Anti-inflammatory treatment improves high-density lipoprotein function in rheumatoid arthritis

OBJECTIVE: Patients with rheumatoid arthritis (RA) are at increased cardiovascular risk. Recent studies suggest that high-density lipoprotein (HDL) may lose its protective vascular phenotype in inflammatory conditions. However, the effects of common anti-inflammatory treatments on HDL function are not yet known. METHODS: We compared the function of HDL in 18 patients with RA and 18 matched healthy controls. Subsequently, patients were randomised to (methotrexate+infliximab (M+I) (5 mg/kg)) or methotrexate+placebo (M+P) infusions for 54 weeks. At week 54 and thereafter, all patients received infliximab therapy until completion of the trial (110 weeks), enabling assessment of the impact of 1 year of infliximab therapy in all patients. HDL functional properties were assessed at baseline, 54 weeks and 110 weeks by measuring the impact on endothelial nitric oxide (NO) bioavailability and superoxide production (SO), paraoxonase activity (PON-1) and cholesterol efflux. RESULTS: All HDL vascular assays were impaired in patients compared with controls. After 54 weeks, NO in response to HDL was significantly greater in patients who received M+I compared with those who received M+P. Endothelial SO in response to HDL was reduced in both groups, but PON-1 and cholesterol efflux remained unchanged. All vascular measures improved compared with baseline after ≥1 infliximab therapy in the analysis at 110 weeks. No significant trend was noted for cholesterol efflux. CONCLUSIONS: HDL function can be improved with anti-inflammatory treatment in patients with RA. The M+I combination was superior to the M+P alone, suggesting that the tumour necrosis factor-α pathway may have a role in HDL vascular properties

Adrenal steroids modulate the immune response during Brucella abortus infection by a mechanism that depends on the regulation of cytokine production

Human brucellosis is a protean disease with a diversity of clinical signs and symptoms resulting from infection with Brucella species. Recent reports suggest a cross-regulation between adrenal steroids (cortisol and dehydroepiandrosterone [DHEA]) and the immune system. Monocytes and macrophages are the main replication niche for Brucella. Therefore, we investigated the role of adrenal hormones on the modulation of the immune response mediated by macrophages in B. abortus infection. Cortisol treatment during B. abortus infection significantly inhibits cytokine, chemokine, and MMP-9 secretion. In contrast, DHEA treatment had no effect. However, DHEA treatment increases the expression of costimulatory molecules (CD40, CD86), the adhesion molecule CD54, and major histocompatibility complex class I (MHC-I) and MHC-II expression on the surface of B. abortus-infected monocytes. It is known that B. abortus infection inhibits MHC-I and MHC-II expression induced by gamma interferon (IFN-γ) treatment. DHEA reverses B. abortus downmodulation of the MHC-I and -II expression induced by IFN-γ. Taken together, our data indicate that DHEA immune intervention may positively affect monocyte activity during B. abortus infection.Fil: Gentilini, Maria Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Inmunología, Genética y Metabolismo; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Velasquez, Lis Noelia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Barrionuevo, Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Arriola Benitez, Paula Constanza. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Inmunología, Genética y Metabolismo; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Giambartolomei, Guillermo Hernan. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Inmunología, Genética y Metabolismo; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Delpino, María Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Inmunología, Genética y Metabolismo; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentin

Macrophage Subset Sensitivity to Endotoxin Tolerisation by Porphyromonas gingivalis

