The Experts below are selected from a list of 165 Experts worldwide ranked by ideXlab platform
James H. Tonsgard - One of the best experts on this subject based on the ideXlab platform.
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In vitro microelectrode study of neuromuscular transmission in a case of botulism
Muscle & Nerve, 1992Co-Authors: Ricardo A Maselli, Margaret E. Burnett, James H. TonsgardAbstract:We performed in vitro microelectrode studies in the anconeus muscle biopsy of a 6-week-old infant intoxicated with Clostridium botulinum toxin B. The most striking abnormalities were the severe reduction of the Endplate Potential (EPP) quantal content and the marked variability of EPP latencies. The increased variability was often limited to a “single quantum” component of the EPP. Neither the amplitudes nor the frequencies of spontaneous miniature Endplate Potentials (MEEPs) were decreased. However, there was a wide range of amplitudes and frequencies of MEPPs. This unique combination of electrophysiologic findings indicates a severe presynaptic failure of neuromuscular transmission, which appears to result from an impairment of the process of synaptic vesicle release taking place after the stimulus induced influx of calcium into the motor nerve terminals.
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In vitro microelectrode study of neuromuscular transmission in a case of botulism
Muscle & Nerve, 1992Co-Authors: Ricardo A Maselli, Margaret E. Burnett, James H. TonsgardAbstract:We performed in vitro microelectrode studies in the anconeus muscle biopsy of a 6-week-old infant intoxicated with Clostridium botulinum toxin B. The most striking abnormalities were the severe reduction of the Endplate Potential (EPP) quantal content and the marked variability of EPP latencies. The increased variability was often limited to a “single quantum” component of the EPP. Neither the amplitudes nor the frequencies of spontaneous miniature Endplate Potentials (MEEPs) were decreased. However, there was a wide range of amplitudes and frequencies of MEPPs. This unique combination of electrophysiologic findings indicates a severe presynaptic failure of neuromuscular transmission, which appears to result from an impairment of the process of synaptic vesicle release taking place after the stimulus induced influx of calcium into the motor nerve terminals.
Ricardo A Maselli - One of the best experts on this subject based on the ideXlab platform.
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Mutations in MUSK causing congenital myasthenic syndrome impair MuSK–Dok-7 interaction
Human Molecular Genetics, 2010Co-Authors: Ricardo A Maselli, Juan Arredondo, Órla Cagney, Jarae J. Ng, Jennifer A. Anderson, Colette Williams, Bae J. Gerke, Betty Soliven, Robert L WollmannAbstract:We describe a severe congenital myasthenic syndrome (CMS) caused by two missense mutations in the gene encoding the muscle specific receptor tyrosine kinase (MUSK). The identified MUSK mutations M605I and A727V are both located in the kinase domain of MuSK. Intracellular microelectrode recordings and microscopy studies of the neuromuscular junction conducted in an anconeus muscle biopsy revealed decreased miniature Endplate Potential amplitudes, reduced Endplate size and simplification of secondary synaptic folds, which were consistent with postsynaptic deficit. The study also showed a striking reduction of the Endplate Potential quantal content, consistent with additional presynaptic failure. Expression studies in MuSK deficient myotubes revealed that A727V, which is located within the catalytic loop of the enzyme, caused severe impairment of agrin-dependent MuSK phosphorylation, aggregation of acetylcholine receptors (AChRs) and interaction of MuSK with Dok-7, an essential intracellular binding protein of MuSK. In contrast, M605I, resulted in only moderate impairment of agrin-dependent MuSK phosphorylation, aggregation of AChRs and interaction of MuSK with Dok-7. There was no impairment of interaction of mutants with either the low-density lipoprotein receptor-related protein, Lrp4 (a co-receptor of agrin) or with the mammalian homolog of the Drosophila tumorous imaginal discs (Tid1). Our findings demonstrate that missense mutations in MUSK can result in a severe form of CMS and indicate that the inability of MuSK mutants to interact with Dok-7, but not with Lrp4 or Tid1, is a major determinant of the pathogenesis of the CMS caused by MUSK mutations.
