Publications by authors named "Holden Brown"

10 Publications

  • Page 1 of 1

Does a Modified Adhesive Respirator Improve the Face Seal for Health Care Workers Who Previously Failed a Fit Test?: A Pilot Study During the Coronavirus Disease 2019 Pandemic.

A A Pract 2020 Jun;14(8):e01264

From the Department of Anesthesiology, University of Florida College of Medicine, Gainesville, Florida.

Approximately 30% of health care workers (HCWs) fail the respirator fit test. Evidence suggests that addressing face leaks in the 3M respirator enhances its fit and improves its efficacy. Between March 31 and April 9, 2020, HCWs who failed fit tests for 3M 1860 and 1860S respirators were invited to retest with an adhesive modification of the 3M respirator. Sixty-eight percent of HCWs who failed the fit test with their first-choice respirator passed with a modified adhesive respirator. To increase the efficacy and safety of 3M respirators, ineffective face seals need substantial improvement in design.
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http://dx.doi.org/10.1213/XAA.0000000000001264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7323832PMC
June 2020

Association Between Exercise and Low Back Pain Resulting in Modified Duty and Lost Time: A Cross-Sectional Analysis of an Occupational Population.

J Occup Environ Med 2018 10;60(10):896-900

Rocky Mountain Center for Occupational and Environmental Health, University of Utah, Salt Lake City, Utah.

Objective: The aim of the study was to assess the relationship between leisure time exercise and whether workers ever had modified duty or lost time (MD/LT) due to low back pain (LBP) in an occupational cohort.

Methods: Workers (N = 827) completed a structured interview assessing characteristics of their LBP, whether or not the pain caused modified or lost work time, and their participation in leisure time exercise. Odds ratio of modified/lost time and minutes of exercise participation were assessed.

Results: Workers who participated in over 316 min/wk of leisure time exercise incurred significantly less modified/lost time, adjusted odds ratio = 0.46 (95% confidence interval, 0.23 to 0.98). There also lies a significant trend between increases in leisure time exercise and reductions in modified/lost time (P = 0.0016).

Conclusion: These results suggest exercise reduces risk of MD/LT from LBP.
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http://dx.doi.org/10.1097/JOM.0000000000001372DOI Listing
October 2018

Cyclooxygenase inhibition targets neurons to prevent early behavioural decline in Alzheimer's disease model mice.

Brain 2016 07 13;139(Pt 7):2063-81. Epub 2016 May 13.

1 Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA

Identifying preventive targets for Alzheimer's disease is a central challenge of modern medicine. Non-steroidal anti-inflammatory drugs, which inhibit the cyclooxygenase enzymes COX-1 and COX-2, reduce the risk of developing Alzheimer's disease in normal ageing populations. This preventive effect coincides with an extended preclinical phase that spans years to decades before onset of cognitive decline. In the brain, COX-2 is induced in neurons in response to excitatory synaptic activity and in glial cells in response to inflammation. To identify mechanisms underlying prevention of cognitive decline by anti-inflammatory drugs, we first identified an early object memory deficit in APPSwe-PS1ΔE9 mice that preceded previously identified spatial memory deficits in this model. We modelled prevention of this memory deficit with ibuprofen, and found that ibuprofen prevented memory impairment without producing any measurable changes in amyloid-β accumulation or glial inflammation. Instead, ibuprofen modulated hippocampal gene expression in pathways involved in neuronal plasticity and increased levels of norepinephrine and dopamine. The gene most highly downregulated by ibuprofen was neuronal tryptophan 2,3-dioxygenase (Tdo2), which encodes an enzyme that metabolizes tryptophan to kynurenine. TDO2 expression was increased by neuronal COX-2 activity, and overexpression of hippocampal TDO2 produced behavioural deficits. Moreover, pharmacological TDO2 inhibition prevented behavioural deficits in APPSwe-PS1ΔE9 mice. Taken together, these data demonstrate broad effects of cyclooxygenase inhibition on multiple neuronal pathways that counteract the neurotoxic effects of early accumulating amyloid-β oligomers.
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http://dx.doi.org/10.1093/brain/aww117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4939702PMC
July 2016

Microarray analysis of the in vivo response of microglia to Aβ peptides in mice with conditional deletion of the prostaglandin EP2 receptor.

