Duffy antigen receptor for chemokines and CXCL5 are essential for the recruitment of neutrophils in a multicellular model of rheumatoid arthritis synovium

OBJECTIVE: The role of chemokines and their transporters are poorly described in rheumatoid arthritis (RA). Evidence suggests that CXCL5 plays an important role as it is abundant in RA tissue and its neutralization moderates joint damage in animal models of arthritis. The chemokine transporter, Duffy Antigen Receptor for Chemokines (DARC), is also upregulated in early RA. Here we investigate the role of CXCL5 and DARC in regulating neutrophil recruitment using an in vitro model of the RA synovium. METHODS: To model the RA synovium, rheumatoid fibroblasts (RAF) were cocultured with endothelial cells (EC) for 24h. Gene expression in cocultured cells was investigated using TaqMan gene arrays. Roles of CXCL5 and DARC were determined by incorporating cocultures into a flow-based adhesion assay, where their function was demonstrated by blocking neutrophil recruitment with neutralizing reagents. RESULTS: EC-RAF coculture induced chemokine expression in both cell types. While CXC chemokines were modestly upregulated in EC, CXCL1, CXCL5 and CXCL8 expression were greatly increased in RAF. RAF also promoted the recruitment of flowing neutrophils to EC. Anti-CXCL5 antibody abolished neutrophil recruitment by neutralizing CXCL5 expressed on EC, or when used to immuno-deplete coculture conditioned medium. DARC was also induced on EC by coculture and an anti-Fy6 antibody or siRNA targeting of DARC expression effectively abolished neutrophil recruitment. CONCLUSION: For the first time in a model of human disease, the function of DARC has been demonstrated as essential for editing the chemokine signals presented by EC and for promoting unwanted leukocyte recruitment

A novel mechanism of neutrophil recruitment in a co-culture model of the rheumatoid synovium

OBJECTIVE: Rheumatoid arthritis (RA) is classically thought of as a Th1, T lymphocyte–driven disease of the adaptive immune system. However, cells of the innate immune system, including neutrophils, are prevalent within the diseased joint, and accumulate in large numbers. This study was undertaken to determine whether cells of the rheumatoid stromal microenvironment could establish an inflammatory environment in which endothelial cells are conditioned in a disease-specific manner to support neutrophil recruitment. METHODS: Human umbilical vein endothelial cells (ECs) and fibroblasts isolated from the synovium or skin of RA patients were established in coculture on opposite sides of porous transwell filters. After 24 hours of EC conditioning, the membranes were incorporated into a parallel-plate, flow-based adhesion assay and levels of neutrophil adhesion to ECs were measured. RESULTS: ECs cocultured with synovial, but not skin, fibroblasts could recruit neutrophils in a manner that was dependent on the number of fibroblasts. Antibody blockade of P-selectin or E-selectin reduced neutrophil adhesion, and an antibody against CD18 (the β2 integrin) abolished adhesion. Blockade of CXCR2, but not CXCR1, also greatly inhibited neutrophil recruitment. Interleukin-6 (IL-6) was detectable in coculture supernatants, and both IL-6 and neutrophil adhesion were reduced in a dose-dependent manner by hydrocortisone added to cocultures. Antibody blockade of IL-6 also effectively abolished neutrophil adhesion. CONCLUSION: Synovial fibroblasts from the rheumatoid joint play an important role in regulating the recruitment of inflammatory leukocytes during active disease. This process may depend on a previously unsuspected route of IL-6–mediated crosstalk between fibroblasts and endothelial cells

A mixed effect model for bivariate meta-analysis of diagnostic test accuracy studies using a copula representation of the random effects distribution

Diagnostic test accuracy studies typically report the number of true positives, false positives, true negatives and false negatives. There usually exists a negative association between the number of true positives and true negatives, because studies that adopt less stringent criterion for declaring a test positive invoke higher sensitivities and lower specificities. A generalized linear mixed model (GLMM) is currently recommended to synthesize diagnostic test accuracy studies. We propose a copula mixed model for bivariate meta-analysis of diagnostic test accuracy studies. Our general model includes the GLMM as a special case and can also operate on the original scale of sensitivity and specificity. Summary receiver operating characteristic curves are deduced for the proposed model through quantile regression techniques and different characterizations of the bivariate random effects distribution. Our general methodology is demonstrated with an extensive simulation study and illustrated by re-analysing the data of two published meta-analyses. Our study suggests that there can be an improvement on GLMM in fit to data and makes the argument for moving to copula random effects models. Our modelling framework is implemented in the package CopulaREMADA within the open source statistical environment R

Hybrid copula mixed models for combining case-control and cohort studies in meta-analysis of diagnostic tests