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In vitro microelectrode study of neuromuscular transmission in a case of botulism
Muscle & Nerve, 1992Co-Authors: Ricardo A Maselli, Margaret E. Burnett, James H. TonsgardAbstract:We performed in vitro microelectrode studies in the anconeus muscle biopsy of a 6-week-old infant intoxicated with Clostridium botulinum toxin B. The most striking abnormalities were the severe reduction of the Endplate Potential (EPP) quantal content and the marked variability of EPP latencies. The increased variability was often limited to a “single quantum” component of the EPP. Neither the amplitudes nor the frequencies of spontaneous miniature Endplate Potentials (MEEPs) were decreased. However, there was a wide range of amplitudes and frequencies of MEPPs. This unique combination of electrophysiologic findings indicates a severe presynaptic failure of neuromuscular transmission, which appears to result from an impairment of the process of synaptic vesicle release taking place after the stimulus induced influx of calcium into the motor nerve terminals.
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In vitro microelectrode study of neuromuscular transmission in a case of botulism
Muscle & Nerve, 1992Co-Authors: Ricardo A Maselli, Margaret E. Burnett, James H. TonsgardAbstract:We performed in vitro microelectrode studies in the anconeus muscle biopsy of a 6-week-old infant intoxicated with Clostridium botulinum toxin B. The most striking abnormalities were the severe reduction of the Endplate Potential (EPP) quantal content and the marked variability of EPP latencies. The increased variability was often limited to a “single quantum” component of the EPP. Neither the amplitudes nor the frequencies of spontaneous miniature Endplate Potentials (MEEPs) were decreased. However, there was a wide range of amplitudes and frequencies of MEPPs. This unique combination of electrophysiologic findings indicates a severe presynaptic failure of neuromuscular transmission, which appears to result from an impairment of the process of synaptic vesicle release taking place after the stimulus induced influx of calcium into the motor nerve terminals.
Graham M. Nicholson - One of the best experts on this subject based on the ideXlab platform.
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Presynaptic snake β-neurotoxins produce tetanic fade and Endplate Potential run-down during neuromuscular blockade in mouse diaphragm
Naunyn-Schmiedeberg's archives of pharmacology, 1997Co-Authors: Harry I. Wilson, Graham M. NicholsonAbstract:The present study investigated the ability of a number of presynaptic snake neurotoxins (snake β-neurotoxins) to produce nerve-evoked train-of-four fade, tetanic fade and Endplate Potential run-down during the development of neuromuscular blockade in the isolated mouse phrenic-hemidiaphragm nerve-muscle preparation. All the snake β-neurotoxins tested, with the exception of notexin, produced train-of-four and tetanic fade of nerve-evoked isometric muscle contractions. Train-of-four fade was not present during the initial depressant or facilitatory phases of muscle tension produced by the snake β-neurotoxins but developed progressively during the final depressant phase that precedes complete neuromuscular blockade. The ‘non-neurotoxic’ bovine pancreatic phospholipase A2 and the ‘low-toxicity’ phospholipase A2 from Naja naja atra venom failed to elicit train-of-four fade, indicating that the phospholipase activity of the snake β-neurotoxins is not responsible for the development of fade. Intracellular recording of Endplate Potentials (EPPs) elicited by nerve-evoked trains of stimuli showed a progressive run-down in EPP amplitude during the train following incubation with all snake β-neurotoxins except notexin. Again this run-down in EPP amplitude was confined to the final depressant phase of snake β-neurotoxin action. However when EPP amplitude fell to near uniquantal levels (
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presynaptic snake β neurotoxins produce tetanic fade and Endplate Potential run down during neuromuscular blockade in mouse diaphragm
Naunyn-schmiedebergs Archives of Pharmacology, 1997Co-Authors: Harry I. Wilson, Graham M. NicholsonAbstract:The present study investigated the ability of a number of presynaptic snake neurotoxins (snake β-neurotoxins) to produce nerve-evoked train-of-four fade, tetanic fade and Endplate Potential run-down during the development of neuromuscular blockade in the isolated mouse phrenic-hemidiaphragm nerve-muscle preparation. All the snake β-neurotoxins tested, with the exception of notexin, produced train-of-four and tetanic fade of nerve-evoked isometric muscle contractions. Train-of-four fade was not present during the initial depressant or facilitatory phases of muscle tension produced by the snake β-neurotoxins but developed progressively during the final depressant phase that precedes complete neuromuscular blockade. The ‘non-neurotoxic’ bovine pancreatic phospholipase A2 and the ‘low-toxicity’ phospholipase A2 from Naja naja atra venom failed to elicit train-of-four fade, indicating that the phospholipase activity of the snake β-neurotoxins is not responsible for the development of fade. Intracellular recording of Endplate Potentials (EPPs) elicited by nerve-evoked trains of stimuli showed a progressive run-down in EPP amplitude during the train following incubation with all snake β-neurotoxins except notexin. Again this run-down in EPP amplitude was confined to the final depressant phase of snake β-neurotoxin action. However when EPP amplitude fell to near uniquantal levels (<3mV) the extent of toxin induced-fade was reduced. Unlike postjunctional snake α-neurotoxins, prejunctional snake β-neurotoxins interfere with acetylcholine release at the neuromuscular junction during the development of neuromuscular blockade. This study provides further support for the hypothesis that fade in twitch and tetanic muscle tension is due to an underlying rundown in EPP amplitude resulting from a prejunctional alteration of transmitter release rather than a use-dependent block of postjunctional nicotinic receptors.