Genom Data 2015 Sep;5:268-271

Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305.

Amyloid-β (Aβ) peptides accumulate in the brains of patients with Alzheimer's disease (AD), where they generate a persistent inflammatory response from microglia, the innate immune cells of the brain. The immune modulatory cyclooxygenase/prostaglandin E2 (COX/PGE) pathway has been implicated in preclinical AD development, both in human epidemiology studies and in transgenic rodent models of AD. PGE signals through four G-protein-coupled receptors, including the EP2 receptor that has been investigated for its role in mediating the inflammatory and phagocytic responses to Aβ. To identify transcriptional differences in microglia lacking the EP2 receptor, we examined mice with EP2 conditionally deleted in Cd11b-expressing immune cells. We injected Aβ peptides or saline vehicle into the brains of adult mice, isolated primary microglia, and analyzed RNA expression by microarray. The resulting datasets were analyzed in two studies, one describing the basal status of microglia with or without EP2 deletion, and the second study analyzing the microglial response to Aβ. Here we describe in detail the experimental design and data analyses. The raw data from these studies are deposited in GEO, accession GSE57181 (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE57181).
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http://dx.doi.org/10.1016/j.gdata.2015.06.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4522932PMC
September 2015

Prostaglandin signaling suppresses beneficial microglial function in Alzheimer's disease models.

J Clin Invest 2015 Jan 8;125(1):350-64. Epub 2014 Dec 8.

Microglia, the innate immune cells of the CNS, perform critical inflammatory and noninflammatory functions that maintain normal neural function. For example, microglia clear misfolded proteins, elaborate trophic factors, and regulate and terminate toxic inflammation. In Alzheimer's disease (AD), however, beneficial microglial functions become impaired, accelerating synaptic and neuronal loss. Better understanding of the molecular mechanisms that contribute to microglial dysfunction is an important objective for identifying potential strategies to delay progression to AD. The inflammatory cyclooxygenase/prostaglandin E2 (COX/PGE2) pathway has been implicated in preclinical AD development, both in human epidemiology studies and in transgenic rodent models of AD. Here, we evaluated murine models that recapitulate microglial responses to Aβ peptides and determined that microglia-specific deletion of the gene encoding the PGE2 receptor EP2 restores microglial chemotaxis and Aβ clearance, suppresses toxic inflammation, increases cytoprotective insulin-like growth factor 1 (IGF1) signaling, and prevents synaptic injury and memory deficits. Our findings indicate that EP2 signaling suppresses beneficial microglia functions that falter during AD development and suggest that inhibition of the COX/PGE2/EP2 immune pathway has potential as a strategy to restore healthy microglial function and prevent progression to AD.
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http://dx.doi.org/10.1172/JCI77487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4382270PMC
January 2015

Suppression of inflammation with conditional deletion of the prostaglandin E2 EP2 receptor in macrophages and brain microglia.

J Neurosci 2013 Oct;33(40):16016-32

Departments of Neurology and Neurological Sciences, Molecular and Cellular Physiology, Microbiology and Immunology, and Neurosurgery, Stanford University School of Medicine, Stanford, California 94305, Neurosciences Graduate Program, Stanford University, Stanford, California 94305, and Center for Health Sciences, SRI International, Menlo Park, California 94025.