Macrophages (MΦs) determine oral mucosal responses; mediating tolerance to commensal microbes and food whilst maintaining the capacity to activate immune defences to pathogens. MΦ responses are determined by both differentiation and activation stimuli, giving rise to two distinct subsets; pro-inflammatory M1- and anti-inflammatory/regulatory M2- MΦs. M2-like subsets predominate tolerance induction whereas M1 MΦs predominate in inflammatory pathologies, mediating destructive inflammatory mechanisms, such as those in chronic P.gingivalis (PG) periodontal infection. MΦ responses can be suppressed to benefit either the host or the pathogen. Chronic stimulation by bacterial pathogen associated molecular patterns (PAMPs), such as LPS, is well established to induce tolerance. The aim of this study was to investigate the susceptibility of MΦ subsets to suppression by P. gingivalis. CD14hi and CD14lo M1- and M2-like MΦs were generated in vitro from the THP-1 monocyte cell line by differentiation with PMA and vitamin D3, respectively. MΦ subsets were pre-treated with heat-killed PG (HKPG) and PG-LPS prior to stimulation by bacterial PAMPs. Modulation of inflammation was measured by TNFα, IL-1β, IL-6, IL-10 ELISA and NFκB activation by reporter gene assay. HKPG and PG-LPS differentially suppress PAMP-induced TNFα, IL-6 and IL-10 but fail to suppress IL-1β expression in M1 and M2 MΦs. In addition, P.gingivalis suppressed NFκB activation in CD14lo and CD14hi M2 regulatory MΦs and CD14lo M1 MΦs whereas CD14hi M1 pro-inflammatory MΦs were refractory to suppression. In conclusion, P.gingivalis selectively tolerises regulatory M2 MΦs with little effect on pro-inflammatory CD14hi M1 MΦs; differential suppression facilitating immunopathology at the expense of immunity

Computed tomographic pulmonary angiography and pulmonary embolism: predictive value of a d-dimer assay

<p>Abstract</p> <p>Background</p> <p>Computed tomographic pulmonary angiography (CTPA) is increasingly being used as first investigation for suspected pulmonary embolism (PE). The investigation has high predictive value, but is resource and time intensive and exposes patients to considerable radiation. Our aim was to assess the potential value of a negative d-dimer assay to exclude pulmonary emboli and reduce the number of performed CTPAs.</p> <p>Methods</p> <p>All CTPAs performed in a Scottish secondary care hospital for a fourteen month period were retrospectively reviewed. Collected data included the presence or absence of PE, d-dimer results and patient demographics. PE positive CTPAs were reviewed by a specialist panel.</p> <p>Results</p> <p>Pulmonary embolisms were reported for 66/405 (16.3%) CTPAs and d-dimer tests were performed for 216 (53%). 186/216 (86%) patients had a positive and 30 (14%) a negative d-dimer result. The panel agreed 5/66 (7.6%) false positive examinations. The d-dimer assay's negative predictive value was 93.3% (95% CI = 76.5%-98.8%) based on the original number of positive CTPAs and 100% (95% CI = 85.9%-100%) based on expert review. Significant non-PE intrapulmonary pathology was reported for 312/405 (77.0) CTPAs, including 13 new diagnoses of carcinoma.</p> <p>Conclusions</p> <p>We found that a low d-dimer score excluded all pulmonary embolisms, after a further specialist panel review identified initial false positive reports. However, current evidence-based guidelines still recommend that clinicians combine a d-dimer result with a validated clinical risk score when selecting suitable patients for CTPA. This may result in better use of limited resources, prevent patients being exposed to unnecessary irradiation and prevent potential complications as a result of iodinated contrast.</p

Is primary care a neglected piece of the jigsaw in ensuring optimal stroke care? Results of a national study

<p>Abstract</p> <p>Background</p> <p>Stroke is a major cause of mortality and morbidity with potential for improved care and prevention through general practice. A national survey was undertaken to determine current resources and needs for optimal stroke prevention and care.</p> <p>Methods</p> <p>Postal survey of random sample of general practitioners undertaken (N = 204; 46% response). Topics included practice organisation, primary prevention, acute management, secondary prevention, long-term care and rehabilitation.</p> <p>Results</p> <p>Service organisation for both primary and secondary prevention was poor. Home management of acute stroke patients was used at some stage by 50% of responders, accounting for 7.3% of all stroke patients. Being in a structured cardiovascular management scheme, a training practice, a larger practice, or a practice employing a practice nurse were associated with structures and processes likely to support stroke prevention and care.</p> <p>Conclusion</p> <p>General practices were not fulfilling their potential to provide stroke prevention and long-term management. Systems of structured stroke management in general practice are essential to comprehensive national programmes of stroke care.</p

