Child Passenger Safety in the Somali Communities of Columbus, Ohio.

Children (particularly low-income minorities and refugees) are at high risk for serious injury or death from motor vehicle crashes. Interpreter-assisted data collection included key informant interviews, focus groups and face-to-face surveys with the Somali community of Columbus, Ohio about child passenger safety. Measurements included prevalence of child safety seats use, awareness and knowledge of and barriers to proper use in order to inform development, implementation, and initial evaluation of a culturally-appropriate intervention for Somali families. Somali parents regarded child passenger safety as an important topic, but many reported improper restraint behaviors of one or more children and/or did not have an adequate number of child safety seats. Few parents reported having child safety seats installed by a professional technician. Child passenger safety practices in the Somali communities of Columbus are a public health concern that should be addressed with culturally-appropriate interventions.

Paediatric emergency department-based carbon monoxide detector intervention: a randomised trial.

BACKGROUND: Although non-fire-related carbon monoxide (CO) poisoning is almost entirely preventable, over 400 people die and 20 000 people are injured each year in the USA from unintentional CO poisoning. Thus, there is a critical need for evidence-based interventions for preventing CO poisoning and increasing the proper use and installation of CO detectors. METHODS: A randomised, controlled trial (Project CODE, a Carbon Monoxide Detector Education intervention) with 2-week and 6-month follow-up home observations was conducted in 299 parents of children aged ≤18 years recruited in the emergency department of a level 1 paediatric trauma centre. The intervention group received an educational tool, a spiral-bound, laminated booklet that resembled a CO detector containing theory-based safety messages based on the precaution adoption process model, a plug-in CO detector and 9 V battery. The control group received a one page flyer on CO poisoning prevention. RESULTS: Although the difference was not statistically significant, mean CO knowledge score increased at a greater rate for the intervention group than the control group. Intervention group parents were more likely to exhibit 'safe' CO detector use than control group parents at the 2-week follow-up (RR: 2.75; 95% CI 2.06 to 3.69) and 6-month follow-up (RR: 2.78; 95% CI 2.06 to 3.76), after adjusting for self-reported CO detector use behaviour at enrolment and annual per capita income. CONCLUSIONS: An emergency department-delivered intervention containing a theory-based educational tool paired with a CO detector can be an effective method for increasing knowledge about CO poisoning, for prevention and for appropriate use of a CO detector. TRIAL REGISTRATION NUMBER: NCT00959478.

Insulin improves memory and reduces chronic neuroinflammation in the hippocampus of young but not aged brains.

The role of insulin in the brain is still not completely understood. In the periphery, insulin can decrease inflammation induced by lipopolysaccharide (LPS); however, whether insulin can reduce inflammation within the brain is unknown. Experiments administrating intranasal insulin to young and aged adults have shown that insulin improves memory. In our animal model of chronic neuroinflammation, we administered insulin and/or LPS directly into the brain via the fourth ventricle for 4 weeks in young rats; we then analyzed their spatial memory and neuroinflammatory response. Additionally, we administered insulin or artificial cerebral spinal fluid (aCSF), in the same manner, to aged rats and then analyzed their spatial memory and neuroinflammatory response. Response to chronic neuroinflammation in young rats was analyzed in the presence or absence of insulin supplementation. Here, we show for the first time that insulin infused (i.c.v.) to young rats significantly attenuated the effects of LPS by decreasing the expression of neuroinflammatory markers in the hippocampus and by improving performance in the Morris water pool task. In young rats, insulin infusion alone significantly improved their performance as compared to all other groups. Unexpectedly, in aged rats, the responsiveness to insulin was completely absent, that is, spatial memory was still impaired suggesting that an age-dependent insulin resistance may contribute to the cognitive impairment observed in neurodegenerative diseases. Our data suggest a novel therapeutic effect of insulin on neuroinflammation in the young but not the aged brain.

Calcium dysregulation via L-type voltage-dependent calcium channels and ryanodine receptors underlies memory deficits and synaptic dysfunction during chronic neuroinflammation.

