B-lymphocytes from Malignant Hyperthermia-susceptible Patients Have an Increased Sensitivity to Skeletal Muscle Ryanodine Receptor Activators

Malignant hyperthermia (MH) is a pharmacogenetic disease triggered by volatile anesthetics and succinylcholine in genetically predisposed individuals. The underlying feature of MH is a hypersensitivity of the calcium release machinery of the sarcoplasmic reticulum, and in many cases this is a result of point mutations in the skeletal muscle ryanodine receptor calcium release channel (RYR1). RYR1 is mainly expressed in skeletal muscle, but a recent report demonstrated the existence of this isoform in human B-lymphocytes. As B-cells can produce a number of cytokines, including endogenous pyrogens, we investigated whether some of the symptoms seen during MH could be related to the involvement of the immune system. Our results show that (i) Epstein-Barr virus-immortalized B-cells from MH-susceptible individuals carrying the V2168M RYR1 gene mutation were more sensitive to the RYR activator 4-chloro-m-cresol and (ii) their peripheral blood leukocytes produce more interleukin (IL)-1beta after treatment with the RYR activators caffeine and 4-chloro-m-cresol, compared with cells from healthy controls. Our result demonstrate that RYR1-mediated calcium signaling is involved in release of IL-1beta from B-lymphocytes and suggest that some of the symptoms seen during an MH episode may be due to IL-1beta production

Detection of a novel RYR1 mutation in four malignant hyperthermia pedigrees

Malignant hyperthermia (MH) is a potentially fatal autosomal dominant disorder of skeletal muscle and is triggered in susceptible people by all commonly used inhalational anaesthetics and depolarizing muscle relaxants. To date, six mutations in the skeletal muscle ryanodine receptor gene (RYR1) have been identified in malignant hyperthermia susceptible (MHS) and central core disease (CCD) cases. Using SSCP analysis, we have screened the RYR1 gene in affected individuals for novel MHS mutations and have identified a G to A transition mutation which results in the replacement of a conserved Gly at position 2433 with an Arg. The Gly2433Arg mutation was present in four of 104 unrelated MHS individuals investigated and was not detected in a normal population sample. This mutation is adjacent to the previously identified Arg2434His mutation reported in a CCD/MH family and indicates that there may be a second region in the RYR1 gene where MHS/CCD mutations cluste

Enhanced excitation-coupled Ca2+ entry induces nuclear translocation of NFAT and contributes to IL-6 release from myotubes from patients with central core disease

Prolonged depolarization of skeletal muscle cells induces entry of extracellular calcium into muscle cells, an event referred to as excitation-coupled calcium entry. Skeletal muscle excitation-coupled calcium entry relies on the interaction between the 1,4-dihydropyridine receptor on the sarcolemma and the ryanodine receptor on the sarcoplasmic reticulum membrane. In this study, we directly measured excitation-coupled calcium entry by total internal reflection fluorescence microscopy in human skeletal muscle myotubes harbouring mutations in the RYR1 gene linked to malignant hyperthermia (MH) and central core disease (CCD). We found that excitation-coupled calcium entry is strongly enhanced in cells from patients with CCD compared with individuals with MH and controls. Furthermore, excitation-coupled calcium entry induces generation of reactive nitrogen species and enhances nuclear localization of NFATc1, which in turn may be responsible for the increased IL-6 released by myotubes from patients with CC

Rare, potentially fatal, poorly understood propofol infusion syndrome

We present the case of a 7-year old boy with traumatic brain injury who received propofol during 38 h. Thirty-six hours after cessation of propofol infusion asystole occurred. After immediate mechanical and medical resuscitation, unreactive dilated pupils were observed. The following computed tomography scan revealed a generalized brain edema with transtentorial herniation. Prolonged bradyarrhythmia, rhabdomyolysis, and peracute renal failure were observed. Despite immediate craniectomy, barbiturate treatment, hemofiltration, and recovery of appropriate cardiac function, the patient died four days after discontinuation of propofol. In this case, metabolic acidosis, cardiac failure, rhabdomyolysis, and renal failure are in accordance with the symptoms of propofol infusion syndrome (PRIS), while seizure, brain edema, and transtentorial herniation could be caused by traumatic brain injury. However, it may be assumed that the entire clinical picture was caused by PRIS. This view could be explained by a common loss of function of ryanodine receptors in patients presenting with PRIS

