Rapid and reversible impairment of episodic memory by a high-fat diet in mice.

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request. This work was supported by an EASTBIO BBSRC PhD studentship to F.H.M., L.M.W., C.G., A.C.M., G.W.H. and F.M.C. are supported by Scottish Government’s Rural and Environment Science and Analytical Services Division (RESAS).Peer reviewedPublisher PD

Mechanical loading of stem cells for improvement of transplantation outcome in a model of acute myocardial infarction: The role of loading history

Stem cell therapy for tissue repair is a rapidly evolving field and the factors that dictate the physiological responsiveness of stem cells remain under intense investigation. In this study we hypothesized that the mechanical loading history of muscle-derived stem cells (MDSCs) would significantly impact MDSC survival, host tissue angiogenesis, and myocardial function after MDSC transplantation into acutely infarcted myocardium. Mice with acute myocardial infarction by permanent left coronary artery ligation were injected with either nonstimulated (NS) or mechanically stimulated (MS) MDSCs. Mechanical stimulation consisted of stretching the cells with equibiaxial stretch with a magnitude of 10% and frequency of 0.5Hz. MS cell-transplanted hearts showed improved cardiac contractility, increased numbers of host CD31+ cells, and decreased fibrosis, in the peri-infarct region, compared to the hearts treated with NS MDSCs. MS MDSCs displayed higher vascular endothelial growth factor expression than NS cells in vitro. These findings highlight an important role for cyclic mechanical loading preconditioning of donor MDSCs in optimizing MDSC transplantation for myocardial repair. © 2012, Mary Ann Liebert, Inc

Longitudinal analysis of vertebral fracture and BMD in a Canadian cohort of adult cystic fibrosis patients

<p>Abstract</p> <p>Background</p> <p>Vertebral fractures in patients with cystic fibrosis (CF) may contribute to an accelerated decline in lung function and can be a contraindication to lung transplantation. In this study, we examined longitudinal change in bone mineral density (BMD) and the prevalence of vertebral fractures in adult CF patients, without lung-transplant, attending a Canadian specialty clinic.</p> <p>Methods</p> <p>Retrospective chart review of all patients attending an Adult Cystic Fibrosis Clinic at Hamilton Health Sciences in Hamilton, Canada. Forty-nine of 56 adults met inclusion criteria. Chest radiographs were graded by consensus approach using Genant's semi-quantitative method to identify and grade fractured vertebrae. Dual x-ray absorptiometry (DXA) scans were also reviewed.</p> <p>Results</p> <p>The mean age of the cohort was 25.2 years (SD 9.4), 43% were male. The mean body mass index (BMI) was 19.8 (2.8) for males and 21.7 (5.1) for females. At baseline, the rate of at least one vertebral fracture was 16.3%; rising to 21.3% (prevalent and incident) after a 3-year follow-up. The mean BMD T-or Z-scores at baseline were -0.80 (SD 1.1) at the lumbar spine, -0.57 (SD 0.97) at the proximal femur, and -0.71 (SD 1.1) at the whole body. Over approximately 4-years, the mean percent change in BMD was -1.93% at the proximal femur and -0.73% at the lumbar spine.</p> <p>Conclusion</p> <p>Approximately one in five CF patients demonstrated at least one or more vertebral fractures. Moderate declines in BMD were observed. Given the high rate of vertebral fractures noted in this cohort of adult CF patients, and the negative impact they have on compromised lung functioning, regular screening for vertebral fractures should be considered on routine chest radiographs.</p

Early and reversible changes to the hippocampal proteome in mice on a high-fat diet

Funding LMW, FMC, CG, ACM and C-DM were funded by the Scottish Government’s Rural and Environment Science and Analytical Services Division (RESAS). FHM was supported by an EASTBIO DTP BBSRC studentship. DS was supported by a SULSA studentship.Peer reviewedPublisher PD

The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies

Despite the clinical significance of balanced chromosomal abnormalities (BCAs), their characterization has largely been restricted to cytogenetic resolution. We explored the landscape of BCAs at nucleotide resolution in 273 subjects with a spectrum of congenital anomalies. Whole-genome sequencing revised 93% of karyotypes and demonstrated complexity that was cryptic to karyotyping in 21% of BCAs, highlighting the limitations of conventional cytogenetic approaches. At least 33.9% of BCAs resulted in gene disruption that likely contributed to the developmental phenotype, 5.2% were associated with pathogenic genomic imbalances, and 7.3% disrupted topologically associated domains (TADs) encompassing known syndromic loci. Remarkably, BCA breakpoints in eight subjects altered a single TAD encompassing MEF2C, a known driver of 5q14.3 microdeletion syndrome, resulting in decreased MEF2C expression. We propose that sequence-level resolution dramatically improves prediction of clinical outcomes for balanced rearrangements and provides insight into new pathogenic mechanisms, such as altered regulation due to changes in chromosome topology

