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Query: UMLS:C0026850 (muscular dystrophy)
 5,870 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

With recent successes in gene therapy trials for hemophilia and retinal diseases, the promise and prospects for gene therapy are once again garnering significant attention. To build on this momentum, the National Institute of Neurological Disorders and Stroke and the Muscular Dystrophy Association jointly hosted a workshop in April 2014 on "Best Practices for Gene Therapy Programs," with a focus on neuromuscular disorders. Workshop participants included researchers from academia and industry as well as representatives from the regulatory, legal, and patient advocacy sectors to cover the gamut from preclinical optimization to intellectual property concerns and regulatory approval. The workshop focused on three key issues in the field: (1) establishing adequate scientific premise for clinical trials in gene therapy, (2) addressing regulatory process issues, and (3) intellectual property and commercialization issues as they relate to gene therapy. The outcomes from the discussions at this workshop are intended to provide guidance for researchers and funders in the gene therapy field.
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PMID:Perspectives on best practices for gene therapy programs. 2565 29

Epigenetic regulation of neuronal signalling through histone acetylation dictates transcription programs that govern neuronal memory, plasticity and learning paradigms. Histone Acetyl Transferases (HATs) and Histone Deacetylases (HDACs) are antagonistic enzymes that regulate gene expression through acetylation and deacetylation of histone proteins around which DNA is wrapped inside a eukaryotic cell nucleus. The epigenetic control of HDACs and the cellular imbalance between HATs and HDACs dictate disease states and have been implicated in muscular dystrophy, loss of memory, neurodegeneration and autistic disorders. Altering gene expression profiles through inhibition of HDACs is now emerging as a powerful technique in therapy. This review presents evolving applications of HDAC inhibitors as potential drugs in neurological research and therapy. Mechanisms that govern their expression profiles in neuronal signalling, plasticity and learning will be covered. Promising and exciting possibilities of HDAC inhibitors in memory formation, fear conditioning, ischemic stroke and neural regeneration have been detailed.
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PMID:Histone Deacetylase (HDAC) Inhibitors - emerging roles in neuronal memory, learning, synaptic plasticity and neural regeneration. 2648 2

Intra-arterial transplantation of mesoangioblasts proved safe and partially efficacious in preclinical models of muscular dystrophy. We now report the first-in-human, exploratory, non-randomized open-label phase I-IIa clinical trial of intra-arterial HLA-matched donor cell transplantation in 5 Duchenne patients. We administered escalating doses of donor-derived mesoangioblasts in limb arteries under immunosuppressive therapy (tacrolimus). Four consecutive infusions were performed at 2-month intervals, preceded and followed by clinical, laboratory, and muscular MRI analyses. Two months after the last infusion, a muscle biopsy was performed. Safety was the primary endpoint. The study was relatively safe: One patient developed a thalamic stroke with no clinical consequences and whose correlation with mesoangioblast infusion remained unclear. MRI documented the progression of the disease in 4/5 patients. Functional measures were transiently stabilized in 2/3 ambulant patients, but no functional improvements were observed. Low level of donor DNA was detected in muscle biopsies of 4/5 patients and donor-derived dystrophin in 1. Intra-arterial transplantation of donor mesoangioblasts in human proved to be feasible and relatively safe. Future implementation of the protocol, together with a younger age of patients, will be needed to approach efficacy.
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PMID:Intra-arterial transplantation of HLA-matched donor mesoangioblasts in Duchenne muscular dystrophy. 2790 83

