Results of an open label feasibility study of sodium valproate in people with McArdle disease

McArdle disease results from a lack of muscle glycogen phosphorylase in skeletal muscle tissue. Regenerating skeletal muscle fibres can express the brain glycogen phosphorylase isoenzyme. Stimulating expression of this enzyme could be a therapeutic strategy. Animal model studies indicate that sodium valproate (VPA) can increase expression of phosphorylase in skeletal muscle affected with McArdle disease. This study was designed to assess whether VPA can modify expression of brain phosphorylase isoenzyme in people with McArdle disease. This phase II, open label, feasibility pilot study to assess efficacy of six months treatment with VPA (20 mg/kg/day) included 16 people with McArdle disease. Primary outcome assessed changes in VO2peak during an incremental cycle test. Secondary outcomes included: phosphorylase enzyme expression in post-treatment muscle biopsy, total distance walked in 12 min, plasma lactate change (forearm exercise test) and quality of life (SF36). Safety parameters. 14 participants completed the trial, VPA treatment was well tolerated; weight gain was the most frequently reported drug-related adverse event. There was no clinically meaningful change in any of the primary or secondary outcome measures including: VO2peak, 12 min walk test and muscle biopsy to look for a change in the number of phosphorylase positive fibres between baseline and 6 months of treatment. Although this was a small open label feasibility study, it suggests that a larger randomised controlled study of VPA, may not be worthwhile

Continental weathering as a driver of Late Cretaceous cooling : new insights from clay mineralogy of Campanian sediments from the southern Tethyan margin to the Boreal realm

21 pagesInternational audienceNew clay mineralogical analyses have been performed on Campanian sediments from the Tethyan and Boreal realms along a palaeolatitudinal transect from 45° to 20°N (Danish Basin, North Sea, Paris Basin, Mons Basin, Aquitaine Basin, Umbria-Marche Basin and Tunisian Atlas). Significant terrigenous inputs are evidenced by increasing proportions of detrital clay minerals such as illite, kaolinite and chlorite at various levels in the mid- to upper Campanian, while smectitic minerals predominate and represented the background of the Late Cretaceous clay sedimentation. Our new results highlight a distinct latitudinal distribution of clay minerals, with the occurrence of kaolinite in southern sections and an almost total absence of this mineral in northern areas. This latitudinal trend points to an at least partial climatic control on clay mineral sedimentation, with a humid zone developed between 20° and 35°N. The association and co-evolution of illite, chlorite and kaolinite in most sections suggest a reworking of these minerals from basement rocks weathered by hydrolysis, which we link to the formation of relief around the Tethys due to compression associated with incipient Tethyan closure. Diachronism in the occurrence of detrital minerals between sections, with detrital input starting earlier during the Santonian in the south than in the north, highlights the northward progression of the deformation related to the anticlockwise rotation of Africa. Increasing continental weathering and erosion, evidenced by our clay mineralogical data through the Campanian, may have resulted in enhanced CO2 consumption by silicate weathering, thereby contributing to Late Cretaceous climatic cooling