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BackgroundAcute intoxication with organophosphorus (OP) cholinesterase inhibitors can trigger convulsions that progress to life-threatening status epilepticus. Survivors face long-term morbidity including mild-to-severe decline in memory. It is posited that neuroinflammation plays a key role in the pathogenesis of OP-induced neuropsychiatric deficits. Rigorous testing of this hypothesis requires preclinical models that recapitulate relevant phenotypic outcomes. Here, we describe a rat model of acute intoxication with the OP diisopropylfluorophosphate (DFP) that exhibits persistent neuroinflammation and cognitive impairment.MethodsNeuroinflammation, neurodegeneration, and cognitive function were compared in adult male Sprague Dawley rats injected with an acutely toxic dose of DFP vs. vehicle controls at multiple time points up to 36 days post-exposure. Neuroinflammation was quantified using immunohistochemical biomarkers of microglia (ionized calcium-binding adapter molecule 1, IBA1) and activated astrocytes (glial fibrillary acidic protein, GFAP) and positron emission tomography (PET) imaging of [11C]-(R)-PK11195, a ligand for the 18-kDa mitochondrial membrane translocator protein (TSPO). FluoroJade-B staining was used to assess neurodegeneration; Pavlovian conditioning, to assess cognitive function.ResultsAnimals exhibited moderate-to-severe seizures within minutes of DFP injection that continued for up to 6 h post-injection. As indicated by IBA1 and GFAP immunoreactivity and by PET imaging of TSPO, acute DFP intoxication triggered neuroinflammation in the hippocampus and cortex during the first 3 days that peaked at 7 days and persisted to 21 days post-exposure in most animals. Neurodegeneration was detected in multiple brain regions from 1 to 14 days post-exposure. All DFP-intoxicated animals exhibited significant deficits in contextual fear conditioning at 9 and 20 days post-exposure compared to vehicle controls. Whole-brain TSPO labeling positively correlated with seizure severity score, but did not correlate with performance in the contextual fear-conditioning task.ConclusionsWe describe a preclinical model in which acute DFP intoxication causes seizures, persistent neuroinflammation, neurodegeneration, and memory impairment. The extent of the neuroinflammatory response is influenced by seizure severity. However, the observation that a subset of animals with moderate seizures and minimal TSPO labeling exhibited cognitive deficits comparable to those of animals with severe seizures and significant TSPO labeling suggests that DFP may impair learning and memory circuitry via mechanisms independent of seizures or neuroinflammation.

Tetramethylenedisulfotetramine (TETS) is a potent convulsant GABAA receptor blocker. Mice receiving a lethal dose of TETS (0.15 mg/kg i.p.) are rescued from death by a high dose of diazepam (5 mg/kg i.p.) administered shortly after the second clonic seizure (∼20 min post-TETS). However, this high dose of diazepam significantly impairs blood pressure and mobility, and does not prevent TETS-induced neuroinflammation in the brain. We previously demonstrated that TETS alters synchronous Ca(2+) oscillations in primary mouse hippocampal neuronal cell cultures and that pretreatment with the combination of diazepam and allopregnanolone at concentrations having negligible effects individually prevents TETS effects on intracellular Ca(2+) dynamics. Here, we show that treatment with diazepam and allopregnanolone (0.1 μM) 20 min after TETS challenge normalizes synchronous Ca(2+) oscillations when added in combination but not when added singly. Similarly, doses (0.03-0.1 mg/kg i.p.) of diazepam and allopregnanolone that provide minimal protection when administered singly to TETS intoxicated mice increase survival from 10% to 90% when given in combination either 10 min prior to TETS or following the second clonic seizure. This therapeutic combination has negligible effects on blood pressure or mobility. Combined treatment with diazepam and allopregnanolone also decreases TETS-induced microglial activation. Diazepam and allopregnanolone have distinct actions as positive allosteric modulators of GABAA receptors that in combination enhance survival and mitigate neuropathology following TETS intoxication without the adverse side effects associated with high dose benzodiazepines. Combination therapy with a benzodiazepine and neurosteroid represents a novel neurotherapeutic strategy with potentially broad application.

Repeated subcutaneous (s.c.) injection is a common route of administration in chronic studies of neuroactive compounds. However, in a pilot study we noted a significant incidence of skin abnormalities in adult male Long-Evans rats receiving daily s.c. injections of peanut oil (1.0 ml/kg) in the subscapular region for 21 d. Histopathological analyses of the lesions were consistent with a foreign body reaction. Subsequent studies were conducted to determine factors that influenced the incidence or severity of skin abnormalities, and whether these adverse skin reactions influenced a specific neurobehavioral outcome. Rats injected daily for 21 d with food grade peanut oil had an earlier onset and greater incidence of skin abnormalities relative to rats receiving an equal volume (1.0 ml/kg/d) of reagent grade peanut oil or triglyceride of coconut oil. Skin abnormalities in animals injected daily with peanut oil were increased in animals housed on corncob versus paper bedding. Comparison of animals obtained from different barrier facilities exposed to the same injection paradigm (reagent grade peanut oil, 1.0 ml/kg/d s.c.) revealed significant differences in the severity of skin abnormalities. However, animals from different barrier facilities did not perform differently in a Pavlovian fear conditioning task. Collectively, these data suggest that environmental factors influence the incidence and severity of skin abnormalities following repeated s.c. injections, but that these adverse skin responses do not significantly influence performance in at least one test of learning and memory.

Tetramethylenedisulfotetramine (TETS) is a potent convulsant poison for which there is currently no approved antidote. The convulsant action of TETS is thought to be mediated by inhibition of type A gamma-aminobutyric acid receptor (GABAAR) function. We, therefore, investigated the effects of post-exposure administration of diazepam, a GABAAR positive allosteric modulator, on seizure activity, death and neuroinflammation in adult male Swiss mice injected with a lethal dose of TETS (0.15mg/kg, ip). Administration of a high dose of diazepam (5mg/kg, ip) immediately following the second clonic seizure (approximately 20min post-TETS injection) effectively prevented progression to tonic seizures and death. However, this treatment did not prevent persistent reactive astrogliosis and microglial activation, as determined by GFAP and Iba-1 immunoreactivity and microglial cell morphology. Inhibition of soluble epoxide hydrolase (sEH) has been shown to exert potent anti-inflammatory effects and to increase survival in mice intoxicated with other GABAAR antagonists. The sEH inhibitor TUPS (1mg/kg, ip) administered immediately after the second clonic seizure did not protect TETS-intoxicated animals from tonic seizures or death. Combined administration of diazepam (5mg/kg, ip) and TUPS (1mg/kg, ip, starting 1h after diazepam and repeated every 24h) prevented TETS-induced lethality and influenced signs of neuroinflammation in some brain regions. Significantly decreased microglial activation and enhanced reactive astrogliosis were observed in the hippocampus, with no changes in the cortex. Combining an agent that targets specific anti-inflammatory mechanisms with a traditional antiseizure drug may enhance treatment outcome in TETS intoxication.

Purpose Cough is a common symptom of pulmonary sarcoidosis. We analyzed the severity of cough and factors associated with cough in a university sarcoidosis clinic cohort. Methods Consecutive patients completed the Leicester Cough Questionnaire (LCQ) and a cough visual analog scale (VAS). Clinical and demographic data were collected. Means of the LCQ were analyzed in patients who had multiple visits in terms of constant variables (e.g., race, sex). Results 355 patients completed the LCQ and VAS at 874 visits. Cough was significantly worse in blacks than whites as determined by the LCQ-mean (16.5 ± 2.6 vs. 17.8 ± 3.0, p < 0.001) and VAS-mean (3.8 ± 3.0 vs. 2.0 ± 2.6, p < 0.0001). Cough was worse in women than men as measured by the VAS-mean (2.7 ± 2.9 vs. 2.2 ± 2.7, p = 0.002), one of the LCQ-mean domains (LCQ-Social-mean 5.4 ± 0.9 vs. 5.2 ± 1.0, p = 0.03), but not the total LCQ-mean score. Cough was not significantly different by either measure in terms of smoking status, age, or spirometric parameter (FVC % predicted, FEV1 % predicted, FEV1/FVC). In a multivariable linear regression analysis, cough was significantly worse in blacks than whites and in pulmonary sarcoidosis than non-pulmonary sarcoidosis with both cough measures, in women than men for the VAS only, and not for spirometric parameters, Scadding stage, or age. The LCQ and VAS were strongly correlated. Conclusions In a large university outpatient sarcoidosis cohort, cough was worse in blacks than whites. Cough was not statistically significantly different in terms of age, spirometric measures, Scadding stage, or smoking status. The LCQ correlated strongly with a visual analog scale for cough., Author(s): Marc A. Judson [sup.1] , Amit Chopra [sup.1] , Edward Conuel [sup.2] , Efstratios Koutroumpakis [sup.2] , Christopher Schafer [sup.2] , Adam Austin [sup.2] , Robert Zhang [sup.2] , [...]

The present set of studies investigated extra-legal factors in cases depicting bias-motivated assault. Study one focused on sexual orientation motivated hate crime. In this study, participants (N = 240) read a trial transcript depicting an assault on a man during a gay pride parade. The victim's sexual orientation was varied (i.e., he either stated he was or was not gay) as was the victim's involvement in the parade (i.e., he was either a spectator, marching in it quietly, or marching in it and shouting a pro-gay slogan). Results indicated that beliefs about whether or not the defendant should be convicted, victim blame and perceptions of the victim differed significantly among all conditions. Study two focused on hate crime motivated by race, specifically committed against Native American Indians (NAI). Inclusion in the minority group (victim is NAI vs. victim is not NAI) and involvement (watching parade vs. marching quietly in parade vs. marching and shouting in parade) were varied within the context of a bias-motivated assault that occurred during a Native American Heritage Pride Parade. Results indicated differences in victim blame based in group inclusion and differences in beliefs the crime was a hate crime based on involvement. Keywords Hate crime * Bias-motivated assault * Sexual orientation * Native American Indian, According to the Community Relations Service of the US Department of Justice (2010), a hate crime is defined as 'the violence of intolerance and bigotry, intended to hurt and intimidate [...]

Objective: The need for residential care services will grow significantly over the coming years as the general population in Australia continues to age. The aim of this study was to assess the adequacy of residential care services across New South Wales (NSW), Australia, in relation to the current and predicted future aging population. Method: This study was a secondary data analysis. Existing datasets were compiled for analysis by creation of a temporal geodatabase, with predicted population data from 2019 to 2029 linked to corresponding geographic zones. Results: Demand for operational places was over capacity in 2019, at 101.5%. From 2019 to 2029, this will grow to 120.2% of 2019 capacity by 2024 and to 135.6% by 2029. An additional 25 800 operational places will be required by 2029 to meet targets. During the previous decade of 2008–18, operational places grew by only 11 502 places. Conclusions: NSW was not providing an adequate level of residential aged care and, under current allocations, this problem will worsen substantially over time, with flow-on impacts for the health sector. With aged care reform a current federal government focus, the results of this study may guide decisions that better support the provision of residential aged care. What is known about this topic?: The recently completed Australian Royal Commission into aged care noted widespread system failure and highlighted the gaps in medical services that older Australians were experiencing. What does this paper add?: This paper reports that demand for residential aged care places in NSW was already over capacity in 2019 and that the availability of places varies considerably across the state. Further, an additional 25 800 operational places are required by 2029 to meet government targets. If the growth rate from the past decade is maintained, this will result in a shortfall of 14 298 aged care places in NSW alone. What are the implications?: Without significant increases in the current rate of growth for aged care places, the mainstream medical and health sectors will face significant additional pressures arising from unmet need in both older patients and their informal carers. [ABSTRACT FROM AUTHOR]

Sex trafficking is considered a public health emergency, although there is public confusion about the crime. Defendant gender has been demonstrated to affect juror decision-making within crimes of sexual victimisation, but there was no known literature examining the effect of defendant gender on juror decision-making within a sex trafficking case. To address this void in the literature, we investigated the effect of defendant gender on juror decision-making in a mock sex trafficking case. A community sample of jury-eligible individuals (n = 204) were randomly assigned to either a male or female defendant gender condition in which they read a sex trafficking mock trial summary and completed the Juror Decision Scale. The male defendant was found guilty significantly more frequently than the female defendant although the effect size was relatively small. Complainant Believability, Defendant Believability, and Decision Confidence significantly predicted verdict. Implications of these findings for the justice system are discussed. The importance of addressing the crime of sex trafficking is paramount; however, there was a void in the juror decision-making literature. Findings from this experimental simulation of juror decision-making in a mock sex trafficking case indicated that defendant gender plays a role in verdict formation. Juror education is recommended to reduce the effects of gender bias in sex trafficking jury trials. [ABSTRACT FROM AUTHOR]