First Neutrino Observations from the Sudbury Neutrino Observatory

The first neutrino observations from the Sudbury Neutrino Observatory are presented from preliminary analyses. Based on energy, direction and location, the data in the region of interest appear to be dominated by 8B solar neutrinos, detected by the charged current reaction on deuterium and elastic scattering from electrons, with very little background. Measurements of radioactive backgrounds indicate that the measurement of all active neutrino types via the neutral current reaction on deuterium will be possible with small systematic uncertainties. Quantitative results for the fluxes observed with these reactions will be provided when further calibrations have been completed.Comment: Latex, 7 pages, 10 figures, Invited paper at Neutrino 2000 Conference, Sudbury, Canada, June 16-21, 2000 to be published in the Proceeding

Analysis of additivity and synergism in the anti-plasmodial effect of purified compounds from plant extracts

In the search for antimalarials from ethnobotanical origin, plant extracts are chemically fractionated and biological tests guide the isolation of pure active compounds. To establish the responsibility of isolated active compound(s) to the whole antiplasmodial activity of a crude extract, the literature in this field was scanned and results were analysed quantitatively to find the contribution of the pure compound to the activity of the whole extract. It was found that, generally, the activity of isolated molecules could not account on their own for the activity of the crude extract. It is suggested that future research should take into account the “drugs beside the drug”, looking for those products (otherwise discarded along the fractionation process) able to boost the activity of isolated active compounds

Evaluating teaching effectiveness in nursing education:An Iranian perspective

BACKGROUND: The main objective of this study was to determine the perceptions of Iranian nurse educators and students regarding the evaluation of teaching effectiveness in university-based programs. METHODS: An exploratory descriptive design was employed. 143 nurse educators in nursing faculties from the three universities in Tehran, 40 undergraduate, and 30 graduate students from Tehran University composed the study sample. In addition, deans from the three nursing faculties were interviewed. A researcher-developed questionnaire was used to determine the perceptions of both faculty and students about evaluating the teaching effectiveness of nurse educators, and an interview guide was employed to elicit the views of deans of faculties of nursing regarding evaluation policies and procedures. Data were analyzed using parametric and nonparametric statistics to identify similarities and differences in perceptions within the Iranian nurse educator group and the student group, and between these two groups of respondents. RESULTS: While faculty evaluation has always been a major part of university based nursing programs, faculty evaluation must be approached more analytically, objectively, and comprehensively to ensure that all nursing educators receive the fairest treatment possible and that the teaching-learning process is enhanced. CONCLUSION: Educators and students stressed that systematic and continuous evaluation as well as staff development should be the primary goals for the faculty evaluation process. The ultimate goals is the improvement of teaching by nurse educators

A New Model and Method for Understanding Wolbachia-Induced Cytoplasmic Incompatibility

Wolbachia are intracellular bacteria transmitted almost exclusively vertically through eggs. In response to this mode of transmission, Wolbachia strategically manipulate their insect hosts' reproduction. In the most common manipulation type, cytoplasmic incompatibility, infected males can only mate with infected females, but infected females can mate with all males. The mechanism of cytoplasmic incompatibility is unknown; theoretical and empirical findings need to converge to broaden our understanding of this phenomenon. For this purpose, two prominent models have been proposed: the mistiming-model and the lock-key-model. The former states that Wolbachia manipulate sperm of infected males to induce a fatal delay of the male pronucleus during the first embryonic division, but that the bacteria can compensate the delay by slowing down mitosis in fertilized eggs. The latter states that Wolbachia deposit damaging “locks” on sperm DNA of infected males, but can also provide matching “keys” in infected eggs to undo the damage. The lock-key-model, however, needs to assume a large number of locks and keys to explain all existing incompatibility patterns. The mistiming-model requires fewer assumptions but has been contradicted by empirical results. We therefore expand the mistiming-model by one quantitative dimension to create the new, so-called goalkeeper-model. Using a method based on formal logic, we show that both lock-key- and goalkeeper-model are consistent with existing data. Compared to the lock-key-model, however, the goalkeeper-model assumes only two factors and provides an idea of the evolutionary emergence of cytoplasmic incompatibility. Available cytological evidence suggests that the hypothesized second factor of the goalkeeper-model may indeed exist. Finally, we suggest empirical tests that would allow to distinguish between the models. Generalizing our results might prove interesting for the study of the mechanism and evolution of other host-parasite interactions

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente