Estrogen Promotes Pro-resolving Microglial Behavior and Phagocytic Cell Clearance Through the Actions of Annexin A1

Local production of estrogen rapidly follows brain tissue injury, but the role this hormone plays in regulating the response to neural damage or in the modulation of mediators regulating inflammation is in many ways unclear. Using the murine BV2 microglia model as well as primary microglia from wild-type and annexin A1 (AnxA1) null mice, we have identified two related mechanisms whereby estradiol can modulate microglial behavior in a receptor specific fashion. Firstly, estradiol, via estrogen receptor β (ERβ), enhanced the phagocytic clearance of apoptotic cells, acting through increased production and release of the protein AnxA1. Secondly, stimulation of either ERβ or the G protein coupled estrogen receptor GPER promoted the adoption of an anti-inflammatory/pro-resolving phenotype, an action similarly mediated through AnxA1. Together, these data suggest the hypothesis that locally produced estrogen acts through AnxA1 to exert powerful pro-resolving actions, controlling and limiting brain inflammation and ultimately protecting this highly vulnerable organ. Given the high degree of receptor selectivity in evoking these responses, we suggest that the use of selective estrogen receptor ligands may hold therapeutic promise in the treatment of neuroinflammation, avoiding unwanted generalized effects

Nongenomic mechanisms of physiological estrogen-mediated dopamine efflux

<p>Abstract</p> <p>Background</p> <p>Neurological diseases and neuropsychiatric disorders that vary depending on female life stages suggest that sex hormones may influence the function of neurotransmitter regulatory machinery such as the dopamine transporter (DAT).</p> <p>Results</p> <p>In this study we tested the rapid nongenomic effects of several physiological estrogens [estradiol (E₂), estrone (E₁), and estriol (E₃)] on dopamine efflux via the DAT in a non-transfected, NGF-differentiated, rat pheochromocytoma (PC12) cell model that expresses membrane estrogen receptors (ERs) α, β, and GPR30. We examined kinase, ionic, and physical interaction mechanisms involved in estrogenic regulation of the DAT function. E₂-mediated dopamine efflux is DAT-specific and not dependent on extracellular Ca²⁺-mediated exocytotic release from vesicular monoamine transporter vesicles (VMATs). Using kinase inhibitors we also showed that E₂-mediated dopamine efflux is dependent on protein kinase C and MEK activation, but not on PI3K or protein kinase A. In plasma membrane there are ligand-independent associations of ERα and ERβ (but not GPR30) with DAT. Conditions which cause efflux (a 9 min 10^-9M E₂treatment) cause trafficking of ERα (stimulatory) to the plasma membrane and trafficking of ERβ (inhibitory) away from the plasma membrane. In contrast, E₁and E₃can inhibit efflux with a nonmonotonic dose pattern, and cause DAT to leave the plasma membrane.</p> <p>Conclusion</p> <p>Such mechanisms explain how gender biases in some DAT-dependent diseases can occur.</p

Cognitive behaviour therapy versus counselling intervention for anxiety in young people with high-functioning autism spectrum disorders: a pilot randomised controlled trial

The use of cognitive-behavioural therapy (CBT) as a treatment for children and adolescents with autism spectrum disorder (ASD) has been explored in a number of trials. Whilst CBT appears superior to no treatment or treatment as usual, few studies have assessed CBT against a control group receiving an alternative therapy. Our randomised controlled trial compared use of CBT against person-centred counselling for anxiety in 36 young people with ASD, ages 12–18. Outcome measures included parent- teacher- and self-reports of anxiety and social disability. Whilst each therapy produced improvements inparticipants, neither therapy was superior to the other to a significant degree on any measure. This is consistent with findings for adults

Cement leakage causes potential thermal injury in vertebroplasty

<p>Abstract</p> <p>Background</p> <p>Percutaneous vertebroplasty by injecting PMMA bone cement into the fractured vertebrae has been widely accepted in treatment of spinal compression fracture. However, the exothermic polymerization of bone cement may cause osseous or neural tissue injury. This study is thus designed to evaluate the potential risk of thermal damage in percutaneous vertebroplasty.</p> <p>Method</p> <p>Twelve porcine vertebrae were immersed in 37°C saline for the experiment. In the first stage of the study, vertebroplasty without cement leakage (control group, n = 6) was simulated. The anterior cortex, foramen, posterior cortex and the center of the vertebral body were selected for temperature measurement. Parameters including peak temperature and duration above 45°C were recorded. In the second stage, a model (n = 6) simulating bone cement leaking into the spinal canal was designed. The methods for temperature measurement were identical to those used in the first stage.</p> <p>Results</p> <p>In Stage 1 of the study (vertebroplasty of the porcine vertebral body in the absence of cement leakage), the average maximal temperature at the anterior cortex was 42.4 ± 2.2°C; at the neural foramen 39.5 ± 2.1°C; at the posterior cortex 40.0 ± 2.5°C and at the vertebral center, 68.1 ± 3.4°C. The average time interval above 45°C was 0 seconds at the anterior cortex; at the neural foramen, 0 seconds; at the posterior cortex, 0 seconds and at the vertebral center, 223 seconds. Thus, except at the core of the bone cement, temperatures around the vertebral body did not exceed 45°C. In Stage 2 of the study (cement leakage model), the average maximal temperature at the anterior cortex was 42.7 ± 2.4°C; at the neural foramen, 41.1 ± 0.4°C; at the posterior cortex, 59.1 ± 7.6°C and at the vertebral center, 77.3 ± 5.7°C. The average time interval above 45°C at the anterior cortex was 0 seconds; at the neural foramen, 0 seconds; at the posterior cortex, 329.3 seconds and at the vertebral center, 393.2 seconds. Based on these results, temperatures exceeded 45°C at the posterior cortex and at the vertebral center.</p> <p>Conclusions</p> <p>The results indicated that, for bone cement confined within the vertebra, curing temperatures do not directly cause thermal injury to the nearby soft tissue. If bone cement leaks into the spinal canal, the exothermic reaction at the posterior cortex might result in thermal injury to the neural tissue.</p

