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This study investigated the effectiveness of requests for clarification by adults who are deaf or hard of hearing and of partner responses to these requests in overcoming communication breakdowns in everyday conversations. Twenty-five adults with acquired sensorineural hearing losses were videotaped while conversing with normally hearing partners. The conversation samples were analyzed for the occurrence of three types of clarification requests and eight types of partner repair strategies and for the frequency with which the repair strategies successfully solved misperceptions. Overall, nonspecific clarification requests, requests for the repetition of a specific constituent, and requests for confirmation by the participants with hearing losses were all similarly effective in managing communication breakdowns. In contrast, some partner repair strategies were more effective than others, paraphrase and confirmation of the message were the most effective strategies, while message elaboration was the least effective. Partial repetition of the message was highly effective following a request that the partner repeat a specific constituent but not following a nonspecific request for clarification. The effectiveness of full repetition of the message was unaffected by the preceding clarification-request type. Except for requests for confirmation, which nearly always elicited confirmation responses, the type of clarification request used did not consistently elicit the most effective repair strategy from partners. Partners had more control over the facility with which communication breakdowns were repaired, because they could select particular repair strategies, than did the adults who are deaf or hard of hearing through their selection of clarification-request types. This emphasizes the essential role conversational partners play in effective management of communication breakdowns. [ABSTRACT FROM AUTHOR]

Cuprous copper [Cu(I)] is an essential cofactor for enzymes that support many fundamental cellular functions including mitochondrial respiration and suppression of oxidative stress. Neurons are particularly reliant on mitochondrial production of ATP, with many neurodegenerative diseases, including Parkinson's disease, associated with diminished mitochondrial function. The gene MBLAC1 encodes a ribonuclease that targets pre-mRNA of replication-dependent histones, proteins recently found in yeast to reduce Cu(II) to Cu(I), and when mutated disrupt ATP production, elevates oxidative stress, and severely impacts cell growth. Whether this process supports neuronal and/or systemic physiology in higher eukaryotes is unknown. Previously, we identified swip-10 , the putative Caenorhabditis elegans ortholog of MBLAC1 , establishing a role for glial swip-10 in limiting dopamine (DA) neuron excitability and sustaining DA neuron viability. Here, we provide evidence from computational modeling that SWIP-10 protein structure mirrors that of MBLAC1 and locates a loss of function coding mutation at a site expected to disrupt histone RNA hydrolysis. Moreover, we find through genetic, biochemical, and pharmacological studies that deletion of swip-10 in worms negatively impacts systemic Cu(I) levels, leading to deficits in mitochondrial respiration and ATP production, increased oxidative stress, and neurodegeneration. These phenotypes can be offset in swip-10 mutants by the Cu(I) enhancing molecule elesclomol and through glial expression of wildtype swip-10 . Together, these studies reveal a glial-expressed pathway that supports systemic mitochondrial function and neuronal health via regulation of Cu(I) homeostasis, a mechanism that may lend itself to therapeutic strategies to treat devastating neurodegenerative diseases., Competing Interests: Competing interests statement:The authors declare no competing interest.

Background: Cannabis use suppresses the endocannabinoid system in healthy individuals. However, the association between cannabis use with the endocannabinoid system is understudied in individuals with psychosis despite the high rate of cannabis use in these individuals., Methods: We enrolled 83 individuals who were admitted to an inpatient psychiatric unit with psychotic presentations, and measured their plasma levels of main endocannabinoids, Anandamide (AEA) and 2-Acylglycerol (2-AG), and endocannabinoid related compounds, Palmitoylethanolamine, and N-oleoylethanolamine. Cannabis use was assessed with urine toxicology and frequency of cannabis use was assessed using self-reported questionnaires. The Positive and Negative Syndrome Scale was used to assess the severity of psychotic symptoms., Results: Overall, we had 38 individuals in cannabis positive group (CN+) and 45 individuals in cannabis negative group (CN-). Compared to CN-, CN+ group had lower plasma levels of AEA, which remained significant after controlling for age, gender, race/ethnicity, and use of other drugs., Conclusion: Cannabis use is associated with low plasma AEA levels in individuals with psychosis, which is in the same line with reported suppressive effects of cannabis on the endocannabinoid system in healthy individuals. Further studies are needed to investigate the clinical significance of this finding.

Opioids targeting mu;μ (MOP) receptors produce analgesia in the peri-operative period and palliative care. They also produce side effects including respiratory depression, tolerance/dependence and addiction. The N/OFQ opioid receptor (NOP) also produces analgesia but is devoid of the major MOP side effects. Evidence exists for MOP-NOP interaction and mixed MOP-NOP ligands produce analgesia with reduced side effects. We have generated a HEKMOP/NOP human expression system and used bivalent MOP-NOP and fluorescent ligands to (i) probe for receptor interaction and (ii) consequences of that interaction. We used HEKMOP/NOP cells and two bivalent ligands; Dermorphin-N/OFQ (MOP agonist-NOP agonist; DeNO) and Dermorphin-UFP101 (MOP agonist-NOP antagonist; De101). We have determined receptor binding profiles, GTPγ[35S] binding, cAMP formation and ERK1/2 activation. We have also probed MOP and NOP receptor interactions in HEK cells and hippocampal neurones using the novel MOP fluorescent ligand, DermorphinATTO488 and the NOP fluorescent ligand N/OFQATTO594. In HEKMOP/NOP MOP ligands displaced NOP binding and NOP ligands displaced MOP binding. Using fluorescent probes in HEKMOP/NOP cells we demonstrated MOP-NOP probe overlap and a FRET signal indicating co-localisation. MOP-NOP were also co-localised in hippocampal tissue. In GTPγ[35S] and cAMP assays NOP stimulation shifted the response to MOP rightwards. At ERK1/2 the response to bivalent ligands generally peaked later. We provide evidence for MOP-NOP interaction in recombinant and native tissue. NOP activation reduces responsiveness of MOP activation; this was shown with conventional and bivalent ligands., Competing Interests: The authors have declared that no competing interests exist.