Margaret E. Burnett - One of the best experts on this subject based on the ideXlab platform.
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In vitro microelectrode study of neuromuscular transmission in a case of botulism
Muscle & Nerve, 1992Co-Authors: Ricardo A Maselli, Margaret E. Burnett, James H. TonsgardAbstract:We performed in vitro microelectrode studies in the anconeus muscle biopsy of a 6-week-old infant intoxicated with Clostridium botulinum toxin B. The most striking abnormalities were the severe reduction of the Endplate Potential (EPP) quantal content and the marked variability of EPP latencies. The increased variability was often limited to a “single quantum” component of the EPP. Neither the amplitudes nor the frequencies of spontaneous miniature Endplate Potentials (MEEPs) were decreased. However, there was a wide range of amplitudes and frequencies of MEPPs. This unique combination of electrophysiologic findings indicates a severe presynaptic failure of neuromuscular transmission, which appears to result from an impairment of the process of synaptic vesicle release taking place after the stimulus induced influx of calcium into the motor nerve terminals.
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In vitro microelectrode study of neuromuscular transmission in a case of botulism
Muscle & Nerve, 1992Co-Authors: Ricardo A Maselli, Margaret E. Burnett, James H. TonsgardAbstract:We performed in vitro microelectrode studies in the anconeus muscle biopsy of a 6-week-old infant intoxicated with Clostridium botulinum toxin B. The most striking abnormalities were the severe reduction of the Endplate Potential (EPP) quantal content and the marked variability of EPP latencies. The increased variability was often limited to a “single quantum” component of the EPP. Neither the amplitudes nor the frequencies of spontaneous miniature Endplate Potentials (MEEPs) were decreased. However, there was a wide range of amplitudes and frequencies of MEPPs. This unique combination of electrophysiologic findings indicates a severe presynaptic failure of neuromuscular transmission, which appears to result from an impairment of the process of synaptic vesicle release taking place after the stimulus induced influx of calcium into the motor nerve terminals.
William D Phillips - One of the best experts on this subject based on the ideXlab platform.
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muscle specific kinase autoantibodies cause synaptic failure through progressive wastage of postsynaptic acetylcholine receptors
Experimental Neurology, 2012Co-Authors: Marco Morsch, Stephen W Reddel, Nazanin Ghazanfari, Klaus V Toyka, William D PhillipsAbstract:Abstract In myasthenia gravis muscle weakness is caused by autoantibodies against components of the neuromuscular junction. Patient autoantibodies against muscle specific kinase (MuSK) deplete MuSK from the postsynaptic membrane and reproduce signs of myasthenia gravis when injected into mice. Here we have examined the time-course of structural and functional changes that lead up to synaptic failure. C57Bl6J mice received daily injections of anti-MuSK patient IgG for 15 days. Mice began to lose weight from day 12 and demonstrated whole-body weakness by day 14. Electromyography indicated synaptic impairment from day 6 in the gastrocnemius muscle and from day 10 in the diaphragm muscle. Confocal microscopy revealed linear declines in the area and density of postsynaptic acetylcholine receptors (3–5% per day) from day 1 through day 15 of the injection series in all five muscles examined. Intracellular recordings from the diaphragm muscle revealed comparable progressive declines in the amplitude of the Endplate Potential and miniature Endplate Potential of 3–4% per day. Neither quantal content nor the postsynaptic action Potential threshold changed significantly over the injection series. The inverse relationship between the quantal amplitude of a synapse and its quantal content disappeared only late in the injection series (day 10). Our results suggest that the primary myasthenogenic action of anti-MuSK IgG is to cause wastage of postsynaptic acetylcholine receptor density. Consequent reductions in Endplate Potential amplitudes culminated in failure of neuromuscular transmission.