The occurrence and behavior of radium in saline formation water of the U.S. Gulf Coast region.

USGS Publications Warehouse

Kraemer, T.F.; Reid, D.F.

1984-01-01

Ra was measured in deep saline formation waters produced from a variety of US Gulf Coast subsurface environments, including oil and gas reservoirs, and water-producing geopressured aquifers. A strong positive correlation was found between formation-water salinity and Ra activity, resulting from the interaction of formation water with aquifer matrix. Ra isotopes enter the fluid phase after being produced by the decay of parent elements U and Th on and within the solid matrix. The processes believed to be primarily responsible for transfering Ra from matrix to formation water are chemical leaching and alpha -particle recoil. Factors controlling the observed salinity-Ra relationship may be one or a combination of the following: 1) ion exchange; 2) increased solubility of matrix silica surrounding Ra atoms, coupled with a salinity-controlled rate of re-equilibration of silica between solution and quartz grains; and 3) the equilibration of Ra in solution with detrital baryte within the aquifer. No difference was found in the brine-Ra relation in water produced from oil or gas wells and water produced from wells penetrating only water-bearing aquifers, although the relation was more highly correlated for water-bearing aquifers than hydrocarbon-containing reservoirs.-P.Br.

Bexarotene via CBP/p300 induces suppression of NF-κB-dependent cell growth and invasion in thyroid cancer.

PubMed

Cras, Audrey; Politis, Béatrice; Balitrand, Nicole; Darsin-Bettinger, Diane; Boelle, Pierre Yves; Cassinat, Bruno; Toubert, Marie-Elisabeth; Chomienne, Christine

2012-01-15

Retinoic acid (RA) treatment has been used for redifferentiation of metastatic thyroid cancer with loss of radioiodine uptake. The aim of this study was to improve the understanding of RA resistance and investigate the role of bexarotene in thyroid cancer cells. A model of thyroid cancer cell lines with differential response to RA was used to evaluate the biological effects of retinoid and rexinoid and to correlate this with RA receptor levels. Subsequently, thyroid cancer patients were treated with 13-cis RA and bexarotene and response evaluated on radioiodine uptake reinduction on posttherapy scan and conventional imaging. In thyroid cancer patients, 13-cis RA resistance can be bypassed in some tumors by bexarotene. A decreased tumor growth without differentiation was observed confirming our in vitro data. Indeed, we show that ligands of RARs or RXRs exert different effects in thyroid cancer cell lines through either differentiation or inhibition of cell growth and invasion. These effects are associated with restoration of RARβ and RXRγ levels and downregulation of NF-κB targets genes. We show that bexarotene inhibits the transactivation potential of NF-κB in an RXR-dependent manner through decreased promoter permissiveness without interfering with NF-κB nuclear translocation and binding to its responsive elements. Inhibition of transcription results from the release of p300 coactivator from NF-κB target gene promoters and subsequent histone deacetylation. This study highlights dual mechanisms by which retinoids and rexinoids may target cell tumorigenicity, not only via RARs and RXRs, as expected, but also via NF-κB pathway. ©2011 AACR.

The Shock and Vibration Digest. Volume 18, Number 5

DTIC Science & Technology

1986-05-01

response. 16-1067 Seismic Analysis of Azisym metric Shells R.J. Jospin, E.M. Toledo, R.A. Feijoo Laboratorio de Computacao Cientifica, Rio de ...matrices for tapered beam elements, de - rived by various autbots are reviewed. Tapered member framing has been utilized in a variety of building frames of...sectional shape. Dynamic stiffness and consistent mass matrices [2,22] have been de - rived in explicit form for the beam element of closed box of

The occurrence and behavior of radium in saline formation water of the U.S. Gulf Coast region

USGS Publications Warehouse

Kraemer, T.F.; Reid, D.F.

1984-01-01

Radium has been measured in deep saline formation waters produced from a variety of U.S. Gulf Coast subsurface environments, including oil reservoirs, gas reservoirs and water-producing geopressured aquifers. A strong positive correlation has been found between formation-water salinity and Ra activity, resulting from the interaction of formation water with aquifer matrix. Ra isotopes enter the fluid phase after being produced by the decay of parent elements U and Th, which are located at sites on and within the solid matrix. Processes that are belived to be primarily responsible for transferring Ra from matrix to formation water are chemical leaching and alpha-particle recoil. Factors controlling the observed salinity-Ra relationship may be one or a combination of the following factors: (a) ion exchange; (b) increased solubility of matrix silica surrounding Ra atoms, coupled with a salinity-controlled rate of reequilibration of silica between solution and quartz grains; and (c) the equilibration of Ra in solution with detrial barite within the aquifer. No difference was found in the brine-Ra relation in water produced from oil or gas wells and water produced from wells penetrating only water-bearing aquifers, although the relation was more highly correlated for water-bearing aquifers than hydrocarbon-containing reservoirs. ?? 1984.

Retinoic acids and trichostatin A (TSA), a histone deacetylase inhibitor, induce human pyruvate dehydrogenase kinase 4 (PDK4) gene expression.

PubMed

Kwon, Hye-Sook; Huang, Boli; Ho Jeoung, Nam; Wu, Pengfei; Steussy, Calvin N; Harris, Robert A

2006-01-01

Induction of pyruvate dehydrogenase kinase 4 (PDK4) conserves glucose and substrates for gluconeogenesis and thereby helps regulate blood glucose levels during starvation. We report here that retinoic acids (RA) as well as Trichostatin A (TSA), an inhibitor of histone deacetylase (HDAC), regulate PDK4 gene expression. Two retinoic acid response elements (RAREs) to which retinoid X receptor alpha (RXRalpha) and retinoic acid receptor alpha (RARalpha) bind and activate transcription are present in the human PDK4 (hPDK4) proximal promoter. Sp1 and CCAAT box binding factor (CBF) bind to the region between two RAREs. Mutation of either the Sp1 or the CBF site significantly decreases basal expression, transactivation by RXRalpha/RARalpha/RA, and the ability of TSA to stimulate hPDK4 gene transcription. By the chromatin immunoprecipitation assay, RA and TSA increase acetylation of histones bound to the proximal promoter as well as occupancy of CBP and Sp1. Interaction of p300/CBP with E1A completely prevented hPDK4 gene activation by RXRalpha/RARalpha/RA and TSA. The p300/CBP may enhance acetylation of histones bound to the hPDK4 promoter and cooperate with Sp1 and CBF to stimulate transcription of the hPDK4 gene in response to RA and TSA.

Distribution of elements in individual blood cells in metabolic disorders at the cellular level

NASA Astrophysics Data System (ADS)

Johansson, Erland; Lindh, Ulf

1985-08-01

In comparison with controls neutrophil granulocytes from Rheumatoid arthritis (RA), Infantile Neuronal Ceroid Lipofuscinosis (INCL), Chronic Lymphatic Leukemia (L) and Aplastic Anemia (AA) displayed significant alterations in essential and non-essential elements which might be interpreted as fingerprints of these deseases. The neutrophils from RA patients displayed alterations in the concentrations of iron, calcium, strontium, manganese, zinc and copper. INCL displayed alterations in the concentrations of iron and copper but in the INCL disease the iron concentration was about 2 times higher than in RA. In leukemia, aluminium was observed but not in the controls (< 0.5 μg/ g). The zinc concentration was lowered in leukemia. Aplastic anemia displayed alterations in zirconium, arsenic, molybdenum, iron and zinc. The platelets from RA, INCL, L and AA patients also displayed alterations in the elemental profiles. The platelets from AA patients displayed a unique elemental distribution of arsenic, zirconium and molybdenum. The elemental profiles of the thrombocytes and neutrophils might be used as a complement in the diagnosis of the examined diseases and in therapy the elemental profile might be used to monitor drugs at the cellular level.

Differential regulation of ParaHox genes by retinoic acid in the invertebrate chordate amphioxus (Branchiostoma floridae).

PubMed

Osborne, Peter W; Benoit, Gérard; Laudet, Vincent; Schubert, Michael; Ferrier, David E K

2009-03-01

The ParaHox cluster is the evolutionary sister to the Hox cluster. Like the Hox cluster, the ParaHox cluster displays spatial and temporal regulation of the component genes along the anterior/posterior axis in a manner that correlates with the gene positions within the cluster (a feature called collinearity). The ParaHox cluster is however a simpler system to study because it is composed of only three genes. We provide a detailed analysis of the amphioxus ParaHox cluster and, for the first time in a single species, examine the regulation of the cluster in response to a single developmental signalling molecule, retinoic acid (RA). Embryos treated with either RA or RA antagonist display altered ParaHox gene expression: AmphiGsx expression shifts in the neural tube, and the endodermal boundary between AmphiXlox and AmphiCdx shifts its anterior/posterior position. We identified several putative retinoic acid response elements and in vitro assays suggest some may participate in RA regulation of the ParaHox genes. By comparison to vertebrate ParaHox gene regulation we explore the evolutionary implications. This work highlights how insights into the regulation and evolution of more complex vertebrate arrangements can be obtained through studies of a simpler, unduplicated amphioxus gene cluster.

A potential dating technique using 228Th/228Ra ratio for tracing the chronosequence of elemental concentrations in plants.

PubMed

Chao, J H; Niu, H; Chiu, C Y; Lin, C

2007-06-01

We propose a radiometric method based on measurement of the radioactivity of the naturally occurring radionuclides (228)Ra and 228)Th and the derived (228)Th/(228)Ra ratios in plant samples to estimate plant age and the corresponding nutritional conditions in a field-growing fern, Dicranopteris linearis. Plant age (tissue age) was associated with the (228)Th/(228)Ra ratio in fronds, which implies the accumulation time of immobile elements in the plant tissue or the life span of the fronds. Results indicated that the accumulation of alkaline earth elements in D. linearis is relatively constant with increased age, while the K concentration is reversed with age because of translocation among plant tissues. Estimation of dating uncertainty based on measurement conditions revealed that the radiometric technique can be applied to trace chronosequential changes of elemental concentrations and environmental pollutants in plants with ages of less than 10-15 years.

The effects of elemental diet and subsequent food reintroduction on rheumatoid arthritis.

PubMed

Kavanaghi, R; Workman, E; Nash, P; Smith, M; Hazleman, B L; Hunter, J O

1995-03-01

The role of diet in rheumatoid arthritis (RA) remains controversial and there have been no controlled studies on the use of elemental diet in the treatment of RA. Elemental diet is an hypoallergenic protein-free artificial diet consisting of essential amino acids, glucose, trace elements and vitamins. This study was carried out to assess the role of elemental diet and subsequent food reintroduction in RA. Elemental diet (E028) (and a small number of foods) was given to 24 patients with definite RA in order to induce a remission and then foods were gradually introduced. Where a food was suspected of causing symptoms it was removed from the diet. Twenty-three control patients supplemented their usual diet with E028. After the elemental diet there was a statistically significant improvement in the diet group in grip strength (P = 0.008) and Ritchie score (P = 0.006) but not in ESR, CRP, thermographic joint score or functional score. The diet group lost more weight than the control group and this correlated with the improvement in grip strength. This improvement was not present following food reintroduction. As the improvements took place in more subjective disease parameters and because of the difficulties in adequately blinding studies of diet in arthritis, a placebo effect must be considered. There was a high default rate, only 38% of those patients originally enrolled completed the study. In conclusion, this study shows that elemental diet can cause an improvement in a number of disease parameters in RA but this is not sustained by an individualized diet. It also illustrates some of the difficulties involved in the study of diet in arthritis.

SU-G-BRC-06: Evaluation of a Novel Radiosurgery Software for Treating Multiple Brain Metastases Simultaneously in a Single Fraction

DOE Office of Scientific and Technical Information (OSTI.GOV)

Levin, D; Shekel, E; Epstein, D

Purpose: To evaluate a new, automated brain metastases planning software designed to treat up to ten brain metastases simultaneously. Methods: We treated 61 patients with multiple brain metastases using the Elements software by BrainLab (Munich, Germany). Patients had between 2–10 metastases ranging from 0.01–8.64 cc. Dose prescription was 18–24 Gy. Plans use up to 5 non-coplanar arcs with a single isocenter at the metastases’ center of mass. The high degree of automation shortens the planning time to 15–20 minutes per patient.For comparison we planned 21 of the patients using Rapid Arc (Varian, Palo Alto CA) (RA). We used two coplanarmore » arcs so as to keep planning times comparable to the Elements. We also planned 8 patients using iPlan software (BrainLab). We compared conformity index (CI), volume of brain receiving over 12 Gy (V{sub 12}) and mean brain dose (MBD) for the three different planning systems (TPSs). Results: Plans from all TPSs were judged clinically acceptable. V{sub 12} and MBD were not statistically significantly different between TPSs.CI between RA and Elements was similar, however for iPlan CI was significantly worse compared to both RA and Elements (p<0.001). RA plans took approximately 40 minutes to plan (despite fusion and contouring being done in the Elements), and iPlan plans over an hour each. Delivery times were approximately 30 minutes for Elements, 10 minutes for RA, and up to 300 minutes for iPlan. Conclusion: Elements plans had good CI values and low brain doses. While treatment times for Elements were longer than for RA, 30 minutes is a significant improvement over conventional radiosurgery techniques where each metastasis is treated individually and delivery times to 10 metastases are close to 300 minutes.BrainLab Elements is a novel software allowing fast, automated planning and efficient irradiation of multiple brain metastases with minimal dose to healthy brain.« less

Radionuclides, trace elements, and radium residence in phosphogypsum of Jordan

USGS Publications Warehouse

Zielinski, R.A.; Al-Hwaiti, M. S.; Budahn, J.R.; Ranville, J.F.

2011-01-01

Voluminous stockpiles of phosphogypsum (PG) generated during the wet process production of phosphoric acid are stored at many sites around the world and pose problems for their safe storage, disposal, or utilization. A major concern is the elevated concentration of long-lived 226Ra (half-life = 1,600 years) inherited from the processed phosphate rock. Knowledge of the abundance and mode-of-occurrence of radium (Ra) in PG is critical for accurate prediction of Ra leachability and radon (Rn) emanation, and for prediction of radiation-exposure pathways to workers and to the public. The mean (??SD) of 226Ra concentrations in ten samples of Jordan PG is 601 ?? 98 Bq/kg, which falls near the midrange of values reported for PG samples collected worldwide. Jordan PG generally shows no analytically significant enrichment (< 10%) of 226Ra in the finer (< 53 ??m) grain size fraction. Phosphogypsum samples collected from two industrial sites with different sources of phosphate rock feedstock show consistent differences in concentration of 226Ra and rare earth elements, and also consistent trends of enrichment in these elements with increasing age of PG. Water-insoluble residues from Jordan PG constitute <10% of PG mass but contain 30-65% of the 226Ra. 226Ra correlates closely with Ba in the water-insoluble residues. Uniformly tiny (< 10 ??m) grains of barite (barium sulfate) observed with scanning electron microscopy have crystal morphologies that indicate their formation during the wet process. Barite is a well-documented and efficient scavenger of Ra from solution and is also very insoluble in water and mineral acids. Radium-bearing barite in PG influences the environmental mobility of radium and the radiation-exposure pathways near PG stockpiles. ?? 2010 US Government.

Does a family history of RA influence the clinical presentation and treatment response in RA?

PubMed

Frisell, Thomas; Saevarsdottir, Saedis; Askling, Johan

2016-06-01

To assess whether family history of rheumatoid arthritis (RA), among the strongest risk factors for developing RA, also carries information on the clinical presentation and treatment response. The prospective Swedish Rheumatology register was linked to family history of RA, defined as diagnosed RA in any first-degree relative, ascertained through the Swedish Multi-Generation and Patient registers. Clinical presentation was examined among patients with early RA 2000-2011 (symptom onset <12 months before inclusion, N=6869), and response to methotrexate (MTX) monotherapy in the subset starting this treatment (N=4630). Response to tumour necrosis factor inhibitors (TNFi) was examined among all patients with RA starting a TNFi as the first biological disease-modifying antirheumatic drug 2000-2011 (N=9249). Association of family history with clinical characteristics, drug survival, European League Against Rheumatism (EULAR) response and change in disease activity at 3 and 6 months was estimated using linear and generalised logistic regression models. Correlation in relatives' response measures was also assessed. Patients with early RA with family history of RA were more often rheumatoid factor positive, but with no other clinically meaningful differences in their clinical presentation. Family history of RA did not predict response to MTX or TNFi, with the possible exception of no versus good EULAR response to TNFi at 6 months (OR=1.4, 95% CI 1.1 to 1.7). Having a relative who discontinued TNFi within a year increased the odds of doing the same (OR=3.7, 95% CI 1.8 to 7.5), although we found no significant familial correlations in change in disease activity measures. Family history of RA did not modify the clinical presentation of RA or predict response to standard treatment with MTX or TNFi. Treatment response, particularly drug survival, may itself be familial. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Development and analysis of a finite element model to simulate pulmonary emphysema in CT imaging.

PubMed

Diciotti, Stefano; Nobis, Alessandro; Ciulli, Stefano; Landini, Nicholas; Mascalchi, Mario; Sverzellati, Nicola; Innocenti, Bernardo

2015-01-01

In CT imaging, pulmonary emphysema appears as lung regions with Low-Attenuation Areas (LAA). In this study we propose a finite element (FE) model of lung parenchyma, based on a 2-D grid of beam elements, which simulates pulmonary emphysema related to smoking in CT imaging. Simulated LAA images were generated through space sampling of the model output. We employed two measurements of emphysema extent: Relative Area (RA) and the exponent D of the cumulative distribution function of LAA clusters size. The model has been used to compare RA and D computed on the simulated LAA images with those computed on the models output. Different mesh element sizes and various model parameters, simulating different physiological/pathological conditions, have been considered and analyzed. A proper mesh element size has been determined as the best trade-off between reliable results and reasonable computational cost. Both RA and D computed on simulated LAA images were underestimated with respect to those calculated on the models output. Such underestimations were larger for RA (≈ -44 ÷ -26%) as compared to those for D (≈ -16 ÷ -2%). Our FE model could be useful to generate standard test images and to design realistic physical phantoms of LAA images for the assessment of the accuracy of descriptors for quantifying emphysema in CT imaging.

Retinoic acid signaling and mouse embryonic stem cell differentiation: Cross talk between genomic and non-genomic effects of RA.

PubMed

Rochette-Egly, Cécile

2015-01-01

Retinoic acid (RA), the active derivative of vitamin A, a fat-soluble vitamin, plays key roles in cell growth and differentiation by activating nuclear receptors, RARs (α, β and γ), which are ligand dependent regulators of transcription. The past years highlighted several novelties in the field that increased the complexity of RA effects. Indeed, in addition to its classical genomic effects, RA also has extranuclear and non-transcriptional effects. RA induces the rapid and transient activation of kinase cascades, which are integrated in the nucleus via the phosphorylation of RARs at a conserved serine residue located in the N-terminal domain and their coregulators. In order to investigate the relevance of RARs' phosphorylation in cell differentiation, mouse embryonic stem (mES) cells were used as a model. When treated with RA, these pluripotent cells give rise to neuronal cells. Cells invalidated for each RAR were generated as well as stable rescue lines expressing RARs mutated in phosphor acceptor sites. Such a strategy revealed that RA-induced neuronal differentiation involves the RARγ2 subtype and requires RARγ2 phosphorylation. Moreover, in gene expression profiling experiments, the phosphorylated form of RARγ2 was found to regulate a small subset of genes through binding a novel RA response element consisting of two direct repeats with a 7 base pair spacer. These new findings suggest an important role for RAR phosphorylation during cell differentiation, and pave the way for further investigations with other cell types and during embryonic development. This article is part of a Special Issue entitled Linking transcription to physiology in lipodomics. Copyright © 2014 Elsevier B.V. All rights reserved.

Gemfibrozil, a lipid-lowering drug, upregulates interleukin-1 receptor antagonist in mouse cortical neurons: Implications for neuronal self-defense

PubMed Central

Corbett, Grant T.; Roy, Avik; Pahan, Kalipada

2012-01-01

Chronic inflammation is becoming a hallmark of several neurodegenerative disorders and accordingly, interleukin-1 beta (IL-1β), a proinflammatory cytokine, is implicated in the pathogenesis of neurodegenerative diseases. While IL-1β binds to its high-affinity receptor, interleukin-1 receptor (IL-1R), and upregulates proinflammatory signaling pathways, interleukin-1 receptor antagonist (IL-1Ra) adheres to the same receptor and inhibits proinflammatory cell signaling. Therefore, upregulation of IL-1Ra is considered important in attenuating inflammation. The present study underlines a novel application of gemfibrozil, an FDA-approved lipid-lowering drug, in increasing the expression of IL-1Ra in primary mouse and human neurons. Gemfibrozil alone induced an early and pronounced increase in the expression of IL-1Ra in primary mouse cortical neurons. Activation of type IA p110α phosphatidylinositol 3-kinase (PI3-K) and Akt by gemfibrozil and abrogation of gemfibrozil-induced upregulation of IL-1Ra by inhibitors of PI3-K and Akt indicate a role of the PI3-K – Akt pathway in the upregulation of IL-1Ra. Gemfibrozil also induced the activation of cAMP response element-binding (CREB) via the PI3-K – Akt pathway and siRNA attenuation of CREB abolished the gemfibrozil-mediated increase in IL-1Ra. Furthermore, gemfibrozil was able to protect neurons from IL-1β insult. However, siRNA knockdown of neuronal IL-1Ra abrogated the protective effect of gemfibrozil against IL-1β suggesting that this drug increases the defense mechanism of cortical neurons via upregulation of IL-1Ra. Together, these results highlight the importance of the PI3-K – Akt – CREB pathway in mediating gemfibrozil-induced upregulation of IL-1Ra in neurons and suggest gemfibrozil as a possible therapeutic treatment for propagating neuronal self defense in neuroinflammatory and neurodegenerative disorders. PMID:22706077

Retinoid X receptor and peroxisome proliferator-activated receptor activate an estrogen responsive gene independent of the estrogen receptor.

PubMed

Nuñez, S B; Medin, J A; Braissant, O; Kemp, L; Wahli, W; Ozato, K; Segars, J H

1997-03-14

Estrogen receptors regulate transcription of genes essential for sexual development and reproductive function. Since the retinoid X receptor (RXR) is able to modulate estrogen responsive genes and both 9-cis RA and fatty acids influenced development of estrogen responsive tumors, we hypothesized that estrogen responsive genes might be modulated by RXR and the fatty acid receptor (peroxisome proliferator-activated receptor, PPAR). To test this hypothesis, transfection assays in CV-1 cells were performed with an estrogen response element (ERE) coupled to a luciferase reporter construct. Addition of expression vectors for RXR and PPAR resulted in an 11-fold increase in luciferase activity in the presence of 9-cis RA. Furthermore, mobility shift assays demonstrated binding of RXR and PPAR to the vitellogenin A2-ERE and an ERE in the oxytocin promoter. Methylation interference assays demonstrated that specific guanine residues required for RXR/PPAR binding to the ERE were similar to residues required for ER binding. Moreover, RXR domain-deleted constructs in transfection assays showed that activation required RXR since an RXR delta AF-2 mutant completely abrogated reporter activity. Oligoprecipitation binding studies with biotinylated ERE and (35)S-labeled in vitro translated RXR constructs confirmed binding of delta AF-2 RXR mutant to the ERE in the presence of baculovirus-expressed PPAR. Finally, in situ hybridization confirmed RXR and PPAR mRNA expression in estrogen responsive tissues. Collectively, these data suggest that RXR and PPAR are present in reproductive tissues, are capable of activating estrogen responsive genes and suggest that the mechanism of activation may involve direct binding of the receptors to estrogen response elements.

Diagnosis and treatment of rheumatoid arthritis in the Emilia Romagna region: a prospective population-based study.

PubMed

Addimanda, Olga; Marino, Massimiliano; Farina, Ilaria; Trevisani, Marica; Arrigoni, Eugenio; Lumetti, Federica; Crescentini, Filippo; Sambo, Paola; Bezzi, Alessandra; Bruschi, Marco; Santilli, Daniele; Reta, Massimo; Bosi, Simona; Delsante, Giovanni; Girelli, Francesco; Montaguti, Luca; Meliconi, Riccardo; Sebastiani, Marco; Ferri, Clodoveo; Malavolta, Nazzarena; Govoni, Marcello; Trombetti, Susanna; De Palma, Rossana; Salvarani, Carlo

2017-01-01

To perform a population-based study in rheumatoid arthritis (RA) patients, in order to evaluate the efficacy and safety of pharmacologic treatments. 1087 patients with RA were enrolled; inclusion criteria were: newly diagnosed RA, already diagnosed RA with high disease activity (HDA) (DAS28≥4.2) starting biologic DMARDs (bDMARDs), already diagnosed RA with HDA continuing with conventional DMARDs (cDMARDs). The following data were collected: demographics, clinical and laboratory features, imaging and prescribed drugs. All parameters except immunology and imaging (performed yearly) were repeated at each follow-up evaluations (after 3, 6 and 12 months, and thereafter every 12 months). In order to evaluate clinical response, the EULAR response criteria were used as the gold standard. 414 (38.1%) newly diagnosed patients with RA, 477 (43.9%) RA patients who started bDMARDs and 196 (18.0%) RA patients who continued with cDMARDs were enrolled from April 2012 to March 2015 at 12 Rheumatology Centres in the Emilia Romagna Region. Statistical analyses showed a relative risk ratio (RRR) for moderate response of 1.65 in RA patients who started bDMARDs (p=0.16) and 2.49 for newly diagnosed RA (p=0.01). Sex, age and Health Assessment Questionnaire were not statistically significant. A RRR of 2.00 has been confirmed for RA patients who started bDMARDs (p<0.0005) for a good response as well as 2.20 for newly diagnosed RA (p<0.0005). An increase in adverse events among bDMARDs was found, but when looking at infections or neoplasia, no differences were highlighted between RA which started bDMARDs and RA who continued with cDMARDs. Our results are in line with already published papers from British and Swedish Registries: a greater likelihood to have a good response is demonstrated for not longstanding RA starting cDMARDs or RA with HDA when a bDMARD is started. Also a good safety profile is demonstrated.

Collective Dynamics of Specific Gene Ensembles Crucial for Neutrophil Differentiation: The Existence of Genome Vehicles Revealed

PubMed Central

Giuliani, Alessandro; Tomita, Masaru

2010-01-01

Cell fate decision remarkably generates specific cell differentiation path among the multiple possibilities that can arise through the complex interplay of high-dimensional genome activities. The coordinated action of thousands of genes to switch cell fate decision has indicated the existence of stable attractors guiding the process. However, origins of the intracellular mechanisms that create “cellular attractor” still remain unknown. Here, we examined the collective behavior of genome-wide expressions for neutrophil differentiation through two different stimuli, dimethyl sulfoxide (DMSO) and all-trans-retinoic acid (atRA). To overcome the difficulties of dealing with single gene expression noises, we grouped genes into ensembles and analyzed their expression dynamics in correlation space defined by Pearson correlation and mutual information. The standard deviation of correlation distributions of gene ensembles reduces when the ensemble size is increased following the inverse square root law, for both ensembles chosen randomly from whole genome and ranked according to expression variances across time. Choosing the ensemble size of 200 genes, we show the two probability distributions of correlations of randomly selected genes for atRA and DMSO responses overlapped after 48 hours, defining the neutrophil attractor. Next, tracking the ranked ensembles' trajectories, we noticed that only certain, not all, fall into the attractor in a fractal-like manner. The removal of these genome elements from the whole genomes, for both atRA and DMSO responses, destroys the attractor providing evidence for the existence of specific genome elements (named “genome vehicle”) responsible for the neutrophil attractor. Notably, within the genome vehicles, genes with low or moderate expression changes, which are often considered noisy and insignificant, are essential components for the creation of the neutrophil attractor. Further investigations along with our findings might provide a comprehensive mechanistic view of cell fate decision. PMID:20725638

Unraveling the proteomic profile of mice testis during the initiation of meiosis.

PubMed

Shao, Binbin; Guo, Yueshuai; Wang, Lei; Zhou, Quan; Gao, Tingting; Zheng, Bo; Zheng, Haoyu; Zhou, Tao; Zhou, Zuomin; Guo, Xuejiang; Huang, Xiaoyan; Sha, Jiahao

2015-04-29

In mice, once primordial germ cells (PGCs) are generated, they continue to proliferate and migrate to eventually reach the future gonads. They initiate sexual differentiation after their colonization of the gonads. During this process, retinoic acid (RA) induces meiosis in the female germ cells, which proceeds to the diplotene stage of meiotic prophase I, whereas the male germ cells initiate growth arrest. After birth, meiosis is initiated in mice spermatogonia by their conversion to preleptotene spermatocytes. There are evidences showing the roles of RA in the regulation of spermatogonial differentiation and meiosis initiation. However, it is still not well known on what responds to RA and how RA signaling engages meiosis. Thus, we constructed a proteomic profile of proteins associated with meiosis onset during testis development in mouse and identified 104 differentially expressed proteins (≥1.5 folds). Bioinformatic analysis showed proteins functioning in specific cell processes. The expression patterns of five selected proteins were verified via Western blot, of which we found that Tfrc gene was RA responsive, with a RA responsive element, and could be up regulated by RA in spermatogonial stem cell (SSC) line. Taken together, the results provide an important reference profile for further functional study of meiosis initiation. Spermatogenesis involves mitosis of spermatogonia, meiosis of spermatocytes and spermiogenesis, in which meiosis is a unique event to germ cells, and not in the somatic cells. Till now, the detailed molecular mechanisms of the transition from mitosis to meiosis are still not elucidated. With high-throughput proteomic technology, it is now possible to systemically identify proteins possibly involved. With TMT-6plex based quantification, we identified 104 proteins differentially between testes without meiosis (day 8.5) and those that were meiosis initiated (day 10.5). And a well-known protein essential for meiosis initiation, stra8, was identified to be differentially expressed in the study. And bioinformatic analysis and functional studies revealed several proteins regulated by retinoic acid, a chemical known to regulate the meiosis initiation. Thus, this quantitative proteomic approach can identify meiosis initiation regulating proteins, and further functional studies of these proteins will help elucidate the mechanisms of meiosis initiation. Copyright © 2015. Published by Elsevier B.V.

Rheumatoid Arthritis Risk Allele PTPRC Is Also Associated With Response to Anti–Tumor Necrosis Factor α Therapy

PubMed Central

Cui, Jing; Saevarsdottir, Saedis; Thomson, Brian; Padyukov, Leonid; van der Helm-van Mil, Annette H. M.; Nititham, Joanne; Hughes, Laura B.; de Vries, Niek; Raychaudhuri, Soumya; Alfredsson, Lars; Askling, Johan; Wedrén, Sara; Ding, Bo; Guiducci, Candace; Wolbink, Gert Jan; Crusius, J. Bart A.; van der Horst-Bruinsma, Irene E.; Herenius, Marieke; Weinblatt, Michael E.; Shadick, Nancy A.; Worthington, Jane; Batliwalla, Franak; Kern, Marlena; Morgan, Ann W.; Wilson, Anthony G.; Isaacs, John D.; Hyrich, Kimme; Seldin, Michael F.; Moreland, Larry W.; Behrens, Timothy W.; Allaart, Cornelia F.; Criswell, Lindsey A.; Huizinga, Tom W. J.; Tak, Paul P.; Bridges, S. Louis; Toes, Rene E. M.; Barton, Anne; Klareskog, Lars; Gregersen, Peter K.; Karlson, Elizabeth W.; Plenge, Robert M.

2013-01-01

Objective Anti–tumor necrosis factor α (anti-TNF) therapy is a mainstay of treatment in rheumatoid arthritis (RA). The aim of the present study was to test established RA genetic risk factors to determine whether the same alleles also influence the response to anti-TNF therapy. Methods A total of 1,283 RA patients receiving etanercept, infliximab, or adalimumab therapy were studied from among an international collaborative consortium of 9 different RA cohorts. The primary end point compared RA patients with a good treatment response according to the European League Against Rheumatism (EULAR) response criteria (n = 505) with RA patients considered to be nonresponders (n = 316). The secondary end point was the change from baseline in the level of disease activity according to the Disease Activity Score in 28 joints (ΔDAS28). Clinical factors such as age, sex, and concomitant medications were tested as possible correlates of treatment response. Thirty-one single-nucleotide polymorphisms (SNPs) associated with the risk of RA were genotyped and tested for any association with treatment response, using univariate and multivariate logistic regression models. Results Of the 31 RA-associated risk alleles, a SNP at the PTPRC (also known as CD45) gene locus (rs10919563) was associated with the primary end point, a EULAR good response versus no response (odds ratio [OR] 0.55, P = 0.0001 in the multivariate model). Similar results were obtained using the secondary end point, the ΔDAS28 (P = 0.0002). There was suggestive evidence of a stronger association in autoantibody-positive patients with RA (OR 0.55, 95% confidence interval [95% CI] 0.39–0.76) as compared with autoantibody-negative patients (OR 0.90, 95% CI 0.41–1.99). Conclusion Statistically significant associations were observed between the response to anti-TNF therapy and an RA risk allele at the PTPRC gene locus. Additional studies will be required to replicate this finding in additional patient collections. PMID:20309874

Frequency-dependent response of SI RA-class neurons to vibrotactile stimulation of the receptive field.

PubMed

Whitsel, B L; Kelly, E F; Xu, M; Tommerdahl, M; Quibrera, M

2001-01-01

Three types of experiment were carried out on anesthetized monkeys and cats. In the first, spike discharge activity of rapidly adapting (RA) SI neurons was recorded extracellularly during the application of different frequencies of vibrotactile stimulation to the receptive field (RF). The second used the same stimulus conditions to study the response of RA-I (RA) cutaneous mechanoreceptive afferents. The third used optical intrinsic signal (OIS) imaging and extracellular neurophysiological recording methods together, in the same sessions, to evaluate the relationship between the SI optical and RA neuron spike train responses to low- vs high-frequency stimulation of the same skin site. RA afferent entrainment was high at all frequencies of stimulation. In contrast, SI RA neuron entrainment was much lower on average, and was strongly frequency-dependent, declining in near-linear fashion from 6 to 200 Hz. Even at 200 Hz, however, unambiguous frequency-following responses were present in the spike train activity of som

An assessment of soil-to-plant concentration ratios for some natural analogues of the transuranic elements.

PubMed

Linsalata, P; Morse, R S; Ford, H; Eisenbud, M; Franca, E P; de Castro, M B; Lobao, N; Sachett, I; Carlos, M

1989-01-01

A field study was conducted in an area of enhanced, natural radioactivity to assess the soil to edible vegetable concentration ratios (CR = concentration in dry vegetable/concentration in dry soil) of 232Th, 230Th, 226Ra, 228Ra, and the light rare earth elements (REE's) La, Ce and Nd. Twenty-nine soil and 42 vegetable samples consisting of relatively equal numbers of seven varieties were obtained from 11 farms on the Pocos de Caldas Plateau in the state of Minas Gerais, Brazil. This region is the site of a major natural analogue study to assess the mobilization and retardation processes affecting Th and the REE's at the Morro do Ferro ore body and U series radionuclides at a nearby open pit U mine. Thorium (IV) serves as a chemical analogue for quadrivalent Pu and the light REE's (III) as chemical analogues for trivalent Am and Cm. The geometric mean CR's (all times 10(-4] decreased as 228Ra (148) greater than 226Ra (76) greater than La (5.4) greater than Nd (3.0) = Ce (2.6) greater than 232Th (0.6), or simply as M (II) greater than M (III) greater than M (IV). These differences may reflect the relative availability of these metals for plant uptake. Significant differences were found in the CR's (for any given analyte) among many of the vegetables sampled. The CR's for the different analytes were also highly correlated. The reasons for the correlations in CR's seen among elements with such diverse chemistries as Ra-REE or Ra-Th are not clear but are apparently related to the essential mineral requirements or mineral status of the different vegetables sampled. This conclusion is based on the significant correlations obtained between the Ca content of the dried vegetables and the CR's for all of the elements studied.

Achaete-Scute Homolog 1 Expression Controls Cellular Differentiation of Neuroblastoma

PubMed Central

Kasim, Mumtaz; Heß, Vicky; Scholz, Holger; Persson, Pontus B.; Fähling, Michael

2016-01-01

Neuroblastoma, the major cause of infant cancer deaths, results from fast proliferation of undifferentiated neuroblasts. Treatment of high-risk neuroblastoma includes differentiation with retinoic acid (RA); however, the resistance of many of these tumors to RA-induced differentiation poses a considerable challenge. Human achaete-scute homolog 1 (hASH1) is a proneural basic helix-loop-helix transcription factor essential for neurogenesis and is often upregulated in neuroblastoma. Here, we identified a novel function for hASH1 in regulating the differentiation phenotype of neuroblastoma cells. Global analysis of 986 human neuroblastoma datasets revealed a negative correlation between hASH1 and neuron differentiation that was independent of the N-myc (MYCN) oncogene. Using RA to induce neuron differentiation in two neuroblastoma cell lines displaying high and low levels of hASH1 expression, we confirmed the link between hASH1 expression and the differentiation defective phenotype, which was reversed by silencing hASH1 or by hypoxic preconditioning. We further show that hASH1 suppresses neuronal differentiation by inhibiting transcription at the RA receptor element. Collectively, our data indicate hASH1 to be key for understanding neuroblastoma resistance to differentiation therapy and pave the way for hASH1-targeted therapies for augmenting the response of neuroblastoma to differentiation therapy. PMID:28066180

Identification of heparin-binding EGF-like growth factor as a target in intercellular regulation of epidermal basal cell growth by suprabasal retinoic acid receptors.

PubMed Central

Xiao, J H; Feng, X; Di, W; Peng, Z H; Li, L A; Chambon, P; Voorhees, J J

1999-01-01

The role of retinoic acid receptors (RARs) in intercellular regulation of cell growth was assessed by targeting a dominant-negative RARalpha mutant (dnRARalpha) to differentiated suprabasal cells of mouse epidermis. dnRARalpha lacks transcriptional activation but not DNA-binding and receptor dimerization functions. Analysis of transgenic mice revealed that dnRARalpha dose-dependently impaired induction of basal cell proliferation and epidermal hyperplasia by all-trans RA (tRA). dnRARalpha formed heterodimers with endogenous retinoid X receptor-alpha (RXRalpha) over RA response elements in competition with remaining endogenous RARgamma-RXRalpha heterodimers, and dose-dependently impaired retinoid-dependent gene transcription. To identify genes regulated by retinoid receptors and involved in cell growth control, we analyzed the retinoid effects on expression of the epidermal growth factor (EGF) receptor, EGF, transforming growth factor-alpha, heparin-binding EGF-like growth factor (HB-EGF) and amphiregulin genes. In normal epidermis, tRA rapidly and selectively induced expression of HB-EGF but not the others. This induction occurred exclusively in suprabasal cells. In transgenic epidermis, dnRARalpha dose-dependently inhibited tRA induction of suprabasal HB-EGF and subsequent basal cell hyperproliferation. Together, our observations suggest that retinoid receptor heterodimers located in differentiated suprabasal cells mediate retinoid induction of HB-EGF, which in turn stimulates basal cell growth via intercellular signaling. These events may underlie retinoid action in epidermal regeneration during wound healing. PMID:10075925

Quantification of 226Ra at environmental relevant levels in natural waters by ICP-MS: Optimization, validation and limitations of an extraction and preconcentration approach.

PubMed

Lagacé, François; Foucher, Delphine; Surette, Céline; Clarisse, Olivier

2017-05-15

Radium (Ra) at environmental relevant levels in natural waters was determined by ICP-MS after an off-line pre-concentration procedure. The latter consisted of Ra selective elution from potential interfering elements (i.e. other alkaline earth cations: Ba 2+ , Sr 2+ , Ca 2+ , Mg 2+ ) on a series of two different ion exchange resins (AG50W-X8 and Sr-resin). The overall analytical method was optimized according to the instrumental performance, the volume of water sample loaded on resins, and the sample salinity. Longer acquisition time (up to 150 s) was required to ensure stable measurement of Ra by ICP-MS at ultra trace level (1.0pgL -1 ). For a synthetic groundwater spiked with Ra at 10.0pgL -1 , the analytical procedure demonstrated efficient separation of the analyte from its potential interfering elements and a complete recovery, independent of the sample volume tested from 10 up to 100mL. For synthetic seawater spiked at a level of 10.0pgL -1 of Ra, the total load of salts on the two resins should not exceed 0.35g in order to ensure a complete separation and recovery of Ra. The method was validated on natural waters (i.e. groundwater, freshwater and seawater samples) spiked with Ra at different levels (0.0, 0.5, 1.0 and 5.0pgL -1 ). Absolute Ra detection limits were determined at 0.020pgL -1 (0.73mBqL -1 ) and 0.12pgL -1 (4.4mBqL -1 ) respectively for 60.0mL of freshwater sample and for 10.0mL of seawater. Copyright © 2017 Elsevier B.V. All rights reserved.

Eruption Recurrence Rates and Compositional Variability of Discrete Lava Flows on the S-EPR from 238U-230Th-226Ra- 210Pb-232Th

NASA Astrophysics Data System (ADS)

Rubin, K. H.; Smith, M. C.; Sinton, J. M.; Sacks, L. F.; Bergmanis, E.

2001-12-01

Quantification of the absolute ages and geochemistry of individual seafloor lava flows provides important constraints on the magmatic processes responsible for building the oceanic crust. Here we present new 238U-230Th-226Ra-210Pb radioactive disequilibrium age constraints (decadal to millennial time scale) for 3 mid-ocean ridge lava flows at 17° 26'S on the East Pacific Rise (EPR): Aldo-Kihi, Rehu-Marka, and a neighboring unnamed flow. Our continuing study using high-resolution surveys and manned-submersible sampling (NAUDUR, 1993, and STOWA, 1991, expeditions) has previously shown that Aldo-Kihi is compositionally variable, is probably one of the youngest axial lavas in the 17° -19° S region, and was most likely erupted from a series of fissures extending >18 km along the ridge axis (Sinton et al., JGR, in revision). Rehu Marka has a more trace element enriched and evolved composition. The strongest age constraints in our U-series data set are from the 210Pb-226Ra (half-life = 22.3 yrs) and 226Ra-230Th (half life = 1600 yrs) systems. 210Pb-226Ra disequilibrium (as 5-7% Pb deficits) is common in lavas from our S-EPR study area and slightly lower than disequilibria we have measured in lavas erupted in 1991 and 1992 at 9° 50'N EPR. Although we are still developing our understanding of how this disequilibrium arises in MORB (e.g., how the radioactive "clock" is set for this isotope pair) a number of features of our preliminary data support the idea that these lavas are very young and that geologically observed contact relationships in the field separate the products of chronologically distinguishable eruptions. Also, the extent of 226Ra-210Pb disequilibrium in 3 Aldo-Kihi samples compared to that observed at 9° 50'N indicates that the Aldo-Kihi lava probably erupted within the last 10-20 yrs, and the higher but still <1 (210Pb/226Ra) activity ratio in a lava sampled near to but outside the boundaries of Aldo-Kihi indicates it is slightly older, but probably only by a decade or so. Although the older lava's major element composition is very similar to Aldo-Kihi, it has distinct U-Th-Ra chemistry, indicating it is from a different parental magma. Finally, the compositionally very distinct Rehu Marka flow just to the north has no 226Ra-210Pb disequilibrium, indicating it is likely older than the maximum resolvable age with this method (100-120 years). An age estimate (about 750 yrs) of the latter can be made from its 226Ra excess. Together, these preliminary age constraints provide insight into eruption recurrence rates and the processes that allow for preservation of compositional variability within proximally located (in space and time) lava flows along this magmatically robust segment of the EPR.

Proactive Problem Avoidance and Quality of Service (QOS) Guarantees for Large Heterogeneous Networks

DTIC Science & Technology

2002-03-01

host, and can be used to monitor and provide problem response data to multiple network elements. A blowup of the components of an RA is shown in...developed based on stati signal processing and learning. T ts to stical here are two salient features on the intelligent gents developed: (1) an...For multiple routers, the physical connections between interfaces along with the respective health of terface are represented. in In addition to

Rheumatoid arthritis and periodontitis – inflammatory and infectious connections. Review of the literature

PubMed Central

Rutger Persson, G.

2012-01-01

An association between oral disease/periodontitis and rheumatoid arthritis (RA) has been considered since the early 1820s. The early treatment was tooth eradication. Epidemiological studies suggest that the prevalence of RA and periodontitis may be similar and about 5% of the population are aged 50 years or older. RA is considered as an autoimmune disease whereas periodontitis has an infectious etiology with a complex inflammatory response. Both diseases are chronic and may present with bursts of disease activity. Association studies have suggested odds ratios of having RA and periodontitis varying from 1.8:1 (95% CI: 1.0–3.2, NS) to 8:1 (95% CI: 2.9–22.1, p<0.001). Genetic factors are driving the host responses in both RA and periodontitis. Tumor necrosis factor-α, a proinflammatory cytokine, regulates a cascade of inflammatory events in both RA and periodontitis. Porphyromonas gingivalis is a common pathogen in periodontal infection. P. gingivalis has also been identified in synovial fluid. The specific abilities of P. gingivalis to citrullinate host peptides by proteolytic cleavage at Arg-X peptide bonds by arginine gingipains can induce autoimmune responses in RA through development of anticyclic citrullinated peptide antibodies. In addition, P. gingivalis carries heat shock proteins (HSPs) that may also trigger autoimmune responses in subjects with RA. Data suggest that periodontal therapies combined with routine RA treatments further improve RA status. Conclusions Periodontal infection (P. gingivalis) carries a unique risk for development of autoimmune antibodies associated with RA. Patients with RA have either lost many teeth or usually have severe periodontitis. Additional research, both in regards to basic mechanisms as well as clinical studies, are necessary before it can be said that there are causative links between RA and periodontitis. Cross-disciplinary research in well-defined populations should be performed to further enhance knowledge and develop clinical strategies how to coordinate therapy and risk assessments of RA and periodontitis. PMID:22347541

Synergistic Activation of Steroidogenic Acute Regulatory Protein Expression and Steroid Biosynthesis by Retinoids: Involvement of cAMP/PKA Signaling

PubMed Central

Manna, Pulak R.; Slominski, Andrzej T.; King, Steven R.; Stetson, Cloyce L.

2014-01-01

Both retinoic acid receptors (RARs) and retinoid X receptors (RXRs) mediate the action of retinoids that play important roles in reproductive development and function, as well as steroidogenesis. Regulation of steroid biosynthesis is principally mediated by the steroidogenic acute regulatory protein (StAR); however, the modes of action of retinoids in the regulation of steroidogenesis remain obscure. In this study we demonstrate that all-trans retinoic acid (atRA) enhances StAR expression, but not its phosphorylation (P-StAR), and progesterone production in MA-10 mouse Leydig cells. Activation of the protein kinase A (PKA) cascade, by dibutyrl-cAMP or type I/II PKA analogs, markedly increased retinoid-responsive StAR, P-StAR, and steroid levels. Targeted silencing of endogenous RARα and RXRα, with small interfering RNAs, resulted in decreases in 9-cis RA-stimulated StAR and progesterone levels. Truncation of and mutational alterations in the 5′-flanking region of the StAR gene demonstrated the importance of the −254/−1-bp region in retinoid responsiveness. An oligonucleotide probe encompassing an RXR/liver X receptor recognition motif, located within the −254/−1-bp region, specifically bound MA-10 nuclear proteins and in vitro transcribed/translated RXRα and RARα in EMSAs. Transcription of the StAR gene in response to atRA and dibutyrl-cAMP was influenced by several factors, its up-regulation being dependent on phosphorylation of cAMP response-element binding protein (CREB). Chromatin immunoprecipitation studies revealed the association of phosphorylation of CREB, CREB binding protein, RXRα, and RARα to the StAR promoter. Further studies elucidated that hormone-sensitive lipase plays an important role in atRA-mediated regulation of the steroidogenic response that involves liver X receptor signaling. These findings delineate the molecular events by which retinoids influence cAMP/PKA signaling and provide additional and novel insight into the regulation of StAR expression and steroidogenesis in mouse Leydig cells. PMID:24265455

Analysis of SF and plasma cytokines provides insights into the mechanisms of inflammatory arthritis and may predict response to therapy.

PubMed

Wright, Helen L; Bucknall, Roger C; Moots, Robert J; Edwards, Steven W

2012-03-01

Biologic drugs have revolutionized the care of RA, but are expensive and not universally effective. To further understand the inflammatory mechanisms underlying RA and identify potential biomarkers predicting response to therapy, we measured multiple cytokine concentrations in SF of patients with inflammatory arthritides (IAs) and, in a subset of patients with RA, correlated this with response to TNF-α inhibition. SF from 42 RA patients and 19 non-RA IA patients were analysed for 12 cytokines using a multiplex cytokine assay. Cytokines were also measured in the plasma of 16 RA patients before and following treatment with anti-TNF-α. Data were analysed using Mann-Whitney U-test, Spearman's rank correlation and cluster analysis with the Kruskal-Wallis test with Dunn's post-test analysis. RA SF contained significantly elevated levels of IL-1β, IL-1ra, IL-2, IL-4, IL-8, IL-10, IL-17, IFN-γ, G-CSF, GM-CSF and TNF-α compared with other IA SF. RA patients who did not respond to anti-TNF therapy had elevated IL-6 in their SF pre-therapy (P < 0.05), whereas responders had elevated IL-2 and G-CSF (P < 0.05). Plasma cytokine concentrations were not significantly modulated by TNF inhibitors, with the exception of IL-6, which decreased after 12 weeks (P < 0.05). Cytokine profiles in RA SF vary with treatment and response to therapy. Cytokine concentrations are significantly lower in plasma than in SF and relatively unchanged by TNF inhibitor therapy. Concentrations of IL-6, IL-2 and G-CSF in SF may predict response to TNF inhibitors.

Inhibition of proliferation and induction of apoptosis in soft tissue sarcoma cells by interferon-α and retinoids

PubMed Central

Brodowicz, T; Wiltschke, C; Kandioler-Eckersberger, D; Grunt, T W; Rudas, M; Schneider, S M; Hejna, M; Budinsky, A; Zielinski, C C

1999-01-01

Uncontrolled proliferation and a defect of apoptosis constitute crucial elements in the development and progression of tumours. Among many other biological response modifiers known to influence these mechanisms, the efficacy of retinoids and interferons in the treatment of various malignant entities is currently matter of discussion. In the present study, we have investigated the effects of 9-cis-retinoic acid (9cRA), 13-cis-retinoic acid (13cRA), all-trans-retinoic acid (tRA) and interferon-α on proliferation and apoptosis of human soft tissue sarcoma (STS) cell lines HTB-82 (rhabdomyosarcoma), HTB-91 (fibrosarcoma), HTB-92 (liposarcoma), HTB-93 (synovial sarcoma) and HTB-94 (chondrosarcoma) in relation to p53 genotype as well as p53 expression. HTB-91, HTB-92 and HTB-94 STS cells exhibited mutant p53, whereas wild-type p53 was found in HTB-93 STS cells, and a normal p53 status in HTB-82 STS cells, carrying a silent point mutation only. Interferon-α, irrespective of p53 status, inhibited the proliferation of all five cell lines dose- and time-dependently. Similarly, 9cRA, 13cRA and tRA decreased the proliferation of HTB-82 and HTB-93 STS cells, whereas the proliferation of p53-mutated HTB-91, HTB-92 and HTB-94 STS cells remained unchanged. Furthermore, only 9cRA and tRA were capable of inducing apoptosis in HTB-82 and HTB-93 STS cells, whereas HTB-91, HTB-92 and HTB-94 STS cells did not undergo apoptosis under the influence of 9cRA or tRA. Retinoic acid receptor (RAR)-α and RAR-β mRNA were not detectable by Northern blot analysis in the five STS cell lines, whereas mRNA for the universal retinoic acid receptor, RAR-γ, was expressed in all STS cell lines indicating that retinoid resistance was not associated with a lack of RAR expression. Apoptosis was not induced by interferon-α or 13cRA in any of the five STS cell lines tested. Our results indicate that within the panel of tested STS cell lines, inhibition of proliferation and induction of apoptosis result from different mechanisms which differ in their dependence upon the presence of intact p53. © 1999 Cancer Research Campaign PMID:10424735

Comparison of bone cancer risks in beagle dogs for inhaled plutonium-238 dioxide, inhaled strontium-90 chloride, and injected strontium-90

DOE Office of Scientific and Technical Information (OSTI.GOV)

Griffith, W.C.; Muggenburg, B.A.; Hahn, F.F.

1995-12-01

There is a continuing need to understand dose-response relationships for ionizing radiation in order to protect the health of the public and nuclear workers from undue exposures. However, relatively few human populations have been exposed to doses of radiation high enough to cause observable, long-term health effects from which to derive dose-response relationships. This is particularly true for internally deposited radionuclides, although much effort has been devoted to epidemiological studies of the few types of exposures available, including lung cancers in uranium miners form the inhalation of the radioactive decay products of Ra, liver cancers in patients injected with Thorotrastmore » X-ray contrast medium containing Th, bone cancers in radium dial painters who ingested Ra, and bone cancers in patients who received therapeutic doses of Ra. These four types of exposures to internally deposited radionuclides provide a basis for understanding the health effects of many other radionuclides for which a potential for exposure exists. However, potential exposures to internally deposited radionuclides may differ in many modifying factors, such as route of exposure, population differences, and physical, chemical, and elemental forms of radionuclides. The only means available to study many of these modifying factors has been in laboratory animals, and to then extrapolate the results to humans. Three conclusions can be drawn from this example.« less

Uptake of trace elements and radionuclides from uranium mill tailings by four-wing saltbush (Atriplex canescens) and alkali sacaton (Sporobolus airoides). [Radium 226; Uranium; Molybdenum; Selenium; Vanadium; Astatine

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dreesen, D.R.; Marple, M.L.