The successful treatment of depressive disorders critically depends on adherence to prescribed treatment regimens. Despite increasing rates of antidepressant medication prescription, adherence to the full treatment course remains poor. Rates of antidepressant non-adherence are higher for uninsured patients and members of some marginalized racial and ethnic communities due to factors such as inequities in healthcare and access to insurance. Among patients treated in a free, student-run and faculty-supervised clinic serving uninsured patients in a majority Hispanic community in East Harlem, adherence rates are lower than those observed in patients with private or public New York State health insurance coverage. A prior study of adherence in these patients revealed that difficulty in obtaining medications from an off-site hospital pharmacy was a leading factor that patients cited for non-adherence. To alleviate this barrier to obtaining prescriptions, we tested the effectiveness of on-site, in-clinic medication dispensing for improving antidepressant medication adherence rates among uninsured patients. We found that dispensing medications directly to patients in clinic was associated with increased visits at which patients self-reported proper adherence and increased overall adherence rates. Furthermore, we found evidence that higher rates of antidepressant medication adherence were associated with more favorable treatment outcomes. All patients interviewed reported increased satisfaction with on-site dispensing. Overall, this study provides promising evidence that on-site antidepressant dispensing in a resource-limited setting improves medication adherence rates and leads to more favorable treatment outcomes with enhanced patient satisfaction., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Cerebral ischemic stroke is a leading cause of death and disability, but current pharmacological therapies are limited in their utility and effectiveness. In vitro and in vivo models of ischemic stroke have been developed which allow us to further elucidate the pathophysiological mechanisms of injury and investigate potential drug targets. In vitro models permit mechanistic investigation of the biochemical and molecular mechanisms of injury but are reductionist and do not mimic the complexity of clinical stroke. In vivo models of ischemic stroke directly replicate the reduction in blood flow and the resulting impact on nervous tissue. The most frequently used in vivo model of ischemic stroke is the intraluminal suture middle cerebral artery occlusion (iMCAO) model, which has been fundamental in revealing various aspects of stroke pathology. However, the iMCAO model produces lesion volumes with large standard deviations even though rigid surgical and data collection protocols are followed. There is a need to refine the MCAO model to reduce variability in the standard outcome measure of lesion volume. The typical approach to produce vessel occlusion is to induce an obstruction at the origin of the middle cerebral artery and reperfusion is reliant on the Circle of Willis (CoW). However, in rodents the CoW is anatomically highly variable which could account for variations in lesion volume. Thus, we developed a refined approach whereby reliance on the CoW for reperfusion was removed. This approach improved reperfusion to the ischemic hemisphere, reduced variability in lesion volume by 30%, and reduced group sizes required to determine an effective treatment response by almost 40%. This refinement involves a methodological adaptation of the original surgical approach which we have shared with the scientific community via publication of a visualised methods article and providing hands-on training to other experimental stroke researchers., Competing Interests: No competing interests were disclosed., (Copyright: © 2021 Trotman-Lucas M and Gibson CL.)

Overdose of stimulant drugs has been associated with increased risk of adverse cardiovascular events (ACVE), some of which may be ascribed to endothelial dysfunction. The aims of this study were to evaluate biomarkers of endothelial dysfunction in emergency department (ED) patients with acute cocaine overdose and to assess the association between in-hospital ACVE in ED patients with any acute drug overdose. This was a prospective consecutive cohort study over 9 months (2015-2016) at two urban, tertiary-care hospital EDs. Consecutive adults (≥18 years) presenting with suspected acute drug overdose were eligible and separated into three groups: cocaine (n = 47), other drugs (n = 128), and controls (n = 11). Data were obtained from medical records and linked to waste serum specimens, sent as part of routine clinical care, for biomarker analysis. Serum specimens were collected and analyzed using enzyme-linked immunosorbent assay kit for three biomarkers of endothelial dysfunction: (a) endothelin-1 (ET-1), (b) regulated upon activation normal T cell expressed and secreted (RANTES), and (c) soluble intercellular adhesion molecule-1 (siCAM-1). Mean siCAM was elevated for cocaine compared with controls and other drugs (p < .01); however, mean RANTES and ET-1 levels were not significantly different for any drug exposure groups. Receiver operating characteristics curve analysis for prediction of in-hospital ACVE revealed excellent performance of siCAM-1 (area under curve, 0.86; p < .001) but lack of predictive utility for either RANTES or ET-1. These results suggest that serum siCAM-1 is a viable biomarker for acute cocaine overdose and that endothelial dysfunction may be an important surrogate for adverse cardiovascular events following any drug overdose., (© 2020 Society for the Study of Addiction.)

Inflammatory abnormalities are well-documented in individuals with chronic psychotic disorders. Particular attention has focused on interleukin-6 (IL-6) and its correlation with psychotic symptom severity. Cannabis use is associated with an increased risk of psychosis and also has immunomodulating properties. It has been hypothesized that inflammatory disturbances are a common underlying pathology between cannabis use and psychosis. We measured inflammatory markers in individuals admitted to a psychiatric unit with acute psychosis who had toxicology positive for natural and/or synthetic cannabinoids (n = 59) compared to patients with negative cannabinoid toxicology (n = 60). Psychosis severity was assessed using the Positive and Negative Syndrome Scale (PANSS). While PANSS scores were similar between groups, cannabinoid-positive participants were more likely to receive pro re nata (PRN or as-needed) medications for agitation in the psychiatric emergency room, particularly synthetic cannabinoid-positive participants. In unadjusted models, cannabinoid-positive participants had lower interferon-γ (IFN-γ) levels (p = 0.046), but this finding was not significant after adjusting for covariates and multiple comparisons. Among cannabinoid-positive participants, IL-6 levels negatively correlated with PANSS total score (p = 0.040), as well as positive (p = 0.035) and negative (p = 0.024) subscales. Results suggest inflammatory alterations among psychotic individuals with comorbid cannabinoid use., (Copyright © 2020. Published by Elsevier B.V.)

Hypertension is an important risk factor for age-related cognitive decline and neuronal pathologies. Studies have shown a correlation between hypertension, disruption in neurovascular coupling and cerebral autoregulation, and cognitive decline. However, the mechanisms behind this are unclear. To further understand this, it is advantageous to study neurovascular coupling as hypertension progresses in a rodent model. Here, we use a longitudinal functional MRI (fMRI) protocol to assess the impact of hypertension on neurovascular coupling in spontaneously hypertensive rats (SHRs). Eight female SHRs were studied at 2, 4, and 6 months of age, as hypertension progressed. Under an IV infusion of propofol, animals underwent fMRI, functional MR spectroscopy, and cerebral blood flow (CBF) quantification to study changes in neurovascular coupling over time. Blood pressure significantly increased at 4 and 6 months (P < .0001). CBF significantly increased at 4 months old (P < .05), in the acute stage of hypertension. The size of the active region decreased significantly at 6 months old (P < .05). Change in glutamate signal during activation, and N-acetyl-aspartate (NAA) signal, remained constant. This study shows that, while cerebral autoregulation is impaired in acute hypertension, the blood oxygenation-level-dependent (BOLD) response remains unaltered until later stages. At this stage, the consistent NAA and glutamate signals show that neuronal death has not occurred, and that neuronal activity is not affected at this stage. This suggests that neuronal activity and viability is not lost until much later, and changes observed here in BOLD activity are due to vascular effects., (© 2020 The Authors. Journal of Neuroimaging published by Wiley Periodicals LLC on behalf of American Society of Neuroimaging.)