How do you say ‘hello’? Personality impressions from brief novel voices

On hearing a novel voice, listeners readily form personality impressions of that speaker. Accurate or not, these impressions are known to affect subsequent interactions; yet the underlying psychological and acoustical bases remain poorly understood. Furthermore, hitherto studies have focussed on extended speech as opposed to analysing the instantaneous impressions we obtain from first experience. In this paper, through a mass online rating experiment, 320 participants rated 64 sub-second vocal utterances of the word ‘hello’ on one of 10 personality traits. We show that: (1) personality judgements of brief utterances from unfamiliar speakers are consistent across listeners; (2) a two-dimensional ‘social voice space’ with axes mapping Valence (Trust, Likeability) and Dominance, each driven by differing combinations of vocal acoustics, adequately summarises ratings in both male and female voices; and (3) a positive combination of Valence and Dominance results in increased perceived male vocal Attractiveness, whereas perceived female vocal Attractiveness is largely controlled by increasing Valence. Results are discussed in relation to the rapid evaluation of personality and, in turn, the intent of others, as being driven by survival mechanisms via approach or avoidance behaviours. These findings provide empirical bases for predicting personality impressions from acoustical analyses of short utterances and for generating desired personality impressions in artificial voices

Soluble and Cell-Associated Insulin Receptor Dysfunction Correlates with Severity of HAND in HIV-Infected Women

Blood sugar metabolism abnormalities have been identified in HIV-infected individuals and associated with HIV-associated neurocognitive disorders (HAND). These abnormalities may occur as a result of chronic HIV infection, long-term use of combined antiretroviral treatment (CART), aging, genetic predisposition, or a combination of these factors, and may increase morbidity and mortality in this population.To determine if changes in soluble and cell-associated insulin receptor (IR) levels, IR substrate-1 (IRS-1) levels, and IRS-1 tyrosine phosphorylation are associated with the presence and severity of HAND in a cohort of HIV-seropositive women.This is a retrospective cross-sectional study using patient database information and stored samples from 34 HIV-seropositive women and 10 controls without history of diabetes from the Hispanic-Latino Longitudinal Cohort of Women. Soluble IR subunits [sIR, ectodomain (α) and full-length or intact (αβ)] were assayed in plasma and CSF samples by ELISA. Membrane IR levels, IRS-1 levels, and IRS-1 tyrosine phosphorylation were analyzed in CSF white cell pellets (WCP) using flow cytometry. HIV-seropositive women had significantly increased levels of intact or full-length sIR in plasma (p<0.001) and CSF (p<0.005) relative to controls. Stratified by HAND, increased levels of full-length sIR in plasma were associated with the presence (p<0.001) and severity (p<0.005) of HAND. A significant decrease in IRS-1 tyrosine-phosphorylation in the WCP was also associated with the presence (p<0.02) and severity (p<0.02) of HAND.This study provides evidence that IR secretion is increased in HIV-seropositive women, and increased IR secretion is associated with cognitive impairment in these women. Thus, IR dysfunction may have a role in the progression of HAND and could represent a biomarker for the presence and severity of HAND

Impact of treatment policies on patient outcomes and resource utilization in acute cholecystitis in Japanese hospitals

