Brain : a journal of neurology
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Demyelinating disorders of the central nervous system are among the most crippling neurological diseases affecting patients at various stages of life. In the most prominent demyelinating disease, multiple sclerosis, the regeneration of myelin sheaths often fails due to a default of the resident stem/precursor cells (oligodendrocyte precursor cells) to differentiate into mature myelin forming cells. Significant advances have been made in our understanding of the molecular and cellular processes involved in remyelination. ⋯ The pattern by which remyelination inducers and inhibitors are expressed in multiple sclerosis lesions may determine a window of opportunity during which oligodendrocyte precursor cells can successfully differentiate. As the first molecules aiming at promoting remyelination are about to enter clinical trials, this review critically evaluates recent advances in our understanding of the biology of oligodendrocyte precursor cells and of the stage-dependent molecular pathology of multiple sclerosis lesions relevant to the regeneration of myelin sheaths. We propose a model that may help to provide cues for how remyelination can be therapeutically enhanced in clinical disease.
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Gain-of-function missense mutations of voltage-gated sodium channel Na(V)1.7 have been linked to the painful disorder inherited erythromelalgia. These mutations hyperpolarize activation, slow deactivation and enhance currents evoked by slow ramp stimuli (ramp currents). A correlation has recently been suggested between the age of onset of inherited erythromelalgia and the extent of hyperpolarizing shifts in mutant Na(V)1.7 channel activation; mutations causing large activation shifts have been linked to early age of onset inherited erythromelalgia, while mutations causing small activation shifts have been linked to age of onset within the second decade of life. ⋯ The mutation also produces an approximately -40 mV shift in slow inactivation, which reduces channel availability. Comparison of the effects of the Del-L955 mutation on dorsal root ganglion neuron hyperexcitability with those produced by another inherited erythromelalgia mutation (L858F) that does not enhance slow inactivation suggests that a delayed age of onset and milder symptoms in association with a large shift of channel activation, enhanced persistent and enhanced ramp currents may be related to the approximately -40 mV shift in slow inactivation for Del-L955, the largest shift thus far demonstrated in mutant Na(V)1.7 channels. Our results suggest that despite the pivotal role of activation shift in inherited erythromelalgia development, slow inactivation may regulate clinical phenotype by altering channel availability.
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The life and achievements are described of (William) Ian McDonald, BMedSc MBChB PhD FRACP FRCP FRCOpth FMedSci: neurologist, National Hospital for Neurology and Neurosurgery (1966-98); physician, Moorfields Eye Hospital (1969-96); professor of neurology, Institute of Neurology and Institute of Ophthalmology, University of London (1974-98); Editor of Brain (1991-97); Harveian Librarian, Royal College of Physicians of London (1996-2004); born Wellington, New Zealand, 15 April 1933; died London, 13 December 2006. At his death, Ian McDonald left 33 box files of largely unsorted material relating to his private and professional life. The archive has not been catalogued but this biographical account of his life and work draws on the material contained therein. Where possible the date and provenance of material are identified and cited in the text; his curriculum vitae is provided as a supplementary file with individual papers identified by number within each category.
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The impact of traumatic spinal cord injury on structural integrity, cortical reorganization and ensuing disability is variable and may depend on a dynamic interaction between the severity of local damage and the capacity of the brain for plastic reorganization. We investigated trauma-induced anatomical changes in the spinal cord and brain, and explored their relationship to functional changes in sensorimotor cortex. Structural changes were assessed using cross-sectional cord area, voxel-based morphometry and voxel-based cortical thickness of T1-weighted images in 10 subjects with cervical spinal cord injury and 16 controls. ⋯ Increased sensory deficits were associated with increased activations in the left primary sensory cortex face area due to median nerve stimulation. In conclusion, spinal cord injury leads to cord atrophy, cortical atrophy of primary motor and sensory cortex, and cortical reorganization of the sensorimotor system. The degree of cortical reorganization is predicted by spinal atrophy and is associated with significant disability.
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Multicenter Study
Infarction of 'non-core-non-penumbral' tissue after stroke: multivariate modelling of clinical impact.
There is considerable intersubject variability in early neurological course after anterior circulation stroke, yet the pathophysiology underlying this variability is not fully understood. Here, we hypothesize that, although not predicted by current pathophysiological models, infarction of 'non-core-non-penumbral' (i.e. clinically silent) brain tissue may nevertheless occur, and negatively influence clinical course over and above the established positive impact of penumbral salvage. In order to test this hypothesis, non-core-non-penumbral tissue was identified in two independent prospectively recruited cohorts, using computed tomography perfusion, and magnetic resonance perfusion- and diffusion-weighted imaging, respectively. ⋯ This is the first systematic study to document infarction of acutely silent tissue after anterior circulation stroke, and to show that it affects a sizeable fraction of patients and has the predicted negative impact on clinical course. These findings were replicated in two independent cohorts, regardless of the perfusion imaging modality used. Preventing infarction of the tissue not initially at risk should have direct clinical benefit.