That\u27s An Irish Lullaby (Too-ra-loo-ra-loo-ral)

[Verse 1] Over in Killarney, Many years ago, Me Mither sang a song to me In tones so sweet and low, Just a simple little ditty, In her good ould Irish way, And I’d give the world if she could sing That song to me this day. [Chorus] “Too-ra-loo-ra-loo-ral, Too-ra-loo-ra-li, Too-ra-loo-ra-loo-ral, Hush now, don’t you cry! Too-ra-loo-ra-loo-ral, Too-ra-loo-ra-li, Too-ra-loo-ra-loo-ral, That’s an Irish lullaby.” [Verse 2] Oft, in dreams, I wander To that cot again, I feel her arms a huggin’ me As when she held me then. And I hear her voice a hummin’ To me as in days of yore, When she used to tuck me fast asleep Outside the cabin door. [Chorus

Is incident rheumatoid arthritis interstitial lung disease associated with methotrexate treatment? Results from a multivariate analysis in the ERAS and ERAN inception cohorts

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.Objectives To assess predictive factors for rheumatoid arthritis interstitial lung disease (RA-ILD) in two early RA inception cohorts with a focus on methotrexate (MTX) exposure. Design Multicenter prospective early RA inception cohort studies; the early RA study (ERAS) and the early RA network (ERAN) Setting Secondary care, ERAS 9 centers, ERAN 23 centers in England, Wales and the Republic of Ireland Participants Patients with new diagnosis of RA, n=2701.Standardised data including demographics, drug therapies and clinical outcomes including the presence of RA-ILD were collected at baseline, within 3- 6 months, at 12 months and annually thereafter. Primary and secondary outcome measures Primary outcome was the association of MTX exposure on RA-ILD diagnosis. Secondary outcomes were the association of demographic, comorbid and RA specific factors on RA-ILD diagnosis and the association of MTX exposure on time to RA-ILD diagnosis. Results Of 92 eligible ILD cases, 39 occurred in 1578 (2.5%) MTX exposed and 53 in 1114 (4.8%) non-MTX exposed cases. The primary analysis of RA-ILD cases only developing after any csDMARD treatment (n=67) showed MTX exposure not to be associated with incident RA-ILD (O.R. 0.85 CI 0.49, 1.49 p=0.578) and a non-significant trend for delayed ILD diagnosis (O.R. 0.54 CI 0.28, 1.06 p=0.072). In an extended analysis including RA-ILD cases present at RA diagnosis (n=92), MTX exposure was associated with a significantly reduced risk of incident RA-ILD (O.R. 0.48, CI 0.3, 0.79 p=0.004) and longer time to ILD diagnosis (O.R. 0.41, CI 0.23, 0.75 p=0.004). Other independent baseline associations with incident RA-ILD were higher age of RA onset, ever smoking, male gender, rheumatoid nodules and longer time from first RA symptom to first out-patient visit. Conclusions MTX treatment was not associated with an increased risk of RA-ILD diagnosis. On the contrary evidence suggested that MTX may delay the onset of ILD.Peer reviewe

Citrullinated vimentin as an important antigen in immune complexes from synovial fluid of rheumatoid arthritis patients with antibodies against citrullinated proteins

Introduction: Rheumatoid arthritis (RA) is an inflammatory disease, which results in destruction of the joint. The presence of immune complexes (IC) in serum and synovial fluid of RA patients might contribute to this articular damage through different mechanisms, such as complement activation. Therefore, identification of the antigens from these IC is important to gain more insight into the pathogenesis of RA. Since RA patients have antibodies against citrullinated proteins (ACPA) in their serum and synovial fluid (SF) and since elevated levels of citrullinated proteins are detected in the joints of RA patients, citrullinated antigens are possibly present in IC from RA patients. Methods: IC from serum of healthy persons, serum of RA patients and IC from synovial fluid of RA patients and Spondyloarthropathy (SpA) patients were isolated by immunoprecipitation. Identification of the antigens was performed by SDS-PAGE, mass spectrometry and immunodetection. The presence of citrullinated proteins was evaluated by anti-modified citrulline (AMC) staining. Results: Circulating IC in the serum of RA patients and healthy controls contain fibrinogen beta and fibronectin, both in a non-citrullinated form. Additionally, in IC isolated from RA SF, fibrinogen. and vimentin were identified as well. More importantly, vimentin and a minor portion of fibrinogen beta were found to be citrullinated in the isolated complexes. Moreover these citrullinated antigens were only found in ACPA+ patients. No citrullinated antigens were found in IC from SF of SpA patients. Conclusions: Citrullinated fibrinogen beta and citrullinated vimentin were found in IC from SF of ACPA+ RA patients, while no citrullinated antigens were found in IC from SF of ACPA-RA patients or SpA patients or in IC from serum of RA patients or healthy volunteers. The identification of citrullinated vimentin as a prominent citrullinated antigen in IC from SF of ACPA+ RA patients strengthens the hypothesis that citrullinated vimentin plays an important role in the pathogenesis of RA

