The thalamic reticular nucleus: a functional hub for thalamocortical network dysfunction in schizophrenia and a target for drug discovery

The thalamus (comprising many distinct nuclei) plays a key role in facilitating sensory discrimination and cognitive processes through connections with the cortex. Impaired thalamocortical processing has long been considered to be involved in schizophrenia. In this review we focus on the thalamic reticular nucleus (TRN) providing evidence for it being an important communication hub between the thalamus and cortex and how it may play a key role in the pathophysiology of schizophrenia. We first highlight the functional neuroanatomy, neurotransmitter localisation and physiology of the TRN. We then present evidence of the physiological roles of the TRN in relation to oscillatory activity, cognition and behaviour. Next we discuss the role of the TRN in rodent models of risk factors for schizophrenia (genetic and pharmacological) and provide evidence for TRN deficits in schizophrenia. Finally we discuss new drug targets for schizophrenia in relation to restoring TRN circuitry dysfunction

Schizophrenia in the 21st century : new insights and translation into improved therapies

Over 100 years have elapsed since schizophrenia was first described and over 50 years since chlorpromazine was utilised to alleviate hallucinations and delusions characteristic of the disorder. With the introduction of a swathe of antipsychotic drugs from the 1970s to date, there have been waves of optimism for improvements in the clinical efficacy of these drugs. Unfortunately, these treatments have not fulfilled expectations. As with chlorpromazine, current medications provide relief for the positive symptoms through dopamine D2 receptor antagonism, but have limited impact on the negative symptoms and cognitive deficits. Moreover, potential drug-induced side effects such as motor dysfunction and weight gain are highly undesirable. Lack of understanding of the causes of schizophrenia together with the continued use of dopamine-based preclinical models in drug discovery, with read-outs of limited translational relevance, are arguably key factors in the lack of major breakthroughs for improved treatments

Alterations in functional brain network structure induced by subchronic phencyclidine (PCP) treatment parallel those seen in schizophrenia

Abstract of poster presentation shown at the 2nd Biennial Schizophrenia International Research Conference on Alterations in functional brain network structure induced by subchronic phencyclidine (PCP) treatment parallel those seen in schizophrenia

BDNF and JNK-signalling modulate cortical interneuron and perineuronal net development: implications for schizophrenia-linked 16p11.2 duplication syndrome

Schizophrenia is a neurodevelopmental disorder caused by the interaction of genetic and environmental risk factors. One of the strongest genetic risk variants is duplication of chr.16p11.2. Schizophrenia is characterised by cortical GABAergic interneuron dysfunction, and disruption to surrounding extracellular matrix structures, perineuronal nets (PNNs). Developmental maturation of GABAergic interneurons, and also the resulting closure of the critical period of cortical plasticity, is regulated by brain derived neurotrophic factor (BDNF), although the mechanisms involved are unknown. Here, we show that BDNF promotes GABAergic interneuron and PNN maturation through JNK signalling. In mice reproducing the 16p11.2 duplication, where the JNK upstream activator Taok2 is overexpressed, we find that JNK is overactive and there are developmental abnormalities in PNNs which persist into adulthood. Prefrontal cortex parvalbumin expression is reduced while PNN intensity is increased. Additionally, we report a unique role for TAOK2 signalling in the regulation of parvalbumin interneurons. Our work implicates TAOK2-JNK signalling in cortical interneuron and PNN development, and in the responses to BDNF. It also demonstrates that over-activation of this pathway in conditions associated with schizophrenia risk causes long-lasting disruption in cortical interneurons

Assessing the needs of older people in urban settings : integration of emotive, physiological and built environment data

Design of the built environment for navigability and walkability is an increasingly important aspect of urban planning. This focus derives in part from increasing interest in lifestyles and behaviours including level of physical activity and health outcomes. Geographical Information Systems and virtual realities are playing a significant role in advancing this agenda: examples exist of integrating qualitative data (words about or visual images of places) and quantitative data (numerical descriptions of places). However there remain opportunities for exploring alternative ways of linking different types of data (physiological measurements, emotional response, street walkability and urban design quality) to address issues of urban planning and renewal. Using a case study approach this paper explores the application of geographic information science and systems to participatory approaches in built environment planning with the aim of exploring older people’s response to an unfamiliar urban environment. It examines different ways of combining temporally and spatial referenced qualitative and quantitative data. The participants in the study were a group of 44 older people (60+) from Swansea, Wales, who viewed a filmed walking route around Colchester, England. Whilst viewing the film they gave an oral commentary and physiological readings were made, which have been integrated with primary data collected on the built environment along the walking route. Proximity and inverse distance weighting approaches for combining these datasets produce complementary results in respect of older people’s physiological and emotive response to variation in the walkability and design quality of a walking route through an unfamiliar town centre. The results reveal participants experienced an elevated average heart close to Colchester Town railway station and expressed a comparatively negative emotional response to this location. Conversely participants experienced lower average heart rate, indicating reduced stress, in Brook Street where the overall Urban Design Quality score was relatively low

