Subtle deregulation of the Wnt-signalling pathway through loss of Apc2 reduces the fitness of intestinal stem cells

The importance of the Wnt-signaling pathway on the regulation and maintenance of the intesti- nal stem cell (ISC) population is well recognized. However, our current knowledge base is founded on models using systems of gross deregulation of the Wnt-signaling pathway. Given the importance of this signaling pathway on intestinal homeostasis, there is a need to explore the role of more subtle alterations in Wnt-signaling levels within this tissue. Herein, we have used a model of Apc2 loss to meet this aim. Apc2 is a homolog of Apc which can also form a destruction complex capable of binding b-catenin, albeit less efficiently than Apc. We show that systemic loss of Apc2 results in an increase in the number of cells displaying nuclear b-catenin at the base of the intestinal crypt. This subsequently impacts the expression levels of several ISC markers and the fitness of ISCs as assessed by organoid formation efficiency. This work pro- vides the first evidence that the function and fitness of ISCs can be altered by even minor mis- regulation of the Wnt-signaling pathway. Our data highlights the importance of correct maintenance of this crucial signaling pathway in the maintenance and function of the ISC popu- lation

Coordinated Spindle Assembly and Orientation Requires Clb5p-Dependent Kinase in Budding Yeast

The orientation of the mitotic spindle along a polarity axis is critical in asymmetric cell divisions. In the budding yeast, Saccharomyces cerevisiae, loss of the S-phase B-type cyclin Clb5p under conditions of limited cyclin-dependent kinase activity (cdc28-4 clb5Δ cells) causes a spindle positioning defect that results in an undivided nucleus entering the bud. Based on time-lapse digital imaging microscopy of microtubules labeled with green fluorescent protein fusions to either tubulin or dynein, we observed that the asymmetric behavior of the spindle pole bodies during spindle assembly was lost in the cdc28-4 clb5Δ cells. As soon as a spindle formed, both poles were equally likely to interact with the bud cell cortex. Persistent dynamic interactions with the bud ultimately led to spindle translocation across the bud neck. Thus, the mutant failed to assign one spindle pole body the task of organizing astral microtubules towards the mother cell. Our data suggest that Clb5p-associated kinase is required to confer mother-bound behavior to one pole in order to establish correct spindle polarity. In contrast, B-type cyclins, Clb3p and Clb4p, though partially redundant with Clb5p for an early role in spindle morphogenesis, preferentially promote spindle assembly

A quantitative analysis of the impact of a computerised information system on nurses' clinical practice using a realistic evaluation framework

Objective: To explore nurses' perceptions of the impact on clinical practice of the use of a computerised hospital information system. Design: A realistic evaluation design based on Pawson and Tilley's work has been used across all the phases of the study. This is a theory-driven approach and focuses evaluation on the study of what works, for whom and in what circumstances. These relationships are constructed as context-mechanisms-outcomes (CMO) configurations. Measurements: A questionnaire was distributed to all nurses working in in-patient units of a university hospital in Spain (n = 227). Quantitative data were analysed using SPSS 13.0. Descriptive statistics were used for an overall overview of nurses' perception. Inferential analysis, including both bivariate and multivariate methods (path analysis), was used for cross-tabulation of variables searching for CMO relationships. Results: Nurses (n = 179) participated in the study (78.8% response rate). Overall satisfaction with the IT system was positive. Comparisons with context variables show how nursing units' context had greater influence on perceptions than users' characteristics. Path analysis illustrated that the influence of unit context variables are on outcomes and not on mechanisms. Conclusion: Results from the study looking at subtle variations in users and units provide insight into how important professional culture and working practices could be in IT (information technology) implementation. The socio-technical approach on IT systems evaluation suggested in the recent literature appears to be an adequate theoretical underpinning for IT evaluation research. Realistic evaluation has proven to be an adequate method for IT evaluation. (C) 2009 Elsevier Ireland Ltd. All rights reserved

Involving older people in research: practical considerations when using the authenticity criteria in constructivist inquiry

