BAFF and MyD88 signals promote a lupuslike disease independent of T cells

Systemic lupus erythernatosus (SLE) is a systemic autoimmune disease characterized by the production of autoantibodies. However, the underlying cause of disease appears to relate to defects in T cell tolerance or T cell help to 13 cells. Transgenic (Tg) mice over-expressing the cytokine 13 cell-activating factor of the tumor necrosis factor family (BAFF) develop an autoimmune disorder similar to SLE and show impaired B cell tolerance and altered T cell differentiation. We generated BAFF Tg mice that were completely deficient in T cells, and, surprisingly, these mice developed an SLE-like disease indistinguishable from that of BAFF Tg mice. Autoimmunity in BAFF Tg mice did, however, require 13 cell-intrinsic signals through the Toll-like receptor (TLR)-associated signaling adaptor MyD88, which controlled the production of proinflammatory autoantibody isotypes. TLR7/9 activation strongly up-regulated expression of transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), which is a receptor for BAFF involved in 13 cell responses to T cell-independent antigens. Moreover, BAFF enhanced TLR7/9 expression on 13 cells and TLR-mediated production of autoantibodies. Therefore, autoirnmunity in BAFF Tg mice results from altered 13 cell tolerance, but requires TLR signaling and is independent of T cell help. It is possible that SLE patients with elevated levels of BAFF show a similar basis for disease

Dynamic microtubules produce an asymmetric E-cadherin-Bazooka complex to maintain segment boundaries.

Distributing junctional components around the cell periphery is key for epithelial tissue morphogenesis and homeostasis. We discovered that positioning of dynamic microtubules controls the asymmetric accumulation of E-cadherin. Microtubules are oriented preferentially along the dorso-ventral axis in Drosophila melanogaster embryonic epidermal cells, and thus more frequently contact E-cadherin at dorso-ventral cell-cell borders. This inhibits RhoGEF2, reducing membrane recruitment of Rho-kinase, and increasing a specific E-cadherin pool that is mobile when assayed by fluorescence recovery after photobleaching. This mobile E-cadherin is complexed with Bazooka/Par-3, which in turn is required for normal levels of mobile E-cadherin. Mobile E-cadherin-Bazooka prevents formation of multicellular rosette structures and cell motility across the segment border in Drosophila embryos. Altogether, the combined action of dynamic microtubules and Rho signaling determines the level and asymmetric distribution of a mobile E-cadherin-Bazooka complex, which regulates cell behavior during the generation of a patterned epithelium

Behavioural activation therapy for depression after stroke (BEADS): a study protocol for a feasibility randomised controlled pilot trial of a psychological intervention for post-stroke depression

Background There is currently insufficient evidence for the clinical and cost-effectiveness of psychological therapies for treating post-stroke depression. Methods/Design BEADS is a parallel group feasibility multicentre randomised controlled trial with nested qualitative research and economic evaluation. The aim is to evaluate the feasibility of undertaking a full trial comparing behavioural activation (BA) to usual stroke care for 4 months for patients with post-stroke depression. We aim to recruit 72 patients with post-stroke depression over 12 months at three centres, with patients identified from the National Health Service (NHS) community and acute services and from the voluntary sector. They will be randomly allocated to receive behavioural activation in addition to usual care or usual care alone. Outcomes will be measured at 6 months after randomisation for both participants and their carers, to determine their effectiveness. The primary clinical outcome measure for the full trial will be the Patient Health Questionnaire-9 (PHQ-9). Rates of consent, recruitment and follow-up by centre and randomised group will be reported. The acceptability of the intervention to patients, their carers and therapists will also be assessed using qualitative interviews. The economic evaluation will be undertaken from the National Health Service and personal social service perspective, with a supplementary analysis from the societal perspective. A value of information analysis will be completed to identify the areas in which future research will be most valuable. Discussion The feasibility outcomes from this trial will provide the data needed to inform the design of a definitive multicentre randomised controlled trial evaluating the clinical and cost-effectiveness of behavioural activation for treating post-stroke depression