BHPR research: qualitative1. Complex reasoning determines patients' perception of outcome following foot surgery in rheumatoid arhtritis

Background: Foot surgery is common in patients with RA but research into surgical outcomes is limited and conceptually flawed as current outcome measures lack face validity: to date no one has asked patients what is important to them. This study aimed to determine which factors are important to patients when evaluating the success of foot surgery in RA Methods: Semi structured interviews of RA patients who had undergone foot surgery were conducted and transcribed verbatim. Thematic analysis of interviews was conducted to explore issues that were important to patients. Results: 11 RA patients (9 ♂, mean age 59, dis dur = 22yrs, mean of 3 yrs post op) with mixed experiences of foot surgery were interviewed. Patients interpreted outcome in respect to a multitude of factors, frequently positive change in one aspect contrasted with negative opinions about another. Overall, four major themes emerged. Function: Functional ability & participation in valued activities were very important to patients. Walking ability was a key concern but patients interpreted levels of activity in light of other aspects of their disease, reflecting on change in functional ability more than overall level. Positive feelings of improved mobility were often moderated by negative self perception ("I mean, I still walk like a waddling duck”). Appearance: Appearance was important to almost all patients but perhaps the most complex theme of all. Physical appearance, foot shape, and footwear were closely interlinked, yet patients saw these as distinct separate concepts. Patients need to legitimize these feelings was clear and they frequently entered into a defensive repertoire ("it's not cosmetic surgery; it's something that's more important than that, you know?”). Clinician opinion: Surgeons' post operative evaluation of the procedure was very influential. The impact of this appraisal continued to affect patients' lasting impression irrespective of how the outcome compared to their initial goals ("when he'd done it ... he said that hasn't worked as good as he'd wanted to ... but the pain has gone”). Pain: Whilst pain was important to almost all patients, it appeared to be less important than the other themes. Pain was predominately raised when it influenced other themes, such as function; many still felt the need to legitimize their foot pain in order for health professionals to take it seriously ("in the end I went to my GP because it had happened a few times and I went to an orthopaedic surgeon who was quite dismissive of it, it was like what are you complaining about”). Conclusions: Patients interpret the outcome of foot surgery using a multitude of interrelated factors, particularly functional ability, appearance and surgeons' appraisal of the procedure. While pain was often noted, this appeared less important than other factors in the overall outcome of the surgery. Future research into foot surgery should incorporate the complexity of how patients determine their outcome Disclosure statement: All authors have declared no conflicts of interes

Increasing frailty is associated with higher prevalence and reduced recognition of delirium in older hospitalised inpatients: results of a multi-centre study

Purpose: Delirium is a neuropsychiatric disorder delineated by an acute change in cognition, attention, and consciousness. It is common, particularly in older adults, but poorly recognised. Frailty is the accumulation of deficits conferring an increased risk of adverse outcomes. We set out to determine how severity of frailty, as measured using the CFS, affected delirium rates, and recognition in hospitalised older people in the United Kingdom. Methods: Adults over 65 years were included in an observational multi-centre audit across UK hospitals, two prospective rounds, and one retrospective note review. Clinical Frailty Scale (CFS), delirium status, and 30-day outcomes were recorded. Results: The overall prevalence of delirium was 16.3% (483). Patients with delirium were more frail than patients without delirium (median CFS 6 vs 4). The risk of delirium was greater with increasing frailty [OR 2.9 (1.8–4.6) in CFS 4 vs 1–3; OR 12.4 (6.2–24.5) in CFS 8 vs 1–3]. Higher CFS was associated with reduced recognition of delirium (OR of 0.7 (0.3–1.9) in CFS 4 compared to 0.2 (0.1–0.7) in CFS 8). These risks were both independent of age and dementia. Conclusion: We have demonstrated an incremental increase in risk of delirium with increasing frailty. This has important clinical implications, suggesting that frailty may provide a more nuanced measure of vulnerability to delirium and poor outcomes. However, the most frail patients are least likely to have their delirium diagnosed and there is a significant lack of research into the underlying pathophysiology of both of these common geriatric syndromes

