Evaluation of LMP1 of Epstein-Barr virus as a therapeutic target by its inhibition

BACKGROUND:The latent membrane protein-1 (LMP1) encoded by Epstein-Barr virus (EBV) is an oncoprotein which acts by constitutive activation of various signalling pathways, including NF-kappaB. In so doing it leads to deregulated cell growth intrinsic to the cancer cell as well as having extrinsic affects upon the tumour microenvironment. These properties and that it is a foreign antigen, lead to the proposition that LMP1 may be a good therapeutic target in the treatment of EBV associated disease. LMP1 is expressed in several EBV-associated malignancies, notably in Hodgkin's lymphoma and nasopharyngeal carcinoma (NPC). However, the viral protein is only detected in approximately 30%-50% of NPC samples, as such its role in carcinogenesis and tumour maintenance can be questioned and thus its relevance as a therapeutic target.RESULTS:In order to explore if LMP1 has a continuous function in established tumours, its activity was inhibited through expression of a dominant negative LMP1 mutant in tumour cell lines derived from transgenic mice. LMP1 is the tumour predisposing oncogene in two different series of transgenic mice which separately give rise to either B-cell lymphomas or carcinomas. Inhibition of LMP1 activity in the carcinoma cell lines lead to a reduction in clonagenicity and clone viability in all of the cell lines tested, even those with low or below detection levels of LMP1. Inhibition of LMP1 activity in the transgenic B-cell lines was incompatible with growth and survival of the cells and no clones expressing the dominant negative LMP1 mutant could be established.CONCLUSIONS:LMP1 continues to provide a tumour cell growth function in cell lines established from LMP1 transgenic mouse tumours, of both B-cell and epithelial cell origin. LMP1 can perform this function, even when expressed at such low levels as to be undetectable, whereby evidence of its expression can only be inferred by its inhibition being detrimental to the growth of the cell. This raises the possibility that LMP1 still performs a pro-oncogenic function in the 50% to 70% of NPC tumours wherein LMP1 protein expression cannot be detected. This reinforces the basis for pursuing LMP1 as a therapeutic target in EBV associated LMP1-expressing malignancie

Traditions of research in community mental health care planning and care coordination: A systematic meta-narrative review of the literature

Context: In response to political and social factors over the last sixty years mental health systems internationally have endeavoured to transfer the delivery of care from hospitals into community settings. As a result, there has been increased emphasis on the need for better quality care planning and care coordination between hospital services, community services and patients and their informal carers. The aim of this systematic review of international research is to explore which interventions have proved more or less effective in promoting personalized, recovery oriented care planning and coordination for community mental health service users. Methods: A systematic meta-narrative review of research from 1990 to the present was undertaken. From an initial return of 3940 papers a total of 50 research articles fulfilled the inclusion criteria, including research from the UK, Australia and the USA. Findings: Three research traditions are identified consisting of (a) research that evaluates the effects of government policies on the organization, management and delivery of services; (b) evaluations of attempts to improve organizational and service delivery efficiency; (c) service-users and carers experiences of community mental health care coordination and planning and their involvement in research. The review found no seminal papers in terms of high citation rates, or papers that were consistently cited over time. The traditions of research in this topic area have formed reactively in response to frequent and often unpredictable policy changes, rather than proactively as a result of intrinsic academic or intellectual activity. This may explain the absence of seminal literature within the subject field. As a result, the research tradition within this specific area of mental health service delivery has a relatively short history, with no one dominant researcher or researchers, tradition or seminal studies amongst or across the three traditions identified. Conclusions: The research findings reviewed suggests a gap has existed internationally over several decades between policy aspirations and service level interventions aimed at improving personalised care planning and coordination and the realities of everyday practices and experiences of service users and carers. Substantial barriers to involvement are created through poor information exchange and insufficient opportunities for care negotiation

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Care Coordination as Imagined, Care Coordination as Done: Findings from a Cross-national Mental Health Systems Study