Copula mixed models for trivariate (or bivariate) meta-analysis of diagnostic test accuracy studies accounting (or not) for disease prevalence have been proposed in the biostatistics literature to synthesize information. However, many systematic reviews often include case-control and cohort studies, so one can either focus on the bivariate meta-analysis of the case-control studies or the trivariate meta-analysis of the cohort studies, as only the latter contains information on disease prevalence. In order to remedy this situation of wasting data we propose a hybrid copula mixed model via a combination of the bivariate and trivariate copula mixed model for the data from the case-control studies and cohort studies, respectively. Hence, this hybrid model can account for study design and also due to its generality can deal with dependence in the joint tails. We apply the proposed hybrid copula mixed model to a review of the performance of contemporary diagnostic imaging modalities for detecting metastases in patients with melanoma

Quasi-static imaged-based immersed boundary-finite element model of human left ventricle in diastole

SUMMARY: Finite stress and strain analyses of the heart provide insight into the biomechanics of myocardial function and dysfunction. Herein, we describe progress toward dynamic patient-specific models of the left ventricle using an immersed boundary (IB) method with a finite element (FE) structural mechanics model. We use a structure-based hyperelastic strain-energy function to describe the passive mechanics of the ventricular myocardium, a realistic anatomical geometry reconstructed from clinical magnetic resonance images of a healthy human heart, and a rule-based fiber architecture. Numerical predictions of this IB/FE model are compared with results obtained by a commercial FE solver. We demonstrate that the IB/FE model yields results that are in good agreement with those of the conventional FE model under diastolic loading conditions, and the predictions of the LV model using either numerical method are shown to be consistent with previous computational and experimental data. These results are among the first to analyze the stress and strain predictions of IB models of ventricular mechanics, and they serve both to verify the IB/FE simulation framework and to validate the IB/FE model. Moreover, this work represents an important step toward using such models for fully dynamic fluid–structure interaction simulations of the heart

Harnessing global fisheries to tackle micronutrient deficiencies

Micronutrient deficiencies account for an estimated one million premature deaths annually, and for some nations can reduce gross domestic product1,2 by up to 11%, highlighting the need for food policies that focus on improving nutrition rather than simply increasing the volume of food produced3. People gain nutrients from a varied diet, although fish—which are a rich source of bioavailable micronutrients that are essential to human health4—are often overlooked. A lack of understanding of the nutrient composition of most fish5 and how nutrient yields vary among fisheries has hindered the policy shifts that are needed to effectively harness the potential of fisheries for food and nutrition security6. Here, using the concentration of 7 nutrients in more than 350 species of marine fish, we estimate how environmental and ecological traits predict nutrient content of marine finfish species. We use this predictive model to quantify the global spatial patterns of the concentrations of nutrients in marine fisheries and compare nutrient yields to the prevalence of micronutrient deficiencies in human populations. We find that species from tropical thermal regimes contain higher concentrations of calcium, iron and zinc; smaller species contain higher concentrations of calcium, iron and omega-3 fatty acids; and species from cold thermal regimes or those with a pelagic feeding pathway contain higher concentrations of omega-3 fatty acids. There is no relationship between nutrient concentrations and total fishery yield, highlighting that the nutrient quality of a fishery is determined by the species composition. For a number of countries in which nutrient intakes are inadequate, nutrients available in marine finfish catches exceed the dietary requirements for populations that live within 100 km of the coast, and a fraction of current landings could be particularly impactful for children under 5 years of age. Our analyses suggest that fish-based food strategies have the potential to substantially contribute to global food and nutrition security

When is giving an impulse? An ERP investigation of intuitive prosocial behavior

Human prosociality is often assumed to emerge from exerting reflective control over initial, selfish impulses. However, recent findings suggest that prosocial actions can also stem from processes that are fast, automatic and intuitive. Here, we attempt to clarify when prosocial behavior may be intuitive by examining prosociality as a form of reward seeking. Using event-related potentials (ERPs), we explored whether a neural signature that rapidly encodes the motivational salience of an event\u2014the P300\u2014can predict intuitive prosocial motivation. Participants allocated varying amounts of money between themselves and charities they initially labelled as high- or low-empathy targets under conditions that promoted intuitive or reflective decision making. Consistent with our predictions, P300 amplitude over centroparietal regions was greater when giving involved high-empathy targets than low-empathy targets, but only when deciding under intuitive conditions. Reflective conditions, alternatively, elicited an earlier frontocentral positivity related to response inhibition, regardless of target. Our findings suggest that during prosocial decision making, larger P300 amplitude could (i) signal intuitive prosocial motivation and (ii) predict subsequent engagement in prosocial behavior. This work offers novel insight into when prosociality may be driven by intuitive processes and the roots of such behaviors

