Health status in non-dystrophic myotonias: close relation with pain and fatigue

To determine self-reported health status in non-dystrophic myotonias (NDM) and its relationship to painful myotonia and fatigue. In a cross-sectional study, 32 NDM patients with chloride and 30 with sodium channelopathies, all off treatment, completed a standardised interview, the fatigue assessment scale (FAS), and the 36-item Short-Form Health Survey (SF-36). Beside formal assessment of pain, assessment of painful or painless myotonia was determined. The domain scores of the SF-36 were compared with Dutch community scores. Apart from the relationship among SF-36 scores and (1) painful myotonia and (2) fatigue, regression analyses in both NDM groups were conducted to determine the strongest determinants of the SF-36 domains general health perception, physical component (PCS) and mental component summary (MCS). All physically oriented SF-36 domains in both NDM groups (P ≤ 0.01) and social functioning in the patients with sodium channelopathies (P = 0.048) were substantially lower relative to the Dutch community scores. The patients with painful myotonia (41.9%) scored substantially (P < 0.05) lower on most SF-36 domains than the patients without painful myotonia (58.1%). Fatigued patients (53.2%) scored substantially lower (P ≤ 0.01) on all SF-36 domains than their non-fatigued counterparts (46.8%). The regression analysis showed that fatigue was the strongest predictor for the general-health perception and painful myotonia for the physical-component summary. None of the patients showed below-norm scores on the domain mental-component summary. The impact of NDM on the physical domains of patients’ health status is substantial, and particularly painful myotonia and fatigue tend to impede their physical functioning

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field

Porous Magnesium Aluminometasilicate Tablets as Carrier of a Cyclosporine Self-Emulsifying Formulation

The aim of this study was to investigate the ability of liquid loadable tablets (LLT) to be loaded with a self-microemulsifying drug delivery system (SMEDDS) containing cyclosporine (CyA). LLT were prepared by direct compression of the porous carrier magnesium aluminometasilicate and subsequently loaded with SMEDDS by a simple absorption method. SMEDDS was evaluated regarding visual appearance and droplet size distribution after dispersion in aqueous media. The developed SMEDDS was found to be similar to Neoral®. LLT were characterized before and after loading regarding weight variation, tablet hardness, disintegration time, and in vitro drug release. It was found that LLT with high porosities suitable for liquid loading and further processing could be prepared. Adding a tablet disintegrant was found to improve in vitro drug release. Additionally, the volume-based loading capacity of LLT was evaluated and found to be comparable to soft gelatin and hard two-piece capsules. Furthermore, the pharmacokinetic performance of CyA from loaded LLT was tested in two PK-studies in dogs. Absorption of CyA from SMEDDS loaded into LLT was found in the first study to be significantly lower than the absorption of CyA from SMEDDS filled into a capsule. However, addition of a superdisintegrant improved the absorption markedly. The bioavailability of CyA from SMEDDS loaded into disintegrating LLT was found in the second study to be at the same level as from capsule formulation. In conclusion, the LLT technology is therefore seen as a promising alternative way of achieving a solid dosage form from liquid drug delivery systems

Feedback between erosion and active deformation : geomorphic constraints from the frontal Jura fold-and-thrust belt (eastern France)

A regional tectono-geomorphic analysis indicates a Pliocene to recent rock uplift of the outermost segment of the Jura fold-and-thrust belt, which spatially coincides with the intra-continental Rhine-Bresse Transfer Zone. Elevated remnants of the partly eroded Middle Pliocene Sundgau-Foreˆt de Chaux Gravels identified by heavy mineral analyses allow for a paleo-topographic reconstruction that yields minimum regional Latest Pliocene to recent rock uplift rates of 0.05 ± 0.02 mm/year. This uplift also affected the Pleistocene evolution of the Ognon and Doubs drainage basins and is interpreted as being tectonically controlled. While the Ognon River was deflected from the uplifted region the Doubs deeply incised into it. Focused incision of the Doubs possibly sustained ongoing deformation along anticlines which were initiated during the Neogene evolution of the thin-skinned Jura fold-and-thrust belt. At present, this erosion-related active deformation is taking place synchronously with thick-skinned tectonics, controlling the inversion of the Rhine-Bresse Transfer Zone. This suggests local decoupling between seismogenic basement faulting and erosion-related deformation of the Mesozoic cover sequences