-
Heart Rhythm O2 Nov 2023The current antiarrhythmic paradigm is mainly centered around modulating membrane voltage. However, abnormal cytosolic calcium (Ca) signaling, which plays an important... (Review)
Review
Uncoupling cytosolic calcium from membrane voltage by transient receptor potential melastatin 4 channel (TRPM4) modulation: A novel strategy to treat ventricular arrhythmias.
The current antiarrhythmic paradigm is mainly centered around modulating membrane voltage. However, abnormal cytosolic calcium (Ca) signaling, which plays an important role in driving membrane voltage, has not been targeted for therapeutic purposes in arrhythmogenesis. There is clear evidence for bidirectional coupling between membrane voltage and intracellular Ca. Cytosolic Ca regulates membrane voltage through Ca-sensitive membrane currents. As a component of Ca-sensitive currents, Ca-activated nonspecific cationic current through the TRPM4 (transient receptor potential melastatin 4) channel plays a significant role in Ca-driven changes in membrane electrophysiology. In myopathic and ischemic ventricles, upregulation and/or enhanced activity of this current is associated with the generation of afterdepolarization (both early and delayed), reduction of repolarization reserve, and increased propensity to ventricular arrhythmias. In this review, we describe a novel concept for the management of ventricular arrhythmias in the remodeled ventricle based on mechanistic concepts from experimental studies, by uncoupling the Ca-induced changes in membrane voltage by inhibition of this TRPM4-mediated current.
PubMed: 38034891
DOI: 10.1016/j.hroo.2023.10.001 -
Anesthesiology and Pain Medicine Jun 2023Schwartz-Jampel syndrome (SJS) is a rare autosomal recessive disease characterized by muscle weakness and stiffness, abnormal bone development, short stature, joint...
INTRODUCTION
Schwartz-Jampel syndrome (SJS) is a rare autosomal recessive disease characterized by muscle weakness and stiffness, abnormal bone development, short stature, joint contractures, and facial dysmorphisms. Myopathy, anatomical deformities, and malignant hyperthermia are challenging for anesthesiologists.
CASE PRESENTATION
This case report describes one case of SJS. The female patient was scheduled for Blepharoplasty in Rasuol Akram General Hospital.
CONCLUSIONS
These patients may have difficult intubation and be prone to malignant hyperthermia. We managed this patient by applying Rocuronium, propofol, and C-MAC video laryngoscopy.
PubMed: 38021333
DOI: 10.5812/aapm-129305 -
International Journal of Molecular... Nov 2023Exertional heat illness (EHI) is an occupational health hazard for athletes and military personnel-characterised by the inability to thermoregulate during exercise. The...
Exertional heat illness (EHI) is an occupational health hazard for athletes and military personnel-characterised by the inability to thermoregulate during exercise. The ability to thermoregulate can be studied using a standardised heat tolerance test (HTT) developed by The Institute of Naval Medicine. In this study, we investigated whole blood gene expression (at baseline, 2 h post-HTT and 24 h post-HTT) in male subjects with either a history of EHI or known susceptibility to malignant hyperthermia (MHS): a pharmacogenetic condition with similar clinical phenotype. Compared to healthy controls at baseline, 291 genes were differentially expressed in the EHI cohort, with functional enrichment in inflammatory response genes (up to a four-fold increase). In contrast, the MHS cohort featured 1019 differentially expressed genes with significant down-regulation of genes associated with oxidative phosphorylation (OXPHOS). A number of differentially expressed genes in the inflammation and OXPHOS pathways overlapped between the EHI and MHS subjects, indicating a common underlying pathophysiology. Transcriptome profiles between subjects who passed and failed the HTT (based on whether they achieved a plateau in core temperature or not, respectively) were not discernable at baseline, and HTT was shown to elevate inflammatory response gene expression across all clinical phenotypes.
Topics: Humans; Male; Transcriptome; Malignant Hyperthermia; Heat Stress Disorders; Exercise; Survivors
PubMed: 38003313
DOI: 10.3390/ijms242216124 -
Genes Oct 2023Remimazolam 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...
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. Ten patients had myotubes obtained from skeletal muscle cultures, and the genes associated with malignant hyperthermia in these patients were analyzed. The EC of caffeine, cresol, and remimazolam to induce intracellular calcium concentration change were compared between myotubes from CICR-negative genetic test patients and myotubes from other patients. Eight of the ten were CICR-positive, five of whom had RYR1 causative gene mutations or variants. Two patients had CICR-negative genetic tests, and as expected had the highest EC (the concentration of a drug that gives a half-maximal response) in response to caffeine, 4CmC and remimazolam. Three patients had a positive CICR but no known variants in RYR1 or CACNA1S (voltage-gated calcium channel subunit alpha1S). Myotubes in these patients had significantly lower EC50s for all agents than myotubes in CICR-negative patients. When myotubes from a patient who was CICR-negative and had no gene variant were used as a control, myotubes from CICR-positive patients were more hyper-responsive than controls to all stimulants used. The EC for remimazolam was lowest for myotubes from CICR-positive, RYR1-mutant patients, at 206 µM (corresponding to 123 µg/mL). The concentration was more than 80-times higher than the clinical concentration. gene variants in R4645Q and W5020G were shown to be causative gene mutations for MH. Intracellular calcium in myotubes from MH patients are elevated at high concentrations of remimazolam but not at clinically used concentrations of remimazolam. Remimazolam appears to be safe to use in patients with MH.