BACKGROUND: Chronic neuroinflammation and calcium (Ca(+2)) dysregulation are both components of Alzheimer's disease. Prolonged neuroinflammation produces elevation of pro-inflammatory cytokines and reactive oxygen species which can alter neuronal Ca(+2) homeostasis via L-type voltage-dependent Ca(+2) channels (L-VDCCs) and ryanodine receptors (RyRs). Chronic neuroinflammation also leads to deficits in spatial memory, which may be related to Ca(+2) dysregulation. METHODS: The studies herein use an in vivo model of chronic neuroinflammation: rats were infused intraventricularly with a continuous small dose of lipopolysaccharide (LPS) or artificial cerebrospinal fluid (aCSF) for 28 days. The rats were treated with the L-VDCC antagonist nimodipine or the RyR antagonist dantrolene. RESULTS: LPS-infused rats had significant memory deficits in the Morris water maze, and this deficit was ameliorated by treatment with nimodipine. Synaptosomes from LPS-infused rats had increased Ca(+2) uptake, which was reduced by a blockade of L-VDCCs either in vivo or ex vivo. CONCLUSIONS: Taken together, these data indicate that Ca(+2) dysregulation during chronic neuroinflammation is partially dependent on increases in L-VDCC function. However, blockade of the RyRs also slightly improved spatial memory of the LPS-infused rats, demonstrating that other Ca(+2) channels are dysregulated during chronic neuroinflammation. Ca(+2)-dependent immediate early gene expression was reduced in LPS-infused rats treated with dantrolene or nimodipine, indicating normalized synaptic function that may underlie improvements in spatial memory. Pro-inflammatory markers are also reduced in LPS-infused rats treated with either drug. Overall, these data suggest that Ca(+2) dysregulation via L-VDCCs and RyRs play a crucial role in memory deficits resulting from chronic neuroinflammation.

Differential neuroprotective and anti-inflammatory effects of L-type voltage dependent calcium channel and ryanodine receptor antagonists in the substantia nigra and locus coeruleus.

Neuroinflammation and degeneration of catecholaminergic brainstem nuclei occur early in neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Neuroinflammation increases levels of pro-inflammatory cytokines and reactive oxygen species which can alter neuronal calcium (Ca(+2)) homoeostasis via L-type voltage dependent calcium channels (L-VDCCs) and ryanodine receptors (RyRs). Alterations in Ca(+2) channel activity in the SN and LC can lead to disruption of normal pacemaking activity in these areas, contributing to behavioral deficits. Here, we utilized an in vivo model of chronic neuroinflammation: rats were infused intraventricularly with a continuous small dose (0.25 µg/h) of lipopolysaccharide (LPS) or artificial cerebrospinal fluid (aCSF) for 28 days. Rats were treated with either the L-VDCC antagonist nimodipine or the RyR antagonist dantrolene. LPS-infused rats had significant motor deficits in the accelerating rotarod task as well as abnormal behavioral agitation in the forced swim task and open field. Corresponding with these behavioral deficits, LPS-infused rats also had significant increases in microglia activation and loss of tyrosine hydroxylase (TH) immunoreactivity in the substantia nigra pars compacta (SNpc) and locus coeruleus (LC). Treatment with nimodipine or dantrolene normalized LPS-induced abnormalities in the rotarod and forced swim, restored the number of TH-immunoreactive cells in the LC, and significantly reduced microglia activation in the SNpc. Only nimodipine significantly reduced microglia activation in the LC, and neither drug increased TH immunoreactivity in the SNpc. These findings demonstrate that the Ca(+2) dysregulation in the LC and SN brainstem nuclei is differentially altered by chronic neuroinflammation. Overall, targeting Ca + 2 dysregulation may be an important target for ameliorating neurodegeneration in the SNpc and LC.

Impaired trace fear conditioning and diminished ERK1/2 phosphorylation in the dorsal hippocampus of adult rats administered alcohol as neonates.

