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BioRxiv : the Preprint Server For... Jan 2024As the primary Ca release channel in skeletal muscle sarcoplasmic reticulum (SR), mutations in the type 1 ryanodine receptor (RyR1) or its binding partners underlie a...
As the primary Ca release channel in skeletal muscle sarcoplasmic reticulum (SR), mutations in the type 1 ryanodine receptor (RyR1) or its binding partners underlie a constellation of muscle disorders, including malignant hyperthermia (MH). In patients with MH mutations, exposure to triggering drugs such as the halogenated volatile anesthetics biases RyR1 to an open state, resulting in uncontrolled Ca release, sarcomere tension and heat production. Restoration of Ca into the SR also consumes ATP, generating a further untenable metabolic load. When anesthetizing patients with known MH mutations, the non-triggering intravenous general anesthetic propofol is commonly substituted for triggering anesthetics. Evidence of direct binding of anesthetic agents to RyR1 or its binding partners is scant, and the atomic-level interactions of propofol with RyR1 are entirely unknown. Here, we show that propofol decreases RyR1 opening in heavy SR vesicles and planar lipid bilayers, and that it inhibits activator-induced Ca release from SR in human skeletal muscle. In addition to confirming direct binding, photoaffinity labeling using azipropofol (AziP ) revealed several putative propofol binding sites on RyR1. Prediction of binding affinity by molecular dynamics simulation suggests that propofol binds at least one of these sites at clinical concentrations. These findings invite the hypothesis that in addition to propofol not triggering MH, it may also be protective against MH by inhibiting induced Ca flux through RyR1.
PubMed: 38260485
DOI: 10.1101/2024.01.10.575040 -
Stem Cell Research Jun 2024RYR1 variants are the most common genetic cause of congenital myopathies, and typically cause central core disease (CCD) and/or malignant hyperthermia (MH). Here, we...
Generation of two iPSC lines from patients with inherited central core disease and concurrent malignant hyperthermia caused by dominant missense variants in the RYR1 gene.
RYR1 variants are the most common genetic cause of congenital myopathies, and typically cause central core disease (CCD) and/or malignant hyperthermia (MH). Here, we generated iPSC lines from two patients with CCD and MH caused by dominant RYR1 variants within the central region of the protein (p.Val2168Met and p.Arg2508Cys). Both lines displayed typical iPSC morphology, uniform expression of pluripotency markers, trilineage differentiation potential, and had normal karyotypes. These are the first RYR1 iPSC lines from patients with both CCD and MH. As these are common CCD/MH variants, these lines should be useful to study these conditions and test therapeutics.
Topics: Humans; Ryanodine Receptor Calcium Release Channel; Malignant Hyperthermia; Induced Pluripotent Stem Cells; Mutation, Missense; Myopathy, Central Core; Male; Female; Cell Line; Cell Differentiation
PubMed: 38583293
DOI: 10.1016/j.scr.2024.103410 -
African Journal of Paediatric Surgery :... Jan 2024Transanal endorectal pull-through (TERPT) has become one of the preferred treatments for Hirschsprung's disease (HD) in our setting. This report aims to evaluate the...
BACKGROUND
Transanal endorectal pull-through (TERPT) has become one of the preferred treatments for Hirschsprung's disease (HD) in our setting. This report aims to evaluate the current outcome of TERPT in the setting.
MATERIALS AND METHODS
A retrospective review of 71 children who had TERPT for histologically-confirmed HD in 11 years (2006-2017) in Nigeria.
RESULTS
There were 48 boys and 23 girls; aged 3 days-12 years at initial presentation (median = 10 months). Three (4.2%) patients had associated anomalies (duodenal atresia; anorectal malformation and sensorineural deafness with hypopigmented skin patches each). Age at TERPT was 2 months to 15 years (median = 3 years), with surgery waiting time of 1 month-14.9 years (median = 18 months). Sixty-six (93.0%) patients had rectosigmoid, four (5.6%) patients had long segment and one (1.4%) had total colonic disease. Five (7.0%) patients with large megacolon and one (1.4%) with the total colonic disease had assisted abdominal resection of the colon at TERPT. Seventeen (23.9%) patients had post-operative complications, including post-operative enterocolitis 8 (11.3%); anastomotic dehiscence 3 (4.2%); retained aganglionic segment 2 (2.8%); anastomotic stenosis 2 (2.8%), resulting in prolonged hospital stay (P = 0.0001; range = 1-30 days; median = 5 days). The mortality rate was 4.2% (3) from malignant hyperthermia in one patient and in 2 patients, the cause of mortality was unclear. Patients were followed up for 3-6 years (median = 3.5 years). Bowel movement stabilised to 2-4 times daily by 6 weeks after surgery.
