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Genetic strategies to treat inherited muscle disease
Abstracts / Journal of the Neurological Sciences 357 (2015) e457–e512
The Hypothermia is a thecnics that reduce the body temperature and control to CMRo2 and ameliorate the ICH. In cardiac arrest the control of temperature and your reduction show in many papers publish in differents journal increase the patients number without severe neurological damage and increase the pátients with minimun neurological failure after cardiac arrest specificly to tachicardia and Ventricular fibrilation. In the lasts five years also show two very interesting papers that the use of 33 °C or 35 °C degree is the same for the aim the objective, the brain protection after cardiac arrest,however the guidelines are not change yet in the emergency and cardiac field. I show you this information. doi:10.1016/j.jns.2015.09.202
1629 WFN15-1821 Neurocritical Care MT 4.3 - Topics in Neurocritical Care II Prognosis of neurological outcome after cardiac arrest S. Hocker, E. Wijdicks. Neurology, Mayo Clinic, Rochester, USA Despite improving resuscitation practices, neurologicimpairment caused by anoxic-ischemic brain injury during circulatory arrest remainscommon. Important principles in the prognostication of outcome after cardiacarrest include assessing the severity of brain injury, allowing appropriatetime for assessment and excluding confounders. Hypothermia protocols have been increasingly used totreat comatose patients after resuscitation and experience with prognosticationin the setting of therapeutic hypothermia has led to an improved understandingof the impact of sedation, organ injuries and hypothermia itself on brainfunction. Early identification of patients with limited chance for meaningfulneurologic recovery can assist relatives in decision making and avoidinappropriately aggressive treatments, and alternatively identification ofpatients with inconclusive initial assessments provides justification forprolonged observation with repeated assessments. Evidence for predictors ofpoor outcome in adult comatose survivors of cardiac arrest are discussedincluding those treated or not treated with temperature modulation. Knowledgegaps are identified and an evidence based prognostication approach is reviewed. doi:10.1016/j.jns.2015.09.203
1630 WFN15-1809 Neuromuscular Disorders MT 7.3 Genetic strategies to treat inherited muscle disease K. Davies. Physiology Anatomy and Genetics, Univesrity of Oxford, Oxford, United Kingdom Genetic approaches for thetreatment of inherited muscle diseases have advanced rapidly in recent years.Most of the advances have occurred in the treatment of Duchenne MuscularDystrophy (DMD), a muscle wasting disease where patients present withdifficulties walking upstairs around the age of 3-5 years and are typicallywheelchair bound by age 12 years. Theygenerally die from respiratory failure or cardiomyopathy in theirtwenties. DMD is caused by mutations inthe dystrophin gene encoding the large cytoskeletal protein which associateswith other proteins at the sarcolemma to form the dystrophin-associated proteincomplex (DAPC). In the absence ofdystrophin, the DAPC is lost at the sarcolemma which subsequently becomes moresusceptible to contraction-induced injury. Currently the only treatmentapproved is in the form of corticosteroids, which have very limit benefits andare plagued by a number of side effects.
e473
Genetic approachesto treat DMD being pursued include exonskipping, read-through of stop codons, deliveryof dystrophin minigenes and the modulation of expression of the dystrophinrelated protein, utrophin. Despite significant progress,the problem of targeting all muscles (40% of the total body mass) including diaphragmand heart, at sufficiently high levels remains a challenge. Any therapy alsoneeds to take account of the immune system and some of these treatments aremutation specific. The current status ofdevelopment of therapies will be presented. doi:10.1016/j.jns.2015.09.204
1631 WFN15-1851 Neuromuscular Disorders MT 7.3 The use of steroids in the management of Duchenne muscular dystrophy A. Dubrovsky, L. Mesa. Neurology, Fundacion Favaloro - Institute of Neuroscience - Neuromuscular Unit, Buenos Aires, Argentina At the moment, corticosteroid are widely accepted as standard treatment in DMD, efficacy having been proved in several clinical trials. The most frequently used corticosteroids are Deflazacort and Prednisone, Deflazacort is preferred because of milder side effects. Recent large natural history studies have demonstrated benefits of corticosteroid treatment in DMD patients, among them prolonged ambulation, improved pulmonary function, prevention of scoliosis and cardiac complications. Cushing features, weight gain, delayed growth, cataracts and osteoporosis are among the worrysome side effects due to long term use of the medication. Even though treatment with steroids is intended to continue for many years in DMD, the optimum maintenance dose has not been established. Dose management after several years of administration is completely empirical and subjective, it varies depending on the patient and the physician. The mechanism of action of steroids is uncertain and is probably related to its anti-inflammatory action, protein synthesis and expression, and calcium metabolism. A low percentage of DMD patients appear not to respond so well to steroid treatment. The “non responder” condition may be partly related to genetic modifiers such as nucleotide polymorphisms in SPP1 and LTBP4 genes. Nevertheless, it is important to keep in mind that appropriate care of DMD patients relies not only on CS treatment but also on a multidisciplinary medical, and rehabilitative approach including respiratory support as well as adequate cardiac managment. While major advances in molecular therapies are expected, proper management of DMD has profound implications for the future of patients and families. doi:10.1016/j.jns.2015.09.205
1632 WFN15-1783 Neuromuscular Disorders MT 7.3 Cardiorespiratory management in neuromuscular disease K. Bushby, K.A.T.E. Bushby. MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Newcastle Upon Tyne, United Kingdom Cardiorespiratory management in neuromuscular diseases Neuromuscular diseases (NMD) are often multisystem conditions, with implications for management beyond the weakness of skeletal