As the population ages, the incidence of age-related neurological diseases and cognitive decline increases. To further understand disease-related changes in brain function it is advantageous to examine brain activity changes in healthy aging rodent models to permit mechanistic investigation. Here, we examine the suitability, in rodents, of using a novel, minimally invasive anaesthesia protocol in combination with a functional MRI protocol to assess alterations in neuronal activity due to physiological aging. 11 Wistar Han female rats were studied at 7, 9, 12, 15 and 18 months of age. Under an intravenous infusion of propofol, animals underwent functional magnetic resonance imaging (fMRI) and functional magnetic resonance spectroscopy (fMRS) with forepaw stimulation to quantify neurotransmitter activity, and resting cerebral blood flow (CBF) quantification using arterial spin labelling (ASL) to study changes in neurovascular coupling over time. Animals showed a significant decrease in size of the active region with age (P ​< ​0.05). fMRS results showed a significant decrease in glutamate change with stimulation (ΔGlu) with age (P ​< ​0.05), and ΔGlu became negative from 12 months onwards. Global CBF remained constant for the duration of the study. This study shows age related changes in the blood oxygen level dependent (BOLD) response in rodents that correlate with those seen in humans. The results also suggest that a reduction in synaptic glutamate turnover with age may underlie the reduction in the BOLD response, while CBF is preserved., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Auxin is transported in plants with distinct polarity, defined by transport proteins of the PIN-formed (PIN) family. Components of the complex trafficking machinery responsible for polar PIN protein localization have been identified by genetic approaches, but severe developmental phenotypes of trafficking mutants complicate dissection of this pathway. We utilized a temperature sensitive allele of Arabidopsis thaliana SCD1 ( stomatal cytokinesis defective1 ) that encodes a RAB-guanine nucleotide exchange factor. Auxin transport, lateral root initiation, asymmetric auxin-induced gene expression after gravitropic reorientation, and differential gravitropic growth were reduced in the roots of the scd1-1 mutant relative to wild type at the restrictive temperature of 25°C, but not at the permissive temperature of 18°C. In scd1-1 at 25°C, PIN1- and PIN2-GFP accumulated in endomembrane bodies. Transition of seedlings from 18 to 25°C for as little as 20 min resulted in the accumulation of PIN2-GFP in endomembranes, while gravitropism and root developmental defects were not detected until hours after transition to the non-permissive temperature. The endomembrane compartments that accumulated PIN2-GFP in scd1-1 exhibited FM4-64 signal colocalized with ARA7 and ARA6 fluorescent marker proteins, consistent with PIN2 accumulation in the late or multivesicular endosome. These experiments illustrate the power of using a temperature sensitive mutation in the gene encoding SCD1 to study the trafficking of PIN2 between the endosome and the plasma membrane. Using the conditional feature of this mutation, we show that altered trafficking of PIN2 precedes altered auxin transport and defects in gravitropism and lateral root development in this mutant upon transition to the restrictive temperature., (Copyright © 2020 Gibson, Isley, Falbel, Mattox, Lewis, Metcalf and Muday.)

Background : Following ischemic stroke, recanalisation and restoration of blood flow to the affected area of the brain is critical and directly correlates with patient recovery.  In vivo models of ischemic stroke show high variability in outcomes, which may be due to variability in reperfusion.  We previously reported that a surgical refinement in the middle cerebral artery occlusion (MCAO) model of stroke, via repair of the common carotid artery (CCA), removes the reliance on the Circle of Willis for reperfusion and reduced infarct variability.  Here we further assess this refined surgical approach on reperfusion characteristics following transient MCAO in mice. Methods : Mice underwent 60 min of MCAO, followed by either CCA repair or ligation at reperfusion.  All mice underwent laser speckle contrast imaging at baseline, 24 h and 48 h post-MCAO. Results : CCA ligation reduced cerebral perfusion in the ipsilateral hemisphere compared to baseline (102.3 ± 4.57%) at 24 h (85.13 ± 16.09%; P < 0.01) and 48 h (75.04 ± 12.954%; P < 0.001) post-MCAO. Repair of the CCA returned perfusion to baseline (94.152 ± 2.44%) levels and perfusion was significantly improved compared to CCA ligation at both 24 h (102.83 ± 8.41%; P < 0.05) and 48 h (102.13 ± 9.34%; P < 0.001) post-MCAO. Conclusions : Our findings show CCA repair, an alternative surgical approach for MCAO, results in improved ischemic hemisphere perfusion during the acute phase., Competing Interests: No competing interests were disclosed., (Copyright: © 2020 Trotman-Lucas M et al.)

Background: Cerebral ischemic stroke is a significant cause of morbidity and mortality. Sex differences exist following stroke in terms of incidence, symptoms, outcomes and response to some treatments. Importantly, molecular mechanisms of injury, activated following ischemia may differ between the sexes and if so may account, at least in part, for sex differences seen in treatment response. Here we aimed to determine, using single-sex organotypic hippocampal slice cultures, whether the effectiveness of a potential treatment option, i.e. sex steroids, exhibited any sexual dimorphism and whether sex affected the mechanisms of apoptosis activated following ischemia., Results: Following exposure to ischemia, male-derived tissue exhibited higher levels of cell death than female-derived tissue. Various sex steroid hormones, i.e. progesterone, allopregnanolone, and estradiol, were protective in terms of reducing the amount of cell death in male- and female-derived tissue whereas medoxyprogesterone acetate (MPA) was only protective in female-derived tissue. The protective effect of progesterone was abolished in the presence of finasteride, a 5α-reductase inhibitor, suggesting it was largely mediated via its conversion to allopregnanolone. To test the hypothesis that sex differences exist in the activation of specific elements of the apoptotic pathway activated following ischemia we administered Q-VD-OPH, a caspase inhibitor, or PJ34, an inhibitor of poly (ADP ribose) polymerase (PARP). Caspase inhibition was only effective, in terms of reducing cell death, in female-derived tissue, whereas PARP inhibition was only protective in male-derived tissue. However, in both sexes, the protective effects of progesterone and estradiol were not observed in the presence of either caspase or PARP inhibition., Conclusions: Sex differences exist in both the amount of cell death produced and those elements of the cell death pathway activated following an ischemic insult. There are also some sex differences in the effectiveness of steroid hormones to provide neuroprotection following an ischemic insult-namely MPA was only protective in female-derived tissue. This adds further support to the notion sex is an important factor to consider when investigating future drug targets for CNS disorders, such as ischemic stroke.

Disability and effectiveness of physical therapy are highly variable following ischemic stroke due to different brain regions being affected. Functional magnetic resonance imaging (fMRI) studies of patients in the months and years following stroke have given some insight into how the brain recovers lost functions. Initially, new pathways are recruited to compensate for the lost region, showing as a brighter blood oxygen-level-dependent (BOLD) signal over a larger area during a task than in healthy controls. Subsequently, activity is reduced to baseline levels as pathways become more efficient, mimicking the process of learning typically seen during development. Preclinical models of ischemic stroke aim to enhance understanding of the biology underlying recovery following stroke. However, the pattern of recruitment and focusing seen in humans has not been observed in preclinical fMRI studies that are highly variable methodologically. Resting-state fMRI studies show more consistency; however, there are still confounding factors to address. Anesthesia and method of stroke induction are the two main sources of variability in preclinical studies; improvements here can reduce variability and increase the intensity and reproducibility of the BOLD response detected by fMRI. Differences in task or stimulus and differences in analysis method also present a source of variability. This review compares clinical and preclinical fMRI studies of recovery following stroke and focuses on how refinement of preclinical models and MRI methods may obtain more representative fMRI data in relation to human studies., (© 2019 The Authors. Journal of Neuroimaging published by Wiley Periodicals, Inc. on behalf of American Society of Neuroimaging.)