CONCLUSION
TERPT is a safe treatment for HD in this setting with good short-term outcomes. Longer follow-up is necessary to further evaluate the long-term bowel movement outcomes.!
Topics: Male; Child; Female; Humans; Hirschsprung Disease; Colonic Diseases; Anastomosis, Surgical; Anorectal Malformations
PubMed: 38259012
DOI: 10.4103/ajps.ajps_93_22 -
The Journal of International Medical... Jun 2024Malignant hyperthermia (MH), characterized by severe myoclonus, pyrexia, tachycardia, hypertension, elevated muscle enzymes, and hypercapnia, often occurs in patients...
Malignant hyperthermia (MH), characterized by severe myoclonus, pyrexia, tachycardia, hypertension, elevated muscle enzymes, and hypercapnia, often occurs in patients with congenital deformities or genetic disorders. Although the reported incidence rate is as low as 1:5000 to 1:100,000, patients with MH exhibit rapid aggravation and an elevated mortality rate. Thus, MH is associated with substantial perioperative risk. Successful treatment of patients with MH largely depends on early diagnosis and timely effective treatment. This clinical report provides a detailed description of a patient with newly diagnosed MH who developed a rapid rise in body temperature, end-tidal carbon dioxide, and heart rate during maxillary osteotomy. After successful rescue, the patient recovered smoothly during the postoperative period, indicating the importance of intraoperative monitoring, early diagnosis, effective treatment, and postoperative monitoring. This case is expected to serve as a reference for future interventions and healthcare practices in managing other patients with MH.
Topics: Humans; Malignant Hyperthermia; Anesthesia, General; Male; Female; Adult; Osteotomy
PubMed: 38907364
DOI: 10.1177/03000605241261962 -
Biomedicine & Pharmacotherapy =... Sep 2023Although hyperthermia-based photothermal therapy (PTT) has achieved great success in the battle against malignant tumors, various commonly used photothermal sensitizers...
BACKGROUND
Although hyperthermia-based photothermal therapy (PTT) has achieved great success in the battle against malignant tumors, various commonly used photothermal sensitizers still suffer from non-selective tumor accumulation, limited photothermal conversion efficiency, potential toxicity and side effects, as well as complex and low cost-effective preparation process. Therefore, novel photothermal sensitizers are urgently required. The well-organized self-assembling of natural bacteriochlorophylls with superior photothermal property may provide an interesting option for the engineering of ideal PTS.
METHODS
Inspired by the self-assembly peripheral light-harvesting antennas of natural bacteriochlorin in microorganisms, a biomimetic light-harvesting nanosystem (Nano-Bc) was developed via bacteriochlorophylls self-arranging in aqueous phase. The characterization of Nano-Bc were measured using DLS, TEM, UV-vis-near-infrared spectroscopy and preclinical PA imaging system. The cytotoxicity of Nano-Bc was quantitatively evaluated via a standard MTT assay using mouse breast cancer 4T1 cells, and the in vivo photothermal eradication of tumor was investigated in the 4T1 breast tumor-bearing mouse model.
RESULTS
The obtained bacteriochlorin nanoparticles (Nano-Bc) exhibited ultra-high photothermal performance within the biological transparent window, showing superior heating capacity compared to commonly used photothermal sensitizers of organic dye indocyanine green and inorganic gold nanorods. Guiding by the inherent photoacoustic imaging of Nano-Bc, complete tumor elimination in vitro and vivo was evidenced upon laser irradiation.
CONCLUSION
The green and facile preparation, ultra-high photothermal effect in the transparent window, excellent photoacoustic imaging capacity, and great biosafety prompt, the bio-inspired Nano-Bc as a promising theranostic platform against cancer in the areas of healthcare.