Language difficulties in outpatients and their impact on a chronic pain unit in Northwest Switzerland

Many foreign patients attending our pain clinic are unable to understand one of the four Swiss national languages and are also unable to speak English. Therefore, communication with these patients can be very difficult or even impossible. Consequently, diagnosis and treatment may also prove difficult. Recognizing that language barriers can have deleterious effects, the use of an interpreter is at times the only way to communicate, however, the financial responsibility becomes that of the health care provider

Molecular genetic testing for malignant hyperthermia susceptibility

BACKGROUND: For more than 30 yr, the in vitro contracture test (IVCT) was the only appropriate diagnostic tool for malignant hyperthermia (MH). After the introduction of molecular genetics into MH research, guidelines for molecular genetic diagnosis of MH susceptibility were published. The aim of this study was to establish applicability of the guidelines, sensitivity, and specificity of genetic testing in MH and advantages for studied patients. METHODS: The IVCT was performed following the guidelines of the European MH Group. Mutation analyses were performed by amplification of genomic DNA by polymerase chain reaction and restriction enzyme digestion. RESULTS: Two hundred eight individuals underwent MH testing between January 2001 and April 2003. In 32 of 67 initially genetic-tested patients, the familial mutation was identified, and they were diagnosed as MH susceptible. The IVCT followed negative genetic test results in 20 patients, and all but one had negative IVCT results. Three patients were scheduled to undergo elective surgery, and IVCT and genetic testing were performed simultaneously. All three had positive IVCT results and were carriers of their familial mutation. CONCLUSIONS: In families with known MH mutations, there is a 50% chance of reliably confirming MH susceptibility by noninvasive testing. The authors found the negative predictive value of genetic testing to be 0.95 (95% confidence interval, 0.75-0.99), but for patient safety, they still recommend following the guidelines for genetic testing in MH and therefore performing an IVCT in case of negative genetic results

Tropisetron blocks analgesic action of acetaminophen : a human pain model study

Because the mechanism underlying the analgesic action of acetaminophen remains unclear, we investigated the possible interaction of acetaminophen with central serotonergic pathways. The effects of acetaminophen, tropisetron, the combination of both drugs, and saline on pain perception and central sensitization in healthy volunteers were compared. Sixteen healthy volunteers were included in this randomized, double-blind, placebo-controlled crossover study. Intracutaneous electrical stimulation (46.1 ± 19.1 mA) induced acute pain (numeric rating scale, 6 of 10) and stable areas of hyperalgesia and allodynia. Pain intensities and areas of hyperalgesia and allodynia were regularly assessed before, during, and after a 15-min infusion of acetaminophen, tropisetron, the combination of both drugs, and saline. Acetaminophen concentrations were measured to rule out any pharmacokinetic interaction. Both acetaminophen and tropisetron led to decreased pain ratings as compared to saline. However, when acetaminophen and tropisetron were administered simultaneously, the pain ratings were not affected. There was no significant difference in the evolution of the hyperalgesic and allodynic areas during the study period between the study groups (P = .06 and P = .33, respectively). Acetaminophen serum levels were not significantly different when associated with tropisetron (P = .063), although we observed a trend toward lower acetaminophen concentrations when both drugs were concurrently administered. In summary, while the combination of acetaminophen and tropisetron showed no analgesic action, each drug administered alone led to decreased pain ratings as compared to saline. In an electrically evoked human pain model, the combination of acetaminophen with tropisetron was free of any analgesic potential. However, when administered on its own, both acetaminophen and tropisetron were mildly analgesic