Background: Marriage is one of the most frequently examined sources of social support and has been shown to protect against alcohol use and abuse. This study examines the relationship between perceived marital strain and support, and alcohol use controlling for additive genetic influence. Methods: Data from monozygotic (MZ) ( n  = 320) and dizygotic (DZ) ( n  = 464) twin pairs from the second wave of the National Survey of Midlife Development in the United States (MIDUS II) were used to test whether past year marital strain and support were associated with recent alcohol use. Generalized linear mixed models (GLMM) were estimated, allowing us to control for additive genetic and shared environmental influences as variance components. Results: Marital strain and support had positive, statistically significant associations with alcohol use. However, only the relationship between marital strain and alcohol use remained after controlling for variance in alcohol use attributed to genetics. Conclusions: After accounting for genetics, midlife adults still appear to cope with marital strain via alcohol use. However, this coping is unlikely to result in heavy episodic drinking or alcohol use disorder without other compounding factors.

We analyzed effects of peer teaching on non-science major undergraduates' knowledge, perceptions, and opinions about genetically modified (GM) crops and their use in agriculture. Undergraduates enrolled in an introductory nonmajors biology course participated in a service-learning program (SLP) in which they acted as cross-age peer teachers to high school students, teaching about the role of genetics in crop improvement through traditional breeding and GM approaches. Using pre/postassessments, we found that undergraduates' opinions shifted to favor the use of GM organisms (GMOs) in agriculture after SLP participation, rising from 46 to 97%. Perceptions about risks and benefits of GMOs also shifted from 43% stating that GMOs are harmful or suspect to no students describing GMOs in that way. Knowledge about GMOs became more accurate after SLP participation. There were significant correlations between students who had negative perceptions of GMOs and negative opinions or inaccurate knowledge about them. Students recognized the effect of peer teaching on their knowledge and perceptions, identifying the repeated peer teaching as an important factor in knowledge gain. Our results suggest students developed an informed opinion about the use of GMOs through first learning the science of genetic engineering and then teaching this information to younger students.

The ischemic stroke is a major cause of adult long-term disability and death worldwide. The current treatments available are limited, with only tissue plasminogen activator (tPA) as an approved drug treatment to target ischemic strokes. Current research in the field of ischemic stroke focuses on better understanding the pathophysiology of stroke, to develop and investigate novel pharmaceutical targets. Reliable experimental stroke models are crucial for the progression of potential treatments. The middle cerebral artery occlusion (MCAO) model is clinically relevant and the most frequently used surgical model of ischemic stroke in rodents. However, the outcomes of this model, such as lesion volume, are associated with high levels of variability, particularly in mice. The alternative MCAO model described here allows the reperfusion of the common carotid artery (CCA) and the increased perfusion of the middle cerebral artery (MCA) territory, using a tissue pad with fibrinogen-based sealant to repair the vessel, and the improved welfare of the mice by avoiding external carotid artery (ECA) ligation. This reduces the reliance on the Circle of Willis, which is known to be highly anatomically variable in mice. Representative data show that using this alternative surgical approach decreases the variability in lesion volumes between the traditional MCAO approach and the alternative approach described here.

Experimental stroke in rodents, via middle cerebral artery occlusion (MCAO), can be associated with a negative impact on wellbeing and mortality. In hypertensive rodents, pre-stroke craniotomy increased survival and decreased body weight loss post-MCAO. Here we determined the effect, in normotensive Sprague-Dawley rats following 60 minutes MCAO, with or without pre-surgical craniotomy, on post-stroke outcomes in terms of weight loss, neurological deficit, lesion volume and functional outcomes. There was no effect of pre-stroke craniotomy on indicators of wellbeing including survival rate (P = 0.32), body weight loss (P = 0.42) and neurological deficit (P = 0.75). We also assessed common outcome measures following experimental stroke and found no effect of pre-stroke craniotomy on lesion volume as measured by T2-weighted MRI (P = 0.846), or functional performance up to 28 days post-MCAO (staircase test, P = 0.32; adhesive sticker test, P = 0.49; cylinder test, P = 0.38). Thus, pre-stroke craniotomy did not improve animal welfare in terms of body weight loss and neurological deficit. However, it is important, given that a number of drug delivery studies utilise the craniotomy procedure, to note that there was no effect on lesion volume or functional outcome following experimental stroke., Competing Interests: The authors have declared that no competing interests exist.

The C. elegans gene swip-10 encodes an orphan metallo β-lactamase that genetic studies indicate is vital for limiting neuronal excitability and viability. Sequence analysis indicates that the mammalian gene Mblac1 is the likely ortholog of swip-10, with greatest sequence identity localized to the encoded protein's single metallo β-lactamase domain. The substrate for the SWIP-10 protein remains unknown and to date no functional roles have been ascribed to MBLAC1, though we have shown that the protein binds the neuroprotective β-lactam antibiotic, ceftriaxone. To gain insight into the functional role of MBLAC1 in vivo, we used CRISPR/Cas9 methods to disrupt N-terminal coding sequences of the mouse Mblac1 gene, resulting in a complete loss of protein expression in viable, homozygous knockout (KO) animals. Using serum from both WT and KO mice, we performed global, untargeted metabolomic analyses, resolving small molecules via hydrophilic interaction chromatography (HILIC) based ultra-performance liquid chromatography, coupled to mass spectrometry (UPLC-MS/MS). Unsupervised principal component analysis reliably segregated the metabolomes of MBLAC1 KO and WT mice, with 92 features subsequently nominated as significantly different by ANOVA, and for which we made tentative and putative metabolite assignments. Bioinformatic analyses of these molecules nominate validated pathways subserving bile acid biosynthesis and linoleate metabolism, networks known to be responsive to metabolic and oxidative stress. Our findings lead to hypotheses that can guide future targeted studies seeking to identify the substrate for MBLAC1 and how substrate hydrolysis supports the neuroprotective actions of ceftriaxone.

Across phylogeny, glutamate (Glu) signaling plays a critical role in regulating neural excitability, thus supporting many complex behaviors. Perturbed synaptic and extrasynaptic Glu homeostasis in the human brain has been implicated in multiple neuropsychiatric and neurodegenerative disorders including Parkinson's disease, where theories suggest that excitotoxic insults may accelerate a naturally occurring process of dopamine (DA) neuron degeneration. In C. elegans, mutation of the glial expressed gene, swip-10, results in Glu-dependent DA neuron hyperexcitation that leads to elevated DA release, triggering DA signaling-dependent motor paralysis. Here, we demonstrate that swip-10 mutations induce premature and progressive DA neuron degeneration, with light and electron microscopy studies demonstrating the presence of dystrophic dendritic processes, as well as shrunken and/or missing cell soma. As with paralysis, DA neuron degeneration in swip-10 mutants is rescued by glial-specific, but not DA neuron-specific expression of wildtype swip-10, consistent with a cell non-autonomous mechanism. Genetic studies implicate the vesicular Glu transporter VGLU-3 and the cystine/Glu exchanger homolog AAT-1 as potential sources of Glu signaling supporting DA neuron degeneration. Degeneration can be significantly suppressed by mutations in the Ca2+ permeable Glu receptors, nmr-2 and glr-1, in genes that support intracellular Ca2+ signaling and Ca2+-dependent proteolysis, as well as genes involved in apoptotic cell death. Our studies suggest that Glu stimulation of nematode DA neurons in early larval stages, without the protective actions of SWIP-10, contributes to insults that ultimately drive DA neuron degeneration. The swip-10 model may provide an efficient platform for the identification of molecular mechanisms that enhance risk for Parkinson's disease and/or the identification of agents that can limit neurodegenerative disease progression.