Persistent Nociceptor Hyperactivity as a Painful Evolutionary Adaptation

Chronic pain caused by injury or disease of the nervous system (neuropathic pain) has been linked to persistent electrical hyperactivity of the sensory neurons (nociceptors) specialized to detect damaging stimuli and/or inflammation. This pain and hyperactivity are considered maladaptive because both can persist long after injured tissues have healed and inflammation has resolved. While the assumption of maladaptiveness is appropriate in many diseases, accumulating evidence from diverse species, including humans, challenges the assumption that neuropathic pain and persistent nociceptor hyperactivity are always maladaptive. We review studies indicating that persistent nociceptor hyperactivity has undergone evolutionary selection in widespread, albeit selected, animal groups as a physiological response that can increase survival long after bodily injury, using both highly conserved and divergent underlying mechanisms

EEG neurofeedback for executive functions in children with neurodevelopmental challenges

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the effectiveness of EEG neurofeedback as treatment for inhibition and updating problems in children facing neurodevelopmental challenges

Intra-operative pneumatic tourniquet – perceptions of use and complications in the orthopaedic community of South Africa

OBJECTIVES: To assess views on use, maintenance and side-effects of the pneumatic tourniquet in the South African orthopaedic community. METHODS: A census-type questionnaire study was conducted of all 475 orthopaedic surgeons registered with the Orthopaedic Association of South Africa during 1993/94. The chi-square test was used to determine statistical significance between different groups of respondents. RESULTS: Seventy-seven per cent of the questionnaires were returned. Ninety-nine per cent of respondents used a pneumatic tourniquet. Eighty-four per cent believed that the tourniquet may damage underlying tissue both as a result of applied pressure effects and ischaemic consequences. Fifty-four per cent of respondents personally checked the calibration of the pneumatic tourniquet, although 76% of respondents believe that the apparatus needs to be checked at least once per month. More respondents who did not check the tourniquet apparatus than respondents who did check it believe that applied pressure does not cause tissue damage (P < 0.001), that the operating room technician or hospital engineer should be responsible for checking equipment (P < 0.001), and that equipment did not need to be checked more than once every 6 months (P < 0.001). CONCLUSIONS: Although most orthopaedic surgeons are aware of the pneumatic tourniquet's side-effects, a minority appear to be unaware of the hazards of excessive applied pressure alone or excessive applied pressure caused by use of faulty equipment. It needs to be emphasised to these surgeons that regular checking of the pneumatic tourniquet apparatus is necessary in order to prevent postoperative complications ascribed to use of the tourniquet

The relationship between SF-6D utility scores and lifestyle factors across three life-stages: Evidence from the Australian Longitudinal Study on Women’s Health

Purpose: To investigate how SF-6D utility scores change with age between generations of women, and to quantify the relationship of SF-6D with lifestyle factors across life-stages. Methods: Up to seven waves of self-reported, longitudinal data were drawn for the 1973-78 (young, N=13772), 1946-51 (mid-age, N=12792), 1921-26 (older, N=9972) cohorts from the Australian Longitudinal Study on Women’s Health. Mixed effects models were employed for analysis. Results: Young and mid-age women had similar average SF-6D scores at baseline (0.63-0.64), which remained consistent over 16 year period. However, older women had lower scores at baseline at 0.57 which steadily declined over 15 years. Across cohorts, low education attainment, greater difficulty in managing on income, obesity, physical inactivity, heavy smoking, non-drinking and increasing stress levels were associated with lower SF-6D scores. The magnitude of effect varied between cohorts. SF-6D scores were lower amongst young women with high risk drinking behaviours than low-risk drinkers. Mid-age women who were underweight, never married, or underwent surgical menopause also reported lower SF-6D scores. Older women who lived in remote areas, who were ex-smokers, or were underweight reported lower SF-6D scores. Conclusion: The SF-6D utility score is sensitive to differences in lifestyle factors across adult lifestages. Gradual loss of physical functioning may explain the steady decline in health for older women. Key factors associated with SF-6D include physical activity, body mass index, menopause status, smoking, alcohol use and stress. Factors associated with poorer SF-6D scores vary in type and magnitude at different life stages

