Non-state nations: Structure, rescaling, and the role of territorial policy communities, illustrated by the cases of Wales and Sardinia

This paper explores the role of non-state nations’ identity and agency with regard to relations with their host nation states. The particular focus here is on the means by which such regions might express their individuality. To this end, we employ a comparative case study analysis of two non-state nations with a range of differing yet in other ways similar qualities – namely Wales (UK) and Sardinia (Italy). We suggest that this is a valuable exercise, allowing as it does for the exploring of evidence ‘on the ground’ of the processes involved. The conceptual rationale for the paper is provided by new regionalism – regions as actors beyond the nation state. Following this, the idea of the ‘territorial policy community’ is presented as a point of departure, with the scope of the paper being to develop a diachronic framework for regional change. Given the focus on identity and interest articulation, the role of regional political parties is a particular subject of the empirical investigation, with non-state nations and nation states linked by opportunistic relationships based on political and electoral support. We then consider what this might mean with regard to the capacity of non-state nations to build on the past to successfully negotiate future policy-making agendas. Finally, we reflect on the limitations of the study, and consider the implications of its findings for further research agendas

Complement membrane attack and tumorigenesis: a systems biology approach

Tumor development driven by inflammation is now an established phenomenon, but the role that complement plays remains uncertain. Recent evidence has suggested that various components of the complement (C) cascade may influence tumor development in disparate ways; however, little attention has been paid to that of the membrane attack complex (MAC). This is despite abundant evidence documenting the effects of this complex on cell behavior, including cell activation, protection from/induction of apoptosis, release of inflammatory cytokines, growth factors, and ECM components and regulators, and the triggering of the NLRP3 inflammasome. Here we present a novel approach to this issue by using global gene expression studies in conjunction with a systems biology analysis. Using network analysis of MAC-responsive expression changes, we demonstrate a cluster of co-regulated genes known to have impact in the extracellular space and on the supporting stroma and with well characterized tumor-promoting roles. Network analysis highlighted the central role for EGF receptor activation in mediating the observed responses to MAC exposure. Overall, the study sheds light on the mechanisms by which sublytic MAC causes tumor cell responses and exposes a gene expression signature that implicates MAC as a driver of tumor progression. These findings have implications for understanding of the roles of complement and the MAC in tumor development and progression, which in turn will inform future therapeutic strategies in cancer

The sensory dimension of tourist experiences: capturing meaningful sensory-based themes in Southwest Portugal

aspects of destinations have recently been in focus as an important dimension in the process of facilitating positive tourist experiences. The countryside embraces local resources rich in multi-sensory stimuli that could be utilized in the planning and marketing of appealing tourist experiences addressed to segments of tourists, while fitting sustainable local development. This study follows a holistic approach to the five external human senses, aiming to capture meaningful sensory-informed themes adequate for segmenting rural tourists. A self-administered survey in four languages was collected from 181 tourists in Southwest Portugal. A multiple correspondence analysis suggests four sensory-informed themes, tentatively named generic beach-related experience, nature-based experience, balanced experience, and rural experience. The proposed themes correspond to a four-solution cluster of tourists presenting different profiles. The largest segment (73 tourists) corresponds to the rural experience, regarding which tourists mainly refer to the taste of local food and the smell of fresh air

Improving care for people with dementia: development and initial feasibility study for evaluation of life story work in dementia care