This study analyzed data from a prospective longitudinal study of Swedish preschoolers to examine whether psychopathic traits and concurrent conduct problems predict future conduct problems (CP) across 1- and 2-year follow-ups into early childhood. We tested the predictive ability of psychopathic traits while controlling for concurrent CP, and also by combining psychopathic traits with concurrent CP. A community sample of 1,867 preschoolers (47% girls) ages 3 to 5 years at baseline was recruited from a Swedish medium-sized municipality. Results from multivariate regression analyses showed that psychopathic traits alone (without co-occurring CP) did not consistently predict continuing childhood CP, but did so, among both boys and girls, in combination with concurrent conduct problems. It is important to note that, the combination of concurrent CP and the entire psychopathic personality, that is, a 3-dimensional psychopathic construct, was a stronger predictor of continuing childhood CP than the combination of concurrent CP and Callous-Unemotional (CU) traits among boys but not among girls. (PsycINFO Database Record, ((c) 2018 APA, all rights reserved).)

Most in vivo models of ischaemic stroke target the middle cerebral artery and a spectrum of stroke severities, from mild to substantial, can be achieved. This review describes opportunities to improve the in vivo modelling of ischaemic stroke and animal welfare. It provides a number of recommendations to minimise the level of severity in the most common rodent models of middle cerebral artery occlusion, while sustaining or improving the scientific outcomes. The recommendations cover basic requirements pre-surgery, selecting the most appropriate anaesthetic and analgesic regimen, as well as intraoperative and post-operative care. The aim is to provide support for researchers and animal care staff to refine their procedures and practices, and implement small incremental changes to improve the welfare of the animals used and to answer the scientific question under investigation. All recommendations are recapitulated in a summary poster (see supplementary information).

Animal models are essential for understanding the pathology of stroke and investigating potential treatments. However, in vivo stroke models are associated, particularly in mice, with high variability in lesion volume. We investigated whether a surgical refinement where reperfusion is not reliant on the Circle of Willis reduced outcome variability. Mice underwent 60 min of transient middle cerebral artery occlusion avoiding ligation of the external carotid artery. During reperfusion, the common carotid artery was either ligated (standard approach), or it was repaired to allow re-establishment of blood flow through the common carotid artery. All mice underwent MRI scanning for assessment of infarct volume, apparent diffusion coefficient and fractional anisotropy, along with terminal assessment of infarct volume by 2,3,5-triphenyltetrazolium chloride (TTC) staining. Repairing the common carotid artery following middle cerebral artery occlusion enhanced reperfusion ( P <0.01) and reduced the variability seen in both total (histological analysis, P =0.008; T2-weighted MRI, P =0.015) and core (diffusion tensor MRI, P =0.043) lesion volume. Avoiding external carotid artery ligation may improve animal wellbeing, through reduced weight loss, while using an alternative surgical approach that enabled reperfusion through the common carotid artery decreased the variability in lesion volume seen within groups., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2017. Published by The Company of Biologists Ltd.)

Background: Combined therapy with epidermal growth factor (EGF) and growth hormone-releasing peptide 6 (GHRP-6) in stroke models has accumulated evidence of neuroprotective effects from several studies, but needs further support before clinical translation. Comparing EGF + GHRP-6 to hypothermia, a gold neuroprotection standard, may contribute to this purpose., Objectives: The aims of this study were to compare the neuroprotective effects of a combined therapy based on EGF + GHRP-6 with hypothermia in animal models of (a) global ischemia representing myocardial infarction and (b) focal brain ischemia representing ischemic stroke., Methods: (a) Global ischemia was induced in Mongolian gerbils by a 15-min occlusion of both carotid arteries, followed by reperfusion. (b) Focal brain ischemia was achieved by intracerebral injection of endothelin 1 in Wistar rats. In each experiment, three ischemic treatment groups - vehicle, EGF + GHRP-6, and hypothermia - were compared to each other and to a sham-operated control group. End points were survival, neurological scores, and infarct volume., Results: (a) In global ischemia, neurological score at 48-72 h, infarct volume, and neuronal density of hippocampal CA1 zone in gerbils treated with EGF + GHRP-6 were similar to the hypothermia-treated group. (b) In focal ischemia, the neurologic score and infarct volume of rats receiving EGF + GHRP-6 were also similar to animals in the hypothermia group., Discussion: With hypothermia being a good standard neuroprotectant reference, these results provide additional proof of principle for EGF and GHRP-6 co-administration as a potentially neuroprotective stroke therapy.

Child maltreatment has been demonstrated to have many short- and long-term harmful consequences for victims, but whether or not child abuse is associated with an increased risk of peer victimization during adolescence is unclear. This study analyzed prospective data from 831 children and parents participating in the Longitudinal Studies on Child Abuse and Neglect (LONGSCAN) to investigate the relationships between child physical and sexual abuse and adolescent victimization by peers, as well as the potential for gender to moderate these relationships. Results from ordinal logit regression models indicated that children who were physically abused prior to age 12, based on official reports, parent reports, and child reports, had a greater risk of experiencing more intimidation and physical assault by peers at age 16. Having a history of sexual abuse predicted more physical assault but not intimidation. There was no evidence that gender moderated these relationships; in all cases, the relationship between abuse and revictimization was similar for boys and girls. The findings emphasize the need to provide victims of abuse with assistance to help prevent a cycle of victimization., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Cerebral ischemic stroke is a leading cause of mortality and functional disability. However, unfortunately few effective treatments exist to counteract the deleterious pathological mechanisms triggered following an ischemic event. Epidemiological and experimental studies have revealed a significant difference in the vulnerability of males versus females to both the incidence of stroke and amount of resulting pathology following an ischemic stroke which is also dependent on the stage of lifespan. Here we review the evidence for gender differences in both the overall pathology and cellular mechanisms of injury following ischemic stroke. In addition, we discuss the evidence for any gender differences that may occur in the effectiveness of treatments and how this supports the need for the investigation and development of gender-specific therapies., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Aims: Parenting practices are associated with adolescents' alcohol consumption, however not all youth respond similarly to challenging family situations and harsh environments. This study examines the relationship between perceived parental rejection and adolescent alcohol use, and specifically evaluates whether youth who possess greater genetic sensitivity to their environment are more susceptible to negative parental relationships., Methods: Analyzing data from the National Longitudinal Study of Adolescent Health, we estimated a series of regression models predicting alcohol use during adolescence. A multiplicative interaction term between parental rejection and a genetic index was constructed to evaluate this potential gene-environment interaction., Results: Results from logistic regression analyses show a statistically significant gene-environment interaction predicting alcohol use. The relationship between parental rejection and alcohol use was moderated by the genetic index, indicating that adolescents possessing more 'risk alleles' for five candidate genes were affected more by stressful parental relationships., Conclusions: Feelings of parental rejection appear to influence the alcohol use decisions of youth, but they do not do so equally for all. Higher scores on the constructed genetic sensitivity measure are related to increased susceptibility to negative parental relationships., (© The Author 2016. Medical Council on Alcohol and Oxford University Press. All rights reserved.)