Prostaglandin E2 (PGE2), a potent lipid signaling molecule, modulates inflammatory responses through activation of downstream G-protein coupled EP(1-4) receptors. Here, we investigated the cell-specific in vivo function of PGE2 signaling through its E-prostanoid 2 (EP2) receptor in murine innate immune responses systemically and in the CNS. In vivo, systemic administration of lipopolysaccharide (LPS) resulted in a broad induction of cytokines and chemokines in plasma that was significantly attenuated in EP2-deficient mice. Ex vivo stimulation of peritoneal macrophages with LPS elicited proinflammatory responses that were dependent on EP2 signaling and that overlapped with in vivo plasma findings, suggesting that myeloid-lineage EP2 signaling is a major effector of innate immune responses. Conditional deletion of the EP2 receptor in myeloid lineage cells in Cd11bCre;EP2(lox/lox) mice attenuated plasma inflammatory responses and transmission of systemic inflammation to the brain was inhibited, with decreased hippocampal inflammatory gene expression and cerebral cortical levels of IL-6. Conditional deletion of EP2 significantly blunted microglial and astrocytic inflammatory responses to the neurotoxin MPTP and reduced striatal dopamine turnover. Suppression of microglial EP2 signaling also increased numbers of dopaminergic (DA) neurons in the substantia nigra independent of MPTP treatment, suggesting that microglial EP2 may influence development or survival of DA neurons. Unbiased microarray analysis of microglia isolated from adult Cd11bCre;EP2(lox/lox) and control mice demonstrated a broad downregulation of inflammatory pathways with ablation of microglial EP2 receptor. Together, these data identify a cell-specific proinflammatory role for macrophage/microglial EP2 signaling in innate immune responses systemically and in brain.
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http://dx.doi.org/10.1523/JNEUROSCI.2203-13.2013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3787507PMC
October 2013

The selective serotonin reuptake inhibitor, escitalopram, enhances inhibition of prepotent responding and spatial reversal learning.

J Psychopharmacol 2012 Nov 4;26(11):1443-55. Epub 2012 Jan 4.

Department of Psychology, University of Illinois at Chicago, Chicago, IL, USA.

Previous findings indicate treatment with a selective serotonin reuptake inhibitor (SSRI) facilitates behavioral flexibility when conditions require inhibition of a learned response pattern. The present experiment investigated whether acute treatment with the SSRI, escitalopram, affects behavioral flexibility when conditions require inhibition of a naturally biased response pattern (elevated conflict test) and/or reversal of a learned response pattern (spatial reversal learning). An additional experiment was carried out to determine whether escitalopram, at doses that affected behavioral flexibility, also reduced anxiety as tested in the elevated plus-maze. In each experiment, Long-Evans rats received an intraperitoneal injection of either saline or escitalopram (0.03, 0.3 or 1.0 mg/kg) 30 min prior to behavioral testing. Escitalopram, at all doses tested, enhanced acquisition in the elevated conflict test, but did not affect performance in the elevated plus-maze. Escitalopram (0.3 and 1.0 mg/kg) did not alter acquisition of the spatial discrimination, but facilitated reversal learning. In the elevated conflict and spatial reversal learning test, escitalopram enhanced the ability to maintain the relevant strategy after being initially selected. The present findings suggest that enhancing serotonin transmission with an SSRI facilitates inhibitory processes when conditions require a shift away from either a naturally biased response pattern or a learned choice pattern.
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http://dx.doi.org/10.1177/0269881111430749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3345307PMC
November 2012

Primary food reward and reward-predictive stimuli evoke different patterns of phasic dopamine signaling throughout the striatum.

Eur J Neurosci 2011 Dec 29;34(12):1997-2006. Epub 2011 Nov 29.

Graduate Program in Neuroscience, University of Illinois at Chicago, Chicago, IL, USA.

Phasic changes in dopamine activity play a critical role in learning and goal-directed behavior. Unpredicted reward and reward-predictive cues evoke phasic increases in the firing rate of the majority of midbrain dopamine neurons--results that predict uniformly broadcast increases in dopamine concentration throughout the striatum. However, measurement of dopamine concentration changes during reward has cast doubt on this prediction. We systematically measured phasic changes in dopamine in four striatal subregions [nucleus accumbens shell and core (Core), dorsomedial (DMS) and dorsolateral striatum] in response to stimuli known to activate a majority of dopamine neurons. We used fast-scan cyclic voltammetry in awake and behaving rats, which measures changes in dopamine on a similar timescale to the electrophysiological recordings that established a relationship between phasic dopamine activity and reward. Unlike the responses of midbrain dopamine neurons, unpredicted food reward and reward-predictive cues evoked a phasic increase in dopamine that was subregion specific. In rats with limited experience, unpredicted food reward evoked an increase exclusively in the Core. In rats trained on a discriminative stimulus paradigm, both unpredicted reward and reward-predictive cues evoked robust phasic dopamine in the Core and DMS. Thus, phasic dopamine release in select target structures is dynamic and dependent on context and experience. Because the four subregions assayed receive different inputs and have differential projection targets, the regional selectivity of phasic changes in dopamine has important implications for information flow through the striatum and plasticity that underlies learning and goal-directed behavior.
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http://dx.doi.org/10.1111/j.1460-9568.2011.07914.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3237906PMC
December 2011

The parafascicular thalamic nucleus concomitantly influences behavioral flexibility and dorsomedial striatal acetylcholine output in rats.

