194 research outputs found

    ISCOMATRIX vaccines mediate CD8+ T-cell cross-priming by a MyD88-dependent signaling pathway

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    Generating a cytotoxic CD8+ T-cell response that can eradicate malignant cells is the primary objective of cancer vaccine strategies. In this study we have characterized the innate and adaptive immune response to the ISCOMATRIX adjuvant, and the ability of vaccine antigens formulated with this adjuvant to promote antitumor immunity. ISCOMATRIX adjuvant led to a rapid innate immune cell response at the injection site, followed by the activation of natural killer and dendritic cells (DC) in regional draining lymph nodes. Strikingly, major histocompatibility complex (MHC) class I cross-presentation by CD8α+ and CD8α− DCs was enhanced by up to 100-fold when antigen was formulated with ISCOMATRIX adjuvant. These coordinated features enabled efficient CD8+ T-cell cross-priming, which exhibited prophylactic and therapeutic tumoricidal activity. The therapeutic efficacy of an ISCOMATRIX vaccine was further improved when co-administered with an anti-CD40 agonist antibody, suggesting that ISCOMATRIX-based vaccines may combine favorably with other immune modifiers in clinical development to treat cancer. Finally, we identified a requirement for the myeloid differentiation primary response gene 88 (MyD88) adapter protein for both innate and adaptive immune responses to ISCOMATRIX vaccines in vivo. Taken together, our findings support the utility of the ISCOMATRIX adjuvant for use in the development of novel vaccines, particularly those requiring strong CD8+ T-cell immune responses, such as therapeutic cancer vaccines

    Tobacco use and asking prices of used cars: prevalence, costs, and new opportunities for changing smoking behavior

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    Secondhand smoke (SHS) causes premature death and disease in children and adults, and the scientific evidence indicates that there is no risk-free level of exposure to SHS. Smoking tobacco in a car can pollute the microenvironment of the car with residual SHS, leaving telltale signs to potential buyers (e.g., odor, used ash tray). This study examined (a) the proportion of used cars sold in the private party market that may be polluted with tobacco smoke and (b) whether asking prices of smoker and nonsmoker cars differed for cars of otherwise equivalent value. A random sample of 1,642 private party sellers were interviewed by telephone, and content analyses of print advertisements were conducted. Findings indicate that 22% of used cars were advertised by smokers or had been smoked in during the previous year. Among nonsmokers, 94% did not allow smoking in their car during the past year. Only 33% of smokers had the same restrictions. The smoking status of the seller and tobacco use in the car were significantly (p < .01) associated with the asking price independent of a car's Kelley Blue Book value (KBB). Used nonsmoker cars were offered at a considerable premium above their KBB value (>11%) and above comparable smoker cars (7–9%). These findings suggest that community preferences are affecting the value of smoke-free cars. New directions for research, tobacco control policies, and health education are discussed to further reduce smoking behavior, to help consumers make informed purchasing decisions, and to protect nonsmokers from SHS exposure

    A qualitative study exploring midlife women’s stages of change from domestic violence towards freedom

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    Gold OABackground Domestic Violence (DV) remains a significant global health problem for women in contemporary society. Existing literature on midlife women’s experiences of domestic violence is limited and focuses on health implications. Leaving a violent relationship is a dynamic process that often requires multiple attempts and separations prior to final termination. The aim of this study was to explore the process of leaving a violent relationship for midlife women. Methods This qualitative study involved fifteen women aged between 40–55 who had accessed residential and non-residential community support services for domestic violence within the UK. Community-based support agencies provided these women with access to letters of invitation and participant information sheet explaining the study. The women notified agency staff who contacted the research team to arrange a mutually convenient time to meet within a safe place for both the women and researchers. It was stressed to all potential participants that no identifiable information would be shared with the agency staff. Women were considered survivors of DV if they defined themselves as such. Data were gathered through semi structured interviews, transcribed verbatim and thematically analysed. Results Midlife women appear to differ from younger women by transitioning quickly though the stages of change, moving rapidly through the breaking free onto the maintenance stage. This rapid transition is the resultant effect of living with long-term violence causing a shift in the women’s perception towards the violent partner, with an associated reclamation of power from within the violent relationship. A realisation that rapid departure from the violence may be critical in terms of personal safety, and the realisation that there was something ‘wrong’ within the relationship, a ‘day of dawning’ that had not been apparent previously appears to positively affect the trajectory of leaving. Conclusions Midlife women appeared to navigate through the stages of change in a rapid linear process, forging ahead and exiting the relationship with certainty and without considering options. Whilst these findings appear to differ from younger women’s process of leaving, further research is needed to explore and understand the optimum time for intervention and support to maximise midlife women’s opportunities to escape an abusive partner, before being reflected appropriately in policy and practice.This study received funding from The Research and Knowledge Transfer Office, The University of Chester, and from the Western Australian Health Promotion Foundation – ‘Healthway