Utilizing a rat model of fetal alcohol spectrum disorder (FASD), ethanol was administered over postnatal days (PD) 4 to 9. As adults, control and ethanol rats underwent trace fear conditioning (TFC), in which a tone conditioned stimulus (CS) and footshock unconditioned stimulus (US) were repeatedly paired, though the two stimuli never overlapped in time. Following training in Experiment 1, conditioned fear (freezing) to the tone CS was dose-dependently reduced in ethanol rats relative to controls. Experiment 2 was designed to test whether the TFC deficit varied based on the duration of the trace interval (TI; time from CS offset to US onset). Holding the time separating CS onset from US onset constant at 20 sec, control and ethanol rats were trained with a 5 or 15 sec tone CS, followed 15 or 5 sec later, respectively, by the US. Conditioned fear to the tone CS was significantly reduced in high dose ethanol rats trained with the 15 sec TI only. Acquisition and consolidation of trace fear memories relies on forebrain N-methyl-d-aspartate receptor (NMDAR) signaling, including the downstream phosphorylation of extracellular signal-regulated kinase 1/2 (pERK1/2). Separate rats were trained with the 5 or 15 sec TI and then sacrificed 1 hr later. Significant reductions in pERK1/2-positive neurons were seen in areas CA1 and CA3 of the dorsal hippocampus (DH) following training at both TIs in ethanol rats. The disruption of DH learning-dependent plasticity appears tied to freezing behavior in ethanol rats, but only when the training stimuli are separated by more than 5 sec.

Age-associated alterations in the time-dependent profile of pro- and anti-inflammatory proteins within the hippocampus in response to acute exposure to interleukin-1ß.

The pro-inflammatory cytokine IL-1ß is known to play a role in several models of aging, neuroinflammation, and neurodegenerative diseases. Here, we document a detailed time- and age-dependent pattern of pro- and anti-inflammatory biomarkers following bilateral intrahippocampal injection of interleukin-1ß. During the first 12h several pro- and anti-inflammatory cytokines increased in the aged (24 mo old) rats, some of which returned to baseline levels by 24h post-injection while others remained elevated for 72 h post-injection. In contrast, no such increases were observed in the young (3 mo old) rats. Interestingly, young rats up-regulated mRNA of two pro-inflammatory cytokines, interleukin-1ß and tumor necrosis factor-α, but did not translate these transcripts into functional proteins, which may be related to expression of suppressor of cytokine signaling type-2. These results contribute to our understanding of how neuroinflammation may contribute to the pathogenesis of age-related neurodegenerative disorders due to an age-related bias towards a hyper-reactive immune response that is not selective for a pro- or anti-inflammatory phenotype following an inflammatory stimulus.

Age and duration of inflammatory environment differentially affect the neuroimmune response and catecholaminergic neurons in the midbrain and brainstem.

Neuroinflammation and degeneration of ascending catecholaminergic systems occur early in the neurodegenerative process. Age and the duration of a pro-inflammatory environment induced by continuous intraventricular lipopolysaccharide (LPS) differentially affect the expression profile of pro- and anti-inflammatory genes and proteins as well as the number of activated microglia (express major histocompatibility complex II; MHC II) and the integrity and density of ascending catecholaminergic neural systems originating from the locus coeruleus (LC) and substantia nigra pars compacta (SNpc) in rats. LPS infusion increased gene expression and/or protein levels for both pro- and anti-inflammatory biomarkers. Although LPS infusion stimulated a robust increase in IL-1ß gene and protein expression, this increase was blunted with age. LPS infusion also increased the density of activated microglia cells throughout the midbrain and brainstem. Corresponding to the development of a pro-inflammatory environment, LC and SNpc neurons immunopositive for tyrosine-hydroxylase (the rate-limiting synthetic enzyme for dopamine and norepinephrine) decreased in number, along with a decrease in tyrosine-hydroxylase gene expression in the midbrain and/or brainstem region. Our data support the concept that continuous exposure to a pro-inflammatory environment drives exaggerated changes in the production and release of inflammatory mediators that interact with age to impair functional capacity of the SNpc and LC.

Differential effects of duration and age on the consequences of neuroinflammation in the hippocampus.

