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ABSTRACT: In 1628 the English physician William Harvey (1578-1657) published his revolutionary theory that blood circulates through the body driven by the heart. This challenged the long-standing teachings of Hippocrates and Galen concerning 4 different bodily fluids or 'humours' that flowed through separate arterial and venous vascular systems. Harvey gained considerable influence in society as a member of the prestigious Royal College of Physicians in London and as personal physician to King James I and King Charles I. He strove for a more empirical foundation of medicine by means of anatomic demonstrations and vivisections. Despite enduring considerable criticism he managed to disseminate his ideas around the influential universities of Europe in the course of his lifetime. However, consequent changes in practice would not be brought about until decades after Harvey's death, when Galenist treatments such as blood-letting were gradually abandoned.
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ABSTRACT: Arm-amputation involves two powerful drivers for brain plasticity—sensory deprivation and altered use. However, research has largely focused on sensory deprivation and maladaptive change. Here we show that adaptive patterns of limb usage after amputation drive cortical plasticity. We report that individuals with congenital or acquired limb-absence vary in whether they preferentially use their intact hand or residual arm in daily activities. Using fMRI, we show that the deprived sensorimotor cortex is employed by whichever limb individuals are over-using. Individuals from either group that rely more on their intact hands (and report less frequent residual arm usage) showed increased intact hand representation in the deprived cortex, and increased white matter fractional anisotropy underlying the deprived cortex, irrespective of the age at which deprivation occurred. Our results demonstrate how experience-driven plasticity in the human brain can transcend boundaries that have been thought to limit reorganisation after sensory deprivation in adults. DOI: http://dx.doi.org/10.7554/eLife.01273.001
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ABSTRACT: Antiepileptic drugs have been used for treating different types of neuropathic pain, and sometimes fibromyalgia. Our understanding of quality standards in chronic pain trials has improved to include new sources of potential bias. Individual Cochrane reviews using these new standards have assessed individual antiepileptic drugs. An early review from this group, originally published in 1998, was titled 'Anticonvulsants for acute and chronic pain'. This overview now covers the neuropathic pain aspect of that original review, which was withdrawn in 2009. To provide an overview of the relative analgesic efficacy of antiepileptic drugs that have been compared with placebo in neuropathic pain and fibromyalgia, and to report on adverse events associated with their use. We included reviews published in theCochrane Database of Systematic Reviews up to August 2013 (Issue 7). We extracted information from each review on measures of efficacy and harm, and methodological details concerning the number of participants, the duration of studies, and the imputation methods used, in order to judge potential biases in available data.We analysed efficacy data for each painful condition in three tiers, according to outcome and freedom from known sources of bias. The first tier met current best standards - at least 50% pain intensity reduction over baseline (or its equivalent), without the use of last observation carried forward (LOCF) for dropouts, an intention-to-treat (ITT) analysis, in parallel group studies with at least 200 participants lasting eight weeks or more. The second tier used data from at least 200 participants where one or more of the above conditions were not met. The third tier of evidence related to data from fewer than 200 participants, or with several important methodological problems that limited interpretation. No studies reported top tier results.For gabapentin and pregabalin only we found reasonably good second tier evidence for efficacy in painful diabetic neuropathy and postherpetic neuralgia. In addition, for pregabalin, we found evidence of efficacy in central neuropathic pain and fibromyalgia. Point estimates of numbers needed to treat for an additional beneficial effect (NNTs) were in the range of 4 to 10 for the important outcome of pain intensity reduction over baseline of 50% or more.For other antiepileptic drugs there was no evidence (clonazepam, phenytoin), so little evidence that no sensible judgement could be made about efficacy (valproic acid), low quality evidence likely to be subject to a number of biases overestimating efficacy (carbamazepine), or reasonable quality evidence indicating little or no effect (lamotrigine, oxcarbazepine, topiramate). Lacosamide recorded such a trivial statistical superiority over placebo that it was unreliable to conclude that it had any efficacy where there was possible substantial bias.Any benefits of treatment came with a high risk of adverse events and withdrawal because of adverse events, but serious adverse events were not significantly raised, except with oxcarbazepine. Clinical trial evidence supported the use of only gabapentin and pregabalin in some neuropathic pain conditions (painful diabetic neuropathy, postherpetic neuralgia, and central neuropathic pain) and fibromyalgia. Only a minority of people achieved acceptably good pain relief with either drug, but it is known that quality of life and function improved markedly with the outcome of at least 50% pain intensity reduction. For other antiepileptic drugs there was no evidence, insufficient evidence, or evidence of a lack of effect; this included carbamazepine. Evidence from clinical practice and experience is that some patients can achieve good results with antiepileptics other than gabapentin or pregabalin.There is no firm evidence to answer the important pragmatic questions about which patients should have which drug, and in which order the drugs should be used. There is a clinical effectiveness research agenda to provide evidence about strategies rather than interventions, to produce the overall best results in a population, in the shortest time, and at the lowest cost to healthcare providers.
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