1979-01-01

A greenhouse experiment was performed to determine the uptake of trace elements and radionuclides from uranium mill tailings by native plant species. Four-wing saltbush and alkali sacaton were grown in alkaline tailings covered with soil and in soil alone as controls. The tailings material was highly enriched in Ra-226, Mo, U, Se, V, and As compared with three local soils. The shrub grown in tailings had elevated concentrations of Mo, Se, Ra-226, U, As, and Na compared with the controls. Alkali sacaton contained high concentrations of Mo, Se, Ra-226, and Ni when grown on tailings. Molybdenum and selenium concentrations inmore » plants grown in tailings are above levels reported to be toxic to grazing animals. These results indicate that the bioavailability of Mo and Se in alkaline environments makes these elements among the most hazardous contaminants present in uranium mill wastes.« less

32 CFR 344.5 - Relationships.

Code of Federal Regulations, 2011 CFR

2011-07-01

... CHARTERS ASSISTANT SECRETARY OF DEFENSE FOR RESERVE AFFAIRS (ASD(RA)) § 344.5 Relationships. (a) In the performance of assigned functions and responsibilities, the ASD(RA) shall serve under the authority, direction... ASD(RA) on all matters related to the responsibilities and functions cited in § 344.4. ...

Affective disturbance in rheumatoid arthritis: psychological and disease-related pathways

PubMed Central

Sturgeon, John A.; Finan, Patrick H.; Zautra, Alex J.

2017-01-01

In addition to recurrent pain, fatigue, and increased rates of physical disability, individuals with rheumatoid arthritis (RA) show an increased prevalence of some mental health disorders, particularly those involving mood disturbances. This narrative Review provides an overview of mental health comorbidities in RA, and discusses how these comorbidities interact with disease processes, including dysregulation of inflammatory responses, prolonged difficulties with pain and fatigue, and the development of cognitive and behavioural responses that could exacerbate the physical and psychological difficulties associated with RA. This article describes how the social context of individuals with RA affects both their coping strategies and psychological responses to the disease, and can also impair responses to treatment through disruption of therapeutic alliance and treatment adherence. Evidence from the literature on chronic pain suggests that the resulting alterations in neural pathways of reward processing could yield new insights into the connections between disease processes in RA and psychological distress. Finally, the role of psychological interventions in the effective and comprehensive treatment of RA is discussed. PMID:27411910

The RA Role Revisited: Differences in Perspectives of RA Responsibilities.

ERIC Educational Resources Information Center

Schuh, John H.; And Others

1982-01-01

Determined resident assistants' (RA) role perceptions of students, parents, faculty, and administrators, full-time professional residence life staff, and resident assistants. Compared various constituent groups' perceptions of the RA role. (RC)

The retinoic acid signaling pathway regulates anterior/posterior patterning in the nerve cord and pharynx of amphioxus, a chordate lacking neural crest.

PubMed

Escriva, Hector; Holland, Nicholas D; Gronemeyer, Hinrich; Laudet, Vincent; Holland, Linda Z

2002-06-01

Amphioxus, the closest living invertebrate relative of the vertebrates, has a notochord, segmental axial musculature, pharyngeal gill slits and dorsal hollow nerve cord, but lacks neural crest. In amphioxus, as in vertebrates, exogenous retinoic acid (RA) posteriorizes the embryo. The mouth and gill slits never form, AmphiPax1, which is normally downregulated where gill slits form, remains upregulated and AmphiHox1 expression shifts anteriorly in the nerve cord. To dissect the role of RA signaling in patterning chordate embryos, we have cloned the single retinoic acid receptor (AmphiRAR), retinoid X receptor (AmphiRXR) and an orphan receptor (AmphiTR2/4) from amphioxus. AmphiTR2/4 inhibits AmphiRAR-AmphiRXR-mediated transactivation in the presence of RA by competing for DR5 or IR7 retinoic acid response elements (RAREs). The 5' untranslated region of AmphiTR2/4 contains an IR7 element, suggesting possible auto- and RA-regulation. The patterns of AmphiTR2/4 and AmphiRAR expression during embryogenesis are largely complementary: AmphiTR2/4 is strongly expressed in the cerebral vesicle (homologous to the diencephalon plus anterior midbrain), while AmphiRAR expression is high in the equivalent of the hindbrain and spinal cord. Similarly, while AmphiTR2/4 is expressed most strongly in the anterior and posterior thirds of the endoderm, the highest AmphiRAR expression is in the middle third. Expression of AmphiRAR is upregulated by exogenous RA and completely downregulated by the RA antagonist BMS009. Moreover, BMS009 expands the pharynx posteriorly; the first three gill slit primordia are elongated and shifted posteriorly, but do not penetrate, and additional, non-penetrating gill slit primordia are induced. Thus, in an organism without neural crest, initiation and penetration of gill slits appear to be separate events mediated by distinct levels of RA signaling in the pharyngeal endoderm. Although these compounds have little effect on levels of AmphiTR2/4 expression, RA shifts pharyngeal expression of AmphiTR2/4 anteriorly, while BMS009 extends it posteriorly. Collectively, our results suggest a model for anteroposterior patterning of the amphioxus nerve cord and pharynx, which is probably applicable to vertebrates as well, in which a low anterior level of AmphiRAR (caused, at least in part, by competitive inhibition by AmphiTR2/4) is necessary for patterning the forebrain and formation of gill slits, the posterior extent of both being set by a sharp increase in the level of AmphiRAR. Supplemental data available on-line

The retinoic acid signaling pathway regulates anterior/posterior patterning in the nerve cord and pharynx of amphioxus, a chordate lacking neural crest

NASA Technical Reports Server (NTRS)

Escriva, Hector; Holland, Nicholas D.; Gronemeyer, Hinrich; Laudet, Vincent; Holland, Linda Z.

2002-01-01

Amphioxus, the closest living invertebrate relative of the vertebrates, has a notochord, segmental axial musculature, pharyngeal gill slits and dorsal hollow nerve cord, but lacks neural crest. In amphioxus, as in vertebrates, exogenous retinoic acid (RA) posteriorizes the embryo. The mouth and gill slits never form, AmphiPax1, which is normally downregulated where gill slits form, remains upregulated and AmphiHox1 expression shifts anteriorly in the nerve cord. To dissect the role of RA signaling in patterning chordate embryos, we have cloned the single retinoic acid receptor (AmphiRAR), retinoid X receptor (AmphiRXR) and an orphan receptor (AmphiTR2/4) from amphioxus. AmphiTR2/4 inhibits AmphiRAR-AmphiRXR-mediated transactivation in the presence of RA by competing for DR5 or IR7 retinoic acid response elements (RAREs). The 5' untranslated region of AmphiTR2/4 contains an IR7 element, suggesting possible auto- and RA-regulation. The patterns of AmphiTR2/4 and AmphiRAR expression during embryogenesis are largely complementary: AmphiTR2/4 is strongly expressed in the cerebral vesicle (homologous to the diencephalon plus anterior midbrain), while AmphiRAR expression is high in the equivalent of the hindbrain and spinal cord. Similarly, while AmphiTR2/4 is expressed most strongly in the anterior and posterior thirds of the endoderm, the highest AmphiRAR expression is in the middle third. Expression of AmphiRAR is upregulated by exogenous RA and completely downregulated by the RA antagonist BMS009. Moreover, BMS009 expands the pharynx posteriorly; the first three gill slit primordia are elongated and shifted posteriorly, but do not penetrate, and additional, non-penetrating gill slit primordia are induced. Thus, in an organism without neural crest, initiation and penetration of gill slits appear to be separate events mediated by distinct levels of RA signaling in the pharyngeal endoderm. Although these compounds have little effect on levels of AmphiTR2/4 expression, RA shifts pharyngeal expression of AmphiTR2/4 anteriorly, while BMS009 extends it posteriorly. Collectively, our results suggest a model for anteroposterior patterning of the amphioxus nerve cord and pharynx, which is probably applicable to vertebrates as well, in which a low anterior level of AmphiRAR (caused, at least in part, by competitive inhibition by AmphiTR2/4) is necessary for patterning the forebrain and formation of gill slits, the posterior extent of both being set by a sharp increase in the level of AmphiRAR. Supplemental data available on-line.

32 CFR 344.4 - Responsibilities and functions.

Code of Federal Regulations, 2011 CFR

2011-07-01

...) ORGANIZATIONAL CHARTERS ASSISTANT SECRETARY OF DEFENSE FOR RESERVE AFFAIRS (ASD(RA)) § 344.4 Responsibilities and... Deputy Secretary of Defense for Reserve component matters in the Department of Defense. The ASD(RA) is... capacity, the ASD(RA) shall: (a) Develop policies, conduct analyses, provide advice, and make...

Rheumatoid arthritis patients exhibit impaired Candida albicans-specific Th17 responses.

PubMed

Bishu, Shrinivas; Su, Ee Wern; Wilkerson, Erich R; Reckley, Kelly A; Jones, Donald M; McGeachy, Mandy J; Gaffen, Sarah L; Levesque, Marc C

2014-02-11

Accumulating data implicate the CD4+ T cell subset (Th17 cells) in rheumatoid arthritis (RA). IL-17 is an inflammatory cytokine that induces tumor necrosis factor (TNF)α, IL-1β and IL-6, all of which are targets of biologic therapies used to treat RA. RA patients are well documented to experience more infections than age-matched controls, and biologic therapies further increase the risk of infection. The Th17/IL-17 axis is vital for immunity to fungi, especially the commensal fungus Candida albicans. Therefore, we were prompted to examine the relationship between RA and susceptibility to C. albicans because of the increasing interest in Th17 cells and IL-17 in driving autoimmunity, and the advent of new biologics that target this pathway. We analyzed peripheral blood and saliva from 48 RA and 33 healthy control subjects. To assess C. albicans-specific Th17 responses, PBMCs were co-cultured with heat-killed C. albicans extract, and IL-17A levels in conditioned supernatants were measured by ELISA. The frequency of Th17 and Th1 cells was determined by flow cytometry. As a measure of IL-17A-mediated effector responses, we evaluated C. albicans colonization rates in the oral cavity, salivary fungicidal activity and levels of the antimicrobial peptide β-defensin 2 (BD2) in saliva. Compared to controls, PBMCs from RA subjects exhibited elevated baseline production of IL-17A (P = 0.004), although they had similar capacity to produce IL-17A in response to Th17 cell differentiating cytokines (P = 0.91). However RA PBMCs secreted less IL-17A in response to C. albicans antigens (P = 0.006). Significantly more RA patients were colonized with C. albicans in the oral cavity than healthy subjects (P = 0.02). Concomitantly, RA saliva had reduced concentrations of salivary BD2 (P = 0.02). Nonetheless, salivary fungicidal activity was preserved in RA subjects (P = 0.70). RA subjects exhibit detectable impairments in oral immune responses to C. albicans, a strongly Th17-dependent opportunistic pathogen, despite an overall elevated baseline production of IL-17A.

Evaluation of Systems Engineering Methods, Processes and Tools on Department of Defense and Intelligence Community Programs - Phase 2

DTIC Science & Technology

2009-12-15

O 0 0 1, T O 0 0 2...ber: H 9 8 230 -0 8 -D -0 171 D O 0 0 1, T O 0 0 2. R T 0 0 9 4 7 C O N TIN UO US IN TEG RA TIO N Theme Elements...D O 0 0 1, T O 0 0 2. R T 0 0 9 51 RA PID PRO TO TYPIN G Theme Elements Time-boxed development process Delivery

210Pb-226Ra and Other U-Series Disequilibria in Very Young MORB and Loihi Tholeiites

NASA Astrophysics Data System (ADS)

van der Zander, I.; Rubin, K. H.; Smith, M.; Perfit, M.; Bergmanis, E. C.

2003-12-01

Direct observations of submarine volcanic eruptions are very sparse. Radiometric age constraints on submarine lava flows are thus an essential component for understanding even the most recent histories of oceanic crust formation. Chronometers in the decadal to century time frame have heretofore been lacking. This study focuses on the development and application of 210Pb-226Ra disequilibria as a geochronometer to provide quantitative eruption age constraints over the past 100 years, using submersible-collected samples from the North Cleft segment of the Juan de Fuca Ridge (JDFR) and adjacent Axial seamount, 9° 50'N East Pacific Rise (EPR) and Loihi (Hawaii), areas with known stratigraphic field relations between mapped lava flows. The data set provides a unique opportunity to calibrate the 210Pb-226Ra geochronometer because it represents a broad selection of "zero age" (210Po-210Pb dated) and near-zero-age submarine lavas (glasses). 238U-230Th-226Ra-210Pb radioactive disequilibria in these samples will be discussed to rationalize the range of conditions responsible for producing 210Pb-226Ra disequilibria (effective half life = 22 yrs) as an initial step towards using this signature to constrain eruption ages and petrogenetic time scales. We will also investigate the temporal aspects of petrogenetic conditions responsible for producing the other disequilibria in these rocks, without the uncertainty imposed by decay corrections for rocks of unknown age. These data augment those we previously reported from the Aldo-Kihi and neighboring lava flows at 17° 26'S EPR (Rubin et al., EOS, 82, F1279, 2001). Systematic differences between and within study areas exist: most normal zero age MORB display modest 210Pb deficits (3-10%); older MORB (the N-cleft sheet flow) have smaller deficits (0-3%); rocks erupted in 1998 from Axial seamount have 8-15% 210Pb excesses; and, rocks erupted in 1996 at Loihi are in equilibrium within error. Disequilibria amongst other nuclides are all within the range of previously published values. Data broadly fall within the negatively correlated array of (226Ra/230Th) and (230Th/238U) (Sims et al., GCA, 66, 2002), yet within each geographic locale data are positively correlated. Although (210Pb/226Ra) covaries with some major/trace element signatures of low pressure crystal fractionation, it also covaries negatively with (226Ra/230Th) in all but the Loihi samples, raising the intriguing possibility that some or all of the 210Pb-226Ra disequilibria arises deeper within the mantle (i.e., during melting or transport. This would shorten dramatically the time scales over which those processes occur). The suite of petrogenetic variations will be examined in the context of existing models for basaltic melt genesis.

Retinoic Acid 4-Hydroxylase Inducibility and Clinical Response to Isotretinoin in Acne Patients

PubMed Central

Wang, Frank; Kwak, Heh Shin R.; Elbuluk, Nada; Kaczmarek, Anya L.; Hamilton, Ted; Voorhees, John J.; Fisher, Gary J.; Kang, Sewon

2011-01-01

Background The cytochrome P450 enzyme CYP26 (retinoic acid 4-hydroxylase) initiates the catabolism of all-trans retinoic acid (tRA) and limits the effects of tRA. The CYP26 enzyme acts on tRA, but not 13-cis RA (isotretinoin), a retinoid used to treat severe acne. However, 13-cis RA can isomerize to tRA, which can then be metabolized by CYP26. Objective In healthy subjects, we assessed the variability of CYP26 enzymatic activity. We then investigated whether response to oral 13-cis RA among acne patients correlates with variability in CYP26 expression. Methods In healthy subjects, we isolated microsomal fractions from the epidermis of keratome biopsies and measured CYP26 enzymatic activity in untreated skin and skin treated with tRA. Enzymatic activity was determined based on rate of formation of 4-hydroxy RA (pg/min) per mg microsomal protein. Using real-time PCR we quantified CYP26 mRNA induction after tRA application in acne patients who responded or did not respond to one course of 13-cis RA. Results In normal skin (N=118), CYP26 enzymatic activity was widely variable (1–180 pg/min per mg microsomal fraction; mean 42.7 ± 3.5). Furthermore, CYP26 enzymatic activity was inducible in a dose-dependent manner in normal skin following tRA application, but not correlated with age or sex (N=29). In acne patients, CYP26 mRNA induction following 0.1% tRA application did not differ (P>0.05) between subjects who responded (N=8, 587±325 fold) or did not respond (N=8, 657±227 fold) to one course of 13-cis RA. Limitations The small number of acne patients treated with 13-cis RA was a major limitation. Conclusion Factors other than CYP26 activity may determine response to isotretinoin in acne. PMID:19525031

Evaluation of some pollutant levels in environmental samples collected from the area of the new campus of Taif University.

PubMed

Sharshar, Taher; Hassan, H Ebrahim; Arida, Hassan A; Aydarous, Abdulkadir; Bazaid, Salih A; Ahmed, Mamdouh A

2013-01-01

The levels of radioactivity and heavy metals in soil, plant and groundwater samples collected from the area of the new campus of Taif University, Saudi Arabia, and its neighbouring areas have been determined. High-resolution gamma-ray spectroscopy was used for radioactivity measurements, and inductively coupled plasma atomic emission spectroscopy was used to determine the concentration of heavy metals. The means of (226)Ra, (228)Ra and (40)K concentrations in water samples collected from four wells were found to be 0.13 ± 0.03, 0.05 ± 0.03 and 1.3 ± 0.5 Bq l(-1), respectively. The means of (238)U, (226)Ra, (228)Ra ((232)Th for soil samples) and (40)K concentrations in wild plant and soil samples were found to be 3.7 ± 4.1, 8.8 ± 11.6, 3.8 ± 2.9 and 1025 ± 685, and 8.6 ± 3.4, 12.8 ± 3.4, 16.6 ± 7.1 and 618 ± 82 Bq kg(-1) dry weight (DW), respectively. The (137)Cs of artificial origin was also detected in soil samples with a mean concentration of 3.8 ± 2.2 Bq kg(-1) DW. Evaluating the results, it can be concluded that the concentrations of (238)U, (226)Ra, (232)Th and (40)K in soil samples fall within the world average. Furthermore, 19 trace and major elements in groundwater samples and 22 elements in soil and plant samples were determined. The sampling locations of soil can be classified into three groups (relatively high, medium and low polluted) according to their calculated metal pollution index using the contents of trace and major elements. A cluster analysis of the contents of radioactivity and trace element contents in soil samples shows the presence of two main distinct clusters of sampling locations.

Interferon regulatory factor 5 is a potential target of autoimmune response triggered by Epstein-barr virus and Mycobacterium avium subsp. paratuberculosis in rheumatoid arthritis: investigating a mechanism of molecular mimicry.

PubMed

Bo, Marco; Erre, Gian Luca; Niegowska, Magdalena; Piras, Marco; Taras, Loredana; Longu, Maria Giovanna; Passiu, Giuseppe; Sechi, Leonardo A

2018-01-01

Rheumatoid arthritis (RA) is a chronic disease characterised by a pro-inflammatory cytokines linked erosive joint damage and by humoral and cellular response against a broad range of self-peptides. Molecular mimicry between Epstein-Barr virus (EBV), Mycobacterium avium subsp. paratuberculosis (MAP) and host peptides has long been regarded as an RA pathogenetic mechanism. Using bioinformatic analysis we identified high sequence homology among interferon regulatory factor 5 (IRF5), EBV antigen BOLF1 and MAP antigen MAP_4027. Our objective was to evaluate the presence in sera of RA patients of antibodies (Abs) directed against human homologous IRF5 cross-reacting with BOLF1 and MAP_4027. Frequency of reactivity against IRF5424-434, BOLF1305-320 and MAP_402718-32 was tested by indirect ELISA in sera from 71 RA patients and 60 healthy controls (HCs). RA sera show a remarkable high frequency of reactivity against IRF5424-434 in comparison to HCs (69% vs. 8%; p<0.0001). Similarly, seroreactivity against BOLF1305-320 was more frequently detected in RA sera than in HCs counterpart (58% vs. 8%; p<0.0001). Frequency of Abs against MAP_402718-32 was 17% in RA sera vs. 5% in HCs with a p-value at the threshold level (p<0.051). Prevalence of Abs against at least one of the assessed epitopes reached 72% in RA patients and 15% among HCs. Levels of Abs in RA patients were significantly related to systemic inflammation. IRF5 is a potential autoimmune target of RA. Our results support the hypothesis that EBV and MAP infections may be involved in the pathogenesis of RA, igniting a secondary immune response that cross-reacts against RA self-peptides.

NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis

PubMed Central

Khandpur, Ritika; Carmona-Rivera, Carmelo; Vivekanandan-Giri, Anuradha; Gizinski, Alison; Yalavarthi, Srilakshmi; Knight, Jason S.; Friday, Sean; Li, Sam; Patel, Rajiv M.; Subramanian, Venkataraman; Thompson, Paul; Chen, Pojen; Fox, David A.; Pennathur, Subramaniam; Kaplan, Mariana J.

2013-01-01

The early events leading to the development of rheumatoid arthritis (RA) remain unclear but formation of autoantibodies to citrullinated antigens (ACPA) is considered a key pathogenic phenomenon. Neutrophils isolated from patients with various autoimmune diseases display enhanced extracellular trap formation (NETs), a phenomenon that externalizes autoantigens and immunostimulatory molecules. We investigated whether aberrant NETosis occurs in RA, determined its triggers and examined its deleterious inflammatory consequences. Enhanced NETosis was observed in circulating and synovial fluid RA neutrophils, compared to neutrophils from healthy controls and from patients with osteoarthritis. Further, netting neutrophils infiltrated RA synovial tissue, rheumatoid nodules and skin. NETosis correlated with ACPA presence and levels and with systemic inflammatory markers. RA sera and immunoglobulin fractions from RA patients with high levels of ACPA and/or rheumatoid factor significantly enhanced NETosis, and the NETs induced by these autoantibodies displayed distinct protein content. During NETosis, neutrophils externalized citrullinated autoantigens implicated in RA pathogenesis, whereas anti-citrullinated vimentin antibodies potently induced NET formation. The inflammatory cytokines IL-17A and TNF-α induced NETosis in RA neutrophils. In turn, NETs significantly augmented inflammatory responses in RA and OA synovial fibroblasts, including induction of IL-6, IL-8, chemokines and adhesion molecules. These observations implicate accelerated NETosis in RA pathogenesis, through externalization of citrullinated autoantigens and immunostimulatory molecules that may promote aberrant adaptive and innate immune responses in the joint and in the periphery, and perpetuate pathogenic mechanisms in this disease. PMID:23536012

Pre-silencing of genes involved in the electron transport chain (ETC) pathway is associated with responsiveness to abatacept in rheumatoid arthritis.

PubMed

Derambure, C; Dzangue-Tchoupou, G; Berard, C; Vergne, N; Hiron, M; D'Agostino, M A; Musette, P; Vittecoq, O; Lequerré, T

2017-05-25

In the current context of personalized medicine, one of the major challenges in the management of rheumatoid arthritis (RA) is to identify biomarkers that predict drug responsiveness. From the European APPRAISE trial, our main objective was to identify a gene expression profile associated with responsiveness to abatacept (ABA) + methotrexate (MTX) and to understand the involvement of this signature in the pathophysiology of RA. Whole human genome microarrays (4 × 44 K) were performed from a first subset of 36 patients with RA. Data validation by quantitative reverse-transcription (qRT)-PCR was performed from a second independent subset of 32 patients with RA. Gene Ontology and WikiPathways database allowed us to highlight the specific biological mechanisms involved in predicting response to ABA/MTX. From the first subset of 36 patients with RA, a combination including 87 transcripts allowed almost perfect separation between responders and non-responders to ABA/MTX. Next, the second subset of patients 32 with RA allowed validation by qRT-PCR of a minimal signature with only four genes. This latter signature categorized 81% of patients with RA with 75% sensitivity, 85% specificity and 85% negative predictive value. This combination showed a significant enrichment of genes involved in electron transport chain (ETC) pathways. Seven transcripts from ETC pathways (NDUFA6, NDUFA4, UQCRQ, ATP5J, COX7A2, COX7B, COX6A1) were significantly downregulated in responders versus non-responders to ABA/MTX. Moreover, dysregulation of these genes was independent of inflammation and was specific to ABA response. Pre-silencing of ETC genes is associated with future response to ABA/MTX and might be a crucial key to susceptibility to ABA response.

De-repression of RaRF-mediated RAR repression by adenovirus E1A in the nucleolus.

PubMed

Um, Soo-Jong; Youn, Hye Sook; Kim, Eun-Joo

2014-02-21

Transcriptional activity of the retinoic acid receptor (RAR) is regulated by diverse binding partners, including classical corepressors and coactivators, in response to its ligand retinoic acid (RA). Recently, we identified a novel corepressor of RAR called the retinoic acid resistance factor (RaRF) (manuscript submitted). Here, we report how adenovirus E1A stimulates RAR activity by associating with RaRF. Based on immunoprecipitation (IP) assays, E1A interacts with RaRF through the conserved region 2 (CR2), which is also responsible for pRb binding. The first coiled-coil domain of RaRF was sufficient for this interaction. An in vitro glutathione-S-transferase (GST) pull-down assay was used to confirm the direct interaction between E1A and RaRF. Further fluorescence microscopy indicated that E1A and RaRF were located in the nucleoplasm and nucleolus, respectively. However, RaRF overexpression promoted nucleolar translocation of E1A from the nucleoplasm. Both the RA-dependent interaction of RAR with RaRF and RAR translocation to the nucleolus were disrupted by E1A. RaRF-mediated RAR repression was impaired by wild-type E1A, but not by the RaRF binding-defective E1A mutant. Taken together, our data suggest that E1A is sequestered to the nucleolus by RaRF through a specific interaction, thereby leaving RAR in the nucleoplasm for transcriptional activation. Copyright © 2014 Elsevier Inc. All rights reserved.

LBH Gene Transcription Regulation by the Interplay of an Enhancer Risk Allele and DNA Methylation in Rheumatoid Arthritis.

PubMed

Hammaker, Deepa; Whitaker, John W; Maeshima, Keisuke; Boyle, David L; Ekwall, Anna-Karin H; Wang, Wei; Firestein, Gary S

2016-11-01

To identify nonobvious therapeutic targets for rheumatoid arthritis (RA), we performed an integrative analysis incorporating multiple "omics" data and the Encyclopedia of DNA Elements (ENCODE) database for potential regulatory regions. This analysis identified the limb bud and heart development (LBH) gene, which has risk alleles associated with RA/celiac disease and lupus, and can regulate cell proliferation in RA. We identified a novel LBH transcription enhancer with an RA risk allele (rs906868 G [Ref]/T) 6 kb upstream of the LBH gene with a differentially methylated locus. The confluence of 3 regulatory elements, rs906868, an RA differentially methylated locus, and a putative enhancer, led us to investigate their effects on LBH regulation in fibroblast-like synoviocytes (FLS). We cloned the 1.4-kb putative enhancer with either the rs906868 Ref allele or single-nucleotide polymorphism (SNP) variant into reporter constructs. The constructs were methylated in vitro and transfected into cultured FLS by nucleofection. We found that both variants increased transcription, thereby confirming the region's enhancer function. Unexpectedly, the transcriptional activity of the Ref risk allele was significantly lower than that of the SNP variant and is consistent with low LBH levels as a risk factor for aggressive FLS behavior. Using RA FLS lines with a homozygous Ref or SNP allele, we confirmed that homozygous Ref lines expressed lower LBH messenger RNA levels than did the SNP lines. Methylation significantly reduced enhancer activity for both alleles, indicating that enhancer function is dependent on its methylation status. This study shows how the interplay between genetics and epigenetics can affect expression of LBH in RA. © 2016, American College of Rheumatology.

Antiviral effect of vitamin A on norovirus infection via modulation of the gut microbiome

PubMed Central

Lee, Heetae; Ko, GwangPyo

2016-01-01

The effect and underlying mechanism of vitamin A on norovirus infection are largely unknown. This study aimed to investigate how vitamin A administration affects the gut microbiome after norovirus infection. Here, we demonstrate that treatment with either retinol or retinoic acid (RA) inhibits murine norovirus (MNV) replication using both in vitro and in vivo models. Compositional changes in the gut microbiome associated with RA administration and/or norovirus infection were also investigated. Oral administration of RA and/or MNV significantly altered intestinal microbiome profiles. Particularly, bacterial species belonging to the Lactobacillaceae families were remarkably increased by MNV inoculation and RA administration, suggesting that the antiviral effects of RA occur via the modulation of specific microbiota. The antiviral causal effect of Lactobacillus was identified and demonstrated using in vitro models in RAW264.7 cells. The antiviral immune response to MNV was mediated by IFN-β upregulation. This study represents the first comprehensive profiling of gut microbiota in response to RA treatment against norovirus infection. Moreover, we conclude that the abundance of Lactobacillus through gut microbiota modulation by RA is at least partially responsible for norovirus inhibition. PMID:27180604

Comparative transcriptional profiling-based identification of raphanusanin-inducible genes

PubMed Central

2010-01-01

Background Raphanusanin (Ra) is a light-induced growth inhibitor involved in the inhibition of hypocotyl growth in response to unilateral blue-light illumination in radish seedlings. Knowledge of the roles of Ra still remains elusive. To understand the roles of Ra and its functional coupling to light signalling, we constructed the Ra-induced gene library using the Suppression Subtractive Hybridisation (SSH) technique and present a comparative investigation of gene regulation in radish seedlings in response to short-term Ra and blue-light exposure. Results The predicted gene ontology (GO) term revealed that 55% of the clones in the Ra-induced gene library were associated with genes involved in common defence mechanisms, including thirty four genes homologous to Arabidopsis genes implicated in R-gene-triggered resistance in the programmed cell death (PCD) pathway. Overall, the library was enriched with transporters, hydrolases, protein kinases, and signal transducers. The transcriptome analysis revealed that, among the fifty genes from various functional categories selected from 88 independent genes of the Ra-induced library, 44 genes were up-regulated and 4 were down-regulated. The comparative analysis showed that, among the transcriptional profiles of 33 highly Ra-inducible genes, 25 ESTs were commonly regulated by different intensities and duration of blue-light irradiation. The transcriptional profiles, coupled with the transcriptional regulation of early blue light, have provided the functional roles of many genes expected to be involved in the light-mediated defence mechanism. Conclusions This study is the first comprehensive survey of transcriptional regulation in response to Ra. The results described herein suggest a link between Ra and cellular defence and light signalling, and thereby contribute to further our understanding of how Ra is involved in light-mediated mechanisms of plant defence. PMID:20553608

A multicenter report of biologic agents for the treatment of secondary amyloidosis in Turkish rheumatoid arthritis and ankylosing spondylitis patients.

PubMed

Pamuk, Ömer Nuri; Kalyoncu, Umut; Aksu, Kenan; Omma, Ahmet; Pehlivan, Yavuz; Çağatay, Yonca; Küçükşahin, Orhan; Dönmez, Salim; Çetin, Gözde Yıldırım; Mercan, Rıdvan; Bayındır, Özün; Çefle, Ayşe; Yıldız, Fatih; Balkarlı, Ayşe; Kılıç, Levent; Çakır, Necati; Kısacık, Bünyamin; Öksüz, Mustafa Ferhat; Çobankara, Veli; Onat, Ahmet Mesut; Sayarlıoğlu, Mehmet; Öztürk, Mehmet Akif; Pamuk, Gülsüm Emel; Akkoç, Nurullah

2016-07-01

In this multicenter, retrospective study, we evaluated the efficacy and safety of biologic therapies, including anti-TNFs, in secondary (AA) amyloidosis patients with ankylosing spondylitis (AS) and rheumatoid arthritis (RA). In addition, the frequency of secondary amyloidosis in RA and AS patients in a single center was estimated. Fifty-one AS (39M, 12F, mean age: 46.7) and 30 RA patients (11M, 19F, mean age: 51.7) with AA amyloidosis from 16 different centers in Turkey were included. Clinical and demographical features of patients were obtained from medical charts. A composite response index (CRI) to biologic therapy-based on creatinine level, proteinuria and disease activity-was used to evaluate the efficacy of treatment. The mean annual incidence of AA amyloidosis in RA and AS patients was 0.23 and 0.42/1000 patients/year, respectively. The point prevalence in RA and AS groups was 4.59 and 7.58/1000, respectively. In RA group with AA amyloidosis, effective response was obtained in 52.2 % of patients according to CRI. RA patients with RF positivity and more initial disease activity tended to have higher response rates to therapy (p values, 0.069 and 0.056). After biologic therapy (median 17 months), two RA patients died and two developed tuberculosis. In AS group, 45.7 % of patients fulfilled the criteria of good response according to CRI. AS patients with higher CRP levels at the time of AA diagnosis and at the beginning of anti-TNF therapy had higher response rates (p values, 0.011 and 0.017). During follow-up after anti-TNF therapy (median 38 months), one patient died and tuberculosis developed in two patients. Biologic therapy seems to be effective in at least half of RA and AS patients with AA amyloidosis. Tuberculosis was the most important safety concern.

The Work Instability Scale for Rheumatoid Arthritis (RA-WIS): Does it work in osteoarthritis?

PubMed

Tang, Kenneth; Beaton, Dorcas E; Lacaille, Diane; Gignac, Monique A M; Zhang, Wei; Anis, Aslam H; Bombardier, Claire

2010-09-01

To validate the 23-item Work Instability Scale for Rheumatoid Arthritis (RA-WIS) for use in osteoarthritis (OA) using both classical test theory and item response theory approaches. Baseline and 12-month follow-up data were collected from workers with OA recruited from community and clinical settings (n = 130). Fit of RA-WIS data to the Rasch model was evaluated by item- and person-fit statistics (size of residual, chi-sq), assessments of differential item functioning, and tests of unidimensionality and local independence. Internal consistency was assessed by KR-20. Convergent construct validity (Spearman r, known-groups) was evaluated against theoretical constructs that assess impact of health on work. Responsiveness to global indicators of change was assessed by standardized response means (SRM) and area under the receiver operating characteristic curves. Data structure of the RA-WIS showed adequate fit to the Rasch model (chi-sq = 83.2, P = 0.03) after addressing local dependency in three item pairs by creating testlets. High internal consistency (KR-20 = 0.93) and convergent validity with work-oriented constructs (|r| = 0.55-0.77) were evident. The RA-WIS correlated most strongly with the concept of illness intrusiveness (r = 0.77) and was highly responsive to changes (SRM = 1.05 [deterioration]; -0.78 [improvement]). Although developed for RA, the RA-WIS is psychometrically sound for OA and demonstrates interval-level property.

Changes in Pulse Character and Mental Status are Late Responses to Central Hypovolemia

DTIC Science & Technology

2008-06-01

central hypovolemia 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Ryan K. L., Batchinsky A. I., McManus J . G...Sauaia A, Moore FA, Moore EE, Moser KS, Brennan R, Read RA, Pons PT. Epidemiology of trauma deaths: a reassessment. J Trauma. 1995;38:185–193. 2... J Trauma. 1996;40:S165–S169. 4. Champion H, Sacco W, Carnazzo A, Copes W, Fouty W: Trauma score. Crit Care Med. 1981;9:672–676. 5. Meredith W

Rheumatoid arthritis synovial fibroblasts produce a soluble form of the interleukin-7 receptor in response to pro-inflammatory cytokines

PubMed Central

Badot, V; Durez, P; Van den Eynde, BJ; Nzeusseu-Toukap, A; Houssiau, FA; Lauwerys, BR

2011-01-01

Abstract We previously demonstrated that baseline synovial overexpression of the interleukin-7 receptor α-chain (IL-7R) is associated with poor response to tumour necrosis factor (TNF) blockade in rheumatoid arthritis (RA). We found that IL-7R gene expression is induced in fibroblast-like synovial cells (FLS) by the addition of TNF-α, IL-1β and combinations of TNF-α+ IL-1β or TNF-α+ IL-17, thereby suggesting that these cytokines play a role in the resistance to TNF blockade in RA. Because FLS and CD4 T cells also produce a soluble form of IL-7R (sIL-7R), resulting from an alternative splicing of the full-length transcript, we wondered whether expression of sIL-7R is similarly regulated by pro-inflammatory cytokines. We also investigated whether sIL-7R is detectable in the serum of RA patients and associated with response to TNF blockade. RA FLS were cultured in the presence of pro-inflammatory cytokines and sIL-7R concentrations were measured in culture supernatants. Similarly, sIL-7R titres were measured in sera obtained from healthy individuals, early untreated RA patients with active disease and disease-modifying anti-rheumatic drug (DMARD)-resistant RA patients prior to initiation of TNF-blockade. Baseline serum sIL-7R titres were correlated with validated clinical measurements of disease activity. We found that exposure of RA FLS to pro-inflammatory cytokines (TNF-α, IL-1β and combinations of TNF-α and IL-1β or TNF-α and IL-17) induces sIL-7R secretion. Activated CD4 T cells also produce sIL-7R. sIL-7R serum levels are higher in RA patients as compared to controls. In DMARD-resistant patients, high sIL-7R serum concentrations are strongly associated with poor response to TNF-blockade. In conclusion, sIL-7R is induced by pro-inflammatory cytokines in RA FLS. sIL-7R could qualify as a new biomarker of response to therapy in RA. PMID:21129157

The Rapid Disaster Evaluation System (RaDES): A Plan to Improve Global Disaster Response by Privatizing the Assessment Component.

PubMed

Iserson, Kenneth V

2017-09-01

Emergency medicine personnel frequently respond to major disasters. They expect to have an effective and efficient management system to elegantly allocate available resources. Despite claims to the contrary, experience demonstrates this rarely occurs. This article describes privatizing disaster assessment using a single-purposed, accountable, and well-trained organization. The goal is to achieve elegant disaster assessment, rather than repeatedly exhorting existing groups to do it. The Rapid Disaster Evaluation System (RaDES) would quickly and efficiently assess a postdisaster population's needs. It would use an accountable nongovernmental agency's teams with maximal training, mobility, and flexibility. Designed to augment the Inter-Agency Standing Committee's 2015 Emergency Response Preparedness Plan, RaDES would provide the initial information needed to avoid haphazard and overlapping disaster responses. Rapidly deployed teams would gather information from multiple sources and continually communicate those findings to their base, which would then disseminate them to disaster coordinators in a concise, coherent, and transparent way. The RaDES concept represents an elegant, minimally bureaucratic, and effective rapid response to major disasters. However, its implementation faces logistical, funding, and political obstacles. Developing and maintaining RaDES would require significant funding and political commitment to coordinate the numerous agencies that claim to be performing the same tasks. Although simulations can demonstrate efficacy and deficiencies, only field tests will demonstrate RaDES' power to improve interagency coordination and decrease the cost of major disaster response. At the least, the RaDES concept should serve as a model for discussing how to practicably improve our current chaotic disaster responses. Copyright © 2016 Elsevier Inc. All rights reserved.

IL-6 inhibitors for treatment of rheumatoid arthritis: past, present, and future.

PubMed

Kim, Go Woon; Lee, Na Ra; Pi, Ryo Han; Lim, Yee Seul; Lee, Yu Mi; Lee, Jong Min; Jeong, Hye Seung; Chung, Sung Hyun

2015-01-01

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by polyarthritis. Numerous agents with varying mechanisms are used in the treatment of RA, including non-steroidal anti-inflammatory drugs, disease-modifying anti-rheumatic drugs, and some biological agents. Studies to uncover the cause of RA have recently ended up scrutinizing the importance of pro-inflammatory cytokine such as tumor necrosis factor α (TNF-α) and interleukin (IL)-6 in the pathogenesis of RA. TNF-α inhibitors are increasingly used to treat RA patients who are non-responsive to conventional anti-arthritis drugs. Despite its effectiveness in a large patient population, up to two thirds of RA patients are found to be partially responsive to anti-TNF therapy. Therefore, agents targeting IL-6 such as tocilizumab (TCZ) attracted significant attention as a promising agent in RA treatment. In this article, we review the mechanism of anti-IL-6 in the treatment of RA, provide the key efficacy and safety data from clinical trials of approved anti-IL-6, TCZ, as well as six candidate IL-6 blockers including sarilumab, ALX-0061, sirukumab, MEDI5117, clazakizumab, and olokizumab, and their future perspectives in the treatment of RA.

13-cis Retinoic Acid Inhibits Development and Progression of Chronic Allograft Nephropathy

PubMed Central

Adams, Judith; Kiss, Eva; Arroyo, Ana B.V.; Bonrouhi, Mahnaz; Sun, Qiang; Li, Zhen; Gretz, Norbert; Schnitger, Anna; Zouboulis, Christos C.; Wiesel, Manfred; Wagner, Jürgen; Nelson, Peter J.; Gröne, Hermann-Josef

2005-01-01

Chronic allograft nephropathy is characterized by chronic inflammation and fibrosis. Because retinoids exhibit anti-proliferative, anti-inflammatory, and anti-fibrotic functions, the effects of low and high doses of 13-cis-retinoic acid (13cRA) were studied in a chronic Fisher344→Lewis transplantation model. In 13cRA animals, independent of dose (2 or 20 mg/kg body weight/day) and start (0 or 14 days after transplantation) of 13cRA administration, serum creatinine was significantly lower and chronic rejection damage was dramatically reduced, including subendothelial fibrosis of preglomerular vessels and chronic tubulointerstitial damage. The number of infiltrating mononuclear cells and their proliferative activity were significantly diminished. The mRNA expression of chemokines (MCP-1/CCL2, MIP-1α/CCL3, IP-10/CXCL10, RANTES/CCL5) and proteins associated with fibrosis (plasminogen activator inhibitor-1, transforming growth factor-β1, and collagens I and III) were strikingly lower in treated allografts. In vitro, activated peritoneal macrophages of 13cRA-treated rats showed a pronounced decrease in protein secretion of inflammatory cytokines (eg, tumor necrosis factor-α, interleukin-6). The suppression of the proinflammatory chemokine RANTES/CCL5 × 13cRA in fibroblasts could be mapped to a promoter module comprising IRF-1 and nuclear factor-κB binding elements, but direct binding of retinoid receptors to promoter elements could be excluded. In summary, 13cRA acted as a potent immunosuppressive and anti-fibrotic agent able to prevent and inhibit progression of chronic allograft nephropathy. PMID:15972972

Differing specificities and isotypes of anti-citrullinated peptide/protein antibodies in palindromic rheumatism and rheumatoid arthritis.

PubMed

Cabrera-Villalba, Sonia; Gomara, María José; Cañete, Juan D; Ramírez, Julio; Salvador, Georgina; Ruiz-Esquide, Virginia; Hernández, Maria Victoria; Inciarte-Mundo, José; Haro, Isabel; Sanmartí, Raimon

2017-06-15

To analyze differences in the recognition of anti-citrullinated peptide/protein antibody (ACPA) citrullinated epitopes and isotypes in patients with palindromic rheumatism (PR) and rheumatoid arthritis (RA). ACPA fine specificities (citrullinated peptides of enolase, fibrin, and vimentin) and isotypes (IgG, IgM, and IgA) were analyzed in 54 patients with longstanding PR and 54 patients with established RA. CCP2 tested positive in 66.7% of patients with PR and RA. The ACPA distribution of fine specificities and isotypes differed between PR and RA patients. PR patients had a lower frequency of fine ACPA specificities than RA patients, which was significant in the case of a peptide derived from vimentin (PR 24.1% vs. 59.3% RA; p < 0.001). The mean number of ACPA specificities was lower in PR than in RA patients, and only 25.9% of PR patients recognized ≥2 additional specificities compared with 46.3% of RA patients. Significantly less isotype usage, especially IgA, was observed in PR patients. The ACPA immune response differed in patients with PR and RA, with fewer fine specificities and isotype usage in patients with PR. Some patients with PR may have impaired maturation of the B-cell response against citrullinated peptides with no progression to RA.

Purification of lanthanides for double beta decay experiments

DOE Office of Scientific and Technical Information (OSTI.GOV)

Polischuk, O. G.; Barabash, A. S.; Belli, P.

2013-08-08

There are several potentially double beta active isotopes among the lanthanide elements. However, even high purity grade lanthanide compounds contain {sup 238}U, {sup 226}Ra and {sup 232,228}Th typically on the level of ∼ (0.1 - 1) Bq/kg. The liquid-liquid extraction technique was used to remove traces of U, Ra and Th from CeO{sub 2}, Nd{sub 2}O{sub 3} and Gd{sub 2}O{sub 3}. The radioactive contamination of the samples before and after the purification was tested by using ultra-low-background HPGe γ spectrometry at the underground Gran Sasso National Laboratories of the INFN (Italy). After the purification the radioactive contamination of gadolinium oxidemore » by Ra and Th was decreased at least one order of magnitude. The efficiency of the approach to purify cerium oxide from Ra was on same level, while the radioactive contamination of neodymium sample before and after the purification is below the sensitivity of analytical methods. The purification method is much less efficient for chemically very similar radioactive elements like lanthanum, lutetium and actinium. R and D of the methods to remove the pollutions with improved efficiency is in progress.« less

The isotype repertoire of antibodies against novel UH-RA peptides in rheumatoid arthritis.

PubMed

De Winter, Liesbeth M; Geusens, Piet; Lenaerts, Jan; Vanhoof, Johan; Stinissen, Piet; Somers, Veerle

2016-06-07

Recently, autoantibodies against novel UH-RA peptides (UH-RA.1 and UH-RA.21) were identified as candidate biomarkers for patients with rheumatoid arthritis (RA) who are seronegative for the current diagnostic markers rheumatoid factor and anticitrullinated protein antibodies. Previously, screening for anti-UH-RA autoantibodies was based on measuring the immunoglobulin (Ig) G response. We aimed to investigate whether measurement of other isotypes could improve the performance of diagnostic testing. In addition, assigning the isotype profile might provide valuable information on effector functions of the antibodies. The isotype profile of antibodies against UH-RA.1 and UH-RA.21 was studied. The IgG, IgM, and IgA classes, together with the 4 different IgG subclasses, were determined in 285 patients with RA, 88 rheumatic control subjects, and 90 healthy control subjects. Anti-UH-RA.1 antibodies were primarily of the IgM isotype and twice as prevalent as IgG (IgG3-dominated) and IgA. RA sensitivity when testing for anti-UH-RA.1 IgM was shown to be higher than when testing for the IgG isotype: 18 % versus 9 % sensitivity when RA specificity was set to 90 %. Within antibodies against UH-RA.21, IgG and IgA were more common than IgM. Different anti-UH-RA.21 IgG subclasses were found, with the highest prevalence found for IgG2. Combined testing for IgG and IgA slightly increased RA sensitivity of UH-RA.21-specific antibody testing to 27 % compared with solely testing for IgG (23 %). Notably, a higher number of anti-UH-RA.21 antibody isotypes was related to increased levels of erythrocyte sedimentation rate. Finally, for both antibody responses, the full antibody isotype use was demonstrated in early and seronegative disease. The isotype distribution of anti-UH-RA.1 and anti-UH-RA.21 antibodies was successfully outlined, and, for antibodies against UH-RA.1, we found that isotype-specific testing might have implications for diagnostic testing. The exact mechanisms by which the different antibody isotypes act still have to be unraveled.

Tenosynovitis US scoring systems follow synovitis and clinical scoring systems in RA and are responsive to change after biologic therapy.

PubMed

Vlad, Violeta; Berghea, Florian; Micu, Mihaela; Varzaru, Luminita; Bojinca, Mihai; Milicescu, Mihaela; Ionescu, Ruxandra; Naredo, Esperanza

2015-09-01

To investigate by ultrasonography (US) in a cohort of active RA patients starting biologic therapy the responsiveness of tenosynovitis of wrist and hands compared to the responsiveness of synovitis in a 6 month period follow-up, to compare the responsiveness of finger flexor tenosynovitis with the responsiveness of wrist extensor tenosynovitis and to describe the subclinical synovitis and tenosynovitis in RA patients in clinical remission. Fifty seven patients with active RA starting biologic therapy were included. Clinical, laboratory, and US evaluations were performed at baseline, 1, and 6 months. US evaluation included wrist and MCPs 2-5 joints, bilaterally for synovitis and extensor tendons compartments 2, 4, and 6 and finger flexors 2-5 for tenosynovitis. Eighteen US scores based on semiquantitative or binary grades were calculated at each visit. Responsiveness of synovitis and tenosynovitis scores was calculated using the standardized response mean (SRM). The responsiveness of US tenosynovitis was lower comparing with the responsiveness of US synovitis but both showed large effect of therapy. Furthermore, tenosynovitis responsiveness was similar to CRP responsiveness (SRM -0.90). Finger flexors tenosynovitis showed a higher responsiveness than extensor tenosynovitis on GS (-0.94 compared to -0.63) and a lower SRM on PD (-0.56 compared to -0.85). Tenosynovitis scores remission was overlapping clinical remission according to CDAI and SDAI in 100% of cases. Overall there was less subclinical tenosynovitis than subclinical synovitis at final visit according to clinical activity indices. Tenosynovitis US scoring in RA may be as good as synovitis scoring for characterization of disease activity and responsiveness.

Identification of key regulators for the migration and invasion of rheumatoid synoviocytes through a systems approach

PubMed Central

You, Sungyong; Yoo, Seung-Ah; Choi, Susanna; Kim, Ji-Young; Park, Su-Jung; Ji, Jong Dae; Kim, Tae-Hwan; Kim, Ki-Jo; Cho, Chul-Soo; Hwang, Daehee; Kim, Wan-Uk

2014-01-01

Rheumatoid synoviocytes, which consist of fibroblast-like synoviocytes (FLSs) and synovial macrophages (SMs), are crucial for the progression of rheumatoid arthritis (RA). Particularly, FLSs of RA patients (RA-FLSs) exhibit invasive characteristics reminiscent of cancer cells, destroying cartilage and bone. RA-FLSs and SMs originate differently from mesenchymal and myeloid cells, respectively, but share many pathologic functions. However, the molecular signatures and biological networks representing the distinct and shared features of the two cell types are unknown. We performed global transcriptome profiling of FLSs and SMs obtained from RA and osteoarthritis patients. By comparing the transcriptomes, we identified distinct molecular signatures and cellular processes defining invasiveness of RA-FLSs and proinflammatory properties of RA-SMs, respectively. Interestingly, under the interleukin-1β (IL-1β)–stimulated condition, the RA-FLSs newly acquired proinflammatory signature dominant in RA-SMs without losing invasive properties. We next reconstructed a network model that delineates the shared, RA-FLS–dominant (invasive), and RA-SM–dominant (inflammatory) processes. From the network model, we selected 13 genes, including periostin, osteoblast-specific factor (POSTN) and twist basic helix–loop–helix transcription factor 1 (TWIST1), as key regulator candidates responsible for FLS invasiveness. Of note, POSTN and TWIST1 expressions were elevated in independent RA-FLSs and further instigated by IL-1β. Functional assays demonstrated the requirement of POSTN and TWIST1 for migration and invasion of RA-FLSs stimulated with IL-1β. Together, our systems approach to rheumatoid synovitis provides a basis for identifying key regulators responsible for pathological features of RA-FLSs and -SMs, demonstrating how a certain type of cells acquires functional redundancy under chronic inflammatory conditions. PMID:24374632

Identifying key genes in rheumatoid arthritis by weighted gene co-expression network analysis.

PubMed

Ma, Chunhui; Lv, Qi; Teng, Songsong; Yu, Yinxian; Niu, Kerun; Yi, Chengqin

2017-08-01

This study aimed to identify rheumatoid arthritis (RA) related genes based on microarray data using the WGCNA (weighted gene co-expression network analysis) method. Two gene expression profile datasets GSE55235 (10 RA samples and 10 healthy controls) and GSE77298 (16 RA samples and seven healthy controls) were downloaded from Gene Expression Omnibus database. Characteristic genes were identified using metaDE package. WGCNA was used to find disease-related networks based on gene expression correlation coefficients, and module significance was defined as the average gene significance of all genes used to assess the correlation between the module and RA status. Genes in the disease-related gene co-expression network were subject to functional annotation and pathway enrichment analysis using Database for Annotation Visualization and Integrated Discovery. Characteristic genes were also mapped to the Connectivity Map to screen small molecules. A total of 599 characteristic genes were identified. For each dataset, characteristic genes in the green, red and turquoise modules were most closely associated with RA, with gene numbers of 54, 43 and 79, respectively. These genes were enriched in totally enriched in 17 Gene Ontology terms, mainly related to immune response (CD97, FYB, CXCL1, IKBKE, CCR1, etc.), inflammatory response (CD97, CXCL1, C3AR1, CCR1, LYZ, etc.) and homeostasis (C3AR1, CCR1, PLN, CCL19, PPT1, etc.). Two small-molecule drugs sanguinarine and papaverine were predicted to have a therapeutic effect against RA. Genes related to immune response, inflammatory response and homeostasis presumably have critical roles in RA pathogenesis. Sanguinarine and papaverine have a potential therapeutic effect against RA. © 2017 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.

NRF2 Mediates Neuroblastoma Proliferation and Resistance to Retinoic Acid Cytotoxicity in a Model of In Vitro Neuronal Differentiation.