J Neurosci 2010 Oct;30(43):14390-8

Program in Neuroscience, Department of Psychology, and Laboratory of Integrative Neuroscience, University of Illinois at Chicago, Chicago, Illinois 60607, USA.

Recent evidence suggests that a circuit involving the centromedian-parafascicular (Pf) thalamus and basal ganglia is critical for a shift away from biased actions. In particular, excitatory input from the Pf onto striatal cholinergic neurons may facilitate behavioral flexibility. Accumulating evidence indicates that an endogenous increase in dorsomedial striatal acetylcholine (ACh) output enhances behavioral flexibility. The present experiments investigated whether the rat (Rattus norvegicus) Pf supports flexibility during reversal learning, in part, by modifying dorsomedial striatal ACh output. This was determined first by examining the effects of Pf inactivation, through infusion of the GABA agonists baclofen and muscimol, on place acquisition and reversal learning. Additional experiments examined Pf inactivation on dorsomedial striatal ACh output during reversal learning and a resting condition. Behavioral testing was performed in a cross-maze. In vivo microdialysis combined with HPLC/electrochemical detection was used to sample ACh from the dorsomedial striatum. Pf inactivation selectively impaired reversal learning in a dose-dependent manner. A subsequent study showed that an increase in dorsomedial striatal ACh efflux (∼30% above basal levels) during reversal learning was blocked by Pf inactivation, which concomitantly impaired reversal learning. In the resting condition, a dose of baclofen and muscimol that blocked a behaviorally induced increase in dorsomedial striatal ACh output did not reduce basal ACh efflux. Together, the present findings indicate that the Pf is an intralaminar thalamic nucleus critical for behavioral flexibility, in part, by directly affecting striatal ACh output under conditions that require a shift in choice patterns.
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http://dx.doi.org/10.1523/JNEUROSCI.2167-10.2010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3096060PMC
October 2010

Toward a neuro-cognitive animal model of the cognitive symptoms of schizophrenia: disruption of cortical cholinergic neurotransmission following repeated amphetamine exposure in attentional task-performing, but not non-performing, rats.

Neuropsychopharmacology 2007 Oct 14;32(10):2074-86. Epub 2007 Feb 14.

Department of Psychology, University of Michigan, Ann Arbor, MI 48109-1043, USA.

Impairments in attentional functions and capacities represent core aspects of the cognitive symptoms of schizophrenia. Attentional performance has been demonstrated to depend on the integrity and activity of cortical cholinergic inputs. The neurobiological, behavioral, and cognitive effects of repeated exposure to psychostimulants model important aspects of schizophrenia. In the present experiment, prefrontal acetylcholine (ACh) release was measured in attentional task-performing and non-performing rats pretreated with an escalating dosing regimen of amphetamine (AMPH) and following challenges with AMPH. In non-performing rats, pretreatment with AMPH did not affect the increases in ACh release produced by AMPH-challenges. In contrast, attentional task performance-associated increases in ACh release were attenuated in AMPH-pretreated and AMPH-challenged rats. This effect of repeated AMPH exposure on ACh release was already present before task-onset, suggesting that the loss of cognitive control that characterized these animals' performance was a result of cholinergic dysregulation. The findings indicate that the demonstration of repeated AMPH-induced dysregulation of the prefrontal cholinergic input system depends on interactions between the effects of repeated AMPH exposure and cognitive performance-associated recruitment of this neuronal system. Repeated AMPH-induced disruption of prefrontal cholinergic activity and attentional performance represents a useful model to investigate the cholinergic mechanisms contributing to the cognitive impairments of schizophrenia.
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http://dx.doi.org/10.1038/sj.npp.1301352DOI Listing
October 2007