Exploring the interactions between land-based industries and communities in rural England

A reported characteristic of rural society in the UK is an increasing detachment from the land among the wider population, and a declining involvement by land managers in community activities. This paper reports on a recent project for the Commission for Rural Communities that employed ethnographic techniques to assess the various interactions between five English rural communities and the land-based industries that surround them. In particular, it examines the relationships between land-based industries and rural communities and explores whether existing theories relating to rural change, including the multifunctional rural transition, and variation within the differentiated countryside, are appropriate for explaining some of the key findings. The project found three overarching conclusions. First, the decline in jobs from agriculture and forestry has to some extent been offset by an increase in jobs from other land-based industries such as nature conservation, equine businesses and recreation. Second, those in the land-based sector have a declining influence on local governance, in line with demographic changes. Third, the picture varies considerably from place-to-place, reflecting a wide range of factors including the local social structure, influence of key individuals and the nature of the land-based sector

Timing of initiation, patterns of breastfeeding, and infant survival: prospective analysis of pooled data from three randomised trials.

BACKGROUND: Although the benefits of exclusive breastfeeding for child health and survival, particularly in the post-neonatal period, are established, the independent beneficial effect of early breastfeeding initiation remains unclear. We studied the association between timing of breastfeeding initiation and post-enrolment neonatal and post-neonatal mortality up to 6 months of age, as well as the associations between breastfeeding pattern and mortality. METHODS: We examined associations between timing of breastfeeding initiation, post-enrolment neonatal mortality (enrolment 28 days), and post-neonatal mortality up to 6 months of age (29-180 days) in a large cohort from three neonatal vitamin A trials in Ghana, India, and Tanzania. Newborn babies were eligible for these trials if their mother reported that they were likely to stay in the study area for the next 6 months, they could feed orally, were aged less than 3 days, and the primary caregiver gave informed consent. We excluded infants who initiated breastfeeding after 96 h, did not initiate, or had missing initiation status. We pooled the data from both randomised groups of the three trials and then categorised time of breastfeeding initiation as: at ≤1 h, 2-23 h, and 24-96 h. We defined breastfeeding patterns as exclusive, predominant, or partial breastfeeding at 4 days, 1 month, and 3 months of age. We estimated relative risks using log binomial regression and Poisson regression with robust variances. Multivariate models controlled for site and potential confounders. FINDINGS: Of 99 938 enrolled infants, 99 632 babies initiated breastfeeding by 96 h of age and were included in our prospective cohort. 56 981 (57·2%) initiated breastfeeding at ≤1 h, 38 043 (38·2%) at 2-23 h, and 4608 (4·6%) at 24-96 h. Compared with infants initiating breastfeeding within the first hour of life, neonatal mortality between enrolment and 28 days was higher in infants initiating at 2-23 h (adjusted relative risk 1·41 [95% CI 1·24-1·62], p<0·0001), and in those initiating at 24-96 h (1·79 [1·39-2·30], p<0·0001). These associations were similar when deaths in the first 4 days of life were excluded (1·32 [1·10-1·58], p=0·003, for breastfeeding initiation at 2-23 h, and 1·90 [1·38-2·62], p=0·0001, for initiation at 24-96 h). When data were stratified by exclusive breastfeeding status at 4 days of age (p value for interaction=0·690), these associations were also similar in magnitude but with wider confidence intervals for initiation at 2-23 h (1·41 [1·12-1·77], p=0·003) and for initiation at 24-96 h (1·51 [0·63-3·65], p=0·357). Exclusive breastfeeding was also associated with the lower mortality during the first 6 months of life (1-3 months mortality: exclusive vs partial breastfeeding at 1 month 1·83 [1·45-2·32], p<0·0001, and exclusive breastfeeding vs no breastfeeding at 1 month 10·88 [8·27-14·31], p<0·0001). INTERPRETATION: Our findings suggest that early initiation of breastfeeding reduces neonatal and early infant mortality both through increasing rates of exclusive breastfeeding and by additional mechanisms. Both practices should be promoted by public health programmes and should be used in models to estimate lives saved. FUNDING: Bill & Melinda Gates Foundation through a grant to the WHO