PubMed

de Miranda Ramos, Vitor; Zanotto-Filho, Alfeu; de Bittencourt Pasquali, Matheus Augusto; Klafke, Karina; Gasparotto, Juciano; Dunkley, Peter; Gelain, Daniel Pens; Moreira, José Cláudio Fonseca

2016-11-01

Retinoic acid (RA) morphogenetic properties have been used in different kinds of therapies, from neurodegenerative disorders to some types of cancer such as promyelocytic leukemia and neuroblastoma. However, most of the pathways responsible for RA effects remain unknown. To investigate such pathways, we used a RA-induced differentiation model in the human neuroblastoma cells, SH-SY5Y. Our data showed that n-acetyl-cysteine (NAC) reduced cells' proliferation rate and increased cells' sensitivity to RA toxicity. Simultaneously, NAC pre-incubation attenuated nuclear factor erythroid 2-like factor 2 (NRF2) activation by RA. None of these effects were obtained with Trolox ® as antioxidant, suggesting a cysteine signalization by RA. NRF2 knockdown increased cell sensibility to RA after 96 h of treatment and diminished neuroblastoma proliferation rate. Conversely, NRF2 overexpression limited RA anti-proliferative effects and increased cell proliferation. In addition, a rapid and non-genomic activation of the ERK 1/2 and PI3K/AKT pathways revealed to be equally required to promote NRF2 activation and necessary for RA-induced differentiation. Together, we provide data correlating NRF2 activity with neuroblastoma proliferation and resistance to RA treatments; thus, this pathway could be a potential target to optimize neuroblastoma chemotherapeutic response as well as in vitro neuronal differentiation protocols.

6-Formylindolo(3,2-b)Carbazole (FICZ) Modulates the Signalsome Responsible for RA-Induced Differentiation of HL-60 Myeloblastic Leukemia Cells

PubMed Central

Bunaciu, Rodica P.; LaTocha, Dorian H.; Varner, Jeffrey D.; Yen, Andrew

2015-01-01

6-Formylindolo(3,2-b)carbazole (FICZ) is a photoproduct of tryptophan and an endogenous high affinity ligand for aryl hydrocarbon receptor (AhR). It was previously reported that, in patient-derived HL-60 myeloblastic leukemia cells, retinoic acid (RA)-induced differentiation is driven by a signalsome containing c-Cbl and AhR. FICZ enhances RA-induced differentiation, assessed by expression of the membrane differentiation markers CD38 and CD11b, cell cycle arrest and the functional differentiation marker, inducible oxidative metabolism. Moreover, FICZ augments the expression of a number of the members of the RA-induced signalsome, such as c-Cbl, Vav1, Slp76, PI3K, and the Src family kinases Fgr and Lyn. Pursuing the molecular signaling responsible for RA-induced differentiation, we characterized, using FRET and clustering analysis, associations of key molecules thought to drive differentiation. Here we report that, assayed by FRET, AhR interacts with c-Cbl upon FICZ plus RA-induced differentiation, whereas AhR constitutively interacts with Cbl-b. Moreover, correlation analysis based on the flow cytometric assessment of differentiation markers and western blot detection of signaling factors reveal that Cbl-b, p-p38α and pT390-GSK3β, are not correlated with other known RA-induced signaling components or with a phenotypic outcome. We note that FICZ plus RA elicited signaling responses that were not typical of RA alone, but may represent alternative differentiation-driving pathways. In clusters of signaling molecules seminal to cell differentiation, FICZ co-administered with RA augments type and intensity of the dynamic changes induced by RA. Our data suggest relevance for FICZ in differentiation-induction therapy. The mechanism of action includes modulation of a SFK and MAPK centered signalsome and c-Cbl-AhR association. PMID:26287494

Role of Diet in Influencing Rheumatoid Arthritis Disease Activity.

PubMed

Badsha, Humeira

2018-01-01

Patients with Rheumatoid Arthritis (RA) frequently ask their doctors about which diets to follow, and even in the absence of advice from their physicians, many patients are undertaking various dietary interventions. However, the role of dietary modifications in RA is not well understood. Several studies have tried to address these gaps in our understanding. Intestinal microbial modifications are being studied for the prevention and management of RA. Some benefits of vegan diet may be explained by antioxidant constituents, lactobacilli and fibre, and by potential changes in intestinal flora. Similarly, Mediterranean diet shows anti-inflammatory effects due to protective properties of omega-3 polyunsaturated fatty acids and vitamins, but also by influencing the gut microbiome. Gluten-free and elemental diets have been associated with some benefits in RA though the existing evidence is limited. Long-term intake of fish and other sources of long-chain polyunsaturated fatty acids are protective for development of RA. The benefits of fasting, anti-oxidant supplementation, flavanoids, and probiotics in RA are not clear. Vitamin D has been shown to influence autoimmunity and specifically decrease RA disease activity. The role of supplements such as fish oils and vitamin D should be explored in future trials to gain new insights in disease pathogenesis and develop RA-specific dietary recommendations. Specifically more research is needed to explore the association of diet and the gut microbiome and how this can influence RA disease activity.

Disequilibrium in the uranium and actinium series in oil scale samples.

PubMed

Landsberger, S; Tamalis, D; Leblanc, C; Yoho, M D

2017-01-01

We have investigated the disequilibrium of the uranium and actinium series and have found both 226 Ra (90,200 ± 4300 Bq/kg) and 228 Ra have activity concentrations orders of magnitude higher that 238 U (1.83 ± 0.36 Bq/kg) and 232 Th (7.0 ± 0.4) which are at the head of the decay series. As well the activity concentration of 210 Pb (24,400 ± 1200 Bg/kg) was about 3.6 times less than 226 Ra. Once an efficiency curve was constructed summing corrections for specific isotopes in the decay change also needed to be taken in consideration. Furthermore, self-attenuation of the photons especially the 46.5 keV belonging to 210 Pb was calculated to be 78% since the scale had elevated elemental concentrations of high-Z elements such as barium and strontium. Copyright © 2016 Elsevier Ltd. All rights reserved.

Local sources of retinoic acid coincide with retinoid-mediated transgene activity during embryonic development.

PubMed Central

Colbert, M C; Linney, E; LaMantia, A S

1993-01-01

We have assessed whether retinoic acid (RA) comes from local sources or is available widely to activate gene expression in embryos. We used an RA-responsive indicator cell line, L-C2A5, to localize RA sources. In these cells, an RA-sensitive promoter/lacZ reporter construct used previously by us to produce indicator transgenic mice is induced globally by RA in medium or locally by RA released at physiological concentrations (1 nM) from AG-1X2 resin beads. Furthermore, the cells are differentially responsive to the 9-cis and all-trans isomers of RA at low concentrations. Indicator transgenic mice with the same promoter/reporter construct were used to identify regions of RA-mediated gene activation. There are distinct domains of lacZ expression in the cervical and lumbar spinal cords of embryonic indicator mice. This pattern might reflect localized RA sources or restricted spatial and temporal expression of RA receptors, binding proteins, or other factors. To resolve this issue we compared the pattern of transgene activation in indicator cell monolayers cocultured with normal embryonic spinal cords with that in transgenic spinal cords. The explants induced reporter gene expression in L-C2A5 monolayers in a pattern identical to that in transgenic mice: alar regions of the cervical and lumbar cord were positive whereas those in the thoracic and sacral regions were not. We conclude that restricted sources of RA in the developing spinal cord mediate the local activation of RA-inducible genes. Thus, region-specific gene activation in embryos can be mediated by precisely localized sources of inductive molecules like RA. Images Fig. 1 Fig. 2 Fig. 3 PMID:8341670

Arsenic as an endocrine disruptor: arsenic disrupts retinoic acid receptor-and thyroid hormone receptor-mediated gene regulation and thyroid hormone-mediated amphibian tail metamorphosis.

PubMed

Davey, Jennifer C; Nomikos, Athena P; Wungjiranirun, Manida; Sherman, Jenna R; Ingram, Liam; Batki, Cavus; Lariviere, Jean P; Hamilton, Joshua W

2008-02-01

Chronic exposure to excess arsenic in drinking water has been strongly associated with increased risks of multiple cancers, diabetes, heart disease, and reproductive and developmental problems in humans. We previously demonstrated that As, a potent endocrine disruptor at low, environmentally relevant levels, alters steroid signaling at the level of receptor-mediated gene regulation for all five steroid receptors. The goal of this study was to determine whether As can also disrupt gene regulation via the retinoic acid (RA) receptor (RAR) and/or the thyroid hormone (TH) receptor (TR) and whether these effects are similar to previously observed effects on steroid regulation. Human embryonic NT2 or rat pituitary GH3 cells were treated with 0.01-5 microM sodium arsenite for 24 hr, with or without RA or TH, respectively, to examine effects of As on receptor-mediated gene transcription. At low, noncytotoxic doses, As significantly altered RAR-dependent gene transcription of a transfected RAR response element-luciferase construct and the native RA-inducible cytochrome P450 CYP26A gene in NT2 cells. Likewise, low-dose As significantly altered expression of a transfected TR response element-luciferase construct and the endogenous TR-regulated type I deiodinase (DIO1) gene in a similar manner in GH3 cells. An amphibian ex vivo tail metamorphosis assay was used to examine whether endocrine disruption by low-dose As could have specific pathophysiologic consequences, because tail metamorphosis is tightly controlled by TH through TR. TH-dependent tail shrinkage was inhibited in a dose-dependent manner by 0.1- 4.0 microM As. As had similar effects on RAR- and TR-mediated gene regulation as those previously observed for the steroid receptors, suggesting a common mechanism or action. Arsenic also profoundly affected a TR-dependent developmental process in a model animal system at very low concentrations. Because RAR and TH are critical for both normal human development and adult function and their dysregulation is associated with many disease processes, disruption of these hormone receptor-dependent processes by As is also potentially relevant to human developmental problems and disease risk.

Cyclic GMP-AMP Synthase Is Required for Cell Proliferation and Inflammatory Responses in Rheumatoid Arthritis Synoviocytes.

PubMed

Wang, Yan; Su, Guo-Hua; Zhang, Fang; Chu, Jing-Xue; Wang, Yun-Shan

2015-01-01

Rheumatoid arthritis (RA) is characterized by inflammatory cell infiltration, fibroblast-like synoviocytes (FLS) invasive proliferation, and joint destruction. Cyclic GMP-AMP synthase (cGAS) is a cytosolic DNA sensor that induces immune activation. In this study, we examined whether cGAS plays a role in RA FLS. In this study, cGAS was overexpressed in RA-FLS compared with OA FLS. TNFα stimulation induced cGAS expression in RA FLS. Overexpression of cGAS promoted the proliferation and knockdown of cGAS inhibited the proliferation of RA FLS. cGAS overexpression enhanced the production of proinflammatory cytokines and matrix metalloproteinases (MMPs) as well as AKT and ERK phosphorylation in TNFα-stimulated FLS. In contrast, cGAS silencing inhibited production of proinflammatory cytokines and matrix metalloproteinases (MMPs) as well as AKT and ERK phosphorylation in TNFα-stimulated FLS. These results suggest that cGAS activates the AKT and ERK pathways to promote the inflammatory response of RA FLS, and the development of strategies targeting cGAS may have therapeutic potential for human RA.

Elements of Employment Related Disclosure of Disability after Brain Injury

ERIC Educational Resources Information Center

Burnhill, David A.

2012-01-01

Few studies have examined the elements of disclosing a disability in the workplace. Those few studies had a primary focus on reasonable accommodations (RA) where the disclosure process was either secondary or tertiary to the study. Further, there have been no studies to date which have examined elements of disclosure for individuals with brain…

Mantle source beneath Turrialba volcano (Costa Rica): a geochemical investigation

NASA Astrophysics Data System (ADS)

Di Piazza, A.; Rizzo, A. L.; Barberi, F.; Carapezza, M. L.; Sortino, F.; De Astis, G.; Romano, C.

2014-12-01

In this study we analysed rocks and noble gas composition of fluid inclusions (FIs) hosted in olivine crystals contained in a suite of eruptive products of the last 10ka of activity of Turrialba volcano, Cordillera Central, Costa Rica. The suite of analyzed rocks display a calc-alkaline affinity, ranging in composition from basaltic-andesite to dacite. Trace element patterns indicate a typical behavior of subduction-related magmas and also the clear contribution of an OIB-like signature at source. A group of andesites displays also adakite-like geochemical features, as evidenced by their constant depletion in HFSE elements. Sr isotope (0.703593 - 0.703678) and Nd isotope ratios (0.512960 - 0.512968) suggest that Turrialba magmas belong to one of the less contaminated mantle source of Central America. The 3He/4He ratio of fluid inclusions from the most mafic eruptive products (basaltic-andesites) varies from 7.86 to 8.07 Ra, while that from andesite lavas varies from 7.03 to 7.18 Ra. In order to understand the mantle source feeding Turrialba volcano, we performed a geochemical investigation on fumarolic gases of summit craters. The He isotope composition of dry gases of Turrialba volcano is characterized by extremely high R/Ra values (7.08-7.96 Ra). The highest 3He/4He ratios were measured at both West and Central Craters (7.93-7.96 Ra and 7.78-7.88 Ra, respectively), and are the highest values of the entire Central America. Despite the observed variability, the 3He/4He ratio of fumarolic gases and FIs from Turrialba volcano is well in the range of arc related volcanism (~7-8 Ra; Hilton et al., 2002), and represents the signature of a mantle wedge in which the contamination by crustal fluids is small to negligible. In addition the occurrence of recent adakite-like magmatism suggests the presence of an abnormal heating of the subducting lithosphere under Turrialba volcano, allowing even old or cold oceanic crust to melt.

Impact of tocilizumab therapy on antibody response to influenza vaccine in patients with rheumatoid arthritis.

PubMed

Mori, Shunsuke; Ueki, Yukitaka; Hirakata, Naoyuki; Oribe, Motohiro; Hidaka, Toshihiko; Oishi, Kazunori

2012-12-01

We assessed the influence of tocilizumab (TCZ), a humanised monoclonal anti-interleukin-6 receptor antibody, on antibody response following influenza vaccination in patients with rheumatoid arthritis (RA). A total of 194 RA patients received inactive trivalent influenza vaccination (A/H1N1, A/H3N2 and B/B1 strains). All patients were classified into the TCZ (n=62), TCZ+methotrexate (MTX) (n=49), MTX (n=65) and RA control (n=18) groups. Antibody titres were measured before and 4-6 weeks after vaccination using the haemagglutination inhibitory assay. For the A/H1N1 and A/H3N2 strains, the TCZ and TCZ+MTX groups achieved fold increases of 9.9-14.5, postvaccination seroprotection rates greater than 70% and seroresponse rates greater than 40%. For the B/B1 strain, seroresponse rates were approximately 30%, but fold increases and seroprotection rates were 5.0-5.4 and greater than 70%, respectively, in these treatment groups. MTX had a negative impact on vaccination efficacy, but adequate responses for protection were nevertheless demonstrated in the MTX group. Neither severe adverse effects nor RA flares were observed. TCZ does not hamper antibody response to influenza vaccine in RA patients. Influenza vaccination is considered effective in protecting RA patients receiving TCZ therapy with or without MTX.

Oxidative Stress Relevance in the Pathogenesis of the Rheumatoid Arthritis: A Systematic Review

PubMed Central

Quiñonez-Flores, Celia María; González-Chávez, Susana Aideé; Del Río Nájera, Danyella; Pacheco-Tena, César

2016-01-01

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease whose pathogenic mechanisms remain to be elucidated. The oxidative stress and antioxidants play an important role in the disease process of RA. The study of oxidants and antioxidants biomarkers in RA patients could improve our understanding of disease pathogenesis; likely determining the oxidative stress levels in these patients could prove helpful in assessing disease activity and might also have prognostic implications. To date, the usefulness of oxidative stress biomarkers in RA patients is unclear and the evidence supporting them is heterogeneous. In order to resume and update the information in the status of oxidants and antioxidants and their connection as biomarkers in RA, we performed a systematic literature search in the PubMed database, including clinical trials published in the last five years using the word combination “rheumatoid arthritis oxidative stress”. In conclusion, this review supports the fact that the oxidative stress is an active process in RA pathogenesis interrelated to other better known pathogenic elements. However, some controversial results preclude a definite conclusion. PMID:27340664

The all-trans retinoic acid (atRA)-regulated gene Calmin (Clmn) regulates cell cycle exit and neurite outgrowth in murine neuroblastoma (Neuro2a) cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Marzinke, Mark A.; Clagett-Dame, Margaret, E-mail: dame@biochem.wisc.edu; Pharmaceutical Science Division, University of Wisconsin-Madison, Madison, WI 53705-2222

2012-01-01

The vitamin A metabolite all-trans retinoic acid (atRA) functions in nervous system development and regulates cell proliferation and differentiation. Neuroblastoma cells (SH-SY5Y and Neuro2a or N2A) exposed to atRA undergo growth inhibition and neuronal differentiation, both of which are preceded by an increase in Clmn mRNA. Treatment of N2A cells with atRA produces a reduction in phosphohistone 3 immunostaining and BrdU incorporation, both indicators of a reduction in cell proliferation. These effects are nearly eliminated in atRA-treated shClmn knockdown cells. Loss of Clmn in the mouse N2A cell line also results in a significant reduction of atRA-mediated neurite outgrowth, amore » response that can be rescued by reintroduction of the Clmn sequence. In contrast, ectopic overexpression of Clmn produces an increase in the cyclin dependent kinase inhibitor, p21{sup Cip1}, a decrease in cyclin D1 protein and an increase in hypophosphorylated Rb, showing that Clmn participates in G{sub 1}/S arrest. Clmn overexpression alone is sufficient to inhibit N2A cell proliferation, whereas both Clmn and atRA must be present to induce neurite outgrowth. This study shows that the atRA-responsive gene Clmn promotes exit from the cell cycle, a requisite event for neuronal differentiation. -- Highlights: Black-Right-Pointing-Pointer Calmin is a retinoic acid-responsive gene. Black-Right-Pointing-Pointer Calmin promotes cell cycle exit in N2A cells. Black-Right-Pointing-Pointer Calmin overexpression increases p21Cip1 and decreases cyclin D1. Black-Right-Pointing-Pointer Calmin is required for RA-induced growth inhibition and neurite outgrowth.« less

Roles and contributions of pharmacists in regulatory affairs at the Centers for Disease Control and Prevention for public health emergency preparedness and response.

PubMed

Bhavsar, Tina R; Kim, Hye-Joo; Yu, Yon

To provide a general description of the roles and contributions of three pharmacists from the Regulatory Affairs program (RA) at the Centers for Disease Control and Prevention (CDC) who are involved in emergency preparedness and response activities, including the 2009 pandemic influenza A (H1N1) public health emergency. Atlanta, GA. RA consists of a staff of nine members, three of whom are pharmacists. The mission of RA is to support CDC's preparedness and emergency response activities and to ensure regulatory compliance for critical medical countermeasures against potential threats from natural, chemical, biological, radiological, or nuclear events. RA was well involved in the response to the H1N1 outbreak through numerous activities, such as submitting multiple Emergency Use Authorization (EUA) requests to the Food and Drug Administration, including those for medical countermeasures to be deployed from the Strategic National Stockpile, and developing the CDC EUA website (www.cdc.gov/h1n1flu/eua). RA will continue to support current and future preparedness and emergency response activities by ensuring that the appropriate regulatory mechanisms are in place for the deployment of critical medical countermeasures from the Strategic National Stockpile against threats to public health.

Patterns of brain and cardiovascular activation while solving rule-discovery and rule-application numeric tasks.

PubMed

Sosnowski, Tytus; Rynkiewicz, Andrzej; Wordecha, Małgorzata; Kępkowicz, Anna; Majewska, Adrianna; Pstrągowska, Aleksandra; Oleksy, Tomasz; Wypych, Marek; Marchewka, Artur

2017-07-01

It is known that solving mental tasks leads to tonic increase in cardiovascular activity. Our previous research showed that tasks involving rule application (RA) caused greater tonic increase in cardiovascular activity than tasks requiring rule discovery (RD). However, it is not clear what brain mechanisms are responsible for this difference. The aim of two experimental studies was to compare the patterns of brain and cardiovascular activity while both RD and the RA numeric tasks were being solved. The fMRI study revealed greater brain activation while solving RD tasks than while solving RA tasks. In particular, RD tasks evoked greater activation of the left inferior frontal gyrus and selected areas in the parietal, and temporal cortices, including the precuneus, supramarginal gyrus, angular gyrus, inferior parietal lobule, and the superior temporal gyrus, and the cingulate cortex. In addition, RA tasks caused larger increases in HR than RD tasks. The second study, carried out in a cardiovascular laboratory, showed greater increases in heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) while solving RA tasks than while solving RD tasks. The results support the hypothesis that RD and RA tasks involve different modes of information processing, but the neuronal mechanism responsible for the observed greater cardiovascular response to RA tasks than to RD tasks is not completely clear. Copyright © 2017. Published by Elsevier B.V.

Nuclear CD38 in retinoic acid-induced HL-60 cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yalcintepe, Leman; Albeniz, Isil; Adin-Cinar, Suzan

2005-02-01

The cell surface antigen, CD38, is a 45-kDa transmembrane protein which is predominantly expressed on hematopoietic cells during differentiation. As a bifunctional ectoenzyme, it catalyzes the synthesis of cyclic ADP-ribose (cADPR) from NAD{sup +} and hydrolysis of either NAD{sup +} or cADPR to ADP-ribose. All-trans-retinoic acid (RA) is a potent and specific inducer of CD38 in myeloid cells. In this report, we demonstrate that the nuclei of RA-treated human HL-60 myeloblastic cells reveal enzymatic activities inherent to CD38. Thus, GDP-ribosyl cyclase and NAD{sup +} glycohydrolase activities in the nuclear fraction increased very significantly in response to incubation with RA. Withmore » Western blotting, we detected in the nuclear protein fraction from RA-treated cells a {approx}43-kDa protein band which was reactive with the CD38-specific monoclonal antibody OKT10. The expression of CD38 in HL-60 nuclei was also shown with FACScan analysis. RA treatment gave rise to an increase in in vitro ADP ribosylation of the {approx}43-kDa nuclear protein. Moreover, nuclei isolated from RA-treated HL-60 cells revealed calcium release in response to cADPR, whereas a similar response was not observed in control nuclei. These results suggest that CD38 is expressed in HL-60 cell nuclei during RA-induced differentiation.« less

Helminth antigens selectively differentiate unsensitized CD45RA+ CD4+ human T cells in vitro.

PubMed

Steel, C; Nutman, T B

1998-01-01

Human filarial helminth infections are characterized by type 2 immune responses to parasite Ag that can persist for the life of the individual; one possible cause for this may be prenatal exposure to the blood-borne microfilarial (Mf) stage of the parasite. To examine the relationship between early exposure to filarial Ag and subsequent immune responsiveness, CD45RA+ CD4+ cells frp, normal unsensitized donors were stimulated in vitro with soluble microfilarial Ag (MfAg) from the filarial parasite Brugia malayi in the presence of APCs. MfAg alone induced proliferation and IFN-gamma and IL-5 production in unsensitized CD45RA+ CD4+ cells, demonstrating the ability of filarial Ags to prime naive T cells in the absence of exogenous cytokines and dendritic cells. Adding exogenous cytokine(s) (particularly IL-12 and IL-4) during priming was able to alter the MfAg-specific responses of CD45RA+ CD4+ cells as well as subsequent responses to Ag. Interestingly, priming solely with MfAg led to enhanced IL-5 production following Ag restimulation, suggesting that MfAg preferentially primes for type 2 responses. These data demonstrate that filarial Ags by themselves can specifically prime CD45RA+ CD4+ cells in vitro and do so in such a way as to deviate the immune response.

Radium geochemical monitoring in well waters at regional and local scales: an environmental impact indicator-based approach.

PubMed

Lagacé, François; Foucher, Delphine; Surette, Céline; Clarisse, Olivier

2018-04-18

To assess radium ( 226 Ra) as a potential indicator of impact in well waters, we investigated its behavior under natural conditions using a case study approach. 226 Ra geochemistry was investigated in 67 private wells of southeastern New Brunswick, Canada, a region targeted for potential shale gas exploitation. Objectives were to i) establish 226 Ra baseline in groundwater; ii) characterize 226 Ra spatial distribution and temporal variability; iii) characterize 226 Ra partitioning between dissolved phase and particulate forms in well waters; and iv) understand the mechanisms controlling 226 Ra mobility under natural environmental settings. 226 Ra levels were generally low (median = 0.061 pg L -1 , or 2.2 mBq L -1 ), stable over time, and randomly distributed. A principal component analysis revealed that concentrations of 226 Ra were controlled by key water geochemistry factors: the highest levels were observed in waters with high hardness, and/or high concentrations of individual alkaline earth elements (i.e. Mg, Ca, Sr, Ba), high concentrations of Mn and Fe, and low pH. As for partitioning, 226 Ra was essentially observed in the dissolved phase (106 ± 19%) suggesting that the geochemical conditions of groundwater in the studied regions are prone to limit 226 Ra sorption, enhancing its mobility. Overall, this study provided comprehensive knowledge on 226 Ra background distribution at local and regional scales. Moreover, it provided a framework to establish 226 Ra baselines and determine which geochemical conditions to monitor in well waters in order to use this radionuclide as an indicator of environmental impact caused by anthropogenic activities (e.g. unconventional shale gas exploitation, uranium mining, or nuclear generating power plants). Copyright © 2018 Elsevier Ltd. All rights reserved.

Push-Pull and Feedback Mechanisms Can Align Signaling System Outputs with Inputs.

PubMed

Andrews, Steven S; Peria, William J; Yu, Richard C; Colman-Lerner, Alejandro; Brent, Roger

2016-11-23

Many cell signaling systems, including the yeast pheromone response system, exhibit "dose-response alignment" (DoRA), in which output of one or more downstream steps closely matches the fraction of occupied receptors. DoRA can improve the fidelity of transmitted dose information. Here, we searched systematically for biochemical network topologies that produced DoRA. Most networks, including many containing feedback and feedforward loops, could not produce DoRA. However, networks including "push-pull" mechanisms, in which the active form of a signaling species stimulates downstream activity and the nominally inactive form reduces downstream activity, enabled perfect DoRA. Networks containing feedbacks enabled DoRA, but only if they also compared feedback to input and adjusted output to match. Our results establish push-pull as a non-feedback mechanism to align output with variable input and maximize information transfer in signaling systems. They also suggest genetic approaches to determine whether particular signaling systems use feedback or push-pull control. Copyright © 2016 Elsevier Inc. All rights reserved.

Increasing the intracellular availability of all-trans retinoic acid in neuroblastoma cells.

PubMed

Armstrong, J L; Ruiz, M; Boddy, A V; Redfern, C P F; Pearson, A D J; Veal, G J

2005-02-28

Recent data indicate that isomerisation to all-trans retinoic acid (ATRA) is the key mechanism underlying the favourable clinical properties of 13-cis retinoic acid (13cisRA) in the treatment of neuroblastoma. Retinoic acid (RA) metabolism is thought to contribute to resistance, and strategies to modulate this may increase the clinical efficacy of 13cisRA. The aim of this study was to test the hypothesis that retinoids, such as acitretin, which bind preferentially to cellular retinoic acid binding proteins (CRABPs), or specific inhibitors of the RA hydroxylase CYP26, such as R116010, can increase the intracellular availability of ATRA. Incubation of SH-SY5Y cells with acitretin (50 microM) or R116010 (1 or 10 microM) in combination with either 10 microM ATRA or 13cisRA induced a selective increase in intracellular levels of ATRA, while 13cisRA levels were unaffected. CRABP was induced in SH-SY5Y cells in response to RA. In contrast, acitretin had no significant effect on intracellular retinoid concentrations in those neuroblastoma cell lines that showed little or no induction of CRABP after RA treatment. Both ATRA and 13cisRA dramatically induced the expression of CYP26A1 in SH-SY5Y cells, and treatment with R116010, but not acitretin, potentiated the RA-induced expression of a reporter gene and CYP26A1. The response of neuroblastoma cells to R116010 was consistent with inhibition of CYP26, indicating that inhibition of RA metabolism may further optimise retinoid treatment in neuroblastoma.

Increasing the intracellular availability of all-trans retinoic acid in neuroblastoma cells

PubMed Central

Armstrong, J L; Ruiz, M; Boddy, A V; Redfern, C P F; Pearson, A D J; Veal, G J

2005-01-01

Recent data indicate that isomerisation to all-trans retinoic acid (ATRA) is the key mechanism underlying the favourable clinical properties of 13-cis retinoic acid (13cisRA) in the treatment of neuroblastoma. Retinoic acid (RA) metabolism is thought to contribute to resistance, and strategies to modulate this may increase the clinical efficacy of 13cisRA. The aim of this study was to test the hypothesis that retinoids, such as acitretin, which bind preferentially to cellular retinoic acid binding proteins (CRABPs), or specific inhibitors of the RA hydroxylase CYP26, such as R116010, can increase the intracellular availability of ATRA. Incubation of SH-SY5Y cells with acitretin (50 μM) or R116010 (1 or 10 μM) in combination with either 10 μM ATRA or 13cisRA induced a selective increase in intracellular levels of ATRA, while 13cisRA levels were unaffected. CRABP was induced in SH-SY5Y cells in response to RA. In contrast, acitretin had no significant effect on intracellular retinoid concentrations in those neuroblastoma cell lines that showed little or no induction of CRABP after RA treatment. Both ATRA and 13cisRA dramatically induced the expression of CYP26A1 in SH-SY5Y cells, and treatment with R116010, but not acitretin, potentiated the RA-induced expression of a reporter gene and CYP26A1. The response of neuroblastoma cells to R116010 was consistent with inhibition of CYP26, indicating that inhibition of RA metabolism may further optimise retinoid treatment in neuroblastoma. PMID:15714209

Changing trends in residents-as-teachers across graduate medical education

PubMed Central

Al Achkar, Morhaf; Hanauer, Mathew; Morrison, Elizabeth H; Davies, M Kelly; Oh, Robert C

2017-01-01

Background Teaching residents how to teach is a critical part of residents’ training in graduate medical education (GME). The purpose of this study was to assess the change in resident-as-teacher (RaT) instruction in GME over the past 15 years in the US. Methods We used a quantitative and qualitative survey of all program directors (PDs) across specialties. We compared our findings with a previous work from 2000–2001 that studied the same matter. Finally, we qualitatively analyzed PDs’ responses regarding the reasons for implementing and not implementing RaT instruction. Results Two hundred and twenty-one PDs completed the survey, which yields a response rate of 12.6%. Over 80% of PDs implement RaT, an increase of 26.34% compared to 2000–2001. RaT instruction uses multiple methods with didactic lectures reported as the most common, followed by role playing in simulated environments, then observing and giving feedback. Residents giving feedback, clinical supervision, and bedside teaching were the top three targeted skills. Through our qualitative analysis we identified five main reasons for implementing RaT: teaching is part of the residents’ role; learners desire formal RaT training; regulatory bodies require RaT training; RaT improves residents’ education; and RaT prepares residents for their current and future roles. Conclusion The use of RaT instruction has increased significantly in GME. More and more PDs are realizing its importance in the residents’ formative training experience. Future studies should examine the effectiveness of each method for RaT instruction. PMID:28496376

Induced Pluripotent Stem Cell‐Derived Endothelial Cells Overexpressing Interleukin‐8 Receptors A/B and/or C‐C Chemokine Receptors 2/5 Inhibit Vascular Injury Response

PubMed Central

Giordano, Samantha; Zhao, Xiangmin; Chen, Yiu‐Fai; Litovsky, Silvio H.; Hage, Fadi G.; Townes, Tim M.; Sun, Chiao‐Wang; Wu, Li‐Chen; Oparil, Suzanne

2017-01-01

Abstract Recruitment of neutrophils and monocytes/macrophages to the site of vascular injury is mediated by binding of chemoattractants to interleukin (IL) 8 receptors RA and RB (IL8RA/B) C‐C chemokine receptors (CCR) 2 and 5 expressed on neutrophil and monocyte/macrophage membranes. Endothelial cells (ECs) derived from rat‐induced pluripotent stem cells (RiPS) were transduced with adenovirus containing cDNA of IL8RA/B and/or CCR2/5. We hypothesized that RiPS‐ECs overexpressing IL8RA/B (RiPS‐IL8RA/B‐ECs), CCR2/5 (RiPS‐CCR2/5‐ECs), or both receptors (RiPS‐IL8RA/B+CCR2/5‐ECs) will inhibit inflammatory responses and neointima formation in balloon‐injured rat carotid artery. Twelve‐week‐old male Sprague‐Dawley rats underwent balloon injury of the right carotid artery and intravenous infusion of (a) saline vehicle, (b) control RiPS‐Null‐ECs (ECs transduced with empty virus), (c) RiPS‐IL8RA/B‐ECs, (d) RiPS‐CCR2/5‐ECs, or (e) RiPS‐IL8RA/B+CCR2/5‐ECs. Inflammatory mediator expression and leukocyte infiltration were measured in injured and uninjured arteries at 24 hours postinjury by enzyme‐linked immunosorbent assay (ELISA) and immunohistochemistry, respectively. Neointima formation was assessed at 14 days postinjury. RiPS‐ECs expressing the IL8RA/B or CCR2/5 homing device targeted the injured arteries and decreased injury‐induced inflammatory cytokine expression, neutrophil/macrophage infiltration, and neointima formation. Transfused RiPS‐ECs overexpressing IL8RA/B and/or CCR2/5 prevented inflammatory responses and neointima formation after vascular injury. Targeted delivery of iPS‐ECs with a homing device to inflammatory mediators in injured arteries provides a novel strategy for the treatment of cardiovascular diseases. Stem Cells Translational Medicine 2017;6:1168–1177 PMID:28233474

Antibody Responses to Citrullinated and Noncitrullinated Antigens in the Sputum of Subjects With Rheumatoid Arthritis and Subjects at Risk for Development of Rheumatoid Arthritis.

PubMed

Demoruelle, M Kristen; Bowers, Emily; Lahey, Lauren J; Sokolove, Jeremy; Purmalek, Monica; Seto, Nickie L; Weisman, Michael H; Norris, Jill M; Kaplan, Mariana J; Holers, V Michael; Robinson, William H; Deane, Kevin D

2018-04-01

The location and mechanisms involved in the initial generation of autoantibodies to citrullinated and noncitrullinated proteins/peptides during the natural history of rheumatoid arthritis (RA) development is incompletely understood. This study sought to explore individual antibody responses to citrullinated and noncitrullinated proteins/peptides in the sputum and associations with neutrophil extracellular traps (NETs) in subjects at risk for the future development of RA. Serum and sputum samples were obtained from 41 RA-free subjects who were considered at risk for the development of RA based on familial or serologic risk factors, from 20 subjects classified as having RA, and from 22 healthy control subjects. Samples were evaluated using a bead-based array for IgG reactivity to 29 citrullinated proteins/peptides and 21 noncitrullinated proteins/peptides. Cutoff levels for antibody positivity were established in a separate control group. NET levels in the sputum were measured using sandwich enzyme-linked immunosorbent assays that quantitate DNA-myeloperoxidase and DNA-neutrophil elastase complexes. In at-risk subjects, antibody responses to the citrullinated forms of fibrinogen, apolipoprotein E, and fibronectin were highly prevalent. The most citrulline-specific antibodies in the sputum of at-risk subjects were those to fibrinogen, vimentin, and peptides of fibrinogen A and apolipoprotein A1. Patterns of sputum autoantibody positivity differed between at-risk subjects and subjects with RA. In at-risk subjects, increasing sputum NET levels significantly correlated with several citrullinated and some noncitrullinated antibody reactivities. These findings suggest that sputum antibody reactivity to particular citrullinated and noncitrullinated proteins/peptides is specific for RA and for subjects at risk of RA, and the association of these proteins/peptides with NETs may be a key feature of early RA-related autoimmunity in the lung. These results further support the hypothesis that the lung plays a role in early RA-related autoimmunity. © 2017, American College of Rheumatology.

Materials and methods for the separation of oxygen from air

DOEpatents

MacKay, Richard; Schwartz, Michael; Sammells, Anthony F.

2003-07-15

Metal oxides particularly useful for the manufacture of catalytic membranes for gas-phase oxygen separation processes having the formula: O.sub.5+z where: x and x' are greater than 0; y and y' are greater than 0; x+x' is equal to 2; y+y' is less than or equal to 2; z is a number that makes the metal oxide charge neutral; A is an element selected from the lanthanide elements; A' is an element selected from Be, Mg, Ca, Sr, Ba and Ra; A" is an element selected from the f block lanthanides, Be, Mg, Ca, Sr, Ba and Ra; B is an element selected from the group consisting of Al, Ga, In or mixtures thereof and B" is Co or Mg, with the exception that when B" is Mg, A' and A" are not Mg. The metal oxides are useful for preparation of dense membranes which may be formed from dense thin films of the mixed metal oxide on a porous metal oxide element. The invention also provides methods and catalytic reactors for oxygen separation and oxygen enrichment of oxygen deficient gases which employ mixed conducting metal oxides of the above formula.

ERK-dependent T cell receptor threshold calibration in rheumatoid arthritis.

PubMed

Singh, Karnail; Deshpande, Pratima; Pryshchep, Sergey; Colmegna, Inés; Liarski, Vladimir; Weyand, Cornelia M; Goronzy, Jörg J

2009-12-15

Immune responses to citrullinated neoantigens and clinical efficacy of costimulation blockade indicate a general defect in maintaining T cell tolerance in rheumatoid arthritis (RA). To examine whether TCR threshold calibration contributes to disease pathogenesis, signaling in RA T cells was quantified. RA patients had a selective increase in ERK phosphorylation compared with demographically matched controls due to a mechanism distal of Ras activation. Increased ERK responses included naive and memory CD4 and CD8 T cells and did not correlate with disease activity. The augmented ERK activity delayed SHP-1 recruitment to the TCR synapse and sustained TCR-induced Zap70 and NF-kappaB signaling, facilitating responses to suboptimal stimulation. Increased responsiveness of the ERK pathway was also a characteristic finding in the SKG mouse model of RA where it preceded clinical symptoms. Treatment with subtherapeutic doses of a MEK-1/2 inhibitor delayed arthritis onset and reduced severity, suggesting that increased ERK phosphorylation predisposes for autoimmunity and can be targeted to prevent disease.

Role of Diet in Influencing Rheumatoid Arthritis Disease Activity

PubMed Central

Badsha, Humeira

2018-01-01

Background: Patients with Rheumatoid Arthritis (RA) frequently ask their doctors about which diets to follow, and even in the absence of advice from their physicians, many patients are undertaking various dietary interventions. Discussion: However, the role of dietary modifications in RA is not well understood. Several studies have tried to address these gaps in our understanding. Intestinal microbial modifications are being studied for the prevention and management of RA. Some benefits of vegan diet may be explained by antioxidant constituents, lactobacilli and fibre, and by potential changes in intestinal flora. Similarly, Mediterranean diet shows anti-inflammatory effects due to protective properties of omega-3 polyunsaturated fatty acids and vitamins, but also by influencing the gut microbiome. Gluten-free and elemental diets have been associated with some benefits in RA though the existing evidence is limited. Long-term intake of fish and other sources of long-chain polyunsaturated fatty acids are protective for development of RA. The benefits of fasting, anti-oxidant supplementation, flavanoids, and probiotics in RA are not clear. Vitamin D has been shown to influence autoimmunity and specifically decrease RA disease activity. The role of supplements such as fish oils and vitamin D should be explored in future trials to gain new insights in disease pathogenesis and develop RA-specific dietary recommendations. Conclusion: Specifically more research is needed to explore the association of diet and the gut microbiome and how this can influence RA disease activity. PMID:29515679

Utilization of DR1 as true RARE in regulating the Ssm, a novel retinoic acid-target gene in the mouse testis.

PubMed

Han, Kyuyong; Song, Haengseok; Moon, Irene; Augustin, Robert; Moley, Kelle; Rogers, Melissa; Lim, Hyunjung

2007-03-01

Various nuclear receptors form dimers to activate target genes via specific response elements located within promoters or enhancers. Retinoid X receptor (RXR) serves as a dimerization partner for many nuclear receptors including retinoic acid receptor (RAR) and peroxisome proliferator-activated receptor (PPAR). Dimers show differential preference towards directly repeated response elements with 1-5 nucleotide spacing, and direct repeat 1 (DR1) is a promiscuous element which recruits RAR/RXR, RXR/RXR, and PPAR/RXR in vitro. In the present investigation, we report identification of a novel RAR/RXR target gene which is regulated by DR1s in the promoter region. This gene, namely spermatocyte-specific marker (Ssm), recruits all the three combinations of nuclear receptors in vitro, but in vivo regulation is observed by trans-retinoic acid-activated RAR/RXR dimer. Indeed, chromatin immunoprecipitation experiment demonstrates binding of RARbeta and RXRalpha in the promoter region of the Ssm. Interestingly, expression of Ssm is almost exclusively observed in spermatocytes in the adult mouse testis, where RA signaling is known to regulate developmental program of male germ cells. The results show that Ssm is a RAR/RXR target gene uniquely using DR1 and exhibits stage-specific expression in the mouse testis with potential function in later stages of spermatogenesis. This finding exemplifies usage of DR1s as retinoic acid response element (RARE) under a specific in vivo context.

FLT-1 gene polymorphisms and protein expression profile in rheumatoid arthritis

PubMed Central

Paradowska-Gorycka, Agnieszka; Sowinska, Anna; Pawlik, Andrzej; Malinowski, Damian; Stypinska, Barbara; Haladyj, Ewa; Romanowska-Prochnicka, Katarzyna; Olesinska, Marzena

2017-01-01

Objectives Inflammation and angiogenesis are a significant element of pathogenesis in rheumatoid arthritis (RA). The FLT-1- triggering factor for production of proinflammatory cytokines-might contributes to inflammation in patients with RA. Association of the FLT-1 polymorphisms with different “angiogenic diseases” suggests that it may be a novel genetic risk factor also for RA. The aim of the study was to identify FLT-1 genetic variants and their possible association with sFLT-1 levels, susceptibility to and severity of RA. Methods The FLT-1 gene polymorphisms were genotyped for 471 RA patients and 684 healthy individuals. Correlation analysis was performed with clinical parameters, cardiovascular disease (CVD) and anti-citrullinated peptide/protein antibody (ACPA) presence. The sFLT-1 serum levels were evaluated. Results The FLT-1 gene polymorphisms showed no significant differences in the proportion of cases and controls. Furthermore, the FLT-1 rs2296188 T/C polymorphism was associated with ACPA-positive RA. Overall, rs9943922 T/C and rs2296283 G/A are in almost completed linkage disequilibrium (LD) with D’ = 0.97 and r2 = 0.83. The FLT-1 rs7324510 A allele has shown association with VAS score (p = 0.035), DAS-28 score (p = 0.013) and ExRA presence (p = 0.027). Moreover, other clinical parameters were also higher in RA patients with this allele. In addition, FLT-1 genetic variants conferred higher sFLT-1 levels in RA patients compared to controls. Conclusion FLT-1 rs7324510 C/A variant may be a new genetic risk factor for severity of RA. Examined factor highly predispose to more severe disease activity as well as higher sFLT-1 levels in RA. PMID:28323906

Impairment of neutrophil Fc gamma receptor mediated transmembrane signalling in active rheumatoid arthritis.

PubMed Central

Goulding, N J; Guyre, P M

1992-01-01

Neutrophil Fc gamma receptor (Fc gamma R) signalling responses were compared in healthy subjects, patients with definite rheumatoid arthritis (RA), ankylosing spondylitis, and osteoarthritis. The patients with A were subdivided into those with active synovitis and those with quiescent disease. Basal intracellular calcium ion concentrations in patients with inactive RA were significantly higher than in control subjects, which in turn were greater than in patients with active RA. Transient cytosolic calcium ion fluxes were observed after binding Fc gamma RII or Fc gamma RIII with specific monoclonal antibodies and cross linking with the F(ab')2 fragment of antimouse IgG. Response times were significantly faster for Fc gamma RII than for Fc gamma RIII. Peak concentrations of intracellular calcium ions after neutrophil stimulation were comparable for Fc gamma RII and RIII in healthy subjects. Neutrophils in patients with ankylosing spondylitis and osteoarthritis responded to Fc gamma R triggering, but in the group with active RA fluxes of calcium ions were severely depressed. Neutrophils isolated from patients with RA with quiescent disease showed exaggerated responses when compared with controls. Expression of all three Fc gamma R types on neutrophils from patients with active RA, as measured by monoclonal antibody binding, was comparable with control cells. Impairment of neutrophil Fc gamma R cytosolic signalling in active RA could reflect a receptor signalling defect with potential effects on Fc mediated functions, or a fundamental defect in calcium ion homeostasis within these cells. PMID:1535494

Influence of crustal cumulates on 210Pb disequilibria in basalts

NASA Astrophysics Data System (ADS)

Van Orman, James A.; Saal, Alberto E.

2009-07-01

In historical basalts from a wide range of tectonic settings, 210Pb is often found to have an activity deficit relative to its predecessor 226Ra. Several processes have been hypothesized as causes of 210Pb deficits in basalts. In subduction zone and ocean island environments, 210Pb deficits have often been attributed to shallow magmatic degassing. At mid-ocean ridges, 210Pb deficits have been inferred to result from mantle melting, limiting the time between melt production and eruption to 100 years or less. Here we present an alternative mechanism for producing 210Pb deficits in magmas, by diffusive exchange between a melt and cumulate minerals (plagioclase and/or clinopyroxene) in the crust. The deficit in 210Pb develops in response to its decay toward secular equilibrium with 226Ra within the mineral grains; decay provides an internal sink for 210Pb that drives continuous diffusive exchange with the melt. Deficits in 210Pb develop under a broad range of conditions, in enriched and depleted melts and during interaction with young or old cumulate minerals. The magnitude of the deficit depends mainly on the equilibrium mineral/melt partition coefficients for Pb and Ra and on the melt/rock ratio during diffusive interaction, and is only weakly dependent on the relative diffusivities of Ra and Pb in the minerals or the trace element disequilibrium between the melt and cumulate minerals. Plagioclase in the crust has greater leverage on the 210Pb- 226Ra system than any silicate mineral present during mantle melting, and is capable of inducing significant 210Pb deficits in the melt even at melt fractions above 50%. Its influence on the melt is also rapid, with a substantial 210Pb deficit developing in less than a year and approaching a steady state value after several decades or less. The strong control crustal cumulates are capable of exerting on 210Pb- 226Ra fractionation in melts indicates that they may have a significant role in a wide range of tectonic environments, and suggests caution in interpreting 210Pb deficits as a signature of mantle melting, or as a product of 222Rn degassing.

Synergistic growth inhibition by acyclic retinoid and vitamin K2 in human hepatocellular carcinoma cells.

PubMed

Kanamori, Toh; Shimizu, Masahito; Okuno, Masataka; Matsushima-Nishiwaki, Rie; Tsurumi, Hisashi; Kojima, Soichi; Moriwaki, Hisataka

2007-03-01

Hepatocellular carcinoma (HCC) is one of the most prevalent cancers worldwide. However, effective chemopreventive and chemotherapeutic agents for this cancer have not yet been developed. In clinical trials acyclic retinoid (ACR) and vitamin K(2) (VK(2)) decreased the recurrence rate of HCC. In the present study we examined the possible combined effects of ACR or another retinoid 9-cis retinoic acid (9cRA) plus VK(2) in the HuH7 human HCC cell line. We found that the combination of 1.0 microM ACR or 1.0 microM 9cRA plus 10 microM VK(2) synergistically inhibited the growth of HuH7 cells without affecting the growth of Hc normal human hepatocytes. The combined treatment with ACR plus VK(2) also acted synergistically to induce apoptosis in HuH7 cells. Treatment with VK(2) alone inhibited phosphorylation of the retinoid X receptor (RXR)alpha protein, which is regarded as a critical factor for liver carcinogenesis, through inhibition of Ras activation and extracellular signal-regulated kinase phosphorylation. Moreover, the inhibition of RXRalpha phosphorylation by VK(2) was enhanced when the cells were cotreated with ACR. The combination of retinoids plus VK(2) markedly increased both the retinoic acid receptor responsive element and retinoid X receptor responsive element promoter activities in HuH7 cells. Our results suggest that retinoids (especially ACR) and VK(2) cooperatively inhibit activation of the Ras/MAPK signaling pathway, subsequently inhibiting the phosphorylation of RXRalpha and the growth of HCC cells. This combination might therefore be effective for the chemoprevention and chemotherapy of HCC.

Using noble gases and 87Sr/86Sr to constrain heat sources and fluid evolution at the Los Azufres Geothermal Field, Mexico

NASA Astrophysics Data System (ADS)

Wen, T.; Pinti, D. L.; Castro, M. C.; Lopez Hernandez, A.; Hall, C. M.; Shouakar-Stash, O.; Sandoval-Medina, F.

2017-12-01

Geothermal wells and hot springs were sampled for noble gases' volume fraction and isotopic measurements and 87Sr/86Sr in the Los Azufres Geothermal Field (LAGF), Mexico, to understand the evolution of fluid circulation following three decades of exploitation and re-injection of used brines. The LAGF, divided into the Southern Production Zone (SPZ) and the Northern Production Zone (NPZ), is hosted in a Miocene to Pliocene andesitic volcanic complex covered by Quaternary rhyolitic-dacitic units. Air contamination corrected 3He/4He ratios (Rc) normalized to the atmospheric ratio (Ra=1.384 x 10-6), show a median value of 6.58 indicating a dominant mantle helium component. Contributions of crustal helium up to 53% and 18% are observed in NPZ and SPZ, respectively. Observations based on Rc/Ra and 87Sr/86Sr ratios points to the mixing of three magmatic sources supplying mantle helium to the LAGF: (1) a pure mantle He (Rc/Ra = 8) and Sr (87Sr/86Sr = 0.7035) source; (2) a pure mantle helium (Rc/Ra = 8) with some radiogenic Sr (87Sr/86Sr = 0.7049) source possibly resulting from Quaternary rhyolitic volcanism; and (3) a fossil mantle He component (Rc/Ra = 3.8) with some radiogenic Sr (87Sr/86Sr = 0.7038), corresponding possibly to the Miocene andesite reservoir. Intrusions within the last 50 kyrs from sources (1) and (2) are likely responsible for the addition of mantle volatiles and heat to the hydrothermal system of Los Azufres. He and Ar isotopes indicate that heat flow is transported by both convection and conduction. Atmospheric noble gas elemental ratios suggest that geothermal wells located closer to the western re-injection zone are beginning to be dominated by re-injection of used brines (injectate). The area affected by boiling in LAGF has further extended to the north and west since the last noble gas sampling campaign in 2009.

FcγRIIIa Expression on Monocytes in Rheumatoid Arthritis: Role in Immune-Complex Stimulated TNF Production and Non-Response to Methotrexate Therapy

PubMed Central

Cooper, Dawn L.; Martin, Stephen G.; Robinson, James I.; Mackie, Sarah L.; Charles, Christopher J.; Nam, Jackie; Consortium, YEAR; Isaacs, John D.; Emery, Paul; Morgan, Ann W.

2012-01-01

Objective The expression of FcγRIIIa/CD16 may render monocytes targets for activation by IgG-containing immune complexes (IC). We investigated whether FcγRIIIa/CD16 was upregulated in rheumatoid arthritis (RA), associated with TNF production in response to IC-stimulation, and if this predicted response to methotrexate therapy. Methods FcγRIIIa/CD16 expression on CD14low and CD14++ monocytes was measured by flow cytometry in healthy controls and RA patients (early and long-standing disease). Intracellular TNF-staining was carried out after in vitro LPS or heat-aggregated immunoglobulin (HAG) activation. FcγRIIIa/CD16 expression pre- and post-steroid/methotrexate treatment was examined. Results Increased FcγRIIIa/CD16 expression on CD14++ monocytes in long-standing RA patients compared to controls was demonstrated (p = 0.002) with intermediate levels in early-RA patients. HAG-induced TNF-production in RA patients was correlated with the percentage of CD14++ monocytes expressing FcγRIIIa/CD16 (p<0.001). The percentage of CD14++ monocytes expressing FcγRIIIa/CD16 at baseline in early DMARD-naïve RA patients was negatively correlated with DAS28-ESR improvement 14-weeks post-methotrexate therapy (p = 0.003) and was significantly increased in EULAR non-responders compared to moderate (p = 0.01) or good responders (p = 0.003). FcγRIIIa/CD16 expression was not correlated with age, presence of systemic inflammation or autoantibody titers. Conclusion Increased FcγRIIIa/CD16 expression on CD14++ monocytes in RA may result in a cell that has increased responsiveness to IC-stimulation. This monocyte subset may contribute to non-response to methotrexate therapy. PMID:22235253

Malondialdehyde-acetaldehyde adducts (MAA) and anti-MAA antibody in rheumatoid arthritis

PubMed Central

Thiele, Geoffrey M.; Duryee, Michael J.; Anderson, Daniel R.; Klassen, Lynell W.; Mohring, Stephen M.; Young, Kathleen A.; Benissan-Messan, Dathe; Sayles, Harlan; Dusad, Anand; Hunter, Carlos D.; Sokolove, Jeremy; Robinson, William; O’Dell, James R.; Nicholas, Anthony P.; Tuma, Dean; Mikuls, Ted R.