Topics: Humans; Ryanodine Receptor Calcium Release Channel; Malignant Hyperthermia; Calcium; Caffeine; Muscle Fibers, Skeletal
PubMed: 38002952
DOI: 10.3390/genes14112009 -
Neuromuscular Disorders : NMD Dec 2023Malignant hyperthermia is a pharmacogenetic disorder triggered by halogenated anesthetic agents in genetically predisposed individuals. Approximately 70 % of these...
Malignant hyperthermia is a pharmacogenetic disorder triggered by halogenated anesthetic agents in genetically predisposed individuals. Approximately 70 % of these individuals carry mutations in RYR1, the gene encoding the ryanodine receptor calcium channel of skeletal muscle. In this study, we performed functional analysis of 5 RYR1 variants identified in members from 8 families who had been diagnosed by the IVCT. Of the 68 individuals enrolled in the study, 43 were diagnosed as MHS, 23 as MHN, and 2 individuals were not tested. Here we demonstrate that the 5 RyR1 variants cause hypersensitivity to RyR1 agonist-mediated calcium release. According to the EMHG scoring matrix these five genetic variants can be classified as follows: c.8638G>A (p.E2880K) and c.11314C>T (p.R3772W) likely pathogenic, c.11416G>A (p.G3806R), c.14627A>G (p.K4876R) and c.14813T>C (p.I4938T), pathogenic (RefSeq NM_000540.3). We propose that the newly functionally characterized RYR1 variants, be included in the panel of variants to be used for the molecular diagnosis of MHS.
Topics: Humans; Calcium; Genetic Predisposition to Disease; Malignant Hyperthermia; Muscle, Skeletal; Mutation; Ryanodine Receptor Calcium Release Channel
PubMed: 37996280
DOI: 10.1016/j.nmd.2023.10.019 -
Biomaterials Research Nov 2023Malignant bone tumors are characterized by severe disability rate, mortality rate, and heavy recurrence rate owing to the complex pathogenesis and insidious disease... (Review)
Review
Malignant bone tumors are characterized by severe disability rate, mortality rate, and heavy recurrence rate owing to the complex pathogenesis and insidious disease progression, which seriously affect the terminal quality of patients' lives. Photothermal therapy (PTT) has emerged as an attractive adjunctive treatment offering prominent hyperthermal therapeutic effects to enhance the effectiveness of surgical treatment and avoid recurrence. Simultaneously, various advanced biomaterials with photothermal capacity are currently created to address malignant bone tumors, performing distinctive biological functions, including nanomaterials, bioceramics (BC), polymers, and hydrogels et al. Furthermore, PTT-related combination therapeutic strategies can provide more significant curative benefits by reducing drug toxicity, improving tumor-killing efficiency, stimulating anti-cancer immunity, and improving immune sensitivity relative to monotherapy, even in complex tumor microenvironments (TME). This review summarizes the current advanced biomaterials applicable in PTT and relevant combination therapies on malignant bone tumors for the first time. The multiple choices of advanced biomaterials, treatment methods, and new prospects for future research in treating malignant bone tumors with PTT are generalized to provide guidance. Malignant bone tumors seriously affect the terminal quality of patients' lives. Photothermal therapy (PTT) has emerged as an attractive adjunctive treatment enhancing the effectiveness of surgical treatment and avoiding recurrence. In this review, advanced biomaterials applicable in the PTT of malignant bone tumors and their distinctive biological functions are comprehensively summarized for the first time. Simultaneously, multiple PTT-related combination therapeutic strategies are classified to optimize practical clinical issues, contributing to the selection of biomaterials, therapeutic alternatives, and research perspectives for the adjuvant treatment of malignant bone tumors with PTT in the future.
PubMed: 37968707
DOI: 10.1186/s40824-023-00453-z -
Neuromuscular Disorders : NMD Dec 2023
Topics: Humans; Myopathies, Structural, Congenital; Orthognathic Surgery; Ryanodine Receptor Calcium Release Channel; Female; Adult
PubMed: 37945484
DOI: 10.1016/j.nmd.2023.10.005 -
International Journal of Nanomedicine 2023Radiotherapy is a pivotal method for treating malignant tumors, and enhancing the therapeutic gain ratio of radiotherapy through physical techniques is the direction of... (Review)
Review
The Refined Application and Evolution of Nanotechnology in Enhancing Radiosensitivity During Radiotherapy: Transitioning from Gold Nanoparticles to Multifunctional Nanomaterials.
