Journal of neurotrauma
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Journal of neurotrauma · May 2006
Early morphologic and spectroscopic magnetic resonance in severe traumatic brain injuries can detect "invisible brain stem damage" and predict "vegetative states".
A precise evaluation of the brain damage in the first days of severe traumatic brain injured (TBI) patients is still uncertain despite numerous available cerebral evaluation methods and imaging. In 5-10% of severe TBI patients, clinicians remain concerned with prolonged coma and long-term marked cognitive impairment unexplained by normal morphological T2 star, flair, and diffusion magnetic resonance imaging (MRI). For this reason, we prospectively assessed the potential value of magnetic resonance spectroscopy (MRS) of the brain stem to evaluate the functionality of the consciousness areas. ⋯ However, a principal component analysis of combined MRI and MRS data enabled a clear-cut separation between GOS 1-2, GOS 3, and GOS 4-5 patients with no overlap between groups. This study showed that combined MRI and MRS provide a reliable evaluation of patients presenting in deep coma, specially when there are insufficient MRI lesions of the consciousness pathways to explain their status. In the first few days post-trauma metabolic (brainstem spectroscopy) and morphological (T2 star and Flair) MRI studies can predict the long-term neurological outcome, especially the persistent vegetative states and minimally conscious state.
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Journal of neurotrauma · May 2006
Inhibition of Fas-mediated apoptosis through administration of soluble Fas receptor improves functional outcome and reduces posttraumatic axonal degeneration after acute spinal cord injury.
Fas receptor activation has been implicated in inflammatory responses, programmed cell death, Wallerian degeneration in neural injury and the axotomy induced death of motoneurons. Recent work using transection models of spinal cord injury (SCI) demonstrated that neutralization of Fas ligand with antibodies may promote axonal regeneration and functional recovery. Moreover, recent studies from our laboratory in mutant mice with deficient expression of Fas, show reduced cell death and enhanced behavioural recovery after SCI. ⋯ An in vitro model of SCI demonstrated that sFasR administration decreases cell death as assessed by propidium iodide fluorescence. Furthermore, in a moderately severe in vivo clip compression model of SCI at C7-T1, we demonstrate that subarachnoid infusion of sFasR results in increased neuron and oligodendrocyte survival, improved tissue and long tract axonal preservation, reduced apoptotic cell death and enhanced functional neurological outcome after acute SCI. These results strongly suggest that inhibiting Fas receptor activation is neuroprotective after acute SCI and that this strategy may have important translational significance.
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Progress in promoting axonal plasticity and regeneration in animal models of spinal cord injury (SCI) has led to novel prospects for the initiation of human clinical trials in the near future. This review discusses a number of considerations in the path to translating a preclinical candidate from the laboratory to clinical testing. We will also briefly discuss issues associated with the design, performance, analysis, and reporting of human clinical trials in SCI. It is important, for both the medical community and the spinal cord injured community, that objective scientific and medical standards are adopted in the clinical translation of potentially promising, but as yet unproven, therapies for SCI.
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Myelin of the adult mammalian central nervous system (CNS) has been attributed to suppress structural plasticity and to impede regenerating nerve fibers. Nogo-A is possibly the best characterized of a variety of neurite growth inhibitors present in CNS myelin. Neutralizing its activity results in improved axon regrowth and functional recovery in experimental CNS lesion models of adult rodents and primates. While Nogo-A has become a major target for therapeutic intervention to promote axon regeneration in the CNS, it is realized that such an approach will likely have to be combined with other therapeutic strategies to maximize functional recovery after spinal cord injury (SCI).
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Journal of neurotrauma · Mar 2006
Decorin promotes plasminogen/plasmin expression within acute spinal cord injuries and by adult microglia in vitro.
Spinal cord scar tissue presents a combined physical and molecular barrier to axon regeneration. Theoretically, spinal cord injuries (SCIs) can be rendered more permissive to axon growth by either suppressing synthesis of misaligned, fibrotic scar tissue and associated axon growth inhibitors, or enzymatically degrading them. We have previously shown that acute infusion of human recombinant decorin core protein into discreet stab injuries of the rat dorsal column pathways effected a major suppression of inflammation, astrogliosis, and multiple axon growth inhibitory chondroitin sulfate proteoglycans, which combined to promote rapid axon growth across the injury site. ⋯ Infusion of hr-decorin over the first 8 days post-SCI induced 10- and 17-fold increases in plasminogen and plasmin protein levels, respectively, within sites of injury and a threefold increase in microglial plasminogen mRNA in vitro. In addition to potentially degrading multiple axon growth inhibitory components of the glial scar, plasmin is known to play major roles in activating neurotrophins and promoting central nervous system (CNS) plasticity. The wider implications of decorin induction of plasmin in the injured spinal cord for axon regeneration, and recovery of function at acute and chronic time points post-SCI are reviewed.