2017-01-01

Objective As a product of oxidative stress associated with tolerance loss in other disease states, we investigated the presence of malondialdehyde-acetaldehyde (MAA) adducts and circulating anti-MAA antibody in rheumatoid arthritis (RA). Methods Synovial tissues from RA and osteoarthritis patients were examined for the presence of MAA-modified and citrullinated proteins. Anti-MAA antibody isotypes were measured in RA cases (n = 1720) and healthy controls (n = 80) by ELISA. Antigen-specific anti-citrullinated protein antibody (ACPA) was measured in RA cases using a multiplex antigen array. Anti-MAA isotype concentrations were compared in a subset of cases (n = 80) and matched controls (n = 80). Associations of anti-MAA antibody isotypes with disease characteristics, including ACPA, were examined in all RA cases. Results MAA adducts were increased in RA synovial tissues relative to osteoarthritis and co-localized with citrullinated protein. Anti-MAA antibody isotypes were increased in RA cases vs. controls (p < 0.001). Among RA cases, anti-MAA antibody isotypes were associated with ACPA and RF positivity (p < 0.001) in addition to select measures of disease activity. Higher anti-MAA antibody concentrations were associated with a higher number of positive antigen-specific ACPA analytes in high titer (p < 0.001) and a higher ACPA score (p < 0.001) independent of other covariates. Conclusion MAA adduct formation is increased in RA and appears to result in robust antibody responses that are strongly associated with ACPA. These results support speculation that MAA formation may be a co-factor that drives tolerance loss resulting in the autoimmune responses characteristic of RA. PMID:25417811

Establishing cross-discipline consensus on contraception, pregnancy and breast feeding-related educational messages and clinical practices to support women with rheumatoid arthritis: an Australian Delphi study

PubMed Central

Jordan, Joanne E; Ackerman, Ilana N; Van Doornum, Sharon

2016-01-01

Objective Recognising the need for a best-practice and consistent approach in providing care to women with rheumatoid arthritis (RA) in relation to (1) general health, (2) contraception, (3) conception and pregnancy, (4) breast feeding and (5) early parenting, we sought to achieve cross-discipline, clinical consensus on key messages and clinical practice behaviours in these 5 areas. Design 3-round eDelphi study. In round 1, panellists provided free-text responses to open-ended questions about care for women with RA across the 5 areas. Subsequently, panellists refined and scored the synthesised responses, presented as metathemes, themes and detailed elements. Where ≥5% of panellists did not support a theme in a given round, it was removed. Setting Panel of practicing Australian rheumatologists (n=22), obstetricians/obstetric medicine physicians (n=9) and pharmacists (n=5). Results 34 (94.4%) panellists participated in all 3 rounds. The panel supported 18 themes across the 5 areas (support/strongly support: 88.2–100%) underpinned by 5 metathemes. Metathemes focused on coordination in information delivery, the mode and timing of information delivery, evidence underpinning information, engagement of the right health professionals at the right time and a non-judgemental approach to infant feeding. Themes included practices for primary prevention of chronic disease and their sequelae, the importance of contraception and planning pregnancy and breast feeding, close monitoring of medications, supporting mental well-being, managing disease activity and providing practical support for early parenting. Conclusions A cross-disciplinary clinical panel highly supported key information and clinical practices in the care for women with RA across the continuum of contraception to early parenting within a whole-person, chronic disease management approach. PMID:27633637

Substance P ameliorates collagen II-induced arthritis in mice via suppression of the inflammatory response

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hong, Hyun Sook; Son, Youngsook, E-mail: ysson@khu.ac.kr

Highlights: • SP can increase IL-10 levels and reduce TNF-α and IL-17 levels in RA. • SP causes the increase in T{sub reg}, M2 macrophage, and MSCs in RA. • SP-induced immune suppression leads to the blockade of RA progression. • SP can be used as the therapeutics for autoimmune-related inflammatory diseases. - Abstract: Current rheumatoid arthritis (RA) therapies such as biologics inhibiting pathogenic cytokines substantially delay RA progression. However, patient responses to these agents are not always complete and long lasting. This study explored whether substance P (SP), an 11 amino acids long endogenous neuropeptide with the novel abilitymore » to mobilize mesenchymal stem cells (MSC) and modulate injury-mediated inflammation, can inhibit RA progression. SP efficacy was evaluated by paw swelling, clinical arthritis scoring, radiological analysis, histological analysis of cartilage destruction, and blood levels of tumor necrosis factor-alpha (TNF-α) interleukin (IL)-10, and IL-17 in vivo. SP treatment significantly reduced local inflammatory signs, mean arthritis scores, degradation of joint cartilage, and invasion of inflammatory cells into the synovial tissues. Moreover, the SP treatment markedly reduced the size of spleens enlarged by excessive inflammation in CIA, increased IL-10 levels, and decreased TNF-α and IL-17 levels. Mobilization of stem cells and induction of T{sub reg} and M2 type macrophages in the circulation were also increased by the SP treatment. These effect of SP might be associated with the suppression of inflammatory responses in RA and, furthermore, blockade of RA progression. Our results propose SP as a potential therapeutic for autoimmune-related inflammatory diseases.« less

Sympathetic skin response and R-R interval variation in cases with rheumatoid arthritis.

PubMed

Gozke, E; Erdogan, N; Akyuz, G; Turan, B; Akyuz, E; Us, O

2003-03-01

To investigate the autonomic nervus system involvement in cases with rheumatoid arthritis (RA) by assesing sympathetic skin response (SSR) and R-R interval variation (RRIV), 14 healthy women and 10 women with RA, all of them without clinic dysautonomies were examined. SSR's were recorded palmar surface of both hands and soles of both feet, after stimulating median and tibial nerves individually. RRIV's were assessed at rest and during six deep breathing in one minute with electrodes placed on dorsal surfaces of both hands. SSR could not be obtained from lower extremities of one case with RA. We could not find any significant difference between two groups in terms of SSR latencies. RRIV values obtained during deep breathing to those recorded at rest (D%/R%) was found to be significantly lower in RA cases than healthy controls. RRIV values increased with deep breathing in healthy subjects, while they decreased in 50% of the RA cases. We conclude that assessment of SSR and RRIV are valuble methods for revelation of subclinical autonomic involvement in cases with RA.

Impact of anti-rheumatic treatment on immunogenicity of pandemic H1N1 influenza vaccine in patients with arthritis.

PubMed

Kapetanovic, Meliha C; Kristensen, Lars-Erik; Saxne, Tore; Aktas, Teodora; Mörner, Andreas; Geborek, Pierre

2014-01-02

An adjuvanted pandemic H1N1 influenza (pH1N1) vaccine (Pandemrix) was reported as highly immunogenic resulting in seroconversion in 77 to 94% of adults after administration of a single dose. The aim of the study was to investigate the impact of different anti-rheumatic treatments on antibody response to pH1N1 vaccination in patients with rheumatoid arthritis (RA) and spondylarthropathy (SpA). Patients with arthritis (n = 291; mean age 57 years, 64% women) participated. Hemagglutination inhibition (HI) assay was performed on blood samples drawn before and after a mean (SD) of 8.3 (4) months following vaccination. A positive immune response i.e. seroconversion was defined as negative prevaccination serum and postvaccination HI titer ≥40 or a ≥4-fold increase in HI titer. All patients were divided into predefined groups based on diagnosis (RA or SpA) and ongoing treatment: methotrexate (MTX), anti-tumor necrosis factor (anti-TNF) as monotherapy, MTX combined with anti-TNF, other biologics (abatacept, rituximab, tocilizumab) and non-steroidal anti-inflammatory drugs (NSAIDs)/analgesics. Predictors of positive immune response were studied using logistic regression analysis. The percentage of patients with positive immune response in the different treatment groups was: 1. RA on MTX 42%; 2. RA on anti-TNF monotherapy 53%; 3. RA on anti-TNF + MTX 43%; 4. RA on other biologics (abatacept 20%, rituximab 10% and tocilizumab 50%); 5. SpA on anti-TNF monotherapy 76%; 6. SpA on anti-TNF + MTX 47%; and 7. SpA on NSAIDs/analgesics 59%. RA patients on rituximab had significantly lower (P < 0.001) and SpA on anti-TNF monotherapy significantly better response rates compared to other treatment groups (P 0.001 to 0.033). Higher age (P < 0.001) predicted impaired immune response. Antibody titers 3 to 6 months after vaccination was generally lower compared to those within the first 3 months but no further decrease in titers were observed 6 to 22 months after vaccination. Rituximab treatment severely reduced antibody response to pH1N1 influenza vaccine. The other treatment groups showed acceptable antibody responses. Protective antibody titers could be detected up to 22 months after vaccination in the current patient population, with the exception of rituximab treated patients.

Retinoic acid treated human dendritic cells induce T regulatory cells via the expression of CD141 and GARP which is impaired with age.

PubMed

Agrawal, Sudhanshu; Ganguly, Sreerupa; Tran, Alexander; Sundaram, Padmaja; Agrawal, Anshu

2016-06-01

Aged subjects display increased susceptibility to mucosal diseases. Retinoic Acid (RA) plays a major role in inducing tolerance in the mucosa. RA acts on Dendritic cells (DCs) to induce mucosal tolerance. Here we compared the response of DCs from aged and young individuals to RA with a view to understand the role of DCs in age-associated increased susceptibility to mucosal diseases. Our investigations revealed that compared to young DCs, RA stimulated DCs from aged subjects are defective in inducing IL-10 and T regulatory cells. Examinations of the underlying mechanisms indicated that RA exposure led to the upregulation of CD141 and GARP on DCs which rendered the DCs tolerogenic. CD141(hi), GARP(+) DCs displayed enhanced capacity to induce T regulatory cells compared to CD141(lo) and GARP(-) DCs. Unlike RA stimulated DCs from young, DCs from aged subjects exhibited diminished upregulation of both CD141 and GARP. The percentage of DCs expressing CD141 and GARP on RA treatment was significantly reduced in DCs from aged individuals. Furthermore, the remaining CD141(hi), GARP(+) DCs from aged individuals were also deficient in inducing T regs. In summary, reduced response of aged DCs to RA enhances mucosal inflammation in the elderly, increasing their susceptibility to mucosal diseases.

Retinoic acid treated human dendritic cells induce T regulatory cells via the expression of CD141 and GARP which is impaired with age

PubMed Central

Agrawal, Sudhanshu; Ganguly, Sreerupa; Tran, Alexander; Sundaram, Padmaja; Agrawal, Anshu

2016-01-01

Aged subjects display increased susceptibility to mucosal diseases. Retinoic Acid (RA) plays a major role in inducing tolerance in the mucosa. RA acts on Dendritic cells (DCs) to induce mucosal tolerance. Here we compared the response of DCs from aged and young individuals to RA with a view to understand the role of DCs in age-associated increased susceptibility to mucosal diseases. Our investigations revealed that compared to young DCs, RA stimulated DCs from aged subjects are defective in inducing IL-10 and T regulatory cells. Examinations of the underlying mechanisms indicated that RA exposure led to the upregulation of CD141 and GARP on DCs which rendered the DCs tolerogenic. CD141hi, GARP+ DCs displayed enhanced capacity to induce T regulatory cells compared to CD141lo and GARP− DCs. Unlike RA stimulated DCs from young, DCs from aged subjects exhibited diminished upregulation of both CD141 and GARP. The percentage of DCs expressing CD141 and GARP on RA treatment was significantly reduced in DCs from aged individuals. Furthermore, the remaining CD141hi, GARP+ DCs from aged individuals were also deficient in inducing T regs. In summary, reduced response of aged DCs to RA enhances mucosal inflammation in the elderly, increasing their susceptibility to mucosal diseases. PMID:27244900

Epstein-Barr virus and rheumatoid arthritis.

PubMed

Balandraud, Nathalie; Roudier, Jean

2018-03-01

Rheumatoid arthritis (RA) is one of the most common autoimmune diseases, with a 0.5% worldwide prevalence. The cause of RA remains unknown, however both genetic and environmental factors may contribute to its development. Among these is the Epstein-Barr virus (EBV). Here, we discuss several aspects of the close relationship between EBV and RA. Patients with RA have impaired control of EBV infection. Indeed, they have high titres of antibodies against EBV antigens. Their peripheral blood T lymphocytes are less efficient at controlling the outgrowth of EBV-infected B cells. RA patients have more EBV-infected B cells than normal controls, leading to a 10-fold systemic EBV overload. Post-transplant lymphoproliferative disorder (PTLPD) is a polyclonal EBV-positive B lymphocyte proliferation, which can evolve into an EBV-positive B cell lymphoma. RA patients also have an increased risk of developing EBV-associated lymphoproliferative disorder (LPD). Hence the need to monitor EBV load when treating RA patients with immunosuppressors. EBV, a widespread virus, highly recognized by antibodies but never eliminated, is an ideal candidate to trigger chronic immune complex disease. Anti-EBV antibody responses should be considered as one of the chronic autoantibody responses linked to the development of RA, in the same way as anti-citrullinated protein antibodies. Copyright © 2017 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.

Development of a cell-based qualitative assay for detection of neutralizing anti-human interleukin-1 receptor antagonist (hIL-1Ra) antibodies in rats.

PubMed

Gao, Jin; Li, Jingjing; Yang, Minmin; Wu, Mingyuan; Tu, Ping; Yu, Yan; Han, Wei

2015-01-01

To determine the incidence of the positive neutralizing anti-human interleukin receptor antagonist (anti-IL-1Ra), a novel assay based on the proliferation of human melanoma A375.S2 cells was developed and validated. In the presence of a growth-limiting concentration of IL-1β, A375.S2 cells were able to regain proliferation following the addition of IL-1Ra in a concentration-dependent manner. This dose-response effect enabled the validation of a standard curve for calculation of the concentration of IL-1Ra or, inversely, the concentration of neutralizing anti-IL-1Ra antibodies in cell culture medium or sera. The assay used CCK-8 as an indicator of proliferation. The dose-response relationship between rhIL-1Ra (dose range of 5-75 ng/ml rhIL-1Ra) and A375.S2 cell proliferation was sigmoidal and fitted a four-parameter logistic model. The percent coefficients of variation (%CVs) of quality control samples were 12.5 and 11.9% for intra-assay repeatability and 14.5 and 19.5% for inter-assay repeatability, while the total accuracy was in the range of 97.2-103.6%. For the neutralization assay, the optimal sample dilution factor was found to be 40-fold and the reasonable standard for positive and negative decision was calculated to be 59.4% neutralization rate. The %CVs of quality control samples were 12.7 and 24.0% for intra-assay repeatability and 11.6 and 30.0% for inter-assay repeatability. Analysis using the assay showed that rats could produce neutralizing anti-IL-1Ra antibodies after repeated intramuscular injection with rhIL-1Ra, and this response was not significantly dependent on the dose injected.

Retinoic Acid Therapy Resistance Progresses from Unilineage to Bilineage in HL-60 Leukemic Blasts

PubMed Central

Jensen, Holly A.; Bunaciu, Rodica P.; Ibabao, Christopher N.; Myers, Rebecca; Varner, Jeffrey D.; Yen, Andrew

2014-01-01

Emergent resistance can be progressive and driven by global signaling aberrations. All-trans retinoic acid (RA) is the standard therapeutic agent for acute promyelocytic leukemia, but 10–20% of patients are not responsive, and initially responsive patients relapse and develop retinoic acid resistance. The patient-derived, lineage-bipotent acute myeloblastic leukemia (FAB M2) HL-60 cell line is a potent tool for characterizing differentiation-induction therapy responsiveness and resistance in t(15;17)-negative cells. Wild-type (WT) HL-60 cells undergo RA-induced granulocytic differentiation, or monocytic differentiation in response to 1,25-dihydroxyvitamin D3 (D3). Two sequentially emergent RA-resistant HL-60 cell lines, R38+ and R38-, distinguishable by RA-inducible CD38 expression, do not arrest in G1/G0 and fail to upregulate CD11b and the myeloid-associated signaling factors Vav1, c-Cbl, Lyn, Fgr, and c-Raf after RA treatment. Here, we show that the R38+ and R38- HL-60 cell lines display a progressive reduced response to D3-induced differentiation therapy. Exploiting the biphasic dynamic of induced HL-60 differentiation, we examined if resistance-related defects occurred during the first 24 h (the early or “precommitment” phase) or subsequently (the late or “lineage-commitment” phase). HL-60 were treated with RA or D3 for 24 h, washed and retreated with either the same, different, or no differentiation agent. Using flow cytometry, D3 was able to induce CD38, CD11b and CD14 expression, and G1/G0 arrest when present during the lineage-commitment stage in R38+ cells, and to a lesser degree in R38- cells. Clustering analysis of cytometry and quantified Western blot data indicated that WT, R38+ and R38- HL-60 cells exhibited decreasing correlation between phenotypic markers and signaling factor expression. Thus differentiation induction therapy resistance can develop in stages, with initial partial RA resistance and moderate vitamin D3 responsiveness (unilineage maturation block), followed by bilineage maturation block and progressive signaling defects, notably the reduced expression of Vav1, Fgr, and c-Raf. PMID:24922062

Prealbumin, platelet factor 4 and S100A12 combination at baseline predicts good response to TNF alpha inhibitors in Rheumatoid Arthritis.

PubMed

Nguyen, Minh Vu Chuong; Baillet, Athan; Romand, Xavier; Trocmé, Candice; Courtier, Anaïs; Marotte, Hubert; Thomas, Thierry; Soubrier, Martin; Miossec, Pierre; Tébib, Jacques; Grange, Laurent; Toussaint, Bertrand; Lequerré, Thierry; Vittecoq, Olivier; Gaudin, Philippe

2018-06-06

Tumour necrosis factor-alpha inhibitors (TNFi) are effective treatments for Rheumatoid Arthritis (RA). Responses to treatment are barely predictable. As these treatments are costly and may induce a number of side effects, we aimed at identifying a panel of protein biomarkers that could be used to predict clinical response to TNFi for RA patients. Baseline blood levels of C-reactive protein, platelet factor 4, apolipoprotein A1, prealbumin, α1-antitrypsin, haptoglobin, S100A8/A9 and S100A12 proteins in bDMARD naive patients at the time of TNFi treatment initiation were assessed in a multicentric prospective French cohort. Patients fulfilling good EULAR response at 6 months were considered as responders. Logistic regression was used to determine best biomarker set that could predict good clinical response to TNFi. A combination of biomarkers (prealbumin, platelet factor 4 and S100A12) was identified and could predict response to TNFi in RA with sensitivity of 78%, specificity of 77%, positive predictive values (PPV) of 72%, negative predictive values (NPV) of 82%, positive likelihood ratio (LR+) of 3.35 and negative likelihood ratio (LR-) of 0.28. Lower levels of prealbumin and S100A12 and higher level of platelet factor 4 than the determined cutoff at baseline in RA patients are good predictors for response to TNFi treatment globally as well as to Infliximab, Etanercept and Adalimumab individually. A multivariate model combining 3 biomarkers (prealbumin, platelet factor 4 and S100A12) accurately predicted response of RA patients to TNFi and has potential in a daily practice personalized treatment. Copyright © 2018. Published by Elsevier Masson SAS.

Prenatal treatment with retinoic acid activates parathyroid hormone-related protein signaling in the nitrofen-induced hypoplastic lung.

PubMed

Doi, Takashi; Sugimoto, Kaoru; Ruttenstock, Elke; Dingemann, Jens; Puri, Prem

2011-01-01

Prenatal treatment with retinoic acid (RA) has been reported to stimulate alveologenesis in hypoplastic lungs (HL) in the nitrofen model of congenital diaphragmatic hernia (CDH). Parathyroid hormone-related protein (PTHrP) promotes alveolar maturation by stimulating surfactant production, regulated by PTHrP receptor (PTHrP-R). PTHrP knockout and PTHrP-R null mice both exhibit pulmonary hypoplasia. We have recently reported that nitrofen inhibits PTHrP signaling in the nitrofen-induced HL. Because both PTHrP and PTHrP-R genes have RA-inducible element, we hypothesized that prenatal administration of RA upregulates pulmonary gene expression of PTHrP and PTHrP-R in the nitrofen-induced HL. Pregnant rats were exposed to either olive oil or nitrofen on day 9 of gestation (D9). RA was given on days D18, D19 and D20. Fetal lungs were obtained on D21 and divided into four groups: control, control + RA, nitrofen, nitrofen + RA. RT-PCR and Immunohistochemistry were performed to investigate the pulmonary PTHrP and PTHrP-R gene and protein expression in each group, respectively. The pulmonary gene expression levels of PTHrP and PTHrP-R were significantly increased in nitrofen + RA group compared to nitrofen group (p < 0.05). Immunoreactivity of PTHrP and PTHrP-R was also remarkably increased in nitrofen + RA group compared to nitrofen group. Upregulation of PTHrP and PTHrP-R genes after prenatal treatment with RA in the nitrofen-induced HL suggests that RA may have a therapeutic potential in reverting lung hypoplasia in CDH, by stimulating surfactant production and alveolar maturation.

Air pollution as a determinant of rheumatoid arthritis.

PubMed

Sigaux, Johanna; Biton, Jérôme; André, Emma; Semerano, Luca; Boissier, Marie-Christophe

2018-03-07

Pollution has long been incriminated in many cardiovascular and respiratory diseases. More recently, studies evaluated the potential role for particulate pollutants in autoimmune diseases, including rheumatoid arthritis (RA). The incidence of RA was found to be higher in urban areas. Living near air pollution emitters was associated with higher risks of developing RA and of producing RA-specific autoantibodies. Nevertheless, no strong epidemiological evidence exists to link one or more specific air pollution particles to RA. The presence in the bronchi of lymphoid satellite islands (inducible bronchus-associated lymphoid tissue, iBALT) is strongly associated with both inflammatory lung disease and RA-associated lung disease. Diesel exhaust particles can stimulate iBALT formation. The induction by air pollution of an inflammatory environment with high citrullination levels in the lung may induce iBALT formation, thereby causing a transition toward a more specific immune response via the production of anti-citrullinated peptide antibodies. Air pollution not only triggers innate immune responses at the molecular level, increasing the levels of proinflammatory cytokines and reactive oxygen species, but is also involved in adaptive immune responses. Thus, via the aryl hydrocarbon receptor (AHR), diesel exhaust particles can trigger a T-cell switch to the Th17 profile. Finally, in the murine collagen-induced arthritis model, animals whose lymphocytes lack the AHR develop milder arthritis. Copyright © 2018. Published by Elsevier SAS.

Non-Enzymatic Decomposition of Collagen Fibers by a Biglycan Antibody and a Plausible Mechanism for Rheumatoid Arthritis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Antipova, Olga; Orgel, Joseph P.R.O.

Rheumatoid arthritis (RA) is a systemic autoimmune inflammatory and destructive joint disorder that affects tens of millions of people worldwide. Normal healthy joints maintain a balance between the synthesis of extracellular matrix (ECM) molecules and the proteolytic degradation of damaged ones. In the case of RA, this balance is shifted toward matrix destruction due to increased production of cleavage enzymes and the presence of (autoimmune) immunoglobulins resulting from an inflammation induced immune response. Herein we demonstrate that a polyclonal antibody against the proteoglycan biglycan (BG) causes tissue destruction that may be analogous to that of RA affected tissues. The effectmore » of the antibody is more potent than harsh chemical and/or enzymatic treatments designed to mimic arthritis-like fibril de-polymerization. In RA cases, the immune response to inflammation causes synovial fibroblasts, monocytes and macrophages to produce cytokines and secrete matrix remodeling enzymes, whereas B cells are stimulated to produce immunoglobulins. The specific antigen that causes the RA immune response has not yet been identified, although possible candidates have been proposed, including collagen types I and II, and proteoglycans (PG's) such as biglycan. We speculate that the initiation of RA associated tissue destruction in vivo may involve a similar non-enzymatic decomposition of collagen fibrils via the immunoglobulins themselves that we observe here ex vivo.« less

Whole-body CO2 production as an index of the metabolic response to sepsis

USDA-ARS?s Scientific Manuscript database

Whole-body carbon dioxide (CO2) production (RaCO2) is an index of substrate oxidation and energy expenditure; therefore, it may provide information about the metabolic response to sepsis. Using stable isotope techniques, we determined RaCO2 and its relationship to protein and glucose metabolism in m...

MicroRNA-146a suppresses rheumatoid arthritis fibroblast-like synoviocytes proliferation and inflammatory responses by inhibiting the TLR4/NF-kB signaling

PubMed Central

Liu, Wei; Wu, Yuan-Hao; Zhang, Lei; Xue, Bin; Wang, Yi; Liu, Bin; Liu, Xiao-Ya; Zuo, Fang; Yang, Xiao-Yan; Chen, Fu-Yu; Duan, Ran; Cai, Yue; Zhang, Bo; Ji, Yang

2018-01-01

This study investigated whether microRNA-146a (miR-146a) mediating TLR4/NF-κB pathway affected proliferation and inflammatory responses of rheumatoid arthritis fibroblast-like synoviocytes from 12 RA patients (RA-FLSs). FLSs in the logarithmic growth phase were assigned into the control, miR-146a mimic miR-146a inhibitor, Tak-242 (treated with TLR4/NF-κB pathway inhibitor) and mimic + lipopolysaccharide (LPS) groups. Cell proliferation and apoptosis were detected using CCK-8 assay and flow cytometry. The expression of miR-146a, TLR4/NF-κB pathway-related proteins and cytokines were determined by RT-qPCR, western blotting and ELISA, and the release of NO by Greiss reaction. RA rat models were constructed and the primary cells were classified into the control, negative control (NC), miR-146a mimic, miR-146a inhibitor, Tak-242, mimic + LPS, and TLR4 groups. Immunohistochemistry was used to detect the expression of proliferating cell nuclear antigen (PCNA) and intercellular adhesion molecular-1 (ICAM-1). The results showed that miR-146a levels were lower in RA-FLSs than control fibroblasts. miR-146a mimic and Tak-242 decreased RA-FLS proliferation and increased RA-FLS apoptosis, while miR-146a inhibitor had an opposite trend. miR-146a mimic and Tak-242 also decreased expression of TLR4, NF-κB, IL-1β, IL-6, IL-8, IL-17, COX-2, MMP-3, Seprase, and iNOS, as well as reduced NO level in RA-FLSs while miR-146a inhibitor and TLR4 increased them. TLR4 and NF-κB levels and the positive rates of PCNA and ICAM-1 expressions were lower in RA-FLSs from RA rats given miR-146a mimic from control or miR-146a inhibitor-treated rats. These results suggest that miR-146a inhibits the proliferation and inflammatory response of RA-FLSs by down-regulating TLR4/NF-κB pathway.

Fixed versus Removable Appliance for Palatal Expansion; A 3D Analysis Using the Finite Element Method

PubMed Central

Geramy, Allahyar; Shahroudi, Atefe Saffar

2014-01-01

Objective: Several appliances have been used for palatal expansion for treatment of posterior cross bite. The purpose of this study was to evaluate the stress induced in the apical and crestal alveolar bone and the pattern of tooth displacement following expansion via removable expansion plates or fixed-banded palatal expander using the finite element method (FEM) analysis. Materials and Methods: Two 3D FEM models were designed from a mesio-distal slice of the maxilla containing the upper first molars, their periodontium and alveolar bone. Two palatal expanders (removable and fixed) were modeled. The models were designed in SolidWorks 2006 and then transferred to ANSYS Workbench. The appliance halves were displaced 0.1 mm laterally. The von Mises stress in the apical, crestal, and PDL areas and also the vertical displacement of the cusps (palatal and buccal) was were evaluated. Results: The total PDL stress was 0.40003 MPa in the removable appliance (RA) model and 4.88e-2 MPa in the fixed appliance (FA) model and the apical stress was 9.9e-2 and 1.17e-2 MPa, respectively. The crestal stress was 2.99e-1 MPa in RA and 7.62e-2 MPa in the FA. The stress in the cortical bone crest was 0.30327 and 7.9244e-2 MPa for RA and FA, respectively and 3.7271 and 7.4373e-2 MPa in crestal area of spongy bone, respectively. The vertical displacement of the buccal cusp and palatal cusp was 1.64e-2 and 5.90e-2 mm in RA and 1.05e-4 and 1.7e-4 mm in FA, respectively. Conclusion: The overall stress as well as apical and crestal stress in periodontium of anchor teeth was higher in RA than FA; RA elicited higher stress in both cortical and spongy bone. The vertical displacement of molar cusps was more in removable than fixed palatal expander model. PMID:24910679

Reproductive allocation in plants as affected by elevated carbon dioxide and other environmental changes: a synthesis using meta-analysis and graphical vector analysis.

PubMed

Wang, Xianzhong; Taub, Daniel R; Jablonski, Leanne M

2015-04-01

Reproduction is an important life history trait that strongly affects dynamics of plant populations. Although it has been well documented that elevated carbon dioxide (CO2) in the atmosphere greatly enhances biomass production in plants, the overall effect of elevated CO2 on reproductive allocation (RA), i.e., the proportion of biomass allocated to reproductive structures, is little understood. We combined meta-analysis with graphical vector analysis to examine the overall effect of elevated CO2 on RA and how other environmental factors, such as low nutrients, drought and elevated atmospheric ozone (O3), interacted with elevated CO2 in affecting RA in herbaceous plants. Averaged across all species of different functional groups and environmental conditions, elevated CO2 had little effect on RA (-0.9%). RA in plants of different reproductive strategies and functional groups, however, differed in response to elevated CO2. For example, RA in iteroparous wild species decreased by 8%, while RA in iteroparous crops increased significantly (+14%) at elevated CO2. RA was unaffected by CO2 in plants grown with no stress or in low-nutrient soils. RA decreased at elevated CO2 and elevated O3, but increased in response to elevated CO2 in drought-stressed plants, suggesting that elevated CO2 could ameliorate the adverse effect of drought on crop production to some extent. Our results demonstrate that elevated CO2 and other global environmental changes have the potential to greatly alter plant community composition through differential effects on RA of different plant species and thus affect the dynamics of natural and agricultural ecosystems in the future.

Acute hepatitis in three patients with systemic juvenile idiopathic arthritis taking interleukin-1 receptor antagonist.

PubMed

Canna, Scott; Frankovich, Jennifer; Higgins, Gloria; Narkewicz, Michael R; Nash, S Russell; Hollister, J Roger; Soep, Jennifer B; Dragone, Leonard L

2009-12-22

We investigated the etiology of acute hepatitis in three children with systemic Juvenile Idiopathic Arthritis (sJIA) taking Interleukin-1 receptor antagonist (IL1RA). Laboratory and clinical data for three children with sJIA diagnosed at ages 13 months to 8 years who developed acute hepatitis during treatment with IL1RA were reviewed for evidence of sJIA flare, infection, macrophage activation syndrome (MAS), malignancy, and drug reaction. In all patients, hepatitis persisted despite cessation of known hepatotoxic drugs and in absence of known infectious triggers, until discontinuation of IL1RA. Liver biopsies had mixed inflammatory infiltrates with associated hepatocellular injury suggestive of an exogenous trigger. At the time of hepatitis, laboratory data and liver biopsies were not characteristic of MAS. In two patients, transaminitis resolved within one week of discontinuing IL1RA, the third improved dramatically in one month. Although sJIA symptoms improved significantly on IL1RA, it appeared that IL1RA contributed to the development of acute hepatitis. Hepatitis possibly occurred as a result of an altered immune response to a typical childhood infection while on IL1RA. Alternatively, hepatitis could have represented an atypical presentation of MAS in patients with sJIA taking IL1RA. Further investigation is warranted to determine how anti-IL1 therapies alter immune responsiveness to exogenous triggers in patients with immune dysfunction such as sJIA. Our patients suggest that close monitoring for hepatic and other toxicities is indicated when treating with IL1RA.

No adaptive response is induced by chronic low-dose radiation from Ra-226 in the CHSE/F fish embryonic cell line and the HaCaT human epithelial cell line

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shi, Xiaopei, E-mail: shix22@mcmaster.ca; Mothersi

Purpose: To determine whether chronic low-dose α-particle radiation from Ra-226 over multiple cell generations can lead to an adaptive response in CHSE/F fish embryonic cells or HaCaT human epithelial cells receiving subsequent acute high-dose γ-ray radiation. Methods: CHSE/F and HaCaT cells were exposed to very low doses of Ra-226 in medium for multiple generations prior to being challenged by a higher dose γ-ray radiation. The clonogenic assay was used to test the clonogenic survival of cells with or without being pretreated by radiation from Ra-226. Results: In general, pretreatment with chronic radiation has no significant influence on the reaction ofmore » cells to the subsequent challenge radiation. Compared to unprimed cells, the change in clonogenic survival of primed cells after receiving challenge radiation is mainly due to the influence of the chronic exposure, and there's little adaptive response induced. However at several dose points, pretreatment of CHSE/F fish cells with chronic radiation resulted in a radiosensitive response to a challenge dose of γ-ray radiation, and pretreatment of HaCaT cells resulted in no effect except for a slightly radioresistant response to the challenge radiation which was not significant. Conclusion: The results suggest that chronic low-dose radiation is not effective enough to induce adaptive response. There was a difference between human and fish cells and it may be important to consider results from multiple species before making conclusions about effects of chronic or low doses of radiation in the environment. The term “radiosensitive” or “adaptive” make no judgment about whether such responses are ultimately beneficial or harmful. - Highlights: • No obvious adaptive response is induced by chronic low-dose radiation from Ra-226. • Priming radiation from Ra-226 sensitized CHSE/F cells to the challenge radiation. • Linear model is inconsistent with current work using chronic low-dose radiation.« less

REST, regulated by RA through miR-29a and the proteasome pathway, plays a crucial role in RPC proliferation and differentiation.

PubMed

Wang, Yuyao; Zhang, Dandan; Tang, Zhimin; Zhang, Yi; Gao, Huiqin; Ni, Ni; Shen, Bingqiao; Sun, Hao; Gu, Ping

2018-04-18

One of the primary obstacles in the application of retinal progenitor cells (RPCs) to the treatment of retinal degenerative diseases, such as age-related macular degeneration (AMD) and retinitis pigmentosa (RP), is their limited ability to proliferate and differentiate into specific retinal neurons. In this study, we revealed that repressor element-1-silencing transcription factor (REST), whose expression could be transcriptionally and post-transcriptionally mediated by retinoic acid (RA, one isomeride of a vitamin A derivative used as a differentiation-inducing agent in many disease treatments), plays a pivotal role in the regulation of proliferation and differentiation of RPCs. Our results show that direct knockdown of endogenous REST reduced RPC proliferation but accelerated RPC differentiation toward retinal neurons, which phenocopied the observed effects of RA on RPCs. Further studies disclosed that the expression level of REST could be downregulated by RA not only through upregulating microRNA (miR)-29a, which directly interacted with the 3'-untranslated region (3'-UTR) of the REST mRNA, but also through promoting REST proteasomal degradation. These results show us a novel functional protein, REST, which regulates RPC proliferation and differentiation, can be mediated by RA. Understanding the mechanisms of REST and RA in RPC fate determination enlightens a promising future for the application of REST and RA in the treatment of retinal degeneration diseases.

Study of chromosomal region 5p13.1 in Crohn's disease, ulcerative colitis, and rheumatoid arthritis.

PubMed

Perdigones, Nieves; Martín, Ezequiel; Robledo, Gema; Lamas, José Ramón; Taxonera, Carlos; Díaz-Rubio, Manuel; de la Concha, Emilio G; López-Nevot, Miguel Angel; García, Antonio; Gómez-García, María; Fernández-Gutiérrez, Benjamín; Martín, Javier; Urcelay, Elena

2010-08-01

Chromosomal region 5p13 includes regulatory elements of the prostaglandin receptor EP4 (PTGER4) gene and is associated with inflammatory bowel disease (IBD) susceptibility. We aimed at corroborating the association of the PTGER4 risk variant in IBD. Given the proinflammatory activity of prostaglandin E(2) in rheumatoid arthritis (RA), the reduction in incidence and severity of collagen-induced arthritis observed in mice deficient in the prostaglandin receptor EP4, and a modest signal of association found in an RA genome-wide scan, we proposed to extend the investigation of this locus to RA patients. A total of 709 Crohn's disease (CD) patients, 662 ulcerative colitis (UC) patients, and 1369 control subjects were genotyped for rs17234657. This polymorphism was also analyzed in 605 RA patients, and rs6871834 was studied in the RA patient group. Replication of the previous finding in CD was achieved in our independent collections, although with a milder effect (odds ratios = 1.23) than that originally described. No further association of the previously mentioned polymorphisms was detected with either UC or RA patients. We validated this 5p13 signal as a genuine susceptibility factor for CD in Caucasian populations. Our data seem to rule out a major influence of these polymorphisms on UC or RA predisposition. Copyright 2010 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

Tocilizumab treatment leads to improvement in disease activity regardless of CCP status in rheumatoid arthritis.

PubMed

Cappelli, Laura C; Palmer, Judy Lynn; Kremer, Joel; Bingham, Clifton O

2017-10-01

Autoantibodies can be useful in predicting response to certain treatments in rheumatoid arthritis (RA). We aimed to evaluate initial response to tocilizumab (TCZ) by change in physician and patient-reported outcomes and laboratory parameters in a real-world cohort of patients with RA. We analyzed the data by autoantibody status to determine whether patients with seronegative RA had improved response to tocilizumab when compared to their seropositive counterparts. Data from the CORRONA RA registry were analyzed. Patients were included if they were started on TCZ and had data from a follow-up visit 4-8 months after initiation, as well as having information on serologic status. Serologic status was determined by presence of anti-cyclic citrullinated peptide (CCP) antibodies. Changes in disease activity measures from baseline to follow-up visit were evaluated. Both CCP-negative and -positive groups had statistically significant improvement in physician-reported measurements (physician rating of disease activity and joint counts), patient-reported measures (disease activity, pain, and fatigue), and acute phase reactants after 4-8 months of treatment with tocilizumab. The magnitude of improvement, however, did not differ significantly by CCP status. Tocilizumab led to statistically significant improvement in all patient- and physician-reported measures of disease activity evaluated in this cohort of patient with RA. The response to tocilizumab did not differ by CCP status. Copyright © 2017 Elsevier Inc. All rights reserved.

Cellular alterations and enhanced induction of cleft palate after coadministration of retinoic acid and TCDD

DOE Office of Scientific and Technical Information (OSTI.GOV)

Abbott, B.D.; Birnbaum, L.S.

1989-06-15

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and retinoic acid (RA) are both teratogenic in mice. TCDD is a highly toxic, stable environmental contaminant, while RA is a naturally occurring form of vitamin A. Exposure to TCDD induces hydronephrosis and cleft palate, and exposure to RA induces limb defects and cleft palate. Teratology studies previously have shown that the incidence of clefting is higher after exposure to RA + TCDD than would be observed for the same doses of either compound given alone. This study examines the cellular effects which result in cleft palate, after po administration on gestation Day (GD) 10 or 12 ofmore » RA + TCDD in corn oil (10 ml/kg total volume). Exposure on GD 10 to 6 micrograms TCDD + 40 mg RA/kg inhibited early growth of the shelves and clefting was due to a failure of shelves to meet and fuse. This effect on mesenchyme was observed in previous studies to occur after exposure on GD 10 to 40 mg/kg RA alone, but not after TCDD alone. After exposure on GD 12 to 6 micrograms TCDD + 80 mg RA/kg, clefting was due to a failure of shelves to fuse after making contact, because the medial cells differentiated into an oral-like epithelium. This response was observed in previous studies to occur after exposure to TCDD alone, but RA alone on GD 12 resulted in differentiation toward nasal-like cells. The interaction between TCDD and RA results in RA-like clefting after exposure on GD 10 and TCDD-like clefting after exposure on GD 12, and this clefting occurs at higher incidences than would occur after the same levels of either agent alone. After exposure on either GD 10 or 12 to RA + TCDD, the programmed cell death of the medial cells does not occur, and these cells continue to express EGF receptors and to bind 125I-EGF. The effects of RA and TCDD may involve modulation of the cells responses to embryonic growth and differentiation factors.« less

De Novo-Synthesized Retinoic Acid in Ovarian Antral Follicles Enhances FSH-Mediated Ovarian Follicular Cell Differentiation and Female Fertility

PubMed Central

Kawai, Tomoko; Yanaka, Noriyuki; Richards, JoAnne S.

2016-01-01

Retinoic acid (RA) is the active form of vitamin A and is synthesized from retinol by two key enzymes, alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH). As the physiological precursor of RA, retinol impacts female reproductive functions and fertility. The expression of Adh1 and Adh5 as well as Aldh1a1 and Aldh1a7 are significantly increased in the ovaries of mice treated with equine chorionic gonadotropin/FSH. The RA receptor is expressed and localized in granulosa cells and is activated by endogenous RA as indicated by LacZ expression in granulosa cells of RA-responsive transgene-LacZ transgenic mice (RA reporter mice). Coinjection of the ADH inhibitor, 4-methylpyrazole, with equine chorionic gonadotropin significantly decreases the number and developmental competence of oocytes ovulated in response to human chorionic gonadotropin/LH as compared with controls. Injections of RA completely reverse the effects of the inhibitor of ovulation and oocyte development. When mice were fed a retinol-free, vitamin A-deficient diet that significantly reduced the serum levels of retinol, the expression of the LH receptor (Lhcgr) was significantly lower in the ovaries of the vitamin A-deficient mice, and injections of human chorionic gonadotropin failed to induce genes controlling ovulation. These results indicate that ovarian de novo biosynthesis of RA is required for the follicular expression of Lhcgr in granulosa cells and their ability to respond to the ovulatory LH surge. PMID:27022678

Polymorphisms in Protein Tyrosine Phosphatase Non-receptor Type 2 and 22 (PTPN2/22) Are Linked to Hyper-Proliferative T-Cells and Susceptibility to Mycobacteria in Rheumatoid Arthritis

PubMed Central

Sharp, Robert C.; Beg, Shazia A.; Naser, Saleh A.

2018-01-01

A shared genetic pre-disposition, chronic inflammation, and treatment with similar biologics between Rheumatoid arthritis (RA) and Crohn's disease (CD) have intrigued us to investigate whether the two disorders share trigger association or possible causation. We hypothesized earlier that Single Nucleotide Polymorphisms (SNPs) in the negative regulators Protein Tyrosine Phosphatase Non-receptor type 2 and 22 (PTPN2/22) lead to a dysregulated immune response, susceptibility to environmental triggers, and continued apoptosis as seen in chronic inflammation in RA and CD. To test the hypothesis, peripheral leukocytes samples from 132 consented subjects were genotyped for 9 SNPs in PTPN2/22 using TaqMan™ genotyping. The effect of the SNPs on PTPN2/22 and IFN-γ expression was determined using real time PCR. T-cell proliferation and response to phytohematoagglutonin (PHA) mitogen and mycobacterial antigens were determined by BrdU proliferation assay. Blood samples were also analyzed for the Mycobacterium avium subspecies paratuberculosis (MAP) IS900 gene by nPCR. Out of 9 SNPs examined, heterozygous (TC) or minor (CC) alleles of PTPN2:rs478582 occurred in 79% RA compared to 60% healthy controls (p-values ≤ 0.05; OR = 2.28). Similarly, heterozygous (GA) or minor (AA) alleles of PTPN22:rs2476601 occurred in 29% RA compared to 6% healthy controls (p-values ≤ 0.05; OR = 5.90). PTPN2/22 expression in RA was decreased by 1.2-fold compared to healthy controls. PTPN2:rs478582 upregulated IFN-γ in RA by 1.5-fold. Combined PTPN2:rs478582 and PTPN22:rs2476601 increased T-cell proliferation by 2.7-fold when treated with PHA. Surprisingly, MAP DNA was detected in 34% of RA samples compared to 8% healthy controls, (p-values ≤ 0.05, OR = 5.74). RA samples with PTPN2:rs478582 and/or PTPN22:rs2476601 were more positive for MAP than samples without polymorphisms. Combined occurrence of PTPN2:rs478582 and PTPN22:rs2476601 in association with the presence of MAP has significantly increased T-cell response and elevated IFN-γ expression in RA samples. The data suggest that genetic polymorphisms may play vital role in T-cell regulation, susceptibility to mycobacteria and ultimately response to treatment. This is the first study to report the detection of MAP DNA in the blood of RA patients; further studies are needed using larger number of samples. PMID:29423382

IL-17 Receptor Signaling in Oral Epithelial Cells Is Critical for Protection against Oropharyngeal Candidiasis.

PubMed

Conti, Heather R; Bruno, Vincent M; Childs, Erin E; Daugherty, Sean; Hunter, Joseph P; Mengesha, Bemnet G; Saevig, Danielle L; Hendricks, Matthew R; Coleman, Bianca M; Brane, Lucas; Solis, Norma; Cruz, J Agustin; Verma, Akash H; Garg, Abhishek V; Hise, Amy G; Richardson, Jonathan P; Naglik, Julian R; Filler, Scott G; Kolls, Jay K; Sinha, Satrajit; Gaffen, Sarah L

2016-11-09

Signaling through the IL-17 receptor (IL-17R) is required to prevent oropharyngeal candidiasis (OPC) in mice and humans. However, the IL-17-responsive cell type(s) that mediate protection are unknown. Using radiation chimeras, we were able to rule out a requirement for IL-17RA in the hematopoietic compartment. We saw remarkable concordance of IL-17-controlled gene expression in C. albicans-infected human oral epithelial cells (OECs) and in tongue tissue from mice with OPC. To interrogate the role of the IL-17R in OECs, we generated mice with conditional deletion of IL-17RA in superficial oral and esophageal epithelial cells (Il17ra ΔK13 ). Following oral Candida infection, Il17ra ΔK13 mice exhibited fungal loads and weight loss indistinguishable from Il17ra -/- mice. Susceptibility in Il17ra ΔK13 mice correlated with expression of the antimicrobial peptide β-defensin 3 (BD3, Defb3). Consistently, Defb3 -/- mice were susceptible to OPC. Thus, OECs dominantly control IL-17R-dependent responses to OPC through regulation of BD3 expression. Copyright © 2016 Elsevier Inc. All rights reserved.

Uncoupling RARA transcriptional activation and degradation clarifies the bases for APL response to therapies

PubMed Central

Ablain, Julien; Leiva, Magdalena; Peres, Laurent; Fonsart, Julien; Anthony, Elodie

2013-01-01

In PML/RARA-driven acute promyelocytic leukemia (APL), retinoic acid (RA) induces leukemia cell differentiation and transiently clears the disease. Molecularly, RA activates PML/RARA-dependent transcription and also initiates its proteasome-mediated degradation. In contrast, arsenic, the other potent anti-APL therapy, only induces PML/RARA degradation by specifically targeting its PML moiety. The respective contributions of RA-triggered transcriptional activation and proteolysis to clinical response remain disputed. Here, we identify synthetic retinoids that potently activate RARA- or PML/RARA-dependent transcription, but fail to down-regulate RARA or PML/RARA protein levels. Similar to RA, these uncoupled retinoids elicit terminal differentiation, but unexpectedly fail to impair leukemia-initiating activity of PML/RARA-transformed cells ex vivo or in vivo. Accordingly, the survival benefit conferred by uncoupled retinoids in APL mice is dramatically lower than the one provided by RA. Differentiated APL blasts sorted from uncoupled retinoid–treated mice retain PML/RARA expression and reinitiate APL in secondary transplants. Thus, differentiation is insufficient for APL eradication, whereas PML/RARA loss is essential. These observations unify the modes of action of RA and arsenic and shed light on the potency of their combination in mice or patients. PMID:23509325

Uncoupling RARA transcriptional activation and degradation clarifies the bases for APL response to therapies.

PubMed

Ablain, Julien; Leiva, Magdalena; Peres, Laurent; Fonsart, Julien; Anthony, Elodie; de Thé, Hugues

2013-04-08

In PML/RARA-driven acute promyelocytic leukemia (APL), retinoic acid (RA) induces leukemia cell differentiation and transiently clears the disease. Molecularly, RA activates PML/RARA-dependent transcription and also initiates its proteasome-mediated degradation. In contrast, arsenic, the other potent anti-APL therapy, only induces PML/RARA degradation by specifically targeting its PML moiety. The respective contributions of RA-triggered transcriptional activation and proteolysis to clinical response remain disputed. Here, we identify synthetic retinoids that potently activate RARA- or PML/RARA-dependent transcription, but fail to down-regulate RARA or PML/RARA protein levels. Similar to RA, these uncoupled retinoids elicit terminal differentiation, but unexpectedly fail to impair leukemia-initiating activity of PML/RARA-transformed cells ex vivo or in vivo. Accordingly, the survival benefit conferred by uncoupled retinoids in APL mice is dramatically lower than the one provided by RA. Differentiated APL blasts sorted from uncoupled retinoid-treated mice retain PML/RARA expression and reinitiate APL in secondary transplants. Thus, differentiation is insufficient for APL eradication, whereas PML/RARA loss is essential. These observations unify the modes of action of RA and arsenic and shed light on the potency of their combination in mice or patients.

Blood autoantibody and cytokine profiles predict response to anti-tumor necrosis factor therapy in rheumatoid arthritis

PubMed Central

Hueber, Wolfgang; Tomooka, Beren H; Batliwalla, Franak; Li, Wentian; Monach, Paul A; Tibshirani, Robert J; Van Vollenhoven, Ronald F; Lampa, Jon; Saito, Kazuyoshi; Tanaka, Yoshiya; Genovese, Mark C; Klareskog, Lars; Gregersen, Peter K; Robinson, William H

2009-01-01

Introduction Anti-TNF therapies have revolutionized the treatment of rheumatoid arthritis (RA), a common systemic autoimmune disease involving destruction of the synovial joints. However, in the practice of rheumatology approximately one-third of patients demonstrate no clinical improvement in response to treatment with anti-TNF therapies, while another third demonstrate a partial response, and one-third an excellent and sustained response. Since no clinical or laboratory tests are available to predict response to anti-TNF therapies, great need exists for predictive biomarkers. Methods Here we present a multi-step proteomics approach using arthritis antigen arrays, a multiplex cytokine assay, and conventional ELISA, with the objective to identify a biomarker signature in three ethnically diverse cohorts of RA patients treated with the anti-TNF therapy etanercept. Results We identified a 24-biomarker signature that enabled prediction of a positive clinical response to etanercept in all three cohorts (positive predictive values 58 to 72%; negative predictive values 63 to 78%). Conclusions We identified a multi-parameter protein biomarker that enables pretreatment classification and prediction of etanercept responders, and tested this biomarker using three independent cohorts of RA patients. Although further validation in prospective and larger cohorts is needed, our observations demonstrate that multiplex characterization of autoantibodies and cytokines provides clinical utility for predicting response to the anti-TNF therapy etanercept in RA patients. PMID:19460157

Genetic polymorphisms of enzyme proteins and transporters related to methotrexate response and pharmacokinetics in a Japanese population.

PubMed

Hashiguchi, Masayuki; Shimizu, Mikiko; Hakamata, Jun; Tsuru, Tomomi; Tanaka, Takanori; Suzaki, Midori; Miyawaki, Kumika; Chiyoda, Takeshi; Takeuchi, Osamu; Hiratsuka, Jiro; Irie, Shin; Maruyama, Junya; Mochizuki, Mayumi

2016-01-01

Methotrexate (MTX) is currently the anchor drug widely used worldwide in the treatment of rheumatoid arthritis (RA). However, the therapeutic response to MTX has been shown to vary widely among individuals, genders and ethnic groups. The reason for this has been not clarified but it is considered to be partially due to several mechanisms in the cellular pathway of MTX including single-nucleotide polymorphisms (SNPs). The purpose of this study was to investigate the allelic frequencies in different ethnic and/or population groups in the 10 polymorphisms of enzyme proteins and transporters related to the MTX response and pharmacokinetics including MTHFR, TYMS, RFC1, FPGS, GGH, ABCB1, ABCC2 and ABCG2 in unrelated healthy Japanese adults and patients with RA. Ten polymorphisms, methylenetetrahydrofolate reductase (MTHFR) 1298, thymidylate synthase (TYMS) 3'-UTR, reduced folate carrier 1 (RFC1) 80 and-43, folypolyglutamyl synthase (FPGS) 1994, γ-glutamyl hydrolase (GGH) 452 and-401, the ABC transporters (ABCB1 3435, ABCC2 IVS23 + 56, ABCG2 914) of enzyme proteins and transporters related to MTX response and pharmacokinetics in 299 unrelated healthy Japanese adults and 159 Japanese patients with RA were investigated to clarify their contributions to individual variations in response and safety to MTX and establish personalized MTX therapy. SNPs were evaluated using real-time polymerase chain reaction (PCR). Comparison of allelic frequencies in our study with other ethnic/population groups of healthy adults and RA patients showed significant differences in 10 polymorphisms among healthy adults and 7 among RA patients. Allelic frequencies of MTHFR 1298 C, FPGS 1994A and ABCB1 3435 T were lower in Japanese than in Caucasian populations and those of ABCC2 IVS23 + 56 C and ABCG2 914A were higher in Japanese than in Caucasian/European populations in both healthy adults and RA patients. Allelic frequencies of MTHFR 1298 C, GGH-401 T, ABCB1 3435 T, and ABCG2 914A were higher in healthy Japanese adults than in an African population, and those of RFC1 80A, RFC1-43C and ABCC2 IVS23 + 56 C in healthy Japanese adults were lower than in Africans. However, no significant differences were seen in the distribution of allelic frequencies between healthy Japanese adults and RA patients. The variations in allelic frequencies in different ethnic and/or population groups in healthy adults and RA patients may contribute to individual variations in MTX response and toxicity.

Thiamin

MedlinePlus

... 23193625 . Mason JB. Vitamins, trace minerals, and other micronutrients. In: Goldman L, Schafer AI, eds. Goldman-Cecil ... Saunders; 2016:chap 218. Salwen MJ. Vitamins and trace elements. In: McPherson RA, Pincus MR, eds. Henry's Clinical ...

