An investigation into dystroglycan deficiency in fibroblasts and a role for dystroglycan in cytokinesis

Dystroglycan is a heterodimeric cell adhesion molecule consisting of alpha and beta subunits, which links the actin cytoskeleton to the extracellular matrix. Dystroglycan has an important structural role and is integral for maintaining tissue integrity, but new avenues have research have implicated it in other roles within the cell due to its ability to bind a number of interacting proteins including cytoskeletal components and proteins involved in signal transduction. To elucidate the functions of dystroglycan at the cellular level, fibroblasts were differentiated from dystroglycan null embryonic stem cells. Analysis of these cells by western blot, however, showed them to be expressing dystroglycan and this was confirmed by RT-PCR, genomic PCR and northern blot. Subsequently, Swiss 3T3 fibroblasts with greater than 60% reduction in dystroglycan expression were generated by stable retroviral infection of a shRNA construct. Dystroglycan deficient cells were smaller and were found to have a reduction in cell-substrate adhesions, when compared to a control cell line. Dystroglycan deficiency did not affect cell motility or polarity in fibroblasts, but did result in a reduction in the rate of cell proliferation, which was thought to be the consequence of an increase in apoptosis. Dystroglycan deficiency also inhibited the formation of filopodia and lamellipodia in response to dominant active Cdc42 or Rac1 respectively, suggesting that it an important mediator of Rho GTPase-mediated cytoskeletal rearrangements. This study has also identified a possible new function for dystroglycan during cytokinesis. Endogenous dystroglycan was localised to the cleavage furrow and midbody of dividing fibroblasts, where it was found to co-localise with the ERM family member, ezrin. Expression of mutated and truncated dystroglycan-GFP constructs in dividing HeLa cells revealed that the cytoplasmic domain is required for cleavage furrow localisation, but ezrin-binding is not. A model for dystroglycan function at the cleavage furrow is presented whereby dystroglycan recruits ezrin to the site of furrow ingression and together they serve to tether the actomyosin contractile ring to the plasma membrane during cytokinesis. These findings provide further insight into the multifaceted functions of dystroglycan within the cell and also raised interesting questions about possible new roles for dystroglycan

The Public Interest: A Matter of Discretion?

15 pages

Current incentives for scientists lead to underpowered studies with erroneous conclusions

We can regard the wider incentive structures that operate across science, such as the priority given to novel findings, as an ecosystem within which scientists strive to maximise their fitness (i.e., publication record and career success). Here, we develop an optimality model that predicts the most rational research strategy, in terms of the proportion of research effort spent on seeking novel results rather than on confirmatory studies, and the amount of research effort per exploratory study. We show that, for parameter values derived from the scientific literature, researchers acting to maximise their fitness should spend most of their effort seeking novel results and conduct small studies that have only 10%-40% statistical power. As a result, half of the studies they publish will report erroneous conclusions. Current incentive structures are in conflict with maximising the scientific value of research; we suggest ways that the scientific ecosystem could be improved

Study protocol: Delayed intervention randomised controlled trial within the Medical Research Council (MRC) Framework to assess the effectiveness of a new palliative care service

Background: Palliative care has been proposed to help meet the needs of patients who suffer progressive non-cancer conditions but there have been few evaluations of service development initiatives. We report here a novel protocol for the evaluation of a new palliative care service in this context. Methods/Design: Using the MRC Framework for the Evaluation of Complex Interventions we modelled a new palliative care and neurology service for patients severely affected by Multiple Sclerosis (MS). We conducted qualitative interviews with patients, families and staff, plus a literature review to model and pilot the service. Then we designed a delayed intervention randomised controlled trial to test its effectiveness as part of phase II of the MRC framework. Inclusion criteria for the trial were patients identified by referring clinicians as having unresolved symptoms or psychological concerns. Referrers were advised to use a score of greater than 8 on the Expanded Disability Scale was a benchmark. Consenting patients newly referred to the new service were randomised to either receive the palliative care service immediately (fast-track) or after a 12-week wait (standard best practice). Face to face interviews were conducted at baseline (before intervention), and at 4–6, 10–12 (before intervention for the standard-practice group), 16– 18 and 22–24 weeks with patients and their carers using standard questionnaires to assess symptoms, palliative care outcomes, function, service use and open comments. Ethics committee approval was granted separately for the qualitative phase and then for the trial. Discussion: We publish the protocol trial here, to allow methods to be reviewed in advance of publication of the results. The MRC Framework for the Evaluation of Complex Interventions was helpful in both the design of the service, methods for evaluation in convincing staff and the ethics committee to accept the trial. The research will provide valuable information on the effects of palliative care among non-cancer patients and a method to evaluate palliative care in this context