The current study investigated the hypothesis that the duration of the proinflammatory environment plays a critical role in the brain's response that results in negative consequences on cognition, biochemistry, and pathology. Lipopolysaccharide or artificial cerebrospinal fluid was slowly (250 ηg/h) infused into the fourth ventricle of young (3-month-old), adult (9-month-old), or aged (23-month-old) male F-344 rats for 21 or 56 days. The rats were then tested in the water pool task and endogenous hippocampal levels of pro- and anti-inflammatory proteins and genes and indicators of glutamatergic function were determined. The duration of the lipopolysaccharide infusion, compared with the age of the rat, had the greatest effect on (1) spatial working memory; (2) the density and distribution of activated microglia within the hippocampus; and (3) the cytokine protein and gene expression profiles within the hippocampus. The duration- and age-dependent consequences of neuroinflammation might explain why human adults respond positively to anti-inflammatory therapies and aged humans do not.

Riluzole partially rescues age-associated, but not LPS-induced, loss of glutamate transporters and spatial memory.

Impaired memory may result from synaptic glutamatergic dysregulation related to chronic neuroinflammation. GLT1 is the primary excitatory amino acid transporter responsible for regulating extracellular glutamate levels in the hippocampus. We tested the hypothesis that if impaired spatial memory results from increased extracellular glutamate due to age or experimentally induced chronic neuroinflammation in the hippocampus, then pharmacological augmentation of the glutamate transporter GLT1 will attenuate deficits in a hippocampal-dependent spatial memory task. The profile of inflammation-related genes and proteins associated with normal aging, or chronic neuroinflammation experimentally-induced via a four-week LPS infusion into the IV(th) ventricle, were correlated with performance in the Morris water maze following treatment with Riluzole, a drug that can enhance glutamate clearance by increasing GLT1 expression. Age-associated inflammation was qualitatively different from LPS-induced neuro-inflammation in young rats. LPS produced a pro-inflammatory phenotype characterized by increased IL-1ß expression in the hippocampus, whereas aging was not associated with a strong central pro-inflammatory response but with a mixed peripheral immune phenotype. Riluzole attenuated the spatial memory impairment, the elevation of serum cytokines and the decrease in GLT1 gene expression in Aged rats, but had no effect on young rats infused with LPS. Our findings highlight the therapeutic potential of reducing glutamatergic function upon memory impairment in neurodegenerative diseases associated with aging.

Time-Dependent Compensatory Responses to Chronic Neuroinflammation in Hippocampus and Brainstem: The Potential Role of Glutamate Neurotransmission.

Chronic neuroinflammation is characteristic of neurodegenerative diseases and is present during very early stages, yet significant pathology and behavioral deficits do not manifest until advanced age. We investigated the consequences of experimentally-induced chronic neuroinflammation within the hippocampus and brainstem of young (4 mo) F-344 rats. Lipopolysaccharide (LPS) was infused continuously into the IVth ventricle for 2, 4 or 8 weeks. The number of MHC II immunoreactive microglia in the brain continued to increase throughout the infusion period. In contrast, performance in the Morris water maze was impaired after 4 weeks but recovered by 8 weeks. Likewise, a transient loss of tyrosine hydroxylase immunoreactivity in the substantia nigra and locus coeruleus was observed after 2 weeks, but returned to control levels by 4 weeks of continuous LPS infusion. These data suggest that direct activation of microglia is sufficient to drive, but not sustain, spatial memory impairment and a decrease in tyrosine hydroxylase production in young rats. Our previous studies suggest that chronic neuroinflammation elevates extracellular glutamate and that this elevation underlies the spatial memory impairment. In the current study, increased levels of GLT1 and SNAP25 in the hippocampus corresponded with the resolution of performance deficit. Increased expression of SNAP25 is consistent with reduced glutamate release from axonal terminals while increased GLT1 is consistent with enhanced clearance of extracellular glutamate. These data demonstrate the capacity of the brain to compensate for the presence of chronic neuroinflammation, despite continued activation of microglia, through changes in the regulation of the glutamatergic system.