Co-receptor and co-stimulation blockade for mixed chimerism and tolerance without myelosuppressive conditioning

BACKGROUND: A major challenge in the application of marrow transplantation as a route to immunological tolerance of a transplanted organ is to achieve hematopoietic stem cell (HSC) engraftment with minimal myelosuppressive treatments. RESULTS: We here describe a combined antibody protocol which can achieve long-term engraftment with clinically relevant doses of MHC-mismatched bone marrow, without the need for myelosuppressive drugs. Although not universally applicable in all strains, we achieved reliable engraftment in permissive strains with a two-stage strategy: involving first, treatment with anti-CD8 and anti-CD4 in advance of transplantation; and second, treatment with antibodies targeting CD4, CD8 and CD40L (CD154) at the time of marrow transplantation. Long-term mixed chimerism through co-receptor and co-stimulation blockade facilitated tolerance to donor-type skin grafts, without any evidence of donor-antigen driven regulatory T cells. CONCLUSION: We conclude that antibodies targeting co-receptor and co-stimulatory molecules synergise to enable mixed hematopoietic chimerism and central tolerance, showing that neither cytoreductive conditioning nor 'megadoses' of donor bone marrow are required for donor HSC to engraft in permissive strains

Comprehensive methylome map of lineage commitment from haematopoietic progenitors.

Epigenetic modifications must underlie lineage-specific differentiation as terminally differentiated cells express tissue-specific genes, but their DNA sequence is unchanged. Haematopoiesis provides a well-defined model to study epigenetic modifications during cell-fate decisions, as multipotent progenitors (MPPs) differentiate into progressively restricted myeloid or lymphoid progenitors. Although DNA methylation is critical for myeloid versus lymphoid differentiation, as demonstrated by the myeloerythroid bias in Dnmt1 hypomorphs, a comprehensive DNA methylation map of haematopoietic progenitors, or of any multipotent/oligopotent lineage, does not exist. Here we examined 4.6 million CpG sites throughout the genome for MPPs, common lymphoid progenitors (CLPs), common myeloid progenitors (CMPs), granulocyte/macrophage progenitors (GMPs), and thymocyte progenitors (DN1, DN2, DN3). Marked epigenetic plasticity accompanied both lymphoid and myeloid restriction. Myeloid commitment involved less global DNA methylation than lymphoid commitment, supported functionally by myeloid skewing of progenitors following treatment with a DNA methyltransferase inhibitor. Differential DNA methylation correlated with gene expression more strongly at CpG island shores than CpG islands. Many examples of genes and pathways not previously known to be involved in choice between lymphoid/myeloid differentiation have been identified, such as Arl4c and Jdp2. Several transcription factors, including Meis1, were methylated and silenced during differentiation, indicating a role in maintaining an undifferentiated state. Additionally, epigenetic modification of modifiers of the epigenome seems to be important in haematopoietic differentiation. Our results directly demonstrate that modulation of DNA methylation occurs during lineage-specific differentiation and defines a comprehensive map of the methylation and transcriptional changes that accompany myeloid versus lymphoid fate decisions

The equity impact of brief opportunistic interventions to promote weight loss in primary care:secondary analysis of the BWeL randomised trial