Symptoms and quality of life in late stage Parkinson syndromes: a longitudinal community study of predictive factors

BACKGROUND Palliative care is increasingly offered earlier in the cancer trajectory but rarely in Idiopathic Parkinson's Disease(IPD), Progressive Supranuclear Palsy(PSP) or Multiple System Atrophy(MSA). There is little longitudinal data of people with late stage disease to understand levels of need. We aimed to determine how symptoms and quality of life of these patients change over time; and what demographic and clinical factors predicted changes. METHODS We recruited 82 patients into a longitudinal study, consenting patients with a diagnosis of IPD, MSA or PSP, stages 3-5 Hoehn and Yahr(H&Y). At baseline and then on up to 3 occasions over one year, we collected self-reported demographic, clinical, symptom, palliative and quality of life data, using Parkinson's specific and generic validated scales, including the Palliative care Outcome Scale (POS). We tested for predictors using multivariable analysis, adjusting for confounders. FINDINGS Over two thirds of patients had severe disability, over one third being wheelchair-bound/bedridden. Symptoms were highly prevalent in all conditions - mean (SD) of 10.6(4.0) symptoms. More than 50% of the MSA and PSP patients died over the year. Over the year, half of the patients showed either an upward (worsening, 24/60) or fluctuant (8/60) trajectory for POS and symptoms. The strongest predictors of higher levels of symptoms at the end of follow-up were initial scores on POS (AOR 1.30; 95%CI:1.05-1.60) and being male (AOR 5.18; 95% CI 1.17 to 22.92), both were more predictive than initial H&Y scores. INTERPRETATION The findings point to profound and complex mix of non-motor and motor symptoms in patients with late stage IPD, MSA and PSP. Symptoms are not resolved and half of the patients deteriorate. Palliative problems are predictive of future symptoms, suggesting that an early palliative assessment might help screen for those in need of earlier intervention

Some Effects of Lubricant Starvation in Cylindrical Roller Bearings

Experiments on cylindrical roller bearings of 50-mm bore lubricated by an air/oil mist show that friction torque and operating temperatures are much reduced by running at low lubricant supply rates

Impact of a hospice rapid response service on preferred place of death, and costs

Background: Many people with a terminal illness would prefer to die at home. A new palliative rapid response service (RRS) provided by a large hospice provider in South East England was evaluated (2010) to provide evidence of impact on achieving preferred place of death and costs. The RRS was delivered by a team of trained health care assistants and available 24/7. The purpose of this study was to (i) compare the characteristics of RRS users and non-users, (ii) explore differences in the proportions of users and non-users dying in the place of their choice, (iii) monitor the whole system service utilisation of users and non-users, and compare costs. Methods: All hospice patients who died with a preferred place of death recorded during an 18 month period were included. Data (demographic, preferences for place of death) were obtained from hospice records. Dying in preferred place was modelled using stepwise logistic regression analysis. Service use data (period between referral to hospice and death) were obtained from general practitioners, community providers, hospitals, social services, hospice, and costs calculated using validated national tariffs. Results: Of 688 patients referred to the hospice when the RRS was operational, 247 (35.9 %) used it. Higher proportions of RRS users than non-users lived in their own homes with a co-resident carer (40.3 % vs. 23.7 %); more non-users lived alone or in residential care (58.8 % vs. 76.3 %). Chances of dying in the preferred place were enhanced 2.1 times by being a RRS user, compared to a non-user, and 1.5 times by having a co-resident carer, compared to living at home alone or in a care home. Total service costs did not differ between users and non-users, except when referred to hospice very close to death (users had higher costs). Conclusions: Use of the RRS was associated with increased likelihood of dying in the preferred place. The RRS is cost neutral

Managing bereavement in the classroom: a conspiracy of silence?

The ways in which teachers in British schools manage bereaved children are under-reported. This article reports the impact of students' bereavement and their subsequent management in primary and secondary school classrooms in Southeast London. Thirteen school staff working in inner-city schools took part in in-depth interviews that focused on the impact of bereaved children on the school and how teachers responded to these children. All respondents had previously had contact with a local child bereavement service that aims to provide support, advice, and consultancy to children, their parents, and teachers. Interviews were audiotaped, transcribed verbatim, and analyzed using ATLAS-ti. Three main themes were identified from analysis of interview data. Firstly, British society, culture, local communities, and the family were significant influences in these teachers' involvement with bereaved students. Secondly, school staff managed bereaved students through contact with other adults and using practical classroom measures such as "time out" cards and contact books. Lastly, teachers felt they had to be strong, even when they were distressed. Surprise was expressed at the mature reaction of secondary school students to deaths of others. The article recommends that future research needs to concentrate on finding the most effective way of supporting routinely bereaved children, their families, and teachers