Expression and regulation of VCAM-1 and CD44 by cultured fibroblast-like synoviocytes.

The fibroblast-like synoviocyte (FLS) has been implicated in the destructive process associated with rheumatoid arthritis. In this thesis I demonstrate the expression and regulation of several adhesion molecules expressed on cultured FLSs obtained from inflamed synovium. Unlike fibroblasts from other areas of the body, FLSs constitutively express vascular cell adhesion molecule-1 (VCAM-1). VCAM-1 on RA FLSs is constitutively expressed at high levels during the first 2 weeks of culture. At later time points (4 weeks in culture), VCAM-1 expression declined to low basal levels. A number of strategies were employed to determine the exogenous factors that determine the initially high levels of VCAM-1 in FLSs. Of the extracellular matrix components examined only collagen type I enhanced VCAM-1 expression but this had only limited success. The pro-inflammatory cytokines, IL-1β (10 ng/ml) and TNF-α (10 ng/ml), were also tested and found to induce only transient increases in cell surface VCAM-1 expression. However, the chronic administration of IL-4 or IL-13 in combination with TNF-α resulted in elevated levels of VCAM-1 with prolonged expression Prolonged VCAM-1 expression was found to result in part from the capacity of IL-4 and IL-13 to stabilize VCAM-1 mRNA transcripts. CD44 splice variants, isoforms of the CD44 receptor, that are implicated in the progression of a number of human tumours were also expressed by FLSs isolated from inflamed synovium. Immunohistochemistry, flow cytometry and RT-PCR analysis of CD44 splice variant expression revealed differential expression of a number of variant isoforms. Splice variant expression, at both the mRNA and cell surface protein level, was observed in a large percentage of RA FLSs, it is variable in those from OA synovium, and is absent in cells isolated from non-inflamed joints. However, RA FLSs showed a greater intensity of staining for variants v3, v5 and v7/8. VCAM-1-positive FLSs also demonstrated complex splice variant mRNA transcripts, comprising v3, v6, v7, v8, v9 and v10 in a variety of splicing combinations. These results indicate that the nature of CD44-splice variant expression is closely linked to the inflammatory state of the synovial joint. Moreover, expression of the CD44v7/8 epitope is associated with an increased cellular proliferation rate and could thus be functionally implicated in the hyperplasia observed in RA synovium

The uneven impact of recession on the voluntary and community sectors:Bristol and Liverpool

There has been much debate about the impact of recession and austerity on the voluntary and community sector over recent years. Using secondary data from the 2008 National Survey of Third Sector Organisations, Clifford et al. (2013), writing in this journal, have argued that voluntary sector organisations located in more deprived local authorities are likely to suffer most due to the combined effect of cuts in government funding in these areas and their greater dependency on statutory funding. This paper develops this argument by exploring the sector’s changing relationship with the state through an empirical analysis of the differential impact of recession and austerity on voluntary and community organisations involved in public service delivery in the two English core cities of Bristol and Liverpool. This paper highlights how the scale and unevenness of public spending cuts, the levels of voluntary sector dependency on statutory funding and the rising demands for the sector’s services in a period of recession and austerity are being experienced locally. It portrays a sector whose resilience is being severely tested and one that is being forced rapidly to restructure and reposition itself in an increasingly challenging funding environment. </jats:p

Obstacle avoidance in social groups: : new insights from asynchronous models

For moving animals, the successful avoidance of hazardous obstacles is an important capability. Despite this, few models of collective motion have addressed the relationship between behavioural and social features and obstacle avoidance. We develop an asynchronous individual-based model for social movement which allows social structure within groups to be included. We assess the dynamics of group navigation and resulting collision risk in the context of information transfer through the system. In agreement with previous work, we find that group size has a nonlinear effect on collision risk. We implement examples of possible network structures to explore the impact social preferences have on collision risk. We show that any social heterogeneity induces greater obstacle avoidance with further improvements corresponding to groups containing fewer influential individuals. The model provides a platform for both further theoretical investigation and practical application. In particular, we argue that the role of social structures within bird flocks may have an important role to play in assessing the risk of collisions with wind turbines, but that new methods of data analysis are needed to identify these social structures

Notes

Notes and Letters Notes Thiepval Ridge and Minas Tirith. Proposes a specific source for certain imagery associated with the Battle of the Pelennor Fields in Tolkien’s The Lord of the Rings. By Nancy Martsch . In Memoriam: Terry Pratchett in Mythlore. A listing of Terry Pratchett’s appearances in Mythlore as the subject of articles. By Janet Brennan Croft . In Memoriam: Tom Loback in Mythlore. A listing of artist Tom Loback’s appearances in Mythlore as illustrator or author. By Janet Brennan Croft and Edith Crowe . Letters Corrects and expands on items in his Mythcon Guest of Honor speech (“Where Fantasy Fits”) printed in Mythlore 33.1 (#125). By Richard Wes

Trinidadian guppies use a social heuristic that can support cooperation among non-kin

This is the author accepted manuscript. The final version is available from the Royal Society via the DOI in this recordThe dataset associated with this article is available in ORE at: http://hdl.handle.net/10871/18463Cooperation among non-kin is well documented in humans and widespread in non-human animals, but explaining the occurrence of cooperation in the absence of inclusive fitness benefits has proven a significant challenge. Current theoretical explanations converge on a single point: co-operators can prevail when they cluster in social space. However, we know very little about the real-world mechanisms that drive such clustering, particularly in systems where cognitive limitations make it unlikely that mechanisms such as score keeping and reputation are at play. Here we show that Trinidadian guppies (Poecilia reticulata) use a ‘Walk Away’ strategy, a simple social heuristic by which assortment by cooperativeness can come about among mobile agents. Guppies cooperate during predator inspection and we found that when experiencing defection in this context, individuals prefer to move to a new social environment, despite having no prior information about this new social group. Our results provide evidence in non-human animals that individuals use a simple social partner updating strategy in response to defection, supporting theoretical work applying heuristics to understanding the proximate mechanisms underpinning the evolution of cooperation among non-kin.Leverhulme TrustDanish Research Council for Nature and UniverseCarlsberg Foundatio

The capacity of health service commissioners to use evidence: a case study

Clinical Commissioning Groups (CCGs) lead a network of organisations that plan and make decisions about what services to provide through the NHS. By examining decision-making about service interventions designed to reduce potentially avoidable elderly care admissions into acute hospitals, our study explores the capacity of CCG-led commissioning networks to make decisions that are based on evidence. Empirically, we study 13 cases of representative (region, size, urban/rural) commissioning networks in England, drawing on interviews with commissioning managers, general practitioners (GPs), patient and public involvement (PPI) representatives and other relevant stakeholders. CCGs can not only draw on evidence about what is most clinically effective or cost-effective, but can also consider patient experience and local knowledge held by doctors. However, the inclusion of GPs and PPI representatives is limited, so the local knowledge of doctors and the patient experience are not considered as fully as they might be in commissioning decisions. CCGs can use government agencies, such as commissioning support units, that provide external information about local population and existing service provision, but they fail to do so adequately. The voluntary sector can play a key role in providing local knowledge about individual patients and their needs. Finally, given the need for health and social care organisations to collaborate to support older people so that they do not experience potentially avoidable admissions to acute hospitals, there is a need for organisations to develop joint evidence-based strategies and work together in real time to exchange information. From our research, in collaboration with a PPI reference group, a self-assessment questionnaire for CCG-led commissioning networks was developed, which allows CCGs to assess and develop their capacity to acquire and use different types of evidence in their decision-making.questionnaire for CCG-led commissioning networks was developed, which allows CCGs to assess and develop their capacity to acquire and use different types of evidence in their decision-making