BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) may cause sudden cardiac death (SCD) despite medical therapy. Therefore, implantable cardioverter-defibrillators (ICDs) are commonly advised. However, there is limited data on the outcomes of ICD use in children.
OBJECTIVE: The purpose of this study was to compare the risk of arrhythmic events in pediatric patients with CPVT with and without an ICD.
METHODS: We compared the risk of SCD in patients with RYR2 (ryanodine receptor 2) variants and phenotype-positive symptomatic CPVT patients with and without an ICD who were younger than 19 years and had no history of sudden cardiac arrest at phenotype diagnosis. The primary outcome was SCD; secondary outcomes were composite end points of SCD, sudden cardiac arrest, or appropriate ICD shocks with or without arrhythmic syncope.
RESULTS: The study included 235 patients, 73 with an ICD (31.1%) and 162 without an ICD (68.9%). Over a median follow-up of 8.0 years (interquartile range 4.3-13.4 years), SCD occurred in 7 patients (3.0%), of whom 4 (57.1%) were noncompliant with medications and none had an ICD. Patients with ICD had a higher risk of both secondary composite outcomes (without syncope: hazard ratio 5.85; 95% confidence interval 3.40-10.09; P < .0001; with syncope: hazard ratio 2.55; 95% confidence interval 1.50-4.34; P = .0005). Thirty-one patients with ICD (42.5%) experienced appropriate shocks, 18 (24.7%) inappropriate shocks, and 21 (28.8%) device-related complications.
CONCLUSIONS: SCD events occurred only in patients without an ICD and mostly in those not on optimal medical therapy. Patients with an ICD had a high risk of appropriate and inappropriate shocks, which may be reduced with appropriate device programming. Severe ICD complications were common, and risks vs benefits of ICDs need to be considered.

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In order to develop anthranilic diamides with novel chemotypes, a series of anthranilic diamides with acrylamide linkers were designed and synthesized. The results of preliminary bioassays indicated that compounds with a monofluoroalkene amide linker (Z-isomer) exhibited good larvicidal activity against lepidopteran pests. The LC50 values of compound A23 against Mythimna separata and Plutella xylostella were 1.44 and 3.48 mg·L-1, respectively, while those of chlorantraniliprole were 0.08 and 0.06 mg·L-1, respectively. Compound A23 also exhibited the same level of lethal potency against resistant and susceptible strains of Spodoptera frugiperda at 50 mg·L-1. Compound A23 exhibited similar symptoms as chlorantraniliprole in test larvae. Comparative molecular field analysis was conducted to demonstrate the structure-activity relationship. Central neuron calcium imaging experiments indicated that monofluoroalkene compounds were potential ryanodine receptor (RyR) activators and activated calcium channels in both the endoplasmic reticulum and the cell membrane. Molecular docking suggested that A23 had a better binding potency to P. xylostella RyR than chlorantraniliprole. The MM|GBSA dG bind value of A23 with P. xylostella RyR was 117.611 kcal·mol-1. Monofluoroalkene was introduced into anthranilic diamide insecticides for the first time and brought a novel chemotype for insect RyR activators. The feasibility of fluoroalkenes as insecticide fragments was explored.

Background: Cognitive impairment is very common in Parkinson\'s disease (PD) and constitutes the most debilitating complication of this disease. However, to date, few studies have investigated a genome-wide association in the development of cognitive impairment of PD. We aimed to identify the genetic loci associated with cognitive impairment in patients with sporadic PD by ethnicity-specific genotyping. Materials and methods: We recruited 1,070 patients with PD and performed a genome-wide association study using the Korean Chip, a microarray chip containing 827,400 single-nucleotide polymorphisms (SNPs) optimized for the Korean population. Multiple logistic regression models adjusting for age, sex, years of education, and disease duration were used to compare between patients with and without cognitive impairment, which was defined using the Mini-Mental Status Examination (MMSE) score (MMSE score ≥ 26 vs. < 26) or the Montreal Cognitive Assessment (MoCA) score (MoCA score ≥24 vs. < 24). Results: RYR2 SNP rs10495397 was most significantly associated with cognitive impairment based on the MMSE scores (OR = 3.21; 95% CI = 1.96-5.25, P = 3.36 × 10-6) and CASC17 showed the strongest association with cognitive impairment based on the MoCA scores. However, none of the SNPs were statistically significant after Bonferroni correction. Conclusion: RYR2 may play a role in cognitive impairment in PD by the pathogenic mechanism of neuroinflammation. However, more studies are needed to replicate and validate the results of our functional study.

Leakage of Ca2+ from the sarcoplasmic reticulum (SR) is a critical contributing factor to heart failure pathophysiology. Therefore, reducing SR Ca2+ leaks may provide significant additive benefits when used in combination with conventional therapies. Dantrolene, a drug routinely used to treat malignant hyperthermia, also stabilizes the cardiac isoform of the release channel (RyR2), thus decreasing SR Ca2+ leaks. The purpose of this study is to evaluate the effect of chronic administration of dantrolene on heart failure and lethal arrhythmia in patients with chronic heart failure and reduced ejection fraction in a multicenter, randomized, double-blind, controlled study.
Patients with chronic heart failure who had functional status of New York Heart Association class II and III and a left ventricular ejection fraction <40% were treated according to the Japanese Circulation Society, the European Society of Cardiology, and the American Heart Association/the American College of Cardiology guidelines for diagnosis and treatment of acute and chronic heart failure. Patients were randomized and divided into two groups in a double-blind fashion: dantrolene group and placebo group (target sample size: 300 cases). These drugs were administered for 96 weeks. The primary endpoint is cardiovascular death, first hospitalization for exacerbation of heart failure, or lethal arrhythmia [ventricular tachycardia (VT) storm, sustained VT, ventricular fibrillation] for 2 years after starting administration of dantrolene 1 cap (25mg) three times daily (if not tolerable, two times daily) or matching placebo.
This paper presents the rationale and trial design of the study. Recruitment for the study started on 8 December 2017.
The results of this trial will clarify the efficacy and safety of dantrolene for ventricular arrhythmia, as well as mortality and morbidity in patients with chronic heart failure and reduced ejection fraction during guideline-directed medical treatment.

BACKGROUND: Diamide insecticides, including phthalic and anthranilic diamides, target insect ryanodine receptors (RyRs) and cause misregulation of calcium signaling in insect muscles and neurons. Several resistance mutations have been reported to reduce the efficacy of the diamides, but the exact binding sites and mechanism of resistance mutations are not clear.
RESULTS: The recent breakthrough in structural studies of mammalian RyRs has deepened our understanding of these giant calcium-release channels, but structural information about insect RyRs is still scarce. The only reported high-resolution structure is from the N-terminal domain of diamondback moth (DBM) RyR determined by our group. Here, we generate several homology models of full-length DBM RyR representing different functional states and dock the diamide insecticides into the structural models using Schrodinger software. These models reveal the specific structural features, activation mechanism, structural difference between functional states, ligand-binding sites and insecticide-binding sites of DBM RyR. By comparing the structures of wild-type and insecticide-resistant mutants, we propose a model depicting how the mutations affect the insecticide binding. We also identify the key difference between mammalian and insect RyRs that may explain the species-specific binding properties of diamides.
CONCLUSIONS: The binding sites for three activators Ca2+ , ATP and caffeine, and regulator ryanodine are conserved in insect and mammalian RyRs, but the binding site for diamide insecticides is species-specific. The phthalic and anthranilic diamides have distinct binding properties in DBM, which can be interfered by resistance mutations located in the transmembrane region. © 2019 Society of Chemical Industry.

The aim of this study was to investigate the effects of an enzymatic removal of glycogen on excitation-contraction coupling in mechanically skinned fibres of rat fast-twitch muscles, with a focus on the changes in the function of Na+-K+-pump and ryanodine receptor (RyR). Glycogen present in the skinned fibres and binding to microsomes was removed using glucoamylase (GA). Exposure of whole muscle to 20 U mL-1 GA for 6 min resulted in a 72% decrease in the glycogen content. Six minutes of GA treatment led to an 18 and a 22% reduction in depolarization- and action potential-induced forces in the skinned fibres, respectively. There was a minor but statistically significant increase in the repriming period, most likely because of an impairment of the Na+-K+-pump function. GA treatment exerted no effect on the maximum Ca2+ release rate from the RyR in the microsomes and the myofibrillar Ca2+ sensitivity in the skinned fibres. These results indicate that reduced glycogen per se can decrease muscle performance due to the impairment of SR Ca2+ release and suggest that although Na+-K+-pump function is adversely affected by reduced glycogen, the extent of the impairment is not sufficient to reduce Ca2+ release from the sarcoplasmic reticulum. This study provides direct evidence that glycogen above a certain amount is required for the preservation of the functional events preceding Ca2+ release from the sarcoplasmic reticulum.

