2,470 research outputs found

    Polyubiquitin binding to ABIN1 is required to prevent autoimmunity

    Get PDF
    The protein ABIN1 possesses a polyubiquitin-binding domain homologous to that present in nuclear factor kappa B (NF-kappa B) essential modulator (NEMO), a component of the inhibitor of NF-kappa B (I kappa B) kinase (IKK) complex. To address the physiological significance of polyubiquitin binding, we generated knockin mice expressing the ABIN1[D485N] mutant instead of the wild-type (WT) protein. These mice developed all the hallmarks of autoimmunity, including spontaneous formation of germinal centers, isotype switching, and production of autoreactive antibodies. Autoimmunity was suppressed by crossing to MyD88(-/-) mice, demonstrating that toll-like receptor (TLR)-MyD88 signaling pathways are needed for the phenotype to develop. The B cells and myeloid cells of the ABIN1[D485N] mice showed enhanced activation of the protein kinases TAK, IKK-alpha/beta, c-Jun N-terminal kinases, and p38 alpha mitogen-activated protein kinase and produced more IL-6 and IL-12 than WT. The mutant B cells also proliferated more rapidly in response to TLR ligands. Our results indicate that the interaction of ABIN1 with polyubiquitin is required to limit the activation of TLR-MyD88 pathways and prevent autoimmunity

    An educational game for teaching clinical practice guidelines to Internal Medicine residents: development, feasibility and acceptability

    Get PDF
    <p>Abstract</p> <p>Background</p> <p>Adherence to Clinical Practice Guidelines (CPGs) remains suboptimal among internal medicine trainees. Educational games are of growing interest and have the potential to improve adherence to CPGs. The objectives of this study were to develop an educational game to teach CPGs in Internal Medicine residency programs and to evaluate its feasibility and acceptability.</p> <p>Methods</p> <p>We developed the Guide-O-Game<sup>© </sup>in the format of a TV game show with questions based on recommendations of CPGs. The development of the Guide-O-Game<sup>© </sup>consisted of the creation of a multimedia interactive tool, the development of recommendation-based questions, and the definition of the game's rules. We evaluated its feasibility through pilot testing and its acceptability through a qualitative process.</p> <p>Results</p> <p>The multimedia interactive tool uses a Macromedia Flash web application and consists of a manager interface and a user interface. The user interface allows the choice of two game styles. We created so far 16 sets of questions relating to 9 CPGs. The pilot testing proved that the game was feasible. The qualitative evaluation showed that residents considered the game to be acceptable.</p> <p>Conclusion</p> <p>We developed an educational game to teach CPGs to Internal Medicine residents that is both feasible and acceptable. Future work should evaluate its impact on educational outcomes.</p

    Shear wave elastography and grey scale assessment of palpable probably benign masses:is biopsy always required?

    Get PDF
    OBJECTIVE: To establish if palpable breast masses with benign greyscale ultrasound features that are soft on shear-wave elastography (SWE) (mean stiffness <50 kPa) have a low enough likelihood of malignancy to negate the need for biopsy or follow-up. METHODS: The study group comprised 694 lesions in 682 females (age range 17–95 years, mean age 56 years) presenting consecutively to our institution with palpable lesions corresponding to discrete masses at ultrasound. All underwent ultrasound, SWE and needle core biopsy. Static greyscale images were retrospectively assigned Breast Imaging Reporting and Data System (BI-RADS) scores by two readers blinded to the SWE and pathology findings, but aware of the patient's age. A mean stiffness of 50 kPa was used as the SWE cut-off for calling a lesion soft or stiff. Histological findings were used to establish ground truth. RESULTS: No cancer had benign characteristics on both modalities. 466 (99.8%) of the 467 cancers were classified BI-RADS 4a or above. The one malignant lesion classified as BI-RADS 3 was stiff on SWE. 446 (96%) of the 467 malignancies were stiff on SWE. No cancer in females under 40 years had benign SWE features. 74 (32.6%) of the 227 benign lesions were BI-RADS 3 and soft on SWE; so, biopsy could potentially have been avoided in this group. CONCLUSION: Lesions which appear benign on greyscale ultrasound and SWE do not require percutaneous biopsy or short-term follow-up, particularly in females under 40 years. ADVANCES IN KNOWLEDGE: None of the cancers had benign characteristics on both greyscale ultrasound and SWE, and 32% of benign lesions were BI-RADS 3 and soft on SWE; lesions that are benign on both ultrasound and SWE may not require percutaneous biopsy or short-term follow-up

    Engineers and planners: Sustainable water management alliances

    Get PDF
    Copyright © 2011 ICE Publishing Ltd. Permission is granted by ICE Publishing to print one copy for personal use. Any other use of these PDF files is subject to reprint fees.In the future, increasing pressure will inevitably be placed on the spatial planning system to improve its consideration of water management issues. Emerging challenges include designing for climatic extremes, reducing flood risk, managing increasingly scarce water resources and improving water quality. These issues need to be balanced with a range of other spatial planning priorities and objectives, including meeting new housing needs, facilitating economic growth, and creating and maintaining quality places. The sheer complexity of the issues surrounding water management and the impacts upon spatial planning mean that partnership working is essential to achieve an integrated approach. Planners need the expertise, and crucially the understanding, of engineers and hydrologists. However, there can be considerable misunderstanding and miscommunication between disciplines, often concerning the institutional context in which the various parties operate. A plethora of policies, tools and assessments exist, which can make integrated water management an overwhelming prospect for the planner. This paper attempts to identify and address some of the issues faced, as well as examining how planners embed hydrological issues in decision making and how engineers could better facilitate this