Topics: Animals; Mice; Phototherapy; Bacteriochlorophylls; Cell Line, Tumor; Hyperthermia, Induced; Nanoparticles; Theranostic Nanomedicine
PubMed: 37327585
DOI: 10.1016/j.biopha.2023.115014 -
Cureus Jan 2024Intracranial immature teratomas are rare, highly malignant, and fast-growing with a poor prognosis. We report the case of an infant with a large immature teratoma in the...
Intracranial immature teratomas are rare, highly malignant, and fast-growing with a poor prognosis. We report the case of an infant with a large immature teratoma in the intracranial compartment. A two-month-old child presented to the emergency room with drowsiness and seizures. CT and cranial MRI showed hydrocephalus with a large expansive process in the right cerebral hemisphere extending to the infratentorial compartment, compressing the cerebellum and brainstem. It was then decided to partially resect the lesion. Postoperatively, due to the aggressiveness of the residual tumor, the patient developed complications (status epilepticus, hyperthermia, and electrolyte disorders) and died. Histopathological and immunohistochemical studies confirmed an immature teratoma. Teratomas are a subtype of germ cell tumors. Immature teratomas contain a population of cells that retain embryonic characteristics and tissues with more primitive components derived from all or some of the three germ layers (ectoderm, mesoderm, and endoderm). The prognosis of immature teratomas is associated with the degree of tumor differentiation, and those composed of undifferentiated embryonic tissues have a poor prognosis. This case report illustrates the rare and severe occurrence of a bulky immature cerebral teratoma in an infant. Unfortunately, despite undergoing a planned partial resection, the infant ended up having complications and died. Therefore, due to the size of the lesion in an infant, these cases are always complex when deciding on a surgical approach.
PubMed: 38196986
DOI: 10.7759/cureus.51891 -
The American Journal of Case Reports Dec 2023BACKGROUND The anesthetic management of patients with Charcot-Marie-Tooth disease (CMT) requires special deliberation. Previous literature has suggested that patients...
BACKGROUND The anesthetic management of patients with Charcot-Marie-Tooth disease (CMT) requires special deliberation. Previous literature has suggested that patients with CMT may have increased sensitivity to non-depolarizing neuromuscular blocking agents, and hyperkalemia associated with the administration of succinylcholine has been reported. The potential risk of malignant hyperthermia and underlying cardiopulmonary abnormalities, such as pre-existing arrhythmias, cardiomyopathy, or respiratory muscle weakness, must also be considered in patients with CMT. CASE REPORT We describe a case of a patient with a history of CMT and multivessel coronary artery disease who underwent coronary artery bypass grafting (CABG). Careful consideration was given to the anesthetic plan, which consisted of thorough pre- and perioperative evaluation of cardiac function, total intravenous anesthesia with propofol and remifentanil infusions, the use of a non-depolarizing neuromuscular blocking agent, and utilization of a malignant hyperthermia protocol with avoidance of volatile anesthetics to decrease the possible risk of malignant hyperthermia. Following a 3-vessel CABG, no anesthetic or surgical complications were noted and the patient was discharged on postoperative day 6 after an uneventful hospital course. CONCLUSIONS Exacerbation of underlying cardiac and pulmonary abnormalities associated with the pathophysiology of CMT, as well as patient response to neuromuscular blocking and volatile agents, should be of concern for the anesthesiologist when anesthetizing a patient with CMT. Therefore, CMT patients undergoing surgery require special consideration of their anesthetic management plan in order to ensure patient safety and optimize perioperative outcomes.
Topics: Humans; Coronary Artery Disease; Charcot-Marie-Tooth Disease; Malignant Hyperthermia; Anesthetics; Coronary Artery Bypass
PubMed: 38117749
DOI: 10.12659/AJCR.940284 -
The American Journal of Case Reports Dec 2023BACKGROUND Malignant mesotheliomas are rare, yet highly malignant tumors. Mesotheliomas are tumors that develop from mesothelial surfaces, with the pleura being the most...
A 51-Year-Old Woman with Advanced Peritoneal Mesothelioma and Stage 3b Chronic Kidney Disease Treated with Cytoreductive Surgery and Bidirectional Intraperitoneal Cisplatin and Ifosfamide Chemotherapy: A Case Report.
