81 research outputs found
Increased disease activity, severity and autoantibody positivity in rheumatoid arthritis patients with co-existent bronchiectasis.
PublishedArticleCopyright © 2015 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty LtdAim: Patients with rheumatoid arthritis (RA) and co-existent Bronchiectasis (BRRA) have a 5-fold increased mortality compared to rheumatoid arthritis alone. Yet previous studies have found no difference in clinical and serological markers of RA disease severity between BRRA patients and RA alone. RA disease activity measures such as DAS28-CRP and anti-cyclic citrullinated peptide antibodies (anti-CCP) however have not been studied, so we assessed these parameters in patients with BRRA and RA alone. Methods: BRRA patients (n = 53) had HRCT proven bronchiectasis without any interstitial lung disease and ≥2 respiratory infections/year. RA alone patients (n = 50) had no clinical or radiological evidence of lung disease. DAS28-CRP, rheumatoid factor (IgM) and anti-CCP were measured in all patients, together with detailed clinical and radiology records. Results: In BRRA, BR predated RA in 58% of patients. BRRA patients had higher DAS28 scores (3.51 vs. 2.59), higher levels of anti-CCP (89 vs. 46%) and RF (79 vs. 52%) (p = 0.003) compared to RA alone. Where hand and foot radiology findings were recorded, 29/37 BRRA (78%) and 13/30 (43%) RA alone had evidence of erosive change (p = 0.003). There were no significant differences between groups in smoking history or DMARD/biologic therapy. Conclusions: Increased levels of RA disease activity, severity and RA autoantibodies are demonstrated in patients with RA and co-existent bronchiectasis compared to patients with RA alone, despite lower tobacco exposure. This study demonstrates that BRRA is a more severe systemic disease than RA alone.Arthritis Research UKHEFCECornwall Arthritis TrustNorthcott Devon Medical FoundationDutchy Health CharityNIHR CLR
Bronchiectasis: a model for chronic bacterial infection inducing autoimmunity in rheumatoid arthritis.
ArticleCopyright © 2015 The Authors. Arthritis & Rheumatology is published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology.Objective: Bronchiectasis (BR) is a risk factor for rheumatoid arthritis (RA). Here we examine the potential of BR in generating rheumatoid factors (RFs) and anti-citrullinated peptide antibodies (ACPA) in patients with BR alone and in patients with BR and RA (BRRA). Methods: We studied 122 patients with BR alone, 50 BRRA, 50 RA without lung disease, with 87 asthma and 79 healthy subjects as controls. RFs were measured by an automated analyzer, and ACPA using CCP2. Fine specificities to citrullinated α-enolase (CEP-1), citrullinated vimentin (cVim) and fibrinogen (cFib) with their arginine control peptides (REP-1, Vim and Fib) measured by ELISA. Results: In the BR patients 39% were ever smokers compared to 42% of the controls. Serum samples from BR patients had an increased frequency of RF (25%; p< 0.05) and 5% to CCP2, 7% to CEP-1, 7% to cVIM (all p=ns) and 12% cFib (p <0.05). There was also a corresponding increase in antibodies to the arginine-containing control peptides in the BR patients; REP-1, 19% (p< 0.01) and Vim, 16% (p<0.05), demonstrating that the ACPA response in BR is not citrulline-specific. Lack of citrulline specificity was further confirmed by absorption studies. In BRRA all ACPA specificities were highly citrulline-specific. Conclusion: Bronchiectasis is an unusual but potent model for the induction of autoimmunity in RA by bacterial infection in the lung. Our study suggests that in the early stages of tolerance breakdown, the ACPA response is not citrulline-specific, but becomes more so in those patients with BR that develop BRRA.Arthritis Research UKEuropean UnionIMI project BTCure7th Framework Programme project Gums and Joint
Tourist species bias estimates of extrapolated species density in dispersive taxa: a case study from a litter beetle assemblage in temperate woodland
Extrapolative nonparametric estimators of species density are commonly used in community ecology. However, they are
dependent on either (1) their use on non-dispersive taxa, or (2) the ability to separate tourists from residents in dispersive
taxa. We undertook ten years of leaf litter sampling in an ancient woodland in the New Forest, Southern England. We identi-
fied all the beetles from those samples and assigned them a residency status (residents, stratum tourists, and habitat tourists).
