Aquaporin-4 (AQP4) is the major water channel in the central nervous system (CNS) and is primarily expressed in astrocytes. Little is known about the potential for AQP4 to influence synaptic plasticity, although many studies have shown that it regulates the response of the CNS to injury. Therefore, we evaluated long-term potentiation (LTP), and long-term depression (LTD) in AQP4 knockout (KO) and wild type (WT) mice. KO mice exhibited a selective defect in LTP and LTD without a change in basal transmission or short-term plasticity. Interestingly, the impairment in LTP in KO mice was specific for the type of LTP that depends on the neurotrophin BDNF, which is induced by stimulation at theta rhythm (TBS-LTP), but there was no impairment in a form of LTP that is BDNF-independent, induced by high frequency stimulation (HFS-LTP). LTD was also impaired in KO mice, which was rescued by a scavenger of BDNF or blockade of Trk receptors. TrkB receptors, which mediate effects of BDNF on TBS-LTP, were not altered in KO mice, but p75NTR, the receptor that binds all neurotrophins and has been implicated in some types of LTD, was decreased. The KO mice also exhibited a cognitive defect, which suggests a new role for AQP4 and astrocytes in normal cognitive function. This defect was evident using a test for location-specific object memory but not Morris water maze or contextual fear conditioning. The results suggest that AQP4 channels in astrocytes play an unanticipated role in neurotrophin-dependent plasticity and influence behavior.
Pain following stroke is commonly reported but often incompletely managed, which prevents optimal recovery. This is in part due to the esoteric nature of post-stroke pain and its limited presence in current discussions of stroke management. The major specific afflictions that affect patients with stroke who develop pain include central post-stroke pain (CPSP), complex regional pain syndrome (CRPS), and pain associated with spasticity and shoulder subluxation. Each disorder carries its own intricacies that require specific approaches to treatment and understanding. This review aims to present and clarify the major pain syndromes that affect patients who have suffered from stroke in order to aid in their diagnosis and treatment.
Objective To determine the safety, tolerability, and efficacy of fluoxetine for proven or presumptive enterovirus (EV) D68-associated acute flaccid myelitis (AFM). Methods A multicenter cohort study of US patients with AFM in 2015-2016 compared serious adverse events (SAEs), adverse effects, and outcomes between fluoxetine-treated patients and untreated controls. Fluoxetine was administered at the discretion of treating providers with data gathered retrospectively. The primary outcome was change in summative limb strength score (SLSS; sum of Medical Research Council strength in all 4 limbs, ranging from 20 [normal strength] to 0 [complete quadriparesis]) between initial examination and latest follow-up, with increased SLSS reflecting improvement and decreased SLSS reflecting worsened strength. Results Fifty-six patients with AFM from 12 centers met study criteria. Among 30 patients exposed to fluoxetine, no SAEs were reported and adverse effect rates were similar to unexposed patients (47% vs 65%, p = 0.16). The 28 patients treated with >1 dose of fluoxetine were more likely to have EV-D68 identified (57.1% vs 14.3%, p < 0.001). Their SLSS was similar at initial examination (mean SLSS 12.9 vs 14.3, p = 0.31) but lower at nadir (mean SLSS 9.25 vs 12.82, p = 0.02) and latest follow-up (mean SLSS 12.5 vs 16.4, p = 0.005) compared with the 28 patients receiving 1 (n = 2) or no (n = 26) doses. In propensity-adjusted analysis, SLSS from initial examination to latest follow-up decreased by 0.2 (95% confidence interval [CI] −1.8 to +1.4) in fluoxetine-treated patients and increased by 2.5 (95% CI +0.7 to +4.4) in untreated patients (p = 0.015). Conclusion Fluoxetine was well-tolerated. Fluoxetine was preferentially given to patients with AFM with EV-D68 identified and more severe paralysis at nadir, who ultimately had poorer long-term outcomes. Classification of evidence This study provides Class IV evidence that for patients with EV-D68-associated AFM, fluoxetine is well-tolerated and not associated with improved neurologic outcomes.
Meningitis and encephalitis are two inflammatory, often infectious, disorders of the meninges and the central nervous system. Both are associated with significant morbidity and mortality, and require early and aggressive targeted treatment. This article reviews pharmacologic treatment strategies for infectious meningitis and encephalitis, using the latest available research and guidelines. It provides an overview of empiric antimicrobial treatment approaches for a variety of organisms, including a discussion of trends in antibiotic resistance where applicable. Key steps in diagnosis and general management are briefly reviewed.
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