Preclinical Development of an In Vivo BCG Challenge Model for Testing Candidate TB Vaccine Efficacy

There is an urgent need for an immunological correlate of protection against tuberculosis (TB) with which to evaluate candidate TB vaccines in clinical trials. Development of a human challenge model of Mycobacterium tuberculosis (M.tb) could facilitate the detection of such correlate(s). Here we propose a novel in vivo Bacille Calmette-Guérin (BCG) challenge model using BCG immunization as a surrogate for M.tb infection. Culture and quantitative PCR methods have been developed to quantify BCG in the skin, using the mouse ear as a surrogate for human skin. Candidate TB vaccines have been evaluated for their ability to protect against a BCG skin challenge, using this model, and the results indicate that protection against a BCG skin challenge is predictive of BCG vaccine efficacy against aerosol M.tb challenge. Translation of these findings to a human BCG challenge model could enable more rapid assessment and down selection of candidate TB vaccines and ultimately the identification of an immune correlate of protection

Work satisfaction of professional nurses in South Africa: a comparative analysis of the public and private sectors

<p>Abstract</p> <p>Background</p> <p>Work satisfaction of nurses is important, as there is sufficient empirical evidence to show that it tends to affect individual, organizational and greater health and social outcomes. Although there have been several studies of job satisfaction among nurses in South Africa, these are limited because they relate to studies of individual organizations or regions, use small samples or are dated. This paper presents a national study that compares and contrasts satisfaction levels of nurses in both public and private sectors.</p> <p>Methods</p> <p>This was a cross-sectional survey of professional nurses conducted throughout South Africa using a pretested and self-administered questionnaire. Univariate and bivariate statistical models were used to evaluate levels of satisfaction with various facets of work and to elicit the differences in satisfaction levels between different groups of nurses. A total of 569 professional nurses participated in the study.</p> <p>Results</p> <p>Private-sector nurses were generally satisfied, while public-sector nurses were generally dissatisfied. Public-sector nurses were most dissatisfied with their pay, the workload and the resources available to them. They were satisfied only with the social context of the work. Private-sector nurses were dissatisfied only with their pay and career development opportunities. Professional nurses in the more rural provinces, those intending to change sectors and those more likely not to be in their current positions within the next five years were also more likely to be dissatisfied with all facets of their work.</p> <p>Conclusion</p> <p>This study highlighted the overall dissatisfaction among South African nurses and confirmed the disparity between the levels of job satisfaction between the public and private sectors. Health managers should address those factors that affect job satisfaction, and therefore retention, of nurses in South Africa. Improving the work environment so that it provides a context congruent with the aspirations and values systems of nurses is more likely to increase the satisfaction of nurses and consequently have a positive effect on individual, organizational and health outcomes.</p

NICE : A Computational solution to close the gap from colour perception to colour categorization

The segmentation of visible electromagnetic radiation into chromatic categories by the human visual system has been extensively studied from a perceptual point of view, resulting in several colour appearance models. However, there is currently a void when it comes to relate these results to the physiological mechanisms that are known to shape the pre-cortical and cortical visual pathway. This work intends to begin to fill this void by proposing a new physiologically plausible model of colour categorization based on Neural Isoresponsive Colour Ellipsoids (NICE) in the cone-contrast space defined by the main directions of the visual signals entering the visual cortex. The model was adjusted to fit psychophysical measures that concentrate on the categorical boundaries and are consistent with the ellipsoidal isoresponse surfaces of visual cortical neurons. By revealing the shape of such categorical colour regions, our measures allow for a more precise and parsimonious description, connecting well-known early visual processing mechanisms to the less understood phenomenon of colour categorization. To test the feasibility of our method we applied it to exemplary images and a popular ground-truth chart obtaining labelling results that are better than those of current state-of-the-art algorithms

The Tyrosine Kinase Inhibitor Dasatinib Induces a Marked Adipogenic Differentiation of Human Multipotent Mesenchymal Stromal Cells

