Annals of the New York Academy of Sciences
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Ann. N. Y. Acad. Sci. · Sep 2012
ReviewImaging-based selection in acute ischemic stroke trials - a quest for imaging sweet spots.
Ischemic stroke is a very heterogeneous disease that limits the efficacy of acute stroke treatments. Future trials will require advanced imaging to select patients for specific treatments. ⋯ As an alternative to mismatch when addressing stroke, one needs to know the size of the initial irreversible lesion (core), the presence and site/extent of occlusion (clot), and presence of leptomeningeal back filling and Willisian filling (collaterals). These can be summarized as the "3C" approach of core, clot, and collateral interpretation, which together can represent an imaging sweet spot, particularly for time-efficient endovascular treatment trial design.
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Hemorrhagic transformation (HT) associated with recombinant tissue plasminogen activator (rt-PA) complicates and limits its use in stroke. Here, we provide a focused review on the involvement of matrix metalloproteinase 9 (MMP-9) in rt-PA-associated HT in cerebral ischemia, and we review emerging evidence that the selective inhibitor of the sulfonylurea receptor 1 (Sur1), glibenclamide (U. ⋯ A retrospective clinical study comparing outcomes in diabetic patients with stroke treated with rt-PA showed that those who were previously on and were maintained on a sulfonylurea fared significantly better than those whose diabetes was managed without sulfonylureas. Inhibition of Sur1 with injectable glyburide holds promise for ameliorating rt-PA-associated HT in stroke.
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Ann. N. Y. Acad. Sci. · Aug 2012
ReviewMoving toward a generalizable application of central thalamic deep brain stimulation for support of forebrain arousal regulation in the severely injured brain.
This review considers the challenges ahead for developing a generalizable strategy for the use of central thalamic deep brain stimulation (CT/DBS) to support arousal regulation mechanisms in the severely injured brain. Historical efforts to apply CT/DBS to patients with severe brain injuries and a proof-of-concept result from a single-subject study are discussed. Circuit and cellular mechanisms underlying the recovery of consciousness are considered for their relevance to the application of CT/DBS, to improve consciousness and cognition in nonprogressive brain injuries. Finally, directions for development, and testing of generalizable criteria for CT/DBS are suggested, which aim to identify neuronal substrates and behavioral profiles that may optimally benefit from support of arousal regulation mechanisms.
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Ann. N. Y. Acad. Sci. · Jul 2012
ReviewExperimental endotoxemia as a model to study neuroimmune mechanisms in human visceral pain.
The administration of bacterial endotoxin (i.e., lipopolysaccharide, LPS) constitutes a well-established experimental approach to study the effects of an acute and transient immune activation on physiological, behavioral, and emotional aspects of sickness behavior in animals and healthy humans. However, little is known about possible effects of experimental endotoxemia on pain in humans. ⋯ Considering the recent findings of visceral hyperalgesia after LPS application in humans, in this review, we propose that experimental endotoxemia with its complex peripheral and central effects constitutes an experimental model to study neuroimmune communication in human pain research. We summarize and attempt to integrate relevant animal and human studies concerning neuroimmune communication in visceral and somatic pain, discuss putative mechanisms, and conclude with future research directions.
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Ann. N. Y. Acad. Sci. · Jun 2012
ReviewRelevance of endothelial junctions in leukocyte extravasation and vascular permeability.
Inflammation and immune surveillance rely on the ability of leukocytes to leave the blood stream and enter tissue. Cytokines and chemokines regulate expression and the activation state of adhesion molecules that enable leukocytes to adhere and arrest at sites of leukocyte exit. ⋯ This work has revealed the dominant importance of the junctional pathway between endothelial cells in vivo. In addition, recent progress has improved our understanding of the molecular mechanisms that regulate junctional stability, the opening of endothelial junctions during leukocyte extravasation, and the induction of vascular permeability.