BACKGROUND Malignant mesotheliomas are rare, yet highly malignant tumors. Mesotheliomas are tumors that develop from mesothelial surfaces, with the pleura being the most common, followed by the peritoneum. The diagnosis of malignant peritoneal mesothelioma (MPM) is usually established when the disease is advanced, owing to the nonspecific clinical appearance and abdominal symptoms. Initially, MPM was treated with palliative systemic chemotherapy, with or without palliative surgery. However, cytoreductive surgery (CRS) combined with bidirectional intraoperative chemotherapy (BDIC) has recently emerged as a treatment option for MPM. BDIC creates a bidirectional chemotherapy gradient in the peritoneal tumor cells through the simultaneous use of intraperitoneal and intravenous chemotherapy. CRS, combined with BDIC (CRS-BDIC), allows the complete elimination of residual tiny tumor cells after complete removal of the visible tumor nodules. CASE REPORT Herein, we present a case of a 51-year-old woman with MPM and chronic kidney disease (CKD) stage 3b. Her treatment consisted of neoadjuvant chemotherapy and immunotherapy, followed by CRS-BDIC using intraperitoneal cisplatin and doxorubicin, and intravenous ifosfamide. The surgery was successful, with no immediate complications or decline in the patient's kidney function. On follow up 2 months later, the patient denies suffering any chemotherapy-related adverse effects, and her kidney profile remains stable. CONCLUSIONS In conclusion, nephrotoxicity, a known adverse effect of cisplatin and ifosfamide, might not be a contraindication for the use of these potentially nephrotoxic drugs in CRS-BDIC in patients with renal impairment.
Topics: Female; Humans; Middle Aged; Mesothelioma, Malignant; Cisplatin; Peritoneal Neoplasms; Ifosfamide; Cytoreduction Surgical Procedures; Combined Modality Therapy; Hyperthermia, Induced; Mesothelioma; Antineoplastic Combined Chemotherapy Protocols; Renal Insufficiency; Renal Insufficiency, Chronic
PubMed: 38093612
DOI: 10.12659/AJCR.941726 -
Anesthesiology Oct 2023
Topics: Animals; Mice; Malignant Hyperthermia; Calcium; Halothane
PubMed: 37535934
DOI: 10.1097/ALN.0000000000004676 -
Scientific Reports Dec 2023Malignant neoplasms are one of the main causes of death, especially in children, on a global scale, despite strenuous efforts made at advancing both diagnostic and...
Malignant neoplasms are one of the main causes of death, especially in children, on a global scale, despite strenuous efforts made at advancing both diagnostic and therapeutic modalities. In this regard, a new nanocarrier Vincristine (VCR)-loaded Pluronic f127 polymer-coated magnetic nanoparticles conjugated with folic acid and transferrin (PMNP-VCR-FA-TF) were synthesized and characterized by various methods. The cytotoxicity of these nanoparticles was evaluated in vitro and ex vivo conditions. The in vitro anti-tumor effect of the nanoparticles was evaluated by colony formation assay (CFA) and reactive oxygen species (ROS) in Y79 cell line. The results showed that nanoparticles with two ligands conferred greater toxicity toward Y79 cancer cells than ARPE19 normal cells. Under an alternating magnetic field (AMF), these nanoparticles demonstrated a high specific absorption rate. The CFA and ROS results indicated that the AMF in combination with PMNP-VCR-FA-TF conferred the highest cytotoxicity toward Y79 cells compared with other groups (P < 0.05). PMNP-VCR-FA-TF could play an important role in converting externally applied radiofrequency energy into heat in cancer cells. The present study confirmed that dual targeting chemo-hyperthermia using PMNP-VCR-FA-TF was significantly more effective than hyperthermia or chemotherapy alone, providing a promising platform for precision drug delivery as an essential component in the chemotherapy of retinoblastoma.
Topics: Child; Humans; Retinoblastoma; Reactive Oxygen Species; Folic Acid; Transferrin; Magnetite Nanoparticles; Hyperthermia, Induced; Vincristine; Retinal Neoplasms; Nanoparticles; Cell Line, Tumor
PubMed: 38102193
DOI: 10.1038/s41598-023-49171-5