Background: Stroke continues to be a leading cause of mortality and morbidity worldwide, and novel therapeutic options for ischaemic stroke are urgently needed. In this context, drug combination therapies seem to be a viable approach, which has not been fully explored in preclinical studies., Objectives: In this work, we assessed the dose-response relationship and therapeutic time window, in global brain ischaemia, of a combined therapeutic approach of recombinant human epidermal growth factor (EGF) and growth hormone-releasing peptide-6 (GHRP-6)., Methods: Mongolian gerbils underwent 15 minutes occlusion of both common carotid arteries. Four different doses of rhEGF, GHRP-6 and these combined agents were intraperitoneally administered immediately after the onset of reperfusion. Having identified a better response with both agents, rhEGF+GHRP-6 were administered at 2, 4, 6, 8 or 24 hours after the onset of reperfusion to assess the time window of effectiveness. Animals were evaluated daily for neurological deficits. Three days post-occlusion, the animals were sacrificed and 2,3,5-triphenyltetrazolium chloride was used to quantify infarcted tissues., Results: The coadministration of rhEGF and GHRP-6 at doses of 100 and 600 μg/kg, respectively, administered up to 4 hours following the ischaemic insult, significantly improved survival and neurological outcome, and reduced infarct volume compared with vehicle treatment. These results are considered as an additional proof of concept as supporting a combined therapeutic approach and justify the further development of this preclinical research.

Two multi-centre phase III clinical trials examining the protective potential of progesterone following traumatic brain injury have recently failed to demonstrate any improvement in outcome. Thus, it is timely to consider how this impacts on the translational potential of progesterone treatment for ischaemic stroke. A wealth of experimental evidence supports the neuroprotective properties of progesterone, and associated metabolites, following various types of central nervous system injury. In particular, for ischaemic stroke, studies have also begun to reveal possible mechanisms of such neuroprotection. However, the results in traumatic brain injury now question whether further clinical development of progesterone for ischaemic stroke is relevant., (© The Author(s) 2015.)

Excitotoxicity is a major contributor to cell death during the acute phase of ischemic stroke but aggressive pharmacological targeting of excitotoxicity has failed clinically. Here we investigated whether pretreatment with low doses of memantine, within the range currently used and well tolerated for the treatment of Alzheimer's disease, produce a protective effect in stroke. A coculture preparation exposed to modeled ischemia showed cell death associated with rapid glutamate rises and cytotoxic Ca(2+) influx. Cell death was significantly enhanced in the presence of high memantine concentrations. However, low memantine concentrations significantly protected neurons and glia via excitotoxic cascade interruption. Mice were systemically administered a range of memantine doses (0.02, 0.2, 2, 10, and 20 mg/kg/day) starting 24 hours before 60 minutes reversible focal cerebral ischemia and continuing for a 48-hour recovery period. Low dose (0.2 mg/kg/day) memantine treatment significantly reduced lesion volume (by 30% to 50%) and improved behavioral outcomes in stroke lesions that had been separated into either small/striatal or large/striatocortical infarcts. However, higher doses of memantine (20 mg/kg/day) significantly increased injury. These results show that clinically established low doses of memantine should be considered for patients 'at risk' of stroke, while higher doses are contraindicated.

This study tests the hypothesis that undergraduates who peer teach genetics will have greater understanding of genetic and molecular biology concepts as a result of their teaching experiences. Undergraduates enrolled in a non-majors biology course participated in a service-learning program in which they led middle school (MS) or high school (HS) students through a case study curriculum to discover the cause of a green tomato variant. The curriculum explored plant reproduction and genetic principles, highlighting variation in heirloom tomato fruits to reinforce the concept of the genetic basis of phenotypic variation. HS students were taught additional activities related to mole-cular biology techniques not included in the MS curriculum. We measured undergraduates' learning outcomes using pre/postteaching content assessments and the course final exam. Undergraduates showed significant gains in understanding of topics related to the curriculum they taught, compared with other course content, on both types of assessments. Undergraduates who taught HS students scored higher on questions specific to the HS curriculum compared with undergraduates who taught MS students, despite identical lecture content, on both types of assessments. These results indicate the positive effect of service-learning peer-teaching experiences on undergraduates' content knowledge, even for non-science major students., (© 2014 H. E. Chrispeels et al. CBE—Life Sciences Education © 2014 The American Society for Cell Biology. This article is distributed by The American Society for Cell Biology under license from the author(s). It is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).)

Background: Progesterone is neuroprotective in numerous preclinical CNS injury models including cerebral ischaemia. The aim of this study was two-fold; firstly, we aimed to determine whether progesterone delivery via osmotic mini-pump would confer neuroprotective effects and whether such neuroprotection could be produced in co-morbid animals., Results: Animals underwent transient middle cerebral artery occlusion. At the onset of reperfusion, mice were injected intraperitoneally with progesterone (8 mg/kg in dimethylsulfoxide). Adult and aged C57 Bl/6 mice were dosed additionally with subcutaneous infusion (1.0 μl/h of a 50 mg/ml progesterone solution) via implanted osmotic minipumps. Mice were allowed to survive for up to 7 days post-ischaemia and assessed for general well-being (mass loss and survival), neurological score, foot fault and t-maze performance. Progesterone reduced neurological deficit [F(1,2) = 5.38, P = 0.027] and number of contralateral foot-faults [F(1,2) = 7.36, P = 0.0108] in adult, but not aged animals, following ischaemia. In hypertensive animals, progesterone treatment lowered neurological deficit [F(1,6) = 18.31, P = 0.0001], reduced contralateral/ipsilateral alternation ratio % [F(1,2) = 17.05, P = 0.0006] and time taken to complete trials [F(1,2) = 15.92, P = 0.0009] for t-maze., Conclusion: Post-ischemic progesterone administration via mini-pump delivery is effective in conferring functional improvement in a transient MCAO model in adult mice. Preliminary data suggests such a treatment regimen was not effective in producing a protective effect in aged mice. However, in hypertensive mice, who received post-ischemic progesterone intraperitoneally at the onset of reperfusion had better functional outcomes than control hypertensive mice.