Regulating Retinoic Acid Availability during Development and Regeneration: The Role of the CYP26 Enzymes.

This review focuses on the role of the Cytochrome p450 subfamily 26 (CYP26) retinoic acid (RA) degrading enzymes during development and regeneration. Cyp26 enzymes, along with retinoic acid synthesising enzymes, are absolutely required for RA homeostasis in these processes by regulating availability of RA for receptor binding and signalling. Cyp26 enzymes are necessary to generate RA gradients and to protect specific tissues from RA signalling. Disruption of RA homeostasis leads to a wide variety of embryonic defects affecting many tissues. Here, the function of CYP26 enzymes is discussed in the context of the RA signalling pathway, enzymatic structure and biochemistry, human genetic disease, and function in development and regeneration as elucidated from animal model studies

Regulating Retinoic Acid Availability during Development and Regeneration: The Role of the CYP26 Enzymes.

This review focuses on the role of the Cytochrome p450 subfamily 26 (CYP26) retinoic acid (RA) degrading enzymes during development and regeneration. Cyp26 enzymes, along with retinoic acid synthesising enzymes, are absolutely required for RA homeostasis in these processes by regulating availability of RA for receptor binding and signalling. Cyp26 enzymes are necessary to generate RA gradients and to protect specific tissues from RA signalling. Disruption of RA homeostasis leads to a wide variety of embryonic defects affecting many tissues. Here, the function of CYP26 enzymes is discussed in the context of the RA signalling pathway, enzymatic structure and biochemistry, human genetic disease, and function in development and regeneration as elucidated from animal model studies

A Global Treatment Of VMD Physics Up To The ϕ\phi: I. e+e−e^+e^- Annihilations, Anomalies And Vector Meson Partial Widths

The HLS Model, equipped with a mechanism providing the breaking of U(3)/SU(3) symmetry and an isospin symmetry breaking leading naturally to vector meson mixing, has been recently shown to successfully account for e^+ e^- \ra \pi^+\pi^- cross section and for the dipion spectrum in $\tau$ decay. The present study shows that the full anomalous sector of the HLS model can be considered and is validated by the experimental data. Indeed, this extended model provides a successful simultaneous fit to the e^+ e^- \ra \pi^+\pi^- data together with the available data on e^+ e^- \ra \pi^0\gamma, e^+ e^- \ra \eta\gamma and e^+ e^- \ra \pi^0 \pi^+\pi^- cross sections. It is shown that the fit of these data sets also predicts an accurate description of the \eta/\eta^\prime \ra \pi^+ \pi^- \gamma decays fully consistent with the reported information on their branching fractions and spectra. Finally, one also derives from our global fits products of widths of the form \Gamma (V \ra f_1)\Gamma(V \ra e^+ e^-) and ratios of the form \Gamma (V \ra f_1)/\Gamma (V \ra f_2) describing decays of vector mesons to several non--leptonic final states.Comment: 58 pages, 10 figures Corrected a few misprints. Footnote 10 change

Microbiota and bile acid profiles in retinoic acid-primed mice that exhibit accelerated liver regeneration.