Decision-making in percutaneous coronary intervention: a survey

<p>Abstract</p> <p>Background</p> <p>Few researchers have examined the perceptions of physicians referring cases for angiography regarding the degree to which collaboration occurs during percutaneous coronary intervention (PCI) decision-making. We sought to determine perceptions of physicians concerning their involvement in PCI decisions in cases they had referred to the cardiac catheterization laboratory at a major academic medical center.</p> <p>Methods</p> <p>An anonymous survey was mailed to internal medicine faculty members at a major academic medical center. The survey elicited whether responders perceived that they were included in decision-making regarding PCI, and whether they considered such collaboration to be the best process of decision-making.</p> <p>Results</p> <p>Of the 378 surveys mailed, 35% (133) were returned. Among responding non-cardiologists, 89% indicated that in most cases, PCI decisions were made solely by the interventionalist at the time of the angiogram. Among cardiologists, 92% indicated that they discussed the findings with the interventionalist prior to any PCI decisions. When asked what they considered the best process by which PCI decisions are made, 66% of non-cardiologists answered that they would prefer collaboration between either themselves or a non-interventional cardiologist and the interventionalist. Among cardiologists, 95% agreed that a collaborative approach is best.</p> <p>Conclusion</p> <p>Both non-cardiologists and cardiologists felt that involving another decision-maker, either the referring physician or a non-interventional cardiologist, would be the best way to make PCI decisions. Among cardiologists, there was more concordance between what they believed was the best process for making decisions regarding PCI and what they perceived to be the actual process.</p

Viral Hepatitis and Rapid Diagnostic Test Based Screening for HBsAg in HIV-infected Patients in Rural Tanzania.

\ud \ud Co-infection with hepatitis B virus (HBV) is highly prevalent in people living with HIV in Sub-Saharan Africa. Screening for HBV surface antigen (HBsAg) before initiation of combination antiretroviral therapy (cART) is recommended. However, it is not part of diagnostic routines in HIV programs in many resource-limited countries although patients could benefit from optimized antiretroviral therapy covering both infections. Screening could be facilitated by rapid diagnostic tests for HBsAg. Operating experience with these point of care devices in HIV-positive patients in Sub-Saharan Africa is largely lacking. We determined the prevalence of HBV and Hepatitis C virus (HCV) infection as well as the diagnostic accuracy of the rapid test device Determine HBsAg in an HIV cohort in rural Tanzania. Prospectively collected blood samples from adult, HIV-1 positive and antiretroviral treatment-naïve patients in the Kilombero and Ulanga antiretroviral cohort (KIULARCO) in rural Tanzania were analyzed at the point of care with Determine HBsAg, a reference HBsAg EIA and an anti-HCV EIA. Samples of 272 patients were included. Median age was 38 years (interquartile range [IQR] 32-47), 169/272 (63%) subjects were females and median CD4+ count was 250 cells/µL (IQR 97-439). HBsAg was detected in 25/272 (9.2%, 95% confidence interval [CI] 6.2-13.0%) subjects. Of these, 7/25 (28%) were positive for HBeAg. Sensitivity of Determine HBsAg was rated at 96% (95% CI 82.8-99.6%) and specificity at 100% (95% CI, 98.9-100%). Antibodies to HCV (anti-HCV) were found in 10/272 (3.7%, 95% CI 2.0-6.4%) of patients. This study reports a high prevalence of HBV in HIV-positive patients in a rural Tanzanian setting. The rapid diagnostic test Determine HBsAg is an accurate assay for screening for HBsAg in HIV-1 infected patients at the point of care and may further help to guide cART in Sub-Saharan Africa

Long-term exposure to environmental concentrations of the pharmaceutical ethynylestradiol causes reproductive failure in fish

International audienceHeightened concern over endocrine-disrupting chemicals is driven by the hypothesis that they could reduce reproductive success and affect wildlife populations, but there is little evidence for this expectation. The pharmaceutical ethynylestradiol (EE(2)) is a potent endocrine modulator and is present in the aquatic environment at biologically active concentrations. To investigate impacts on reproductive success and mechanisms of disruption, we exposed breeding populations (n = 12) of zebrafish (Danio rerio) over multiple generations to environmentally relevant concentrations of EE(2). Life-long exposure to 5 ng/L EE(2) in the F, generation caused a 56% reduction in fecundity and complete population failure with no fertilization. Conversely, the same level of exposure for up to 40 days in mature adults in the parental F(0) generation had no impact on reproductive success. Infertility in the F, generation after life-long exposure to 5 ng/L EE(2) was due to disturbed sexual differentiation, with males having no functional testes and either undifferentiated or intersex gonads. These F, males also showed a reduced vitellogenic response when compared with F(0) males, indicating an acclimation to EE(2) exposure. Deputation studies found only a partial recovery in reproductive capacity after 5 months. Significantly, even though the F(0) males lacked functional testes, they showed male-pattern reproductive behavior, inducing the spawning act and competing with healthy males to disrupt fertilization. Endocrine disruption is therefore likely to affect breeding dynamics and reproductive success in group-spawning fish. Our findings raise major concerns about the population-level impacts for wildlife of long-term exposure to low concentrations of estrogenic endocrine disruptors