[Ca2+] transients inside the sarcoplasmic reticulum (SR) were recorded in frog skeletal muscle twitch fibers under voltage clamp using the low affinity indicator Mag Fluo 4 (loaded in its AM form) with the purpose of studying the effect on Ca2+ release of extrinsic Ca2+ buffers (i.e. BAPTA) added at high concentration to the myoplasm. When the extrinsic Ca2+ buffer is added to the myoplasm, part of the released Ca2+ binds to it, reducing the Ca2+ signal reported by a myoplasmic indicator. This, in turn, hinders the quantification of the amount of Ca2+ released. Monitoring release by measuring [Ca2+] inside the SR avoids this problem. The application of extrinsic buffers at high concentration reduced the resting [Ca2+] in the SR ([Ca2+]SR) continuously from a starting value close to 400 μM reaching the range of 100 μM in about half an hour. The effect of reducing resting [Ca2+]SR on the Ca2+ permeability of the SR activated by voltage clamp depolarization to 0 mV was studied in cells where the myoplasmic [Ca2+] ([Ca2+]myo) transients were simultaneously recorded with Rhod2. The Ca2+ release flux was calculated from [Ca2+]myo and divided by [Ca2+]SR to obtain the permeability. Peak permeability was significantly reduced, from 0.026 ± 0.005 ms-1 at resting [Ca2+]SR = 372 ± 5 μM to 0.021 ± 0.004 ms-1 at resting [Ca2+]SR = 120 ± 16 μM (n = 4, p = 0.03). The time averaged permeability was not significantly changed (0.009 ± 0.003 and 0.010 ± 0.003 ms-1, at the higher and lower [Ca2+]SR respectively). Once the cells were equilibrated with the high buffer intracellular solution, the change in [Ca2+]SR (Δ[Ca2+]SR) in response to voltage clamp depolarization (0 mV, 200 ms) in 20 mM BAPTA was significantly lower (Δ[Ca2+]SR = 30.2 ± 3.5 μM from resting [Ca2+]SR = 88.8 ± 13.6 μM, n = 5) than in 40 mM EGTA (Δ[Ca2+]SR = 72.2 ± 10.4 μM from resting [Ca2+]SR = 98.2 ± 15.6 μM, n = 4) suggesting that a Ca2+ activated component of release was suppressed by BAPTA.

Subarachnoid hemorrhage (SAH) remains a challenging neurosurgical disease. The ryanodine receptor type 1 Ca2+ channel (RyR1) plays a crucial role in vasoconstriction and hemostasis. Mutations of the encoding gene, RYR1, are known to cause susceptibility to malignant hyperthermia (MH). Recently, a RYR1 mutation was found to be associated with abnormal bleeding times. Therefore, an assessment of the RYR1 gene might be of high relevance in patients with aneurysmatic SAH. In the presented pilot study, we screened 10 patients suffering from SAH for RYR1 variants and, for the first time in SAH, performed an assessment of pathogenicity of these variants using protein prediction software. Four of the patients showed a RYR1 variant. For three of the variants, p.Glu79Lys, p.Arg885C, p.Glu2635 Val, all three programs predicted pathogenicity. Their prevalence in the general population is very low i.e. under 0.005%. For the fourth variant, p.Pro4501Leu (RS73933023), the results of the prediction programs were discrepant and the prevalence in the general population was high, i.e. almost 0.5%, which is too frequent to be associated with the rare SAH phenotype. Clinical evaluation revealed that no differences concerning neurological outcome, presence of vasospasm, ischemic deficits and mean hospital stay between patients with and without variants were found. However, in our series SAH patients have an increased frequency of rare RYR1 variants. Hence, potentially contributing to the pathogenesis of SAH. Further data is needed to confirm this preliminary result.

Raising the intracellular [Ca2+] ([Ca2+]i) was previously found to produce uncoupling between the electrical depolarization of the transverse tubules and contraction in skinned muscle fibers. Here we study the effect of elevated [Ca2+]i in voltage clamped cut fibers of frog skeletal muscle to establish how the charge movement, a measure of the activation of the dihydropyridine receptors (DHPR)-voltage sensors, and Ca2+ release, a consequence of the opening of the ryanodine receptor (RyR)-release channels, were affected. [Ca2+]i was raised by various procedures (pharmacological release from the sarcoplasmic reticulum, application of high [Ca2+]i intracellular solution, permeabilization of the plasma membrane by a Ca2+ ionophore) all of which produced impairment of excitation-contraction coupling. The charge movement was reduced from 20.2 ± 1.24 to 9.9 ± 0.94 nC/μF meanwhile the Ca2+ release flux was reduced from 13.5 + 0.7 to 2.2 ± 0.3 μM/ms (n = 33). This suggests that a significant fraction of the DHPRs that remained functional, could not activate RyRs, and were therefore presumably disconnected. These results are broadly consistent with the original reports in skinned fibers. Uncoupling was prevented by the addition to the intracellular solution of the protease inhibitor leupeptin. In approximately 40 % of the uncoupled cells we observed that the [Ca2+]i transient continued to rise after the voltage clamp pulse was turned off. This loss of control by membrane voltage suggests that the uncoupled release channels might have another mechanism of activation, likely by Ca2+.