Biology subjects

Hopkins, P. M.

Publications and source records attributed to Hopkins, P. M..

2 recordsLinked to original sources

bioRxiv2020

A COMPARATIVE STUDY OF ANAESTHETIC AGENTS ON HIGH VOLTAGE ACTIVATED CALCIUM CHANNEL CURRENTS IN IDENTIFIED MOLLUSCAN NEURONS

O_LIUsing the two electrode voltage clamp configuration, a high voltage activated whole-cell Ca2+ channel current (IBa) was recorded from a cluster of neurosecretory Light Yellow Cells (LYC) in the right parietal ganglion of the pond snail Lymnaea stagnalis. C_LIO_LIRecordings of IBa from LYCs show a reversible concentration-dependent depression of current amplitude in the presence of the volatile anaesthetics halothane, isoflurane and sevoflurane, or the non-volatile anaesthetic pentobarbitone at clinical concentrations. C_LIO_LIIn the presence of the anaesthetics investigated, IBa measured at the end of the depolarizing test pulse showed proportionally greater depression than that at measured peak amplitude, as well as significant decrease in the rate of activation or increase in inactivation or both. C_LIO_LIWithin the range of concentrations used, the concentration-response plots for all the anaesthetics investigated correlate strongly to straight line functions, with linear regression R2 values > 0.99 in all instances. C_LIO_LIFor volatile anaesthetics, the dose-response regression slopes for IBa increase in magnitude, in order of gradient: sevoflurane, isoflurane and halothane, a sequence which reflects their order of clinical potency in terms of MAC value. C_LI

pharmacology and toxicology↗

bioRxiv2020

Variant Curation Expert Panel Recommendations for RYR1 Pathogenicity Assertions in Malignant Hyperthermia Susceptibility

PurposePrevention of malignant hyperthermia (MH) requires an understanding of RYR1 variant pathogenicity to assess the risk of exposure to triggering agents. Personalized medicine, especially secondary findings and eventually genomic screening, will contribute toward this goal. MethodsWe specified ACMG/AMP criteria for variant interpretation for RYR1 and MH. Proposed rules were piloted on 84 variants. We applied quantitative evidence calibration for several criteria using likelihood ratios based on the Bayesian framework. ResultsSeven ACMG/AMP criteria were adopted without changes, ten were adopted with RYR1-specific modifications, and nine were dropped. The in silico (PP3 and BP4) and hot spot criteria (PM1) were evaluated quantitatively. REVEL gave an OR of 23:1 for PP3 and 16:1 for BP4 using trichotomized cut-offs of >0.85 (pathogenic) and <0.5 (benign). The PM1 hotspot criterion had an OR of 24:1. PP3 and PM1 were implemented at moderate strength. Applying the revised ACMG criteria to 44 recognized MH variants, 30 were assessed as pathogenic, 12 as likely pathogenic, and two as VUS. ConclusionCuration of these variants will facilitate interpretation of RYR1/MH genomic testing results, which is especially important for secondary findings analyses. Our approach to quantitatively calibrating criteria are generalizable to other variant curation expert panels.

genetics↗