Radiotherapy is a pivotal method for treating malignant tumors, and enhancing the therapeutic gain ratio of radiotherapy through physical techniques is the direction of modern precision radiotherapy. Due to the inherent physical properties of high-energy radiation, enhancing the therapeutic gain ratio of radiotherapy through radiophysical techniques inevitably encounters challenges. The combination of hyperthermia and radiotherapy can enhance the radiosensitivity of tumor cells, reduce their radioresistance, and holds significant clinical utility in radiotherapy. Multifunctional nanomaterials with excellent biocompatibility and safety have garnered widespread attention in tumor hyperthermia research, demonstrating promising potential. Utilizing nanotechnology as a sensitizing carrier in conjunction with radiotherapy, and high atomic number nanomaterials can also serve independently as radiosensitizing carriers. This synergy between tumor hyperthermia and radiotherapy may overcome many challenges currently limiting tumor radiotherapy, offering new opportunities for its further advancement. In recent years, the continuous progress in the synthesis and design of novel nanomaterials will propel the future development of medical imaging and cancer treatment. This article summarizes the radiosensitizing mechanisms and effects based on gold nanotechnology and provides an overview of the advancements of other nanoparticles (such as bismuth-based nanomaterials, magnetic nanomaterials, selenium nanomaterials, etc.) in the process of radiation therapy.
Topics: Humans; Gold; Metal Nanoparticles; Nanostructures; Nanotechnology; Radiation Tolerance; Neoplasms
PubMed: 37936951
DOI: 10.2147/IJN.S436268 -
Indian Journal of Critical Care... Nov 2023: Accamma K, Shamarao S, Ram A, Devananda NS, Krishna M, Bandagi LS, . Severe Diabetic Ketoacidosis with Malignant Hyperthermia Like Syndrome and Rhabdomyolysis Treated...
: Accamma K, Shamarao S, Ram A, Devananda NS, Krishna M, Bandagi LS, . Severe Diabetic Ketoacidosis with Malignant Hyperthermia Like Syndrome and Rhabdomyolysis Treated with ECMO: Unusual Severity and a Rare Occurrence. Indian J Crit Care Med 2023;27(11):859-860.
PubMed: 37936798
DOI: 10.5005/jp-journals-10071-24569 -
European Radiology Experimental Nov 2023Malignant tumors routinely present with irregular shapes and complex configurations. The lack of customization to individual tumor shapes and standardization of...
BACKGROUND
Malignant tumors routinely present with irregular shapes and complex configurations. The lack of customization to individual tumor shapes and standardization of procedures limits the success and application of thermal ablation.
METHODS
We introduced an automated treatment model consisting of (i) trajectory and ablation profile planning, (ii) ablation probe insertion, (iii) dynamic energy delivery (including robotically driven control of the energy source power and location over time, according to a treatment plan bespoke to the tumor shape), and (iv) quantitative ablation margin verification. We used a microwave ablation system and a liver phantom (acrylamide polymer with a thermochromic ink) to mimic coagulation and measure the ablation volume. We estimated the ablation width as a function of power and velocity following a probabilistic model. Four representative shapes of liver tumors < 5 cm were selected from two publicly available databases. The ablated specimens were cut along the ablation probe axis and photographed. The shape of the ablated volume was extracted using a color-based segmentation method.
RESULTS
The uncertainty (standard deviation) of the ablation width increased with increasing power by ± 0.03 mm (95% credible interval [0.02, 0.043]) per watt increase in power and by ± 0.85 mm (95% credible interval [0, 2.5]) per mm/s increase in velocity. Continuous ablation along a straight-line trajectory resulted in elongated rotationally symmetric ablation shapes. Simultaneous regulation of the power and/or translation velocity allowed to modulate the ablation width at specific locations.
CONCLUSIONS
This study offers the proof-of-principle of the dynamic energy delivery system using ablation shapes from clinical cases of malignant liver tumors.
RELEVANCE STATEMENT
The proposed automated treatment model could favor the customization and standardization of thermal ablation for complex tumor shapes.
KEY POINTS
• Current thermal ablation systems are limited to ellipsoidal or spherical shapes. • Dynamic energy delivery produces elongated rotationally symmetric ablation shapes with varying widths. • For complex tumor shapes, multiple customized ablation shapes could be combined.
Topics: Humans; Microwaves; Liver Neoplasms; Ablation Techniques; Models, Theoretical
PubMed: 37932631
DOI: 10.1186/s41747-023-00381-6