Transport of prion protein across the blood-brain barrier.

The cellular form of the prion protein (PrP(c)) is necessary for the development of prion diseases and is a highly conserved protein that may play a role in neuroprotection. PrP(c) is found in both blood and cerebrospinal fluid and is likely produced by both peripheral tissues and the central nervous system (CNS). Exchange of PrP(c) between the brain and peripheral tissues could have important pathophysiologic and therapeutic implications, but it is unknown whether PrP(c) can cross the blood-brain barrier (BBB). Here, we found that radioactively labeled PrP(c) crossed the BBB in both the brain-to-blood and blood-to-brain directions. PrP(c) was enzymatically stable in blood and in brain, was cleared by liver and kidney, and was sequestered by spleen and the cervical lymph nodes. Circulating PrP(c) entered all regions of the CNS, but uptake by the lumbar and cervical spinal cord, hypothalamus, thalamus, and striatum was particularly high. These results show that PrP(c) has bidirectional, saturable transport across the BBB and selectively targets some CNS regions. Such transport may play a role in PrP(c) function and prion replication

The effects of maintenance schedules following pulmonary rehabilitation in patients with chronic obstructive pulmonary disease: a randomised controlled trial.

OBJECTIVES: Pulmonary rehabilitation (PR) provides benefit for patients with chronic obstructive pulmonary disease (COPD) in terms of quality of life (QoL) and exercise capacity; however, the effects diminish over time. Our aim was to evaluate a maintenance programme for patients who had completed PR. SETTING: Primary and secondary care PR programmes in Norfolk. PARTICIPANTS: 148 patients with COPD who had completed at least 60% of a standard PR programme were randomised and data are available for 110 patients. Patients had greater than 20 pack year smoking history and less than 80% predicted forced expiratory volume in 1 s but no other significant disease or recent respiratory tract infection. INTERVENTIONS: Patients were randomised to receive a maintenance programme or standard care. The maintenance programme consisted of 2 h (1 h individually tailored exercise training and 1 h education programme) every 3 months for 1 year. PRIMARY AND SECONDARY OUTCOME MEASURES: The Chronic Respiratory Questionnaire (CRQ) (primary outcome), endurance shuttle walk test (ESWT), EuroQol (EQ5D), hospital anxiety and depression score (HADS), body mass index (BMI), body fat, activity levels (overall score and activity diary) and exacerbations were assessed before and after 12 months. RESULTS: There was no statistically significant difference between the groups for the change in CRQ dyspnoea score (primary end point) at 12 months which amounted to 0.19 (-0.26 to 0.64) units or other domains of the CRQ. There was no difference in the ESWT duration (-10.06 (-191.16 to 171.03) seconds), BMI, body fat, EQ5D, MET-minutes, activity rating, HADS, exacerbations or admissions. CONCLUSIONS: A maintenance programme of three monthly 2 h sessions does not improve outcomes in patients with COPD after 12 months. We do not recommend that our maintenance programme is adopted. Other methods of sustaining the benefits of PR are required. TRIAL REGISTRATION NUMBER: NCT00925171.This paper presents independent research funded by the National Institute for Health Research (NIHR) under its Research for Patient Benefit (RfPB) Programme (Grant Reference Number PB-PG-0408-16225). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.This is the final published version. It first appeared at http://bmjopen.bmj.com/content/5/3/e005921.full?g=w_thorax_open_tab

Immunochip analysis identifies multiple susceptibility loci for systemic sclerosis

In this study, 1,833 systemic sclerosis (SSc) cases and 3,466 controls were genotyped with the Immunochip array. Classical alleles, amino acid residues, and SNPs across the human leukocyte antigen (HLA) region were imputed and tested. These analyses resulted in a model composed of six polymorphic amino acid positions and seven SNPs that explained the observed significant associations in the region. In addition, a replication step comprising 4,017 SSc cases and 5,935 controls was carried out for several selected non-HLA variants, reaching a total of 5,850 cases and 9,401 controls of European ancestry. Following this strategy, we identified and validated three SSc risk loci, including DNASE1L3 at 3p14, the SCHIP1-IL12A locus at 3q25, and ATG5 at 6q21, as well as a suggested association of the TREH-DDX6 locus at 11q23. The associations of several previously reported SSc risk loci were validated and further refined, and the observed peak of association in PXK was related to DNASE1L3. Our study has increased the number of known genetic associations with SSc, provided further insight into the pleiotropic effects of shared autoimmune risk factors, and highlighted the power of dense mapping for detecting previously overlooked susceptibility loci

Social and situational dynamics surrounding workplace mistreatment: Context matters

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/163449/2/job2479_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/163449/1/job2479.pd