Galaxy cluster X-ray luminosity scaling relations from a representative local sample (REXCESS)

We examine the X-ray luminosity scaling relations of 31 nearby galaxy clusters from the Representative XMM-Newton Cluster Structure Survey (REXCESS). The objects are selected only in X-ray luminosity, optimally sampling the cluster luminosity function. Temperatures range from 2 to 9 keV, and there is no bias toward any particular morphological type. To reduce measurement scatter we extract pertinent values in an aperture corresponding to R500, estimated using the tight correlation between (the product of gas mass and temperature) and total mass. The data exhibit power law relations between bolometric X-ray luminosity and temperature, and total mass, all with slopes that are significantly steeper than self-similar expectations. We examine the possible causes for the steepening, finding that structural variations have little effect and that the primary driver appears to be a systematic variation of the gas content with mass. Scatter about the relations is dominated in all cases by the presence of cool cores. The natural logarithmic scatter about the raw X-ray luminosity-temperature relation is about 70 per cent, and about the X-ray luminosity- relation it is 40 per?cent. Systems with more morphological substructure show similar scatter about scaling relations than clusters with less substructure, due to the preponderance of cool core systems in the regular cluster subsample. Cool core and morphologically disturbed systems occupy distinct regions in the residual space with respect to the best fitting mean relation, the former lying systematically at the high luminosity side, the latter lying systematically at the low luminosity side. Simple exclusion of the central regions serves to reduce the scatter about the scaling relations by more than a factor of two. The scatter reduces by a similar amount with the use of the central gas density as a third parameter. Using as a total mass proxy, we derive a Malmquist bias-corrected local luminosity-mass relation and compare with other recent determinations. Our results indicate that luminosity can be a reliable mass proxy with controllable scatter, which has important implications for upcoming all-sky cluster surveys, such as those to be undertaken with Planck and eROSITA, and ultimately for the use of the cluster population for cosmological purposes.<br/

Patient and researcher perspectives on facilitating patient and public involvement in rheumatology research

No abstract available

Family-centred care for hospitalised children aged 0-12 years (Review)

This is an update of the Cochrane systematic review of family-centred care published in 2007 (Shields 2007). Family-centred care (FCC) is a widely used model in paediatrics, is thought to be the best way to provide care to children in hospital and is ubiquitous as a way of delivering care. When a child is admitted, the whole family is affected. In giving care, nurses, doctors and others must consider the impact of the child's admission on all family members. However, the effectiveness of family-centred care as a model of care has not been measured systematically. To assess the effects of family-centred models of care for hospitalised children aged from birth (unlike the previous version of the review, this update excludes premature neonates) to 12 years, when compared to standard models of care, on child, family and health service outcomes. In the original review, we searched up until 2004. For this update, we searched: the Cochrane Central Register of Controlled Trials (CENTRAL,The Cochrane Library, Issue 12 2011); MEDLINE (Ovid SP); EMBASE (Ovid SP); PsycINFO (Ovid SP); CINAHL (EBSCO Host); and Sociological Abstracts (CSA). We did not search three that were included in the original review: Social Work Abstracts, the Australian Medical Index and ERIC. We searched EMBASE in this update only and searched from 2004 onwards. There was no limitation by language.\ua0We performed literature searches in May and June 2009 and updated them again in December 2011. We searched for randomised controlled trials (RCTs) including cluster randomised trials in which family-centred care models are compared with standard models of care for hospitalised children (0 to 12 years, but excluding premature neonates). Studies had to meet criteria for family-centredness. In order to assess the degree of family-centredness, we used a modified rating scale based on a validated instrument, (same instrument used in the initial review), however, we decreased the family-centredness score for inclusion from 80% to 50% in this update. We also changed several other selection criteria in this update: eligible study designs are now limited to randomised controlled trials (RCTs) only; single interventions not reflecting a FCC model of care have been excluded; and the selection criterion whereby studies with inadequate or unclear blinding of outcome assessment were excluded from the review has been removed. Two review authors undertook searches, and four authors independently assessed studies against the review criteria, while two were assigned to extract data. We contacted study authors for additional information. Six studies found since 2004 were originally viewed as possible inclusions, but when the family-centred score assessment was tested, only one met the minimum score of family-centredness and was included in this review. This was an unpublished RCT involving 288 children post-tonsillectomy in a care-by-parent unit (CBPU) compared with standard inpatient care.The study used a range of behavioural, economic and physical measures. It showed that children in the CBPU were significantly less likely to receive inadequate care compared with standard inpatient admission, and there were no significant differences for their behavioural outcomes or other physical outcomes. Parents were significantly more satisfied with CBPU care than standard care, assessed both before discharge and at 7 days after discharge. Costs were lower for CPBU care compared with standard inpatient care. No other outcomes were reported. The study was rated as being at low to unclear risk of bias. This update of a review has found limited, moderate-quality evidence that suggests some benefit of a family-centred care intervention for children's clinical care, parental satisfaction, and costs, but this is based on a small dataset and needs confirmation in larger RCTs. There is no evidence of harms. Overall, there continues to be little high-quality quantitative research available about the effects of family-centred care. Further rigorous research on the use of family-centred care as a model for care delivery to children and families in hospitals is needed. This research should implement well-developed family-centred care interventions, ideally in randomised trials. It should investigate diverse participant groups and clinical settings, and should assess a wide range of outcomes for children, parents, staff and health services