Aim The purpose of this paper is to identify practical suggestions that could enable other researchers to consider how quality may be evidenced using constructivist principles including the perspectives of older people and their caregivers. Background Constructivism suggests that reality is part of a social construction, which holds different meanings for each person, in which people are active agents, making autonomous decisions. This approach to research has been identified as suitable for health and social care professionals because these underpinning principles reflect the values of these professions, facilitating the involvement of users and carers. The authenticity criteria have been developed to reflect these philosophical principles but have been criticized for their inaccessible language. To incorporate user and carer perspectives, the criteria have been revised into a more accessible model matrix known as the AldreVast Sjuharad criteria. Discussion This paper reports on two constructivist studies that explored relationships between older people, families and staff in different settings – the community and care homes. Examples from both settings demonstrate how the perspectives of users and carers were incorporated throughout the research process. Following the AldreVast Sjuharad model matrix, practical guidance is provided on how the quality of constructivist research may be implemented in nursing research. Conclusions The different settings in this paper influenced how the AldreVast Sjuharad model matrix was applied. Further work is needed in exploring how the perspective of users and carers may be incorporated into the quality process of constructivist research

Head-Up : co-designing novel neck orthosis for neck weakness in MND

Introduction : People with Motor Neurone Disease (MND) often develop weak neck muscles, leading to pain, restricted movement and problems with swallowing, breathing and communication. Ideally, a neck collar would help alleviate these. However, neck collars currently available are of limited use for people with MND and often rejected by patients. The same is true for patients with neck weakness due to other conditions. The Head-Up project is a 2 year study funded by the National Institute for Health Research's Invention for Innovation, or i4i, programme with a budget of £400k. Its principal aim is to develop a novel neck orthosis for neck weakness that supports whilst allowing freedom to move without negatively impacting quality of life. The research is a collaboration between clinicians, engineers, creative designers, patients and carer who will be working closely together is a co-design process. Manufacturers will be brought into this process at a later date. Ethical approval has been granted where necessary for all participatory elements. Methods The co-design process will inherently elicit subjective views. As such, prior to starting this workpackage, it was considered necessary to create a measure for this subjectivity and to give the design team a greater empathetic understanding of the inadequacies of current provision for this user group. This has been achieved by a combined clinical comfort assessment and engineering simulation. An engineering simulation of the head, neck and upper torso has been developed using Finite Element Analysis. This has been called the Neck Assessment Tool (NAT). Real body geometry was obtained via a 3D laser scan. The neck has been modelled without any structural integrity such that the head will drop without support. The body model has been meshed and constrained to represent this scenario. The geometry of different neck collar models were created in separate files and meshed. Individually they are imported into the body model, appropriate contact conditions applied and the model is processed. Each model tells the researchers where there is contact between body and collar and, relatively, the pressure of that contact. A clinical comfort assessment pilot study has been conducted using the design team members. This is based on location mapping from the McGill pain questionnaire and a Visual Analogue Scale. 5 different neck collars were identified based on common usage and distinct design differences. The members of the research team wore each collar for a day with recovery periods between. During each test period the participants recorded locations of pain/discomfort and perceptions of relative associated scales. They recorded other data relating to emotional reactions caused by the collars, impact on specific Activities of Daily Living (ADL's) and aesthetic considerations. Results The NAT has been conducted on 2 collars and the comfort assessment on 5, 2 of which are those tested in NAT. Comparisons between the comfort assessment and NAT demonstrate acceptable correlation, validating the simulation. The comfort assessment participant reporting forms have been refined and recruitment is under way to roll out to a wider population of health volunteers and use with MND volunteers to report about experiences of their specific collars as and when used. The design team reported significant differences in their perceptions of neck collars before and after the comfort assessment that will positively impact the co-design process. References 1. Ambrogio N et al, 'A Comparison of Three Types of Neck Support in Fibromyalgia Patients', Arthritis Care and Research (1998), v11, n5, pp 405-410 2. Bowen SJ, Chamberlain PM, 'Engaging the Ageing: Designing Artefacts to Provoke Dialogue', Designing Inclusive Futures (2008) Part I, 35-44, DOI: 10.1007/978-1-84800-211-1_4 3. Carlsson AM, 'Assessment of chronic pain. I. Aspects of the reliability and validity of the visual analogue scale', Pain (1983) v16, n1, pp 87–101 4. Escalante A, Lichtenstein MJ, Lawrence VA, Roberson M, Hazuda HP, ' Where does it hurt? Stability of recordings of pain location using the McGill Pain Map', The Journal of Rheumatology (1996) v23, n10, pp 1788-93 5. Huges TJR, 'The Finite Element Method: Linear Static and Dynamic Finite Element Analysis', Inform (2000), v682, n2, p 682, Publisher: Dover Publications, ISSN: 00457825, ISBN: 0486411818 6. Latimer N, Dixon S, Mcdermott C, Shaw P, McCarthy A, Tindale W, Heron N, 'Modelling the cost effectiveness of potential new neck collar for patients with motor neurone disease', http://www.sheffield.ac.uk/scharr/sections/heds/dps-2011 7. Miller RG et al, ' Practice Parameter update: The care of the patient with amyotrophic lateral sclerosis: Multidisciplinary care, symptom management and cognitive/behavioural impairment(an evidence based review)', Neurology (2009), v73, pp 1218-1225 8. Motor Neurone Disease Association, 'Head Supports', www.mndassociation.org/documents.rm?id=28 9. Thumbikat P, Bailey C and Datta D, 'Orthoses for neck control', ACNR (2006) v6, pp 18-19 10. Qing Hang Zhanga, Ee Chon Teoa, Hong Wan Nga, Vee Sin Lee, 'Finite element analysis of moment-rotation relationships for human cervical spine', Journal of Biomechanics (2006), v39, n1, pp1 89–19

