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Selva-O'Callaghan A.,Autonomous University of Barcelona | Trallero-Araguas E.,Autonomous University of Barcelona | Grau J.M.,Muscle Research Unit | Grau J.M.,University of Barcelona
Autoimmunity Reviews | Year: 2014

Eosinophilia-associated myopathies are clinically and pathologically heterogeneous conditions characterized by the presence of peripheral and/or muscle eosinophilia. There are at least three distinct subtypes: focal eosinophilic myositis, eosinophilic polymyositis, and eosinophilic perimyositis. Infiltrating eosinophils are not always identified in conventional muscle histologic examination, but the eosinophil major basic protein, whose extracellular diffusion is considered a hallmark of eosinophilic cytotoxicity, is usually detected by immunostaining in muscle biopsy. Whereas focal eosinophilic myositis seems to be a benign and isolated condition, and perimyositis is usually related with the inflammatory infiltrate due to fasciitis, eosinophilic polymyositis can be associated with muscular dystrophy or be a feature of multiorgan hypereosinophilic syndrome. Muscle biopsy remains the cornerstone for the diagnosis. Parasitic infections, connective tissue disorders, hematologic and non-hematologic malignancies, drugs, and toxic substances are the main etiologic agents of eosinophilia-associated myopathy. However, in some cases, no known etiologic factor is identified, and these are considered idiopathic. Glucocorticoids are the mainstay therapy in idiopathic forms. Imatinib and mepolizumab, a humanized anti-interleukin 5 monoclonal antibody, may be useful in patients with eosinophilic myositis as part of a hypereosinophilic syndrome. © 2014 Elsevier B.V. Source

Garrabou G.,University of Barcelona | Garrabou G.,Muscle Research Unit | Moren C.,University of Barcelona | Lopez S.,University of Barcelona | And 4 more authors.
Journal of Infectious Diseases | Year: 2012

Background. Sepsis is associated with mitochondrial dysfunction and impaired oxygen consumption, which may condition clinical outcome independent of tissue oxygenation. However, mitochondrial role in sepsis severity remains unknown. We aimed to characterize mitochondrial function in sepsis, establish its origin and cellular consequences, and determine its correlation with clinical symptoms and outcome. Methods. Different markers of mitochondrial activity, nitrosative and oxidative stress, apoptosis, and inflammation were measured in peripheral blood mononuclear cells (PBMCs) and plasma of 19 septic patients and 20 controls. Plasma capacity to induce mitochondrial dysfunction was assessed in muscle mitochondria from 5 healthy individuals incubated with plasma of septic patients or controls. Results. Despite unaltered mitochondrial mass and protein synthesis, enzymatic mitochondrial complexes I, III, and IV and oxygen consumption were significantly inhibited in sepsis. Septic plasma tended to reduce oxygen consumption of healthy mitochondria and showed significantly increased amounts of extracellular mitochondrial DNA and inflammatory cytokines, especially in patients presenting adverse outcome. Active nuclear factor kappa-light-chain enhancer of activated B cells (NFKB) was also significantly increased, together with nitric oxide, oxidative stress and apoptosis. Additionally, sepsis severity significantly correlated with complex I inhibition, NFKB activation and intercellular adhesion molecule expression. Conclusions. A plasmatic factor such as nitric oxide, increased in inflammation and able to induce mitochondrial dysfunction, oxidative stress and apoptosis, may be responsible for cell damage in sepsis. Together with bacterial infection, leakage of mitochondrial DNA from damaged cells into circulation could contribute to systemic inflammatory response syndrome. Mitochondrial dysfunction and inflammation correlate with sepsis severity and outcome, becoming targets for supporting therapies. © The Author 2011. Published by Oxford University Press on behalf of the Infectious. Source

Pinal-Fernandez I.,Autonomous University of Barcelona | Selva-O' Callaghan A.,Autonomous University of Barcelona | Grau J.M.,Muscle Research Unit | Grau J.M.,University of Barcelona
Autoimmunity Reviews | Year: 2014