Lamin B1 regulates somatic mutations and progression of B-cell malignancies

Somatic hypermutation (SHM) is a pivotal process in adaptive immunity that occurs in the germinal centre and allows B cells to change their primary DNA sequence and diversify their antigen receptors. Here, we report that genome binding of Lamin B1, a component of the nuclear envelope involved in epigenetic chromatin regulation, is reduced during B-cell activation and formation of lymphoid germinal centres. Chromatin immunoprecipitation-Seq analysis showed that kappa and heavy variable immunoglobulin domains were released from the Lamin B1 suppressive environment when SHM was induced in B cells. RNA interference-mediated reduction of Lamin B1 resulted in spontaneous SHM as well as kappa-light chain aberrant surface expression. Finally, Lamin B1 expression level correlated with progression-free and overall survival in chronic lymphocytic leukaemia, and was strongly involved in the transformation of follicular lymphoma. In summary, here we report that Lamin B1 is a negative epigenetic regulator of SHM in normal B-cells and a 'mutational gatekeeper', suppressing the aberrant mutations that drive lymphoid malignancy

Evidence for models of diagnostic service provision in the community: literature mapping exercise and focused rapid reviews

Background Current NHS policy favours the expansion of diagnostic testing services in community and primary care settings. Objectives Our objectives were to identify current models of community diagnostic services in the UK and internationally and to assess the evidence for quality, safety and clinical effectiveness of such services. We were also interested in whether or not there is any evidence to support a broader range of diagnostic tests being provided in the community. Review methods We performed an initial broad literature mapping exercise to assess the quantity and nature of the published research evidence. The results were used to inform selection of three areas for investigation in more detail. We chose to perform focused reviews on logistics of diagnostic modalities in primary care (because the relevant issues differ widely between different types of test); diagnostic ultrasound (a key diagnostic technology affected by developments in equipment); and a diagnostic pathway (assessment of breathlessness) typically delivered wholly or partly in primary care/community settings. Databases and other sources searched, and search dates, were decided individually for each review. Quantitative and qualitative systematic reviews and primary studies of any design were eligible for inclusion. Results We identified seven main models of service that are delivered in primary care/community settings and in most cases with the possible involvement of community/primary care staff. Not all of these models are relevant to all types of diagnostic test. Overall, the evidence base for community- and primary care-based diagnostic services was limited, with very few controlled studies comparing different models of service. We found evidence from different settings that these services can reduce referrals to secondary care and allow more patients to be managed in primary care, but the quality of the research was generally poor. Evidence on the quality (including diagnostic accuracy and appropriateness of test ordering) and safety of such services was mixed. Conclusions In the absence of clear evidence of superior clinical effectiveness and cost-effectiveness, the expansion of community-based services appears to be driven by other factors. These include policies to encourage moving services out of hospitals; the promise of reduced waiting times for diagnosis; the availability of a wider range of suitable tests and/or cheaper, more user-friendly equipment; and the ability of commercial providers to bid for NHS contracts. However, service development also faces a number of barriers, including issues related to staffing, training, governance and quality control. Limitations We have not attempted to cover all types of diagnostic technology in equal depth. Time and staff resources constrained our ability to carry out review processes in duplicate. Research in this field is limited by the difficulty of obtaining, from publicly available sources, up-to-date information about what models of service are commissioned, where and from which providers. Future work There is a need for research to compare the outcomes of different service models using robust study designs. Comparisons of ‘true’ community-based services with secondary care-based open-access services and rapid access clinics would be particularly valuable. There are specific needs for economic evaluations and for studies that incorporate effects on the wider health system. There appears to be no easy way of identifying what services are being commissioned from whom and keeping up with local evaluations of new services, suggesting a need to improve the availability of information in this area. Funding The National Institute for Health Research Health Services and Delivery Research programme

A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.

This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/ng.3448Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.We thank all participants of all the studies included for enabling this research by their participation in these studies. Computer resources for this project have been provided by the high-performance computing centers of the University of Michigan and the University of Regensburg. Group-specific acknowledgments can be found in the Supplementary Note. The Center for Inherited Diseases Research (CIDR) Program contract number is HHSN268201200008I. This and the main consortium work were predominantly funded by 1X01HG006934-01 to G.R.A. and R01 EY022310 to J.L.H