The repair (sealing) of plasmalemmal damage, consisting of small holes to complete transections, is critical for cell survival, especially for neurons that rarely regenerate cell bodies. We first describe and evaluate different measures of cell sealing. Some measures, including morphological/ultra-structural observations, membrane potential, and input resistance, provide very ambiguous assessments of plasmalemmal sealing. In contrast, measures of ionic current flow and dye barriers can, if appropriately used, provide more accurate assessments. We describe the effects of various substances (calcium, calpains, cytoskeletal proteins, ESCRT proteins, mUNC-13, NSF, PEG) and biochemical pathways (PKA, PKC, PLC, Epac, cytosolic oxidation) on plasmalemmal sealing probability, and suggest that substances, pathways, and cellular events associated with plasmalemmal sealing have undergone a very conservative evolution. During sealing, calcium ion influx mobilizes vesicles and other membranous structures (lysosomes, mitochondria, etc.) in a continuous fashion to form a vesicular plug that gradually restricts diffusion of increasingly smaller molecules and ions over a period of seconds to minutes. Furthermore, we find no direct evidence that sealing occurs through the collapse and fusion of severed plasmalemmal leaflets, or in a single step involving the fusion of one large wound vesicle with the nearby, undamaged plasmalemma. We describe how increases in perikaryal calcium levels following axonal transection account for observations that cell body survival decreases the closer an axon is transected to the perikaryon. Finally, we speculate on relationships between plasmalemmal sealing, Wallerian degeneration, and the ability of polyethylene glycol (PEG) to seal cell membranes and rejoin severed axonal ends - an important consideration for the future treatment of trauma to peripheral nerves. A better knowledge of biochemical pathways and cytoplasmic structures involved in plasmalemmal sealing might provide insights to develop treatments for traumatic nerve injuries, stroke, muscular dystrophy, and other pathologies.
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PMID:Repair of traumatic plasmalemmal damage to neurons and other eukaryotic cells. 2763 Jun 71

Lower limb exoskeletons have already proven the capability to give back mobility to people suffering from spinal cord injury (SCI). Other important populations such as people with multiple sclerosis or muscular dystrophy, frail elderly and stroke victims, suffer from severe gait impairments and could benefit from similar technology. The work presented in the current paper describes a novel design of a 6-actuated degrees of freedom (DOFs) assistive lower limb exoskeleton for people with moderate mobility impairments. The electrical actuators are all remotely located on the back of the user for a more compact design with high dynamics. Cable driven solutions are used to transmit the flexion/extension of the hip and knee joints, while a powerful ballscrew carries out the hip adduction/abduction. The design of this exoskeleton, named AUTONOMYO, follows the key specifications of being highly back-drivable and able to perform dynamic motions at low energy consumption. AUTONOMYO is capable to assist the user's balance by providing complementary torques at the hip and the knee. Results show that the projected level of assistance for sit-to-stand transition varies from 50% to 100% in function of the user's bodyweight and height while higher level of assistance are reached for walking and stairs climbing activities.
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PMID:An assistive lower limb exoskeleton for people with neurological gait disorders. 2881 59

Eye-movements are the only directly observable behavioural signals that are highly correlated with actions at the task level, and proactive of body movements and thus reflect action intentions. Moreover, eye movements are preserved in many movement disorders leading to paralysis (or amputees) from stroke, spinal cord injury, Parkinson's disease, multiple sclerosis, and muscular dystrophy among others. Despite this benefit, eye tracking is not widely used as control interface for robotic interfaces in movement impaired patients due to poor human-robot interfaces. We demonstrate here how combining 3D gaze tracking using our GT3D binocular eye tracker with custom designed 3D head tracking system and calibration method enables continuous 3D end-point control of a robotic arm support system. The users can move their own hand to any location of the workspace by simple looking at the target and winking once. This purely eye tracking based system enables the end-user to retain free head movement and yet achieves high spatial end point accuracy in the order of 6 cm RMSE error in each dimension and standard deviation of 4 cm. 3D calibration is achieved by moving the robot along a 3 dimensional space filling Peano curve while the user is tracking it with their eyes. This results in a fully automated calibration procedure that yields several thousand calibration points versus standard approaches using a dozen points, resulting in beyond state-of-the-art 3D accuracy and precision.
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PMID:Towards free 3D end-point control for robotic-assisted human reaching using binocular eye tracking. 2881 60

Post-stroke spasticity is associated with restriction in the range of motion of the shoulder. Reducing muscular dystrophy may help relieve muscular dysfunction in patients with post-stroke shoulder spasticity. Dry needle therapy is a method of needling the trigger points using a syringe needle without the use of a drug. Dry needle therapy is commonly used for pain at the shoulder, neck, waist, and back. In this case study, a 62-year-old male patient affected with cerebral hemorrhage of the right frontal lobe had received rehabilitative treatment for 12 years. However, he still experienced shoulder spasticity. The patient received daily dry needling at the trigger points of infraspinatus, teres minor, posterior deltoid, and pectoralis major on 9 days. After the first and ninth treatment, the Modified Ashworth Scale and the passive range of motion of the shoulder was used to assess the effect of the treatment. The spasticity and range of motion of the shoulder showed obvious improvement. These results indicate that dry needling at the myofascial trigger points can effectively treat chronic post-stroke shoulder spasticity.
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PMID:Dry needling at myofascial trigger points mitigates chronic post-stroke shoulder spasticity. 2972 19

Skeletal muscle contractures represent the permanent shortening of a muscle-tendon unit, resulting in loss of elasticity and, in extreme cases, joint deformation. They may result from cerebral palsy, spinal cord injury, stroke, muscular dystrophy, and other neuromuscular disorders. Contractures are the prototypic and most severe clinical presentation of increased passive mechanical muscle force in humans, often requiring surgical correction. Intraoperative experiments demonstrate that high muscle passive force is associated with sarcomeres that are abnormally stretched, although otherwise normal, with fewer sarcomeres in series. Furthermore, changes in the amount and arrangement of collagen in the extracellular matrix also increase muscle stiffness. Structural light and electron microscopy studies demonstrate that large bundles of collagen, referred to as perimysial cables, may be responsible for this increased stiffness and are regulated by interaction of a number of cell types within the extracellular matrix. Loss of muscle satellite cells may be related to changes in both sarcomeres and extracellular matrix. Future studies are required to determine the underlying mechanism for changes in muscle satellite cells and their relationship (if any) to contracture. A more complete understanding of this mechanism may lead to effective nonsurgical treatments to relieve and even prevent muscle contractures.
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PMID:Muscle contracture and passive mechanics in cerebral palsy. 3057 Dec 85

Deficits in the ankle plantarflexor muscles, such as weakness and contracture, occur commonly in conditions such as cerebral palsy, stroke, muscular dystrophy, Charcot-Marie-Tooth disease, and sarcopenia. While these deficits likely contribute to observed gait pathologies, determining cause-effect relationships is difficult due to the often co-occurring biomechanical and neural deficits. To elucidate the effects of weakness and contracture, we systematically introduced isolated deficits into a musculoskeletal model and generated simulations of walking to predict gait adaptations due to these deficits. We trained a planar model containing 9 degrees of freedom and 18 musculotendon actuators to walk using a custom optimization framework through which we imposed simple objectives, such as minimizing cost of transport while avoiding falling and injury, and maintaining head stability. We first generated gaits at prescribed speeds between 0.50 m/s and 2.00 m/s that reproduced experimentally observed kinematic, kinetic, and metabolic trends for walking. We then generated a gait at self-selected walking speed; quantitative comparisons between our simulation and experimental data for joint angles, joint moments, and ground reaction forces showed root-mean-squared errors of less than 1.6 standard deviations and normalized cross-correlations above 0.8 except for knee joint moment trajectories. Finally, we applied mild, moderate, and severe levels of muscle weakness or contracture to either the soleus (SOL) or gastrocnemius (GAS) or both of these major plantarflexors (PF) and retrained the model to walk at a self-selected speed. The model was robust to all deficits, finding a stable gait in all cases. Severe PF weakness caused the model to adopt a slower, "heel-walking" gait. Severe contracture of only SOL or both PF yielded similar results: the model adopted a "toe-walking" gait with excessive hip and knee flexion during stance. These results highlight how plantarflexor weakness and contracture may contribute to observed gait patterns.
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PMID:Predicting gait adaptations due to ankle plantarflexor muscle weakness and contracture using physics-based musculoskeletal simulations. 3158 97

Many people living with neurological disorders, such as cerebral palsy, stroke, muscular dystrophy or dystonia, experience upper limb impairments (muscle spasticity, loss of selective motor control, muscle weakness or tremors) and are unable to eat independently. This article presents the development of a new device to assist with eating, aimed at stabilizing the movement of people who have movement disorders. The design was guided by insights gathered through focus groups, with occupational therapists and engineers, about the challenges faced by individuals who have movement disorders and difficulty in eating autonomously. The proposed assistive device prototype is designed to be fixed on a table and to support a spoon. The mechanism is designed so that the spoon maintains a position parallel to the ground for the user. Dampers and inertia allow stabilizing the user's motion. A preliminary trial with five individuals living with cerebral palsy is presented to assess the prototype's performance and to guide future iterations of the prototype. Task completion time generally decreased and movement fluidity generally improved when using the assistive device prototype. The prototype showed good potential in stabilizing the spoon for the user and improving movement fluidity.
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PMID:Mechanical design of a new device to assist eating in people with movement disorders. 3210 99


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