BACKGROUND: Although currently available evidence predominantly recommends early laparoscopic cholecystectomy (LC) for the treatment of acute cholecystitis, this strategy has not been widely adopted in Japan. Herein, we describe a hospital-based study of patients with acute cholecystitis in 9 Japanese teaching hospitals in order to evaluate the impact of different institutional strategies in treating acute cholecystitis on overall patient outcomes and medical resource utilization. METHODS: From an administrative database and chart review, we identified 228 patients diagnosed with acute cholecystitis who underwent cholecystectomy between April 2001 and June 2003. In order to examine the relationship between hospitals' propensity to perform LC and patient outcomes and/or medical resource utilization, we divided the hospitals into three groups according to the observed to expected ratio of performing LC (LC propensity), and compared the postoperative complication rate, length of hospitalization (LOS), and medical charges. RESULTS: No hospital adopted the policy of early surgery, and the mean overall LOS among the subjects was 30.9 days. The use of laparoscopic surgery varied widely across the hospitals; the adjusted rates of LC to total cholecystectomies ranged from 9.5% to 77%. Although intra-operative complication rate was significantly higher among patients whom LC was initially attempted when compared to those whom OC was initially attempted (9.7% vs. 0%), there was no significant association between LC propensity and postoperative complication rates. Although the postoperative time to oral intake and postoperative LOS was significantly shorter in hospitals with high use of LC, the overall LOS did not differ among hospital groups with different LC propensities. Medical charges were not associated with LC propensity. CONCLUSION: Under the prevailing policy of delayed surgery, in terms of the postoperative complication rate and medical resource utilization, our study did not show the superiority of LC in treating acute cholecystitis patients. The timing of surgery and discharge was mainly determined by the institutional policy in Japan, rather than by the clinical course of the patient; however, considering the substantially less postoperative pain and shorter recovery time of LC compared to OC, LC should be actively applied for the treatment of acute cholecystitis. If the policy of early surgery were universally applied, the advantage of LC over OC may be more clearly demonstrated

Mechanisms of initiation and reversal of drug-seeking behavior induced by prenatal exposure to glucocorticoids

We would like to thank the members of the Neuroscience Research Domain at ICVS for all the helpful discussions and suggestions. We are especially thankful to the animal facility caretakers, and to Drs Sara Silva, António Melo and Ana Paula Silva and Dieter Fischer for their helpStress and exposure to glucocorticoids (GC) during early life render individuals vulnerable to brain disorders by inducing structural and chemical alterations in specific neural substrates. Here we show that adult rats that had been exposed to in utero GCs (iuGC) display increased preference for opiates and ethanol, and are more responsive to the psychostimulatory actions of morphine. These animals presented prominent changes in the nucleus accumbens (NAcc), a key component of the mesolimbic reward circuitry; specifically, cell numbers and dopamine (DA) levels were significantly reduced, whereas DA receptor 2 (Drd2) mRNA expression levels were markedly upregulated in the NAcc. Interestingly, repeated morphine exposure significantly downregulated Drd2 expression in iuGC-exposed animals, in parallel with increased DNA methylation of the Drd2 gene. Administration of a therapeutic dose of L-dopa reverted the hypodopaminergic state in the NAcc of iuGC animals, normalized Drd2 expression and prevented morphine-induced hypermethylation of the Drd2 promoter. In addition, L-dopa treatment promoted dendritic and synaptic plasticity in the NAcc and, importantly, reversed drug-seeking behavior. These results reveal a new mechanism through which drug-seeking behaviors may emerge and suggest that a brief and simple pharmacological intervention can restrain these behaviors in vulnerable individuals.This work was supported by the Institute for the Study of Affective Neuroscience (ISAN). AJR, BC and MC were supported by Fundação para a Ciência e Tecnologia (FCT) fellowship

Dysregulation of Macrophage-Secreted Cathepsin B Contributes to HIV-1-Linked Neuronal Apoptosis

Chronic HIV infection leads to the development of cognitive impairments, designated as HIV-associated neurocognitive disorders (HAND). The secretion of soluble neurotoxic factors by HIV-infected macrophages plays a central role in the neuronal dysfunction and cell death associated with HAND. One potentially neurotoxic protein secreted by HIV-1 infected macrophages is cathepsin B. To explore the potential role of cathepsin B in neuronal cell death after HIV infection, we cultured HIV-1ADA infected human monocyte-derived macrophages (MDM) and assayed them for expression and activity of cathepsin B and its inhibitors, cystatins B and C. The neurotoxic activity of the secreted cathepsin B was determined by incubating cells from the neuronal cell line SK-N-SH with MDM conditioned media (MCM) from HIV-1 infected cultures. We found that HIV-1 infected MDM secreted significantly higher levels of cathepsin B than did uninfected cells. Moreover, the activity of secreted cathepsin B was significantly increased in HIV-infected MDM at the peak of viral production. Incubation of neuronal cells with supernatants from HIV-infected MDM resulted in a significant increase in the numbers of apoptotic neurons, and this increase was reversed by the addition of either the cathepsin B inhibitor CA-074 or a monoclonal antibody to cathepsin B. In situ proximity ligation assays indicated that the increased neurotoxic activity of the cathepsin B secreted by HIV-infected MDM resulted from decreased interactions between the enzyme and its inhibitors, cystatins B and C. Furthermore, preliminary in vivo studies of human post-mortem brain tissue suggested an upregulation of cathepsin B immunoreactivity in the hippocampus and basal ganglia in individuals with HAND. Our results demonstrate that HIV-1 infection upregulates cathepsin B in macrophages, increases cathepsin B activity, and reduces cystatin-cathepsin interactions, contributing to neuronal apoptosis. These findings provide new evidence for the role of cathepsin B in neuronal cell death induced by HIV-infected macrophages