Background: Improving dementia care quality is an urgent priority nationally and internationally. Life story work (LSW) is an intervention that aims to improve individual outcomes and care for people with dementia and their carers. LSW gathers information and artefacts about the person, their history and interests, and produces a tangible output: the ‘life story’. Objective: To establish whether or not full evaluation of LSW was feasible. Design: Mixed-methods feasibility study. Methods: In-depth interviews and focus groups explored experiences of LSW and best practice with people with dementia, family members and dementia care staff. A systematic review explored best practice and theories of change for LSW. These stages helped to identify the outcomes and resources to explore in the feasibility study. A representative sample survey of health and social care dementia care providers in England established LSW practice in different settings. A survey of a self-selected sample of family members of people with dementia explored how LSW is experienced. Two small outcome studies (stepped-wedge study in six care homes and pre-test post-test study in inpatient specialist dementia care wards) explored the feasibility of full evaluation of LSW in these settings. Settings: Survey: generalist and specialist care homes; NHS dementia care settings; and community dementia services. Feasibility study: care homes and NHS inpatient dementia care wards. Participants: NHS and social care services, people with dementia, family carers, care home staff and NHS staff. Interventions: LSW. Main outcome measures: Spread of LSW and good practice, quality of life (QoL) for the person with dementia and carers, relationships between people with dementia and family carers, staff attitudes about dementia, staff burnout, resource use and costs. Review methods: Narrative review and synthesis, following Centre for Review and Dissemination guidelines. Results: Good practice in LSW is identifiable, as are theories of change about how it might affect given outcomes. Indicators of best practice were produced. LSW is spreading but practice and use vary between care settings and are not always in line with identified good practice. Two different models of LSW are evident; these are likely to be appropriate at different stages of the dementia journey. The feasibility study showed some positive changes in staff attitudes towards dementia and, for some people with dementia, improvements in QoL. These may be attributable to LSW but these potential benefits require full evaluation. The feasibility work established the likely costs of LSW and highlighted the challenges of future evaluation in care homes and inpatient dementia care settings. Limitations: There was insufficient evidence in the literature to allow estimation of outcome size. We did not carry out planned Markov chain modelling to inform decisions about carrying out future evaluation because of the dearth of outcome data in the literature; low levels of data return for people with dementia in the hospital settings; lack of detected effect for most people with dementia; and questions about implementation in the research settings. Conclusions: LSW is used across different health and social care settings in England, but in different ways, not all of which reflect ‘good practice’. This large, complex study identified a wide range of challenges for future research, but also the possibility that LSW may help to improve care staff attitudes towards dementia and QoL for some people with dementia. Future work: Full evaluation of LSW as an intervention to improve staff attitudes and care is feasible with researchers based in or very close to care settings to ensure high-quality data collection. Funding: The National Institute for Health Research Health Services and Delivery Research programme. Keywords

T-cell regulation in Erythema Nodosum Leprosum.

Leprosy is a disease caused by Mycobacterium leprae where the clinical spectrum correlates with the patient immune response. Erythema Nodosum Leprosum (ENL) is an immune-mediated inflammatory complication, which causes significant morbidity in affected leprosy patients. The underlying cause of ENL is not conclusively known. However, immune-complexes and cell-mediated immunity have been suggested in the pathogenesis of ENL. The aim of this study was to investigate the regulatory T-cells in patients with ENL. Forty-six untreated patients with ENL and 31 non-reactional lepromatous leprosy (LL) patient controls visiting ALERT Hospital, Ethiopia were enrolled to the study. Blood samples were obtained before, during and after prednisolone treatment of ENL cases. Peripheral blood mononuclear cells (PBMCs) were isolated and used for immunophenotyping of regulatory T-cells by flow cytometry. Five markers: CD3, CD4 or CD8, CD25, CD27 and FoxP3 were used to define CD4+ and CD8+ regulatory T-cells. Clinical and histopathological data were obtained as supplementary information. All patients had been followed for 28 weeks. Patients with ENL reactions had a lower percentage of CD4+ regulatory T-cells (1.7%) than LL patient controls (3.8%) at diagnosis of ENL before treatment. After treatment, the percentage of CD4+regulatory T-cells was not significantly different between the two groups. The percentage of CD8+ regulatory T-cells was not significantly different in ENL and LL controls before and after treatment. Furthermore, patients with ENL had higher percentage of CD4+ T-ells and CD4+/CD8+ T-cells ratio than LL patient controls before treatment. The expression of CD25 on CD4+ and CD8+ T-cells was not significantly different in ENL and LL controls suggesting that CD25 expression is not associated with ENL reactions while FoxP3 expression on CD4+ T-cells was significantly lower in patients with ENL than in LL controls. We also found that prednisolone treatment of patients with ENL reactions suppresses CD4+ T-cell but not CD8+ T-cell frequencies. Hence, ENL is associated with lower levels of T regulatory cells and higher CD4+/CD8+ T-cell ratio. We suggest that this loss of regulation is one of the causes of ENL