BACKGROUND: The introduction of specific BCR-ABL inhibitors in chronic myelogenous leukemia therapy has entirely mutated the prognosis of this hematologic cancer from being a fatal disorder to becoming a chronic disease. Due to the probable long lasting treatment with tyrosine-kinase inhibitors (TKIs), the knowledge of their effects on normal cells is of pivotal importance. DESIGN AND METHODS: We investigated the effects of dasatinib treatment on human bone marrow-derived mesenchymal stromal cells (MSCs). RESULTS: Our findings demonstrate, for the first time, that dasatinib induces MSCs adipocytic differentiation. Particularly, when the TKI is added to the medium inducing osteogenic differentiation, a high MSCs percentage acquires adipocytic morphology and overexpresses adipocytic specific genes, including PPARγ, CEBPα, LPL and SREBP1c. Dasatinib also inhibits the activity of alkaline phosphatase, an osteogenic marker, and remarkably reduces matrix mineralization. The increase of PPARγ is also confirmed at protein level. The component of osteogenic medium required for dasatinib-induced adipogenesis is dexamethasone. Intriguingly, the increase of adipocytic markers is also observed in MSCs treated with dasatinib alone. The TKI effect is phenotype-specific, since fibroblasts do not undergo adipocytic differentiation or PPARγ increase. CONCLUSIONS: Our data demonstrate that dasatinib treatment affects bone marrow MSCs commitment and suggest that TKIs therapy might modify normal phenotypes with potential significant negative consequences

Pulsed radiofrequency treatment in interventional pain management: mechanisms and potential indications—a review

Item does not contain fulltextBACKGROUND: The objective of this review is to evaluate the efficacy of Pulsed Radiofrequency (PRF) treatment in chronic pain management in randomized clinical trials (RCTs) and well-designed observational studies. The physics, mechanisms of action, and biological effects are discussed to provide the scientific basis for this promising modality. METHODS: We systematically searched for clinical studies on PRF. We searched the MEDLINE (PubMed) and EMBASE database, using the free text terms: pulsed radiofrequency, radio frequency, radiation, isothermal radiofrequency, and combination of these. We classified the information in two tables, one focusing only on RCTs, and another, containing prospective studies. Date of last electronic search was 30 May 2010. The methodological quality of the presented reports was scored using the original criteria proposed by Jadad et al. FINDINGS: We found six RCTs that evaluated the efficacy of PRF, one against corticosteroid injection, one against sham intervention, and the rest against conventional RF thermocoagulation. Two trials were conducted in patients with lower back pain due to lumbar zygapophyseal joint pain, one in cervical radicular pain, one in lumbosacral radicular pain, one in trigeminal neuralgia, and another in chronic shoulder pain. CONCLUSION: From the available evidence, the use of PRF to the dorsal root ganglion in cervical radicular pain is compelling. With regards to its lumbosacral counterpart, the use of PRF cannot be similarly advocated in view of the methodological quality of the included study. PRF application to the supracapular nerve was found to be as efficacious as intra-articular corticosteroid in patients with chronic shoulder pain. The use of PRF in lumbar facet arthropathy and trigeminal neuralgia was found to be less effective than conventional RF thermocoagulation techniques

Effects of non-steroidal anti-inflammatory drugs on cancer sites other than the colon and rectum: a meta-analysis

BACKGROUND: Observational studies have consistently shown that aspirin and non-steroidal anti-inflammatory drug (NSAID) use is associated with a close to 50% reduced risk of colorectal cancer. Studies assessing the effects of NSAIDs on other cancers have shown conflicting results. Therefore, we conducted a meta-analysis to evaluate the relationship between NSAID use and cancer other than colorectal. METHODS: We performed a search in Medline (from 1966 to 2002) and identified a total of 47 articles (13 cohort and 34 case-control studies). Overall estimates of the relative risk (RR) were calculated for each cancer site using random effects models. RESULTS: Aspirin use was associated with a reduced risk of cancer of the esophagus and the stomach (RR, 0.51; 95%CI (0.38–0.69), and 0.73; 95%CI (0.63–0.84)). Use of NSAIDs was similarly associated with a lower risk of esophageal and gastric cancers (RR,0.65; 95% CI(0.46–0.92) and RR,0.54; 95%CI (0.39–0.75)). Among other cancers, only the results obtained for breast cancer were fairly consistent in showing a slight reduced risk among NSAID and aspirin users (RR, 0.77; 95%CI (0.66–0.88), and RR, 0.77; 95%CI (0.69–0.86) respectively)). CONCLUSIONS: The results of this meta-analysis show that the potential chemopreventive role of NSAIDs in colorectal cancer might be extended to other gastrointestinal cancers such as esophagus and stomach. Further research is required to evaluate the role of NSAIDs at other cancers sites

