The Role of Parvalbumin-positive Interneurons in Auditory Steady-State Response Deficits in Schizophrenia

© The Author(s) 2019. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.Despite an increasing body of evidence demonstrating subcellular alterations in parvalbumin-positive (PV+) interneurons in schizophrenia, their functional consequences remain elusive. Since PV+ interneurons are involved in the generation of fast cortical rhythms, these changes have been hypothesized to contribute to well-established alterations of beta and gamma range oscillations in patients suffering from schizophrenia. However, the precise role of these alterations and the role of different subtypes of PV+ interneurons is still unclear. Here we used a computational model of auditory steady-state response (ASSR) deficits in schizophrenia. We investigated the differential effects of decelerated synaptic dynamics, caused by subcellular alterations at two subtypes of PV+ interneurons: basket cells and chandelier cells. Our simulations suggest that subcellular alterations at basket cell synapses rather than chandelier cell synapses are the main contributor to these deficits. Particularly, basket cells might serve as target for innovative therapeutic interventions aiming at reversing the oscillatory deficits.Peer reviewe

An examination of the temporal and geographical patterns of psychiatric emergency service use by multiple visit patients as a means for their early detection

<p>Abstract</p> <p>Background:</p> <p>Frequent users of the psychiatric emergency service (PES) place a heavy burden upon the mental health care delivery system. The aim of this study was to identify distinct temporal or geographical patterns of PES use by these patients as potential markers for their early detection.</p> <p>Methods:</p> <p>Diagnostic profiles were obtained for patients making an intermediate (4 to 10) or a high (11 or more) number of visits to a general hospital PES in Montreal (Canada) between 1985 and 2004. Between-group comparisons were made with regards to several parameters. These included the time intervals between consecutive visits, visit clustering (single, repeating, and the time interval to the first cluster) and visits made to three other services where data was similarly acquired from 2002 to 2004.</p> <p>Results:</p> <p>The two multiple visit groups differed with regards to diagnostic profiles and actual time between consecutive visits (significantly shorter in patients with 11 or more visits). Patients with 11 or more visits were more likely to have a single cluster (3 or more visits/3 months) or repeating clusters (4 visits/3 months) in their patterns of use. Personality disorders were more prevalent in patients with single clusters as they were, along with schizophrenia, in those with repeating clusters. In addition, clusters were found to occur sufficiently early so as to be potentially useful as markers for early detection. Ten percent of those with 11 or more visits and 16% of those with an intermediate number of visits frequented at least one other PES. A small number of patients, primarily those with substance abuse, made over 50% of their visits to other services.</p> <p>Conclusion:</p> <p>Temporal and geographical patterns of use differed significantly between the multiple visit groups. These patterns, combined with distinct diagnostic profiles, could potentially lead to the more rapid identification and treatment of specific sub-groups of multiple visit patients.</p

The impact of different DNA extraction kits and laboratories upon the assessment of human gut microbiota composition by 16S rRNA gene sequencing

Peer reviewedPublisher PD

The elderly in the psychiatric emergency service (PES); a descriptive study

<p>Abstract</p> <p>Background</p> <p>The impact of an aging population on the psychiatric emergency service (PES) has not been fully ascertained. Cognitive dysfunctions aside, many DSM-IV disorders may have a lower prevalence in the elderly, who appear to be underrepresented in the PES. We therefore attempted to more precisely assess their patterns of PES use and their clinical and demographic characteristics.</p> <p>Methods</p> <p>Close to 30,000 visits to a general hospital PES (Montreal, Quebec, Canada) were acquired between 1990 and 2004 and pooled with over 17,000 visits acquired using the same methodology at three other services in Quebec between 2002 and 2004.</p> <p>Results</p> <p>The median age of PES patients increased over time. However, the proportion of yearly visits attributable to the elderly (compared to those under 65) showed no consistent increase during the observation period. The pattern of return visits (two to three, four to ten, eleven or more) did not differ from that of patients under 65, although the latter made a greater number of total return visits per patient. The elderly were more often women (62%), widowed (28%), came to the PES accompanied (42%) and reported « illness » as an important stressor (29%). About 39% were referred for depression or anxiety. They were less violent (10%) upon their arrival. Affective disorders predominated in the diagnostic profile, they were less co-morbid and more likely admitted than patients under 65.</p> <p>Conclusion</p> <p>Although no proportional increase in PES use over time was found the elderly do possess distinct characteristics potentially useful in PES resource planning so as to better serve this increasingly important segment of the general population.</p

Deficiency of G1 regulators P53, P21Cip1 and/or pRb decreases hepatocyte sensitivity to TGFβ cell cycle arrest