Cutaneous lesions of the nose

Skin diseases on the nose are seen in a variety of medical disciplines. Dermatologists, otorhinolaryngologists, general practitioners and general plastic and dermatologic surgeons are regularly consulted regarding cutaneous lesions on the nose. This article is the second part of a review series dealing with cutaneous lesions on the head and face, which are frequently seen in daily practice by a dermatologic surgeon. In this review, we focus on those skin diseases on the nose where surgery or laser therapy is considered a possible treatment option or that can be surgically evaluated

Association between age at disease onset of anti-neutrophil cytoplasmic antibody-associated vasculitis and clinical presentation and short-term outcomes

Objectives: ANCA-associated vasculitis (AAV) can affect all age groups. We aimed to show that differences in disease presentation and 6 month outcome between younger- A nd older-onset patients are still incompletely understood. Methods: We included patients enrolled in the Diagnostic and Classification Criteria for Primary Systemic Vasculitis (DCVAS) study between October 2010 and January 2017 with a diagnosis of AAV. We divided the population according to age at diagnosis: <65 years or ≥65 years. We adjusted associations for the type of AAV and the type of ANCA (anti-MPO, anti-PR3 or negative). Results: A total of 1338 patients with AAV were included: 66% had disease onset at <65 years of age [female 50%; mean age 48.4 years (s.d. 12.6)] and 34% had disease onset at ≥65 years [female 54%; mean age 73.6 years (s.d. 6)]. ANCA (MPO) positivity was more frequent in the older group (48% vs 27%; P = 0.001). Younger patients had higher rates of musculoskeletal, cutaneous and ENT manifestations compared with older patients. Systemic, neurologic,cardiovascular involvement and worsening renal function were more frequent in the older-onset group. Damage accrual, measured with the Vasculitis Damage Index (VDI), was significantly higher in older patients, 12% of whom had a 6 month VDI ≥5, compared with 7% of younger patients (P = 0.01). Older age was an independent risk factor for early death within 6 months from diagnosis [hazard ratio 2.06 (95% CI 1.07, 3.97); P = 0.03]. Conclusion: Within 6 months of diagnosis of AAV, patients >65 years of age display a different pattern of organ involvement and an increased risk of significant damage and mortality compared with younger patients

Integrative Structural Model of DNA-PKcs in the Initial Steps of Non-Homologous End Joining

Non-homologous end joining (NHEJ) performs untemplated repair of DNA double strand breaks (DSBs). Despite lack of a template, intricate repair, coordinated by the core NHEJ factors, can repair breaks with minimal to no alterations. Initiating repair, Ku70/80 binds to the free DNA ends, and interacts with the large protein kinase, DNA dependent protein kinase catalytic subunit (DNA-PKcs), forming the holoenzyme DNA-PK. Holoenzymes can synapse across the break to tether the DNA ends. Assembly of the initial synaptic complex and its role in NHEJ is poorly understood, as final ligation requires a structural rearrangement of this initial complex. To better understand DNA-PKcs’ role in NHEJ, an integrative structural model of DNA-PKcs in the initial stages of NHEJ was developed using mass spectrometry (MS) techniques. Due to technical challenges working with DNA-PKcs, each of the MS techniques were optimized for the system. Hydrogen deuterium exchange (HX) methods were optimized on a nano-spray HX system, allowing for differential HX analysis of bead bound DNA-PKcs complexes with high sequence coverage, and 5X improvement in protein consumption. Reversible crosslinking and peptide fingerprinting (RCAP) was optimized to allow for direct detection of DNA binding peptides, using a single sample. Finally, given the benefits of DNA-PKcs complex assembly on beads to limit heterogeneity, an on-bead crosslinking method was developed. Mass Spec Studio was used to accurately identify many crosslinks, which can be utilized for a label free quantitation comparison of states. Using HX-MS to explore DNA-PKcs conformational changes from binding to activation of the kinase, an allosteric pathway was identified in DNA-PKcs connecting DNA-binding with the kinase domain. Nucleotide loading of the kinase domain revealed that DNA-PK occupies a tensed state when active. From integrative structural modelling, with the XL-MS restraints, a model with a precision of 13.5Å was reported, revealing a symmetric DNA-PK dimer, with head-to-head interactions. In our synaptic model, the DNA ends are positioned with a large offset, protected by a previously uncharacterized plug domain of DNA-PKcs. We propose the initial formation of the synaptic complex allows for a hierarchical processing of DNA ends and assembly of a core NHEJ scaffold