Citrullination facilitates cross-reactivity of rheumatoid factor with non-IgG1 Fc epitopes in rheumatoid arthritis

Rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPAs) are the two most prevalent autoantibodies in rheumatoid arthritis (RA), and are thought to have distinct autoantigen targets. Whilst RF targets the Fc region of antibodies, ACPAs target a far broader spectrum of citrullinated peptides. Here we demonstrate significant sequence and structural homology between proposed RF target epitopes in IgG1 Fc and the ACPA target fibrinogen. Two of the three homologous sequences were susceptible to citrullination, and this modification, which occurs extensively in RA, permitted significant cross-reactivity of RF+ patient sera with fibrinogen in both western blots and ELISAs. Crucially, this reactivity was specific to RF as it was absent in RF− patient and healthy control sera, and could be inhibited by pre-incubation with IgG1 Fc. These studies establish fibrinogen as a common target for both RF and ACPAs, and suggest a new mechanism in RF-mediated autoimmune diseases wherein RF may act as a precursor from which the ACPA response evolves

Virus Infection of Plants Alters Pollinator Preference: A Payback for Susceptible Hosts?

Plant volatiles play important roles in attraction of certain pollinators and in host location by herbivorous insects. Virus infection induces changes in plant volatile emission profiles, and this can make plants more attractive to insect herbivores, such as aphids, that act as viral vectors. However, it is unknown if virus-induced alterations in volatile production affect plant-pollinator interactions. We found that volatiles emitted by cucumber mosaic virus (CMV)-infected tomato (Solanum lycopersicum) and Arabidopsis thaliana plants altered the foraging behaviour of bumblebees (Bombus terrestris). Virus-induced quantitative and qualitative changes in blends of volatile organic compounds emitted by tomato plants were identified by gas chromatography-coupled mass spectrometry. Experiments with a CMV mutant unable to express the 2b RNA silencing suppressor protein and with Arabidopsis silencing mutants implicate microRNAs in regulating emission of pollinator-perceivable volatiles. In tomato, CMV infection made plants emit volatiles attractive to bumblebees. Bumblebees pollinate tomato by 'buzzing' (sonicating) the flowers, which releases pollen and enhances self-fertilization and seed production as well as pollen export. Without buzz-pollination, CMV infection decreased seed yield, but when flowers of mock-inoculated and CMV-infected plants were buzz-pollinated, the increased seed yield for CMV-infected plants was similar to that for mock-inoculated plants. Increased pollinator preference can potentially increase plant reproductive success in two ways: i) as female parents, by increasing the probability that ovules are fertilized; ii) as male parents, by increasing pollen export. Mathematical modeling suggested that over a wide range of conditions in the wild, these increases to the number of offspring of infected susceptible plants resulting from increased pollinator preference could outweigh underlying strong selection pressures favoring pathogen resistance, allowing genes for disease susceptibility to persist in plant populations. We speculate that enhanced pollinator service for infected individuals in wild plant populations might provide mutual benefits to the virus and its susceptible hosts.Major funding for this project was provided to JPC by the Leverhulme Trust (Grant numbers RPG-2012-667 and F/09741/F: https://www. leverhulme.ac.uk/). Additional funding to JPC and studentships to support JHW and SCG came from the Biotechnological and Biological Sciences Research Council (Grant number BB/J011762/1: http://www.bbsrc.ac.uk/). Other additional funding was obtained from the Isaac Newton Trust (http://www. newtontrust.cam.ac.uk/: grant number 12.07/I to AMM).This is the final version of the article. It first appeared from the Public Library of Science via http://dx.doi.org/:10.1371/journal.ppat.100579

Natural killer (NK) cells from killers to regulators: Distinct features between peripheral blood and decidual NK cells

Natural killer (NK) cells are a key component of innate immunity, particularly crucial during the early phase of immune responses against certain viruses, parasites, and microbial pathogens. The role of NK cell during pregnancy has been vividly discussed over the past years and it is now becoming increasingly clear that NK cells control pregnancy maintenance at several levels. In normal pregnancy, it appears that they provide benefit by properly secreting cytokines, chemokines and angiogenic factors rather than functioning as cytotoxic effector cells. However, as they are endowed with all the cytolytic weapons, they promptly become capable of attacking fetal and maternal tissues during infection and inflammation. © 2007 The Authors Journal compilation 2007 Blackwell Munksgaard

Rapid tests and urine sampling techniques for the diagnosis of urinary tract infection (UTI) in children under five years: a systematic review

Background: Urinary tract infection (UTI) is one of the most common sources of infection in children under five. Prompt diagnosis and treatment is important to reduce the risk of renal scarring. Rapid, cost-effective, methods of UTI diagnosis are required as an alternative to culture. Methods: We conducted a systematic review to determine the diagnostic accuracy of rapid tests for detecting UTI in children under five years of age. Results: The evidence supports the use of dipstick positive for both leukocyte esterase and nitrite (pooled LR+ = 28.2, 95% CI: 17.3, 46.0) or microscopy positive for both pyuria and bacteriuria (pooled LR+ = 37.0, 95% CI: 11.0, 125.9) to rule in UTI. Similarly dipstick negative for both LE and nitrite (Pooled LR- = 0.20, 95% CI: 0.16, 0.26) or microscopy negative for both pyuria and bacteriuria (Pooled LR- = 0.11, 95% CI: 0.05, 0.23) can be used to rule out UTI. A test for glucose showed promise in potty-trained children. However, all studies were over 30 years old. Further evaluation of this test may be useful. Conclusion: Dipstick negative for both LE and nitrite or microscopic analysis negative for both pyuria and bacteriuria of a clean voided urine, bag, or nappy/pad specimen may reasonably be used to rule out UTI. These patients can then reasonably be excluded from further investigation, without the need for confirmatory culture. Similarly, combinations of positive tests could be used to rule in UTI, and trigger further investigation

Methodological quality of test accuracy studies included in systematic reviews in obstetrics and gynaecology: sources of bias

<p>Abstract</p> <p>Background</p> <p>Obstetrics and gynaecology have seen rapid growth in the development of new tests with research on these tests presented as diagnostic accuracy studies. To avoid errors in judgement it is important that the methodology of these studies is such that bias is minimised. Our objective was to determine the methodological quality of test accuracy studies in obstetrics and gynaecology using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) checklist and to assess sources of bias.</p> <p>Methods</p> <p>A prospective protocol was developed to assess the impact of QUADAS on ten systematic reviews performed over the period 2004-2007.We investigated whether there was an improvement in study quality since the introduction of QUADAS, whether a correlation existed between study sample size, country of origin of study and its quality. We also investigated whether there was a correlation between reporting and methodological quality and by the use of meta-regression analyses explored for items of quality that were associated with bias.</p> <p>Results</p> <p>A total of 300 studies were included. The overall quality of included studies was poor (> 50% compliance with 57.1% of quality items). However, the mean compliance with QUADAS showed an improvement post-publication of QUADAS (54.9% versus 61.4% p = 0.002). There was no correlation with study sample size. Gynaecology studies published from the United States of America showed higher quality (USA versus Western Europe p = 0.002; USA versus Asia p = 0.004). Meta-regression analysis showed that no individual quality item had a significant impact on accuracy. There was an association between reporting and methodological quality (r = 0.51 p < 0.0001 for obstetrics and r = 0.56 p < 0.0001 for gynaecology).</p> <p>Conclusions</p> <p>A combination of poor methodological quality and poor reporting affects the inferences that can be drawn from test accuracy studies. Further compliance with quality checklists is required to ensure that bias is minimised.</p

Uptake and Metabolism of the Novel Peptide Angiotensin-(1-12) by Neonatal Cardiac Myocytes

