Effects of Remimazolam on Intracellular Calcium Dynamics in Myotubes Derived from Patients with Malignant Hyperthermia and Functional Analysis of Type 1 Ryanodine Receptor Gene Variants.

Remimazolam is a novel general anesthetic and its safety in patients with malignant hyperthermia (MH) is unknown. We used myotubes derived from the skeletal muscle of patients with MH to examine the response to ryanodine receptor 1 (RYR1) agonist and remimazolam in MH-susceptible patients. Patients underwent muscle biopsy for the Ca-induced Ca release (CICR) rate test, a diagnostic tool for MH in Japan.

Rapid Dantrolene Administration with Body Temperature Monitoring Is Associated with Decreased Mortality in Japanese Malignant Hyperthermia Events.

Purpose: Malignant hyperthermia (MH) is a rare genetic disorder but one of the most severe complications of general anesthesia. The mortality rate of MH has dropped from 70% in the 1960s to 15% because of dantrolene, the only currently accepted specific treatment for MH. In this study, we retrospectively identified the optimal dantrolene administration conditions to reduce MH mortality further.

The effects of dantrolene in the presence or absence of ryanodine receptor type 1 variants in individuals predisposed to malignant hyperthermia.

Dantrolene is currently the only drug known to specifically treat malignant hyperthermia (MH) crises. Although dantrolene attenuates Ca disorders by acting mainly on the ryanodine receptor type 1 (RYR1), some patients who manifest MH without variants have also been successfully treated with dantrolene. Thus, dantrolene appears to have an inhibitory effect on patients with and without variants.

Age-Specific Clinical Features of Pediatric Malignant Hyperthermia: A Review of 187 Cases Over 60 Years in Japan.

Background: Malignant hyperthermia (MH) is an inherited muscle disorder induced by volatile anesthetics and depolarizing muscle relaxants. While the incidence of MH is high in young, there are few reports on the clinical features of pediatric MH. In this study, we selected pediatric cases from an MH database and analyzed the clinical findings by age group.

Effects of Remimazolam and Propofol on Ca Regulation by Ryanodine Receptor 1 with Malignant Hyperthermia Mutation.

Background: We investigated the potential safety of remimazolam and propofol in malignant hyperthermia- (HM-) susceptible patients using ryanodine receptor 1- (RYR1-) expressing human embryonic kidney- (HEK-) 293 cells.

Methods: We compared the enhanced responsiveness of HEK-293 cells expressing wild-type with that of mutant to caffeine following perfusion with remimazolam or propofol. Furthermore, we investigated whether RYR1 enhanced the responsiveness of cells to remimazolam or propofol and compared the median effective concentration (EC; i.

Retraction Note to: Functional analysis of newly identified RYR1 variants in patients susceptible to malignant hyperthermia.

The authors have retracted this article because they did not have permission to use the data in Tables 1 and 2.

Functional analysis of newly identified RYR1 variants in patients susceptible to malignant hyperthermia.

Purpose: This study aimed to evaluate whether the three ryanodine receptor type 1 (RYR1) variants (p.Ser2345Thr, p.Ser2345Arg, and p.

Branched-chain amino acids-induced cardiac protection against ischemia/reperfusion injury.

Aims: Amino acids, especially branched chain amino acids (BCAAs), have important regulatory roles in protein synthesis. Recently studies revealed that BCAAs protect against ischemia/reperfusion (I/R) injury. We studied the signaling pathway and mitochondrial function affecting a cardiac preconditioning of BCAAs.

Postoperative thoracic and low back pain following endovascular aortic repair associated with stenting location.

Background: We have noted that patients frequently complain of thoracic or low back pain after undergoing an endovascular aortic repair, which we speculated was caused by the indwelling stent.

Methods: We investigated the patients who underwent an elective thoracic or abdominal endovascular aortic repair (TEVAR or EVAR) and noted the location of stent, and postoperative pain. The incidence of either thoracic or low back pain at individual vertebra levels was determined, after which we fitted the sigmoidal function to the discrete data to obtain a cut-off line.

Myotoxicity of local anesthetics is equivalent in individuals with and without predisposition to malignant hyperthermia.

Purpose: Malignant hyperthermia (MH) is an inherited muscle disorder caused by abnormal elevations of intracellular calcium (Ca) in skeletal muscle. There are several reports of myotoxicity caused by local anesthetics, and the increased intracellular Ca is considered to be an important cause. However, there is insufficient evidence regarding myotoxicity in MH-susceptible individuals when large doses of local anesthetics are administered.

Genetic and functional analysis of the RYR1 mutation p.Thr84Met revealed a susceptibility to malignant hyperthermia.

Purpose: The aim of this study was to analyze the genetic and functional role of a novel RYR1 variant c.251 C > T (p.Thr84Met) identified in a patient with muscle weakness demonstrating MH susceptibility.

Transient symptomatic worsening by atropine in opsoclonus-myoclonus syndrome.

Opsoclonus-myoclonus syndrome (OMS) is characterized by abnormal eye and systemic involuntary movements, as well as cerebellar ataxia. Some sedatives and anesthetics worsen movements associated with OMS, while there is no known report of a negative effect of atropine. We report on sedation in two patients with OMS.

Propofol for Anesthesia and Postoperative Sedation Resulted in Fewer Inflammatory Responses than Sevoflurane Anesthesia and Midazolam Sedation after Thoracoabdominal Esophagectomy.

Responses to surgical stress can be modulated by anesthetics. We prospectively compared the effects of two different anesthetic/sedative techniques on the peak postoperative bladder temperature (BT) and the postoperative C-reactive protein (CRP) level. Twenty patients who were scheduled to undergo elective thoracoabdominal esophagectomy were allocated to receive either propofol anesthesia followed by propofol sedation (PP group, n = 10) or sevoflurane anesthesia followed by midazolam sedation (SM group, n = 10).