Riboflavin

MedlinePlus

... 23193625 . Mason JB. Vitamins, trace minerals, and other micronutrients. In: Goldman L, Schafer AI, eds. Goldman-Cecil ... Saunders; 2016:chap 218. Salwen MJ. Vitamins and trace elements. In: McPherson RA, Pincus MR, eds. Henry's Clinical ...

Niacin

MedlinePlus

... 23193625 . Mason JB. Vitamins, trace minerals, and other micronutrients. In: Goldman L, Schafer AI, eds. Goldman-Cecil ... Saunders; 2016:chap 218. Salwen MJ. Vitamins and trace elements. In: McPherson RA, Pincus MR, eds. Henry's Clinical ...

238U sbnd 230Th sbnd 226Ra disequilibria in young Mount St. Helens rocks: time constraint for magma formation and crystallization

NASA Astrophysics Data System (ADS)

Volpe, Alan M.; Hammond, Paul E.

1991-12-01

We use 238U-series nuclides and 230Th/ 232Th ratios measured by mass spectrometry to constrain processes and time scales of calc-alkaline magma genesis at Mount St. Helens, Washington. Olivine basalt, pyroxene andesites and dacites that erupted 10-2 ka ago show 3-14% ( 230Th) sbnd ( 238U) and 6-54% 226Ra sbnd 230Th disequilibria. Mineral phases exhibit robust ( 226Ra) sbnd ( 230Th) fractionation. Plagioclase has large 65-280% ( 226Ra) excesses, and magnetite has large 65% ( 226Ra) deficits relative to ( 230Th). Calculated partition coefficients for Ba, Th, and U in mineral-groundmass pairs, except Ba in plagioclase, are low (⩽ 0.04). Correlation between ( 226Ra/ 230Th ) activity ratios and rm/BaTh element ratios in the minerals suggests that 226Ra partitions similar to Ba during crystallization. Internal ( 230Th) sbnd ( 238U) isochrons for 1982 summit and East Dome dacites and Goat Rocks and Kalama andesites show that closed Th sbnd U system fractionation occurred 2-6 ka ago. Apparent internal isochrons for Castle Creek basalt (34 ka) and andesite (27 ka) suggest longer magma chamber residence times and mixing of old crystals and young melt. Mineral ( 226Ra) sbnd ( 230Th) disequilibrium on Ba-normalized internal isochron diagrams suggests average magma chamber residence times of 500-3000 years. In addition, radioactive ( 226Ra/ 230Th ) heterogeneity between minerals and groundmass or whole rock is evidence for open-system Ra sbnd Th behavior. This heterogeneity suggests there has been recent, post-crystallization, changes in melt chemical composition that affected 226Ra more than 230Th. Clearly, magma fractionation, residence and transport of crystal-melt before eruption of chemically diverse lavas at Mount St. Helens occurs over geologically short periods.

Visible-IR and Raman microspectroscopic investigation of three Itokawa particles collected by Hayabusa: Mineralogy and degree of space weathering based on nondestructive analyses

NASA Astrophysics Data System (ADS)

Bonal, L.; Brunetto, R.; Beck, P.; Dartois, E.; Dionnet, Z.; Djouadi, Z.; Duprat, J.; Füri, E.; Kakazu, Y.; Montagnac, G.; Oudayer, P.; Quirico, E.; Engrand, C.

2015-09-01

Hayabusa-returned samples offer a unique perspective for understanding the link between asteroids and cosmomaterials available in the laboratory, and provide insights on the early stages of surface space weathering. This study characterizes the mineralogy and the extent of space weathering of the three Itokawa particles RA-QD02-0163, RA-QD02-0174, and RA-QD02-0213 provided by JAXA to our consortium. We report here a series of results based on nondestructive analyses through visible-near-infrared reflectance and Raman spectroscopy. Results were obtained on the raw particles, both in their original containers and deposited on diamond windows. Identification of the minerals, characterization of their elemental compositions, and measurements of their relative abundances were led through Raman spectroscopy in punctual and automatic mode. Reflectance spectra in the visible and near-IR wavelengths constrain the mineralogy of the grains and allow direct comparison with the surface of Itokawa. The spectra reflect the extent of space weathering experienced by the three particles. Particle RA-QD02-0163 consists of a heterogeneous mixture of minerals: olivine (Fo76) dominates an assemblage with both Ca-rich (En50, Wo50) and Ca-poor (En85) pyroxenes. The elemental compositions of the silicates are consistent with those previously reported for distinct Hayabusa particles. Particles RA-QD-0174 and RA-QD02-0213 are solely composed of olivine, whose chemical composition is similar to that observed in RA-QD02-0163. It has been previously shown that the S-type asteroid 25143 Itokawa is a breccia of poorly equilibrated LL4 and highly equilibrated LL5 and LL6 materials. The three particles studied here can be related to the least metamorphosed lithology (LL4) based on the high forsterite content of the olivine. Neither carbonaceous matter nor hydrated minerals were detected through Raman on the three allocated particles. The NIR-VIS reflectance (incidence = 45°, light collection at e = 0°) spectra of the three particles, in particular the 1 μm band, are consistent with the presence of both olivine and pyroxene detected via Raman. The spectra of particles RA-QD02-0163 and RA-QD02-0213 are also fully compatible with the ground-based observations of asteroid (25143) Itokawa in terms of both spectral features and slope. By contrast, particle RA-QD02-0174 has a similar 1 μm band depth but higher (redder) spectral slope than the surface of Itokawa. This probably reveals a variable extent of space weathering among the regolith particles. RA-QD02-0174 may contain a higher amount of nanophase metallic iron and nanophase FeS. Such phases are products by space weathering induced by solar wind, previously detected on other Itokawa particles.

Gene expression analysis in RA: towards personalized medicine

PubMed Central

Burska, A N; Roget, K; Blits, M; Soto Gomez, L; van de Loo, F; Hazelwood, L D; Verweij, C L; Rowe, A; Goulielmos, G N; van Baarsen, L G M; Ponchel, F

2014-01-01

Gene expression has recently been at the forefront of advance in personalized medicine, notably in the field of cancer and transplantation, providing a rational for a similar approach in rheumatoid arthritis (RA). RA is a prototypic inflammatory autoimmune disease with a poorly understood etiopathogenesis. Inflammation is the main feature of RA; however, many biological processes are involved at different stages of the disease. Gene expression signatures offer management tools to meet the current needs for personalization of RA patient's care. This review analyses currently available information with respect to RA diagnostic, prognostic and prediction of response to therapy with a view to highlight the abundance of data, whose comparison is often inconclusive due to the mixed use of material source, experimental methodologies and analysis tools, reinforcing the need for harmonization if gene expression signatures are to become a useful clinical tool in personalized medicine for RA patients. PMID:24589910

Emerging role of leptin in rheumatoid arthritis

PubMed Central

Tian, G; Liang, J-N; Wang, Z-Y; Zhou, D

2014-01-01

Numerous studies have suggested the importance of leptin against autoimmune diseases such as systemic lupus erythematosus (SLE), multiple sclerosis (MS) and psoriasis. To summarize our current understanding of the role of leptin in inflammatory responses and rheumatoid arthritis (RA), a systematic review was conducted to assess the discrepancy of leptin in RA and its effect on immunity according to different studies. Recently, emerging data have indicated that leptin is involved in the pathological function of RA, which is common in autoimmune disorders. This review discusses the possible consequences of leptin levels in RA. Blocking the key signal pathways of leptin and inhibiting the leptin activity-like leptin antagonist may be a promising way for potential therapeutic treatment of RA at risk of detrimental effects. However, leptin was increased in patients with RA and may also regulate joint damage. Thus, more understanding of the mechanism of leptin in RA would be advantageous in the future. PMID:24802245

Effects of in utero retinoic acid exposure on mouse pelage hair follicle development.

PubMed

García-Fernández, Rosa A; Pérez-Martínez, Claudia; Escudero-Diez, Alfredo; García-Iglesias, Maria J

2002-06-01

We investigated in vivo the histological and immunohistochemical responses of mouse hair pelage follicle morphogenesis to prenatal exposure to a potentially nonteratogenic dose of all-trans-retinoic acid (RA), as a basis studying the preventive effect of RA on adult mouse skin carcinogenesis. In pregnant mice, a single oral dose of RA at 30 mg kg-1 body weight given on day 11.5 of gestation caused no RA-induced changes in the morphology or temporal expression patterns of keratins during pelage hair follicle morphogenesis. The only differential effect of RA was a statistically significant increase in the number of BrdU-positive nuclei in hair bulbs from RA exposed fetuses compared with nonexposed mice. The absence of adverse RA effects suggests that this experimental design may represent a valuable protocol for use in studies on the in vivo effects of this retinoid on different skin diseases.

Immature blood vessels in rheumatoid synovium are selectively depleted in response to anti-TNF therapy.

PubMed

Izquierdo, Elena; Cañete, Juan D; Celis, Raquel; Santiago, Begoña; Usategui, Alicia; Sanmartí, Raimon; Del Rey, Manuel J; Pablos, José L

2009-12-02

Angiogenesis is considered an important factor in the pathogenesis of Rheumatoid Arthritis (RA) where it has been proposed as a therapeutic target. In other settings, active angiogenesis is characterized by pathologic, immature vessels that lack periendothelial cells. We searched for the presence of immature vessels in RA synovium and analyzed the dynamics of synovial vasculature along the course of the disease, particularly after therapeutic response to TNF antagonists. Synovial arthroscopic biopsies from RA, osteoarthritis (OA) and normal controls were analyzed by double labeling of endothelium and pericytes/smooth muscle mural cells to identify and quantify mature/immature blood vessels. To analyze clinicopathological correlations, a cross-sectional study on 82 synovial biopsies from RA patients with variable disease duration and severity was performed. A longitudinal analysis was performed in 25 patients with active disease rebiopsied after anti-TNF-alpha therapy. We found that most RA synovial tissues contained a significant fraction of immature blood vessels lacking periendothelial coverage, whereas they were rare in OA, and inexistent in normal synovial tissues. Immature vessels were observed from the earliest phases of the disease but their presence or density was significantly increased in patients with longer disease duration, higher activity and severity, and stronger inflammatory cell infiltration. In patients that responded to anti-TNF-alpha therapy, immature vessels were selectively depleted. The mature vasculature was similarly expanded in early or late disease and unchanged by therapy. RA synovium contains a significant fraction of neoangiogenic, immature blood vessels. Progression of the disease increases the presence and density of immature but not mature vessels and only immature vessels are depleted in response to anti-TNFalpha therapy. The different dynamics of the mature and immature vascular fractions has important implications for the development of anti-angiogenic interventions in RA.

Rheumatoid arthritis patient perceptions on the value of predictive testing for treatments: a qualitative study.

PubMed

Kumar, Kanta; Peters, Sarah; Barton, Anne

2016-11-08

Rheumatoid arthritis (RA) is a long term condition that requires early treatment to control symptoms and improve long-term outcomes. Lack of response to RA treatments is not only a waste of healthcare resources, but also causes disability and distress to patients. Identifying biomarkers predictive of treatment response offers an opportunity to improve clinical decisions about which treatment to recommend in patients and could ultimately lead to better patient outcomes. The aim of this study was to explore the understanding of and factors affecting Rheumatoid Arthritis (RA) patients' decisions around predictive treatment testing. A qualitative study was conducted with a purposive sample of 16 patients with RA from three major UK cities. Four focus groups explored patient perceptions of the use of biomarker tests to predict response to treatments. Interviews were audio-recorded, transcribed verbatim and analysed using thematic analysis by three researchers. Data were organised within three interlinking themes: [1] Perceptions of predictive tests and patient preference of tests; [2] Utility of the test to manage expectations; [3] The influence of the disease duration on take up of predictive testing. During consultations for predictive testing, patients felt they would need, first, careful explanations detailing the consequences of untreated RA and delayed treatment response and, second, support to balance the risks of tests, which might be invasive and/or only moderately accurate, with the potential benefits of better management of symptoms. This study provides important insights into predictive testing. Besides supporting clinical decision making, the development of predictive testing in RA is largely supported by patients. Developing strategies which communicate risk information about predictive testing effectively while reducing the psychological burden associated with this information will be essential to maximise uptake.

TH1/TH2 cytokine profile, metalloprotease-9 activity and hormonal status in pregnant rheumatoid arthritis and systemic lupus erythematosus patients

PubMed Central

MUÑOZ-VALLE, J F; VÁZQUEZ-DEL MERCADO, M; GARCÍA-IGLESIAS, T; OROZCO-BAROCIO, G; BERNARD-MEDINA, G; MARTÍNEZ-BONILLA, G; BASTIDAS-RAMÍREZ, B E; NAVARRO, A D; BUENO, M; MARTÍNEZ-LÓPEZ, E; BEST-AGUILERA, C R; KAMACHI, M; ARMENDÁRIZ-BORUNDA, J

2003-01-01

During the course of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), several immune and neuroendocrine changes associated with pregnancy may exert positive (amelioration) or negative (exacerbation) effects on the clinical outcome. In order to shed light on the mechanisms underlying these responses, we performed a prospective longitudinal study in RA and SLE pregnant women, including healthy pregnant women as a control group. Cytokine messenger RNA (mRNA) expression assessed by quantitative competitive polymerase chain reaction (PCR) in peripheral blood mononuclear cells (PBMC), cytokine levels and lymphocyte proliferation responses (LPR) following phytohaemagglutinin (PHA) stimulation of PBMC, plasma metalloprotease-9 activity (MMP-9) and hormonal status during pregnancy were determined. TNFa was the most abundant cytokine mRNA expressed in PBMC in all groups studied (healthy pregnant women, RA and SLE pregnant patients). However, a general TH2 response reflected by high IL-10 levels was found in RA, as well as SLE, patients. A significant change in IFN-γ was observed in RA patients but only during the first trimester of pregnancy. This compared with a major TH1 response in healthy pregnant women. Interestingly, our study showed a homogeneous hormonal pattern in RA and SLE patients. Although decreased cortisol levels were observed in all patients studied, this is possibly related to the remission of disease activity status brought about by steroid treatment before and during pregnancy. In summary, we suggest that complex immune and hormonal networks are involved in pregnancy and that rheumatic diseases are very dynamic immune processes that cannot be described with a clear-cut cytokine profile. Furthermore, the observations in this study may reflect treatment-related immune effects more than those associated with disease. PMID:12562402

Autoimmune-autoinflammatory rheumatoid arthritis overlaps: a rare but potentially important subgroup of diseases

PubMed Central

Savic, Sinisa; Mistry, Anoop; Wilson, Anthony G; Barcenas-Morales, Gabriela; Doffinger, Rainer; Emery, Paul; McGonagle, Dennis

2017-01-01

At the population level, rheumatoid arthritis (RA) is generally viewed as autoimmune in nature with a small subgroup of cases having a palindromic form or systemic autoinflammatory disorder (SAID) phenotype. Herein, we describe resistant cases of classical autoantibody associated RA that had clinical, genetic and therapeutic responses indicative of coexistent autoinflammatory disease. Five patients with clinically overlapping features between RA and SAID including polysynovitis and autoantibody/shared epitope positivity, and who had abrupt severe self-limiting attacks including fevers and serositis, are described. Mutations or single nucleotide polymorphisms in recognised autoinflammatory pathways were evident. Generally, these cases responded poorly to conventional Disease-modifying anti-rheumatic drugs (DMARD) treatment with some excellent responses to colchicine or interleukin 1 pathway blockade. A subgroup of RA cases have a mixed autoimmune-autoinflammatory phenotype and genotype with therapeutic implications. PMID:29177082

Autoimmune-autoinflammatory rheumatoid arthritis overlaps: a rare but potentially important subgroup of diseases.

PubMed

Savic, Sinisa; Mistry, Anoop; Wilson, Anthony G; Barcenas-Morales, Gabriela; Doffinger, Rainer; Emery, Paul; McGonagle, Dennis

2017-01-01

At the population level, rheumatoid arthritis (RA) is generally viewed as autoimmune in nature with a small subgroup of cases having a palindromic form or systemic autoinflammatory disorder (SAID) phenotype. Herein, we describe resistant cases of classical autoantibody associated RA that had clinical, genetic and therapeutic responses indicative of coexistent autoinflammatory disease. Five patients with clinically overlapping features between RA and SAID including polysynovitis and autoantibody/shared epitope positivity, and who had abrupt severe self-limiting attacks including fevers and serositis, are described. Mutations or single nucleotide polymorphisms in recognised autoinflammatory pathways were evident. Generally, these cases responded poorly to conventional Disease-modifying anti-rheumatic drugs (DMARD) treatment with some excellent responses to colchicine or interleukin 1 pathway blockade. A subgroup of RA cases have a mixed autoimmune-autoinflammatory phenotype and genotype with therapeutic implications.

Interleukin-17 receptor A (IL-17RA) as a central regulator of the protective immune response against Giardia.

PubMed

Paerewijck, Oonagh; Maertens, Brecht; Dreesen, Leentje; Van Meulder, Frederik; Peelaers, Iris; Ratman, Dariusz; Li, Robert W; Lubberts, Erik; De Bosscher, Karolien; Geldhof, Peter

2017-08-17

The protozoan parasite Giardia is a highly prevalent intestinal pathogen with a wide host range. Data obtained in mice, cattle and humans revealed the importance of IL-17A in the development of a protective immune response against Giardia. The aim of this study was to further unravel the protective effector mechanisms triggered by IL-17A following G. muris infection in mice, by an RNA-sequencing approach. C57BL/6 WT and C57BL/6 IL-17RA KO mice were orally infected with G. muris cysts. Three weeks post infection, intestinal tissue samples were collected for RNA-sequencing, with samples from uninfected C57BL/6 WT and C57BL/6 IL-17RA KO animals serving as negative controls. Differential expression analysis showed that G. muris infection evoked the transcriptional upregulation of a wide array of genes, mainly in animals with competent IL-17RA signaling. IL-17RA signaling induced the production of various antimicrobial peptides, such as angiogenin 4 and α- and β-defensins and regulated complement activation through mannose-binding lectin 2. The expression of the receptor that regulates the secretion of IgA into the intestinal lumen, the polymeric immunoglobulin receptor, was also dependent on IL-17RA signaling. Interestingly, the transcriptome data showed for the first time the involvement of the circadian clock in the host response following Giardia infection.

Identification of genes modulated in rheumatoid arthritis using complementary DNA microarray analysis of lymphoblastoid B cell lines from disease-discordant monozygotic twins.

PubMed

Haas, Christian S; Creighton, Chad J; Pi, Xiujun; Maine, Ira; Koch, Alisa E; Haines, G Kenneth; Ling, Song; Chinnaiyan, Arul M; Holoshitz, Joseph

2006-07-01

To identify disease-specific gene expression profiles in patients with rheumatoid arthritis (RA), using complementary DNA (cDNA) microarray analyses on lymphoblastoid B cell lines (LCLs) derived from RA-discordant monozygotic (MZ) twins. The cDNA was prepared from LCLs derived from the peripheral blood of 11 pairs of RA-discordant MZ twins. The RA twin cDNA was labeled with cy5 fluorescent dye, and the cDNA of the healthy co-twin was labeled with cy3. To determine relative expression profiles, cDNA from each twin pair was combined and hybridized on 20,000-element microarray chips. Immunohistochemistry and real-time polymerase chain reaction were used to detect the expression of selected gene products in synovial tissue from patients with RA compared with patients with osteoarthritis and normal healthy controls. In RA twin LCLs compared with healthy co-twin LCLs, 1,163 transcripts were significantly differentially expressed. Of these, 747 were overexpressed and 416 were underexpressed. Gene ontology analysis revealed many genes known to play a role in apoptosis, angiogenesis, proteolysis, and signaling. The 3 most significantly overexpressed genes were laeverin (a novel enzyme with sequence homology to CD13), 11beta-hydroxysteroid dehydrogenase type 2 (a steroid pathway enzyme), and cysteine-rich, angiogenic inducer 61 (a known angiogenic factor). The products of these genes, heretofore uncharacterized in RA, were all abundantly expressed in RA synovial tissues. Microarray cDNA analysis of peripheral blood-derived LCLs from well-controlled patient populations is a useful tool to detect RA-relevant genes and could help in identifying novel therapeutic targets.

Ethanol impairs activation of retinoic acid receptors in cerebellar granule cells in a rodent model of fetal alcohol spectrum disorders.

PubMed

Kumar, Ambrish; Singh, Chandra K; DiPette, Donald D; Singh, Ugra S

2010-05-01

Ethanol is the main addictive and neurotoxic constituent of alcohol. Ethanol exposure during embryonic development causes dysfunction of the central nervous system (CNS) and leads to fetal alcohol spectrum disorders. The cerebellum is one of the CNS regions that are particularly vulnerable to ethanol toxic effects. Retinoic acid (RA) is a physiologically active metabolite of vitamin A that is locally synthesized in the cerebellum. Studies have shown that RA is required for neuronal development, but it remains unknown if ethanol impairs RA signaling and thus induces neuronal malformations. In this study, we tested the hypothesis that ethanol impairs the expression and activation of RA receptors in cerebellum and in cerebellar granule cells. The cerebellum of ethanol unexposed and exposed pups was used to study the expression of retinoic acid receptors (RARs or RXRs) by immunohistochemistry and by Western blot analysis. We also studied the effect of ethanol on expression of RA receptors in the cerebellar granule cells. Activation of RA receptors (DNA-binding activities) in response to high-dose ethanol was determined by electrophoretic mobility shift and supershift assays. Findings from these studies demonstrated that ethanol exposure reduced the expression of RARalpha/gamma while it increased the expression of RXRalpha/gamma in the cerebellum and in cerebellar granule neurons. Immuno-histological studies further strengthened the expression pattern of RA receptors in response to ethanol. The DNA-binding activity of RARs was reduced, while DNA-binding activity of RXRs was increased in response to ethanol exposure. For the first time, our studies have demonstrated that high-dose ethanol affects the expression and activation of RA receptors, which could impair the signaling events and induce harmful effects on the survival and differentiation of cerebellar granule cells. Taken together, these findings could provide insight into the treatment options for brain defects caused by excessive ethanol exposure, such as in Fetal Alcohol Spectrum Disorders.

Vitamin D

MedlinePlus

... 25419853 . Mason JB. Vitamins, trace minerals, and other micronutrients. In: Goldman L, Schafer AI, eds. Goldman-Cecil ... Accessed May 5, 2017. Salwen MJ. Vitamins and trace elements. In: McPherson RA, Pincus MR, eds. Henry's Clinical ...

Vitamin K

MedlinePlus

... 25057538 . Mason JB. Vitamins, trace minerals, and other micronutrients. In: Goldman L, Schafer AI, eds. Goldman-Cecil ... Saunders; 2016:chap 218. Salwen MJ. Vitamins and trace elements. In: McPherson RA, Pincus MR, eds. Henry's Clinical ...

Vitamin E

MedlinePlus

... 25077263 . Mason JB. Vitamins, trace minerals, and other micronutrients. In: Goldman L, Schafer AI, eds. Goldman-Cecil ... Saunders; 2016:chap 218. Salwen MJ. Vitamins and trace elements. In: McPherson RA, Pincus MR, eds. Henry's Clinical ...

Retinoic acid prevents immunogenicity of milk lipocalin Bos d 5 through binding to its immunodominant T-cell epitope.

PubMed

Hufnagl, Karin; Ghosh, Debajyoti; Wagner, Stefanie; Fiocchi, Alessandro; Dahdah, Lamia; Bianchini, Rodolfo; Braun, Nina; Steinborn, Ralf; Hofer, Martin; Blaschitz, Marion; Roth, Georg A; Hofstetter, Gerlinde; Roth-Walter, Franziska; Pacios, Luis F; Jensen-Jarolim, Erika

2018-01-25

The major cow's milk allergen Bos d 5 belongs to the lipocalin protein family, with an intramolecular pocket for hydrophobic ligands. We investigated whether Bos d 5 when loaded with the active vitamin A metabolite retinoic acid (RA), would elicit differential immune responses compared to the unloaded state. By in silico docking an affinity energy of -7.8 kcal/mol was calculated for RA into Bos d 5. Loading of RA to Bos d 5 could be achieved in vitro, as demonstrated by ANS displacement assay, but had no effect on serum IgE binding in tolerant or challenge-positive milk allergic children. Bioinformatic analysis revealed that RA binds to the immunodominant T-cell epitope region of Bos d 5. In accordance, Bos d 5 significantly suppressed the CD3+ CD4+ cell numbers, proliferative response and IL-10, IL-13 and IFN-γ secretion from stimulated human PBMCs only when complexed with RA. This phenomenon was neither associated with apoptosis of T-cells nor with the activation of Foxp3+ T-cells, but correlated likely with enhanced stability to lysosomal digestion due to a predicted overlap of Cathepsin S cleavage sites with the RA binding site. Taken together, proper loading of Bos d 5 with RA may suppress its immunogenicity and prevent its allergenicity.

Does physiological acclimation to climate warming stabilize the ratio of canopy respiration to photosynthesis?

PubMed

Drake, John E; Tjoelker, Mark G; Aspinwall, Michael J; Reich, Peter B; Barton, Craig V M; Medlyn, Belinda E; Duursma, Remko A

2016-08-01

Given the contrasting short-term temperature dependences of gross primary production (GPP) and autotrophic respiration, the fraction of GPP respired by trees is predicted to increase with warming, providing a positive feedback to climate change. However, physiological acclimation may dampen or eliminate this response. We measured the fluxes of aboveground respiration (Ra ), GPP and their ratio (Ra /GPP) in large, field-grown Eucalyptus tereticornis trees exposed to ambient or warmed air temperatures (+3°C). We report continuous measurements of whole-canopy CO2 exchange, direct temperature response curves of leaf and canopy respiration, leaf and branch wood respiration, and diurnal photosynthetic measurements. Warming reduced photosynthesis, whereas physiological acclimation prevented a coincident increase in Ra . Ambient and warmed trees had a common nonlinear relationship between the fraction of GPP that was respired above ground (Ra /GPP) and the mean daily temperature. Thus, warming significantly increased Ra /GPP by moving plants to higher positions on the shared Ra /GPP vs daily temperature relationship, but this effect was modest and only notable during hot conditions. Despite the physiological acclimation of autotrophic respiration to warming, increases in temperature and the frequency of heat waves may modestly increase tree Ra /GPP, contributing to a positive feedback between climate warming and atmospheric CO2 accumulation. © 2016 The Authors. New Phytologist © 2016 New Phytologist Trust.

The Crosstalk of Pathways Involved in Immune Response Maybe the Shared Molecular Basis of Rheumatoid Arthritis and Type 2 Diabetes

PubMed Central

Ge, Na; Jiang, Miao; Li, Li; Bian, Yanqin; Xu, Gang; Bian, Zhaoxiang; Zhang, Ge; Lu, Aiping

2015-01-01

Rheumatoid arthritis (RA) and Type 2 diabetes (T2D) are both systemic diseases linked with altered immune response, moderate mortality when present together. The treatment for both RA and T2D are not satisfied, partly because of the linkage between them has not yet been appreciated. A comprehensive study for the potential associations between the two disorders is needed. In this study, we used RNA sequencing to explore the differently expressed genes (DEGs) in peripheral blood mononuclear cells (PBMC) of 10 RA and 10 T2D patients comparing with 10 healthy volunteers (control). We used bioinformatics analysis and the Ingenuity Pathways Analysis (IPA) to predict the commonalities on signaling pathways and molecular networks between those two diseases. 212 DEGs in RA and 114 DEGs in T2D patients were identified compared with healthy controls, respectively. 32 DEGs were shared between the two comparisons. The top 10 shared pathways interacted in cross-talking networks, regulated by 5 shared predicted upstream regulators, leading to the activated immune response were explored, which was considered as partly of the association mechanism of this two disorders. These discoveries would be considered as new understanding on the associations between RA and T2D, and provide novel treatment or prevention strategy. PMID:26252209

Proximity to traffic, ambient air pollution, and community noise in relation to incident rheumatoid arthritis.

PubMed

De Roos, Anneclaire J; Koehoorn, Mieke; Tamburic, Lillian; Davies, Hugh W; Brauer, Michael

2014-10-01

The risk of rheumatoid arthritis (RA) has been associated with living near traffic; however, there is evidence suggesting that air pollution may not be responsible for this association. Noise, another traffic-generated exposure, has not been studied as a risk factor for RA. We investigated proximity to traffic, ambient air pollution, and community noise in relation to RA in the Vancouver and Victoria regions of British Columbia, Canada. Cases and controls were identified in a cohort of adults that was assembled using health insurance registration records. Incident RA cases from 1999 through 2002 were identified by diagnostic codes in combination with prescriptions and type of physician (e.g., rheumatologist). Controls were matched to RA cases by age and sex. Environmental exposures were assigned to each member of the study population by their residential postal code(s). We estimated relative risks using conditional logistic regression, with additional adjustment for median income at the postal code. RA incidence was increased with proximity to traffic, with an odds ratio (OR) of 1.37 (95% CI: 1.11, 1.68) for residence ≤ 50 m from a highway compared with residence > 150 m away. We found no association with traffic-related exposures such as PM2.5, nitrogen oxides, or noise. Ground-level ozone, which was highest in suburban areas, was associated with an increased risk of RA (OR = 1.26; 95% CI: 1.18, 1.36 per interquartile range increase). Our study confirms a previously observed association of RA risk with proximity to traffic and suggests that neither noise levels nor traffic-related air pollutants are responsible for this relationship. Additional investigation of neighborhood and individual correlates of residence near roadways may provide new insight into risk factors for RA.

Transcriptional Profiling of Synovial Macrophages Using Minimally Invasive Ultrasound-Guided Synovial Biopsies in Rheumatoid Arthritis.

PubMed

Mandelin, Arthur M; Homan, Philip J; Shaffer, Alexander M; Cuda, Carla M; Dominguez, Salina T; Bacalao, Emily; Carns, Mary; Hinchcliff, Monique; Lee, Jungwha; Aren, Kathleen; Thakrar, Anjali; Montgomery, Anna B; Bridges, S Louis; Bathon, Joan M; Atkinson, John P; Fox, David A; Matteson, Eric L; Buckley, Christopher D; Pitzalis, Costantino; Parks, Deborah; Hughes, Laura B; Geraldino-Pardilla, Laura; Ike, Robert; Phillips, Kristine; Wright, Kerry; Filer, Andrew; Kelly, Stephen; Ruderman, Eric M; Morgan, Vince; Abdala-Valencia, Hiam; Misharin, Alexander V; Budinger, G Scott; Bartom, Elizabeth T; Pope, Richard M; Perlman, Harris; Winter, Deborah R

2018-06-01

Currently, there are no reliable biomarkers for predicting therapeutic response in patients with rheumatoid arthritis (RA). The synovium may unlock critical information for determining efficacy, since a reduction in the numbers of sublining synovial macrophages remains the most reproducible biomarker. Thus, a clinically actionable method for the collection of synovial tissue, which can be analyzed using high-throughput strategies, must become a reality. This study was undertaken to assess the feasibility of utilizing synovial biopsies as a precision medicine-based approach for patients with RA. Rheumatologists at 6 US academic sites were trained in minimally invasive ultrasound-guided synovial tissue biopsy. Biopsy specimens obtained from patients with RA and synovial tissue from patients with osteoarthritis (OA) were subjected to histologic analysis, fluorescence-activated cell sorting, and RNA sequencing (RNA-seq). An optimized protocol for digesting synovial tissue was developed to generate high-quality RNA-seq libraries from isolated macrophage populations. Associations were determined between macrophage transcriptional profiles and clinical parameters in RA patients. Patients with RA reported minimal adverse effects in response to synovial biopsy. Comparable RNA quality was observed from synovial tissue and isolated macrophages between patients with RA and patients with OA. Whole tissue samples from patients with RA demonstrated a high degree of transcriptional heterogeneity. In contrast, the transcriptional profile of isolated RA synovial macrophages highlighted different subpopulations of patients and identified 6 novel transcriptional modules that were associated with disease activity and therapy. Performance of synovial tissue biopsies by rheumatologists in the US is feasible and generates high-quality samples for research. Through the use of cutting-edge technologies to analyze synovial biopsy specimens in conjunction with corresponding clinical information, a precision medicine-based approach for patients with RA is attainable. © 2018, American College of Rheumatology.

Muscle ultrastructural changes from exhaustive exercise performed after prolonged restricted activity and retraining in dogs

NASA Technical Reports Server (NTRS)

Nazar, K.; Greenleaf, J. E.; Philpott, D.; Pohoska, E.; Olszewska, K.; Kaciuba-Uscilko, H.

1991-01-01

The effect of exhaustive treadmill exercise on ultrastructural changes in the quadriceps femoris muscle was studied in 7 normal, healthy dogs, before and after restricted activity (RA), and following a subsequent 2 month treadmill exercise retraining period for the 5 mo group. Mean time to exhaustion in the 2 mo group decreased from 177 + or - 22 min before to 90 + or - 32 min after RA. Retraining increased tolerance to 219 + or - 73 min; 24 pct. above the before RA and 143 pct. above the after RA time. After RA exhaustion time in the 5 mo group was 25 and 45 min. Before RA, pre-exercise muscle structure was normal and post exercise there was only slight swelling of mitochondria. After RA, pre-exercise, numerous glycogen granules and lipid droplets appeared in the muscle fibers, mitochondria were smaller, and sarcoplasmic reticulum channels widened; post exercise these changes were accentuated and some areas were devoid of glycogen, and there was fiber degradation. After 5 mo RA pre-exercise there were more pronounced changes; mitochondria were very small and dense, there were many lipid droplets, myofibrils were often separated, and the fibers appeared edematous and degenerating; post exercise the sarcoplasmic reticulum was swollen, no glycogen was present, and there was marked swelling and deformation of mitochondria. After retraining, both pre-exercise and post exercise there was still evidence of fiber degeneration. Thus, susceptibility of active skeletal muscle structures and subcellular elements, e.g., mitochondria, to the action of damaging factors occurring during exhaustive exercise is enhanced considerably by prolonged disuse.

Retinoic acid influences anteroposterior positioning of epidermal sensory neurons and their gene expression in a developing chordate (amphioxus)

PubMed Central

Schubert, Michael; Holland, Nicholas D.; Escriva, Hector; Holland, Linda Z.; Laudet, Vincent

2004-01-01

In developing chordates, retinoic acid (RA) signaling patterns the rostrocaudal body axis globally and affects gene expression locally in some differentiating cell populations. Here we focus on development of epidermal sensory neurons in an invertebrate chordate (amphioxus) to determine how RA signaling influences their rostrocaudal distribution and gene expression (for AmphiCoe, a neural precursor gene; for amphioxus islet and AmphiERR, two neural differentiation genes; and for AmphiHox1, -3, -4, and -6). Treatments with RA or an RA antagonist (BMS009) shift the distribution of developing epidermal neurons anteriorly or posteriorly, respectively. These treatments also affect gene expression patterns in the epidermal neurons, suggesting that RA levels may influence specification of neuronal subtypes. Although colinear expression of Hox genes is well known for the amphioxus central nervous system, we find an unexpected comparable colinearity for AmphiHox1, -3, -4, and -6 in the developing epidermis; moreover, RA levels affect the anteroposterior extent of these Hox expression domains, suggesting that RA signaling controls a colinear Hox code for anteroposterior patterning of the amphioxus epidermis. Thus, in amphioxus, the developing peripheral nervous system appears to be structured by mechanisms parallel to those that structure the central nervous system. One can speculate that, during evolution, an ancestral deuterostome that structured its panepidermal nervous system with an RA-influenced Hox code gave rise to chordates in which this patterning mechanism persisted within the epidermal elements of the peripheral nervous system and was transferred to the neuroectoderm as the central nervous system condensed dorsally. PMID:15226493

Diet and Rheumatoid Arthritis Symptoms: Survey Results From a Rheumatoid Arthritis Registry.

PubMed

Tedeschi, Sara K; Frits, Michelle; Cui, Jing; Zhang, Zhi Zack; Mahmoud, Taysir; Iannaccone, Christine; Lin, Tzu-Chieh; Yoshida, Kazuki; Weinblatt, Michael E; Shadick, Nancy A; Solomon, Daniel H

2017-12-01

Patients with rheumatoid arthritis (RA) often ask whether specific foods, popularized as inflammatory or antiinflammatory, can improve or worsen their RA. Patients with RA took a survey on diet and RA symptoms, and the survey data were collected and analyzed. A dietary survey was mailed to 300 subjects in a single-center RA registry at a large academic center. Subjects were asked about their consumption of 20 foods and whether these foods make their RA symptoms better, worse, or unchanged. Semiannual registry data include demographics, medications, comorbidities, and disease activity scores. Fisher's exact test and Wilcoxon's rank sum tests evaluated associations between subject characteristics from the most recent registry assessment and changes in RA symptoms from specific foods. Of the 217 subjects (72% response rate), 83% were female; the median RA duration was 17 years (interquartile range 9-27 years), and 58% were taking a biologic disease-modifying antirheumatic drug. Twenty-four percent of subjects reported that foods affect their RA symptoms, with 15% reporting improvement and 19% reporting worsening. Blueberries and spinach were the foods most often reported to improve RA symptoms, while soda with sugar and desserts were those most often reported to worsen RA symptoms. Younger age and noting that sleep, warm room temperature, and vitamin/mineral supplements improve RA were each associated with reporting that foods affect RA symptoms. Medication use, sex, body mass index, smoking, disease duration, disease activity scores, and self-reported RA flares were not associated with reporting that foods affect RA. Nearly one-quarter of RA subjects with longstanding disease reported that diet had an effect on their RA symptoms. © 2017, American College of Rheumatology.

Vitamin B12

MedlinePlus

... 23193625 . Mason JB. Vitamins, trace minerals, and other micronutrients. In: Goldman L, Schafer AI, eds. Goldman-Cecil ... Saunders; 2016:chap 218. Salwen MJ. Vitamins and trace elements. In: McPherson RA, Pincus MR, eds. Henry's Clinical ...

Zinc in diet

MedlinePlus

... 25077263 . Mason JB. Vitamins, trace minerals, and other micronutrients. In: Goldman L, Schafer AI, eds. Goldman-Cecil ... Saunders; 2016:chap 218. Salwen MJ. Vitamins and trace elements. In: McPherson RA, Pincus MR, eds. Henry's Clinical ...

Vitamin B6

MedlinePlus

... 23193625 . Mason JB. Vitamins, trace minerals, and other micronutrients. In: Goldman L, Schafer AI, eds. Goldman-Cecil ... Saunders; 2016:chap 218. Salwen MJ. Vitamins and trace elements. In: McPherson RA, Pincus MR, eds. Henry's Clinical ...

Geochemistry of uranium and thorium and natural radioactivity levels of the western Anatolian plutons, Turkey

NASA Astrophysics Data System (ADS)

Papadopoulos, Argyrios; Altunkaynak, Şafak; Koroneos, Antonios; Ünal, Alp; Kamaci, Ömer

2017-10-01

Seventy samples from major plutons (mainly granitic) of Western Anatolia (Turkey) have been analyzed by γ-ray spectrometry to determine the specific activities of 238U, 226Ra, 232Th and 40K (Bq/kg). Τhe natural radioactivity ranged up to 264 Bq/kg for 238U, 229.62 Bq/kg for 226Ra, up to 207.32 Bq/kg for 232Th and up to 2541.95 Bq/kg for 40K. Any possible relationship between the specific activities of 226Ra, 238U, 232Th and 40K and some characteristics of the studied samples (age, rock-type, colour, grain size, occurrence, chemical and mineralogical composition) was investigated. Age, major and trace element geochemistry, color, pluton location and mineralogical composition are likely to affect the concentrations of the measured radionuclides. The range of the Th/U ratio was large (0.003-11.374). The latter, along with 226Ra/238U radioactive secular disequilibrium, is also discussed and explained by magmatic processes during differentiation.

Transcriptional response of Hoxb genes to retinoid signalling is regionally restricted along the neural tube rostrocaudal axis.

PubMed

Carucci, Nicoletta; Cacci, Emanuele; Nisi, Paola S; Licursi, Valerio; Paul, Yu-Lee; Biagioni, Stefano; Negri, Rodolfo; Rugg-Gunn, Peter J; Lupo, Giuseppe

2017-04-01

During vertebrate neural development, positional information is largely specified by extracellular morphogens. Their distribution, however, is very dynamic due to the multiple roles played by the same signals in the developing and adult neural tissue. This suggests that neural progenitors are able to modify their competence to respond to morphogen signalling and autonomously maintain positional identities after their initial specification. In this work, we take advantage of in vitro culture systems of mouse neural stem/progenitor cells (NSPCs) to show that NSPCs isolated from rostral or caudal regions of the mouse neural tube are differentially responsive to retinoic acid (RA), a pivotal morphogen for the specification of posterior neural fates. Hoxb genes are among the best known RA direct targets in the neural tissue, yet we found that RA could promote their transcription only in caudal but not in rostral NSPCs. Correlating with these effects, key RA-responsive regulatory regions in the Hoxb cluster displayed opposite enrichment of activating or repressing histone marks in rostral and caudal NSPCs. Finally, RA was able to strengthen Hoxb chromatin activation in caudal NSPCs, but was ineffective on the repressed Hoxb chromatin of rostral NSPCs. These results suggest that the response of NSPCs to morphogen signalling across the rostrocaudal axis of the neural tube may be gated by the epigenetic configuration of target patterning genes, allowing long-term maintenance of intrinsic positional values in spite of continuously changing extrinsic signals.

Antagonism of cytotoxic chemotherapy in neuroblastoma cell lines by 13-cis-retinoic acid is mediated by the anti-apoptotic Bcl-2 family proteins

PubMed Central

Hadjidaniel, Michael Daniel; Reynolds, Charles Patrick

2010-01-01

13-cis-retinoic acid (13-cis-RA), is given at completion of cytotoxic therapy to control minimal residual disease in neuroblastoma. We investigated the effect of combining 13-cis-RA with cytotoxic agents employed in neuroblastoma therapy using a panel of 6 neuroblastoma cell lines. The effect of 13-cis-RA on the mitochondrial apoptotic pathway, was studied by flow cytometry, cytotoxicity by DIMSCAN, and protein expression by immuoblotting. Pre-treatment and direct combination of 13-cis-RA with etoposide, topotecan, cisplatin, melphalan, or doxorubicin markedly antagonized the cytotoxicity of those agents in 4 out of 6 tested neuroblastoma cell lines, increasing fractional cell survival by 1 to 3 logs. The inhibitory concentration of drugs (IC99) increased from clinically achievable levels to non-achievable levels: > 5-fold (cisplatin) to > 7-fold (etoposide). In SMS-KNCR neuroblastoma cells, 13-cis-RA upregulated expression of Bcl-2 and Bcl-xL RNA and protein, and this was associated with protection from etoposide-mediated apoptosis at the mitochondrial level. A small molecule inhibitor of the Bcl-2 family of proteins (ABT-737) restored mitochondrial membrane potential loss and apoptosis in response to cytotoxic agents in 13-cis-RA treated cells. Prior selection for resistance to RA did not diminish the response to cytotoxic treatment. Thus, combining 13-cis-RA with cytotoxic chemotherapy significantly reduced the cytotoxiciity for neuroblastoma in vitro, mediated at least in part via the anti-apoptotic Bcl-2 family of proteins. PMID:21159604

Beta-carotene blood test

MedlinePlus

... 302. Mason JB. Vitamins, trace minerals, and other micronutrients. In: Goldman L, Schafer AI, eds. Goldman-Cecil ... Saunders; 2016:chap 218. Salwen MJ. Vitamins and trace elements. In: McPherson RA, Pincus MR, eds. Henry's Clinical ...

Correlation of radon and thoron concentrations with natural radioactivity of soil in Zonguldak, Turkey

NASA Astrophysics Data System (ADS)

Koray, Abdullah; Akkaya, Gizem; Kahraman, Ayşegül

2017-02-01

Radon and thoron gases are produced by the decay of the radioactive elements those are radium and thorium in the soil. In this study, the correlations between soil radon and thoron concentration with their parent nuclide (226Ra and 232Th) concentrations in collected soil samples from the same locations were evaluated. The result of the measurement shows that the distribution of radon and thoron in soil showed the same tendency as 226Ra and 232Th distribution. It was found a weak correlation between the radon and the 226Ra concentration (R =0.57), and between the thoron and the 232Th concentration (R=0.64). No strong correlation was observed between soil-gas radon and thoron concentration (R = 0.29).

Synoviocytes-derived Interleukin 35 Potentiates B Cell Response in Patients with Osteoarthritis and Rheumatoid Arthritis.

PubMed

Kam, Ngar-Woon; Liu, Dehua; Cai, Zhe; Mak, Wah-Yan; Wong, Chun-Kwok; Chiu, Kwok-Hing; Wong, Kam-Yiu; Tsang, Wai-Leuk; Tam, Lai-Shan

2018-04-01

Elevated expression of interleukin 35 (IL-35) is associated with autoimmune disease, including rheumatoid arthritis (RA). The present study was undertaken to determine the functional interaction among IL-35, B cells, and stromal cells residing in the synovium of patients with RA and osteoarthritis (OA). IL-35 (EBI-3/p35) expression was investigated in RA and OA synovium using quantitative real-time PCR (qRT-PCR) and immunohistochemistry. IL-35 receptor (IL-35R) expression on B cells dissociated from synovium and periphery of patients with RA, OA, and healthy donor controls (HC) was determined by flow cytometry. The degree of B cells activation after IL-4 and/or IL-35 stimulation was measured by flow cytometry and qRT-PCR. Synovial fibroblasts (SF) purified from RA and OA synovium were cocultured with peripheral HC B cells in the presence/absence of tumor necrosis factor-α (TNF-α) and with/without anti-IL-35-blocking antibodies. EBI-3/p35 transcripts were expressed in close proximity to B cells residing in RA and OA synovium. IL-35R subunits, gp130 and IL-27Rα, but not IL-12Rβ2, were expressed in B cells extracted from the synovium and periphery of patients with RA/OA. Notably, RA synovium expressed the highest level of IL-27Rα on their cell surface. IL-35 induced proliferation and IgG production in HC B cells. Cocultures of HC B cells with RASF, but not OASF, exhibited significantly elevated B cells activation. TNF-α-induced, RASF-dependent secretion of IgG in B cells is partly IL-35-dependent. To our knowledge, for the first time we demonstrated that synovial/peripheral B cells expressed IL-35R and were responsive to IL-35 stimulation. SF residing in RA synovium can be linked to B cell activation and maintenance in RA synovium through IL-35.

A sensitive and specific method for measurement of multiple retinoids in human serum with UHPLC-MS/MS

PubMed Central

Arnold, Samuel L. M.; Amory, John K.; Walsh, Thomas J.; Isoherranen, Nina

2012-01-01

Retinol (vitamin A) circulates at 1–4 μM concentration and is easily measured in serum. However, retinol is biologically inactive. Its metabolite, retinoic acid (RA), is believed to be responsible for biological effects of vitamin A, and hence the measurement of retinol concentrations is of limited value. A UHPLC-MS/MS method using isotope-labeled internal standards was developed and validated for quantitative analysis of endogenous RA isomers and metabolites. The method was used to measure retinoids in serum samples from 20 healthy men. In the fed state, the measured concentrations were 3.1 ± 0.2 nM for atRA, 0.1 ± 0.02 nM for 9-cisRA, 5.3 ± 1.3 nM for 13-cisRA, 0.4 ± 0.4 nM for 9,13-dicisRA, and 17.2 ± 6.8 nM for 4oxo-13-cisRA. The concentrations of the retinoids were not significantly different when measured after an overnight fast (3.0 ± 0.1 nM for atRA, 0.09 ± 0.01nM for 9-cisRA, 3.9 ± 0.2 nM for 13-cisRA, 0.3 ± 0.1 nM for 9,13-dicisRA, and 11.9 ± 1.6 nM for 4oxo-13-cisRA). 11-cisRA and 4OH-RA were not detected in human serum. The high sensitivity of the MS/MS method combined with the UHPLC separation power allowed detection of endogenous 9-cisRA and 4oxo-atRA for the first time in human serum. PMID:22192917

Mycobacteria-specific cytokine responses as correlates of treatment response in active and latent tuberculosis.

PubMed

Clifford, Vanessa; Tebruegge, Marc; Zufferey, Christel; Germano, Susie; Forbes, Ben; Cosentino, Lucy; McBryde, Emma; Eisen, Damon; Robins-Browne, Roy; Street, Alan; Denholm, Justin; Curtis, Nigel

2017-08-01

A biomarker indicating successful tuberculosis (TB) therapy would assist in determining appropriate length of treatment. This study aimed to determine changes in mycobacteria-specific antigen-induced cytokine biomarkers in patients receiving therapy for latent or active TB, to identify biomarkers potentially correlating with treatment success. A total of 33 adults with active TB and 36 with latent TB were followed longitudinally over therapy. Whole blood stimulation assays using mycobacteria-specific antigens (CFP-10, ESAT-6, PPD) were done on samples obtained at 0, 1, 3, 6 and 9 months. Cytokine responses (IFN-γ, IL-1ra, IL-2, IL-10, IL-13, IP-10, MIP-1β, and TNF-α) in supernatants were measured by Luminex xMAP immunoassay. In active TB cases, median IL-1ra (with CFP-10 and with PPD stimulation), IP-10 (CFP-10, ESAT-6), MIP-1β (ESAT-6, PPD), and TNF-α (ESAT-6) responses declined significantly over the course of therapy. In latent TB cases, median IL-1ra (CFP-10, ESAT-6, PPD), IL-2 (CFP-10, ESAT-6), and IP-10 (CFP-10, ESAT-6) responses declined significantly. Mycobacteria-specific cytokine responses change significantly over the course of therapy, and their kinetics in active TB differ from those observed in latent TB. In particular, mycobacteria-specific IL-1ra responses are potential correlates of successful therapy in both active and latent TB. Copyright © 2017 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

Successful extension of tocilizumab infusion intervals from 4 weeks to 6 or 5 weeks in 90% of RA patients with good response to 4-week intervals.

PubMed

Saiki, Osamu; Uda, Hiroshi

2017-01-01

A period of 4 weeks (w) has been recommended as the interval between tocilizumab (TCZ) infusions for rheumatoid arthritis (RA). However, treating the patients with TCZ (8 mg/kg), we experienced that longer intervals were also effective. We conducted the study to investigate whether the intervals of TCZ infusions could extend from 4w to 5 or 6w. This was a retrospective observational study. RA patients who had shown good response to TCZ infusions at 4w intervals were enrolled, and the intervals of TCZ infusions were extended to 5w. Next, the intervals of TCZ infusion were extended to 6w for the patients who had maintained good response with 5w intervals. The patients who had maintained good response for more than two years were estimated as responders. One hundred patients were enrolled in the present study, and 62 patients maintained good response with 6w-interval infusions, and 28 patients with 5w-interval infusions, indicating that 90% of patients who had shown good response with 4w intervals could extend the intervals from 4w to 5 or 6w. The present study provides evidence that most of RA patients who showed good response to TCZ infusions at 4w could extend the intervals to 6w or 5w. This finding should be of great interest for both financial and labour reasons.

THE MANUFACTURE OF FUEL ELEMENTS OF THE ARGONAUT TYPE

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kittl, J.; Machado, R.E.; Mazza, J.A.

1958-06-10

The conditions required for the manufacture of the RA-1 Argonant type fuel elements are investigated. The fuel elements are in the form of a plate which is manufactured by the extrusion of a presintered mass of U/sub 3/O/sub 8/ (20% enriched) in an aluminum matrix. Steps in the investigation were obtention and specification of U/sub 3/O/sub 8/ and Al in powder form for testing, filling, and extrusion tests, finishing of the fuel elements, and computation of U/sub 3/O/sub 8/ content. (W.D.M.)

A Dedicated Microprocessor Controller for a Bound Document Scanner.

DTIC Science & Technology

1984-06-01

focused onto the CCD which converts the image into 2048 pixels. After the pixel data are processed by the scanner hardware, they are sent to the display...data in real time after the data on each of the 2048 pixel elements .-.- .---.; . has been transferred out of the device. Display-control commands and...05 06 07 Fig. 4.9 2716 EPROM Block D~iagram and Pin Assignment HE-E 64 BYTES RA ’ FFF 4095 INTERNAL I FCO 4032 EXECUTABLE FBP 4031 RA Soo0 2048 _ _7FF

IMPACT OF CALCIUM-CHANNEL BLOCKERS ON RIGHT HEART FUNCTION IN A CONTROLLED MODEL OF CHRONIC PULMONARY HYPERTENSION

PubMed Central

Zierer, Andreas; Voeller, Rochus K.; Melby, Spencer J.; Steendijk, Paul; Moon, Marc R.

