Wider and Stronger Inhibitory Ring of the Attentional Focus in Schizophrenia.

Anomalies of attentional selection have been repeatedly described in individuals with schizophrenia spectrum disorders. However, a precise analysis of their ability to inhibit irrelevant visual information during attentional selection is not documented. Recent behavioral as well as neurophysiological and computational evidence showed that attentional search among different competing stimuli elicits an area of suppression in the immediate surrounding of the attentional focus. In the present study, the strength and spatial extension of this surround suppression were tested in individuals with schizophrenia and neurotypical controls. Participants were asked to report the orientation of a visual "pop-out" target, which appeared in different positions within a peripheral array of non-target stimuli. In half of the trials, after the target appeared, a probe circle circumscribed a non-target stimulus at various target-to-probe distances; in this case, participants were asked to report the probe orientation instead. Results suggest that, as compared to neurotypical controls, individuals with schizophrenia showed stronger and spatially more extended filtering of visual information in the areas surrounding their attentional focus. This increased filtering of visual information outside the focus of attention might potentially hamper their ability to integrate different elements into coherent percepts and influence higher order behavioral, affective, and cognitive domains.

Genome-wide microRNA profiling of plasma from three different animal models identifies biomarkers of temporal lobe epilepsy.

Epilepsy diagnosis is complex, requires a team of specialists and relies on in-depth patient and family history, MRI-imaging and EEG monitoring. There is therefore an unmet clinical need for a non-invasive, molecular-based, biomarker to either predict the development of epilepsy or diagnose a patient with epilepsy who may not have had a witnessed seizure. Recent studies have demonstrated a role for microRNAs in the pathogenesis of epilepsy. MicroRNAs are short non-coding RNA molecules which negatively regulate gene expression, exerting profound influence on target pathways and cellular processes. The presence of microRNAs in biofluids, ease of detection, resistance to degradation and functional role in epilepsy render them excellent candidate biomarkers. Here we performed the first multi-model, genome-wide profiling of plasma microRNAs during epileptogenesis and in chronic temporal lobe epilepsy animals. From video-EEG monitored rats and mice we serially sampled blood samples and identified a set of dysregulated microRNAs comprising increased miR-93-5p, miR-142-5p, miR-182-5p, miR-199a-3p and decreased miR-574-3p during one or both phases. Validation studies found miR-93-5p, miR-199a-3p and miR-574-3p were also dysregulated in plasma from patients with intractable temporal lobe epilepsy. Treatment of mice with common anti-epileptic drugs did not alter the expression levels of any of the five miRNAs identified, however administration of an anti-epileptogenic microRNA treatment prevented dysregulation of several of these miRNAs. The miRNAs were detected within the Argonuate2-RISC complex from both neurons and microglia indicating these miRNA biomarker candidates can likely be traced back to specific brain cell types. The current studies identify additional circulating microRNA biomarkers of experimental and human epilepsy which may support diagnosis of temporal lobe epilepsy via a quick, cost-effective rapid molecular-based test.

A systems approach delivers a functional microRNA catalog and expanded targets for seizure suppression in temporal lobe epilepsy.

Temporal lobe epilepsy is the most common drug-resistant form of epilepsy in adults. The reorganization of neural networks and the gene expression landscape underlying pathophysiologic network behavior in brain structures such as the hippocampus has been suggested to be controlled, in part, by microRNAs. To systematically assess their significance, we sequenced Argonaute-loaded microRNAs to define functionally engaged microRNAs in the hippocampus of three different animal models in two species and at six time points between the initial precipitating insult through to the establishment of chronic epilepsy. We then selected commonly up-regulated microRNAs for a functional in vivo therapeutic screen using oligonucleotide inhibitors. Argonaute sequencing generated 1.44 billion small RNA reads of which up to 82% were microRNAs, with over 400 unique microRNAs detected per model. Approximately half of the detected microRNAs were dysregulated in each epilepsy model. We prioritized commonly up-regulated microRNAs that were fully conserved in humans and designed custom antisense oligonucleotides for these candidate targets. Antiseizure phenotypes were observed upon knockdown of miR-10a-5p, miR-21a-5p, and miR-142a-5p and electrophysiological analyses indicated broad safety of this approach. Combined inhibition of these three microRNAs reduced spontaneous seizures in epileptic mice. Proteomic data, RNA sequencing, and pathway analysis on predicted and validated targets of these microRNAs implicated derepressed TGF-ß signaling as a shared seizure-modifying mechanism. Correspondingly, inhibition of TGF-ß signaling occluded the antiseizure effects of the antagomirs. Together, these results identify shared, dysregulated, and functionally active microRNAs during the pathogenesis of epilepsy which represent therapeutic antiseizure targets.