Virtual placements to develop employability skills for civil and environmental engineering students

This project work addresses the crucial need to encourage undergraduate civil and environmental engineering students to gain employment skills and training right from the start of their studies so that their overall employability increases; their confidence level in networking with industry and within the workplace increases; and so that they are successfully able to obtain employment after finishing their studies. This initiative is a stepping-stone employability exercise which focuses specifically on first year students to help them engage with industry right from the start of their course. It is proposed that they would gain some realistic work experience both individually and as part of group within a virtual work environment using an action learning approach. The virtual environment used was based on SecondLife, a popular virtual reality programme. A pilot scheme was set up and run at Brunel University during the summer of 2014 using eight self-selecting first year students. The scheme’s outputs were extensively monitored and evaluated to assess its impact on the development of employability skills. This approach may prove a cost effective way of letting students gain an insight into the workplace whilst improving these skills. It may also prove a way for employers to select from a large range of students the best to actually undertake their real work-based internships

PPARδ status and mismatch repair mediated neoplasia in the mouse intestine

BACKGROUND: Therapeutic regulation of PPARδ activity using selective agonists has been proposed for various disorders. However, the consequences of altered peroxisome proliferator-activated receptor delta (PPARδ) activity in the context of intestinal tumourigenesis remain somewhat unclear. Contradictory evidence suggesting PPARδ either attenuates or potentiates intestinal neoplasia. To further investigate the PPARδ dependency of intestinal tumourigenesis, we have analysed the consequences of PPARδ deficiency upon intestinal neoplasia occurring in mice with impaired mismatch DNA repair. METHODS: Mice deficient for both PPARδ and the mismatch repair gene Mlh1 were produced and the incidence and severity of intestinal neoplasia recorded. RESULTS: No significant differences between the control genotypes and the double mutant genotypes were recorded indicating that deficiency of PPARδ does not modify impaired mismatch repair induced neoplasia. CONCLUSION: In contrast with the previously observed acceleration of intestinal neoplasia in the context of the Apc(Min/+ )mouse, PPARδ deficiency does not alter the phenotype of mismatch repair deficiency. This data supports the notion that PPARδ is not required for adenoma formation and indicate that any pro-tumourigenic effect of PPARδ inactivation may be highly context dependent