2009-01-01

Purpose Patients with chronic pulmonary hypertension (CPH) who demonstrate a pulmonary vasodilation following calcium channel blocker (CCB) administration are defined as “responders”. In contrast, “non-responders” are patients who do not show such a pulmonary vasodilation with CCB therapy. The purpose of this investigation was to study the effects of CCB therapy on right heart mechanics in experimental CCB responders versus CCB non-responders. Methods In 12 dogs, right atrial (RA) and ventricular (RV) pressure and volume (conductance catheters) were simultaneously recorded after 3 months of progressive pulmonary artery (PA) banding. Diltiazem was given at 10 mg/hr with the PA constricted (simulated CCB non-responder). Responders were then created by releasing the PA band to unload the ventricle. RA and RV contractility and diastolic stiffness (slope of end-systolic and end-diastolic pressure-volume relations) were calculated and RA reservoir and conduit function were quantified as RA inflow with the tricuspid valve closed versus open, respectively. Results With CCB, RA contractility (p<0.03) and cardiac output (p<0.004) were compromised in simulated non-responders while RA stroke work was pharmacologically depressed in the setting of an unchanged afterload. After simulating a responder by controlled PA band release, the RA became less distensible, causing a shift from reservoir to conduit function (p<0.001) towards physiologic baseline conditions and a recovery in the hyperdynamic compensatory response in both chambers (p<0.007) as evidenced in a declined RA and RV contractility with an improved cardiac output as compared to CPH and simulated non-responders. RA and RV diastolic function in both groups was not affected by CCB. Conclusions CCB did not impact RV function in simulated non-responders, but significantly impaired RA contractility and cardiac output. In simulated responders, afterload fell substantially, thereby allowing the RA and RV to recover from their pathological hyperdynamic contractile response to CPH. This affect was able to outweigh the intrinsic negative effects of CCB therapy on systolic RA function. Current data suggest that the RA in CPH is much more sensitive to CCB therapy than the RV and delineate for the first time why CCB therapy in CPH has been empirically restricted to documented responders. PMID:19237986

Haemophilus parasuis CpxRA two-component system confers bacterial tolerance to environmental stresses and macrolide resistance.

PubMed

Cao, Qi; Feng, Fenfen; Wang, Huan; Xu, Xiaojuan; Chen, Huanchun; Cai, Xuwang; Wang, Xiangru

2018-01-01

Haemophilus parasuis is an opportunistic pathogen localized in the upper respiratory tracts of pigs, its infection begins from bacterial survival under complex conditions, like hyperosmosis, oxidative stress, phagocytosis, and sometimes antibiotics as well. The two-component signal transduction (TCST) system serves as a common stimulus-response mechanism that allows microbes to sense and respond to diverse environmental conditions via a series of phosphorylation reactions. In this study, we investigated the role of TCST system CpxRA in H. parasuis in response to different environmental stimuli by constructing the ΔcpxA and ΔcpxR single deletion mutants as well as the ΔcpxRA double deletion mutant from H. parasuis serotype 4 isolate JS0135. We demonstrated that H. parasuis TCST system CpxRA confers bacterial tolerance to stresses and bactericidal antibiotics. The CpxR was found to play essential roles in mediating oxidative stress, osmotic stresses and alkaline pH stress tolerance, as well as macrolide resistance (i.e. erythromycin), but the CpxA deletion did not decrease bacterial resistance to abovementioned stresses. Moreover, we found via RT-qPCR approach that HAPS_RS00160 and HAPS_RS09425, both encoding multidrug efflux pumps, were significantly decreased in erythromycin challenged ΔcpxR and ΔcpxRA mutants compared with wild-type strain JS0135. These findings characterize the role of the TCST system CpxRA in H. parasuis conferring stress response tolerance and bactericidal resistance, which will deepen our understanding of the pathogenic mechanism in H. parasuis. Copyright © 2017 Elsevier GmbH. All rights reserved.

Comparison of endothelial function of coronary artery bypass grafts in diabetic and nondiabetic patients: Which graft offers the best?

PubMed Central

Gür, Demet Özkaramanlı; Gür, Özcan; Gürkan, Selami; Cömez, Selcem; Gönültaş, Aylin; Yılmaz, Murat

2016-01-01

Objective: Diabetes associated endothelial dysfunction, which determines both long and short term graft patency, is not uniform in all coronary artery bypass surgery (CABG) grafts. Herein this study, we aimed to investigate the degree of endothelial dysfunction in diabetic radial artery (RA), internal mammarian artery (IMA) and saphenous vein (SV) grafts in vitro tissue bath system. Methods: This is a prospective experimental study. Fifteen diabetic and 15 non-diabetic patients were included to the study. A total number of 96 graft samples were collected; 16 graft samples for each graft type from both diabetic and non-diabetic patients. Arterial grafts were harvested with pedicles and SV grafts were harvested by ‘no touch’ technique. Vasodilatation response of vascular rings to carbachol, which induces nitric oxide (NO) mediated vasodilatation, was designated as the measure of endothelial function. Results: The IMA grafts had the most prominent NO mediated vasodilatation in both diabetic and non-diabetic patients, concluding a better preserved endothelial function than SV and RA. The ‘no-touch’ SV and RA grafts had similar vasodilatation responses in non-diabetic patients. In diabetic patients, on the other hand, RA grafts exhibited the least vasodilatation response (ie. worst endothelial function), even less vasodilatation than ‘no touch’ SV grafts (p<0.0001). Conclusion: Deteriorated function of RA grafts in diabetic patients, even worse than SV grafts made evident by this study, encourages the use of ‘no touch’ technique as the method of SV harvesting and more meticulous imaging of RA before its use as a graft in diabetic patients. PMID:26301347

Fatigue Debonding of the Roughened Stem–Cement Interface: Effects of Surface Roughness and Stem Heating Conditions

PubMed Central

Damron, Leatha A.; Kim, Do-Gyoon; Mann, Kenneth A.

2007-01-01

The aim of this study was to determine the effects of cyclic loading on the debond process of a roughened stem– cement interface used in total hip arthroplasty. The specific goals were to assess the effects of two surgeon-controlled variables (stem heating and degree of stem surface roughness) and to determine if an independent finite element-based fracture mechanics model could be used to predict the debond response. A clamped cantilever beam geometry was used to determine the fatigue debond response of the stem– cement interface and was created using an experimental mold that simulated in vivo cementing conditions. A second experiment was performed using a torsion-loading model representative of the stem– cement–bone composite. For both experiments, two stem heating (room temperature and 50°C) and surface roughness conditions (grit blasted: Ra = 2.3 and 5.1 μm) were used. Finally, a finite element model of the torsion experiment with provision for crack growth was developed and compared with the experimental results. Results from both experiments revealed that neither stem preheating nor use of a stem with a greater surface roughness had a marked effect on the fatigue debond response. There was substantial variability in the debond response for all cases; this may be due to microscopic gaps at the interface for all interface conditions. The debond rate from the finite element simulation (10−7.31 m/cycle) had a magnitude similar to the experimental torsion model (10− (6.77 ± 1.25) m/cycle). This suggests that within the context of the experimental conditions studied here that the debond response could be assessed using a linear elastic fracture mechanics-type approach. PMID:16292769

Seronegative rheumatoid arthritis: pathogenetic and therapeutic aspects.

PubMed

Pratt, Arthur G; Isaacs, John D

2014-08-01

Rheumatoid arthritis (RA) has long been recognised as a highly heterogeneous disease of immune dysregulation. Despite an ever-growing appreciation of the role of circulating autoantibodies in the development of 'seropositive' disease, the pathogenesis of seronegative RA remains poorly understood. Accumulating evidence suggests that RA 'serotypes', in fact, reflect distinct disease entities that, despite their clinical overlap, diverge in respect of genetic architecture, cellular pathology and even therapeutic responsiveness. Focussing on seronegative RA, this review considers these concepts and their implications for the management of patients with this challenging, though sometimes overlooked, condition. Crown Copyright © 2014. Published by Elsevier Ltd. All rights reserved.

Postmenopausal osteoporosis in rheumatoid arthritis: The estrogen deficiency-immune mechanisms link.

PubMed

Sapir-Koren, Rony; Livshits, Gregory

2017-10-01

Rheumatoid arthritis (RA) is characterized, among other factors, by systemic bone loss, reaching ~50% prevalence of osteoporosis in postmenopausal women. This is roughly a doubled prevalence in comparison with age-matched non-RA women. Postmenopausal RA women are more likely to be sero-positive for the anti-citrullinated peptide antibody (ACPA). Our extensive review of recent scientific literature enabled us to propose several mechanisms as responsible for the accelerated bone loss in ACPA(+) RA postmenopausal women. Menopause-associated estrogen deficiency plays a major role in these pathological mechanisms, as follows. Copyright © 2017 Elsevier Inc. All rights reserved.

Downregulation of Midkine gene expression and its response to retinoic acid treatment in the nitrofen-induced hypoplastic lung.

PubMed

Doi, Takashi; Shintaku, Mika; Dingemann, Jens; Ruttenstock, Elke; Puri, Prem

2011-02-01

Nitrofen-induced congenital diaphragmatic hernia (CDH) model has been widely used to investigate the pathogenesis of pulmonary hypoplasia (PH) in CDH. Recent studies have suggested that retinoids may be involved in the molecular mechanisms of PH in CDH. Prenatal treatment with retinoic acid (RA) has been reported to improve the growth of hypoplastic lung in the nitrofen CDH model. Midkine (MK), a RA-responsive growth factor, plays key roles in various organogenesis including lung development. In fetal lung, MK mRNA expression has its peak at E13.5-E16.5 and is markedly decreased during mid-to-late gestation, indicating its important role in early lung morphogenesis. We designed this study to investigate the hypothesis that the pulmonary MK gene expression is downregulated in the early lung morphogenesis in the nitrofen-induced PH, and to evaluate the effect of prenatal RA treatment on pulmonary MK gene expression in the nitrofen-induced CDH model. Pregnant rats were exposed to either olive oil or nitrofen on day 9 of gestation (D9). Fetal lungs were harvested on D15, D18, and D21 and divided into control, nitrofen with or without CDH [CDH(+) or CDH(-)]. In addition, RA was given on days D18, D19, and D20 and fetal lungs were harvested on D21, and then divided into control + RA and nitrofen + RA. The pulmonary gene expression levels of MK were evaluated by real-time RT-PCR and statistically analyzed. Immunohistochemistry was also performed to examine protein expression/distribution of MK in fetal lung. The relative mRNA expression levels of MK were significantly downregulated in nitrofen group compared to controls at D15 ((§)p < 0.01), whereas there were no significant differences at D18 and D21. MK gene expression levels were significantly upregulated in nitrofen + RA (0.71 ± 0.17) compared to the control (0.35 ± 0.16), CDH(-) (0.24 ± 0.15), CDH(+) (0.39 ± 0.19) and control + RA (0.47 ± 0.13) (*p < 0.05). Immunoreactivity of MK was also markedly decreased in nitrofen lungs compared to controls on D15, and increased in nitrofen + RA lungs compared to the other lungs on D21. Downregulation of MK gene on D15 may contribute to primary PH in the nitrofen CDH model by disrupting early lung morphogenesis. Upregulation of MK gene after RA treatment in the nitrofen-induced hypoplastic lung suggests that RA may have a therapeutic potential to rescue PH in CDH through RA-responsive growth factor signaling.

Increased autophagy in fibroblast-like synoviocytes leads to immune enhancement potential in rheumatoid arthritis.

PubMed

Yang, Ru; Zhang, Yingzi; Wang, Lin; Hu, Ji; Wen, Jian; Xue, Leixi; Tang, Mei; Liu, Zhichun; Fu, Jinxiang

2017-02-28

The incidence of rheumatoid arthritis (RA) has been reported to be correlated with a disorder of immunregulation. Rheumatoid arthritis fibroblast-like synoviocytes (RA-FLSs) play an important role in regulating the local immune microenvironment. However, the potential mechanism of RA-FLS in regulating the immnue response is not clearly understood. In this study, we demonstrated that the expression of HIF-1α was significantly up-regulated in rheumatoid arthritis tissue which indicated that the hypoxia condition in the microenvironment. We also observed that RA-FLSs demonstrated the potential to up-regulate immune activation. Meanwhile, the level of autophagy increased in RA-FLSs compared with control group. Besides that, the expression of IL-6 was up-regulated not only in RA-FLSs but also in the fibroblasts that treated with hypoxia condition. Accordingly, we found that autophagy inhibitiors could effectively inhibit the immune activation function of RA-FLSs medicated by IL-6. Taken together, the results we demonstrated above indicated that the hypoxia microenvironment could effectively induce the incidence of autophagy and then lead to the immune activation function of RA-FLSs medicated by IL-6.

Retinoic acid-induced nNOS expression depends on a novel PI3K/Akt/DAX1 pathway in human TGW-nu-I neuroblastoma cells.

PubMed

Nagl, Florian; Schönhofer, Katrin; Seidler, Barbara; Mages, Jörg; Allescher, Hans-Dieter; Schmid, Roland M; Schneider, Günter; Saur, Dieter

2009-11-01

Neuronal nitric oxide synthase (nNOS)-derived nitric oxide (NO) acts as a neurotransmitter and intracellular signaling molecule in the central and peripheral nervous system. NO regulates multiple processes like neuronal development, plasticity, and differentiation and is a mediator of neurotoxicity. The nNOS gene is highly complex with 12 alternative first exons, exon 1a-1l, transcribed from distinct promoters, leading to nNOS variants with different 5'-untranslated regions. Transcriptional control of the nNOS gene is not understood in detail. To investigate regulation of nNOS gene expression by retinoic acid (RA), we used the human neuroblastoma cell line TGW-nu-I as a model system. We show that RA induces nNOS transcription in a protein synthesis-dependent fashion. We identify the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway and the atypical orphan nuclear receptor DAX1 (NR0B1) as critical mediators involved in RA-induced nNOS gene transcription. RA treatment increases DAX1 expression via PI3K/Akt signaling. Upregulation of DAX1 expression in turn induces nNOS transcription in response to RA. These results identify nNOS as a target gene of a novel RA/PI3K/Akt/DAX1-dependent pathway in human neuroblastoma cells and stress the functional importance of the transcriptional regulator DAX1 for nNOS gene expression in response to RA treatment.

Modulation of the immune response in rheumatoid arthritis with strategically released rapamycin.

PubMed

Shao, Ping; Ma, Linxiao; Ren, Yile; Liu, Huijie

2017-10-01

Rheumatoid arthritis (RA) is a chronic inflammatory disease, which is associated with symptoms, including synovial membrane inflammatory pain, joint synovitis and stiffness. However, there are no effective methods available to cure this disease. In the present study, rapamycin was used to modulate immunity in RA. To limit the cytotoxicity of rapamycin, rapamycin was loaded into well‑characterized biocompatible nanoparticles. In vitro, rapamycin particles downregulated the activation of dendritic cell surface markers, including CD80+ and CD40+, upon interacting with macrophages. The rapamycin particles reduced the secretion of inflammatory cytokines, including interleukin (IL)‑6, tumor necrosis factor (TNF) and IL‑1β, which are characteristic of RA. In vivo, the rapamycin particles decreased the symptoms of RA in mice, and the production of inflammatory cytokines was associated with the occurrence of RA. The present study partially revealed the interactions between rapamycin and two types of immune cell in RA disease, and may potentially offer a solution to improve the treatment of RA.

Modulation of synovial cell function by somatostatin in patients with rheumatoid arthritis.

PubMed

Takeba, Y; Suzuki, N; Takeno, M; Asai, T; Tsuboi, S; Hoshino, T; Sakane, T

1997-12-01

To elucidate the role of neurologic, endocrine, and immune system interactions in the development of pathologic responses in patients with rheumatoid arthritis (RA), we studied somatostatin (SOM) production and somatostatin receptor (SOMR) expression in RA synovium and its function in patients with RA. The effects of SOM on proinflammatory cytokine (interleukin-6 [IL-6] and IL-8) and collagenase production by RA synovial cells were estimated by enzyme-linked immunosorbent assay, and their messenger RNA expression was assessed by reverse transcription-polymerase chain reaction (RT-PCR) using limiting dilutions of the complementary DNA. The expression of SOMR by RA synovial cells was also studied by RT-PCR. Local production of SOM was estimated by RT-PCR and immunohistochemical staining. Physiologic concentrations (approximately 10(-10)M) of SOM inhibited proliferation of RA synovial cells. The production of proinflammatory cytokines and matrix metalloproteinases by RA synovial cells was also modulated by SOM. SOMR subtypes 1 and 2 were expressed on fibroblast-like synovial cells, and the expression of SOMR-2 was up-regulated by proinflammatory cytokine treatment of the synovial cells from patients with RA. RA fibroblast-like cells synthesized SOM by themselves, suggesting that SOM acts as an autocrine regulator of synovial cell function in patients with RA. SOM inhibited aberrant synovial cell function in patients with RA, suggesting possible clinical applications of this neuropeptide.

IL-11 facilitates a novel connection between RA joint fibroblasts and endothelial cells.

PubMed

Elshabrawy, Hatem A; Volin, Michael V; Essani, Abdul B; Chen, Zhenlong; McInnes, Iain B; Van Raemdonck, Katrien; Palasiewicz, Karol; Arami, Shiva; Gonzalez, Mark; Ashour, Hossam M; Kim, Seung-Jae; Zhou, Guofei; Fox, David A; Shahrara, Shiva

2018-05-01

IL-11 has been detected in inflamed joints; however, its role in the pathogenesis of arthritis is not yet clear. Studies were conducted to characterize the expression and functional significance of IL-11 and IL-11Rα in rheumatoid arthritis (RA). IL-11 levels were elevated in RA synovial fluid (SF) compared to osteoarthritis (OA) SF and plasma from RA, OA and normal individuals (NLs). Morphologic studies established that IL-11 was detected in lining fibroblasts and macrophages in addition to sublining endothelial cells and macrophages at higher levels in RA compared to NL synovial tissues. Since IL-11Rα was exclusively expressed in RA fibroblasts and endothelial cells, macrophages were not involved in IL-11 effector function. Ligation of IL-11 to IL-11Rα strongly provoked fibroblast infiltration into RA joint, while cell proliferation was unaffected by this process. Secretion of IL-8 and VEGF from IL-11 activated RA fibroblasts was responsible for the indirect effect of IL-11 on endothelial cell transmigration and tube formation. Moreover, IL-11 blockade impaired RA SF capacity to elicit endothelial cell transmigration and tube formation. We conclude that IL-11 binding to endothelial IL-11Rα can directly induce RA angiogenesis. In addition, secretion of proangiogenic factors from migrating fibroblasts potentiated by IL-11 can indirectly contribute to RA neovascularization.

Review: Transcriptional Regulation of CD4+ T Cell Differentiation in Experimentally Induced Arthritis and Rheumatoid Arthritis.

PubMed

Kondo, Yuya; Yokosawa, Masahiro; Kaneko, Shunta; Furuyama, Kotona; Segawa, Seiji; Tsuboi, Hiroto; Matsumoto, Isao; Sumida, Takayuki

2018-05-01

Rheumatoid arthritis (RA) is an autoimmune disorder characterized by chronic inflammation of the joint synovium and infiltration by activated inflammatory cells. CD4+ T cells form a large proportion of the inflammatory cells invading the synovial tissue, and are involved in the RA pathologic process. In general, CD4+ T cells differentiate into various T helper cell subsets and acquire the functional properties to respond to specific pathogens, and also mediate some autoimmune disorders such as RA. Because the differentiation of T helper cell subsets is determined by the expression of specific transcription factors in response to the cytokine environment, these transcription factors are considered to have a role in the pathology of RA. Treg cells control an excess of T cell-mediated immune response, and the transcription factor FoxP3 is critical for the differentiation and function of Treg cells. Treg cell dysfunction can result in the development of systemic autoimmunity. In this review, we summarize how the expression of transcription factors modulates T helper cell immune responses and the development of autoimmune diseases, especially in RA. Understanding the role of transcription factors in the pathogenesis of autoimmunity may lead to novel therapeutic strategies to control the differentiation and function of both T helper cells and Treg cells. © 2017 The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.

Crocin reduces the inflammation response in rheumatoid arthritis.

PubMed

Li, Xiang; Jiang, Chao; Zhu, Wenyong

2017-05-01

This study is to determine the role and mechanism of crocin in rheumatoid arthritis (RA). Totally 60 Wistar SD rats were randomly divided into control group, RA model group, methotrexate group, crocin high dose, middle dose, and low dose groups. The paw swelling degree, arthritis score, thymus and spleen index, the mRNA and protein levels of iNOS, and the serum content of TNF-α, IL-1β, and IL-6 were evaluated. Crocin treatment significantly alleviated the paw swelling of RA rats. The arthritis score in crocin treatment groups was significantly lower than that in RA model group. Additionally, the thymus index, but not the spleen index, declined remarkably in crocin treatment groups than in RA model group. Besides, crocin administration significantly reduced the iNOS production and the serum content of TNF-α, IL-1β, and IL-6. Crocin may exert potent anti-RA effects through inhibiting cytokine.

Retinoic acid stimulates interstitial collagenase messenger ribonucleic acid in osteosarcoma cells

NASA Technical Reports Server (NTRS)

Connolly, T. J.; Clohisy, J. C.; Shilt, J. S.; Bergman, K. D.; Partridge, N. C.; Quinn, C. O.

1994-01-01

The rat osteoblastic osteosarcoma cell line UMR 106-01 secretes interstitial collagenase in response to retinoic acid (RA). The present study demonstrates by Northern blot analysis that RA causes an increase in collagenase messenger RNA (mRNA) at 6 h, which is maximal at 24 h (20.5 times basal) and declines toward basal level by 72 h. This stimulation is dose dependent, with a maximal response at 5 x 10(-7) M RA. Nuclear run-on assays show a greater than 20-fold increase in the rate of collagenase mRNA transcription between 12-24 h after RA treatment. Cycloheximide blocks RA stimulation of collagenase mRNA, demonstrating the need for de novo protein synthesis. RA not only causes an increase in collagenase secretion, but is known to decrease collagen synthesis in UMR 106-01 cells. In this study, the increase in collagenase mRNA is accompanied by a concomitant decrease in the level of alpha 1(I) procollagen mRNA, which is maximal at 24 h (70% decrease), with a return to near-control levels by 72 h. Nuclear run-on assays demonstrated that the decrease in alpha 1 (I) procollagen expression does not have a statistically significant transcriptional component. RA did not statistically decrease the stability of alpha 1 (I) procollagen mRNA (calculated t1/2 = 8.06 +/- 0.30 and 9.01 +/- 0.62 h in the presence and absence of RA, respectively). However, transcription and stability together probably contribute to the major decrease in stable alpha 1 (I) procollagen mRNA observed. Cycloheximide treatment inhibits basal level alpha 1 (I) procollagen mRNA accumulation, demonstrating the need for on-going protein synthesis to maintain basal expression of this gene.

Radium-223 IN metastatic hormone-sensitive high-grade prostate cancer: initial experience.

PubMed

Osvaldo, García-Pérez Francisco; Salvador, Medina-Ornelas Sevastián; Zael, Santana-Ríos; Nora, Sobrevilla-Moreno

2017-01-01

Our study evaluates the feasibility of compassionate exemption of Radium-223 ( 223 Ra) treatment in metastatic hormone-sensitive high-grade prostate cancer (mHSHGPC) patients with concomitant androgen deprivation-therapy (ADT). Seven patients with mHSHGPC, were treated with six cycles of 223 Ra plus ADT. All patients had undergone to 18 F-NaF-PET/CT. A qualitative analyses of the 18 F-NaF-PET/CT was performed in conjunction with Alkaline Phosphatase (ALP), Lactate-dehydrogenase (LDH) and Prostatic-Specific Antigen (PSA) values. The mean of SUVmax values were used as a quantitative measure of tumoral burden. Changes in PSA, ALP, LDH from baseline were evaluated, and were defined as increase or decrease of at least 30%. Clinical response was achieved if there was pain reduction using visual analogic scale. Four patients showed a significant reduction in mean SUVmax after 3 cycles of 223 Ra, and one after 6 cycles. Patients who showed reductions in mean SUVmax after Ra-223 also showed reductions in PSA, ALP and LDH. Four weeks after the last cycle of 223 Ra all patients had decreased total PSA, ALP and LDH values ≥ 30% also significant improvement on pain. No progress disease was documented after 14 ± 4 weeks. We found slight to moderate decreases in neutrophils and hemoglobin in two patients. We concluded that 223 Ra plus ADT can be useful in mHSHGPC; the semi-quantitative 18 F-NaF-PET/CT as a method effective to monitor the treatment response. Due to concomitant administration of ADT, 18 F-NaF-PET/CT cannot differentiate whether the findings were due to androgen blockade or the 223 Ra; nevertheless, data supporting the efficacy of 223 Ra is the significant improvement on pain.

Polymorphisms within Genes Involved in Regulation of the NF-κB Pathway in Patients with Rheumatoid Arthritis

PubMed Central

Gębura, Katarzyna; Świerkot, Jerzy; Wysoczańska, Barbara; Korman, Lucyna; Nowak, Beata; Wiland, Piotr; Bogunia-Kubik, Katarzyna

2017-01-01

Genes involved in regulation of the nuclear factor-κB (NF-κB)—pathway are suggested to play a role in pathogenesis of rheumatoid arthritis (RA). In the present study, genetic polymorphisms of TLR2, TLR4, TLR9 and NF-κB1 genes were investigated to assess their associations with RA susceptibility, progression and response to anti-TNF-α therapy. A group of 110 RA patients and 126 healthy individuals were genotyped for TLR2 (rs111200466), TLR4 (rs4986790, rs4986791), TLR9 (rs5743836, rs187084) and NF-κB1 (rs28362491) alleles. The presence of the TLR9 −1486 T variant (p < 0.0001) and its homozygosity (p < 0.0001) were found to be associated with disease susceptibility. The TLR9 −1237 C allele was associated with predisposition to RA in females only (p = 0.005). Moreover, the TLR4 rs4986791 G (rs4986790 T) alleles were more frequently detected among patients with the stage IV disease (p = 0.045), and were associated with more effective response to anti-TNF-α therapy (p = 0.012). More efficient response to anti-TNF-α treatment was also observed in patients with del within the NF-κB1 gene (p = 0.047), while for the TLR9 −1486 T homozygotes, the treatment was ineffective (p = 0.018). TLR polymorphisms affect disease susceptibility and response to therapy with TNF-α inhibitors in RA patients of Caucasian origin. PMID:28677621

Thermo-responsive polymeric nanoparticles for enhancing neuronal differentiation of human induced pluripotent stem cells.

PubMed

Seo, Hye In; Cho, Ann-Na; Jang, Jiho; Kim, Dong-Wook; Cho, Seung-Woo; Chung, Bong Geun

2015-10-01

We report thermo-responsive retinoic acid (RA)-loaded poly(N-isopropylacrylamide)-co-acrylamide (PNIPAM-co-Am) nanoparticles for directing human induced pluripotent stem cell (hiPSC) fate. Fourier transform infrared spectroscopy and (1)H nuclear magnetic resonance analysis confirmed that RA was efficiently incorporated into PNIAPM-co-Am nanoparticles (PCANs). The size of PCANs dropped with increasing temperatures (300-400 nm at room temperature, 80-90 nm at 37°C) due to its phase transition from hydrophilic to hydrophobic. Due to particle shrinkage caused by this thermo-responsive property of PCANs, RA could be released from nanoparticles in the cells upon cellular uptake. Immunocytochemistry and quantitative real-time polymerase chain reaction analysis demonstrated that neuronal differentiation of hiPSC-derived neuronal precursors was enhanced after treatment with 1-2 μg/ml RA-loaded PCANs. Therefore, we propose that this PCAN could be a potentially powerful carrier for effective RA delivery to direct hiPSC fate to neuronal lineage. The use of induced pluripotent stem cells (iPSCs) has been at the forefront of research in the field of regenerative medicine, as these cells have the potential to differentiate into various terminal cell types. In this article, the authors utilized a thermo-responsive polymer, Poly(N-isopropylacrylamide) (PNIPAM), as a delivery platform for retinoic acid. It was shown that neuronal differentiation could be enhanced in hiPSC-derived neuronal precursor cells. This method may pave a way for future treatment of neuronal diseases. Copyright © 2015 Elsevier Inc. All rights reserved.

Quality assessment of websites providing educational content for patients with rheumatoid arthritis.

PubMed

Siddhanamatha, Harish Rajashekarappa; Heung, Eric; Lopez-Olivo, Maria de Los Angeles; Abdel-Wahab, Noha; Ojeda-Prias, Ana; Willcockson, Irmgard; Leong, Amye; Suarez-Almazor, Maria Eugenia

2017-06-01

We performed an environmental scan of currently available websites providing educational information about rheumatoid arthritis (RA) and evaluated the quality of these websites. We searched three separate search engines, Google, Bing, and Ask.com, on August 27, 2015, using two search terms, "arthritis" and "rheumatoid." Only patient education websites were included. Two independent investigators evaluated the accuracy, completeness, technical elements, design and esthetics, readability, usability, and accessibility of the websites. The navigation experience was also evaluated by an adult training expert. We identified 46 websites. Nearly all websites (98%) provided accurate information. However, no website covered all essential RA topics. Common essential topics not covered included epidemiology, pathogenesis, treatment and disease monitoring, complications, self-management, risks and benefits of treatment, prognosis, treatment adherence, questions for patients to ask their doctors, and costs. For the technical elements, all websites disclosed their ownership, but the date that the content was last updated was mentioned in only 10 websites, ranging from 2007 to 2015. The mean reading level was grade 12.1 (standard deviation ±2.3). Most websites (78%) were easy to navigate but only 33% were friendly for people with visual and/or hearing impairments. The navigation experience was rated fair or poor in 41% of the websites. Current patient information on the Internet does not comprehensively address all educational needs of patients with RA, and is often outdated. The findings from our study highlight potential areas for improvement in online education materials for patients with RA. Copyright © 2017. Published by Elsevier Inc.

A Novel Highly Bioavailable Curcumin Formulation Improves Symptoms and Diagnostic Indicators in Rheumatoid Arthritis Patients: A Randomized, Double-Blind, Placebo-Controlled, Two-Dose, Three-Arm, and Parallel-Group Study.

PubMed

Amalraj, Augustine; Varma, Karthik; Jacob, Joby; Divya, Chandradhara; Kunnumakkara, Ajaikumar B; Stohs, Sidney J; Gopi, Sreeraj

2017-10-01

Rheumatoid arthritis (RA) is an autoimmune, chronic systemic inflammatory disorder. The long-term use of currently available drugs for the treatment of RA has many potential side effects. Natural phytonutrients may serve as alternative strategies for the safe and effective treatment of RA, and curcuminoids have been used in Ayurvedic medicine for the treatment of inflammatory conditions for centuries. In this study, a novel, highly bioavailable form of curcumin in a completely natural turmeric matrix was evaluated for its ability to improve the clinical symptoms of RA. A randomized, double-blind, placebo-controlled, three-arm, parallel-group study was conducted to evaluate the comparative efficacy of two different doses of curcumin with that of a placebo in active RA patients. Twelve patients in each group received placebo, 250 or 500 mg of the curcumin product twice daily for 90 days. The responses of the patients were assessed using the American College of Rheumatology (ACR) response, visual analog scale (VAS), C-reactive protein (CRP), Disease Activity Score 28 (DAS28), erythrocyte sedimentation rate (ESR), and rheumatoid factor (RF) values. RA patients who received the curcumin product at both low and high doses reported statistically significant changes in their clinical symptoms at the end of the study. These observations were confirmed by significant changes in ESR, CPR, and RF values in patients receiving the study product compared to baseline and placebo. The results indicate that this novel curcumin in a turmeric matrix acts as an analgesic and anti-inflammatory agent for the management of RA at a dose as low as 250 mg twice daily as evidenced by significant improvement in the ESR, CRP, VAS, RF, DAS28, and ACR responses compared to placebo. Both doses of the study product were well tolerated and without side effects.

Expression of the Inherently Autoreactive Idiotope 9G4 on Autoantibodies to Citrullinated Peptides and on Rheumatoid Factors in Patients with Early and Established Rheumatoid Arthritis

PubMed Central

Cambridge, Geraldine; Moura, Rita A.; Santos, Tania; Khawaja, Akif A.; Polido-Pereira, Joaquim; Canhão, Helena; Leandro, Maria J.; Fonseca, João E.

2014-01-01

Background The pre-symptomatic stage of Rheumatoid arthritis (RA) is associated with pro-inflammatory cytokines and autoantibodies. High levels and epitope spread by Rheumatoid factors (RhF) and autoantibodies to citrullinated proteins signify progression towards disease expression. In established RA, the persistence of high autoantibody levels reflects production by both long-lived plasma cells and short-lived plasmablasts. Neither the relative contributions to pathogenesis by autoantibodies from either source, nor the factors responsible for deciding the fate of autoantigen specific ‘parent’ B-cells, is understood. Phenotypic markers identifying subsets of autoreactive B-cells are therefore of interest in understanding the origin and perpetuation of the autoimmune response in RA. One such phenotypic marker is the rat monoclonal antibody, 9G4, which recognises an idiotope on immunoglobuins derived from the inherently autoreactive VH-gene, VH4-34. We therefore investigated whether the 9G4 idiotope was expressed on autoantibodies in patients with RA. Methodology/Principal Findings Sera from 19 patients with established RA and those with <1year history of untreated polyarthritis either resolving into RA (n = 42) or non-RA diagnosis (n = 31) were included. Autoantibodies to cyclic citrullinated peptides (CCP), RhF and co-expression of the 9G4 idiotope were measured by ELISA. 9G4 recognised a population of anti-CCP antibodies in the majority of sera from patients with established disease and also in samples from patients with early disaese. 9G4+RhF levels were generally lower and not associated with positivity for, or levels of 9G4+CCP. Conclusions/Significance The persistence of 9G4+ immunoglobulins, of any isotype, in serum is rare. We describe here the novel finding of 9G4 expression on anti-CCP antibodies in patients from the earliest symptoms of RA through to established disease. Our results suggest that 9G4 expression on anti-CCP autoantibodies was not due to polyclonal expansion of VH4-34-encoded immunoglobulins. These studies may therefore provide a new focus for investigation into the evolution of the autoimmune response in RA patients. PMID:25222933

Baricitinib in Patients with Rheumatoid Arthritis and an Inadequate Response to Conventional Disease-Modifying Antirheumatic Drugs in United States and Rest of World: A Subset Analysis.

PubMed

Wells, Alvin F; Greenwald, Maria; Bradley, John D; Alam, Jahangir; Arora, Vipin; Kartman, Cynthia E

2018-06-01

This article evaluates the efficacy and safety of baricitinib 4 mg versus placebo in United States including Puerto Rico (US) and rest of the world (ROW) subpopulations using data pooled from RA-BEAM and RA-BUILD, which enrolled patients with moderate-to-severe adult-onset rheumatoid arthritis (RA). In RA-BEAM, patients with an inadequate response (IR) to methotrexate, at least one X-ray erosion, and high sensitivity C-reactive protein (hsCRP) ≥ 6 mg/L were randomized to placebo or orally administered baricitinib 4 mg daily or subcutaneously administered adalimumab 40 mg every other week. In RA-BUILD, patients with an IR to at least one conventional synthetic disease-modifying antirheumatic drug (csDMARD) and with hsCRP ≥ 3.6 mg/L were randomized to placebo or baricitinib 2 or 4 mg daily. Patients in both trials were biologic naive. In this post hoc analysis, data from both studies were pooled (714 baricitinib 4 mg-treated, 716 placebo-treated patients). Overall, 188 US and 1242 ROW patients were included. Subgroups differed in baseline characteristics including race, weight, age, time since RA diagnosis, current corticosteroid use, and previous csDMARD use. At weeks 12 and 24, baricitinib-treated patients had larger responses compared to placebo-treated patients for multiple efficacy outcomes: American College of Rheumatology 20/50/70 response, low disease activity, remission, Disease Activity Score 28-C-reactive protein, and Health Assessment Questionnaire-Disability Index. Overall, similar efficacy was observed in US and ROW subgroups with no notable safety differences between subgroups at weeks 12 or 24. Baricitinib 4 mg was efficacious compared to placebo in US and ROW subpopulations. Safety was similar between subgroups. Eli Lilly & Company and Incyte Corporation. ClinicalTrials.gov identifiers, NCT01721057; NCT01710358.

U-series dating of Lake Nyos maar basalts, Cameroon (West Africa): Implications for potential hazards on the Lake Nyos dam

NASA Astrophysics Data System (ADS)

Aka, Festus T.; Yokoyama, Tetsuya; Kusakabe, Minoru; Nakamura, Eizo; Tanyileke, Gregory; Ateba, Bekoa; Ngako, Vincent; Nnange, Joseph; Hell, Joseph

2008-09-01

From previously published 14C and K-Ar data, the age of formation of Lake Nyos maar in Cameroon is still in dispute. Lake Nyos exploded in 1986, releasing CO 2 that killed 1750 people and over 3000 cattle. Here we report results of the first measurements of major elements, trace elements and U-series disequilibria in ten basanites/trachy-basalts and two olivine tholeiites from Lake Nyos. It is the first time tholeiites are described in Lake Nyos. But for the tholeiites which are in 238U- 230Th equilibrium, all the other samples possess 238U- 230Th disequilibrium with 15 to 28% enrichment of 230Th over 238U. The ( 226Ra/ 230Th) activity ratios of these samples indicate small (2 to 4%) but significant 226Ra excesses. U-Th systematics and evidence from oxygen isotopes of the basalts and Lake Nyos granitic quartz separates show that the U-series disequilibria in these samples are source-based and not due to crustal contamination or post-eruptive alteration. Enrichment of 230Th is strong prima facie evidence that Lake Nyos is younger than 350 ka. The 230Th- 226Ra age of Nyos samples calculated with the ( 226Ra/ 230Th) ratio for zero-age Mt. Cameroon samples is 3.7 ± 0.5 ka, although this is a lower limit as the actual age is estimated to be older than 5 ka, based on the measured mean 230Th/ 238U activity ratio. The general stability of the Lake Nyos pyroclastic dam is a cause for concern, but judging from its 230Th- 226Ra formation age, we do not think that in the absence of a big rock fall or landslide into the lake, a big earthquake or volcanic eruption close to the lake, collapse of the dam from erosion alone is as imminent and alarming as has been suggested.

Differential modulation of right ventricular strain and right atrial mechanics in mild vs. severe pressure overload

PubMed Central

Voeller, Rochus K.; Aziz, Abdulhameed; Maniar, Hersh S.; Ufere, Nneka N.; Taggar, Ajay K.; Bernabe, Noel J.; Cupps, Brian P.

2011-01-01

Increased right atrial (RA) and ventricular (RV) chamber volumes are a late maladaptive response to chronic pulmonary hypertension. The purpose of the current investigation was to characterize the early compensatory changes that occur in the right heart during chronic RV pressure overload before the development of chamber dilation. Magnetic resonance imaging with radiofrequency tissue tagging was performed on dogs at baseline and after 10 wk of pulmonary artery banding to yield either mild RV pressure overload (36% rise in RV pressure; n = 5) or severe overload (250% rise in RV pressure; n = 4). The RV free wall was divided into three segments within a midventricular plane, and circumferential myocardial strain was calculated for each segment, the septum, and the left ventricle. Chamber volumes were calculated from stacked MRI images, and RA mechanics were characterized by calculating the RA reservoir, conduit, and pump contribution to RV filling. With mild RV overload, there were no changes in RV strain or RA function. With severe RV overload, RV circumferential strain diminished by 62% anterior (P = 0.04), 42% inferior (P = 0.03), and 50% in the septum (P = 0.02), with no change in the left ventricle (P = 0.12). RV filling became more dependent on RA conduit function, which increased from 30 ± 9 to 43 ± 13% (P = 0.01), than on RA reservoir function, which decreased from 47 ± 6 to 33 ± 4% (P = 0.04), with no change in RA pump function (P = 0.94). RA and RV volumes and RV ejection fraction were unchanged from baseline during either mild (P > 0.10) or severe RV pressure overload (P > 0.53). In response to severe RV pressure overload, RV myocardial strain is segmentally diminished and RV filling becomes more dependent on RA conduit rather than reservoir function. These compensatory mechanisms of the right heart occur early in chronic RV pressure overload before chamber dilation develops. PMID:21926343

The changing face of nanomaterials: Risk assessment challenges along the value chain.

PubMed

Mattsson, Mats-Olof; Simkó, Myrtill

2017-03-01

Risk assessment (RA) of manufactured nanomaterials (MNM) is essential for regulatory purposes and risk management activities. Similar to RA of "classical" chemicals, MNM RA requires knowledge about exposure as well as of hazard potential and dose response relationships. What makes MNM RA especially challenging is the multitude of materials (which is expected to increase substantially in the future), the complexity of MNM value chains and life cycles, the accompanying possible changes in material properties over time and in contact with various environmental and organismal milieus, and the difficulties to obtain proper exposure data and to consider the proper dose metric. This article discusses these challenges and also critically overviews the current state of the art regarding MNM RA approaches. Copyright © 2016 Elsevier Inc. All rights reserved.

Treatment of rheumatoid arthritis: a global perspective on the use of antirheumatic drugs

PubMed Central

Envalds, Minja; Pincus, Theodore

2008-01-01

Modern therapy for rheumatoid arthritis (RA) is based on knowledge of the severity of the natural history of the disease. RA patients are approached with early and aggressive treatment strategies, methotrexate as an anchor drug, biological targeted therapies in those with inadequate response to methotrexate, and “tight control,” aiming for remission and low disease activity according to quantitative monitoring. This chapter presents a rationale for current treatment strategies for RA with antirheumatic drugs, a review of published reports concerning treatments in clinical cohorts outside of clinical trials, and current treatments at 61 sites in 21 countries in the QUEST-RA database. PMID:18437286

[Garlic effectiveness in rheumatoid arthritis].

PubMed

Denisov, L N; Andrianova, I V; Timofeeva, S S

1999-01-01

To perform of clinical trial of alisate--a garlic preparation produced in Russia. An open controlled trial of alisate enrolled 30 patients with rheumatoid arthritis (RA). 15 patients with RA of varying clinical form, stage and activity were given alisate in a dose 300 mg (1 tablet) twice a day for 4-6 weeks. 15 control RA patients received conventional antirheumatic therapy. The alisate group achieved a good and partial response in 86.5% of cases. The drug was well tolerated and had no side effects. In control group, some parameters changed for the worse. Alisate can be recommended for treatment of RA patients in combined and monotherapy.

Oral Vitamin A and Retinoic Acid Supplementation Stimulates Antibody Production and Splenic Stra6 Expression in Tetanus Toxoid–Immunized Mice12

PubMed Central

Tan, Libo; Wray, Amanda E.; Ross, A. Catharine

2012-01-01

Coadministration of retinoic acid (RA) and polyinosinic acid:polycytidylic acid (PIC) has been shown to cooperatively enhance the anti–tetanus toxoid (anti-TT) vaccine response in adult mice. Germinal center formation in the spleen is critical for a normal antibody response. Recent studies have identified Stimulated by Retinoic Acid-6 (Stra6) as the cell membrane receptor for retinol-binding protein (RBP) in many organs, including spleen. The objectives of the present studies were to test whether orally administered vitamin A (VA) itself, either alone or combined with RA, and/or treatment with PIC regulates Stra6 gene expression in mouse spleen and, concomitantly, antibody production. Eight-week-old C57BL/6 mice were immunized with TT. In an initial kinetic study, oral VA (6 mg/kg) increased anti-TT IgM and IgG production as well as splenic Stra6 mRNA expression. In treatment studies that were analyzed 9 d postimmunization, retinoids including VA, RA, VA and RA combined, and PIC significantly increased plasma anti-TT IgM and IgG (P < 0.05) and splenic Stra6 mRNA (P < 0.05). Treatments that included PIC elevated plasma anti-TT IgM and IgG concentrations >20-fold (P < 0.01). Immunohistochemistry of STRA6 protein in mouse spleen confirmed its increase after immunization and retinoid treatment. In conclusion, retinoid treatments that included VA, RA, VA and RA combined, and the combination of retinoid and PIC stimulated the expression of Stra6 in spleen, which potentially could increase the local uptake of retinol. Concomitantly, these treatments increased the systemic antigen-specific antibody response. The ability of oral retinoids to stimulate systemic immunity has implications for public health and therapeutic use of VA. PMID:22739370

Non-Esterified Fatty Acids Profiling in Rheumatoid Arthritis: Associations with Clinical Features and Th1 Response.

PubMed

Rodríguez-Carrio, Javier; Alperi-López, Mercedes; López, Patricia; Ballina-García, Francisco Javier; Suárez, Ana

2016-01-01

Since lipid compounds are known to modulate the function of CD4+ T-cells and macrophages, we hypothesize that altered levels of serum non-esterified fatty acids (NEFA) may underlie rheumatoid arthritis (RA) pathogenesis. Serum levels of NEFA (palmitic, stearic, palmitoleic, oleic, linoleic, γ-linoleic, arachidonic -AA-, linolenic, eicosapentaenoic -EPA- and docosahexaenoic -DHA-) were quantified by LC-MS/MS after methyl-tert-butylether (MTBE)-extraction in 124 RA patients and 56 healthy controls (HC). CD4+ phenotype was studied by flow cytometry. TNFα, IL-8, VEGF, GM-CSF, IFNγ, IL-17, CCL2, CXCL10, leptin and resistin serum levels were quantified by immunoassays. The effect of FA on IFNγ production by PBMC was evaluated in vitro. Lower levels of palmitic (p<0.0001), palmitoleic (p = 0.002), oleic (p = 0.010), arachidonic (p = 0.027), EPA (p<0.0001) and DHA (p<0.0001) were found in RA patients, some NEFA being altered at onset. Cluster analysis identified a NEFA profile (hallmarked by increased stearic and decreased EPA and DHA) overrepresented in RA patients compared to HC (p = 0.002), being associated with clinical features (RF, shared epitope and erosions), increased IFNγ expression in CD4+ T-cells (p = 0.002) and a Th1-enriched serum milieu (IFNγ, CCL2 and CXCL10, all p<0.005). In vitro assays demonstrated that imbalanced FA could underlie IFNγ production by CD4+ T-cells. Finally, changes on NEFA levels were associated with clinical response upon TNFα-blockade. An altered NEFA profile can be found in RA patients associated with clinical characteristics of aggressive disease and enhanced Th1 response. These results support the relevance of lipidomic studies in RA and provide a rationale for new therapeutic targets.

Cardamonin (2',4'-dihydroxy-6'-methoxychalcone) isolated from Boesenbergia rotunda (L.) Mansf. inhibits CFA-induced rheumatoid arthritis in rats.

PubMed

Voon, Fui-Ling; Sulaiman, Mohd Roslan; Akhtar, Muhammad Nadeem; Idris, Mohamad Fauzi; Akira, Ahmad; Perimal, Enoch Kumar; Israf, Daud Ahmad; Ming-Tatt, Lee

2017-01-05

Boesenbergia rotunda (L.) Mansf. had been traditionally used as herbs to treat pain and rheumatism. Cardamonin (2',4'-dihydroxy-6'-methoxychalcone) is a compound isolated from Boesenbergia rotunda (L.) Mansf.. Previous study had shown the potential of cardamonin in inhibiting the release of pro-inflammatory cytokines such as tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) in vitro. Thus, the possible therapeutic effect of cardamonin in the rheumatoid arthritis (RA) joints is postulated. This study was performed to investigate the anti-arthritic properties of cardamonin in rat model of induced RA, particularly on the inflammatory and pain response of RA. Rheumatoid arthritis paw inflammation was induced by intraplantar (i.pl.) injection of complete Freund's adjuvant (CFA) in Sprague Dawley rats. Using four doses of cardamonin (0.625, 1.25, 2.5, and 5.0mg/kg), anti-arthritic activity was evaluated through the paw edema, mechanical allodynia and thermal hyperalgesia responses. Enzyme-linked immunosorbent assay (ELISA) was carried out to evaluate the plasma level of TNF-α, IL-1β, and IL-6. Histological slides were prepared from the harvested rat paws to observe the arthritic changes in the joints. Behavioral, biochemical, and histological studies showed that cardamonin demonstrated significant inhibition on RA-induced inflammatory and pain responses as well as progression of joint destruction in rats. ELISA results showed that there was significant inhibition in TNF-α, IL-1β, and IL-6 levels in plasma of the cardamonin-treated RA rats. Overall, cardamonin possesses potential anti-arthritic properties in CFA-induced RA rat model. Copyright © 2016 Elsevier B.V. All rights reserved.

Early induction of IL-1 receptor antagonist (IL-1Ra) in infants and children undergoing surgery.

PubMed Central

O Nualláin, E M; Puri, P; Reen, D J

1993-01-01

The cytokine response to injury or trauma is of interest in terms of both its mediation of the acute phase response and its possible relation to the immunological depression observed after major surgery. In this study, the production of cytokines IL-1 beta, tumour necrosis factor-alpha (TNF-alpha), IL-6 and the naturally occurring inhibitor of IL-1, IL-1Ra, have been investigated in infants and children undergoing Swenson's pull-through operation for Hirschsprung's disease. Samples of peripheral blood were taken before, during and after surgery for the measurement of cytokines. IL-1Ra levels increased significantly (P < 0.01) at 2 h after commencement of surgery, with maximal levels for individual patients being attained between 3 h and 5 h (range 7.6-67.9 ng/ml). The mean level of IL-1Ra was maximal (26.2 ng/ml) at 5 h and returned to baseline levels between 24 h and 72 h. There were no changes observed in the circulating levels of IL-1 beta in nine out of 11 patients following commencement of surgery. TNF-alpha levels did not increase in any of the patients studied. IL-6 levels increased significantly (P < 0.02) 3 h after commencement of surgery, reaching maximum concentrations at 24 h (range 20-670 pg/ml), with levels falling between 48 h and 72 h. This study demonstrates, in vivo, the independent induction of IL-1Ra without a concomitant increase of IL-1 beta levels after major surgery. It also shows that IL-1Ra is the earliest cytokine produced in response to surgical stress. PMID:8348747

Blue light potentiates neurogenesis induced by retinoic acid-loaded responsive nanoparticles.

PubMed

Santos, Tiago; Ferreira, Raquel; Quartin, Emanuel; Boto, Carlos; Saraiva, Cláudia; Bragança, José; Peça, João; Rodrigues, Cecília; Ferreira, Lino; Bernardino, Liliana

2017-09-01

Neurogenic niches constitute a powerful endogenous source of new neurons that can be used for brain repair strategies. Neuronal differentiation of these cells can be regulated by molecules such as retinoic acid (RA) or by mild levels of reactive oxygen species (ROS) that are also known to upregulate RA receptor alpha (RARα) levels. Data showed that neural stem cells from the subventricular zone (SVZ) exposed to blue light (405nm laser) transiently induced NADPH oxidase-dependent ROS, resulting in β-catenin activation and neuronal differentiation, and increased RARα levels. Additionally, the same blue light stimulation was capable of triggering the release of RA from light-responsive nanoparticles (LR-NP). The synergy between blue light and LR-NP led to amplified neurogenesis both in vitro and in vivo, while offering a temporal and spatial control of RA release. In conclusion, this combinatory treatment offers great advantages to potentiate neuronal differentiation, and provides an innovative and efficient application for brain regenerative therapies. Controlling the differentiation of stem cells would support the development of promising brain regenerative therapies. Blue light transiently increased reactive oxygen species, resulting in neuronal differentiation and increased retinoic acid receptor (RARα) levels. Additionally, the same blue light stimulation was capable of triggering the release of RA from light-responsive nanoparticles (LR-NP). The synergy between blue light and LR-NP led to amplified neurogenesis, while offering a temporal and spatial control of RA release. In this sense, our approach relying on the modulation of endogenous stem cells for the generation of new neurons may support the development of novel clinical therapies. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Improving B-cell depletion in systemic lupus erythematosus and rheumatoid arthritis.

PubMed

Mota, Pedro; Reddy, Venkat; Isenberg, David

2017-07-01

Rituximab-based B-cell depletion (BCD) therapy is effective in refractory rheumatoid arthritis (RA) and although used to treat patients with refractory systemic lupus erythematosus (SLE) in routine clinical practice, rituximab failed to meet the primary endpoints in two large randomised controlled trials (RCTs) of non-renal (EXPLORER) and renal (LUNAR) SLE. Areas covered: We review how BCD could be improved to achieve better clinical responses in RA and SLE. Insights into the variability in clinical response to BCD in RA and SLE may help develop new therapeutic strategies. To this end, a literature search was performed using the following terms: rheumatoid arthritis, systemic erythematosus lupus, rituximab and B-cell depletion. Expert commentary: Poor trial design may have, at least partly, contributed to the apparent lack of response to BCD in the two RCTs of patients with SLE. Enhanced B-cell depletion and/or sequential therapy with belimumab may improve clinical response at least in some patients with SLE.

Genome-wide association study of response to methotrexate in early rheumatoid arthritis patients.

PubMed

Taylor, John C; Bongartz, Tim; Massey, Jonathan; Mifsud, Borbala; Spiliopoulou, Athina; Scott, Ian C; Wang, Jianmei; Morgan, Michael; Plant, Darren; Colombo, Marco; Orchard, Peter; Twigg, Sarah; McInnes, Iain B; Porter, Duncan; Freeston, Jane E; Nam, Jackie L; Cordell, Heather J; Isaacs, John D; Strathdee, Jenna L; Arnett, Donna; de Hair, Maria J H; Tak, Paul P; Aslibekyan, Stella; van Vollenhoven, Ronald F; Padyukov, Leonid; Bridges, S Louis; Pitzalis, Costantino; Cope, Andrew P; Verstappen, Suzanne M M; Emery, Paul; Barnes, Michael R; Agakov, Felix; McKeigue, Paul; Mushiroda, Taisei; Kubo, Michiaki; Weinshilboum, Richard; Barton, Anne; Morgan, Ann W; Barrett, Jennifer H

2018-05-25

Methotrexate (MTX) monotherapy is a common first treatment for rheumatoid arthritis (RA), but many patients do not respond adequately. In order to identify genetic predictors of response, we have combined data from two consortia to carry out a genome-wide study of response to MTX in 1424 early RA patients of European ancestry. Clinical endpoints were change from baseline to 6 months after starting treatment in swollen 28-joint count, tender 28-joint count, C-reactive protein and the overall 3-component disease activity score (DAS28). No single nucleotide polymorphism (SNP) reached genome-wide statistical significance for any outcome measure. The strongest evidence for association was with rs168201 in NRG3 (p = 10 -7 for change in DAS28). Some support was also seen for association with ZMIZ1, previously highlighted in a study of response to MTX in juvenile idiopathic arthritis. Follow-up in two smaller cohorts of 429 and 177 RA patients did not support these findings, although these cohorts were more heterogeneous.

