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Striated MusclesSkeletal and Cardiac Muscles
Published in Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal, Principles of Physiology for the Anaesthetist, 2020
Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal
The motor nerve action potential depolarizes the nerve terminal and releases acetylcholine from the synaptic vesicles into the junctional cleft. Acetylcholine excites the postjunctional nicotinic receptors, depolarizes the end plate and generates a propagated action potential in the surrounding muscle membrane (Figure 12.9). Muscle shortening then follows by the process of excitation–contraction coupling. Acetylcholine is soon metabolized by acetylcholinesterase, and the end plate returns to the resting state. Neuromuscular transmission is an amplification process whereby a nerve action potential produces a much larger muscle action potential. Acetylcholine therefore has a central role in the process of neuromuscular transmission (Figure 12.10).
Diagnosis and Differential Diagnosis
Published in Marc H. De Baets, Hans J.G.H. Oosterhuis, Myasthenia Gravis, 2019
The diagnosis of MG must meet the following requirements: Symptoms and signs are explained by muscle weakness of a peripheral type and influenced by exertion and rest of the muscle group concerned.In the course of the disease, at least one muscle group innervated by a cranial motor nerve is involved.These features are assessed by history taking and appropriate testing.The weakness is caused by a failure of neuromuscular transmission. This feature is assessed by demonstrating the specific effect of anticholinesterase medicaments (edrophonium, neostigmine, pyridostigmine), or by electromyographic procedures (repetitive nerve stimulation, single fiber EMG).A specific immunologic abnormality is present, i.e., the presence of antibodies to acetylcholine receptors (AChR-ab), which also implies an affection of the neuromuscular synapse.
Myasthenia gravis
Published in Hemanshu Prabhakar, Charu Mahajan, Indu Kapoor, Manual of Neuroanesthesia, 2017
Prasanna U. Bidkar, Lakshmi K. Narmadha
Edrophonium chloride has rapid onset (within 30 s) and short duration (5 min) of action which is administered intravenously. It increases the concentration of acetylcholine by inhibiting acetylcholinesterase at the NMJ, thus improving muscle weakness. If the muscle strength improves, the test results are considered positive. Development of increased weakness suggests abnormal neuromuscular transmission. Hence, resuscitation equipment and drugs should be kept ready. A total of up to 10 mg edrophonium is administered with a small dose to begin with. This is especially to avoid the muscarinic side effects of edrophonium at larger bolus doses. Side effects of edrophonium include bradycardia, increased salivation, sweating, nausea, stomach cramps, and muscle fasciculations. The sensitivity of edrophonium test is 85% for ocular MG and 96% for generalized MG.10
Zilucoplan: An Investigational Complement C5 Inhibitor for the Treatment of Acetylcholine Receptor Autoantibody–Positive Generalized Myasthenia Gravis
Published in Expert Opinion on Investigational Drugs, 2021
James F. Howard, John Vissing, Nils E. Gilhus, M. Isabel Leite, Kimiaki Utsugisawa, Petra W. Duda, Ramin Farzaneh-Far, Hiroyuki Murai, Heinz Wiendl
Normal neuromuscular transmission is mediated by the binding of presynaptic acetylcholine to acetylcholine receptors (AChRs) in the postsynaptic membrane of the neuromuscular junction (NMJ). In MG, this transmission is impaired by autoantibodies that bind to AChRs or to functionally related molecules [1]. Anti-AChR antibodies are present in 80% to 88% of patients with MG, and contribute to early-onset (i.e., prior to 50 years of age), late-onset (i.e., ≥50 years), thymoma-associated, and ocular MG disease subtypes [5,20,21]. A smaller proportion of patients (<10%) harbor autoantibodies against muscle-specific kinase (MuSK) or lipoprotein-related protein 4 or are seronegative for all three autoantibodies [22–25]. The differences in MG antibody subtype have a major impact on treatment decisions [12]. This article focuses primarily on patients with anti-AChR antibody-positive (AChR+) gMG.
Pyrethroid based pesticides – chemical and biological aspects
Published in Critical Reviews in Toxicology, 2021
Anandha Rao Ravula, Suresh Yenugu
OPs or esters of phosphoric acid are ecologically good alternatives to OCs as they are not persistent in the environment. The most common of this class is glyphosate, a weedicide. The other OPs include malathion, parathion, dimethoate and chlorpyrifos. Global usage of organophosphate insecticides is more than 30% and according to Environmental Protection Agency (EPA) reports, more than 50% of total OPs are used in many crops, particularly cotton and corn in USA (Edwards 2006). In insects and mammals, OPs affect neuromuscular transmission by interfering with acetylcholinesterase (AChE) in cholinergic synapsis via phosphorylation of this enzyme resulting in excess accumulation of acetylcholine (Ach). This leads to death due to asphyxia, loss of respiratory control and over stimulation in cholinergic pathways (Reigart and Roberts 2013). Apart from neurotoxicity, they are also associated with aberrations in insulin secretion, metabolism, mitochondrial function and endocrine function (Nicolopoulou-Stamati et al. 2016).
In vitro models of neuromuscular junctions and their potential for novel drug discovery and development
Published in Expert Opinion on Drug Discovery, 2020
Olaia F Vila, Yihuai Qu, Gordana Vunjak-Novakovic
Myasthenia gravis is the most common disorder of neuromuscular transmission. It is an autoimmune condition caused by autoantibodies that bind the AChR or associated proteins in the NMJ, resulting in their destruction through complement-induced damage and receptor endocytosis [63]. Impairment of NMJ function results in muscular weakness of different severities. MG is estimated to affect 15 to 200 per million people, with an incidence of 2–22 new diagnoses per million people each year [64]. Due to its autoimmune nature, the myasthenic phenotype can be recapitulated in these in vitro models by simply adding patient serum to the system. Steinbeck et al. [59] were the first to do this, using an optogenetic monolayer coculture system. Their results show reduced light responsiveness after treatment with immunoglobulins G (IgG) from MG patients and serum containing complement. Normal function was recovered after washing of the MG IgG, recapitulating the therapeutic effect of plasmapheresis during myasthenic crises. Afshar Bakooshli et al. [57] also incorporated MG IgGs in their tissue-engineered model, showing localized deposition of complement on NMJs. Our group [62] has recently reported the use of an automated optical stimulation system to demonstrate that in vitro NMJ models responded heterogeneously to serum from different patients, recapitulating the known variability in phenotype severity.