Predictors of stigma in a sample of mental health professionals: Network and moderator analysis on gender, years of experience, personality traits, and levels of burnout.

BACKGROUND: Stigma is one of the most important barriers to help-seeking and to personal recovery for people suffering from mental disorders. Stigmatizing attitudes are present among mental health professionals with negative effects on the quality of health care. METHODS: Network and moderator analysis were used to identify what path determines stigma, considering demographic and professional variables, personality traits, and burnout dimensions in a sample of mental health professionals (n = 318) from six Community Mental Health Services. The survey included the Attribution Questionnaire-9, the Maslach Burnout Inventory, and the Ten-Item Personality Inventory. RESULTS: The personality trait of openness to new experiences resulted to determine lower levels of stigma. Burnout (personal accomplishment) interacted with emotional stability in predicting stigma, and specifically, for subjects with lower emotional stability lower levels of personal accomplishment were associated with higher levels of stigma. CONCLUSIONS: Some personality traits may be accompanied by better empathic and communication skills, and may have a protective role against stigma. Moreover, burnout can increase stigma, in particular in subjects with specific personality traits. Assessing personality and burnout levels could help in identifying mental health professionals at higher risk of developing stigma. Future studies should determine whether targeted interventions in mental health professionals at risk of developing stigma may be effective in stigma prevention.

Exploring the relationships among personality traits, burnout dimensions and stigma in a sample of mental health professionals.

A sample of mental health professionals (n = 215) from six Community Mental Health Services was examined using a short version of the Attribution Questionnaire-27, the Maslach Burnout Inventory and the Ten Items Personality Inventory to detect possible associations among stigma, burnout dimensions and personality traits. The role of demographic and professional variables was also explored. Perception of workplace safety resulted to significantly affect attitudes toward patients. The concern about being assaulted and a low level of Personal Accomplishment were both related to avoidant attitudes, while the presence of procedures for managing the violent patient was associated with a higher level of Personal Accomplishment. Conversely, Emotional Stability and Openness to new experiences were inversely correlated with burnout dimensions and avoidant attitudes, respectively. Overall, our study supports the view of a significant association among some dimensions of stigma, burnout and personality factors. In particular, avoidant attitudes toward patients may be influenced by Personal Accomplishment and Openness to new experiences.

Oxygenator Is the Main Responsible for Leukocyte Activation in Experimental Model of Extracorporeal Circulation: A Cautionary Tale.

In order to assess mechanisms underlying inflammatory activation during extracorporeal circulation (ECC), several small animal models of ECC have been proposed recently. The majority of them are based on home-made, nonstandardized, and hardly reproducible oxygenators. The present study has generated fundamental information on the role of oxygenator of ECC in activating inflammatory signaling pathways on leukocytes, leading to systemic inflammatory response, and organ dysfunction. The present results suggest that experimental animal models of ECC used in translational research on inflammatory response should be based on standardized, reproducible oxygenators with clinical characteristics.

Synthesis and in vitro antiproliferative activity of amido and amino analogues of the marine alkaloid isogranulatimide.