The Hypothermia is a thecnics that reduce the body temperature and control to CMRo2 and ameliorate the ICH. In cardiac arrest the control of temperature and your reduction show in many papers publish in differents journal increase the patients number without severe neurological damage and increase the pátients with minimun neurological failure after cardiac arrest specificly to tachicardia and Ventricular fibrilation. In the lasts five years also show two very interesting papers that the use of 33 °C or 35 °C degree is the same for the aim the objective, the brain protection after cardiac arrest,however the guidelines are not change yet in the emergency and cardiac field. I show you this information. doi:10.1016/j.jns.2015.09.202
1629 WFN15-1821 Neurocritical Care MT 4.3 - Topics in Neurocritical Care II Prognosis of neurological outcome after cardiac arrest S. Hocker, E. Wijdicks. Neurology, Mayo Clinic, Rochester, USA Despite improving resuscitation practices, neurologicimpairment caused by anoxic-ischemic brain injury during circulatory arrest remainscommon. Important principles in the prognostication of outcome after cardiacarrest include assessing the severity of brain injury, allowing appropriatetime for assessment and excluding confounders. Hypothermia protocols have been increasingly used totreat comatose patients after resuscitation and experience with prognosticationin the setting of therapeutic hypothermia has led to an improved understandingof the impact of sedation, organ injuries and hypothermia itself on brainfunction. Early identification of patients with limited chance for meaningfulneurologic recovery can assist relatives in decision making and avoidinappropriately aggressive treatments, and alternatively identification ofpatients with inconclusive initial assessments provides justification forprolonged observation with repeated assessments. Evidence for predictors ofpoor outcome in adult comatose survivors of cardiac arrest are discussedincluding those treated or not treated with temperature modulation. Knowledgegaps are identified and an evidence based prognostication approach is reviewed. doi:10.1016/j.jns.2015.09.203
1630 WFN15-1809 Neuromuscular Disorders MT 7.3 Genetic strategies to treat inherited muscle disease K. Davies. Physiology Anatomy and Genetics, Univesrity of Oxford, Oxford, United Kingdom Genetic approaches for thetreatment of inherited muscle diseases have advanced rapidly in recent years.Most of the advances have occurred in the treatment of Duchenne MuscularDystrophy (DMD), a muscle wasting disease where patients present withdifficulties walking upstairs around the age of 3-5 years and are typicallywheelchair bound by age 12 years. Theygenerally die from respiratory failure or cardiomyopathy in theirtwenties. DMD is caused by mutations inthe dystrophin gene encoding the large cytoskeletal protein which associateswith other proteins at the sarcolemma to form the dystrophin-associated proteincomplex (DAPC). In the absence ofdystrophin, the DAPC is lost at the sarcolemma which subsequently becomes moresusceptible to contraction-induced injury. Currently the only treatmentapproved is in the form of corticosteroids, which have very limit benefits andare plagued by a number of side effects.
e473
Genetic approachesto treat DMD being pursued include exonskipping, read-through of stop codons, deliveryof dystrophin minigenes and the modulation of expression of the dystrophinrelated protein, utrophin. Despite significant progress,the problem of targeting all muscles (40% of the total body mass) including diaphragmand heart, at sufficiently high levels remains a challenge. Any therapy alsoneeds to take account of the immune system and some of these treatments aremutation specific. The current status ofdevelopment of therapies will be presented. doi:10.1016/j.jns.2015.09.204
1631 WFN15-1851 Neuromuscular Disorders MT 7.3 The use of steroids in the management of Duchenne muscular dystrophy A. Dubrovsky, L. Mesa. Neurology, Fundacion Favaloro - Institute of Neuroscience - Neuromuscular Unit, Buenos Aires, Argentina At the moment, corticosteroid are widely accepted as standard treatment in DMD, efficacy having been proved in several clinical trials. The most frequently used corticosteroids are Deflazacort and Prednisone, Deflazacort is preferred because of milder side effects. Recent large natural history studies have demonstrated benefits of corticosteroid treatment in DMD patients, among them prolonged ambulation, improved pulmonary function, prevention of scoliosis and cardiac complications. Cushing features, weight gain, delayed growth, cataracts and osteoporosis are among the worrysome side effects due to long term use of the medication. Even though treatment with steroids is intended to continue for many years in DMD, the optimum maintenance dose has not been established. Dose management after several years of administration is completely empirical and subjective, it varies depending on the patient and the physician. The mechanism of action of steroids is uncertain and is probably related to its anti-inflammatory action, protein synthesis and expression, and calcium metabolism. A low percentage of DMD patients appear not to respond so well to steroid treatment. The “non responder” condition may be partly related to genetic modifiers such as nucleotide polymorphisms in SPP1 and LTBP4 genes. Nevertheless, it is important to keep in mind that appropriate care of DMD patients relies not only on CS treatment but also on a multidisciplinary medical, and rehabilitative approach including respiratory support as well as adequate cardiac managment. While major advances in molecular therapies are expected, proper management of DMD has profound implications for the future of patients and families. doi:10.1016/j.jns.2015.09.205
1632 WFN15-1783 Neuromuscular Disorders MT 7.3 Cardiorespiratory management in neuromuscular disease K. Bushby, K.A.T.E. Bushby. MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Newcastle Upon Tyne, United Kingdom Cardiorespiratory management in neuromuscular diseases Neuromuscular diseases (NMD) are often multisystem conditions, with implications for management beyond the weakness of skeletal