Immunolocalization of FAS and FAS ligand in inflammatory myopathies.

Fas/Fas ligand (FasL) interaction can induce apoptosis, have a costimulatory role or act as a mechanism by which cytotoxic T cells produce target cell lysis. We used several commercially available antibodies to study Fas and FasL expression in polymyositis (PM), inclusion body myositis (IBM), dermatomyositis (DM) and normal controls. A strong Fas signal occurred on the sarcolemma, and to a lesser extent in the sarcoplasm of neural cell adhesion molecule (NCAM)-positive or developmental myosin heavy chain-positive regenerating muscle fibers and of injured fibers with presumed abortive regenerative activity, including some nonnecrotic invaded fibers in PM and IBM and some of the atrophic perifascicular fibers in DM. Most fibers within groups of atrophic fibers in IBM were strongly Fas-positive, and statistically more muscle fibers were Fas-positive in IBM compared to PM. A subset of the actively invading CD8+ T cells in nonnecrotic muscle fibers in PM and IBM, and scattered CD4+ cells in each inflammatory myopathy, had up-regulated Fas expression, probably reflecting costimulation. No FasL antibody consistently labeled the positive control tissue (testis) or intramuscular elements in control or inflammatory myopathy specimens. Our study identifies regenerating muscle fibers as the main site of Fas immunoreactivity in inflammatory myopathies, and Fas expression may be part of an activated or reactivated developmental program of new gene expression in regenerating or denervated muscle fibers. Our data plead against a specific role of Fas/FasL interaction in the immunopathogenesis of the inflammatory myopathies.

Immunolocalization of tumor necrosis factor-alpha and its receptors in inflammatory myopathies.

Adhesion molecule upregulation occurs in inflammatory myopathies, and is one of the myriad functions of tumor necrosis factor-alpha (TNF-alpha). TNF-alpha acts via two different receptors of 55 (TNF-R55) and 75 kD (TNF-R75). We immunolocalized TNF-alpha and its receptors in polymyositis, inclusion body myositis and dermatomyositis. In each myopathy, TNF-alpha was detected in macrophages, in myonuclei in regenerating muscle fibers, and freely dispersed in endomysial or perimysial connective tissue. Many endothelial cells in dermatomyositis expressed TNF-alpha. TNF-R55 was strongly expressed on myonuclei of regenerating muscle fibers. TNF-R75 was increased on endothelial cells in the midst of inflammatory infiltrates in each myopathy, and on perifascicular and perimysial endothelia, remote from inflammatory foci in dermatomyositis. Possible TNF-alpha-mediated effects include: increased transendothelial cell trafficking, activation of T/B cells and macrophages, induction of MHC-I gene products, and focal muscle fiber atrophy. In dermatomyositis, the upregulated TNF-R75, via its consensus elements for transcription factors, may be involved in endothelial cell degeneration. Strong TNF-R55 expression on regenerating myonuclei is consistent with a role of TNF-alpha and TNF-R55 in muscle regeneration.

Progressive dysarthria. Case reports and a review of the literature.

Two patients presenting with progressive dysarthria as the single initial manifestation of a neurodegenerative condition are described. The nature of the dysarthria as well as the additional symptoms that developed in the course of the disorder are very different in these two cases. Nevertheless, neuroimaging findings are strikingly similar and suggest bilateral involvement of posterior inferior frontal lobe structures, mainly in the dominant cerebral hemisphere. The clinical syndrome of these patients can therefore be considered an example of frontotemporal degeneration presenting without dementia or compartmental alteration, at least in the early stages. This broadens the clinical spectrum of frontotemporal degeneration and demonstrates the need for a syndromal subclassification of this nosological entity.

Quinidine prevents paraoxon-induced necrotizing myopathy in rats.

Acute organophosphorus anticholinesterase poisoning induces a necrotizing end-plate myopathy in rats and patients. Acetylcholine (ACh) excess leads to prolonged synaptic currents and increased influx of cations including calcium through the postsynaptic ACh receptor channels with prolonged muscle membrane depolarization, excess calcium influx into the sarcoplasm, and ultimately muscle fiber necrosis. Quinoline derivatives such as quinidine induce or worsen pre- and postsynaptic disorders of neuromuscular transmission in humans, and are beneficial in patients suffering from a rare congenital myasthenic syndrome called the slow channel congenital myasthenic syndrome. These drugs correct the prolonged opening times of the mutated acetylcholine receptor channels in this myasthenic syndrome. We treated paraoxon-poisoned rats with 4 x 10 or 4 x 50 mg/kg of quinidine and assessed the severity of the necrotizing myopathy in gastrocnemius and diaphragm muscle biopsies. Fasciculations were decreased and the necrotizing myopathy was prevented in most treated rats, with absence of necrotic muscle fibers in most animals in the high-dose group. Survival was not different from untreated poisoned animals. A number of physiological mechanisms, including blocking of presynaptic voltage-gated sodium or calcium channels or inhibition of the postsynaptic ACh receptors channels may have contributed to the attenuation of the myonecrosis. The optimal dose and the drug of choice amongst the clinically available quinoline derivatives remains to be determined.