The treatment of Human African trypanosomiasis remains a major unmet health need in sub-Saharan Africa. Approaches involving new molecular targets are important; pteridine reductase 1 (PTR1), an enzyme that reduces dihydrobiopterin in Trypanosoma spp., has been identified as a candidate target, and it has been shown previously that substituted pyrrolo[2,3-d]pyrimidines are inhibitors of PTR1 from Trypanosoma brucei (J. Med. Chem. 2010, 53, 221-229). In this study, 61 new pyrrolo[2,3-d]pyrimidines have been prepared, designed with input from new crystal structures of 23 of these compounds complexed with PTR1, and evaluated in screens for enzyme inhibitory activity against PTR1 and in vitro antitrypanosomal activity. Eight compounds were sufficiently active in both screens to take forward to in vivo evaluation. Thus, although evidence for trypanocidal activity in a stage I disease model in mice was obtained, the compounds were too toxic to mice for further development.

The nitric oxide synthase (NOS) dimer is stabilized by a Zn(2+) ion coordinated to four symmetry-related Cys residues exactly along the dimer 2-fold axis. Each of the two essential tetrahydrobiopterin (H4B) molecules in the dimer interacts directly with the heme, and each H4B molecule is ~15 Å from the Zn(2+). We have determined the crystal structures of the bovine endothelial NOS dimer oxygenase domain bound to three different pterin analogues, which reveal an intimate structural communication between the H4B and Zn(2+) sites. The binding of one of these compounds, 6-acetyl-2-amino-7,7-dimethyl-7,8-dihydro-4(3H)-pteridinone (1), to the pterin site and Zn(2+) binding are mutually exclusive. Compound 1 both directly and indirectly disrupts hydrogen bonding between key residues in the Zn(2+) binding motif, resulting in destabilization of the dimer and a complete disruption of the Zn(2+) site. Addition of excess Zn(2+) stabilizes the Zn(2+) site at the expense of weakened binding of 1. The unique structural features of 1 that disrupt the dimer interface are extra methyl groups that extend into the dimer interface and force a slight opening of the dimer, thus resulting in disruption of the Zn(2+) site. These results illustrate a very delicate balance of forces and structure at the dimer interface that must be maintained to properly form the Zn(2+), pterin, and substrate binding sites.

Ischaemic strokes evoke blood-brain barrier (BBB) disruption and oedema formation through a series of mechanisms involving Rho-kinase activation. Using an animal model of human focal cerebral ischaemia, this study assessed and confirmed the therapeutic potential of Rho-kinase inhibition during the acute phase of stroke by displaying significantly improved functional outcome and reduced cerebral lesion and oedema volumes in fasudil- versus vehicle-treated animals. Analyses of ipsilateral and contralateral brain samples obtained from mice treated with vehicle or fasudil at the onset of reperfusion plus 4 h post-ischaemia or 4 h post-ischaemia alone revealed these benefits to be independent of changes in the activity and expressions of oxidative stress- and tight junction-related parameters. However, closer scrutiny of the same parameters in brain microvascular endothelial cells subjected to oxygen-glucose deprivation ± reperfusion revealed marked increases in prooxidant NADPH oxidase enzyme activity, superoxide anion release and in expressions of antioxidant enzyme catalase and tight junction protein claudin-5. Cotreatment of cells with Y-27632 prevented all of these changes and protected in vitro barrier integrity and function. These findings suggest that inhibition of Rho-kinase after acute ischaemic attacks improves cerebral integrity and function through regulation of endothelial cell oxidative stress and reorganization of intercellular junctions. Inhibition of Rho-kinase (ROCK) activity in a mouse model of human ischaemic stroke significantly improved functional outcome while reducing cerebral lesion and oedema volumes compared to vehicle-treated counterparts. Studies conducted with brain microvascular endothelial cells exposed to OGD ± R in the presence of Y-27632 revealed restoration of intercellular junctions and suppression of prooxidant NADPH oxidase activity as important factors in ROCK inhibition-mediated BBB protection., (© 2014 International Society for Neurochemistry.)

Objectives: We investigated how street efficacy--the perceived ability to avoid dangerous and unsafe situations--is related to violent victimization across different levels of neighborhood disadvantage., Methods: We used 2 waves of self-report data collected between 1995 and 1999 from 1865 youths in the 9-, 12-, and 15-year-old cohorts of the Project on Human Development in Chicago Neighborhoods to measure violent victimization, street efficacy, and risk factors for violent victimization. We also analyzed data from the 1990 US Census to measure categories of neighborhood concentrated disadvantage for which the cohorts of youths reside. We used logistic regression models to examine the association between street efficacy and violent victimization while we controlled for demographic, family and parenting, self-control, and behavioral and lifestyle variables., Results: Logistic regression results showed that street efficacy had its strongest association with violent victimization in the most disadvantaged neighborhoods (odds ratio = 0.700; 95% confidence interval = 0.55, 0.89)., Conclusions: Our findings support the need to teach youths ways to successfully navigate potentially violent situations in environments that pose moderate to high risks for exposure to violence.

This study uses a life course framework to investigate how police contacts may serve as a potential turning point in a violent crime trajectory. Drawing on the central ideas from deterrence and labeling theories, we determine whether individuals on different violent offending trajectories increase or decrease their offending following a police contact. Analyzing nine waves of data from the Rochester Youth Development Study, an integrated propensity score matching and latent class growth model was used. First, three violent trajectory groups emerged including high offenders, non-offenders, and low offenders. Second, after accounting for selection bias using propensity score matching procedures, experiencing a police contact increased the likelihood of future violent offending for the entire sample and for those who were on a low violent-offending trajectory specifically. These findings are interpreted as partial support for labeling theory. Limitations of the study and directions for future research are discussed.

Drawing on a sample of twin children from the Early Childhood Longitudinal Study, Birth Cohort (ECLS-B; Snow et al., 2009), the current study analyzed 2 of the most prominent predictors of externalizing behavioral problems (EBP) in children: (a) parental use of spankings and (b) childhood self-regulation. A variety of statistical techniques were employed, and, overall, the findings can be summarized into 2 points. First, the results show that the relationships among spanking, self-regulation, and EBP are highly nuanced in that multiple explanations for their intercorrelations appear to fit the data (e.g., bidirectional relationships and shared methods variance). Second, genetic influences accounted for variance in each variable (EBP, spankings received, self-regulation) and even explained a portion of the covariance among the different variables. Thus, research that does not consider genetic influences when analyzing these associations runs a risk of model misspecification., (PsycINFO Database Record (c) 2013 APA, all rights reserved.)