<p>Abstract</p> <p>Background</p> <p>TGFβ is critical to control hepatocyte proliferation by inducing G1-growth arrest through multiple pathways leading to inhibition of E2F transcription activity. The retinoblastoma protein pRb is a key controller of E2F activity and G1/S transition which can be inhibited in viral hepatitis. It is not known whether the impairment of pRb would alter the growth inhibitory potential of TGFβ in disease. We asked how <it>Rb</it>-deficiency would affect responses to TGFβ-induced cell cycle arrest.</p> <p>Results</p> <p>Primary hepatocytes isolated from <it>Rb-floxed </it>mice were infected with an adenovirus expressing CRE-recombinase to delete the <it>Rb </it>gene. In control cells treatment with TGFβ prevented cells to enter S phase via decreased cMYC activity, activation of P16^INK4Aand P21^Cipand reduction of E2F activity. In <it>Rb</it>-null hepatocytes, cMYC activity decreased slightly but P16^INK4Awas not activated and the great majority of cells continued cycling. <it>Rb </it>is therefore central to TGFβ-induced cell cycle arrest in hepatocytes. However some <it>Rb</it>-null hepatocytes remained sensitive to TGFβ-induced cell cycle arrest. As these hepatocytes expressed very high levels of P21^Cip1and P53 we investigated whether these proteins regulate pRb-independent signaling to cell cycle arrest by evaluating the consequences of disruption of <it>p53 </it>and <it>p21</it>^{<it>Cip1</it>}. Hepatocytes deficient in <it>p53 or p21</it>^{<it>Cip1 </it>}showed diminished growth inhibition by TGFβ. Double deficiency had a similar impact showing that in cells containing functional pRb; P21^Cipand P53 work through the same pathway to regulate G1/S in response to TGFβ. In <it>Rb</it>-deficient cells however, <it>p53 </it>but not <it>p21</it>^{<it>Cip </it>}deficiency had an additive effect highlighting a pRb-independent-P53-dependent effector pathway of inhibition of E2F activity.</p> <p>Conclusion</p> <p>The present results show that otherwise genetically normal hepatocytes with disabled <it>p53</it>, <it>p21</it>^{<it>Cip1 </it>}or <it>Rb </it>genes respond less well to the antiproliferative effects of TGFβ. As the function of these critical cellular proteins can be impaired by common causes of chronic liver disease and HCC, including viral hepatitis B and C proteins, we suggest that disruption of pRb function, and to a lesser extend P21^Cip1and P53 in hepatocytes may represent an additional new mechanism of escape from TGFβ-growth-inhibition in the inflammatory milieu of chronic liver disease and contribute to cancer development.</p

Revisiting the Dexamethasone Suppression Test in unipolar major depression: an exploratory study

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An approach to the control of disease transmission in pig-to-human xenotransplantation.

Abstract: Although several major immunologic hurdles need to be overcome, the pig is currently considered the most likely source animal of cells, tissues and organs for transplantation into humans. Concerns have been raised with regard to the potential for the transfer of infectious agents with the transplanted organ to the human recipient. This risk is perceived to be increased as it is likely that the patient will be iatrogenically immunocompromised and the organ-source pig may be genetically engineered in such a way to render its organs particularly susceptible to infection with human viruses. Furthermore, the risk may not be restricted to the recipient, but may have consequences for the health of others in the community. The identification of porcine endogenous retroviruses and of hitherto unknown viruses have given rise to the most concern. We document here the agents we believe should be excluded from the organ-source pigs. We discuss the likelihood of achieving this aim and outline the potential means by which it may best be achieved

Objectively measured physical activity in European adults: cross-sectional findings from the Food4Me study

Background Comparisons of objectively measured physical activity (PA) between residents of European countries measured concurrently with the same protocol are lacking. We aimed to compare PA between the seven European countries involved in the Food4Me Study, using accelerometer data collected remotely via the Internet. Methods Of the 1607 participants recruited, 1287 (539 men and 748 women) provided at least 3 weekdays and 2 weekend days of valid accelerometer data (TracmorD) at baseline and were included in the present analyses. Results Men were significantly more active than women (physical activity level = 1.74 vs. 1.70, p < 0.001). Time spent in light PA and moderate PA differed significantly between countries but only for women. Adherence to the World Health Organization recommendation to accumulate at least 150 min of moderate-equivalent PA weekly was similar between countries for men (range: 54–65%) but differed significantly between countries for women (range: 26–49%). Prevalence estimates decreased substantially for men and women in all seven countries when PA guidelines were defined as achieving 30 min of moderate and vigorous PA per day. Conclusions We were able to obtain valid accelerometer data in real time via the Internet from 80% of participants. Although our estimates are higher compared with data from Sweden, Norway, Portugal and the US, there is room for improvement in PA for all countries involved in the Food4Me Study

Neurotrophic requirements of human motor neurons defined using amplified and purified stem-cell derived cultures

Neurotrophic requirements of human motor neurons defined using amplified and purified stem-cell derived culturesHuman motor neurons derived from embryonic and induced pluripotent stem cells (hESCs and hiPSCs) are a potentially important tool for studying motor neuron survival and pathological cell death. However, their basic survival requirements remain poorly characterized. Here, we sought to optimize a robust survival assay and characterize their response to different neurotrophic factors. First, to increase motor neuron yield, we screened a small-molecule collection and found that the Rho-associated kinase (ROCK) inhibitor Y-27632 enhances motor neuron progenitor proliferation up to 4-fold in hESC and hiPSC cultures. Next, we FACS-purified motor neurons expressing the Hb9::GFP reporter from Y-27632-amplified embryoid bodies and cultured them in the presence of mitotic inhibitors to eliminate dividing progenitors. Survival of these purified motor neurons in the absence of any other cell type was strongly dependent on neurotrophic support. GDNF, BDNF and CNTF all showed potent survival effects (EC(50) 1-2 pM). The number of surviving motor neurons was further enhanced in the presence of forskolin and IBMX, agents that increase endogenous cAMP levels. As a demonstration of the ability of the assay to detect novel neurotrophic agents, Y-27632 itself was found to support human motor neuron survival. Thus, purified human stem cell-derived motor neurons show survival requirements similar to those of primary rodent motor neurons and can be used for rigorous cell-based screening.This work was funded by Project A.L.S., P2ALS and NYSTEM grant number CO24415. The work of N.J.L. was supported by the Portuguese Foundation for Science and Technology SFRH/BD/33421/2008 and the Luso-American Development Foundation. B.J.-K. was supported by the National Institute of Neurological Disorders and Stroke (NINDS). L.R. was supported by the Swedish Brain Foundation/Hjarnfonden. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript