Identification and Cost of Potentially Avoidable Transfers to a Tertiary Care Neurosurgery Service: A Pilot Study.

BACKGROUND: Thousands of neurosurgical emergencies are transferred yearly to tertiary care facilities to assume a higher level of care. Several studies have examined how neurosurgical transfers influence patient outcomes, but characteristics of potentially avoidable transfers have yet to be investigated. OBJECTIVE: To identify whether potentially avoidable transfers represent a significant portion of transfers to a tertiary neurosurgical facility. METHODS: In this cohort study, we evaluated 916 neurosurgical patients transferred to a tertiary care facility over a 2-year period. Transfers were classified as potentially avoidable when no neurosurgical diagnostic test, intervention, or intensive monitoring was deemed necessary (n = 180). The remaining transfers were classified as justifiable (n = 736). The main outcomes and measures were age, sex, diagnosis, insurance status, intervention, distance of transfer, length of hospital and intensive care unit stay, mortality, discharge disposition, and cost. RESULTS: Nearly 20% of transfers were identified as being potentially avoidable. Although some of these patients had suffered devastating, irrecoverable neurological insults, many had innocuous conditions that did not require transfer to a higher level of care. Justifiable transfers tend to involve patients with nontraumatic intracranial hemorrhage and cranial neoplasm. Both groups were admitted to the intensive care unit at the same rate (approximately 70% of patients). Finally, the direct transportation cost of potentially avoidable transfers was $1.46 million over 2 years. CONCLUSION: This study identified the frequency and expense of potentially avoidable transfers. There is a need for closer examination of the clinical and financial implications of potentially avoidable transfers. ABBREVIATIONS: CI, confidence intervalIQR, interquartile rangeJT, justifiable transferOR, odds ratioPAT, potentially avoidable transferUAB, University of Alabama at Birmingham.

Tau-mediated NMDA receptor impairment underlies dysfunction of a selectively vulnerable network in a mouse model of frontotemporal dementia.

Frontotemporal dementia (FTD) is a neurodegenerative behavioral disorder that selectively affects the salience network, including the ventral striatum and insula. Tau mutations cause FTD, but how mutant tau impairs the salience network is unknown. Here, we address this question using a mouse model expressing the entire human tau gene with an FTD-associated mutation (V337M). Mutant, but not wild-type, human tau transgenic mice had aging-dependent repetitive and disinhibited behaviors, with synaptic deficits selectively in the ventral striatum and insula. There, mutant tau depleted PSD-95, resulting in smaller postsynaptic densities and impaired synaptic localization of NMDA receptors (NMDARs). In the ventral striatum, decreased NMDAR-mediated transmission reduced striatal neuron firing. Pharmacologically enhancing NMDAR function with the NMDAR co-agonist cycloserine reversed electrophysiological and behavioral deficits. These results indicate that NMDAR hypofunction critically contributes to FTD-associated behavioral and electrophysiological alterations and that this process can be therapeutically targeted by a Food and Drug Administration-approved drug.

An acetylcholinesterase inhibitor, eserine, induces long-term depression at CA3-CA1 synapses in the hippocampus of adult rats.

Studies in humans and rodents support a role for muscarinic ACh receptor (mAChR) and nicotinic AChR in learning and memory, and both regulate hippocampal synaptic plasticity using complex and often times opposing mechanisms. Acetylcholinesterase (AChE) inhibitors are commonly prescribed to enhance cholinergic signaling in Alzheimer's disease in hopes of rescuing cognitive function, caused, in part, by degeneration of cholinergic innervation to the hippocampus and cortex. Unfortunately, therapeutic efficacy is moderate and inconsistent, perhaps due to unanticipated mechanisms. M1 mAChRs bidirectionally control synaptic strength at CA3-CA1 synapses; weak pharmacological activation using carbachol (CCh) facilitates potentiation, whereas strong agonism induces muscarinic long-term depression (mLTD) via an ERK-dependent mechanism. Here, we tested the prediction that accumulation of extracellular ACh via inhibition of AChE is sufficient to induce LTD at CA3-CA1 synapses in hippocampal slices from adult rats. Although AChE inhibition with eserine induces LTD, it unexpectedly does not share properties with mLTD induced by CCh, as reported previously. Eserine-LTD was prevented by the M3 mAChR-preferring antagonist 1,1-dimethyl-4-diphenylacetoxypiperidinium iodide (4-DAMP), and pharmacological inhibition of MEK was completely ineffective. Additionally, pharmacological inhibition of p38 MAPK prevents mLTD but has no effect on eserine-LTD. Finally, long-term expression of eserine-LTD is partially dependent on a decrease in presynaptic release probability, likely caused by tonic activation of mAChRs by the sustained increase in extracellular ACh. Thus these findings extend current literature by showing that pharmacological AChE inhibition causes a prolonged decrease in presynaptic glutamate release at CA3-CA1 synapses, in addition to inducing a likely postsynaptic form of LTD.

Dissociation of frontotemporal dementia-related deficits and neuroinflammation in progranulin haploinsufficient mice.

Frontotemporal dementia (FTD) is a neurodegenerative disease with hallmark deficits in social and emotional function. Heterozygous loss-of-function mutations in GRN, the progranulin gene, are a common genetic cause of the disorder, but the mechanisms by which progranulin haploinsufficiency causes neuronal dysfunction in FTD are unclear. Homozygous progranulin knock-out (Grn(-/-)) mice have been studied as a model of this disorder and show behavioral deficits and a neuroinflammatory phenotype with robust microglial activation. However, homozygous GRN mutations causing complete progranulin deficiency were recently shown to cause a different neurological disorder, neuronal ceroid lipofuscinosis, suggesting that the total absence of progranulin may have effects distinct from those of haploinsufficiency. Here, we studied progranulin heterozygous (Grn(+/-)) mice, which model progranulin haploinsufficiency. We found that Grn(+/-) mice developed age-dependent social and emotional deficits potentially relevant to FTD. However, unlike Grn(-/-) mice, behavioral deficits in Grn(+/-) mice occurred in the absence of gliosis or increased expression of tumor necrosis factor-α. Instead, we found neuronal abnormalities in the amygdala, an area of selective vulnerability in FTD, in Grn(+/-) mice. Our findings indicate that FTD-related deficits resulting from progranulin haploinsufficiency can develop in the absence of detectable gliosis and neuroinflammation, thereby dissociating microglial activation from functional deficits and suggesting an important effect of progranulin deficiency on neurons.

Bidirectional axonal plasticity during reorganization of adult rat primary somatosensory cortex.

Cortical sensory maps contain discrete functional subregions that are separated by borders that restrict tangential activity flow. Interestingly, the functional organization of border regions remains labile in adults, changing in an activity-dependent manner. Here, we investigated if axon remodeling contributes to this reorganization. We located the border between the forepaw and lower jaw representation (forepaw/lower jaw border,(1) FP/LJ border) in SI of adult rats, and used a retrograde axonal tracer (cholera toxin subunit B(2), Ctb) to determine if horizontal axonal projections change after different durations of forelimb denervation or sham-denervation. In sham-denervated animals, neurons close to the border had axonal projections oriented away from the border (axonal bias). Forelimb denervation resulted in a sustained change in border location and a significant reduction in the axonal bias at the original border after 6 weeks of denervation, but not after 4 or 12 weeks. The change in axonal bias was due to an increase in axons that cross the border at 6 weeks, followed by an apparent loss of these axons by 12 weeks. This suggests that bidirectional axonal rearrangements are associated with relatively long durations of reorganization and could contribute transiently to the maintenance of cortical reorganization.