BACKGROUND:Guidelines recommend that clinicians should make brief opportunistic behavioural interventions to patients who are obese to increase the uptake of effective weight loss programmes. The objective was to assess the effect of this policy on socioeconomic equity. METHODS:One thousand eight hundred eighty-two consecutively attending patients with obesity and who were not seeking support for weight loss from their GP were enrolled in a trial. Towards the end of each consultation, GPs randomly assigned participants to one of two 30-s interventions. In the active intervention (support arm), the GP offered referral to a weight management group. In the control intervention (advice arm), the GP advised the patient that their health would benefit from weight loss. Agreement to attend a behavioural weight loss programme, attendance at the programme and weight loss at 12 months were analysed by socioeconomic status, measured by postcode using the Index of Multiple Deprivation (IMD). RESULTS:Mean weight loss was 2.43 kg (sd 6.49) in the support group and 1.04 kg (sd 5.50) for the advice only group, but these effects were moderated by IMD (p = 0.039 for the interaction). In the support arm, weight loss was greater in higher socioeconomic groups. Participants from lower socioeconomic backgrounds were more likely to accept the offer and equally likely to attend a weight loss referral but attended fewer sessions. Adjusting for these sequentially reduced the gradient for the association of socioeconomic status with weight loss from + 0.035 to - 0.001 kg/IMD point. In the advice only arm, 10% took effective action to promote weight loss. The decision to seek support for weight loss outside of the trial did not differ by socioeconomic status, but weight loss among deprived participants who used external support was greater than among more affluent participants (p = 0.025). CONCLUSION:Participants' responses to GPs' brief opportunistic interventions to promote weight loss differed by socioeconomic status and trial arm. In the support arm, more deprived people lost less weight because they attended fewer sessions at the programme. In the advice arm, more deprived people who sought and paid for support for weight loss themselves lost more weight than more affluent people who sought support. TRIAL REGISTRATION:This trial is registered with the ISRCTN registry, number ISRCTN26563137 . Date of registration: January 3, 2013; date of first participant recruited: June 4, 2014

The occupation of a box as a toy model for the seismic cycle of a fault

We illustrate how a simple statistical model can describe the quasiperiodic occurrence of large earthquakes. The model idealizes the loading of elastic energy in a seismic fault by the stochastic filling of a box. The emptying of the box after it is full is analogous to the generation of a large earthquake in which the fault relaxes after having been loaded to its failure threshold. The duration of the filling process is analogous to the seismic cycle, the time interval between two successive large earthquakes in a particular fault. The simplicity of the model enables us to derive the statistical distribution of its seismic cycle. We use this distribution to fit the series of earthquakes with magnitude around 6 that occurred at the Parkfield segment of the San Andreas fault in California. Using this fit, we estimate the probability of the next large earthquake at Parkfield and devise a simple forecasting strategy.Comment: Final version of the published paper, with an erratum and an unpublished appendix with some proof

Late-Holocene climate dynamics recorded in the peat bogs of Tierra del Fuego, South America

The ombrotrophic peat bogs of Tierra del Fuego are located within the southern westerly wind belt (SWWB), which dominates climate variability in this region. We have reconstructed late-Holocene water-table depths from three peat bogs and aimed to relate these records to shifts in regional climate. Water-table depths were quantified by the analysis of testate amoeba assemblages, and a regional transfer function was used to infer past water-table depths. During the last 2000 years, testate amoeba assemblages have been relatively stable, with a dominance of Difflugia pulex and Difflugia pristis type, and an increase in Assulina muscorum and other Euglyphida at the top of each section. Multivariate analyses show that water-table depth remained the main environmental variable explaining assemblages along the TiA12 core, but reconstructions were not significant for the two other cores. In line with the low variability in assemblages, water tables were relatively stable during the last 2000 years. Slightly wetter conditions were found between ~1400 and 900 cal. BP and a pronounced recent dry shift was reconstructed in all of the three peat profiles. Considering the regional climatic context, this recent shift may have been forced by a decrease in precipitation and warmer conditions linked to an increase in the importance of the SWWB. Nevertheless, we cannot exclude the influence of higher UV-B radiation resulting from the local degradation of the ozone layer since the late 1970s, which may have had an additional effect on the relative presence of A. muscorum in the southern Patagonian region

Physical activity for antenatal and postnatal depression in women attempting to quit smoking: randomised controlled trial

Background: Antenatal depression is associated with harmful consequences for both the mother and child. One intervention that might be effective is participation in regular physical activity although data on this question in pregnant smokers is currently lacking. Methods: Women were randomised to six-weekly sessions of smoking cessation behavioural-support, or to the same support plus 14 sessions combining treadmill exercise and physical activity consultations. Results: Among 784 participants (mean gestation 16-weeks), EPDS was significantly higher in the physical activity group versus usual care at end-of-pregnancy (mean group difference (95% confidence intervals (CIs)): 0.95 (0.08 to 1.83). There was no significant difference at six-months postpartum. Conclusion: A pragmatic intervention to increase physical activity in pregnant smokers did not prevent depression at end-of-pregnancy or at six-months postpartum. More effective physical activity interventions are needed in this population. Trial registration: Current Controlled Trials ISRCTN48600346. The trial was prospectively registered on 21/07/2008

Evidence for the impact of the 8.2-kyBP climate event on Near Eastern early farmers.