Background & aimsAll-trans Retinoic acid (RA) regulates hepatic lipid and bile acid homeostasis. Similar to bile acid (BA), RA accelerates partial hepatectomy (PHx)-induced liver regeneration. Because there is a bidirectional regulatory relationship between gut microbiota and BA synthesis, we examined the effect of RA in altering the gut microbial population and BA composition and established their relationship with hepatic biological processes during the active phases of liver regeneration.MethodsC57BL/6 mice were treated with RA orally followed by 2/3 PHx. The roles of RA in shifting gut microbiota and BA profiles as well as hepatocyte metabolism and proliferation were studied.ResultsRA-primed mice exhibited accelerated hepatocyte proliferation revealed by higher numbers of Ki67-positive cells compared to untreated mice. Firmicutes and Bacteroidetes phyla dominated the gut microbial community (>85%) in both control and RA-primed mice after PHx. RA reduced the ratio of Firmicutes to Bacteroidetes, which was associated with a lean phenotype. Consistently, RA-primed mice lacked transient lipid accumulation normally found in regenerating livers. In addition, RA altered BA homeostasis and shifted BA profiles by increasing the ratio of hydrophilic to hydrophobic BAs in regenerating livers. Accordingly, metabolic regulators fibroblast growth factor 21, Sirtuin1, and their downstream targets AMPK and ERK1/2 were more robustly activated in RA-primed than unprimed regenerating livers.ConclusionsPriming mice with RA resulted in a lean microbiota composition and hydrophilic BA profiles, which were associated with facilitated metabolism and enhanced cell proliferation

Applicability of trials in rheumatoid arthritis and osteoarthritis: A systematic review and meta-analysis of trial populations showing adequate proportion of women, but underrepresentation of elderly people

Objectives: To evaluate whether elderly people and women are adequately represented in randomized controlled trials (RCT) in rheumatoid arthritis (RA) and osteoarthritis (OA). Methods: Four systematic searches in MEDLINE yielded RCT in RA and OA on any intervention published in 2016 and 2017 and population-based studies (PBS) in RA and OA published between 2013 and 2017. Random effects meta-analyses estimated the pooled proportion of elderly people (defined as being ≥ 65 years old), the mean age, its standard deviation (SD), and the proportion of women stratified by disease (RA and OA) and study type (RCT and PBS). Stratified estimates were subsequently compared. Results: 265 RCT comprising 51,240 participants and 53 PBS comprising 523,630 participants were included. In both RA and OA, RCT included lower proportions of elderly people than PBS: RA –0.18 (95% confidence interval –0.22 to –0.13); OA –0.20 (–0.30 to –0.09); had lower mean ages: RA –5.2 years (–6.8 to –3.5); OA –4.7 years (–7.5 to –2.0); and smaller SD: RA –1.9 years (–2.6 to –1.3); OA –2.7 years (–4.2 to –1.2); (all comparisons: p ≤ 0.001). Proportions of women were comparable in RCT compared to PBS in both RA and OA. Conclusions: While women are adequately represented in RA and OA trials, the elderly are underrepresented, probably limiting applicability of current evidence to this growing subgroup. It is urgent to improve the inclusion of elderly people in clinical trials and study age as a determinant for outcome

A Global Treatment Of VMD Physics Up To The ϕ\phi: I. e+e−e^+e^- Annihilations, Anomalies And Vector Meson Partial Widths

The HLS Model, equipped with a mechanism providing the breaking of U(3)/SU(3) symmetry and an isospin symmetry breaking leading naturally to vector meson mixing, has been recently shown to successfully account for e^+ e^- \ra \pi^+\pi^- cross section and for the dipion spectrum in $\tau$ decay. The present study shows that the full anomalous sector of the HLS model can be considered and is validated by the experimental data. Indeed, this extended model provides a successful simultaneous fit to the e^+ e^- \ra \pi^+\pi^- data together with the available data on e^+ e^- \ra \pi^0\gamma, e^+ e^- \ra \eta\gamma and e^+ e^- \ra \pi^0 \pi^+\pi^- cross sections. It is shown that the fit of these data sets also predicts an accurate description of the \eta/\eta^\prime \ra \pi^+ \pi^- \gamma decays fully consistent with the reported information on their branching fractions and spectra. Finally, one also derives from our global fits products of widths of the form \Gamma (V \ra f_1)\Gamma(V \ra e^+ e^-) and ratios of the form \Gamma (V \ra f_1)/\Gamma (V \ra f_2) describing decays of vector mesons to several non--leptonic final states.Comment: 58 pages, 10 figures Corrected a few misprints. Footnote 10 change