The present study assessed the spatial abilities of male and female human participants using different versions of the non-navigational Corsi block-tapping test (CBT) and a search task. Males performed significantly better than females on the standard manual version of the CBT; however, the standard CBT does not allow discrimination between spatial memory span and the role of spatial organisational factors (structure, path length and presence of crossings) in the sequences to recall. These organisational factors were assessed, therefore, in an experiment in which 7-block-sequences had to be recalled in a computerised version of the CBT. No sex differences in performance were observed on the computerised CBT, indicating that males do not make better use of spatial organisational principles. Accordingly, sex differences observed in the manual CBT are likely to rely upon differences in memory span between males and females. In the search task, participants could locate a goal by reference to a Euclidian space (the geometry of a virtual enclose) or to proximal non-geometric cues. Both male and female participants showed a preference for the non-geometric cues, which overshadowed learning about the geometric cues when the two sets were available simultaneously during the training stage. These results indicate that sex differences do exist in those tests which are dependent on memory span. Sex differences were absent, however, in spatial organisational skills or in the usage of Euclidian and egocentric strategies to solve problems relying on spatial ability., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Cerebral stroke is a leading cause of long-term disability and a major cause of death in the developed world. The total incidence of stroke is projected to rise substantially over the next 20 years as a result of the rising elderly population. Although age is one of the most significant prognostic markers for poor outcome after stroke, very few experimental studies have been conducted in aged animals. Importantly, sex differences in both vulnerability to stroke and outcome after cerebral ischaemia have frequently been reported and attributed to the action of steroid hormones. Progesterone is a candidate neuroprotective factor for stroke, although the majority of pre-clinical studies have focused on using young, healthy adult animals. In terms of cerebral stroke, males and postmenopausal females represent the groups at highest risk of cerebral stroke and these categories can be modelled using either aged or ovariectomised female animals. In this review, we discuss the importance of conducting experimental studies in aged animals compared to young, healthy animals, as well as the impact this has on experimental outcomes. In addition, we focus on reviewing the studies that have been conducted to date examining the neuroprotective potential of progesterone in aged animals. Importantly, the limited studies that have been conducted in aged animals do lend further support to progesterone as a therapeutic option after ischaemic stroke that warrants further investigation., (© 2013 British Society for Neuroendocrinology.)

Preclinical studies suggest progesterone is neuroprotective after cerebral ischemia. The gold standard for assessing intervention effects across studies within and between subgroups is to use meta-analysis based on individual animal data (IAD). Preclinical studies of progesterone in experimental stroke were identified from searches of electronic databases and reference lists. Corresponding authors of papers of interest were contacted to obtain IAD and, if unavailable, summary data were obtained from the publication. Data are given as standardized mean differences (SMDs, continuous data) or odds ratios (binary data), with 95% confidence intervals (95% CIs). In an unadjusted analysis of IAD and summary data, progesterone reduced standardized lesion volume (SMD -0.766, 95% CI -1.173 to -0.358, P<0.001). Publication bias was apparent on visual inspection of a Begg's funnel plot on lesion volume and statistically using Egger's test (P=0.001). Using individual animal data alone, progesterone was associated with an increase in death in adjusted analysis (odds ratio 2.64, 95% CI 1.17 to 5.97, P=0.020). Although progesterone significantly reduced lesion volume, it also appeared to increase the incidence of death after experimental stroke, particularly in young ovariectomized female animals. Experimental studies must report the effect of interactions on death and on modifiers, such as age and sex.

Cerebral stroke continues to be a major cause of death and the leading cause of long-term disability in developed countries. Evidence reviewed here suggests that gender influences various aspects of the clinical spectrum of ischemic stroke, in terms of influencing how a patients present with ischemic stroke through to how they respond to treatment. In addition, this review focuses on discussing the various pathologic mechanisms of ischemic stroke that may differ according to gender and compares how intrinsic and hormonal mechanisms may account for such gender differences. All clinical trials to date investigating putative neuroprotective treatments for ischemic stroke have failed, and it may be that our understanding of the injury cascade initiated after ischemic injury is incomplete. Revealing aspects of the pathophysiological consequences of ischemic stroke that are gender specific may enable gender relevant and effective neuroprotective strategies to be identified. Thus, it is possible to conclude that gender does, in fact, have an important role in ischemic stroke and must be factored into experimental and clinical investigations of ischemic stroke.

The learning abilities of planarian worms (Dugesia tigrina) were assessed by using a number of Pavlovian conditioning paradigms. Experiment 1 showed that planaria were susceptible to basic conditioning in that they readily developed a conditioned response to a change in ambient luminance when it was consistently paired with an electric shock over a number of trials. In Experiment 2, the change in luminance was presented in a compound with a vibration stimulus during conditioning. Subsequent tests revealed poor conditioning of the elements compared with control groups in which the animals were conditioned in the presence of the elements alone, an instance of overshadowing. In Experiment 3, pre-training of one of the elements before compound conditioning resulted in blocking of learning about the other element. These results add to other studies that have reported cue competition effects in animal species belonging to different phyla (chordate, mollusk, arthropod), suggesting that learning in these phyla could be ruled by similar principles. The results are discussed adopting an evolutionary-comparative approach.

Although COX-2 inhibition in animal models of ischaemia has shown neuroprotection, clinical trials revealed long term side effects with COX-2 inhibitors. A more focussed approach is necessary to retain the therapeutic effects of prostaglandins. This study investigated the role of the PGE(2) EP(4) receptor using both in vitro and in vivo models of ischaemia. To demonstrate whether targeting the EP(4) receptor is as neuroprotective as COX-2 inhibition, simultaneous experiments were carried out using a selective COX-2 inhibitor. Organotypic hippocampal sliced cultures, exposed to 2 h of oxygen glucose deprivation, were treated with; DMSO only, COX-2 inhibitor (NS-398), EP(4) agonist (L-902688) or EP(4) antagonist (GW627368X) and cell death was assessed. The EP(4) agonist and the COX-2 inhibitor significantly reduced cell death following in vitro ischaemia, whereas treatment with the EP(4) antagonist significantly increased cell death in hippocampal cultures. Following a 1 h occlusion of middle cerebral artery, mice were treated with the COX-2 inhibitor (10 mg kg, I.P), EP(4) agonist (0.75 μg/kg, I.P) or vehicle (I.P), at the onset of reperfusion and again at 24 h post stroke. The COX-2 inhibitor and EP(4) agonist treated animals showed a significant reduction in infarct volume (P < .05) at 48 h post stroke compared to the vehicle treated group. These results show that selective activation of the EP(4) receptor following acute ischaemic damage is neuroprotective, and support the concept of targeting protective prostaglandin receptor signalling as a potential therapeutic target for cerebral stroke., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Evidence suggests that pre-ischeamic conditioning (PIC) offers protection against a subsequent ischeamic event. Although some brain areas such as the hippocampus have received much attention, the receptor mechanisms of PIC in other brain regions are unknown. We have previously shown that 10 min oxygen and glucose deprivation (OGD) evokes tolerance to a second OGD event in the caudate. Here we further examine the effect of length of conditioning event on the second OGD event. Caudate mouse brain slices were superfused with artificial cerebro-spinal fluid (aCSF) bubbled with 95%O(2)/5%CO(2). OGD was achieved by reducing the aCSF glucose concentration and by bubbling with 95%N(2)/5%CO(2). After approximately 5 min OGD a large dopamine efflux was observed, presumably caused by anoxic depolarisation. On applying a second OGD event, 60 min later, dopamine efflux was delayed and reduced. We first examined the effect of varying the length of the conditioning event from 5 to 40 min and found tolerance to PIC increased with increasing duration of conditioning. We then examined the receptor mechanism(s) underlying PIC. We found that pre-incubation with either MK-801 or 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) reduced tolerance to the second OGD event. These data suggest that either N-methyl-D-aspartate (NMDA) or adenosine A(1) receptor activation evokes PIC in the mouse caudate., (Copyright © 2012 Elsevier B.V. All rights reserved.)