The X-ray Properties of Optically Selected Clusters of Galaxies

We present the results of Chandra and Suzaku X-ray observations of nine moderate-redshift (0.16 < z < 0.42) clusters discovered via the Red-sequence Cluster Survey (RCS). Surface brightness profiles are fitted to beta models, gas masses are determined, integrated spectra are extracted within R2500, and X-ray temperatures and luminosities are inferred. The Lx-Tx relationship expected from self-similar evolution is tested by comparing this sample to our previous X-ray investigation of nine high-redshift (0.6 < z < 1.0) optically selected clusters. We find that optically selected clusters are systematically less luminous than X-ray selected clusters of similar X-ray temperature at both moderate and high-z. We are unable to constrain evolution in the Lx-Tx relation with these data, but find it consistent with no evolution, within relatively large uncertainties. To investigate selection effects, we compare the X-ray properties of our sample to those of clusters in the representative X-ray selected REXCESS sample, also determined within R2500. We find that while RCS cluster X-ray properties span the entire range of those of massive clusters selected by other methods, their average X-ray properties are most similar to those of dynamically disturbed X-ray selected clusters. This similarity suggests that the true cluster distribution might contain a higher fraction of disturbed objects than are typically detected in X-ray selected surveys.Comment: 13 pages, 5 figures; accepted for publication in MNRAS. Figure quality reduced to comply with arXiv file size requirement

Star formation and UV colors of the brightest Cluster Galaxies in the representative XMM-Newton Cluster Structure Survey

We present UV broadband photometry and optical emission-line measurements for a sample of 32 Brightest Cluster Galaxies (BCGs) in clusters of the Representative XMM-Newton Cluster Structure Survey (REXCESS) with z = 0.06-0.18. The REXCESS clusters, chosen to study scaling relations in clusters of galaxies, have X-ray measurements of high quality. The trends of star formation and BCG colors with BCG and host properties can be investigated with this sample. The UV photometry comes from the XMM Optical Monitor, supplemented by existing archival GALEX photometry. We detected H\alpha and forbidden line emission in 7 (22%) of these BCGs, in optical spectra. All of the emission-line BCGs occupy clusters classified as cool cores, for an emission-line incidence rate of 70% for BCGs in cool core clusters. Significant correlations between the H\alpha equivalent widths, excess UV production in the BCG, and the presence of dense, X-ray bright intracluster gas with a short cooling time are seen, including the fact that all of the H\alpha emitters inhabit systems with short central cooling times and high central ICM densities. Estimates of the star formation rates based on H\alpha and UV excesses are consistent with each other in these 7 systems, ranging from 0.1-8 solar masses per year. The incidence of emission-line BCGs in the REXCESS sample is intermediate, somewhat lower than in other X-ray selected samples (-35%), and somewhat higher than but statistically consistent with optically selected, slightly lower redshift BCG samples (-10-15%). The UV-optical colors (UVW1-R-4.7\pm0.3) of REXCESS BCGs without strong optical emission lines are consistent with those predicted from templates and observations of ellipticals dominated by old stellar populations. We see no trend in UV-optical colors with optical luminosity, R-K color, X-ray temperature, redshift, or offset between X-ray centroid and X-ray peak ().Comment: 19 pages, 18 figures, 6 tables. Submitted, with minor revisions, to ApJ