Genome-wide profiling in treatment-naive early rheumatoid arthritis reveals DNA methylome changes in T and B lymphocytes

AIM: Although aberrant DNA methylation has been described in rheumatoid arthritis (RA), no studies have interrogated this epigenetic modification in early disease. Following recent investigations of T- and B-lymphocytes in established disease, we now characterize in these cell populations genome-wide DNA methylation in treatment-naive patients with early RA. PATIENTS & METHODS: HumanMethylation450 BeadChips were used to examine genome-wide DNA methylation in lymphocyte populations from 23 early RA patients and 11 healthy individuals. RESULTS: Approximately 2000 CpGs in each cell type were differentially methylated in early RA. Clustering analysis identified a novel methylation signature in each cell type (150 sites in T-lymphocytes, 113 sites in B-lymphocytes) that clustered all patients separately from controls. A subset of sites differentially methylated in early RA displayed similar changes in established disease. CONCLUSION: Treatment-naive early RA patients display novel disease-specific DNA methylation aberrations, supporting a potential role for these changes in the development of RA

Individual component analysis of the multi-parametric cardiovascular magnetic resonance protocol in the CE-MARC trial

Background: The CE-MARC study assessed the diagnostic performance investigated the use of cardiovascular magnetic resonance (CMR) in patients with suspected coronary artery disease (CAD). The study used a multi-parametric CMR protocol assessing 4 components: i) left ventricular function; ii) myocardial perfusion; iii) viability (late gadolinium enhancement (LGE)) and iv) coronary magnetic resonance angiography (MRA). In this pre-specified CE-MARC sub-study we assessed the diagnostic accuracy of the individual CMR components and their combinations. Methods: All patients from the CE-MARC population (n = 752) were included using data from the original blinded-read. The four individual core components of the CMR protocol was determined separately and then in paired and triplet combinations. Results were then compared to the full multi-parametric protocol. Results: CMR and X-ray angiography results were available in 676 patients. The maximum sensitivity for the detection of significant CAD by CMR was achieved when all four components were used (86.5 %). Specificity of perfusion (91.8 %), function (93.7 %) and LGE (95.8 %) on its own was significantly better than specificity of the multi-parametric protocol (83.4 %) (all P < 0.0001) but with the penalty of decreased sensitivity (86.5 % vs. 76.9 %, 47.4 % and 40.8 % respectively). The full multi-parametric protocol was the optimum to rule-out significant CAD (Likelihood Ratio negative (LR-) 0.16) and the LGE component alone was the best to rue-in CAD (LR+ 9.81). Overall diagnostic accuracy was similar with the full multi-parametric protocol (85.9 %) compared to paired and triplet combinations. The use of coronary MRA within the full multi-parametric protocol had no additional diagnostic benefit compared to the perfusion/function/LGE combination (overall accuracy 84.6 % vs. 84.2 % (P = 0.5316); LR- 0.16 vs. 0.21; LR+ 5.21 vs. 5.77). Conclusions: From this pre-specified sub-analysis of the CE-MARC study, the full multi-parametric protocol had the highest sensitivity and was the optimal approach to rule-out significant CAD. The LGE component alone was the optimal rule-in strategy. Finally the inclusion of coronary MRA provided no additional benefit when compared to the combination of perfusion/function/LGE. Trial registration: Current Controlled Trials ISRCTN77246133

Monthly quasi-periodic eruptions from repeated stellar disruption by a massive black hole

In recent years, searches of archival X-ray data have revealed galaxies exhibiting nuclear quasi-periodic eruptions with periods of several hours. These are reminiscent of the tidal disruption of a star by a supermassive black hole. The repeated, partial stripping of a white dwarf in an eccentric orbit around an ~105 M⊙ black hole provides an attractive model. A separate class of periodic nuclear transients, with much longer timescales, have recently been discovered optically and may arise from the partial stripping of a main-sequence star by an ~107 M⊙ black hole. No clear connection between these classes has been made. We present the discovery of an X-ray nuclear transient that shows quasi-periodic outbursts with a period of weeks. We discuss possible origins for the emission and propose that this system bridges the two existing classes outlined above. This discovery was made possible by the rapid identification, dissemination and follow-up of an X-ray transient found by the new live Swift-XRT transient detector, demonstrating the importance of low-latency, sensitive searches for X-ray transients

Peroxisome Proliferator-Activated Receptor alpha (PPAR alpha) down-regulation in cystic fibrosis lymphocytes

Background: PPARs exhibit anti-inflammatory capacities and are potential modulators of the inflammatory response. We hypothesized that their expression and/or function may be altered in cystic fibrosis (CF), a disorder characterized by an excessive host inflammatory response. Methods: PPARα, β and γ mRNA levels were measured in peripheral blood cells of CF patients and healthy subjects via RT-PCR. PPARα protein expression and subcellular localization was determined via western blot and immunofluorescence, respectively. The activity of PPARα was analyzed by gel shift assay. Results: In lymphocytes, the expression of PPARα mRNA, but not of PPARβ, was reduced (-37%; p < 0.002) in CF patients compared with healthy persons and was therefore further analyzed. A similar reduction of PPARα was observed at protein level (-26%; p < 0.05). The transcription factor was mainly expressed in the cytosol of lymphocytes, with low expression in the nucleus. Moreover, DNA binding activity of the transcription factor was 36% less in lymphocytes of patients (p < 0.01). For PPARα and PPARβ mRNA expression in monocytes and neutrophils, no significant differences were observed between CF patients and healthy persons. In all cells, PPARγ mRNA levels were below the detection limit. Conclusion: Lymphocytes are important regulators of the inflammatory response by releasing cytokines and antibodies. The diminished lymphocytic expression and activity of PPARα may therefore contribute to the inflammatory processes that are observed in CF

One-step isolation and biochemical characterization of a highlyactive plant PSII monomeric core

We describe a one-step detergent solubilization protocol for isolating a highly active form of Photosystem II (PSII) from Pisum sativum L. Detailed characterization of the preparation showed that the complex was a monomer having no light harvesting proteins attached. This core reaction centre complex had, however, a range of low molecular mass intrinsic proteins as well as the chlorophyll binding proteins CP43 and CP47 and the reaction centre proteins D1 and D2. Of particular note was the presence of a stoichiometric level of PsbW, a low molecular weight protein not present in PSII of cyanobacteria. Despite the high oxygen evolution rate, the core complex did not retain the PsbQ extrinsic protein although there was close to a full complement of PsbO and PsbR and partial level of PsbP. However, reconstitution of PsbP and PsbPQ was possible. The presence of PsbP in absence of LHCII and other chlorophyll a/b binding proteins confirms that LHCII proteins are not a strict requirement for the assembly of this extrinsic polypeptide to the PSII core in contrast with the conclusion of Caffarri et al. (2009)

Antenatal corticosteroids and cardio-metabolic outcomes in adolescents born with very low birth weight

Exposure to antenatal corticosteroids (ANCS) is associated with adverse cardio-metabolic outcomes in animal models; however long-term outcomes in clinical studies are not well characterized. We hypothesized that exposure to ANCS would be associated with markers of increased cardio-metabolic risk in adolescents born with very low birth weight (VLBW)

Associations of Plasma Selenium with Arsenic and Genomic Methylation of Leukocyte DNA in Bangladesh

Background Global hypomethylation of DNA is thought to constitute an early event in some cancers and occurs in response to arsenic (As) exposure and/or selenium (Se) deficiency in both in vitro and animal models. In addition, antagonism between As and Se, whereby each reduces toxicity of the other, has been well documented in animal models. Se status may therefore modify the health effects of As in As-exposed populations. Objective The primary objectives of our study were to test the hypothesis that Se deficiency is associated with genomic hypomethylation of lymphocyte DNA and to determine whether Se levels are associated with blood As (bAs) and urinary As (uAs) concentrations in adults exposed to As-contaminated groundwater in Bangladesh. A secondary objective was to explore the relationships between plasma Se and As metabolites. Design We assessed plasma Se concentrations, As metabolite profiles in blood and urine, and genomic methylation of leukocyte DNA in a cross-sectional study of 287 adults. Results After adjustment for potential confounders, we observed an inverse association between Se (micrograms per liter) and genomic DNA methylation (disintegrations per minute per 1-μg/L increase in Se): β = 345.6; 95% confidence interval (CI), 59–632. Se concentrations were inversely associated with total As concentrations (micrograms per liter) in blood (β = −0.04; 95% CI, −0.08 to −0.01) and urine (β = −20.1; 95% CI, −29.3 to −10.9). Se levels were negatively associated with the percentage of monomethylarsinic acid (β = −0.59; 95% CI, −1.04 to −0.13) and positively associated with the percentage of dimethylarsinic acid (β = 0.53; 95% CI, 0.04 to 1.01) in blood. Conclusions Our results suggest that Se is inversely associated with genomic DNA methylation. The underlying mechanisms and implications of this observation are unclear and warrant further investigation. In addition, Se may influence bAs and uAs concentrations, as well as relative proportions of As metabolites in blood

Prognostic value of radical cystoprostatectomy in men with bladder cancer infiltrating prostate versus co-existing prostate cancer: a research study

<p>Abstract</p> <p>Background</p> <p>The aim of the following study is to evaluate the advancement of incidentally diagnosed prostate cancer in specimen after cystoprostatectomies caused by muscle-invasive bladder cancer. Secondly we assessed the survival in patients after radical cystoprostatectomy whose postoperative specimen was characterized by the presence of co-existing prostate cancer or prostate infiltration by urothelial bladder cancer.</p> <p>Methods</p> <p>Between 1993 and 2009 a total of 320 patients with muscle-invasive bladder cancer underwent cystoprostatectomy. The first analyzed group consisted of 52 patients with bladder cancer infiltrating prostate, while the second group consisted of 21 patients with co-existing prostate cancer. In all patients cancer specific survival and progression were analyzed. Average follow up was 75.2 months (range: 0 - 181).</p> <p>Results</p> <p>Cancer-specific survival was significantly shorter in group I (p = 0.03). Neoplastic progression in patients from group I was observed in 42.2% of patients, while in patients from group II in 23.6% of patients (p = 0.04). No statistical difference was observed in the percentage of positive lymph nodes between the groups (p = 0.22). The median Gleason score in patients with co-existing prostate cancer was equal to 5. The stage of prostate cancer pT₂/pT₃was equal to 20 (96%)/1 (4%) patients. 12 (57%) prostate cancers were clinically insignificant. Biochemical recurrence occurred in 2 (9%) patients.</p> <p>Conclusions</p> <p indent="1">1. Incidentally diagnosed prostate cancer in specimen after cystoprostatectomies is frequently clinically insignificant and characterized by low progression.</p> <p indent="1">2. Patients with bladder cancer infiltrating prostate are characterized by higher percentage of progression and death in comparison with patients with co-existing prostate cancer.</p