Several Ryanodine Receptor Type 1 Gene Mutations of p.Arg2508 Are Potential Sources of Malignant Hyperthermia.

Background: Malignant hyperthermia (MH) is a pharmacogenetic disorder that occurs in predisposed individuals after exposure to volatile anesthetics or depolarizing muscle relaxants. Genetic mutations of ryanodine receptor 1 (RYR1), which are considered to cause MH, are found mainly in 3 regions called "hotspots." There are sometimes multiple mutations at the same site of RYR1.

Factors related to accidental dural puncture in epidural anesthesia patients.

Objectives: Accidental dural puncture (ADP) is known as a complication of epidural anesthesia. Although puncture site and advanced age have been reported to increase the risk of ADP, all related factors have not been fully investigated. We retrospectively investigated factors related to ADP in patients undergoing surgery.

Intrathecal adrenomedullin modulates acute inflammatory pain in the rat formalin test.

Adrenomedullin (AM), a member of the calcitonin gene-related peptide (CGRP) family, has been demonstrated to be a pronociceptive mediator. This study was undertaken to investigate the role of AM in acute inflammatory pain induced by formalin injection in rats. Interestingly Cerebrospinal fluid (CSF) levels of AM increased 45 min after formalin injection and a selective AM receptor antagonist, AM22-52, administered intrathecally (i.

JP-45/JSRP1 variants affect skeletal muscle excitation-contraction coupling by decreasing the sensitivity of the dihydropyridine receptor.

JP-45 (also JP45; encoded by JSRP1) is an integral protein constituent of the skeletal muscle sarcoplasmic reticulum junctional face membrane interacting with Ca(v) 1.1 (the α.1 subunit of the voltage-sensing dihydropyridine receptor, DHPR) and the luminal calcium-binding protein calsequestrin.

Calcium channel blockers are inadequate for malignant hyperthermia crisis.

Purpose: Malignant hyperthermia (MH) results from disordered calcium (Ca(2+)) homeostasis in skeletal muscle during general anesthesia. Although Ca(2+) channel blockers may be given to treat the tachycardia and circulatory instability, coadministration of Ca(2+) channel blockers and dantrolene is contraindicated during MH crisis. We evaluated the effect of Ca(2+) channel blockers on Ca(2+) homeostasis and their interactions with dantrolene in human skeletal muscle.

Mutated p.4894 RyR1 function related to malignant hyperthermia and congenital neuromuscular disease with uniform type 1 fiber (CNMDU1).

Background: Ryanodine receptor 1 (RyR1) is a Ca(2+) release channel located in the sarcoplasmic reticulum membrane of skeletal muscle. More than 200 variants in RyR1 have been identified in DNA from patients with malignant hyperthermia (MH) and congenital myopathies; only 30 have been sufficiently studied so as to be identified as MH-causative mutations. The Ala4894Thr RyR1 variant was found in a Japanese patient with susceptibility to MH, and the Ala4894Pro variant in a rare case of myopathy: congenital neuromuscular disease with uniform type 1 fiber (CNMDU1).

Functional analysis of ryanodine receptor type 1 p.R2508C mutation in exon 47.

Purpose: Malignant hyperthermia (MH) is a pharmacogenetic disorder of intracellular calcium homeostasis with an autosomal dominant inheritance. Most of the reported mutations in exon 47 were identified in Asian patients. However, no functional analysis of p.

Thiamylal and thiopental attenuate beta-adrenergic signaling pathway by suppressing adenylyl cyclase in rat ventricular myocytes.

The effects of intravenous anesthetics on myocytes have not been fully elucidated. To investigate the effects of various intravenous anesthetics such as fentanyl, morphine, ketamine, diazepam, midazolam, thiamylal, and thiopental on the beta-adrenergic signaling pathway, we measured isoproterenol-stimulated cyclic adenosine monophosphate (cAMP) production in freshly isolated rat ventricular myocytes. Fentanyl, morphine, ketamine, diazepam, and midazolam did not significantly affect isoproterenol-stimulated cAMP production.

Intrathecally administered COX-2 but not COX-1 or COX-3 inhibitors attenuate streptozotocin-induced mechanical hyperalgesia in rats.

Members of the cyclooxygenase (COX) family are known to catalyze the rate-limiting steps of prostaglandins synthesis and reported to be involved in neuropathic pain. Diabetic neuropathy is a type of neuropathic pain, though it is not clear if COX is relevant to the condition. Recently, spinal COX-2 protein was found to be increasing in streptozotocin-induced rats as compared to the constitutive expression.

Liver X receptor ligands inhibit the lipopolysaccharide-induced expression of microsomal prostaglandin E synthase-1 and diminish prostaglandin E2 production in murine peritoneal macrophages.

Microsomal prostaglandin E synthase (mPGES)-1, which is dramatically induced in macrophages by inflammatory stimuli such as lipopolysaccharide (LPS), catalyzes the conversion of cyclooxygenase-2 (COX-2) reaction product prostaglandin H(2) (PGH(2)) into prostaglandin E(2) (PGE(2)). The mPGES-1-derived PGE(2) is thought to help regulate inflammatory responses. On the other hand, excess PGE(2) derived from mPGES-1 contributes to the development of inflammatory diseases such as arthritis and inflammatory pain.

Suppression of inducible nitric oxide synthase and cyclooxygenase-2 gene expression by 22(R)-hydroxycholesterol requires de novo protein synthesis in activated macrophages.

Liver X receptors (LXRs) play an important role in lipid metabolism. Recently, a role for these proteins was identified in suppressing the inflammatory response. However, it is not known whether the natural ligands of LXRs, e.