Assessing the human immune system through blood transcriptomics

Blood is the pipeline of the immune system. Assessing changes in transcript abundance in blood on a genome-wide scale affords a comprehensive view of the status of the immune system in health and disease. This review summarizes the work that has used this approach to identify therapeutic targets and biomarker signatures in the field of autoimmunity and infectious disease. Recent technological and methodological advances that will carry the blood transcriptome research field forward are also discussed

Reducing the Activity and Secretion of Microbial Antioxidants Enhances the Immunogenicity of BCG

BACKGROUND:In early clinical studies, the live tuberculosis vaccine Mycobacterium bovis BCG exhibited 80% protective efficacy against pulmonary tuberculosis (TB). Although BCG still exhibits reliable protection against TB meningitis and miliary TB in early childhood it has become less reliable in protecting against pulmonary TB. During decades of in vitro cultivation BCG not only lost some genes due to deletions of regions of the chromosome but also underwent gene duplication and other mutations resulting in increased antioxidant production. METHODOLOGY/PRINCIPAL FINDINGS:To determine whether microbial antioxidants influence vaccine immunogenicity, we eliminated duplicated alleles encoding the oxidative stress sigma factor SigH in BCG Tice and reduced the activity and secretion of iron co-factored superoxide dismutase. We then used assays of gene expression and flow cytometry with intracellular cytokine staining to compare BCG-specific immune responses in mice after vaccination with BCG Tice or the modified BCG vaccine. Compared to BCG, the modified vaccine induced greater IL-12p40, RANTES, and IL-21 mRNA in the spleens of mice at three days post-immunization, more cytokine-producing CD8+ lymphocytes at the peak of the primary immune response, and more IL-2-producing CD4+ lymphocytes during the memory phase. The modified vaccine also induced stronger secondary CD4+ lymphocyte responses and greater clearance of challenge bacilli. CONCLUSIONS/SIGNIFICANCE:We conclude that antioxidants produced by BCG suppress host immune responses. These findings challenge the hypothesis that the failure of extensively cultivated BCG vaccines to prevent pulmonary tuberculosis is due to over-attenuation and suggest instead a new model in which BCG evolved to produce more immunity-suppressing antioxidants. By targeting these antioxidants it may be possible to restore BCG's ability to protect against pulmonary TB

Why Functional Pre-Erythrocytic and Bloodstage Malaria Vaccines Fail: A Meta-Analysis of Fully Protective Immunizations and Novel Immunological Model

Background: Clinically protective malaria vaccines consistently fail to protect adults and children in endemic settings, and at best only partially protect infants. Methodology/Principal Findings: We identify and evaluate 1916 immunization studies between 1965-February 2010, and exclude partially or nonprotective results to find 177 completely protective immunization experiments. Detailed reexamination reveals an unexpectedly mundane basis for selective vaccine failure: live malaria parasites in the skin inhibit vaccine function. We next show published molecular and cellular data support a testable, novel model where parasite-host interactions in the skin induce malaria-specific regulatory T cells, and subvert early antigen-specific immunity to parasite-specific immunotolerance. This ensures infection and tolerance to reinfection. Exposure to Plasmodium-infected mosquito bites therefore systematically triggers immunosuppression of endemic vaccine-elicited responses. The extensive vaccine trial data solidly substantiate this model experimentally. Conclusions/Significance: We conclude skinstage-initiated immunosuppression, unassociated with bloodstage parasites, systematically blocks vaccine function in the field. Our model exposes novel molecular and procedural strategies to significantly and quickly increase protective efficacy in both pipeline and currently ineffective malaria vaccines, and forces fundamental reassessment of central precepts determining vaccine development. This has major implications fo