Pituitary adenylate cyclase-activating polypeptide type 1 receptor (PAC1) gene is suppressed by transglutaminase 2 activation

Pituitary adenylate cyclase-activating polypeptide (PACAP) functions as a neuroprotective factor through the PACAP type 1 receptor, PAC1. In a previous work, we demonstrated that nerve growth factor augmented PAC1 gene expression through the activation of Sp1 via the Ras/MAPK pathway. We also observed that PAC1 expression in Neuro2a cells was transiently suppressed during in vitro ischemic conditions, oxygen-glucose deprivation (OGD). Because endoplasmic reticulum (ER) stress is induced by ischemia, we attempted to clarify how ER stress affects the expression of PAC1. Tunicamycin, which induces ER stress, significantly suppressed PAC1 gene expression, and salubrinal, a selective inhibitor of the protein kinase RNA-like endoplasmic reticulum kinase signaling pathway of ER stress, blocked the suppression. In luciferase reporter assay, we found that two Sp1 sites were involved in suppression of PAC1 gene expression due to tunicamycin or OGD. Immunocytochemical staining demonstrated that OGD-induced transglutaminase 2 (TG2) expression was suppressed by salubrinal or cystamine, a TG activity inhibitor. Further, the OGD-induced accumulation of cross-linked Sp1 in nuclei was suppressed by cystamine or salubrinal. Together with cystamine, R283, TG2-specific inhibitor, and siRNA specific for TG2 also ameliorated OGD-induced attenuation of PAC1 gene expression. These results suggest that Sp1 cross-linking might be crucial in negative regulation of PAC1 gene expression due to TG2 in OGD-induced ER stress. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.

The management of stress amongst professional carers within a social services department

This thesis considers four broad areas:(i) ANALYSIS OF THE STRESS FIELD.(a) research studies, relevant to the British Social Services considering the cultural setting, and the rigor with which they were conducted; (b) models of stress, specifically examining the theoretical soundness and practical application of the Medical, Engineering and Transactional models;(c) organisational models of stress relating specifically to human service organisations.(ii) QUALITATIVE AND QUANTITATIVE RESEARCH METHODOLOGIES.(a) the appropriate application of each respective methodology and the particular usefulness of qualitative research designs; (b) the relevance of understanding the language and terminology associated with the subject area prior to the implementation of survey methods; (iii) FIELDWORK.(a) Phase 1. By use of focus groups, in-depth interviews and diary keeping amongst a small range of teams and managers, the Researcher develops a basic conceptual framework of stress within a Social Services context. In addition a small scale personality inventory was administered to participants.(b) Phase 2. This consisted of three key elements: 6 case studies in which the Researcher implements and appraises the impact of a range of intervention strategies designed to assist teams and their managers in dealing more effectively with stress; the administration of a large scale survey to all the field social work teams within the Social Services Department; an analysis of the user role within the stress process by way of two focus groups.(iv) THEORETICAL DEVELOPMENT.

Medicines optimisation for young people with juvenile arthritis and other long-term conditions:system-level barriers to engagement