Angiotensin-(1-12) [Ang-(1-12)] functions as an endogenous substrate for the productions of Ang II and Ang-(1-7) by a non-renin dependent mechanism. This study evaluated whether Ang-(1-12) is incorporated by neonatal cardiac myocytes and the enzymatic pathways of ¹²⁵I-Ang-(1-12) metabolism in the cardiac myocyte medium from WKY and SHR rats.The degradation of ¹²⁵I-Ang-(1-12) (1 nmol/L) in the cultured medium of these cardiac myocytes was evaluated in the presence and absence of inhibitors for angiotensin converting enzymes 1 and 2, neprilysin and chymase. In both strains uptake of ¹²⁵I-Ang-(1-12) by myocytes occurred in a time-dependent fashion. Uptake of intact Ang-(1-12) was significantly greater in cardiac myocytes of SHR as compared to WKY. In the absence of renin angiotensin system (RAS) enzymes inhibitors the hydrolysis of labeled Ang-(1-12) and the subsequent generation of smaller Ang peptides from Ang-(1-12) was significantly greater in SHR compared to WKY controls. ¹²⁵I-Ang-(1-12) degradation into smaller Ang peptides fragments was significantly inhibited (90% in WKY and 71% in SHR) in the presence of all RAS enzymes inhibitors. Further analysis of peptide fractions generated through the incubation of Ang-(1-12) in the myocyte medium demonstrated a predominant hydrolytic effect of angiotensin converting enzyme and neprilysin in WKY and an additional role for chymase in SHR.These studies demonstrate that neonatal myocytes sequester angiotensin-(1-12) and revealed the enzymes involved in the conversion of the dodecapeptide substrate to biologically active angiotensin peptides

A cross-sectional study of different patterns of oral contraceptive use among premenopausal women and circulating IGF-1: implications for disease risk

<p>Abstract</p> <p>Background</p> <p>Insulin-like growth factor-1 (IGF-1) is important in normal growth, development, and homeostasis. Current use of oral contraceptives (OC) decreases IGF-1 concentrations; however, the effect of past use, age/timing of use, and type of OC used on IGF-1 levels is unknown. OC are the most commonly used form of birth control worldwide. Both IGF-1 and OC use have been linked to premenopausal breast and colorectal cancers, osteoporosis and cardiovascular disease (CVD). Understanding the effects of different patterns of OC use on IGF-1 levels may offer insight into its influence on disease risk in young women.</p> <p>Methods</p> <p>In a cross-sectional study of 328 premenopausal women ages 18 to 21 and 31 to 40 we examined the relationship between different patterns of OC use and circulating IGF-1 using adjusted linear regression analysis. Information on OC use was obtained through an interviewer administered questionnaire. Plasma IGF-1 was assessed with enzyme linked immunosorbent assay (ELISA).</p> <p>Results</p> <p>Among women aged 18 to 21, ever OC use was significantly associated with decreased IGF-1 levels compared to never use (β = -57.2 ng/ml, 95% confidence interval (CI): -88.7, -25.8). Among women aged 31 to 40, past users who first used OC at 25 years of age or older (β = 43.8 ng/ml, 95% CI: 8.8, 78.8), in the last 15 years (β = 35.1 ng/ml, 95% CI: 9.3, 61.0) or after 1995 (β = 46.6 ng/ml, 95% CI: 13.4, 79.8) had significantly higher IGF-1 levels compared to never users.</p> <p>Conclusion</p> <p>This is the first study to highlight the long term effects of OC use after cessation on IGF-1 levels among premenopausal women, which previously were thought to be transitory. Future studies of past use and IGF-1 levels are required and must consider age/timing of use and type/generation of OC used. Additional studies are needed to confirm the potential mediation of IGF-1 levels in the links between OC use and health outcomes.</p

How does study quality affect the results of a diagnostic meta-analysis?