    Bacterial infections in Lilongwe, Malawi: aetiology and antibiotic resistance

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    <p>Abstract</p> <p>Background</p> <p>Life-threatening infections present major challenges for health systems in Malawi and the developing world because routine microbiologic culture and sensitivity testing are not performed due to lack of capacity. Use of empirical antimicrobial therapy without regular microbiologic surveillance is unable to provide adequate treatment in the face of emerging antimicrobial resistance. This study was conducted to determine antimicrobial susceptibility patterns in order to inform treatment choices and generate hospital-wide baseline data.</p> <p>Methods</p> <p>Culture and susceptibility testing was performed on various specimens from patients presenting with possible infectious diseases at Kamuzu Central Hospital, Lilongwe, Malawi.</p> <p>Results</p> <p>Between July 2006 and December 2007 3104 specimens from 2458 patients were evaluated, with 60.1% from the adult medical service. Common presentations were sepsis, meningitis, pneumonia and abscess. An etiologic agent was detected in 13% of patients. The most common organisms detected from blood cultures were <it>Staphylococcus aureus</it>, <it>Escherichia </it><it>coli</it>, Salmonella species and <it>Streptococcus pneumoniae</it>, whereas <it>Streptococcus pneumoniae </it>and <it>Cryptococcus neoformans </it>were most frequently detected from cerebrospinal fluid. <it>Haemophilus influenzae </it>was rarely isolated. Resistance to commonly used antibiotics was observed in up to 80% of the isolates while antibiotics that were not commonly in use maintained susceptibility.</p> <p>Conclusions</p> <p>There is widespread resistance to almost all of the antibiotics that are empirically used in Malawi. Antibiotics that have not been widely introduced in Malawi show better laboratory performance. Choices for empirical therapy in Malawi should be revised accordingly. A microbiologic surveillance system should be established and prudent use of antimicrobials promoted to improve patient care.</p

    Early Evolution of Conserved Regulatory Sequences Associated with Development in Vertebrates

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    Comparisons between diverse vertebrate genomes have uncovered thousands of highly conserved non-coding sequences, an increasing number of which have been shown to function as enhancers during early development. Despite their extreme conservation over 500 million years from humans to cartilaginous fish, these elements appear to be largely absent in invertebrates, and, to date, there has been little understanding of their mode of action or the evolutionary processes that have modelled them. We have now exploited emerging genomic sequence data for the sea lamprey, Petromyzon marinus, to explore the depth of conservation of this type of element in the earliest diverging extant vertebrate lineage, the jawless fish (agnathans). We searched for conserved non-coding elements (CNEs) at 13 human gene loci and identified lamprey elements associated with all but two of these gene regions. Although markedly shorter and less well conserved than within jawed vertebrates, identified lamprey CNEs are able to drive specific patterns of expression in zebrafish embryos, which are almost identical to those driven by the equivalent human elements. These CNEs are therefore a unique and defining characteristic of all vertebrates. Furthermore, alignment of lamprey and other vertebrate CNEs should permit the identification of persistent sequence signatures that are responsible for common patterns of expression and contribute to the elucidation of the regulatory language in CNEs. Identifying the core regulatory code for development, common to all vertebrates, provides a foundation upon which regulatory networks can be constructed and might also illuminate how large conserved regulatory sequence blocks evolve and become fixed in genomic DNA
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