Understanding the Pathophysiology of Skeletal Muscle Channelopathies

Skeletal muscle channelopathies are rare inherited neuromuscular conditions caused by ion channel gene mutations. They are grouped into the non-dystrophic myotonias and the periodic paralyses (PP). An intriguing but as yet unexplained phenomenon is that phenotype severity varies significantly with species, gender and age. The first part of my thesis explores my hypothesis that this phenotype variability in skeletal muscle channelopathies reflects physiological differences in skeletal muscle excitability. To do this, I reverse translated Muscle Velocity Recovery Cycles (MVRCs), an in vivo technique for assessing ion channel function, from humans to mice. My data suggest that murine skeletal muscle has increased chloride conductance compared to human skeletal muscle. This could explain the species difference seen between mouse models of Myotonia Congenita and humans with clinical disease. I also found gender differences in healthy murine muscle excitability that vary by muscle and are associated with gender difference in the skeletal muscle channelome. On the background of these physiological gender differences in murine muscle excitability, the effect of gain-of-function sodium channel mutation is more severe in male mice. Finally, I found that the phenotype change with age seen in patients with PP also occurs in a mouse model. Surprisingly, an increased resistance to potassium-induced weakness was most pronounced in old wild-type mice, suggesting it is a phenomenon of normal aging. In contrast, the onset of permanent progressive weakness was specific to PP mouse muscle. My experiments suggest this may be due to acquired ryanodine receptor dysfunction resulting in sarcoplasmic reticulum calcium leak and impaired mitochondrial oxidative capacity. The aim of the second part of my thesis was to extend our knowledge of ClC-1 structure-function and improve genetic counselling for patients with Myotonia Congenita (MC). I identified a novel molecular pathomechanism for MC and found that dominant mutations cluster in the first half of the channel sequence. Combining variant location with functional characterisation significantly improves the accuracy of genetic counselling we can provide patients

Polymeric Ablation Induced by Free Burning Arcs in Air

We investigate the influence of switching arcs on different polymers and their interaction. We describe a set of experiments on a simplified model geometry typical for low voltage switchgear. In a broad range of experimental conditions and parameters such as arc current, polymeric material or contact material, the voltage, the mass loss and the corresponding pressure build-up are examined. From this raw data, we deduce the arc influence on the ablation process as well as the feedback on some arc plasma properties

Experimental Assessment of PTFE Post-Arc Ablation

The study addresses the post arc ablation (PAA) of PTFE (Polytetrafluoroethylene) material after being stressed by high current arcs. Arcs were generated in ambient air applying AC or DC current profiles to reach energy input in the range 7-22 kJ. The characterization has been performed essentially based on standard optical measurement techniques. The shadowgraph technique enabled us to show that the PAA flow is composed by a significant amount of carbonaceous soots lasting for several dozens of milliseconds after current interruption. The pyrometry technique allowed to estimate the soots temperature in the range 1400-2200 K

Los discursos gubernamentales acerca de la discapacidad en México y la situación de los discapacitados – Una mirada desde los censos de población.

La población discapacitada en México ha sido siempre un sector aparte de la población y condenada a la marginación económica, social y educativa. A pesar de que su número se incrementó considerablemente a raíz de la Revolución, el Estado mexicano no consideró necesario apoyar este sector poblacional a través de políticas públicas específicas tal como sucedió en Europa. Los discapacitados fungieron sólo como un subsector del enorme ejército de los pobres. Los administradores públicos consideraron que las políticas de combate de la pobreza – que el Estado mexicano adoptó apenas desde la década de los ochenta del siglo XX – atenderían también las necesidades de esta población. Sin embargo, los datos estadísticos disponibles demuestran que esto no ha sido así. La integración económica de la población discapacitada, sus ingresos y su acceso al sistema educativo se encuentran por debajo de la media nacional. Los discapacitados mexicanos constituyen de esta forma los más pobres de los pobres

Mexiletine (NaMuscla) for the treatment of myotonia in non-dystrophic myotonic disorders

Introduction: NaMuscla, (mexiletine), is the first licensed treatment for the Non-Dystrophic Myotonias (NDM). NDM are categorized by genetic ion channel dysfunction and cause significant morbidity. To date, off-license mexiletine, although less costly, has sometimes been subject to breaches in supply causing significant regional and national variation in availability. Areas covered: The evidence supporting mexiletine use in NDM, its mechanism of action, chemistry, and pharmacodynamics is reviewed. The evidence for other, unlicensed medications, used to treat myotonia as well as new antimyotonic compounds in development is also reviewed. Expert opinion: Mexiletine is an effective and safe treatment for NDM. However, while mexiletine is very effective in reducing muscle stiffness, it is less effective at treating the pain associated with NDM and some SCN4A genotypes may not respond to mexiletine treatment. In addition, gastrointestinal discomfort is frequent and may prevent adequate dose titration. Since the designation of mexiletine as an orphan drug for NDM, level 1 evidence for the antimyotonic effect of lamotrigine has emerged. However, no superiority trials have been completed. A head-to-head trial to compare the efficacy of mexiletine and lamotrigine in reducing both muscle stiffness and pain and to determine variation in genotype response would facilitate greater precision medicine in NDM