RESUMO
Guidelines help to facilitate treatment decisions based on available evidence, and also to provide recommendations in areas of uncertainty. In this paper, we compare the recommendations for stroke workup and secondary prevention of ischemic stroke and transient ischemic attack of the American Heart Association (AHA)/American Stroke Association (ASA) with the European Stroke Organization (ESO) guidelines. The primary aim of this paper is to offer clinicians guidance by identifying areas where there is consensus and where consensus is lacking, in the absence or presence of high-level evidence. We compared AHA/ASA with the ESO guideline recommendations for 7 different topics related to diagnostic stroke workup and secondary prevention. We categorized the recommendations based on class and level of evidence to determine whether there were relevant differences in the ratings of evidence that the guidelines used for its recommendations. Finally, we summarized major topics of agreement and disagreement, while also prominent knowledge gaps were identified. In total, we found 63 ESO and 82 AHA/ASA recommendations, of which 38 were on the same subject. Most recommendations are largely similar, but not all are based on high-level evidence. For many recommendations, AHA/ASA and ESO assigned different levels of evidence. For the 10 recommendations with Level A evidence (high quality) in AHA/ASA, ESO only labeled 4 of these as high quality. There are many remaining issues with either no or insufficient evidence, and some topics that are not covered by both guidelines. Most ESO and AHA/ASA Guideline recommendations for stroke workup and secondary prevention were similar. However not all were based on high-level evidence and the appointed level of evidence often differed. Clinicians should not blindly follow all guideline recommendations; the accompanying level of evidence informs which recommendations are based on robust evidence. Topics with lower levels of evidence, or those with recommendations that disagree or are missing, may be an incentive for further clinical research.
Assuntos
Ataque Isquêmico Transitório , AVC Isquêmico , Guias de Prática Clínica como Assunto , Prevenção Secundária , Humanos , Ataque Isquêmico Transitório/prevenção & controle , Ataque Isquêmico Transitório/diagnóstico , Prevenção Secundária/métodos , Prevenção Secundária/normas , AVC Isquêmico/prevenção & controle , AVC Isquêmico/diagnóstico , Europa (Continente) , Estados Unidos , American Heart Association , Medicina Baseada em Evidências/normas , Acidente Vascular Cerebral/prevenção & controle , Acidente Vascular Cerebral/diagnósticoRESUMO
During development, a neuron transitions from a state of rapid growth to a stable morphology, and neurons within the adult mammalian CNS lose their ability to effectively regenerate in response to injury. Here, we identify a novel form of neuronal regeneration, which is remarkably independent of DLK-1/DLK, KGB-1/JNK, and other MAPK signaling factors known to mediate regeneration in Caenorhabditis elegans, Drosophila, and mammals. This DLK-independent regeneration in C. elegans has direct genetic and molecular links to a well-studied form of endogenous activity-dependent ectopic axon outgrowth in the same neuron type. Both neuron outgrowth types are triggered by physical lesion of the sensory dendrite or mutations disrupting sensory activity, calcium signaling, or genes that restrict outgrowth during neuronal maturation, such as SAX-1/NDR kinase or UNC-43/CaMKII. These connections suggest that ectopic outgrowth represents a powerful platform for gene discovery in neuronal regeneration. Moreover, we note numerous similarities between C. elegans DLK-independent regeneration and lesion conditioning, a phenomenon producing robust regeneration in the mammalian CNS. Both regeneration types are triggered by lesion of a sensory neurite via reduction of neuronal activity and enhanced by disrupting L-type calcium channels or elevating cAMP. Taken as a whole, our study unites disparate forms of neuronal outgrowth to uncover fresh molecular insights into activity-dependent control of the adult nervous system's intrinsic regenerative capacity.
Assuntos
Caenorhabditis elegans/genética , Regeneração Nervosa , Animais , Axônios/metabolismo , Proteínas de Caenorhabditis elegans/genética , Canais de Cálcio Tipo LRESUMO
Regulated calcium signals play conserved instructive roles in neuronal repair, but how localized calcium stores are differentially mobilized, or might be directly manipulated, to stimulate regeneration within native contexts is poorly understood. We find here that localized calcium release from the endoplasmic reticulum via ryanodine receptor (RyR) channels is critical in stimulating initial regeneration following traumatic cellular damage in vivo. Using laser axotomy of single neurons in Caenorhabditis elegans, we find that mutation of unc-68/RyR greatly impedes both outgrowth and guidance of the regenerating neuron. Performing extended in vivo calcium imaging, we measure subcellular calcium signals within the immediate vicinity of the regenerating axon end that are sustained for hours following axotomy and completely eliminated within unc-68/RyR mutants. Finally, using a novel optogenetic approach to periodically photo-stimulate the axotomized neuron, we can enhance its regeneration. The enhanced outgrowth depends on both amplitude and temporal pattern of excitation and can be blocked by disruption of UNC-68/RyR. This demonstrates the exciting potential of emerging optogenetic technology to beneficially manipulate cell physiology in the context of neuronal regeneration and indicates a link to the underlying cellular calcium signal. Taken as a whole, our findings define a specific localized calcium signal mediated by RyR channel activity that stimulates regenerative outgrowth, which may be dynamically manipulated for beneficial neurotherapeutic effects.