Background: The use of systematic literature review to inform evidence based practice in diagnostics is rapidly expanding. Although the primary diagnostic literature is extensive, studies are often of low methodological quality or poorly reported. There has been no rigorously evaluated, evidence based tool to assess the methodological quality of diagnostic studies. The primary objective of this study was to determine the extent to which variations in the quality of primary studies impact the results of a diagnostic meta-analysis and whether this differs with diagnostic test type. A secondary objective was to contribute to the evaluation of QUADAS, an evidence-based tool for the assessment of quality in diagnostic accuracy studies. Methods: This study was conducted as part of large systematic review of tests used in the diagnosis and further investigation of urinary tract infection (UTI) in children. All studies included in this review were assessed using QUADAS, an evidence-based tool for the assessment of quality in systematic reviews of diagnostic accuracy studies. The impact of individual components of QUADAS on a summary measure of diagnostic accuracy was investigated using regression analysis. The review divided the diagnosis and further investigation of UTI into the following three clinical stages: diagnosis of UTI, localisation of infection, and further investigation of the UTI. Each stage used different types of diagnostic test, which were considered to involve different quality concerns. Results: Many of the studies included in our review were poorly reported. The proportion of QUADAS items fulfilled was similar for studies in different sections of the review. However, as might be expected, the individual items fulfilled differed between the three clinical stages. Regression analysis found that different items showed a strong association with test performance for the different tests evaluated. These differences were observed both within and between the three clinical stages assessed by the review. The results of regression analyses were also affected by whether or not a weighting (by sample size) was applied. Our analysis was severely limited by the completeness of reporting and the differences between the index tests evaluated and the reference standards used to confirm diagnoses in the primary studies. Few tests were evaluated by sufficient studies to allow meaningful use of meta-analytic pooling and investigation of heterogeneity. This meant that further analysis to investigate heterogeneity could only be undertaken using a subset of studies, and that the findings are open to various interpretations. Conclusion: Further work is needed to investigate the influence of methodological quality on the results of diagnostic meta-analyses. Large data sets of well-reported primary studies are needed to address this question. Without significant improvements in the completeness of reporting of primary studies, progress in this area will be limited

TRY plant trait database - enhanced coverage and open access

Plant traits-the morphological, anatomical, physiological, biochemical and phenological characteristics of plants-determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait-based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits-almost complete coverage for 'plant growth form'. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait-environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives

Bivariate random-effects meta-analysis and the estimation of between-study correlation

BACKGROUND: When multiple endpoints are of interest in evidence synthesis, a multivariate meta-analysis can jointly synthesise those endpoints and utilise their correlation. A multivariate random-effects meta-analysis must incorporate and estimate the between-study correlation (ρ(B)). METHODS: In this paper we assess maximum likelihood estimation of a general normal model and a generalised model for bivariate random-effects meta-analysis (BRMA). We consider two applied examples, one involving a diagnostic marker and the other a surrogate outcome. These motivate a simulation study where estimation properties from BRMA are compared with those from two separate univariate random-effects meta-analyses (URMAs), the traditional approach. RESULTS: The normal BRMA model estimates ρ(B )as -1 in both applied examples. Analytically we show this is due to the maximum likelihood estimator sensibly truncating the between-study covariance matrix on the boundary of its parameter space. Our simulations reveal this commonly occurs when the number of studies is small or the within-study variation is relatively large; it also causes upwardly biased between-study variance estimates, which are inflated to compensate for the restriction on [Formula: see text] (B). Importantly, this does not induce any systematic bias in the pooled estimates and produces conservative standard errors and mean-square errors. Furthermore, the normal BRMA is preferable to two normal URMAs; the mean-square error and standard error of pooled estimates is generally smaller in the BRMA, especially given data missing at random. For meta-analysis of proportions we then show that a generalised BRMA model is better still. This correctly uses a binomial rather than normal distribution, and produces better estimates than the normal BRMA and also two generalised URMAs; however the model may sometimes not converge due to difficulties estimating ρ(B). CONCLUSION: A BRMA model offers numerous advantages over separate univariate synthesises; this paper highlights some of these benefits in both a normal and generalised modelling framework, and examines the estimation of between-study correlation to aid practitioners