Anti-inflammatory cytokines in gingival crevicular fluid in patients with periodontitis and rheumatoid arthritis: a preliminary report.

PubMed

Bozkurt, Fatma Yeşim; Yetkin Ay, Zuhal; Berker, Ezel; Tepe, Eser; Akkuş, Selami

2006-08-01

Cytokines which are produced by host cells play an important role in pathogenesis both rheumatoid arthritis (RA) and chronic periodontitis (CP). In this study, we aim to investigate the levels of Interleukin (IL)-4 and IL-10 in gingival crevicular fluid (GCF). Seventeen patients with CP, 17 patients with RA and 17 healthy controls (HC) were included. The RA group was divided into two groups according to gingival sulcus depths (RA-a: PD < or =3mm, (n=12), RA-b: PD>3mm, (n=5)). For each patient, clinical parameters were recorded. The GCF samples were evaluated by enzyme-linked immunosorbent assay (ELISA) for IL-4 and IL-10 levels. IL-4 levels in the RA-a, RA-b and CP subjects were significantly lower compared to the HC subjects (p<0.05). The mean level of IL-4 in RA-b group was significantly higher than that in CP group (p<0.05). IL-10 mean level in the HC group was higher than those in the other groups (p<0.05). In the RA-a group, higher IL-10 level was found compared to the CP patients (p<0.05). Within the limitations of this preliminary report, it can be concluded that the initiation and progression of periodontal inflammation may be due to a lack or inappropriate response of the anti-inflammatory cytokines in both CP and RA.

Interferon regulatory factor-1 binds c-Cbl, enhances mitogen activated protein kinase signaling and promotes retinoic acid-induced differentiation of HL-60 human myelo-monoblastic leukemia cells.

PubMed

Shen, Miaoqing; Bunaciu, Rodica P; Congleton, Johanna; Jensen, Holly A; Sayam, Lavanya G; Varner, Jeffrey D; Yen, Andrew

2011-12-01

All-trans retinoic acid (RA) and interferons (IFNs) have efficacy in treating certain leukemias and lymphomas, respectively, motivating interest in their mechanism of action to improve therapy. Both RA and IFNs induce interferon regulatory factor-1 (IRF-1). We find that in HL-60 myeloblastic leukemia cells which undergo mitogen activated protien kinase (MAPK)-dependent myeloid differentiation in response to RA, IRF-1 propels differentiation. RA induces MAPK-dependent expression of IRF-1. IRF-1 binds c-Cbl, a MAPK related adaptor. Ectopic IRF-1 expression causes CD38 expression and activation of the Raf/MEK/ERK axis, and enhances RA-induced differentiation by augmenting CD38, CD11b, respiratory burst and G0 arrest. Ectopic IRF-1 expression also decreases the activity of aldehyde dehydrogenase 1, a stem cell marker, and enhances RA-induced ALDH1 down-regulation. Interestingly, expression of aryl hydrocarbon receptor (AhR), which is RA-induced and known to down-regulate Oct4 and drive RA-induced differentiation, also enhances IRF-1 expression. The data are consistent with a model whereby IRF-1 acts downstream of RA and AhR to enhance Raf/MEK/ERK activation and propel differentiation.

Activation of the CRABPII/RAR pathway by curcumin induces retinoic acid mediated apoptosis in retinoic acid resistant breast cancer cells

PubMed Central

Thulasiraman, Padmamalini; Garriga, Galen; Danthuluri, Veena; McAndrews, Daniel J.; Mohiuddin, Imran Q.

2017-01-01

Due to the anti-proliferative and anti-apoptotic effects of retinoic acid (RA), this hormone has emerged as a target for several diseases, including cancer. However, development of retinoid resistance is a critical issue and efforts to understand the retinoid signaling pathway may identify useful biomarkers for future clinical trials. Apoptotic responses of RA are exhibited through the cellular RA-binding protein II (CRABPII)/retinoic acid receptor (RAR) signaling cascade. Delivery of RA to RAR by CRABPII enhances the transcriptional activity of genes involved in cell death and cell cycle arrest. The purpose of this study was to investigate the role of curcumin in sensitizing RA-resistant triple-negative breast cancer (TNBC) cells to RA-mediated apoptosis. We provide evidence that curcumin upregulates the expression of CRABPII, RARβ and RARγ in two different TNBC cell lines. Co-treatment of the cells with curcumin and RA results in increased apoptosis as demonstrated by elevated cleavage of poly(ADP-ribose) polymerase and cleaved caspase-9. Additionally, silencing CRABPII reverses curcumin sensitization of TNBC cells to the apoptotic inducing effects of RA. These findings provide mechanistic insights into sensitizing TNBC cells to RA-mediated cell death by curcumin-induced upregulation of the CRABPII/RAR pathway. PMID:28350049

Epidemiology of Rheumatoid Arthritis in Southern Albania.

PubMed

Koko, Vjollca; Ndrepepa, Ana; Skenderaj, Skender

2015-06-01

The aim of this study was to assess the prevalence, incidence and the burden of rheumatoid arthritis (RA) in the Southern Albania. This is an epidemiologic observational study with cross-sectional analyses of all patients with RA who lived in Southern Albania during the 1995-2011 years. The RA prevalence, incidence and disability-adjusted life years (DALY) were assessed. During the 1995-2011 years, 194 patients (154 females and 40 males) with RA living in Southern Albania were identified. The prevalence of RA in 2011 was 0.25% in general population and 0.34% in adult (>14 years) population. The incidence of RA in 2011 was 0.012% (12 new cases per 100000 inhabitants) and 0.016% (16 new cases per 100000 adults). The prevalence increased (from 0.036% in 1996 to 0.25% in 2011) and the incidence did not change over the study period. The mortality was 3.2% (n=7 deaths). The DALY due to RA was 823 years per 100000 inhabitants during 1995-2011 years. RA in Southern Albania has a prevalence of 0.25 % and an annual incidence of 0.012% in the general population in 2011. RA was responsible for a considerable burden on the health of population during the 1995-2011 years.

Epidemiology of Rheumatoid Arthritis in Southern Albania

PubMed Central

Koko, Vjollca; Ndrepepa, Ana; Skenderaj, Skender

2015-01-01

Objectives: The aim of this study was to assess the prevalence, incidence and the burden of rheumatoid arthritis (RA) in the Southern Albania. Material and Methods: This is an epidemiologic observational study with cross-sectional analyses of all patients with RA who lived in Southern Albania during the 1995-2011 years. The RA prevalence, incidence and disability-adjusted life years (DALY) were assessed. Results: During the 1995-2011 years, 194 patients (154 females and 40 males) with RA living in Southern Albania were identified. The prevalence of RA in 2011 was 0.25% in general population and 0.34% in adult (>14 years) population. The incidence of RA in 2011 was 0.012% (12 new cases per 100000 inhabitants) and 0.016% (16 new cases per 100000 adults). The prevalence increased (from 0.036% in 1996 to 0.25% in 2011) and the incidence did not change over the study period. The mortality was 3.2% (n=7 deaths). The DALY due to RA was 823 years per 100000 inhabitants during 1995-2011 years. Conclusion: RA in Southern Albania has a prevalence of 0.25 % and an annual incidence of 0.012% in the general population in 2011. RA was responsible for a considerable burden on the health of population during the 1995-2011 years. PMID:26236163

Current and future pharmaceutical therapy for rheumatoid arthritis.

PubMed

Ruderman, Eric M

2005-01-01

Rheumatoid arthritis (RA) is a chronic, inflammatory arthritis with a population prevalence of approximately 1%. Pharmaceutical treatment includes both anti-inflammatory medications and disease modifying drugs (DMARDs) that impact the course of the damage associated with this disease. Traditional DMARD therapy includes immunomodulatory agents such as methotrexate, used both alone and in combination. Recently available biologic response modifiers are very effective at reducing both the clinical symptoms of disease and the radiographic damage that accompanies them. This manuscript describes the clinical assessments used to measure response to therapy in RA and reviews the results seen with the various treatment strategies in this disease. In addition, the clinical and structural outcomes seen in trials of newly available and pending biologic therapies are reviewed, along with the specific toxicity issues associated with these agents. Clinical trial data is reviewed for the TNF antagonists, which have become the standard of care in RA patients with an inadequate response to methotrexate. RA has been clearly shown to be a destructive and disabling disease. The widespread use of newer agents, however, along with more aggressive use of existing therapies, appears to limit disease progression very effectively, and should lead to better long-term outcomes for these patients.

Toxic airborne S, PAH, and trace element legacy of the superhigh-organic-sulphur Raša coal combustion: Cytotoxicity and genotoxicity assessment of soil and ash.

PubMed

Medunić, Gordana; Ahel, Marijan; Mihalić, Iva Božičević; Srček, Višnja Gaurina; Kopjar, Nevenka; Fiket, Željka; Bituh, Tomislav; Mikac, Iva

2016-10-01

This paper presents the levels of sulphur, polycyclic aromatic hydrocarbons (PAHs), and potentially toxic trace elements in soils surrounding the Plomin coal-fired power plant (Croatia). It used domestic superhigh-organic-sulphur Raša coal from 1970 until 2000. Raša coal was characterised by exceptionally high values of S, up to 14%, making the downwind southwest (SW) area surrounding the power plant a significant hotspot. The analytical results show that the SW soil locations are severely polluted with S (up to 4%), and PAHs (up to 13,535ng/g), while moderately with Se (up to 6.8mg/kg), and Cd (up to 4.7mg/kg). The composition and distribution pattern of PAHs in the polluted soils indicate that their main source could be airborne unburnt coal particles. The atmospheric dispersion processes of SO2 and ash particles have influenced the composition and distribution patterns of sulphur and potentially toxic trace elements in studied soils, respectively. A possible adverse impact of analysed soil on the local karstic environment was evaluated by cytotoxic and genotoxic methods. The cytotoxicity effects of soil and ash water extracts on the channel catfish ovary (CCO) cell line were found to be statistically significant in the case of the most polluted soil and ash samples. However, the primary DNA-damaging potential of the most polluted soil samples on the CCO cells was found to be within acceptable boundaries. Copyright © 2016 Elsevier B.V. All rights reserved.

Vectra DA for the objective measurement of disease activity in patients with rheumatoid arthritis.

PubMed

Segurado, O G; Sasso, E H

2014-01-01

Quantitative and regular assessment of disease activity in rheumatoid arthritis (RA) is required to achieve treatment targets such as remission and to optimize clinical outcomes. To assess inflammation accurately, predict joint damage and monitor treatment response, a measure of disease activity in RA should reflect the pathological processes resulting in irreversible joint damage and functional disability. The Vectra DA blood test is an objective measure of disease activity for patients with RA. Vectra DA provides an accurate, reproducible score on a scale of 1 to 100 based on the concentrations of 12 biomarkers that reflect the pathophysiologic diversity of RA. The analytical validity, clinical validity, and clinical utility of Vectra DA have been evaluated for patients with RA in registries and prospective and retrospective clinical studies. As a biomarker-based instrument for assessing disease activity in RA, the Vectra DA test can help monitor therapeutic response to methotrexate and biologic agents and assess clinically challenging situations, such as when clinical measures are confounded by non-inflammatory pain from fibromyalgia. Vectra DA scores correlate with imaging of joint inflammation and are predictive for radiographic progression, with high Vectra DA scores being associated with more frequent and severe progression and low scores being predictive for non-progression. In summary, the Vectra DA score is an objective measure of RA disease activity that quantifies inflammatory status. By predicting risk for joint damage more effectively than conventional clinical and laboratory measures, it has the potential to complement these measures and optimise clinical decision making.

Renal responses of trout to chronic respiratory and metabolic acidoses and metabolic alkalosis.

PubMed

Wood, C M; Milligan, C L; Walsh, P J

1999-08-01

Exposure to hyperoxia (500-600 torr) or low pH (4.5) for 72 h or NaHCO(3) infusion for 48 h were used to create chronic respiratory (RA) or metabolic acidosis (MA) or metabolic alkalosis in freshwater rainbow trout. During alkalosis, urine pH increased, and [titratable acidity (TA) - HCO(-)(3)] and net H(+) excretion became negative (net base excretion) with unchanged NH(+)(4) efflux. During RA, urine pH did not change, but net H(+) excretion increased as a result of a modest rise in NH(+)(4) and substantial elevation in [TA - HCO(-)(3)] efflux accompanied by a large increase in inorganic phosphate excretion. However, during MA, urine pH fell, and net H(+) excretion was 3.3-fold greater than during RA, reflecting a similar increase in [TA - HCO(-)(3)] and a smaller elevation in phosphate but a sevenfold greater increase in NH(+)(4) efflux. In urine samples of the same pH, [TA - HCO(-)(3)] was greater during RA (reflecting phosphate secretion), and [NH(+)(4)] was greater during MA (reflecting renal ammoniagenesis). Renal activities of potential ammoniagenic enzymes (phosphate-dependent glutaminase, glutamate dehydrogenase, alpha-ketoglutarate dehydrogenase, alanine aminotransferase, phosphoenolpyruvate carboxykinase) and plasma levels of cortisol, phosphate, ammonia, and most amino acids (including glutamine and alanine) increased during MA but not during RA, when only alanine aminotransferase increased. The differential responses to RA vs. MA parallel those in mammals; in fish they may be keyed to activation of phosphate secretion by RA and cortisol mobilization by MA.

[T-lymphocytes--do they control rheumatic immune responses?].

PubMed

Wagner, U; Schulze-Koops, H

2005-09-01

T cells, in particular CD4(+) T cells, have been implicated in mediating many aspects of rheumatoid inflammation. In rheumatoid arthritis (RA), CD4(+) T cells display various functional abnormalities in the synovium as well as in the peripheral circulation. Current evidence suggests, however, that the role of CD4(+) T cells in the development of rheumatoid inflammation exceeds that of activated pro-inflammatory effector T cells that drive the chronic autoimmune response. Subsets of CD4(+) T cells with regulatory capacity, such as CD25(+) Tregs, have been identified in mice and man, and recent observations suggest that in RA, the function of these regulatory T cells is severely impaired. Thus, in RA, defective regulatory immune mechanisms might allow the breakdown of peripheral tolerance, following which the detrimental CD4(+) T-cell-driven immune response evolves and proceeds to chronic inflammation. Here, we review the functional abnormalities and the contribution of different T-cell subsets to rheumatoid inflammation.

FGF and retinoic acid activity gradients control the timing of neural crest cell emigration in the trunk

PubMed Central

Martínez-Morales, Patricia L.; Diez del Corral, Ruth; Olivera-Martínez, Isabel; Quiroga, Alejandra C.; Das, Raman M.; Barbas, Julio A.; Storey, Kate G.

2011-01-01

Coordination between functionally related adjacent tissues is essential during development. For example, formation of trunk neural crest cells (NCCs) is highly influenced by the adjacent mesoderm, but the molecular mechanism involved is not well understood. As part of this mechanism, fibroblast growth factor (FGF) and retinoic acid (RA) mesodermal gradients control the onset of neurogenesis in the extending neural tube. In this paper, using gain- and loss-of-function experiments, we show that caudal FGF signaling prevents premature specification of NCCs and, consequently, premature epithelial–mesenchymal transition (EMT) to allow cell emigration. In contrast, rostrally generated RA promotes EMT of NCCs at somitic levels. Furthermore, we show that FGF and RA signaling control EMT in part through the modulation of elements of the bone morphogenetic protein and Wnt signaling pathways. These data establish a clear role for opposition of FGF and RA signaling in control of the timing of NCC EMT and emigration and, consequently, coordination of the development of the central and peripheral nervous system during vertebrate trunk elongation. PMID:21807879

Intake of minerals, trace elements and vitamins in bone and raw food rations in adult dogs.

PubMed

Dillitzer, Natalie; Becker, Nicola; Kienzle, Ellen

2011-10-01

The aim of the present study was to evaluate the vitamin and mineral content of bone and raw food rations fed to adult dogs in Germany. Pet owners completed a standardised feeding questionnaire. The composition of 95 rations was calculated from mean data for foodstuffs using nutrition balancing software. Typical ration ingredients were meats, fish, offal, dairy products, eggs, oil, nuts, cod liver oil and natural and commercial supplements. The supply of nutrients was compared with the recommended allowance (RA). Of the rations that were used, 10 % supplied < 25 % of the RA of Ca. In these rations, Ca:P was below 0.6:1, and vitamin D was below RA. About half of the rations supplied less iodine than the minimum requirement. Many of the rations had low Zn and Cu supply, and 25 % of the rations supplied only 70 % of RA for vitamin A or less. A total of 60 % of the rations had one or more of the above-mentioned imbalance. The remaining 40 % of rations either had minor problems like Ca excess from bones or they were balanced.

IL-1 receptor antagonist ameliorates inflammasome-dependent inflammation in murine and human cystic fibrosis

PubMed Central

Iannitti, Rossana G.; Napolioni, Valerio; Oikonomou, Vasilis; De Luca, Antonella; Galosi, Claudia; Pariano, Marilena; Massi-Benedetti, Cristina; Borghi, Monica; Puccetti, Matteo; Lucidi, Vincenzina; Colombo, Carla; Fiscarelli, Ersilia; Lass-Flörl, Cornelia; Majo, Fabio; Cariani, Lisa; Russo, Maria; Porcaro, Luigi; Ricciotti, Gabriella; Ellemunter, Helmut; Ratclif, Luigi; De Benedictis, Fernando Maria; Talesa, Vincenzo Nicola; Dinarello, Charles A.; van de Veerdonk, Frank L.; Romani, Luigina

2016-01-01

Dysregulated inflammasome activation contributes to respiratory infections and pathologic airway inflammation. Through basic and translational approaches involving murine models and human genetic epidemiology, we show here the importance of the different inflammasomes in regulating inflammatory responses in mice and humans with cystic fibrosis (CF), a life-threatening disorder of the lungs and digestive system. While both contributing to pathogen clearance, NLRP3 more than NLRC4 contributes to deleterious inflammatory responses in CF and correlates with defective NLRC4-dependent IL-1Ra production. Disease susceptibility in mice and microbial colonization in humans occurrs in conditions of genetic deficiency of NLRC4 or IL-1Ra and can be rescued by administration of the recombinant IL-1Ra, anakinra. These results indicate that pathogenic NLRP3 activity in CF could be negatively regulated by IL-1Ra and provide a proof-of-concept evidence that inflammasomes are potential targets to limit the pathological consequences of microbial colonization in CF. PMID:26972847

IL-1 receptor antagonist ameliorates inflammasome-dependent inflammation in murine and human cystic fibrosis.

PubMed

Iannitti, Rossana G; Napolioni, Valerio; Oikonomou, Vasilis; De Luca, Antonella; Galosi, Claudia; Pariano, Marilena; Massi-Benedetti, Cristina; Borghi, Monica; Puccetti, Matteo; Lucidi, Vincenzina; Colombo, Carla; Fiscarelli, Ersilia; Lass-Flörl, Cornelia; Majo, Fabio; Cariani, Lisa; Russo, Maria; Porcaro, Luigi; Ricciotti, Gabriella; Ellemunter, Helmut; Ratclif, Luigi; De Benedictis, Fernando Maria; Talesa, Vincenzo Nicola; Dinarello, Charles A; van de Veerdonk, Frank L; Romani, Luigina

2016-03-14

Dysregulated inflammasome activation contributes to respiratory infections and pathologic airway inflammation. Through basic and translational approaches involving murine models and human genetic epidemiology, we show here the importance of the different inflammasomes in regulating inflammatory responses in mice and humans with cystic fibrosis (CF), a life-threatening disorder of the lungs and digestive system. While both contributing to pathogen clearance, NLRP3 more than NLRC4 contributes to deleterious inflammatory responses in CF and correlates with defective NLRC4-dependent IL-1Ra production. Disease susceptibility in mice and microbial colonization in humans occurs in conditions of genetic deficiency of NLRC4 or IL-1Ra and can be rescued by administration of the recombinant IL-1Ra, anakinra. These results indicate that pathogenic NLRP3 activity in CF could be negatively regulated by IL-1Ra and provide a proof-of-concept evidence that inflammasomes are potential targets to limit the pathological consequences of microbial colonization in CF.

Selective Detection of NO2 Using Cr-Doped CuO Nanorods

PubMed Central

Kim, Kang-Min; Jeong, Hyun-Mook; Kim, Hae-Ryong; Choi, Kwon-Il; Kim, Hyo-Joong; Lee, Jong-Heun

2012-01-01

CuO nanosheets, Cr-doped CuO nanosheets, and Cr-doped CuO nanorods were prepared by heating a slurry containing Cu-hydroxide/Cr-hydroxide. Their responses to 100 ppm NO2, C2H5OH, NH3, trimethylamine, C3H8, and CO were measured. For 2.2 at% Cr-doped CuO nanorods, the response (Ra/Rg, Ra: resistance in air, Rg: resistance in gas) to 100 ppm NO2 was 134.2 at 250 °C, which was significantly higher than that of pure CuO nano-sheets (Ra/Rg = 7.5) and 0.76 at% Cr-doped CuO nanosheets (Ra/Rg = 19.9). In addition, the sensitivity for NO2 was also markedly enhanced by Cr doping. Highly sensitive and selective detection of NO2 in 2.2 at% Cr-doped CuO nanorods is explained in relation to Cr-doping induced changes in donor density, morphology, and catalytic effects. PMID:22969384

Toxic element mobility assessment and modeling for regional geo-scientific survey to support Risk Assessment in a European Union context

NASA Astrophysics Data System (ADS)

Abdaal, Ahmed; Jordan, Gyozo; Bartha, Andras; Fugedi, Ubul

2013-04-01

The Mine Waste Directive 2006/21/EC requires the risk-based inventory of all mine waste sites in Europe. The geochemical documentation concerning inert classification and ranking of the mine wastes requires detailed field study and laboratory testing and analyses of waste material to assess the Acid Mine Drainage potential and toxic element mobility. The procedure applied in this study used a multi-level decision support scheme including: 1) expert judgment, 2) data review, 3) representative field sampling and laboratory analysis of formations listed in the Inert Mining Waste List, and 4) requesting available laboratory analysis data from selected operating mines. Based on expert judgment, the listed formations were classified into three categories. A: inert B: probably inert, but has to be checked, C: probably not inert, has to be examined. This paper discusses the heavy metal contamination risk assessment (RA) in leached quarry-mine waste sites in Hungary. In total 34 mine waste sites (including tailing lagoons and heaps of both abandoned mines and active quarries) have been selected for scientific testing using the EU Pre-selection Protocol. Over 93 field samples have been collected from the mine sites including Ore (Andesite and Ryolite), Coal (Lignite, black and brown coals), Peat, Alginite, Bauxite, Clay and Limestone. Laboratory analyses of the total toxic element content (aqua regia extraction), the mobile toxic element content (deionized water leaching) and the analysis of different forms of sulfur (sulfuric acid potential) ) on the base of Hungarian GKM Decree No. 14/2008. (IV. 3) concerning mining waste management. A detailed geochemical study together with spatial analysis and GIS has been performed to derive a geochemically sound contamination RA of the mine waste sites. Key parameters such as heavy metal and sulphur content, in addition to the distance to the nearest surface and ground water bodies, or to sensitive receptors such as settlements and protected areas are calculated and statistically evaluated using STATGRAPHICS® in order to calibrate the RA methods. Results show that some of the waste rock materials assumed to be inert were found non/inert. Thus, regional RA needs more spatial and petrological examination with special care to rock and mineral deposit genetics.

Immune checkpoint inhibitor PD-1 pathway is down-regulated in synovium at various stages of rheumatoid arthritis disease progression

PubMed Central

Wechalekar, Mihir D.; Cole, Suzanne; Yin, Xuefeng; Scott, Brittney; Loza, Mathew; Orr, Carl; McGarry, Trudy; Bombardieri, Michele; Humby, Frances; Proudman, Susanna M.; Pitzalis, Costantino; Smith, Malcolm D.; Friedman, Joshua R.; Anderson, Ian; Madakamutil, Loui; Veale, Douglas J.; Fearon, Ursula

2018-01-01

Immune checkpoint blockade with therapeutic anti-cytotoxic T lymphocyte-associated antigen (CTLA)-4 (Ipilimumab) and anti-programmed death (PD)-1 (Nivolumab and Pembrolizumab) antibodies alone or in combination has shown remarkable efficacy in multiple cancer types, concomitant with immune-related adverse events, including arthralgia and inflammatory arthritis (IA) in some patients. Herein, using Nivolumab (anti-PD-1 antagonist)-responsive genes along with transcriptomics of synovial tissue from multiple stages of rheumatoid arthritis (RA) disease progression, we have interrogated the activity status of PD-1 pathway during RA development. We demonstrate that the expression of PD-1 was increased in early and established RA synovial tissue compared to normal and OA synovium, whereas that of its ligands, programmed death ligand-1 (PD-L1) and PD-L2, was increased at all the stages of RA disease progression, namely arthralgia, IA/undifferentiated arthritis, early RA and established RA. Further, we show that RA patients expressed PD-1 on a majority of synovial tissue infiltrating CD4+ and CD8+ T cells. Moreover, enrichment of Nivolumab gene signature was observed in IA and RA, indicating that the PD-1 pathway was downregulated during RA disease progression. Furthermore, serum soluble (s) PD-1 levels were increased in autoantibody positive early RA patients. Interestingly, most of the early RA synovium tissue sections showed negative PD-L1 staining by immunohistochemistry. Therefore, downregulation in PD-1 inhibitory signaling in RA could be attributed to increased serum sPD-1 and decreased synovial tissue PD-L1 levels. Taken together, these data suggest that agonistic PD1 antibody-based therapeutics may show efficacy in RA treatment and interception. PMID:29489833

Immune checkpoint inhibitor PD-1 pathway is down-regulated in synovium at various stages of rheumatoid arthritis disease progression.

PubMed

Guo, Yanxia; Walsh, Alice M; Canavan, Mary; Wechalekar, Mihir D; Cole, Suzanne; Yin, Xuefeng; Scott, Brittney; Loza, Mathew; Orr, Carl; McGarry, Trudy; Bombardieri, Michele; Humby, Frances; Proudman, Susanna M; Pitzalis, Costantino; Smith, Malcolm D; Friedman, Joshua R; Anderson, Ian; Madakamutil, Loui; Veale, Douglas J; Fearon, Ursula; Nagpal, Sunil

2018-01-01

Immune checkpoint blockade with therapeutic anti-cytotoxic T lymphocyte-associated antigen (CTLA)-4 (Ipilimumab) and anti-programmed death (PD)-1 (Nivolumab and Pembrolizumab) antibodies alone or in combination has shown remarkable efficacy in multiple cancer types, concomitant with immune-related adverse events, including arthralgia and inflammatory arthritis (IA) in some patients. Herein, using Nivolumab (anti-PD-1 antagonist)-responsive genes along with transcriptomics of synovial tissue from multiple stages of rheumatoid arthritis (RA) disease progression, we have interrogated the activity status of PD-1 pathway during RA development. We demonstrate that the expression of PD-1 was increased in early and established RA synovial tissue compared to normal and OA synovium, whereas that of its ligands, programmed death ligand-1 (PD-L1) and PD-L2, was increased at all the stages of RA disease progression, namely arthralgia, IA/undifferentiated arthritis, early RA and established RA. Further, we show that RA patients expressed PD-1 on a majority of synovial tissue infiltrating CD4+ and CD8+ T cells. Moreover, enrichment of Nivolumab gene signature was observed in IA and RA, indicating that the PD-1 pathway was downregulated during RA disease progression. Furthermore, serum soluble (s) PD-1 levels were increased in autoantibody positive early RA patients. Interestingly, most of the early RA synovium tissue sections showed negative PD-L1 staining by immunohistochemistry. Therefore, downregulation in PD-1 inhibitory signaling in RA could be attributed to increased serum sPD-1 and decreased synovial tissue PD-L1 levels. Taken together, these data suggest that agonistic PD1 antibody-based therapeutics may show efficacy in RA treatment and interception.

Delayed Treatment Acceleration in Patients with Rheumatoid Arthritis Who Have Inadequate Response to Initial Tumor Necrosis Factor Inhibitors: Data from the Corrona Registry

PubMed Central

Pappas, Dimitrios A.; Gerber, Robert A.; Litman, Heather J.; Gruben, David; Geier, Jamie; Hua, Winnie D.; Chen, Connie; Li, Youfu; Kremer, Joel M.; Andrews, John S.; Bourret, Jeffrey A.

2018-01-01

Background The implementation of treat-to-target principles in rheumatoid arthritis (RA) has not been fully investigated in patients with inadequate response to tumor necrosis factor (TNF) inhibitor treatment. Objectives To evaluate the prevalence of an inadequate response to initial TNF inhibitor treatment at 6 and 12 months among patients with RA in a real-world patient registry, as well as the delay in therapy adjustment and its impact on disease activity and patient-reported outcome (PRO) measures. Methods This analysis is based on data of patients with moderate or severe disease activity (Clinical Disease Activity Index [CDAI] score >10) who were included in the Consortium of Rheumatology Researchers of North America (Corrona) RA registry, a prospective, observational database. The patients had never received treatment with a biologic disease-modifying antirheumatic drug (DMARD) and had initiated treatment with a TNF inhibitor (adalimumab, certolizumab pegol, etanercept, golimumab, or infliximab) between October 2001 and December 2014. We evaluated treatment response (CDAI score ≤10), select PRO measures, and treatment changes at 6 months. Patients who had an inadequate response to TNF inhibitor therapy at 6 months and continued to use their initial TNF inhibitor were evaluated again at 12 months. Results This retrospective analysis included 2282 patients. At 6 months, 1732 (75.9%) of the patients continued to use their initial TNF inhibitor; of these, 803 (46.4%) patients had an inadequate response to treatment. Of the 803 patients who had an inadequate response at 6 months, 488 (60.8%) continued their initial treatment at 12 months. Of these 488 patients, 315 (64.5%) had an inadequate response at 12 months, and 173 (35.5%) had a response. Numerically greater improvements in all PRO measures were observed for patients who responded to therapy compared with patients with an inadequate response. Conclusions In this real-world analysis of data from the Corrona RA registry, a considerable proportion of patients with RA had an inadequate response to the initial TNF inhibitor therapy at 6 and 12 months. Many patients continued to have moderate or high disease activity, without accelerating treatment (eg, addition or increase in the dose of concurrent conventional synthetic DMARDs or a TNF inhibitor), contrary to treat-to-target principles, thus remaining at risk for accumulating joint damage and disability. PMID:29910846

Mechanism underlying the suppressor activity of retinoic acid on IL4-induced IgE synthesis and its physiological implication.

PubMed

Seo, Goo-Young; Lee, Jeong-Min; Jang, Young-Saeng; Kang, Seung Goo; Yoon, Sung-Il; Ko, Hyun-Jeong; Lee, Geun-Shik; Park, Seok-Rae; Nagler, Cathryn R; Kim, Pyeung-Hyeun

2017-12-01

The present study extends an earlier report that retinoic acid (RA) down-regulates IgE Ab synthesis in vitro. Here, we show the suppressive activity of RA on IgE production in vivo and its underlying mechanisms. We found that RA down-regulated IgE class switching recombination (CSR) mainly through RA receptor α (RARα). Additionally, RA inhibited histone acetylation of germ-line ε (GL ε) promoter, leading to suppression of IgE CSR. Consistently, serum IgE levels were substantially elevated in vitamin A-deficient (VAD) mice and this was more dramatic in VAD-lecithin:retinol acyltransferase deficient (LRAT -/- ) mice. Further, serum mouse mast cell protease-1 (mMCP-1) level was elevated while frequency of intestinal regulatory T cells (Tregs) were diminished in VAD LRAT -/- mice, reflecting that deprivation of RA leads to allergic immune response. Taken together, our results reveal that RA has an IgE-repressive activity in vivo, which may ameliorate IgE-mediated allergic disease. Copyright © 2017 Elsevier Inc. All rights reserved.

Characterization of a TOL-like plasmid from Alcaligenes eutrophus that controls expression of a chromosomally encoded p-cresol pathway.

PubMed Central

Hughes, E J; Bayly, R C; Skurray, R A

1984-01-01

Alcaligenes eutrophus wild-type strain 345 metabolizes m- and p-toluate via a catechol meta-cleavage pathway. DNA analysis, curing studies, and transfer of this phenotype by conjugation and transformation showed that the degradative genes are encoded on a self-transmissible 85-kilobase plasmid, pRA1000. HindIII and XhoI restriction endonuclease analysis of pRA1000 showed it to be similar to the archetypal TOL plasmid, pWWO, differing in the case of HindIII only by the absence of fragments B and D present in pWWO. In strain 345, the presence of pRA1000 prevented the expression of chromosomally encoded enzymes required for the degradation of p-cresol, whereas these enzymes were expressed in strains cured of pRA1000. On the basis of studies with an R68.45-pRA1000 cointegrate plasmid, pRA1001, we conclude that the gene(s) responsible for the effect of p-cresol degradation resides within or near the m- and p-toluate degradative region on pRA1000. Images PMID:6325399

Pharmacokinetic modelling of interleukin-1 receptor antagonist in plasma and cerebrospinal fluid of patients following subarachnoid haemorrhage.

PubMed

Gueorguieva, Ivelina; Clark, Simon R; McMahon, Catherine J; Scarth, Sylvia; Rothwell, Nancy J; Tyrrell, Pippa J; Tyrell, Pippa J; Hopkins, Stephen J; Rowland, Malcolm

2008-03-01

What is already known about this subject? The naturally occurring interlukin-1 receptor antagonist (IL-1RA) markedly protects rodents against ischaemic, excitotoxic and traumatic brain injury, suggesting it may be of therapeutic value. When administered intravenously to patients soon after stroke, IL-1RA is safe and reduces the peripheral inflammatory response. However, IL-1RA is a large protein (17 kDa), which may limit brain penetration, thereby limiting its potential utility in brain injury. What this study adds. The purpose of these experiments was to determine the pharmacokinetics of IL-1RA in cerebrospinal fluid (CSF) of patients, to allow modelling that would aid development of therapeutic regimens. Peripherally administered IL-1RA crosses slowly into and out of the CSF of patients with subarachnoid haemorrhage and, at steady state, CSF IL-1RA concentration (range 115-886 ng ml(-1)) was similar to that found to be neuroprotective in rats (range 91-232 ng ml(-1)), although there was considerable variability among patients. However, there is a large concentration gradient of IL-1RA between plasma and CSF. These CSF:plasma data are consistent with very low permeation of IL-1RA into the CSF and elimination kinetics from it controlled by the volumetric turnover of CSF. The naturally occurring interlukin-1 receptor antagonist (IL-1RA) markedly protects rodents against ischaemic, excitotoxic and traumatic brain injury, suggesting it may be of therapeutic value. The aim was to determine the pharmacokinetics of IL-1RA in cerebrospinal fluid (CSF) of patients, to allow modelling that would aid development of therapeutic regimens. When administered intravenously to patients soon after stroke, IL-1RA is safe and reduces the peripheral inflammatory response. However, IL-1RA is a large protein (17 kDa), which may limit brain penetration, thereby limiting its potential utility in brain injury. In seven patients with subarchnoid haemorrhage (SAH), IL-1RA was administered by intravenous bolus, then infusion for 24 h, and both blood and CSF, via external ventricular drains, were sampled during and after stopping the infusion. Plasma steady-state concentrations were rapidly attained and maintained throughout the infusion, whereas CSF concentrations rose slowly towards a plateau during the 24-h infusion, reaching at best only 4% of that in plasma. Plasma kinetic parameters were within the literature range. Modelling of the combined data yielded rate constants entering and leaving the CSF of 0.0019 h(-1)[relative standard error (RSE) = 19%] and 0.1 h(-1) (RSE = 19%), respectively. Peripherally administered IL-1RA crosses slowly into and out of the CSF of patients with SAH. However, there is a large concentration gradient of IL-1RA between plasma and CSF. These CSF:plasma data are consistent with very low permeation of IL-1RA into the CSF and elimination kinetics from it controlled by the volumetric turnover of CSF.

Elemental concentrations in tropospheric and lower stratospheric air in a Northeastern region of Poland

NASA Astrophysics Data System (ADS)

Braziewicz, Janusz; Kownacka, Ludwika; Majewska, Urszula; Korman, Andrzej

Element concentrations of K, Ca, Ti, Cr, Fe, Ni, Cu, Zn, Se, Br, Sr and Pb as well as the activity of natural radionuclides 210Pb and 226Ra in air were measured. The aerosol samples were collected during tropospheric and stratospheric aircraft flights over the Northeastern region of Poland, which is mostly an agricultural and wooded area. The air volumes were filtered using Petrianov filters at 1, 3, 6, 9, 12 and 15 km above the ground level by special equipment attached to a jet plane. Aircraft flights were provided from September 1997 to August 1998 in 5 separate sampling runs. The long sampling distances served as a good representation of mean aerosol composition and distribution. Concentrations of the same elements were also measured using stationary equipment near the ground level at the outskirts of Warsaw. The vertical profiles of element concentration were obtained and the elemental compositions for the tropospheric and stratospheric aerosols were compared with those from the near-ground level. Contribution of K, Ca, Ti and Fe, which are the main components of soil, in total mass of all detected ones was estimated. Relative concentrations of all measured elements, which show any differences in the composition of the aerosol were calculated. The results obtained confirm the fact that the stratospheric reservoir is observed in the bottom stratosphere. The XRF method based on molybdenum X-ray tube was used as an analytical tool in the determination of aerosols trace elements. The altitude distributions of radioactivity of 226Ra and 210Pb were determined using radiochemical methods.

IgA rheumatoid factor as a serological predictor of poor response to tumour necrosis factor α inhibitors in rheumatoid arthritis.

PubMed

Sakthiswary, Rajalingham; Shaharir, Syahrul S; Mohd Said, Mohd S; Asrul, Abdul W; Shahril, Nor S

2014-11-01

The main objective of this study is to elucidate the role of immunoglobulin A (IgA) rheumatoid factor (RF) in predicting the clinical response to tumour necrosis factor α inhibitors (TNFi) among patients with rheumatoid arthritis (RA). We recruited all patients with RA who were ever on TNFi for a minimum duration of 3 months at our centre. Based on the European League Against Rheumatism response criteria, subjects were further divided into responders and non-responders. Age-matched RA patients who were on conventional disease-modifying anti-rheumatic drugs and in remission were enrolled as controls. Subjects were tested for quantitative values of IgA, IgM, IgG RF and anti-citrulinated cyclic peptides (CCP). Further, all subjects were assessed for the disease activity score that includes 28 joints (DAS28) and Stanford Health Assessment Questionnaire (HAQ) 8-item Disability Index (HAQ-DI). A total of 31 subjects with RA who had received TNFi and 15 controls were enrolled in this study. There was a trend for the non-responders (n = 10) to have higher levels of all isotypes of RF and anti-CCP. However, only the IgA RF and anti-CCP levels were significantly higher in the non-responder group compared to the responders and controls (P = 0.001, P = 0.034, respectively). On multivariate analysis, only the IgA RF remained significant (OR 0.989; 95% CI 0.980-0.999; P = 0.026). IgA RF is potentially a novel predictor of response to TNFi in RA patients. Testing for pretreatment IgA RF levels could be a reasonable consideration before commencement of TNFi. © 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.

Carbamylation of vimentin is inducible by smoking and represents an independent autoantigen in rheumatoid arthritis

PubMed Central

Ospelt, Caroline; Bang, Holger; Feist, Eugen; Camici, Giovanni; Keller, Stephan; Detert, Jacqueline; Krämer, Anette; Gay, Steffen; Ghannam, Khetam; Burmester, Gerd R

2017-01-01

Objectives Smoking has been connected to citrullination of antigens and formation of anti-citrullinated peptide antibodies (ACPAs) in rheumatoid arthritis (RA). Since smoking can modify proteins by carbamylation (formation of homocitrulline), this study was conducted to investigate these effects on vimentin in animal models and RA. Methods The efficiency of enzymatic carbamylation of vimentin was characterised. B-cell response was investigated after immunisation of rabbits with different vimentin isoforms. Effects of tobacco smoke exposure on carbamylation of vimentin and formation of autoantibodies were analysed in mice. The antibody responses against isoforms of vimentin were characterised with respect to disease duration and smoking status of patients with RA. Results Enzymatic carbamylation of vimentin was efficiently achieved. Subsequent citrullination of vimentin was not disturbed by homocitrullination. Sera from rabbits immunised with carbamylated vimentin (carbVim), in addition to carbVim also recognised human IgG-Fc showing rheumatoid factor-like reactivity. Smoke-exposed mice contained detectable amounts of carbVim and developed a broad immune response against carbamylated antigens. Although the prevalence of anti-carbamylated antibodies in smokers and non-smokers was similar, the titres of carbamylated antibodies were significantly increased in sera of smoking compared with non-smoking RA. CarbVim antibodies were observed independently of ACPAs in early phases of disease and double-positive patients for anti-mutated citrullinated vimentin (MCV) and anti-carbVim antibodies showed an extended epitope recognition pattern towards MCV. Conclusions Carbamylation of vimentin is inducible by cigarette smoke exposure. The polyclonal immune response against modified antigens in patients with RA is not exclusively citrulline-specific and carbamylation of antigens could be involved in the pathogenesis of disease. Trial registration number ISRCTN36745608; EudraCT Number: 2006-003146-41. PMID:28183721

The Protein Kinase SmSnRK2.6 Positively Regulates Phenolic Acid Biosynthesis in Salvia miltiorrhiza by Interacting with SmAREB1

PubMed Central

Jia, Yanyan; Bai, Zhenqing; Pei, Tianlin; Ding, Kai; Liang, Zongsuo; Gong, Yuehua

2017-01-01

Subclass III members of the sucrose non-fermenting-1-related protein kinase 2 (SnRK2) play essential roles in both the abscisic acid signaling and abiotic stress responses of plants by phosphorylating the downstream ABA-responsive element (ABRE)-binding proteins (AREB/ABFs). This comprehensive study investigated the function of new candidate genes, namely SmSnRK2.3, SmSnRK2.6, and SmAREB1, with a view to breeding novel varieties of Salvia miltiorrhiza with improved stress tolerance stresses and more content of bioactive ingredients. Exogenous ABA strongly induced the expression of these genes. PlantCARE predicted several hormones and stress response cis-elements in their promoters. SmSnRK2.6 and SmAREB1 showed the highest expression levels in the leaves of S. miltiorrhiza seedlings, while SmSnRK2.3 exhibited a steady expression in their roots, stems, and leaves. A subcellular localization assay revealed that both SmSnRK2.3 and SmSnRK2.6 were located in the cell membrane, cytoplasm, and nucleus, whereas SmAREB1 was exclusive to the nucleus. Overexpressing SmSnRK2.3 did not significantly promote the accumulation of rosmarinic acid (RA) and salvianolic acid B (Sal B) in the transgenic S. miltiorrhiza hairy roots. However, overexpressing SmSnRK2.6 and SmAREB1 increased the contents of RA and Sal B, and regulated the expression levels of structural genes participating in the phenolic acid-branched and side-branched pathways, including SmPAL1, SmC4H, Sm4CL1, SmTAT, SmHPPR, SmRAS, SmCHS, SmCCR, SmCOMT, and SmHPPD. Furthermore, SmSnRK2.3 and SmSnRK2.6 interacted physically with SmAREB1. In summary, our results indicate that SmSnRK2.6 is involved in stress responses and can regulate structural gene transcripts to promote greater metabolic flux to the phenolic acid-branched pathway, via its interaction with SmAREB1, a transcription factor. In this way, SmSnRK2.6 contributes to the positive regulation of phenolic acids in S. miltiorrhiza hairy roots. PMID:28848585

The Protein Kinase SmSnRK2.6 Positively Regulates Phenolic Acid Biosynthesis in Salvia miltiorrhiza by Interacting with SmAREB1.

PubMed

Jia, Yanyan; Bai, Zhenqing; Pei, Tianlin; Ding, Kai; Liang, Zongsuo; Gong, Yuehua

2017-01-01

Subclass III members of the sucrose non-fermenting-1-related protein kinase 2 (SnRK2) play essential roles in both the abscisic acid signaling and abiotic stress responses of plants by phosphorylating the downstream ABA-responsive element (ABRE)-binding proteins (AREB/ABFs). This comprehensive study investigated the function of new candidate genes, namely SmSnRK2.3 , SmSnRK2.6 , and SmAREB1 , with a view to breeding novel varieties of Salvia miltiorrhiza with improved stress tolerance stresses and more content of bioactive ingredients. Exogenous ABA strongly induced the expression of these genes. PlantCARE predicted several hormones and stress response cis -elements in their promoters. SmSnRK2.6 and SmAREB1 showed the highest expression levels in the leaves of S. miltiorrhiza seedlings, while SmSnRK2.3 exhibited a steady expression in their roots, stems, and leaves. A subcellular localization assay revealed that both SmSnRK2.3 and SmSnRK2.6 were located in the cell membrane, cytoplasm, and nucleus, whereas SmAREB1 was exclusive to the nucleus. Overexpressing SmSnRK2.3 did not significantly promote the accumulation of rosmarinic acid (RA) and salvianolic acid B (Sal B) in the transgenic S. miltiorrhiza hairy roots. However, overexpressing SmSnRK2.6 and SmAREB1 increased the contents of RA and Sal B, and regulated the expression levels of structural genes participating in the phenolic acid-branched and side-branched pathways, including SmPAL1 , SmC4H , Sm4CL1 , SmTAT , SmHPPR , SmRAS , SmCHS , SmCCR , SmCOMT , and SmHPPD . Furthermore, SmSnRK2.3 and SmSnRK2.6 interacted physically with SmAREB1. In summary, our results indicate that SmSnRK2.6 is involved in stress responses and can regulate structural gene transcripts to promote greater metabolic flux to the phenolic acid-branched pathway, via its interaction with SmAREB1 , a transcription factor. In this way, SmSnRK2.6 contributes to the positive regulation of phenolic acids in S. miltiorrhiza hairy roots.

Variable domain glycosylation of ACPA-IgG: A missing link in the maturation of the ACPA response?

PubMed

Kempers, Ayla C; Hafkenscheid, Lise; Scherer, Hans Ulrich; Toes, René E M

2018-01-01

Anti-citrullinated Protein Antibodies (ACPA) are excellent markers for Rheumatoid arthritis (RA) and are postulated to have a pathogenic role in the disease process. A multistep model for the evolution of the ACPA response in RA was proposed in which an initial break of tolerance causes, as "first hit", "silent" production of ACPA without any clinical symptoms. The model further proposes that the ACPA immune response matures upon a certain (unknown) trigger, a "second hit", which leads to epitope spreading, an increase in ACPA titres and extended isotype usage before clinical RA manifestations. These occurrences are indicative of an expansion of the citrulline-specific B cell response, though ACPA remain of low avidity even in established disease. This persistence of low avidity is puzzling, as the typical signs of maturation of the immune response seem to be uncoupled from the classical process of affinity maturation. In fact, it suggests that B cells expressing ACPA could bypass selection mechanisms that otherwise control the expansion of auto-reactive B cells. In the established, chronic phase, we recently found that ACPA-IgG are extensively glycosylated in the variable (Fab) domain. More than 90% of ACPA-IgG molecules carry Fab glycans that are highly sialylated. This molecular feature is striking and may provide a missing link in our understanding of the maturation of the ACPA immune response. This review, therefore, describes the current knowledge about ACPA Fab glycosylation in the pathogenesis of RA. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Self-esteem levels and cardiovascular and inflammatory responses to acute stress.

PubMed

O'Donnell, Katie; Brydon, Lena; Wright, Caroline E; Steptoe, Andrew

2008-11-01

Acute mental stress tests have helped to clarify the pathways through which psychosocial factors are linked to disease risk. This methodology is now being used to investigate potentially protective psychosocial factors. We investigated whether global self-esteem might buffer cardiovascular and inflammatory responses to acute stress. One hundred and one students completed the Rosenberg Self-Esteem Scale. Heart rate and heart rate variability (HRV) were recorded for 5 min periods at baseline, during two mental stress tasks, (a speech and a color-word task) and 10, 25 and 40 min into a recovery period. Plasma levels of tumor-necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and interleukin-1 receptor antagonist (IL-1Ra) were assessed at baseline, immediately post-stress and after 45 min recovery. Repeated measures analysis of variance demonstrated that heart rate levels were lower across all time points in those with high self-esteem, although heart rate reactivity to stress was not related to self-esteem. There were no differences in baseline HRV, TNF-alpha, IL-6 or IL-1Ra. Multiple linear regressions revealed that greater self-esteem was associated with a smaller reduction in heart rate variability during the speech task, but not the color-word task. Greater self-esteem was associated with smaller TNF-alpha and IL-1Ra responses immediately following acute stress and smaller IL-1Ra responses at 45 min post-stress. In conclusion, global self-esteem is associated with lower heart rate and attenuated HRV and inflammatory responses to acute stress. These responses could be processes through which self-esteem protects against the development of disease.

Joint-specific DNA methylation and transcriptome signatures in rheumatoid arthritis identify distinct pathogenic processes

PubMed Central

Ai, Rizi; Hammaker, Deepa; Boyle, David L.; Morgan, Rachel; Walsh, Alice M.; Fan, Shicai; Firestein, Gary S.; Wang, Wei

2016-01-01

Stratifying patients on the basis of molecular signatures could facilitate development of therapeutics that target pathways specific to a particular disease or tissue location. Previous studies suggest that pathogenesis of rheumatoid arthritis (RA) is similar in all affected joints. Here we show that distinct DNA methylation and transcriptome signatures not only discriminate RA fibroblast-like synoviocytes (FLS) from osteoarthritis FLS, but also distinguish RA FLS isolated from knees and hips. Using genome-wide methods, we show differences between RA knee and hip FLS in the methylation of genes encoding biological pathways, such as IL-6 signalling via JAK-STAT pathway. Furthermore, differentially expressed genes are identified between knee and hip FLS using RNA-sequencing. Double-evidenced genes that are both differentially methylated and expressed include multiple HOX genes. Joint-specific DNA signatures suggest that RA disease mechanisms might vary from joint to joint, thus potentially explaining some of the diversity of drug responses in RA patients. PMID:27282753

The use of chimeric vimentin citrullinated peptides for the diagnosis of rheumatoid arthritis.

PubMed

Malakoutikhah, Morteza; Gómara, María J; Gómez-Puerta, José A; Sanmartí, Raimon; Haro, Isabel

2011-11-10

Rheumatoid arthritis (RA) is a chronic autoimmune disease that causes inflammation and, in many cases, destruction of the joints. To prevent progressive and irreversible structural damage, early diagnosis of RA is of paramount importance. The present study addresses the search of new RA citrullinated antigens that could supplement or complement diagnostic/prognostic existing tests. With this aim, the epitope anticitrullinated vimentin antibody response was mapped using synthetic peptides. To improve the sensitivity/specificity balance, a vimentin peptide that was selected, and its cyclic analogue, were combined with fibrin- and filaggrin-related peptides to render chimeric peptides. Our findings highlight the putative application of these chimeric peptides for the design of RA diagnosis systems and imply that more than one serological test is required to classify RA patients based on the presence or absence of ACPAs. Each of the target molecules reported here (fibrin, vimentin, filaggrin) has a specific utility in the identification of a particular subset of RA patients.

Dose-response characteristics of Clematis triterpenoid saponins and clematichinenoside AR in rheumatoid arthritis rats by liquid chromatography/mass spectrometry-based serum and urine metabolomics.

PubMed

Li, Rui; Guo, Lin-Xiu; Li, Yi; Chang, Wen-Qi; Liu, Jian-Qun; Liu, Li-Fang; Xin, Gui-Zhong

2017-03-20

Clematidis Radix et Rhizoma is a traditional Chinese medicine widely used for treating arthritic disease. Clematis triterpenoid saponins (TS) and clematichinenoside AR (C-AR) have been considered to be responsible for its antiarthritic effects. However, the underling mechanism is still unclear because of their low bioavailability. To address of this issue, metabolomics tools were performed to determine metabolic variations associated with rheumatoid arthritis (RA) and responses to Clematis TS, C-AR and positive drug (Triptolide, TP) treatments. This metabolomics investigation of RA was conducted in collagen-induced arthritis (CIA) rats. Liquid chromatography/mass spectrometry and multivariate statistical tools were used to identify the alteration of serum and urine metabolites associated with RA and responses to drug treatment. As a result, 45 potential metabolites associated with RA were identified. After treatment, a total of 24 biomarkers were regulated to normal like levels. Among these, PC(18:0/20:4), 9,11-octadecadienoic acid, arachidonic acid, 1-methyladenosine, valine, hippuric acid and pantothenic acid etc, were reversed in Clematis TS and C-AR groups. Tetrahydrocortisol was regulated to normal levels in Clematis TS and TP groups, while 3,7,12-trihydroxycholan-24-oic acid was regulated in C-AR and TP groups. Biomarkers like citric acid, p-cresol glucuronide, creatinine, cortolone were reversed in TP group. Copyright © 2016 Elsevier B.V. All rights reserved.