Extrapolations, using the Chao 2, first- and second-order jackknife, and bootstrap approaches, of all sampled beetles all
showed large overestimates of species richness when compared with extrapolations based on just residents. We recommend
that the estimators should be used with caution as estimates of actual species density for dispersive taxa unless the natural
history of most species in a community is well known. This applies especially to tropical ecosystems where many species
have not been described. This reinforces the need for more descriptive natural history
Galectin-9 Is a Possible Promoter of Immunopathology in Rheumatoid Arthritis by Activation of Peptidyl Arginine Deiminase 4 (PAD-4) in Granulocytes
The aetiology of rheumatoid arthritis (RA) is unknown, but citrullination of proteins is thought to be an initiating event. In addition, it is increasingly evident that the lung can be a potential site for the generation of autoimmune triggers before the development of joint disease. Here, we identified that serum levels of galectin-9 (Gal-9), a pleiotropic immunomodulatory protein, are elevated in RA patients, and are even further increased in patients with comorbid bronchiectasis, a lung disease caused by chronic inflammation. The serum concentrations of Gal-9 correlate with C-reactive protein levels and DAS-28 score. Gal-9 activated polymorphonuclear leukocytes (granulocytes) in vitro, which was characterized by increased cytokine secretion, migration, and survival. Further, granulocytes treated with Gal-9 upregulated expression of peptidyl arginine deiminase 4 (PAD-4), a key enzyme required for RA-associated citrullination of proteins. Correspondingly, treatment with Gal-9 triggered citrullination of intracellular granulocyte proteins that are known contributors to RA pathogenesis (i.e., myeloperoxidase, alpha-enolase, MMP-9, lactoferrin). In conclusion, this study identifies for the first time an immunomodulatory protein, Gal-9, that triggers activation of granulocytes leading to increased PAD-4 expression and generation of citrullinated autoantigens. This pathway may represent a potentially important mechanism for development of RA
Runaway stars as progenitors of supernovae and gamma-ray bursts
When a core collapse supernova occurs in a binary system, the surviving star
as well as the compact remnant emerging from the SN, may reach a substantial
space velocity. With binary population synthesis modelling at solar and one
fifth of solar metallicity, we predict the velocities of such runaway stars or
binaries. We compile predictions for runaway OB stars, red supergiants and
Wolf-Rayet stars. For those stars or binaries which undergo a second stellar
explosion we compute their further evolution and the distance travelled until a
Type II or Type Ibc SN or a long or short gamma-ray burst occurs. We find our
predicted population of OB runaway stars broadly matches the observed
population of stars but, to match the fastest observed WR runaway stars, we
require that black holes receive an asymmetric kick upon formation. We find
that at solar metallicity Type Ic SN progenitors travel shorter distances than
the progenitors of other SN types because they are typically more massive and
thus have shorter lifetimes. Those of Type IIP SN can fly farthest about 48 pc
on average at solar metallicity. In considering the consequences of assuming
that the progenitors of long GRBs are spun-up secondary stars that experience
quasi-homogeneous evolution, we find that such evolution has a dramatic effect
on the population of runaway WR stars and that some 30 per cent of GRBs could
occur a hundred parsecs or more from their initial positions. We also consider
mergers of double compact object binaries consisting of neutron stars and/or
black holes. We find the most common type of visible mergers are neutron
star--black hole mergers that are roughly ten times more common than neutron
star--neutron star mergers. We also find that there may be a population of
low-velocity neutron stars that are ejected from a binary rather than by their
own natal kick.Comment: Accepted for publication in MNRAS, 23 pages, 17 figures and 11
tables. Abstract was editted to fit within arXiv.org submission requirement
Discovery of a parsec-scale bipolar nebula around MWC 349A
We report the discovery of a bipolar nebula around the peculiar emission-line
star MWC 349A using archival Spitzer Space Telescope 24 um data. The nebula
extends over several arcminutes (up to 5 pc) and has the same orientation and
geometry as the well-known subarcsecond-scale (~400 times smaller) bipolar
radio nebula associated with this star. We discuss the physical relationship
between MWC 349A and the nearby B0 III star MWC 349B and propose that both
stars were members of a hierarchical triple system, which was ejected from the
core of the Cyg OB2 association several Myr ago and recently was dissolved into