The 8.2-thousand years B.P. event is evident in multiple proxy records across the globe, showing generally dry and cold conditions for ca. 160 years. Environmental changes around the event are mainly detected using geochemical or palynological analyses of ice cores, lacustrine, marine, and other sediments often distant from human settlements. The Late Neolithic excavated area of the archaeological site of Çatalhöyük East [Team Poznań (TP) area] was occupied for four centuries in the ninth and eighth millennia B.P., thus encompassing the 8.2-thousand years B.P. climatic event. A Bayesian analysis of 56 radiocarbon dates yielded a high-resolution chronological model comprising six building phases, with dates ranging from before 8325-8205 to 7925-7815 calibrated years (cal) B.P. Here, we correlate an onsite paleoclimate record constructed from δ2H values of lipid biomarkers preserved in pottery vessels recovered from these buildings with changes in architectural, archaeozoological, and consumption records from well-documented archaeological contexts. The overall sequence shows major changes in husbandry and consumption practices at ca. 8.2 thousand years B.P., synchronous with variations in the δ2H values of the animal fat residues. Changes in paleoclimate and archaeological records seem connected with the patterns of atmospheric precipitation during the occupation of the TP area predicted by climate modeling. Our multiproxy approach uses records derived directly from documented archaeological contexts. Through this, we provide compelling evidence for the specific impacts of the 8.2-thousand years B.P. climatic event on the economic and domestic activities of pioneer Neolithic farmers, influencing decisions relating to settlement planning and food procurement strategies

A randomised controlled trial to compare a range of commercial or primary care led weight reduction programmes with a minimal intervention control for weight loss in obesity: the Lighten Up trial

<p>Abstract</p> <p>Background</p> <p>Developed countries are facing a huge rise in the prevalence of obesity and its associated chronic medical problems. In the UK Primary Care Trusts are charged with addressing this in the populations they serve, but evidence about the most effective ways of delivering services is not available. The aim of this study is to determine the effectiveness of a range of weight loss programmes for obese patients in primary care and to determine the characteristics of patients who respond to an invitation to a free weight management programme.</p> <p>Methods/Design</p> <p>Lighten Up is a randomised controlled trial comparing a range of 12-week commercial and NHS weight reduction programmes with a comparator group who are provided with 12 vouchers enabling free entrance to a local leisure centre. The weight reduction programmes are: (i) Weight Watchers, (ii) Slimming World, (iii) Rosemary Conley, (iv) a group-based dietetics-led programme (Size Down), (v) general practice one-to-one counselling, (vi) pharmacy-led one-to-one counselling, (vii) choice of any of the 6 programmes. People with obesity or overweight with a co-morbid disorder are invited to take part by a letter from their general practitioner. The sample size is 740 participants.</p> <p>The primary outcome is weight loss at programme-end (3 months). Secondary outcomes are weight-loss at one year, self-reported physical activity at 3 and 12 months follow-up and percentage weight-loss at 3 months and one year.</p> <p>Discussion</p> <p>This trial will provide evidence about the effectiveness of a range of different weight management programmes in a primary care population.</p> <p>Trial registration</p> <p>Current Controlled Trials ISRCTN25072883</p

Critical Thinking in Nursing Education: Literature Review

The need for critical thinking in nursing has been accentuated in response to the rapidly changing health care environment. Nurses must think critically to provide effective care whilst coping with the expansion in role associated with the complexities of current health care systems. This literature review will present a history of inquiry into critical thinking and research to support the conclusion that critical thinking is necessary not only in the clinical practice setting, but also as an integral component of nursing education programs to promote the development of nurses’ critical thinking abilities. The aims of this paper are: (a) to review the literature on critical thinking; (b) to examine the dimensions of critical thinking; (c) to investigate the various critical thinking strategies for their appropriateness to enhance critical thinking in nurses, and; (d) to examine issues relating to evaluation of critical thinking skills in nursing.</ul