Eosinophilic fasciitis (EF) is a rare scleroderma-like syndrome with an unknown etiology and pathogenesis that should be considered an immune-allergic disorder. Painful swelling with progressive induration and thickening of the skin and soft tissues of the limbs and trunk are the clinical hallmarks of the disease. Peripheral blood eosinophilia, hypergammaglobulinemia, and elevated erythrocyte sedimentation rate are the main laboratory findings. Full-thickness wedge biopsy of the clinically affected skin showing inflammation and thickening of deep fascia is essential to establish the diagnosis. The differential diagnosis includes systemic sclerosis and other scleroderma subsets such as morphea, and epidemic fasciitis syndromes caused by toxic agents such as the myalgia-eosinophilia syndrome and toxic oil syndrome. Peripheral T cell lymphomas should also be ruled out. The diagnosis of EF can be established by clinical, laboratory and histological findings, but universally accepted international diagnostic criteria are lacking. Corticosteroids are efficacious and remain the standard therapy for EF, although some patients may improve spontaneously. © 2014 Elsevier B.V. Source

Grounds M.D.,University of Western Australia | Terrill J.R.,University of Western Australia | Radley-Crabb H.G.,University of Western Australia | Radley-Crabb H.G.,Curtin University Australia | And 4 more authors.
American Journal of Pathology | Year: 2014

Dysferlin is a membrane associated protein involved in vesicle trafficking and fusion. Defects in dysferlin result in limb-girdle muscular dystrophy type 2B and Miyoshi myopathy in humans and myopathy in A/Jdys-/- and BLAJ mice, but the pathomechanism of the myopathy is not understood. Oil Red O staining showed many lipid droplets within the psoas and quadriceps muscles of dysferlin-deficient A/Jdys-/- mice aged 8 and 12 months, and lipid droplets were also conspicuous within human myofibers from patients with dysferlinopathy (but not other myopathies). Electron microscopy of 8-month-old A/Jdys-/- psoas muscles confirmed lipid droplets within myofibers and showed disturbed architecture of myofibers. In addition, the presence of many adipocytes was confirmed, and a possible role for dysferlin in adipocytes is suggested. Increased expression of mRNA for a gene involved in early lipogenesis, CCAAT/enhancer binding protein-δ, in 3-month-old A/J dys-/- quadriceps (before marked histopathology is evident), indicates early induction of lipogenesis/adipogenesis within dysferlin-deficient muscles. Similar results were seen for dysferlin-deficient BLAJ mice. These novel observations of conspicuous intermyofibrillar lipid and progressive adipocyte replacement in dysferlin-deficient muscles present a new focus for investigating the mechanisms that result in the progressive decline of muscle function in dysferlinopathies. Copyright © 2014 American Society for Investigative Pathology. Source

Philippi S.,Muscle Research Unit | Philippi S.,University Pierre and Marie Curie | Bigot A.,University Pierre and Marie Curie | Marg A.,Max Delbruck Center for Molecular Medicine | And 3 more authors.
PLoS Currents | Year: 2012

Dysferlin gene mutations causing LGMD2B are associated with defects in muscle membrane repair. Four stable cell lines have been established from primary human dysferlin-deficient myoblasts harbouring different mutations in the dysferlin gene. We have compared immortalized human myoblasts and myotubes carrying disease-causing mutations in dysferlin to their wild-type counterparts. Fusion of myoblasts into myotubes and expression of muscle-specific differentiation markers were investigated with special emphasis on dysferlin protein expression, subcellular localization and function in membrane repair. We found that the immortalized myoblasts and myotubes were virtually indistinguishable from their parental cell line for all of the criteria we investigated. They therefore will provide a very useful tool to further investigate dysferlin function and pathophysiology as well as to test therapeutic strategies at the cellular level. Source

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