a binary system (now MWC 349A) and a single unbound star (MWC 349B). Our
proposal implies that MWC 349A is an evolved massive star (likely a luminous
blue variable) in a binary system with a low-mass star. A possible origin of
the bipolar nebula around MWC 349A is discussed.Comment: 9 pages, 6 figures, accepted for publication in A&
Specialist multidisciplinary input maximises rare disease diagnoses from whole genome sequencing
Diagnostic whole genome sequencing (WGS) is increasingly used in rare diseases. However, standard, semi-automated WGS analysis may overlook diagnoses in complex disorders. Here, we show that specialist multidisciplinary analysis of WGS, following an initial 'no primary findings' (NPF) report, improves diagnostic rates and alters management. We undertook WGS in 102 adults with diagnostically challenging primary mitochondrial disease phenotypes. NPF cases were reviewed by a genomic medicine team, thus enabling bespoke informatic approaches, co-ordinated phenotypic validation, and functional work. We enhanced the diagnostic rate from 16.7% to 31.4%, with management implications for all new diagnoses, and detected strong candidate disease-causing variants in a further 3.9% of patients. This approach presents a standardised model of care that supports mainstream clinicians and enhances diagnostic equity for complex disorders, thereby facilitating access to the potential benefits of genomic healthcare. This research was made possible through access to the data and findings generated by the 100,000 Genomes Project: http://www.genomicsengland.co.uk
Global Soil Biodiversity Atlas
Soils provide numerous ecosystem services. Most people do not know that the key drivers of soil ecosystems are the living organisms within the soil. Soils may be home to over one fourth of all living species on Earth, with a significant part not yet characterized. The first Global Soil Biodiversity Atlas is a product of the Global Soil Biodiversity Initiative. It aims at raising awareness of the importance and beauty of soil biodiversity among the general public and policy makers. Furthermore, it highlights the need to increase efforts to develop a global assessment of soil biodiversity. Data on distribution of soil-dwelling organisms are often difficult to combine. The atlas represents an attempt to create a unique network among soil biodiversity scientists. Such an effort may help in reaching the level of attention that research on soil biodiversity deserves. With contributions from over 80 experts in soil biodiversity from all over the world, and over 170 pages, the atlas will also display distribution maps of the main soil organisms. Furthermore, an exceptionally high number of images will allow non-specialists to get in touch with this fascinating and mysterious world.JRC.D.6-Knowledge for Sustainable Development and Food Securit
The death of massive stars - I. Observational constraints on the progenitors of type II-P supernovae
We present the results of a 10.5 yr, volume limited (28 Mpc) search for
supernova (SN) progenitor stars. We compile all SNe discovered within this
volume (132, of which 27% are type Ia) and determine the relative rates of each
sub-type from literature studies : II-P (59%), Ib/c (29%), IIb (5%), IIn (4%)
and II-L (3%). Twenty II-P SNe have high quality optical or near-IR
pre-explosion images that allow a meaningful search for the progenitor stars.
In five cases they are clearly red supergiants, one case is unconstrained, two
fall on compact coeval star clusters and the other twelve have no progenitor
detected. We review and update all the available data for the host galaxies
(distance, metallicity and extinction) and determine masses and upper mass
estimates using the STARS stellar evolutionary code and a single consistent
homogeneous method. A maximum likelihood calculation suggests that the minimum
stellar mass for a type II-P to form is m(min)=8.5 +1/-1.5 Msol and the maximum
mass for II-P progenitors is m(max)=16.5 +/- 1.5 Msol, assuming a Salpeter
initial mass function (in the range Gamma = -1.35 +0.3/-0.7). The minimum mass
is consistent with current estimates for white dwarf progenitor masses, but the
maximum mass does not appear consistent with massive star populations. Red
supergiants in the Local Group have masses up to 25Msol and the minimum mass to
produce a Wolf-Rayet star in single star evolution (between solar and LMC
metallicity) is similarly 25-30 Msol. We term this discrepancy the "red
supergiant problem" and speculate that these stars could have core masses high
enough to form black holes and SNe which are too faint to have been detected.
Low luminosity SNe with low 56Ni production seem to arise from explosions of
low mass progenitors near the mass threshold for core-collapse. (abridged).Comment: 37 pages, 9 figs, accepted for publication in MNRA
Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility
Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes
- …