ABSTRACT
A resolutive therapy for Duchene muscular dystrophy, a severe degenerative disease of the skeletal muscle, is still lacking. Because autophagy has been shown to be crucial in clearing dysfunctional organelles and in preventing tissue damage, we investigated its pathogenic role and its suitability as a target for new therapeutic interventions in Duchenne muscular dystrophy (DMD). Here we demonstrate that autophagy is severely impaired in muscles from patients affected by DMD and mdx mice, a model of the disease, with accumulation of damaged organelles. The defect in autophagy was accompanied by persistent activation via phosphorylation of Akt, mammalian target of rapamycin (mTOR) and of the autophagy-inhibiting pathways dependent on them, including the translation-initiation factor 4E-binding protein 1 and the ribosomal protein S6, and downregulation of the autophagy-inducing genes LC3, Atg12, Gabarapl1 and Bnip3. The defective autophagy was rescued in mdx mice by long-term exposure to a low-protein diet. The treatment led to normalisation of Akt and mTOR signalling; it also reduced significantly muscle inflammation, fibrosis and myofibre damage, leading to recovery of muscle function. This study highlights novel pathogenic aspects of DMD and suggests autophagy as a new effective therapeutic target. The treatment we propose can be safely applied and immediately tested for efficacy in humans.
Subject(s)
Autophagy , Muscular Dystrophy, Duchenne/physiopathology , Animals , Disease Models, Animal , Humans , Male , Mice , Mice, Inbred mdx , Muscular Dystrophy, Duchenne/genetics , Muscular Dystrophy, Duchenne/metabolism , Muscular Dystrophy, Duchenne/therapy , Oncogene Protein v-akt/genetics , Oncogene Protein v-akt/metabolism , Signal Transduction , TOR Serine-Threonine Kinases/genetics , TOR Serine-Threonine Kinases/metabolismABSTRACT
Two cases of paroxysmal supraventricular tachycardia in children are reported. Associated congenital heart disease were excluded by color-doppler echocardiogram. Electrocardiogram, holter monitoring and transesophageal study (in one case) suggested associated Wolf-Parkinson-White syndrome. The former case was successfully treated with digitalis, the latter, diagnosed "at risk" by transesophageal recording, was long term treated with propafenone. Clinical evaluation at follow-up confirmed the efficacy of the therapy.
Subject(s)
Tachycardia, Paroxysmal , Tachycardia, Supraventricular , Child , Digoxin/therapeutic use , Echocardiography , Electrocardiography, Ambulatory , Humans , Infant, Newborn , Male , Propafenone/therapeutic use , Tachycardia, Paroxysmal/diagnosis , Tachycardia, Paroxysmal/drug therapy , Tachycardia, Supraventricular/diagnosis , Tachycardia, Supraventricular/drug therapyABSTRACT
Phenylalanine ammonia-lyase extracted form Rhodotorula rubra (IFO 1101) was immobilized into cellulose triacetate fibers made hemocompatible by physical blend with a platelet anti-aggregating agent. The entrapped enzyme could operate at physiological values of phenylalanine and tyrosine reducing their level to traces within a few hours. The optimum pH value for the entrapped enzyme shifted from 8.0 to 9.0. At blood pH the activity was about 68 per cent of the maximum. The entrapped enzyme retained its original activity in blood for more than 50 days.
Subject(s)
Ammonia-Lyases/metabolism , Enzymes, Immobilized/metabolism , Phenylalanine Ammonia-Lyase/metabolism , Buffers , Cellulose/analogs & derivatives , Enzymes, Immobilized/blood , In Vitro Techniques , Phenylalanine/metabolism , Phenylalanine Ammonia-Lyase/blood , Temperature , Tyrosine/metabolismABSTRACT
A simple device, consisting of a heat sensor placed in close contact to fibres containing enzymes and connected to a temperature measuring unit has been developed. The system monitors the temperature variations due to the enzymatic reaction when substrate solutions flow through the measuring cell. Fibres containing the enzymes glucose oxidase and catalase for the determination of glucose and fibres containing urease for the determination of urea were tested. A linear relationship between the substrate concentration and the deltaT recorded was obtained in both cases.
Subject(s)
Calorimetry/methods , Catalase , Enzymes, Immobilized , Glucose Oxidase , Glucose/metabolism , Urea/metabolism , Urease , Acetates , Calorimetry/instrumentation , Cellulose , Glucose/analysis , Urea/analysisABSTRACT
There is a general agreement in literature about effects of low frequency vibrations on spine in tractor drivers. Tractor drivers are exposed to noxious vibrations transmitted mostly by the seat. Spine generally presents a picture of degenerative lesions with higher incidence than in control groups. A statistical relation to the precocity of tractor driving can be shown.
Subject(s)
Occupational Diseases/pathology , Spinal Injuries/pathology , Vibration/adverse effects , Humans , Nerve DegenerationABSTRACT
Measurement of histological and cytological parameters can be performed much faster and more accurate by means of a semi-automatic device that is described in detail. The system consists mainly of a medium-sized computer and one or more peripheral terminals. Each terminal incorporates a special measurement table for data acquisition, a keyboard for manual data input, and an interface. The software program for the evaluation and storage of the digital data is simple to write and offers a high degree of flexibility to the user. The system can be operated in real time.