Introduction Care coordination is intended to ensure needs are met and integrated services are provided. Formalised processes for the coordination of mental health care arrived in the UK with the introduction of the care programme approach in the early 1990s. Since then the care coordinator role has become a central one within mental health systems. Theory and methods This paper contrasts care coordination as work that is imagined with care coordination as work that is done. This is achieved via a critical review of policy followed by a qualitative analysis of interviews, focusing on day-to-day work, conducted with 28 care coordinators employed in four NHS organisations in England and two in Wales. Findings Care coordination is imagined as a vehicle for the provision of collaborative, recovery-focused, care. Those who practise care coordination are concerned with the quality of their relationships with service users and the tailoring of services, but limits exist to collaboration and open discussion. Care coordinators describe doing necessary work connecting people and the system of care. However, this work also brings significant administrative demands, is subject to performance management which distorts its primary purpose, and in a context of scarce resources promotes generic professional roles. Conclusion Care coordination must be done. However, it is not consistently being done in the way policymakers imagine, and in the real world of work can be done differently

Shifting Perspectives: How Scrutiny Shapes the Relationship Between CEO Gender and Acquisition Activity

Research Summary: Several upper echelons studies have found that firms led by female executives are less likely to engage in risky endeavors than those led by male top executives. We argue that conceptualizing female CEOs as universally conservative decision-makers may paint too simplistic a picture and that the impact of CEO gender on strategic decision-making may vary significantly depending on the given situation CEOs are experiencing. We integrate executive job demands and gender research to propose that scrutiny will exhibit differential effects on female and male CEOs\u27 acquisition activity. We show that in high-scrutiny contexts, the difference between male and female CEO acquisition activity disappears. In contrast, in low-scrutiny contexts, the difference between male and female CEOs\u27 acquisition activity is exaggerated. Managerial Summary: Substantial research has shown that female executives acquire at a lower rate than male executives. We argue that viewing female CEOs as universally conservative decision-makers may paint too simplistic a picture and that the impact of CEO gender on strategic decision-making may vary significantly depending on the given situation CEOs are experiencing. In particular, we argue and find that in high-scrutiny contexts, the difference between male and female CEO acquisition activity disappears. This research suggests that managers should consider the impact of environmental context—especially the role of scrutiny—when considering the risk propensity of female leaders

What do we know about the risks for young people moving into, through and out of inpatient mental health care? Findings from an evidence synthesis.

Background Young people with complex or severe mental health needs sometimes require care and treatment in inpatient settings. There are risks for young people in this care context, and this study addressed the question: ‘What is known about the identification, assessment and management of risk in young people (aged 11–18) with complex mental health needs entering, using and exiting inpatient child and adolescent mental health services in the UK?’ Methods In phase 1 a scoping search of two electronic databases (MEDLINE and PsychINFO) was undertaken. Items included were themed and presented to members of a stakeholder advisory group, who were asked to help prioritise the focus for phase 2. In phase 2, 17 electronic databases (EconLit; ASSIA; BNI; Cochrane Library; CINAHL; ERIC; EMBASE; HMIC; MEDLINE; PsycINFO; Scopus; Social Care Online; Social Services Abstracts; Sociological Abstracts; OpenGrey; TRiP; and Web of Science) were searched. Websites were explored and a call for evidence was circulated to locate items related to the risks to young people in mental health hospitals relating to ‘dislocation’ and ‘contagion’. All types of evidence including research, policies and service and practice responses relating to outcomes, views and experiences, costs and cost-effectiveness were considered. Materials identified were narratively synthesised. Results In phase 1, 4539 citations were found and 124 items included. Most were concerned with clinical risks. In phase 2, 15,662 citations were found, and 40 addressing the risks of ‘dislocation’ and ‘contagion’ were included supplemented by 20 policy and guidance documents. The quality of studies varied. Materials were synthesised using the categories: Dislocation: Normal Life; Dislocation: Identity; Dislocation: Friends; Dislocation: Stigma; Dislocation: Education; Dislocation: Families; and Contagion. No studies included an economic analysis. Although we found evidence of consideration of risk to young people in these areas we found little evidence to improve practice and services. Conclusions The importance to stakeholders of the risks of ‘dislocation’ and ‘contagion’ contrasted with the limited quantity and quality of evidence to inform policy, services and practice. The risks of dislocation and contagion are important, but new research is needed to inform how staff might identify, assess and manage them

Observations on the Avian Inventory

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Recovery-focused mental health care planning and co-ordination in acute inpatient mental health settings: a cross national comparative mixed methods study