Marine organisms have proven to be a promising source of new compounds with activity against tumor cell lines. Granulatimide and isogranulatimide are marine alkaloids that have been shown to inhibit checkpoint kinase 1 (Chk1), a key protein in the DNA damage response and an emerging target for anticancer therapeutics. Here, we describe the synthesis and preliminary evaluation of amido and amino analogues of isogranulatimide. The new derivatives were prepared in three steps from 2-imidazol-1-yl-1H-indol-5-ylamine. Two of the compounds synthesized exhibited more potent in vitro antiproliferative activity (single-digit micromolar concentration range), by at least one log of magnitude, than the natural product isogranulatimide when evaluated in six human tumor cell lines: non-small-cell lung cancer (A549), colon cancer (LoVo), breast cancer (MCF7), oligodendroglioma (Hs683), glioblastoma (U373), and melanoma (SKMEL28). The mechanism of action of these derivatives remains to be elucidated, given that they did not significantly inhibit Chk1, however these compounds are easily synthesized and exhibit potent anticancer activity and are thus worthy of further study.

Chronic overcirculation-induced pulmonary arterial hypertension in aorto-caval shunt.

Pulmonary arterial hypertension is a common complication of congenital heart defects with left-to-right shunts. Current preclinical models do not reproduce clinical characteristics of shunt-related pulmonary hypertension. Aorto-caval shunt was firstly described as a model of right ventricle volume overload. The pathophysiology and the possible determination of pulmonary arterial hypertension of different periods of shunt exposure are still undefined. A method to create standardized, reproducible aorto-caval shunt was developed in growing rats (260±40 g). Three groups of animals were considered: shunt exposure for 10 weeks, shunt exposure for 20 weeks and control (sham laparotomy). Echocardiography and magnetic resonance revealed increased right ventricular end diastolic area in shunt at 10 weeks compared to control. Hemodynamic analysis demonstrated increased right ventricular afterload and increased effective pulmonary arterial elastance (Ea) in shunt at 20 weeks compared to control (1.29±0.20 vs. 0.14±0.06 mmHg/µl, p=0.004). At the same time point, the maximal slope of end-systolic pressure-volume relationship (Ees) decreased (0.5±0.2 mmHg/ml vs. 1.2±0.3, p<0.001). Consequently, right ventricular-arterial coupling was markedly deteriorated with a ≈50% decrease in the ratio of end-systolic to pulmonary artery elastance (Ees/Ea). Finally, left ventricular preload diminished (≈30% decrease in left ventricular end-diastolic volume). Histology demonstrated medial hypertrophy and small artery luminal narrowing. Chronic exposure to aorto-caval shunt is a reliable model to produce right ventricular volume overload and secondary pulmonary arterial hypertension. This model could be an alternative with low mortality and high reproducibility for investigators on the underlying mechanisms of shunt-related pulmonary hypertension.

The role of rewarding and novel events in facilitating memory persistence in a separate spatial memory task.

Many insignificant events in our daily life are forgotten quickly but can be remembered for longer when other memory-modulating events occur before or after them. This phenomenon has been investigated in animal models in a protocol in which weak memories persist longer if exploration in a novel context is introduced around the time of memory encoding. This study aims to understand whether other types of rewarding or novel tasks, such as rewarded learning in a T-maze and novel object recognition, can also be effective memory-modulating events. Rats were trained in a delayed matching-to-place task to encode and retrieve food locations in an event arena. Weak encoding with only one food pellet at the sample location induced memory encoding but forgetting over 24 h. When this same weak encoding was followed by a rewarded task in a T-maze, the memory persisted for 24 h. Moreover, the same persistence of memory over 24 h could be achieved by exploration in a novel box or by a rewarded T-maze task after a "non-rewarded" weak encoding. When the one-pellet weak encoding was followed by novel object exploration, the memory did not persist at 24 h. Together, the results confirm that place encoding is possible without explicit reward, and that rewarded learning in a separate task lacking novelty can be an effective memory-modulating event. The behavioral and neurobiological implications are discussed.