The therapeutic potential of soluble activin type IIB receptor treatment in a limb girdle muscular dystrophy type 2D mouse model.

Limb girdle muscular dystrophy type 2D (LGMD2D) is characterized by progressive weakening of muscles in the hip and shoulder girdles. It is caused by a mutation in the α-sarcoglycan gene and results in absence of α-sarcoglycan in the dystrophin-glycoprotein complex. The activin type IIB receptor is involved in the activin/myostatin pathway, with myostatin being a negative regulator of muscle growth. In this study, we investigated the effects of sequestering myostatin by a soluble activin type IIB receptor (sActRIIB) on muscle growth in Sgca-null mice, modelling LGMD2D. Treatment was initiated at 3 weeks of age, prior to the disease onset, or at 9 weeks of age when already in an advanced stage of the disease. We found that early sActRIIB treatment resulted in increased muscle size. However, this led to more rapid decline of muscle function than in saline-treated Sgca-null mice. Furthermore, no histopathological improvements were seen after sActRIIB treatment. When initiated at 9 weeks of age, sActRIIB treatment resulted in increased muscle mass too, but to a lesser extent. No effect of the treatment was observed on muscle function or histopathology. These data show that sActRIIB treatment as a stand-alone therapy does not improve muscle function or histopathology in Sgca-null mice.

Cysteamine Decreases Low-Density Lipoprotein Oxidation, Causes Regression of Atherosclerosis, and Improves Liver and Muscle Function in Low-Density Lipoprotein Receptor-Deficient Mice.

Background We have shown previously that low-density lipoprotein (LDL) can be oxidized in the lysosomes of macrophages, that this oxidation can be inhibited by cysteamine, an antioxidant that accumulates in lysosomes, and that this drug decreases atherosclerosis in LDL receptor-deficient mice fed a high-fat diet. We have now performed a regression study with cysteamine, which is of more relevance to the treatment of human disease. Methods and Results LDL receptor-deficient mice were fed a high-fat diet to induce atherosclerotic lesions. They were then reared on chow diet and drinking water containing cysteamine or plain drinking water. Aortic atherosclerosis was assessed, and samples of liver and skeletal muscle were analyzed. There was no regression of atherosclerosis in the control mice, but cysteamine caused regression of between 32% and 56% compared with the control group, depending on the site of the lesions. Cysteamine substantially increased markers of lesion stability, decreased ceroid, and greatly decreased oxidized phospholipids in the lesions. The liver lipid levels and expression of cluster of differentiation 68, acetyl-coenzyme A acetyltransferase 2, cytochromes P450 (CYP)27, and proinflammatory cytokines and chemokines were decreased by cysteamine. Skeletal muscle function and oxidative fibers were increased by cysteamine. There were no changes in the plasma total cholesterol, LDL cholesterol, high-density lipoprotein cholesterol, or triacylglycerol concentrations attributable to cysteamine. Conclusions Inhibiting the lysosomal oxidation of LDL in atherosclerotic lesions by antioxidants targeted at lysosomes causes the regression of atherosclerosis and improves liver and muscle characteristics in mice and might be a promising novel therapy for atherosclerosis in patients.

[Implementation of the ICD-ICF model in rehabilitation medicine: report of a clinical case in neuromotor rehabilitation]. / Implementazione del modello ICD-ICF in medicina riabilitativa: presentazione di un caso clinico in riabilitazione neuromotoria.

SUMMARY: We present the clinical case of a 17-year-old boy who, after an auto-motorbike collision, suffered of bilateral condylar atlo-occipital dislocation with blood in the medullary canal and contusion of the C1-C3 spinal cord, hemothorax and pneumothorax, multiple costal fractures, fractures processes transverse L1 and right iliac wing and displaced fracture of the middle third of the right femur. In the emergency phase the patient, who was in a coma GCS: 3/15, was immediately intubated and taken to the Emergency Department and subsequently to Intensive Care Unit. He was also immediately subjected to chest drainage, reduction of femoral fracture and placement of external fixator and tracheostomy. Upon stabilization of the clinical picture, the patient was subjected to occipital-cervical stabilization with plates and screws and reduction of the fracture of the right femur with an intramedullary rod. Then the patient in hemodynamically stable and in alert condition, in spontaneous breath, was discharged and transferred to our Operative Unit of Intensive Neurorehabilitation. At the entrance, the doctor's evaluation, with the whole multidisciplinary team, enabled to identify the ICD-9 and ICF codes that best described the severity of the clinical picture: the patient showed tetraplegia, dysphonia and dysphagia, bearing a tracheal cannula in breath spontaneous with O2 supplementation, sequelae of multiple costal fractures and right femur, totally dependent on ADL. The rehabilitation intervention was aimed at promoting motor recovery in the 4 limbs, recovery of standing and walking, acquisition of ability to control daily life activities (ADL), recovery of physiological swallowing and removal of the tracheostomy tube. After long and slow physiotherapeutic training, the patient recovered the active motility at the crural and brachial level mainly at the proximal level, which however is not effective for ADL recovery. On the other hand, speech therapy allowed the passage to oral feeding and removal of the tracheostomy tube. Upon discharge, the re-evaluation of the ICF codes identified at the entrance indicated an improvement in the strength of the trunk muscles (b7305) with the possibility of performing transfers with assistance (d420), of dysphonia (b320) and of swallowing (b510) which led to the removal of the PEG and the tracheostomy tube; unfortunately severe deficiency of the muscular force at the distal brachial and crural level (b730, b7304) persists with severe disability in the activities of daily life (d455, d4551, d465, d429, d230).