BACKGROUND: Involving mental health service users in planning and reviewing their care can help personalised care focused on recovery, with the aim of developing goals specific to the individual and designed to maximise achievements and social integration. We aimed to ascertain the views of service users, carers and staff in acute inpatient wards on factors that facilitated or acted as barriers to collaborative, recovery-focused care. METHODS: A cross-national comparative mixed-methods study involving 19 mental health wards in six service provider sites in England and Wales. This included a survey using established standardised measures of service users (n = 301) and staff (n = 290) and embedded case studies involving interviews with staff, service users and carers (n = 76). Quantitative and qualitative data were analysed within and across sites using descriptive and inferential statistics, and framework method. RESULTS: For service users, when recovery-oriented focus was high, the quality of care was rated highly, as was the quality of therapeutic relationships. For staff, there was a moderate correlation between recovery orientation and quality of therapeutic relationships, with considerable variability. Staff members rated the quality of therapeutic relationships higher than service users did. Staff accounts of routine collaboration contrasted with a more mixed picture in service user accounts. Definitions and understandings of recovery varied, as did views of hospital care in promoting recovery. Managing risk was a central issue for staff, and service users were aware of measures taken to keep them safe, although their involvement in discussions was less apparent. CONCLUSIONS: There is positive practice within acute inpatient wards, with evidence of commitment to safe, respectful, compassionate care. Recovery ideas were evident but there remained ambivalence on their relevance to inpatient care. Service users were aware of efforts taken to keep them safe, but despite measures described by staff, they did not feel routinely involved in care planning or risk management decisions. Research on increasing therapeutic contact time, shared decision making in risk assessment and using recovery focused tools could further promote personalised and recovery-focused care planning. This paper arises from a larger study published by National Institute for Health Research (Simpson A, et al, Health Serv Deliv Res 5(26), 2017)

Analysis of ozone and nitric acid in spring and summer Arctic pollution using aircraft, ground-based, satellite observations and MOZART-4 model: source attribution and partitioning

In this paper, we analyze tropospheric O_3 together with HNO_3 during the POLARCAT (Polar Study using Aircraft, Remote Sensing, Surface Measurements and Models, of Climate, Chemistry, Aerosols, and Transport) program, combining observations and model results. Aircraft observations from the NASA ARCTAS (Arctic Research of the Composition of the Troposphere from Aircraft and Satellites) and NOAA ARCPAC (Aerosol, Radiation and Cloud Processes affecting Arctic Climate) campaigns during spring and summer of 2008 are used together with the Model for Ozone and Related Chemical Tracers, version 4 (MOZART-4) to assist in the interpretation of the observations in terms of the source attribution and transport of O_3 and HNO_3 into the Arctic (north of 60° N). The MOZART-4 simulations reproduce the aircraft observations generally well (within 15%), but some discrepancies in the model are identified and discussed. The observed correlation of O_3 with HNO_3 is exploited to evaluate the MOZART-4 model performance for different air mass types (fresh plumes, free troposphere and stratospheric-contaminated air masses). Based on model simulations of O_3 and HNO_3 tagged by source type and region, we find that the anthropogenic pollution from the Northern Hemisphere is the dominant source of O3 and HNO3 in the Arctic at pressures greater than 400 hPa, and that the stratospheric influence is the principal contribution at pressures less 400 hPa. During the summer, intense Russian fire emissions contribute some amount to the tropospheric columns of both gases over the American sector of the Arctic. North American fire emissions (California and Canada) also show an important impact on tropospheric ozone in the Arctic boundary layer. Additional analysis of tropospheric O_3 measurements from ground-based FTIR and from the IASI satellite sounder made at the Eureka (Canada) and Thule (Greenland) polar sites during POLARCAT has been performed using the tagged contributions. It demonstrates the capability of these instruments for observing pollution at northern high latitudes. Differences between contributions from the sources to the tropospheric columns as measured by FTIR and IASI are discussed in terms of vertical sensitivity associated with these instruments. The first analysis of O_3 tropospheric columns observed by the IASI satellite instrument over the Arctic is also provided. Despite its limited vertical sensitivity in the lowermost atmospheric layers, we demonstrate that IASI is capable of detecting low-altitude pollution transported into the Arctic with some limitations