To explore the views of pharmacy and rheumatology stakeholders about system-related barriers to medicines optimisation activities with young people with long-term conditions. A three-phase consensus-building study comprising (1) focus groups with community and hospital pharmacists; (2) semi-structured telephone interviews with lay and professional adolescent rheumatology stakeholders and pharmacy policymakers, and (3) multidisciplinary discussion groups with community and hospital pharmacists and rheumatology staff. Qualitative verbatim transcripts from phases 1 and 2 were subjected to framework analysis. Themes from phase 1 underpinned a briefing for phase 2 interviewees. Themes from phases 1 and 2 generated elements of good pharmacy practice and current/future pharmacy roles for ranking in phase 3. Results from phase 3 prioritisation and ranking exercises were captured on self-completion data collection forms, entered into an Excel spreadsheet and subjected to descriptive statistical analysis. Institutional ethical approval was given by Aston University Health and Life Sciences Research Ethics Committee. Four focus groups were conducted with 18 pharmacists across England, Scotland and Wales (7 hospital, 10 community and 1 community/public health). Fifteen stakeholders took part in telephone interviews (3 pharmacist commissioners; 2 pharmacist policymakers; 2 pharmacy staff members (1 community and 1 hospital); 4 rheumatologists; 1 specialist nurse, and 3 lay juvenile arthritis advocates). Twenty-five participants took part in three discussion groups in adolescent rheumatology centres across England and Scotland (9 community pharmacists; 4 hospital pharmacists; 6 rheumatologists; 5 specialist nurses, and 1 physiotherapist). In all phases of the study, system-level issues were acknowledged as barriers to more engagement with young people and families. Community pharmacists in the focus groups reported that opportunities for engaging with young people were low if parents collected prescriptions alone, which was agreed by other stakeholders. Moreover, institutional/company prescription collection policies – an activity largely disallowed for a young person under 16 without an accompanying parent - were identified by hospital and community pharmacists as barriers to open discussion and engagement. Few community pharmacists reported using Medicines Use Review (England/Wales) or Chronic Medication Service (Scotland) as a medicines optimisation activity with young people; many were unsure about consent procedures. Despite these limitations, rheumatology stakeholders ranked highly the potential of pharmacists empowering young people with general health care skills, such as repeat prescription ordering. The pharmacy profession lacks vision for its role in the care of young people with long-term conditions. Pharmacists and rheumatology stakeholders identified system-level barriers to more engagement with young people who take medicines regularly. We acknowledge that the modest number of participants may have had a specific interest and thus bias for the topic, but this underscores their frank admission of the challenges. Professional guidance and policy, practice frameworks and institutional/company policies must promote flexibility for pharmacy staff to recognise and empower young people who are able to give consent and take responsibility for medicines activities. This will increase mutual confidence and trust, and foster pharmacy’s role in teaching general health care skills. In this way, pharmacists will be able to build long-term relationships with young people and families.

The association between glycated haemoglobin levels and P100 visual evoked potentials in diabetes mellitus

Diabetes mellitus (DM) is a metabolic disorder which is characterised by hyperglycaemia resulting from defects in insulin secretion, insulin action or both. The long-term specific effects of DM include the development of retinopathy, nephropathy and neuropathy. Cardiac disease, peripheral arterial and cerebrovascular disease are also known to be linked with DM. Type 1 diabetes mellitus (T1DM) accounts for approximately 10% of all individuals with DM, and insulin therapy is the only available treatment. Type 2 diabetes mellitus (T2DM) accounts for 90% of all individuals with DM. Diet, exercise, oral hypoglycaemic agents and occasionally exogenous insulin are used to manage T2DM. The diagnosis of DM is made where the glycated haemoglobin (HbA1c) percentage is greater than 6.5%. Pattern-reversal visual evoked potential (PVEP) testing is an objective means of evaluating impulse conduction along the central nervous pathways. Increased peak time of the visual P100 waveform is an expression of structural damage at the level of myelinated optic nerve fibres. This was an observational cross sectional study. The participants were grouped into two phases. Phase 1, the control group, consisted of 30 healthy non-diabetic participants. Phase 2 comprised of 104 diabetic participants of whom 52 had an HbA1c greater than 10% (poorly controlled DM) and 52 whose HbA1c was 10% and less (moderately controlled DM). The aim of this study was to firstly observe the possible association between glycated haemoglobin levels and P100 peak time of pattern-reversal visual evoked potentials (PVEPs) in DM. Secondly, to assess whether the central nervous system (CNS) and in particular visual function is affected by type and/or duration of DM. The cut-off values to define P100 peak time delay was calculated as the mean P100 peak time plus 2.5 X standard deviations as measured for the non-diabetic control group, and were 110.64 ms for the right eye. The proportion of delayed P100 peak time amounted to 38.5% for both diabetic groups, thus the poorly controlled group (HbA1c > 10%) did not pose an increased risk for delayed P100 peak time, relative to the moderately controlled group (HbA1c ≤ 10%). The P100 PVEP results for this study, do however, reflect significant delay (p < 0.001) of the DM group as compared to the non-diabetic group; thus, subclincal neuropathy of the CNS occurs in 38.5% of cases. The duration of DM and type of DM had no influence on the P100 peak time measurements.