The genomes of two key bumblebee species with primitive eusocial organization

Background: The shift from solitary to social behavior is one of the major evolutionary transitions. Primitively eusocial bumblebees are uniquely placed to illuminate the evolution of highly eusocial insect societies. Bumblebees are also invaluable natural and agricultural pollinators, and there is widespread concern over recent population declines in some species. High-quality genomic data will inform key aspects of bumblebee biology, including susceptibility to implicated population viability threats. Results: We report the high quality draft genome sequences of Bombus terrestris and Bombus impatiens, two ecologically dominant bumblebees and widely utilized study species. Comparing these new genomes to those of the highly eusocial honeybee Apis mellifera and other Hymenoptera, we identify deeply conserved similarities, as well as novelties key to the biology of these organisms. Some honeybee genome features thought to underpin advanced eusociality are also present in bumblebees, indicating an earlier evolution in the bee lineage. Xenobiotic detoxification and immune genes are similarly depauperate in bumblebees and honeybees, and multiple categories of genes linked to social organization, including development and behavior, show high conservation. Key differences identified include a bias in bumblebee chemoreception towards gustation from olfaction, and striking differences in microRNAs, potentially responsible for gene regulation underlying social and other traits. Conclusions: These two bumblebee genomes provide a foundation for post-genomic research on these key pollinators and insect societies. Overall, gene repertoires suggest that the route to advanced eusociality in bees was mediated by many small changes in many genes and processes, and not by notable expansion or depauperation

A high-resolution map of human evolutionary constraint using 29 mammals.

The comparison of related genomes has emerged as a powerful lens for genome interpretation. Here we report the sequencing and comparative analysis of 29 eutherian genomes. We confirm that at least 5.5% of the human genome has undergone purifying selection, and locate constrained elements covering ∼4.2% of the genome. We use evolutionary signatures and comparisons with experimental data sets to suggest candidate functions for ∼60% of constrained bases. These elements reveal a small number of new coding exons, candidate stop codon readthrough events and over 10,000 regions of overlapping synonymous constraint within protein-coding exons. We find 220 candidate RNA structural families, and nearly a million elements overlapping potential promoter, enhancer and insulator regions. We report specific amino acid residues that have undergone positive selection, 280,000 non-coding elements exapted from mobile elements and more than 1,000 primate- and human-accelerated elements. Overlap with disease-associated variants indicates that our findings will be relevant for studies of human biology, health and disease

An exploration of the clinical practice of Rheumatology specialist nurses undertaking consultations with patients starting Methotrexate

Background Rheumatology nursing roles have evolved over the last 25 years to include educating patients prior to commencing drugs such as Methotrexate in consultations. The expansion of their role has not been supplemented by specific training in order to prepare them for this undertaking. Thus, this study was developed to explore how Rheumatology Specialist nurses gained knowledge about consulting with patients on Methotrexate, how they delivered information to patients, and to identify elements of their consultation for further development. Methods This was a mixed-methods practice based study undertaken in three phases. Training, confidence and knowledge were explored with a questionnaire, which constituted Phase I. Phase II explored the lived experiences of the nurses with semi-structured interviews. Phase III explored the interaction between the nurses and patients during a consultation which was video-recorded and analysed using qualitative and quantitative approaches, with the interaction scored against items in the Calgary Cambridge consultation model. Findings The results of the survey (n=97) and the semi-structured interviews findings (n=6) revealed significant variability in training received by Rheumatology Specialist nurses. Confidence took three to 12 months to develop and was related to experience, knowledge and training, with nurses expressing a clear desire for more training. Written information was used by all participants during consultations, usually in the form of the Methotrexate information booklet, which had some benefits, including allowing the nurses to structure their consultations, ensuring that all of the information in the booklet was given to patients. However, it also had the disadvantage of becoming the nurses’ agenda which dominated the consultation, leading to overloading the patients with information and restricting discussion and questions from the patients. Analysis of consultation videos (n=10) supported these findings, demonstrating that whilst all of the important information from the booklet was given, there was a lack of involvement during the consultation of the patient agenda such as ideas, concerns and expectations, with little checking by the nurses to ensure the patients understood the information given. The effect of limited time was apparent. Cues from patients were often ignored or missed which may have been as a result of perceived time pressures or lack of confidence in dealing with questions. The comparison of the nurses’ consultations with the Calgary Cambridge consultation model showed variations in the nurses’ scores. It also raised new observations such as in those consultations which scored higher, the nurses used more illustrative and fewer batonic gestures, whilst the patient did the opposite. Conclusions Whilst Rheumatology Specialist nurses are clearly doing many things well, the education of patients starting drugs such as Methotrexate could be improved by training aimed at improving consultation techniques with the adoption of a modified Calgary Cambridge model consultation technique. Such an approach would benefit from further research to identify whether it results in improving patients’ involvement in the consultation process. The findings from this thesis have led directly to the development of “Top Tips”, published online by Versus Arthritis, to guide nurses during their consultations when giving information to patients about Methotrexate. Further work will include writing a handbook that aims to give nurses more knowledge about how to conduct a consultation with patients based on the Calgary Cambridge consultation model

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin