaM-RyR binding properties in pressure-overloaded cells. HA-CaM corrected abnormally increased Ca
spark frequency in the pressure-overloaded cells to the level seen in the sham cells. The frequency of spontaneous Ca
transients in TAC cells during and after 1-5 Hz of field stimulation was 44%, whereas it was significantly attenuated by HA-CaM but not with CaM.
Several disorders in the RyR channel function characteristic of pressure-overloaded cells (increased spontaneous Ca
leakage, delayed afterdepolarization, triggered activity, Ca
spark frequency, spontaneous Ca
transients) are caused by deteriorated CaM binding to RyR2. These disorders could be rectified by restoring normal CaM binding to RyR2.
Steroid therapy, a key therapy for inflammatory, allergic, and immunological disorders, is often associated with steroid myopathy as one of the side effects. Steroid therapy is considered the ...first-line therapy for myositis; however, there have been no reports strictly comparing the muscle mass in patients with myositis before and after steroid therapy. Thus, it is currently unclear whether steroid therapy for such patients affects muscle volume in addition to muscle strength. We aimed to determine the change in muscle mass after steroid therapy via cross-sectional computed tomography (CT) in patients with myositis.
Data from seven patients with myositis and eight controls, who were all treated with high doses of steroids, were assessed before and after steroid therapy. Clinical factors in patients with myositis included serum muscle enzyme levels and muscular strength. The cross-sectional area of skeletal muscle and the low muscle attenuation rate at the level of the caudal end of the third lumbar vertebra were obtained using CT and measured using an image analysis program for all patients. Data were subjected to statistical analysis using several well-established statistical tests. The Wilcoxon signed-rank test was used for comparing paired data for each patient. The Mann-Whitney U test was used to compare sets of data sampled from two groups. The Spearman's rank correlation coefficient was used for determining the correlations between two variables. Statistical significance was set at p < 0.05.
Muscular strength and serum muscle enzyme levels improved following steroid therapy in patients with myositis. In both groups, the cross-sectional areas of skeletal muscles decreased (myositis group: p = 0.0156; control group: p = 0.0391) and the low muscle attenuation rate tended to increase (myositis group: p = 0.0781; control group: p = 0.0547). In the myositis group, patients with chronic obstructive pulmonary disease showed a tendency toward muscle volume loss (p = 0.0571).
In patients with myositis treated with steroid therapy, muscle mass decreased after steroid therapy suggesting that the improvement in muscle strength was due to factors other than a change in muscle volume. Our study suggests the importance of therapies that not only improve muscle mass but also improve the quality of muscle strength.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•The pulmonary vein isolation (PVI) alone strategy was sufficient to suppress persistent atrial fibrillation (AF) in 66% of persistent AF patients.•Superior vena cava isolation (SVCI) suppressed ...persistent AF in some patients with persistent AF resistant to PVI.•A sequential PVI and SVCI suppressed persistent AF in 74% of persistent AF patients.•Persistent AF duration predicted the persistent AF recurrence after sequential PVI and SVCI.
An effective catheter ablation strategy, beyond pulmonary vein isolation (PVI), for persistent atrial fibrillation (AF) is necessary. Pulmonary vein (PV)-reconduction also causes recurrent atrial tachyarrhythmias. The effect of the PVI and additional effect of a superior vena cava (SVC) isolation (SVCI) was strictly evaluated.
Seventy consecutive patients with persistent AF who underwent a strict sequential ablation strategy targeting the PVs and SVC were included in this study. The initial ablation strategy was a circumferential PVI. A segmental SVCI was only applied as a repeat procedure when patients demonstrated no PV-reconduction.
After the initial procedure, persistent AF was suppressed in 39 of 70 (55.7%) patients during a median follow-up of 32 months. After multiple procedures, persistent AF was suppressed in 46 (65.7%) and 52 (74.3%) patients after receiving the PVI alone and PVI plus SVCI strategies, respectively. In 6 of 15 (40.0%) patients with persistent AF resistant to PVI, persistent AF was suppressed. The persistent AF duration independently predicted persistent AF recurrences after multiple PVI alone procedures HR: 1.012 (95% confidence interval: 1.006–1.018); p<0.001 and PVI plus SVCI strategies HR: 1.018 (95% confidence interval: 1.011–1.025); p<0.001. A receiver-operating-characteristic analysis for recurrent persistent AF indicated an optimal cut-off value of 20 and 32 months for the persistent AF duration using the PVI alone and PVI plus SVCI strategies, respectively.
The outcomes of the PVI plus SVCI strategy were favorable for patients with shorter persistent AF durations. The initial SVCI had the additional effect of maintaining sinus rhythm in some patients with persistent AF resistant to PVI.
Aberrant diastolic Ca2+ leak through the cardiac ryanodine receptor（RyR2）is an important cause of heart failure（HF）and lethal arrhythmia. Dantrolene directly binds to the Leu601-Cys620 region of ...RyR2, corrects defective inter-subunit interactions between the N-terminal domain and the central domain within RyR2, and then enhances the binding affinity of calmodulin（CaM）to RyR2, thus subsequently inhibiting diastolic Ca2+ leakage（zipping/unzipping hypothesis）．We demonstrated the anti-HF and anti-arrhythmic effects of dantrolene in a chronic-phase pressure-overloaded HF model or a catecholaminergic polymorphic ventricular tachycardia（CPVT）-associated RyR2（R2474S/+）knock-in mouse model. Furthermore, our single-center, interventional, open-label, uncontrolled study reported the acute effect of an intravenous injection of dantrolene in the context of a VT storm or sustained VT（sVT）in patients with HF resistant to guideline-directed medical therapy with β-blockers and class III anti-arrhythmic drugs. Thus, dantrolene, a RyR2 stabilizer, is a new type of anti-arrhythmic drug without negative inotropic action and QT prolongation. These beneficial effects are different from those of other anti-arrhythmic drugs such as beta-blockers or amiodarone. Hence it would be useful and appropriate for the treatment of patients with HF.
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