    Medication administration errors for older people in long-term residential care

    Get PDF
    Background Older people in long-term residential care are at increased risk of medication errors. The purpose of this study was to evaluate a computerised barcode medication management system designed to improve drug administrations in residential and nursing homes, including comparison of error rates and staff awareness in both settings. Methods All medication administrations were recorded prospectively for 345 older residents in thirteen care homes during a 3-month period using the computerised system. Staff were surveyed to identify their awareness of administration errors prior to system introduction. Overall, 188,249 attempts to administer medication were analysed to determine the prevalence of potential medication administration errors (MAEs). Error classifications included attempts to administer medication at the wrong time, to the wrong person or discontinued medication. Analysis compared data at residential and nursing home level and care and nursing staff groups. Results Typically each resident was exposed to 206 medication administration episodes every month and received nine different drugs. Administration episodes were more numerous (p < 0.01) in nursing homes (226.7 per resident) than in residential homes (198.7). Prior to technology introduction, only 12% of staff administering drugs reported they were aware of administration errors being averted in their care home. Following technology introduction, 2,289 potential MAEs were recorded over three months. The most common MAE was attempting to give medication at the wrong time. On average each resident was exposed to 6.6 potential errors. In total, 90% of residents were exposed to at least one MAE with over half (52%) exposed to serious errors such as attempts to give medication to the wrong resident. MAEs rates were significantly lower (p < 0.01) in residential homes than nursing homes. The level of non-compliance with system alerts was low in both settings (0.075% of administrations) demonstrating virtually complete error avoidance. Conclusion Potentially inappropriate administration of medication is a serious problem in long-term residential care. A computerised barcode system can accurately and automatically detect inappropriate attempts to administer drugs to residents. This tool can reliably be used by care staff as well as nurses to improve quality of care and patient safety

    Altered DNA methylation associated with a translocation linked to major mental illness

    Get PDF
    Recent work has highlighted a possible role for altered epigenetic modifications, including differential DNA methylation, in susceptibility to psychiatric illness. Here, we investigate blood-based DNA methylation in a large family where a balanced translocation between chromosomes 1 and 11 shows genome-wide significant linkage to psychiatric illness. Genome-wide DNA methylation was profiled in whole-blood-derived DNA from 41 individuals using the Infinium HumanMethylation450 BeadChip (Illumina Inc., San Diego, CA). We found significant differences in DNA methylation when translocation carriers (n = 17) were compared to related non-carriers (n = 24) at 13 loci. All but one of the 13 significant differentially methylated positions (DMPs) mapped to the regions surrounding the translocation breakpoints. Methylation levels of five DMPs were associated with genotype at SNPs in linkage disequilibrium with the translocation. Two of the five genes harbouring significant DMPs, DISC1 and DUSP10, have been previously shown to be differentially methylated in schizophrenia. Gene Ontology analysis revealed enrichment for terms relating to neuronal function and neurodevelopment among the genes harbouring the most significant DMPs. Differentially methylated region (DMR) analysis highlighted a number of genes from the MHC region, which has been implicated in psychiatric illness previously through genetic studies. We show that inheritance of a translocation linked to major mental illness is associated with differential DNA methylation at loci implicated in neuronal development/function and in psychiatric illness. As genomic rearrangements are over-represented in individuals with psychiatric illness, such analyses may be valuable more widely in the study of these conditions

    Differential changes in gene expression in human neutrophils following TNF-α stimulation: Up-regulation of anti-apoptotic proteins and down-regulation of proteins involved in death receptor signaling.

    Get PDF
    Responses of human neutrophils to TNF-α are complex and multifactorial. Exposure of human neutrophils to TNF-α in vitro primes the respiratory burst, delays apoptosis and induces the expression of several genes including chemokines, and TNF-α itself. This study aimed to determine the impact of TNF-α exposure on the expression of neutrophil genes and proteins that regulate apoptosis. Quantitative PCR and RNA-Seq, identified changes in expression of several apoptosis regulating genes in response to TNF-α exposure. Up-regulated genes included TNF-α itself, and several anti-apoptotic genes, including BCL2A1, CFLAR (cFLIP) and TNFAIP3, whose mRNA levels increased above control values by between 4-20 fold (n = 3, P < 0.05). In contrast, the expression of pro-apoptotic genes, including CASP8, FADD and TNFRSF1A and TNFRSF1B, were significantly down-regulated following TNF-α treatment. These changes in mRNA levels were paralleled by decreases in protein levels of caspases 8 and 10, TRADD, FADD, TNFRSF1A and TNFRSF1B, and increased cFLIP protein levels, as detected by western blotting. These data indicate that when neutrophils are triggered by TNF-α exposure, they undergo molecular changes in transcriptional expression to up-regulate expression of specific anti-apoptotic proteins and concomitantly decrease expression of specific proteins involved in death receptor signaling which will alter their function in TNF-α rich environments
    corecore