Is ACPA positivity the main driver for rheumatoid arthritis treatment? Pros and cons.

PubMed

Alivernini, Stefano; Galeazzi, Mauro; Peleg, Hagit; Tolusso, Barbara; Gremese, Elisa; Ferraccioli, Gianfranco; Naparstek, Yaakov

2017-11-01

Rheumatoid Arthritis (RA) is an autoimmune chronic disease that is characterized by the positivity of various antibodies, the most specific being autoantibodies against citrullinated antigens (ACPA). Despite ACPA are not arthritogenic by themselves, ACPA positive individuals have high risk of RA development and ACPA positivity is associated with severe erosive phenotype and higher mortality rate compared to seronegative RA. Moreover, ACPA status is associated with favorable response to biologics targeting pathways involving autoantibody producing cells as B lymphocytes. In the current review we have discussed the pros and cons on the available scientific evidences, regarding the diagnostic, prognostic and management implications of ACPAs in RA. Copyright © 2017 Elsevier B.V. All rights reserved.

Methods for separating oxygen from oxygen-containing gases

DOEpatents

Mackay, Richard; Schwartz, Michael; Sammells, Anthony F.

2000-01-01

This invention provides mixed conducting metal oxides particularly useful for the manufacture of catalytic membranes for gas-phase oxygen separation processes. The materials of this invention have the general formula: A.sub.x A'.sub.x A".sub.2-(x+x') B.sub.y B'.sub.y B".sub.2-(y+y') O.sub.5+z ; where x and x' are greater than 0; y and y' are greater than 0; x+x' is less than or equal to 2; y+y' is less than or equal to 2; z is a number that makes the metal oxide charge neutral; A is an element selected from the f block lanthanide elements; A' is an element selected from Be, Mg, Ca, Sr, Ba and Ra; A" is an element selected from the f block lanthanides or Be, Mg, Ca, Sr, Ba and Ra; B is an element selected from the group consisting of Al, Ga, In or mixtures thereof; and B' and B" are different elements and are independently selected from the group of elements Mg or the d-block transition elements. The invention also provides methods for oxygen separation and oxygen enrichment of oxygen deficient gases which employ mixed conducting metal oxides of the above formula. Examples of the materials used for the preparation of the membrane include A.sub.x Sr.sub.x' B.sub.y Fe.sub.y' Co.sub.2-(y+y') O.sub.5+z, where x is about 0.3 to about 0.5, x' is about 1.5 to about 1.7, y is 0.6, y' is between about 1.0 and 1.4 and B is Ga or Al.

The WMO RA VI Regional Climate Centre Network - a support to users in Europe

NASA Astrophysics Data System (ADS)

Rösner, S.

2012-04-01

Climate, like weather, has no limits. Therefore the World Meteorological Organization (WMO), a specialized United Nations organization, has established a three-level infrastructure to better serve its member countries. This structure comprises Global Producing Centres for Long-range Forecasts (GPCs), Regional Climate Centres (RCCs) and National Meteorological or Hydrometeorological Services (NMHSs), in most cases representing their countries in WMO governance bodies. The elements of this infrastructure are also part of and contribute to the Global Framework for Climate Services (GFCS) agreed to be established by World Climate Conference 3 (WCC-3) and last year's Sixteenth World Meteorological Congress (WMO Cg-XVI). RCCs are the core element of this infrastructure at the regional level and are being establish in all WMO Regional Associations (RAs), i.e. Africa (RA I); Asia (II); South America (III); North America, Central America and the Caribbean (IV); South-West Pacific (V); Europe (VI). Addressing inter-regional areas of common interest like the Mediterranean or the Polar Regions may require inter-regional RCCs. For each region the RCCs follow a user driven approach with regard to governance and structure as well as products generated for the users in the respective region. However, there are common guidelines all RCCs do have to follow. This is to make sure that services are provided based on best scientific standards, are routinely and reliably generated and made available in an operational mode. These guidelines are being developed within WMO and make use of decade-long experience gained in the business of operational weather forecast. Based on the requirements of the 50 member countries of WMO RA VI it was agreed to establish the WMO RCC as a network of centres of excellence that create regional products including long-range forecasts that support regional and national climate activities, and thereby strengthen the capacity of WMO Members in the region to deliver better climate services to national users. On 1 June 2009 the WMO RA VI Pilot RCC-Network started its pilot phase to demonstrate its capability to provide, on an operational day-to-day basis, the products agreed upon by the member countries of RA VI. On 5 October 2011 the process to become formally designated WMO RA VI RCC-Network was initiated, and it is expected that the designation will happen mid to end 2012. The presentation will describe the global and regional activities related to RCCs and explain in more details the situation in WMO RA VI (Europe).

Extending Rest between Unloading Cycles Does Not Enhance Bone's Long-Term Recovery.

PubMed

Manske, Sarah L; Vijayaraghavan, Surabhi; Tuthill, Alyssa; Brutus, Olivier; Yang, Jie; Gupta, Shikha; Judex, Stefan

2015-10-01

Multiple exposures to unloading are overall more deleterious to the skeleton than is single exposure, although the rate of bone loss may diminish during multiple exposures. Here, we determined whether extending the reambulation (RA) period from 3 wk to 9 wk will mitigate bone loss during three distinct 3-wk hindlimb unloading (HLU) periods and enhance long-term recovery in skeletally mature, genetically heterogeneous mice. Female adult mice (4 months old) were subjected to three cycles of 3-wk unloading with 3-wk or 9-wk RA periods in between. Mice were terminated 46 wk after initiation of the study. Outcome measures for the distal femur were determined from multiple in vivo micro-computed tomography scans and finite-element modeling. Tripling RA duration enhanced trabecular bone recovery in between HLU periods but also increased the rate of loss of bone volume fraction (bone volume/tissue volume) and metaphyseal stiffness during subsequent HLU periods. With shorter RA periods, the magnitude of bone loss decreased by the second HLU period, whereas this decrease was delayed with longer RA periods. RA duration did not affect long-term recovery 46 wk after the start of the experimental protocol, as both HLU groups had similar levels of bone volume/tissue volume, cortical area, and stiffness. Individual cage activity levels were unrelated to the magnitude of bone loss during HLU or bone recovery during RA. These data suggest that extending recovery duration between periods of unloading may provide temporary benefits but is an ineffective long-term strategy for combating the devastation of trabecular morphology and mechanics, as temporarily enhanced recovery is largely cancelled out by greater susceptibility to unloading. They also emphasize that cortical bone is more amenable to long-term recovery than is trabecular bone.

A multicentre, double blind, randomised, placebo controlled trial of anakinra (Kineret), a recombinant interleukin 1 receptor antagonist, in patients with rheumatoid arthritis treated with background methotrexate

PubMed Central

Cohen, S; Moreland, L; Cush, J; Greenwald, M; Block, S; Shergy, W; Hanrahan, P; Kraishi, M; Patel, A; Sun, G; Bear, M

2004-01-01

Objective: To assess the efficacy and safety of 100 mg daily anakinra (Kineret), a recombinant form of the naturally occurring interleukin 1 receptor antagonist, plus methotrexate (MTX) in reducing the signs and symptoms of rheumatoid arthritis (RA). Methods: Patients with active RA (n = 506) despite current treatment with MTX were enrolled in this multicentre, double blind, randomised, placebo controlled study. Patients received subcutaneous injections of anakinra 100 mg/day or placebo. They were assessed monthly for 6 months for improvement in signs and symptoms of RA and for adverse events. The primary efficacy measure was the percentage of patients attaining ACR20 response at week 24. Results: Significantly greater proportions of patients treated with anakinra compared with placebo achieved ACR20 (38% v 22%; p<0.001), ACR50 (17% v 8%; p<0.01), and ACR70 (6% v 2%; p<0.05) responses. The response to anakinra was rapid; the proportion of patients with an ACR20 response at the first study assessment (4 weeks) was twice as high with anakinra as with placebo (p<0.005). Clinically meaningful and statistically significant responses were also seen in individual components of the ACR response (for example, Health Assessment Questionnaire, pain, C reactive protein levels, and erythrocyte sedimentation rate). Anakinra was well tolerated, with a safety profile, similar to that of placebo with one exception: mild to moderate injection site reactions were more common with anakinra than with placebo (65% v 24%). Conclusions: This study confirms previous observations from a dose-ranging study showing that anakinra, in combination with MTX, is an effective and safe treatment for patients with RA who have inadequate responses to MTX alone. PMID:15082469

Markers of β-Cell Failure Predict Poor Glycemic Response to GLP-1 Receptor Agonist Therapy in Type 2 Diabetes.

PubMed

Jones, Angus G; McDonald, Timothy J; Shields, Beverley M; Hill, Anita V; Hyde, Christopher J; Knight, Bridget A; Hattersley, Andrew T

2016-02-01

To assess whether clinical characteristics and simple biomarkers of β-cell failure are associated with individual variation in glycemic response to GLP-1 receptor agonist (GLP-1RA) therapy in patients with type 2 diabetes. We prospectively studied 620 participants with type 2 diabetes and HbA1c ≥58 mmol/mol (7.5%) commencing GLP-1RA therapy as part of their usual diabetes care and assessed response to therapy over 6 months. We assessed the association between baseline clinical measurements associated with β-cell failure and glycemic response (primary outcome HbA1c change 0-6 months) with change in weight (0-6 months) as a secondary outcome using linear regression and ANOVA with adjustment for baseline HbA1c and cotreatment change. Reduced glycemic response to GLP-1RAs was associated with longer duration of diabetes, insulin cotreatment, lower fasting C-peptide, lower postmeal urine C-peptide-to-creatinine ratio, and positive GAD or IA2 islet autoantibodies (P ≤ 0.01 for all). Participants with positive autoantibodies or severe insulin deficiency (fasting C-peptide ≤0.25 nmol/L) had markedly reduced glycemic response to GLP-1RA therapy (autoantibodies, mean HbA1c change -5.2 vs. -15.2 mmol/mol [-0.5 vs. -1.4%], P = 0.005; C-peptide <0.25 nmol/L, mean change -2.1 vs. -15.3 mmol/mol [-0.2 vs. -1.4%], P = 0.002). These markers were predominantly present in insulin-treated participants and were not associated with weight change. Clinical markers of low β-cell function are associated with reduced glycemic response to GLP-1RA therapy. C-peptide and islet autoantibodies represent potential biomarkers for the stratification of GLP-1RA therapy in insulin-treated diabetes. © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Rhodium self-powered neutron detector as a suitable on-line thermal neutron flux monitor in BNCT treatments

DOE Office of Scientific and Technical Information (OSTI.GOV)

Miller, Marcelo E.; Sztejnberg, Manuel L.; Gonzalez, Sara J.

2011-12-15

Purpose: A rhodium self-powered neutron detector (Rh SPND) has been specifically developed by the Comision Nacional de Energia Atomica (CNEA) of Argentina to measure locally and in real time thermal neutron fluxes in patients treated with boron neutron capture therapy (BNCT). In this work, the thermal and epithermal neutron response of the Rh SPND was evaluated by studying the detector response to two different reactor spectra. In addition, during clinical trials of the BNCT Project of the CNEA, on-line neutron flux measurements using the specially designed detector were assessed. Methods: The first calibration of the detector was done with themore » well-thermalized neutron spectrum of the CNEA RA-3 reactor thermal column. For this purpose, the reactor spectrum was approximated by a Maxwell-Boltzmann distribution in the thermal energy range. The second calibration was done at different positions along the central axis of a water-filled cylindrical phantom, placed in the mixed thermal-epithermal neutron beam of CNEA RA-6 reactor. In this latter case, the RA-6 neutron spectrum had been well characterized by both calculation and measurement, and it presented some marked differences with the ideal spectrum considered for SPND calibrations at RA-3. In addition, the RA-6 neutron spectrum varied with depth in the water phantom and thus the percentage of the epithermal contribution to the total neutron flux changed at each measurement location. Local (one point-position) and global (several points-positions) and thermal and mixed-field thermal neutron sensitivities were determined from these measurements. Thermal neutron flux was also measured during BNCT clinical trials within the irradiation fields incident on the patients. In order to achieve this, the detector was placed on patient's skin at dosimetric reference points for each one of the fields. System stability was adequate for this kind of measurement. Results: Local mixed-field thermal neutron sensitivities and global thermal and mixed-field thermal neutron sensitivities derived from measurements performed at the RA-6 were compared and no significant differences were found. Global RA-6-based thermal neutron sensitivity showed agreement with pure thermal neutron sensitivity measurements performed in the RA-3 spectrum. Additionally, the detector response proved nearly unchanged by differences in neutron spectra from real (RA-6 BNCT beam) and ideal (considered for calibration calculations at RA-3) neutron source descriptions. The results confirm that the special design of the Rh SPND can be considered as having a pure thermal response for neutron spectra with epithermal-to-thermal flux ratios up to 12%. In addition, the linear response of the detector to thermal flux allows the use of a mixed-field thermal neutron sensitivity of 1.95 {+-} 0.05 x 10{sup -21} A n{sup -1}{center_dot}cm{sup 2}{center_dot}s. This sensitivity can be used in spectra with up to 21% epithermal-to-thermal flux ratio without significant error due to epithermal neutron and gamma induced effects. The values of the measured fluxes in clinical applications had discrepancies with calculated results that were in the range of -25% to +30%, which shows the importance of a local on-line independent measurement as part of a treatment planning quality control system. Conclusions: The usefulness of the CNEA Rh SPND for the on-line local measurement of thermal neutron flux on BNCT patients has been demonstrated based on an appropriate neutron spectra calibration and clinical applications.« less

Rhodium self-powered neutron detector as a suitable on-line thermal neutron flux monitor in BNCT treatments.

PubMed

Miller, Marcelo E; Sztejnberg, Manuel L; González, Sara J; Thorp, Silvia I; Longhino, Juan M; Estryk, Guillermo

2011-12-01

A rhodium self-powered neutron detector (Rh SPND) has been specifically developed by the Comisión Nacional de Energía Atómica (CNEA) of Argentina to measure locally and in real time thermal neutron fluxes in patients treated with boron neutron capture therapy (BNCT). In this work, the thermal and epithermal neutron response of the Rh SPND was evaluated by studying the detector response to two different reactor spectra. In addition, during clinical trials of the BNCT Project of the CNEA, on-line neutron flux measurements using the specially designed detector were assessed. The first calibration of the detector was done with the well-thermalized neutron spectrum of the CNEA RA-3 reactor thermal column. For this purpose, the reactor spectrum was approximated by a Maxwell-Boltzmann distribution in the thermal energy range. The second calibration was done at different positions along the central axis of a water-filled cylindrical phantom, placed in the mixed thermal-epithermal neutron beam of CNEA RA-6 reactor. In this latter case, the RA-6 neutron spectrum had been well characterized by both calculation and measurement, and it presented some marked differences with the ideal spectrum considered for SPND calibrations at RA-3. In addition, the RA-6 neutron spectrum varied with depth in the water phantom and thus the percentage of the epithermal contribution to the total neutron flux changed at each measurement location. Local (one point-position) and global (several points-positions) and thermal and mixed-field thermal neutron sensitivities were determined from these measurements. Thermal neutron flux was also measured during BNCT clinical trials within the irradiation fields incident on the patients. In order to achieve this, the detector was placed on patient's skin at dosimetric reference points for each one of the fields. System stability was adequate for this kind of measurement. Local mixed-field thermal neutron sensitivities and global thermal and mixed-field thermal neutron sensitivities derived from measurements performed at the RA-6 were compared and no significant differences were found. Global RA-6-based thermal neutron sensitivity showed agreement with pure thermal neutron sensitivity measurements performed in the RA-3 spectrum. Additionally, the detector response proved nearly unchanged by differences in neutron spectra from real (RA-6 BNCT beam) and ideal (considered for calibration calculations at RA-3) neutron source descriptions. The results confirm that the special design of the Rh SPND can be considered as having a pure thermal response for neutron spectra with epithermal-to-thermal flux ratios up to 12%. In addition, the linear response of the detector to thermal flux allows the use of a mixed-field thermal neutron sensitivity of 1.95 ± 0.05 × 10(-21) A n(-1)[middle dot]cm² [middle dot]s. This sensitivity can be used in spectra with up to 21% epithermal-to-thermal flux ratio without significant error due to epithermal neutron and gamma induced effects. The values of the measured fluxes in clinical applications had discrepancies with calculated results that were in the range of -25% to +30%, which shows the importance of a local on-line independent measurement as part of a treatment planning quality control system. The usefulness of the CNEA Rh SPND for the on-line local measurement of thermal neutron flux on BNCT patients has been demonstrated based on an appropriate neutron spectra calibration and clinical applications.

[Pattern of serum cytokines in patients with rheumatoid artritis according to PPD reactivity].

PubMed

de León Pandolfi, Darío Ponce; Pastor Asurza, César; Beraun, Yasmina; Acevedo-Vásquez, Eduardo; Sánchez-Torres, Alfredo; Alfaro Lozano, José; Perich Campos, Risto; Cucho Venegas, Mariano; Gutiérrez Villafuerte, César; Sánchez Schwartz, César

2006-11-01

We demonstrated, in a recently published study, far more PPD negative reactivity among patients who had RA (70%) than among controls (30%). To evaluate the hypothesis that different response to PPD in RA patients is associated with different profiles of serum cytokines, we compared the serum levels of IL-2, IL-4, IL-6, IL-10, TNF alpha and IFN gamma from PPD negative and PPD positive RA patients. We also evaluated any correlations between serum cytokines and RA activity. Forty RA patients and 21 controls were enrolled. Those with an induration < 5mm were considered as negative and those with ≥ 5mm as positive PPD. Disease activity was calculated using DAS28. Plasma levels of cytokines were determined using the multiplex BD TM Cytometric Bead Array Kit Assay. Of the RA patients, 27 (67.5%) had negative reaction to PPD and 13 (32.5%) a positive reaction to PPD. There was no statistical difference in sex profile, age or activity index between both negative and positive PPD RA patients. There was no significant difference in all the cytokines measured between PPD positive and PPD negative RA patients. Index activity show a positive correlation with IFN gamma (r = 0.433; p = 0.005) and IL-6 (r = 0.325; p = 0.041) in RA patients. Positive and negative tuberculin RA patients seem to show a similar cytokine serum profile. Copyright © 2006 Elsevier España S.L. Barcelona. Published by Elsevier Espana. All rights reserved.

IOOS Data Portals and Uniform On-line Browse Capabilities

NASA Astrophysics Data System (ADS)

Howard, M.; Currier, R. D.; Kobara, S.; Gayanilo, F.

2015-12-01

The Gulf of Mexico Coastal Ocean Observing System Regional Association (GCOOS-RA) is one of eleven Regional Associations organized under the NOAA-led U.S. Integrated Ocean Observing System (IOOS) Program Office. Each of the RAs operate standards-based regional data portals designed to aggregate near real-time and historical observed data and modeled outputs from distributed providers and to offer these and derived products in standardized ways to a diverse set of users. The RA's portals are based on the IOOS Data and Communications Plan which describes the functional elements needed for an interoperable system. One of these elements is called "Uniform On-line Browse" which is an informational service designed primarily to visualize the inventory of a portal. An on-line browse service supports the end user's need to discover what parameters are available, to learn the spatial and temporal extend of the holdings, and to examine the character of the data (e.g, variability, gappiness, etc). These pieces of information help the end user decide if the data are fit for his/her purpose and to construct valid data requests. Note that on-line browse is a distinctly different activity than data analysis because it seeks to yield knowledge about the inventory and not about what the data mean. "Uniform" on-line browse is a service that takes advantage of the standardization of the data portal's data access points. Most portals represent station locations on a map. This is a view of the data inventory but these plots are rarely generated by pulling data through the standards-based services offered to the end users but through methods only available to the portal programmers. This work will present results of Uniform On-line browse tools developed within GCOOS-RA and their applicability to other RA portals.

Radionuclide activities and metal concentrations in sediments of the Sebou Estuary, NW Morocco, following a flooding event.

PubMed

Laissaoui, A; Mas, J L; Hurtado, S; Ziad, N; Villa, M; Benmansour, M

2013-06-01

This study presents metal concentrations (Fe, Mg, Mn, Co, Cu, Zn, Pb, As, Sr and V) and radionuclide activities ((40)K, (137)Cs, (210)Pb, (226)Ra, (228)Ac, (234)Th and (212)Pb) in surface deposits and a sediment core from the Sebou Estuary, Northwest Morocco. Samples were collected in April 2009, about 2 months after a flooding event, and analysed using a well-type coaxial gamma-ray detector and inductively coupled plasma-quadrupole mass spectrometry. Activities of radionuclides and concentrations of almost all elements in surface samples displayed only moderate spatial variation, suggesting homogenous deposition of eroded local soil in response to intense precipitation. Excess (210)Pb displayed relatively constant activity throughout the sediment core, preventing dating and precluding determination of the historical accumulation rates of pollutants at the core site. Some elements showed non-systematic trends with depth and displayed local maxima and minima. Other elements presented relatively systematic concentration trends or relatively constant levels with discrete maxima and/or minima. Except for Mn, Sr and Cr, all metal concentrations in sediment were below levels typical of polluted systems, suggesting little human impact or losses of metals from sediment particles.

Effects of all-trans-retinoic acid on human SH-SY5Y neuroblastoma as in vitro model in neurotoxicity research.

PubMed

Cheung, Yuen-Ting; Lau, Way Kwok-Wai; Yu, Man-Shan; Lai, Cora Sau-Wan; Yeung, Sze-Chun; So, Kwok-Fai; Chang, Raymond Chuen-Chung

2009-01-01

Human neuroblastoma SH-SY5Y is a dopaminergic neuronal cell line which has been used as an in vitro model for neurotoxicity experiments. Although the neuroblastoma is usually differentiated by all-trans-retinoic acid (RA), both RA-differentiated and undifferentiated SH-SY5Y cells have been used in neuroscience research. However, the changes in neuronal properties triggered by RA as well as the subsequent responsiveness to neurotoxins have not been comprehensively studied. Therefore, we aim to re-evaluate the differentiation property of RA on this cell line. We hypothesize that modulation of signaling pathways and neuronal properties during RA-mediated differentiation in SH-SY5Y cells can affect their susceptibility to neurotoxins. The differentiation property of RA was confirmed by showing an extensive outgrowth of neurites, increased expressions of neuronal nuclei, neuron specific enolase, synaptophysin and synaptic associated protein-97, and decreased expression of inhibitor of differentiation-1. While undifferentiated SH-SY5Y cells were susceptible to 6-OHDA and MPP+, RA-differentiation conferred SH-SY5Y cells higher tolerance, potentially by up-regulating survival signaling, including Akt pathway as inhibition of Akt removed RA-induced neuroprotection against 6-OHDA. As a result, the real toxicity cannot be revealed in RA-differentiated cells. Therefore, undifferentiated SH-SY5Y is more appropriate for studying neurotoxicity or neuroprotection in experimental Parkinson's disease research.

Organ- and species-specific biological activity of rosmarinic acid.

PubMed

Iswandana, R; Pham, B T; van Haaften, W T; Luangmonkong, T; Oosterhuis, D; Mutsaers, H A M; Olinga, P

2016-04-01

Rosmarinic acid (RA), a compound found in several plant species, has beneficial properties, including anti-inflammatory and antibacterial effects. We investigated the toxicity, anti-inflammatory, and antifibrotic effects of RA using precision-cut liver slices (PCLS) and precision-cut intestinal slices (PCIS) prepared from human, mouse, and rat tissue. PCLS and PCIS were cultured up to 48 h in the absence or presence of RA. Gene expression of the inflammatory markers: IL-6, IL-8/CXCL1/KC, and IL-1β, as well as the fibrosis markers: pro-collagen 1a1, heat shock protein 47, α-smooth muscle actin, fibronectin (Fn2) and plasminogen activator inhibitor-1 (PAI-1) were evaluated by qPCR. RA was only toxic in murine PCIS. RA failed to mitigate the inflammatory response in most models, while it clearly reduced IL-6 and CXCL1/KC gene expression in murine PCIS at non-toxic concentrations. With regard to fibrosis, RA decreased the gene levels of Fn2 and PAI-1 in murine PCLS, and Fn2 in murine PCIS. Yet, no effect was observed on the gene expression of fibrosis markers in human and rat PCIS. In conclusion, we observed clear organ- and species-specific effects of RA. RA had little influence on inflammation. However, our study further establishes RA as a potential candidate for the treatment of liver fibrosis. Copyright © 2016 Elsevier Ltd. All rights reserved.

The expression of IL10RA in colorectal cancer and its correlation with the proliferation index and the clinical stage of the disease.

PubMed

Zadka, Łukasz; Kulus, Michał J; Kurnol, Krzysztof; Piotrowska, Aleksandra; Glatzel-Plucińska, Natalia; Jurek, Tomasz; Czuba, Magdalena; Nowak, Aleksandra; Chabowski, Mariusz; Janczak, Dariusz; Dzięgiel, Piotr

2018-05-03

Despite the widely described role of IL10 in immune response regulation during carcinogenesis, there is no established model describing the role of its receptor. The aim of this study is to elucidate the relationship between the subunit alpha of IL10 receptor (IL10RA) in the pathogenesis of colorectal cancer (CRC). The study was conducted on archived paraffin blocks of 125 CRC patients, from which tissue microarrays (TMA) were made. These were subsequently used for immunohistochemistry to assess the expression of IL10RA, IL10, phosphorylated STAT3 (pSTAT3) and the Ki67 proliferation index. The intensity of both reactions was assessed by independent researchers using two approaches: digital image analysis and the Remmele and Stegner score (IRS). To assess the possible correlations between the two investigated markers and the clinical stage of CRC, the Pearson correlation coefficient was calculated. The expression of aforementioned proteins was assessed in tumor samples, healthy surgical margins and healthy control samples, obtained from cadavers during autopsy from the Department of Forensic Medicine. Statistical analysis was conducted using Statistica ver. 13.05 software. The final analysis included 105 CRC patients with complete clinical and pathological data, for whom the expressions of IL10RA, IL10, pSTAT3 and Ki67 were assessed using two independent methods. There was a positive correlation between the IL10RA expression and Ki-67 proliferation index (R = 0.63, p < 0.001) and a negative correlation between the IL10RA expression and the clinical stage of CRC (R = -0.21, p = 0.022). IL10RA correlated positively with pSTAT3 and IL10 in neoplastic tissue and tumor margin (with p < 0.01 for all correlations). We also observed a significantly higher expression of IL10RA in healthy surgical margins when compared to the actual tumor (p = 0.023, the paired t-test). The expression of IL10 was significantly higher in tumors than in healthy intestinal endothelium from control group. The correlations between the expression of IL10RA and the proliferation index or the clinical stage of CRC seem to confirm the importance of IL10RA in the pathogenesis of CRC. The higher expression of IL10RA in healthy surgical margins than in the tumor itself may suggest that IL10RA plays a role in regulating immune response to the neoplasm. Copyright © 2018 Elsevier Ltd. All rights reserved.

Oleanolic acid acetate inhibits rheumatoid arthritis by modulating T cell immune responses and matrix-degrading enzymes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Choi, Jin Kyeong; Molecular Immunology Section, Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892; Kim, Sung-Wan

ABSTRACT: Rheumatoid arthritis (RA) is a chronic autoimmune disease associated with a combination of synovium joint inflammation, synovium hyperplasia, and destruction of cartilage and bone. Oleanolic acid acetate (OAA), a compound isolated from Vigna angularis, has been known to possess pharmacological activities, including anti-inflammation and anti-bone destruction. In this study, we investigated the effects of OAA on RA and the underlying mechanisms of action by using a type-II collagen-induced arthritis (CIA) mouse model and tumor necrosis factor (TNF)-α-stimulated RA synovial fibroblasts. Oral administration of OAA decreased the clinical arthritis symptoms, paw thickness, histologic and radiologic changes, and serum total andmore » anti-type II collagen IgG, IgG1, and IgG2a levels. OAA administration reduced Th1/Th17 phenotype CD4{sup +} T lymphocyte expansions and inflammatory cytokine productions in T cell activated draining lymph nodes and spleen. OAA reduced the expression and production of inflammatory mediators, such as cytokines and matrix metalloproteinase (MMP)-1/3, in the ankle joint tissue and RA synovial fibroblasts by down-regulating Akt, mitogen-activated protein kinases, and nuclear factor-κB. Our results clearly support that OAA plays a therapeutic role in RA pathogenesis by modulating helper T cell immune responses and matrix-degrading enzymes. The immunosuppressive effects of OAA were comparable to dexamethasone and ketoprofen. We provide evidences that OAA could be a potential therapeutic candidate for RA. - Highlights: • OAA attenuated chronic CIA symptoms. • OAA had a regulating effect on the T helper cell immune reaction for CIA. • The effect of OAA on the RA was comparable to the dexamethasone or ketoprofen. • OAA might be a candidate for the treatment of arthritic diseases.« less

Interleukin-1 receptor antagonist, a biomarker of response to anti-TB treatment in HIV/TB co-infected patients.

PubMed

Nouhin, Janin; Pean, Polidy; Madec, Yoann; Chevalier, Mathieu F; Didier, Celine; Borand, Laurence; Blanc, François-Xavier; Scott-Algara, Daniel; Laureillard, Didier; Weiss, Laurence

2017-05-01

Despite the high frequency of tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) in human immunodeficiency virus (HIV)/TB co-infected patients, no diagnostic test is available. Here, we investigated whether monocyte/macrophage activation markers can predict TB-IRIS occurrence and if they are modulated by anti-TB treatment. Frozen plasma was obtained from 127 HIV/TB co-infected adults naïve for antiretroviral therapy, enrolled in the CAMELIA trial, 36 of whom developed TB-IRIS. Concentrations of IL-1Ra, sCD14, and sCD163 were measured at anti-TB treatment onset (baseline), after 8 weeks of anti-TB treatment and at TB-IRIS time. At baseline, IL-1Ra and sCD14 concentrations were similar in TB-IRIS and non-IRIS patients. sCD163 concentrations, although significantly higher in TB-IRIS patients, did not remain associated with TB-IRIS occurrence in multivariate analysis. At the time of TB-IRIS, patients displayed higher concentrations of IL-1Ra (p = 0.002) and sCD14 (p < 0.001). The most striking result was the significant decrease in IL-1Ra after 8 weeks of anti-TB treatment (median reduction: -63% (p < 0.0001)). None of the biomarkers tested was associated with TB-IRIS occurrence. However, repeated measurement of IL-1Ra could help for the diagnosis of TB-IRIS. The substantial reduction of IL-1Ra under treatment suggests that IL-1Ra could be a surrogate biomarker of anti-TB treatment response in HIV-infected patients. Copyright © 2017 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

Raised serum IgG and IgA antibodies to mycobacterial antigens in rheumatoid arthritis.

PubMed Central

Tsoulfa, G; Rook, G A; Van-Embden, J D; Young, D B; Mehlert, A; Isenberg, D A; Hay, F C; Lydyard, P M

1989-01-01

Autoantigens cross reactive with mycobacteria are implicated in the pathogenesis of adjuvant arthritis in the rat, and there are reports of changes in the immune response to mycobacteria in human rheumatoid arthritis (RA). We have therefore examined the IgM, IgG, and IgA antibody levels to crude mycobacterial antigens and to two recombinant mycobacterial heat shock/stress proteins (65 kD and 71 kD) in sera from patients with RA, systemic lupus erythematosus (SLE), and Crohn's disease, and from healthy controls. IgA binding to the crude mycobacterial antigens was significantly raised in RA sera, though IgG and IgM binding tended to be lower than in controls. Both IgA and IgG binding to the heat shock proteins were significantly raised in the RA sera. Smaller significant rises in both classes were seen in sera from patients with SLE, and in the IgA class only to the 65 kD protein in Crohn's disease. The rises in IgG and IgA antibodies to the 65 kD protein in RA were significantly higher than in the other diseases, however. It is interesting that this protein is the one responsible for adjuvant arthritis in the rat. PMID:2930263

Histone deacetylases: a common molecular target for differentiation treatment of acute myeloid leukemias?

PubMed

Minucci, S; Nervi, C; Lo Coco, F; Pelicci, P G

2001-05-28

Recent discoveries have identified key molecular events in the pathogenesis of acute promyelocytic leukemia (APL), caused by chromosomal rearrangements of the transcription factor RAR (resulting in a fusion protein with the product of other cellular genes, such as PML). Oligomerization of RAR, through a self-association domain present in PML, imposes an altered interaction with transcriptional co-regulators (NCoR/SMRT). NCoR/SMRT are responsible for recruitment of histone deacetylases (HDACs), which is required for transcriptional repression of PML-RAR target genes, and for the transforming potential of the fusion protein. Oligomerization and altered recruitment of HDACs are also responsible for transformation by the fusion protein AML1-ETO, extending these mechanisms to other forms of acute myeloid leukemias (AMLs) and suggesting that HDAC is a common target for myeloid leukemias. Strikingly, AML1-ETO expression blocks retinoic acid (RA) signaling in hematopoietic cells, suggesting that interference with the RA pathway (genetically altered in APL) by HDAC recruitment may be a common theme in AMLs. Treatment of APLs with RA, and of other AMLs with RA plus HDAC inhibitors (HDACi), results in myeloid differentiation. Thus, activation of the RA signaling pathway and inhibition of HDAC activity might represent a general strategy for the differentiation treatment of myeloid leukemias.

Periodontal Disease and Subgingival Microbiota as Contributors for RA Pathogenesis: Modifiable Risk Factors?

PubMed Central

Scher, Jose U.; Bretz, Walter A.; Abramson, Steven B.

2014-01-01

Purpose of review Since the early 1900s, the role of periodontal disease in the pathogenesis of rheumatoid arthritis has been a matter of intense research. The last decade has witnessed many advances supporting a link between periodontitis, the presence of specific bacterial species (i.e., Porphyromonas ginigivalis) and their effects in immune response. This review will examine available evidence on the subject. Recent findings Epidemiological studies have stressed the commonalities shared by periodontal disease and rheumatoid arthritis. Many groups have focused their attention towards understanding the periodontal microbiota and its alterations in states of health and disease. The presence of circulating antibodies against periodontopathic bacteria and associated inflammatory response has been found in both RA patients and subjects at-risk for disease development. Most recently, the periodontal microbiota of smokers and patients with RA has been elucidated, revealing profound changes in the bacterial communities compared to that of healthy controls. This has led to several small clinical trials of PD treatment as adjuvant for disease-modifying therapy in RA. Summary Smoking and periodontal disease are emerging risk factors for the development of RA. Epidemiological, clinical and basic research has further strengthened this association, pointing towards changes in the oral microbiota as possible contributors to systemic inflammation and arthritis. PMID:24807405

Towards Building an AOP-based Prenatal Developmental Toxicity Ontology (SOT)

EPA Science Inventory

Retinoid signaling plays an important role in embryo-fetal development and its disruption is broadly teratogenic. The retinoic acid (RA) pathway includes elements in retinoid metabolism and nuclear receptor (RAR, RXR) activation and thus serves as an excellent prototype for adver...

Pharmacokinetic modelling of interleukin-1 receptor antagonist in plasma and cerebrospinal fluid of patients following subarachnoid haemorrhage

PubMed Central

Gueorguieva, Ivelina; Clark, Simon R; McMahon, Catherine J; Scarth, Sylvia; Rothwell, Nancy J; Tyrell, Pippa J; Hopkins, Stephen J; Rowland, Malcolm

2008-01-01

Aim The naturally occurring interlukin-1 receptor antagonist (IL-1RA) markedly protects rodents against ischaemic, excitotoxic and traumatic brain injury, suggesting it may be of therapeutic value. The aim was to determine the pharmacokinetics of IL-1RA in cerebrospinal fluid (CSF) of patients, to allow modelling that would aid development of therapeutic regimens. Methods When administered intravenously to patients soon after stroke, IL-1RA is safe and reduces the peripheral inflammatory response. However, IL-1RA is a large protein (17 kDa), which may limit brain penetration, thereby limiting its potential utility in brain injury. In seven patients with subarchnoid haemorrhage (SAH), IL-1RA was administered by intravenous bolus, then infusion for 24 h, and both blood and CSF, via external ventricular drains, were sampled during and after stopping the infusion. Results Plasma steady-state concentrations were rapidly attained and maintained throughout the infusion, whereas CSF concentrations rose slowly towards a plateau during the 24-h infusion, reaching at best only 4% of that in plasma. Plasma kinetic parameters were within the literature range. Modelling of the combined data yielded rate constants entering and leaving the CSF of 0.0019 h−1[relative standard error (RSE) = 19%] and 0.1 h−1 (RSE = 19%), respectively. Conclusions Peripherally administered IL-1RA crosses slowly into and out of the CSF of patients with SAH. However, there is a large concentration gradient of IL-1RA between plasma and CSF. These CSF:plasma data are consistent with very low permeation of IL-1RA into the CSF and elimination kinetics from it controlled by the volumetric turnover of CSF. What is already known about this subject? The naturally occurring interlukin-1 receptor antagonist (IL-1RA) markedly protects rodents against ischaemic, excitotoxic and traumatic brain injury, suggesting it may be of therapeutic value.When administered intravenously to patients soon after stroke, IL-1RA is safe and reduces the peripheral inflammatory response.However, IL-1RA is a large protein (17 kDa), which may limit brain penetration, thereby limiting its potential utility in brain injury. What this study adds The purpose of these experiments was to determine the pharmacokinetics of IL-1RA in cerebrospinal fluid (CSF) of patients, to allow modelling that would aid development of therapeutic regimens.Peripherally administered IL-1RA crosses slowly into and out of the CSF of patients with subarachnoid haemorrhage and, at steady state, CSF IL-1RA concentration (range 115–886 ng ml−1) was similar to that found to be neuroprotective in rats (range 91–232 ng ml−1), although there was considerable variability among patients.However, there is a large concentration gradient of IL-1RA between plasma and CSF.These CSF:plasma data are consistent with very low permeation of IL-1RA into the CSF and elimination kinetics from it controlled by the volumetric turnover of CSF. PMID:17875190

Proximity to Traffic, Ambient Air Pollution, and Community Noise in Relation to Incident Rheumatoid Arthritis

PubMed Central

Koehoorn, Mieke; Tamburic, Lillian; Davies, Hugh W.; Brauer, Michael

2014-01-01

Background: The risk of rheumatoid arthritis (RA) has been associated with living near traffic; however, there is evidence suggesting that air pollution may not be responsible for this association. Noise, another traffic-generated exposure, has not been studied as a risk factor for RA. Objectives: We investigated proximity to traffic, ambient air pollution, and community noise in relation to RA in the Vancouver and Victoria regions of British Columbia, Canada. Methods: Cases and controls were identified in a cohort of adults that was assembled using health insurance registration records. Incident RA cases from 1999 through 2002 were identified by diagnostic codes in combination with prescriptions and type of physician (e.g., rheumatologist). Controls were matched to RA cases by age and sex. Environmental exposures were assigned to each member of the study population by their residential postal code(s). We estimated relative risks using conditional logistic regression, with additional adjustment for median income at the postal code. Results: RA incidence was increased with proximity to traffic, with an odds ratio (OR) of 1.37 (95% CI: 1.11, 1.68) for residence ≤ 50 m from a highway compared with residence > 150 m away. We found no association with traffic-related exposures such as PM2.5, nitrogen oxides, or noise. Ground-level ozone, which was highest in suburban areas, was associated with an increased risk of RA (OR = 1.26; 95% CI: 1.18, 1.36 per interquartile range increase). Conclusions: Our study confirms a previously observed association of RA risk with proximity to traffic and suggests that neither noise levels nor traffic-related air pollutants are responsible for this relationship. Additional investigation of neighborhood and individual correlates of residence near roadways may provide new insight into risk factors for RA. Citation: De Roos AJ, Koehoorn M, Tamburic L, Davies HW, Brauer M. 2014. Proximity to traffic, ambient air pollution, and community noise in relation to incident rheumatoid arthritis. Environ Health Perspect 122:1075–1080; http://dx.doi.org/10.1289/ehp.1307413 PMID:24905961

Phytochemicals as potential antidotes for targeting NF-κB in rheumatoid arthritis.

PubMed

Aravilli, R Kowshik; Vikram, S Laveen; Kohila, V

2017-08-01

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune destructive arthropathy prevalent among people in the age group of 40-70 years. RA induces severe pain, swelling and stiffness of joints resulting in bone damage. RA leads to reduced life expectancy when left untreated. RA is characterized by synovial hyperplasia, infiltration of inflammatory cells resulting in formation of pannus. Synovial hyperplasia is mediated by proinflammatory cytokines, notably IL-1 and TNF-α. NF-κB is a predominant transcription factor in amplifying the inflammatory response. The translocation of activated NF-κB into the nucleus triggers the transcription of several genes that induce proinflammatory cytokine production. The inhibition of NF-κB translocation aids blocking the activation of proinflammatory cascades. The quest for more effective and side-effect free treatment for RA unveiled phytochemicals as efficacious and promising. Phytochemicals have been a source of therapeutic substances for many ailments from ancient times. Their therapeutic ability helps in developing potent and safe drugs targeting immune inflammatory diseases driven by NF-κB including RA. This review highlights the importance of NF-κB inflammatory cascade in RA so as to elucidate the crucial role of phytochemicals that inhibit the activity of NF-κB.

Association study of ghrelin receptor gene polymorphisms in rheumatoid arthritis.

PubMed

Robledo, G; Rueda, B; Gonzalez-Gay, M A; Fernández, B; Lamas, J R; Balsa, A; Pascual-Salcedo, D; García, A; Raya, E; Martín, J

2010-01-01

Ghrelin is a newly characterised growth hormone (GH) releasing peptide widely distributed that may play an important role in the regulation of metabolic balance in inflammatory diseases such as rheumatoid arthritis (RA) by decreasing the pro-inflammatory Th1 responses. In this study we investigated the possible contribution of several polymorphisms in the functional Ghrelin receptor to RA susceptibility. A screening of 3 single nucleotide polymorphisms (SNPs) was performed in a total of 950 RA patients and 990 healthy controls of Spanish Caucasian origin. Genotyping of all 3 SNPs was performed by real-time polymerase chain reaction technology, using the TaqMan 5'-allele discrimination assay. We observed no statistically significant deviation between RA patients and controls for the GHSR SNPs analysed. In addition, we performed a haplotype analysis that did not reveal an association with RA susceptibility. The stratification analysis for the presence of shared epitope (SE), rheumatoid factor (RF) or antibodies anti cyclic citrullinated peptide (anti-CCP) did not detect significant association of the GHSR polymorphisms with RA. These findings suggest that the GHSR gene polymorphisms do not appear to play a major role in RA genetic predisposition in our population.

Low level determination of (226)Ra in water using a micro-precipitate track method for large-scale environmental monitoring.

PubMed

Taheri, M; Sohrabi, M; Jaleh, B; Hosseini, T; Montazer Rahmati, M M

2009-12-01

In the present paper a method has been developed for the determination of (226)Ra in water by the detection, using a solid-state nuclear track detector (SSNTD), of alpha particles from (226)Ra in equilibrium with (222)Rn in micro-precipitates collected on a filter. The micro-precipitates were prepared from environmental water samples by collection of radium with lead as Pb/RaSO(4). Several factors affect the (226)Ra precipitation on the filter and its recovery, in particular the filter pore size. Therefore in this experiment Whatman #42 and Millipore filters with different pore sizes were used. Using a 0.45 microm Millipore filter, the recovery efficiency was increased up to 96%, and the alpha self-absorption and scattering decreased remarkably. For efficient detection of alphas from (226)Ra/(222)Rn in equilibrium, three types of SSNTD were used-polycarbonate (PC) electrochemically etched (ECE), CR-39 and LR-115 chemically etched (CE). By preparing a standard micro-precipitate on a filter with known (226)Ra/(222)Rn characteristics, the calibration response of each detector and its minimum detection limit (MDL) were determined.

Ternary alkali-metal and transition metal or metalloid acetylides as alkali-metal intercalation electrodes for batteries

DOEpatents

Nemeth, Karoly; Srajer, George; Harkay, Katherine C; Terdik, Joseph Z

2015-02-10

Novel intercalation electrode materials including ternary acetylides of chemical formula: A.sub.nMC.sub.2 where A is alkali or alkaline-earth element; M is transition metal or metalloid element; C.sub.2 is reference to the acetylide ion; n is an integer that is 0, 1, 2, 3 or 4 when A is alkali element and 0, 1, or 2 when A is alkaline-earth element. The alkali elements are Lithium (Li), Sodium (Na), Potassium (K), Rubidium (Rb), Cesium (Cs) and Francium (Fr). The alkaline-earth elements are Berilium (Be), Magnesium (Mg), Calcium (Ca), Strontium (Sr), Barium (Ba), and Radium (Ra). M is a transition metal that is any element in groups 3 through 12 inclusive on the Periodic Table of Elements (elements 21 (Sc) to element 30 (Zn)). In another exemplary embodiment, M is a metalloid element.

Retinal toxicity related to hydroxychloroquine in patients with systemic lupus erythematosus and rheumatoid arthritis.

PubMed

Telek, Hande Husniye; Yesilirmak, Nilufer; Sungur, Gulten; Ozdemir, Yaprak; Yesil, Nesibe Karahan; Ornek, Firdevs

2017-12-01

To compare the retinal toxicity due to hydroxychloroquine (HCQ) use in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) using multifocal electroretinography (mfERG), fundus autofluorescence (FAF) and optical coherence tomography (OCT). Patients who were using HCQ due to SLE and RA, and healthy subjects evaluated in this study. Central foveal thickness (CFT), inner-outer segment (IS-OS) junction irregularity, retinal nerve fiber layer thickness, mfERG and FAF measurements were performed to evaluate retinal toxicity. Study included 35 eyes of 35 SLE patients, 40 eyes of 40 RA patients and 20 eyes of 20 healthy subjects. In SLE group, retinal abnormality was found in three eyes with mfERG, in one eye with FAF and in four eyes with OCT. In RA group, retinal abnormality was found in 10 eyes with mfERG, in five eyes with FAF and in nine eyes with OCT. A statistically significant difference was found with respect to mfERG between "eyes with abnormal responses and without abnormal responses" and "eyes with abnormal responses and controls" (p < 0.05). A statistically significant difference was found with respect to CFT between "eyes with IS-OS junction irregularities and without IS-OS junction irregularities" and "eyes with/without IS-OS junction irregularities and controls" (p < 0.05). The use of HCQ seems to cause retinal toxicity more often in RA patients compared to SLE patients. For the early detection of retinal changes, OCT and mfERG can be used as screening tools due to their higher sensitivity rates compared to other tests.

Association of Distinct Fine Specificities of Anti-Citrullinated Peptide Antibodies With Elevated Immune Responses to Prevotella intermedia in a Subgroup of Patients With Rheumatoid Arthritis and Periodontitis.

PubMed

Schwenzer, Anja; Quirke, Anne-Marie; Marzeda, Anna M; Wong, Alicia; Montgomery, Anna B; Sayles, Harlan R; Eick, Sigrun; Gawron, Katarzyna; Chomyszyn-Gajewska, Maria; Łazarz-Bartyzel, Katarzyna; Davis, Simon; Potempa, Jan; Kessler, Benedikt M; Fischer, Roman; Venables, Patrick J; Payne, Jeffrey B; Mikuls, Ted R; Midwood, Kim S

2017-12-01

In addition to the long-established link with smoking, periodontitis (PD) is a risk factor for rheumatoid arthritis (RA). This study was undertaken to elucidate the mechanism by which PD could induce antibodies to citrullinated peptides (ACPAs), by examining the antibody response to a novel citrullinated peptide of cytokeratin 13 (CK-13) identified in gingival crevicular fluid (GCF), and comparing the response to 4 other citrullinated peptides in patients with RA who were well-characterized for PD and smoking. The citrullinomes of GCF and periodontal tissue from patients with PD were mapped by mass spectrometry. ACPAs of CK13 (cCK13), tenascin-C (cTNC5), vimentin (cVIM), α-enolase (CEP-1), and fibrinogen β (cFIBβ) were examined by enzyme-linked immunosorbent assay in patients with RA (n = 287) and patients with osteoarthritis (n = 330), and cross-reactivity was assessed by inhibition assays. A novel citrullinated peptide cCK13-1 ( 444 TSNASGR-Cit-TSDV-Cit-RP 458 ) identified in GCF exhibited elevated antibody responses in RA patients (24%). Anti-cCK13-1 antibody levels correlated with anti-cTNC5 antibody levels, and absorption experiments confirmed this was not due to cross-reactivity. Only anti-cCK13-1 and anti-cTNC5 were associated with antibodies to the periodontal pathogen Prevotella intermedia (P = 0.05 and P = 0.001, respectively), but not with antibodies to Porphyromonas gingivalis arginine gingipains. Levels of antibodies to CEP-1, cFIBβ, and cVIM correlated with each other, and with smoking and shared epitope risk factors in RA. This study identifies 2 groups of ACPA fine specificities associated with different RA risk factors. One is predominantly linked to smoking and shared epitope, and the other links anti-cTNC5 and cCK13-1 to infection with the periodontal pathogen P intermedia. © 2017 The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.

Genetic data: The new challenge of personalized medicine, insights for rheumatoid arthritis patients.

PubMed

Goulielmos, George N; Zervou, Maria I; Myrthianou, Effie; Burska, Agata; Niewold, Timothy B; Ponchel, Frederique

2016-06-01

Rapid advances in genotyping technology, analytical methods, and the establishment of large cohorts for population genetic studies have resulted in a large new body of information about the genetic basis of human rheumatoid arthritis (RA). Improved understanding of the root pathogenesis of the disease holds the promise of improved diagnostic and prognostic tools based upon this information. In this review, we summarize the nature of new genetic findings in human RA, including susceptibility loci and gene-gene and gene-environment interactions, as well as genetic loci associated with sub-groups of patients and those associated with response to therapy. Possible uses of these data are discussed, such as prediction of disease risk as well as personalized therapy and prediction of therapeutic response and risk of adverse events. While these applications are largely not refined to the point of clinical utility in RA, it seems likely that multi-parameter datasets including genetic, clinical, and biomarker data will be employed in the future care of RA patients. Copyright © 2016 Elsevier B.V. All rights reserved.

A single gene for lycopene cyclase, phytoene synthase, and regulation of carotene biosynthesis in Phycomyces

PubMed Central

Arrach, Nabil; Fernández-Martín, Rafael; Cerdá-Olmedo, Enrique; Avalos, Javier

2001-01-01

Previous complementation and mapping of mutations that change the usual yellow color of the Zygomycete Phycomyces blakesleeanus to white or red led to the definition of two structural genes for carotene biosynthesis. We have cloned one of these genes, carRA, by taking advantage of its close linkage to the other, carB, responsible for phytoene dehydrogenase. The sequences of the wild type and six mutants have been established, compared with sequences in other organisms, and correlated with the mutant phenotypes. The carRA and carB coding sequences are separated by 1,381 untranslated nucleotides and are divergently transcribed. Gene carRA contains separate domains for two enzymes, lycopene cyclase and phytoene synthase, and regulates the overall activity of the pathway and its response to physical and chemical stimuli from the environment. The lycopene cyclase domain of carRA derived from a duplication of a gene from a common ancestor of fungi and Brevibacterium linens; the phytoene synthase domain is similar to the phytoene and squalene synthases of many organisms; but the regulatory functions appear to be specific to Phycomyces. PMID:11172012

Exercise-induced sympathetic activation is correlated with cerebral hemisphere laterality, but not handedness.

PubMed

Saito, M

2000-10-01

To investigate whether sympathetic responses are correlated with central laterality or handedness, muscle sympathetic nerve activity (MSNA), heart rate (HR) and blood pressure (BP) were compared between right (RA) and left arm (LA) grip exercise with volitional maximum effort (MVHG) for 2 min and post-exercise arterial occlusion (PEAO) in right- and left-handed volunteers. MVHG and PEAO led to a greater increase in MSNA in RA than in LA exercise (180 vs. 150%, P=0.004; 140 vs. 85%, P=0.005). MVHG elevated HR to a significantly lesser extent in RA than in LA (35 vs. 46%, P=0.030), and the difference was maintained during PEAO. The BP rise during MVHG and PEAO was the same in RA and in LA. Muscle sympathetic nerve activity, HR and BP responses during MVHG and PEAO showed no difference between the dominant and non-dominant arm. These results suggested that the effects of central motor command and metaboreflex on sympathetic outflow to the vasculature and the heart may be selectively modulated partly by hemispherical laterality.

Elucidating ultrafast electron dynamics at surfaces using extreme ultraviolet (XUV) reflection-absorption spectroscopy.

PubMed

Biswas, Somnath; Husek, Jakub; Baker, L Robert

2018-04-24

Here we review the recent development of extreme ultraviolet reflection-absorption (XUV-RA) spectroscopy. This method combines the benefits of X-ray absorption spectroscopy, such as element, oxidation, and spin state specificity, with surface sensitivity and ultrafast time resolution, having a probe depth of only a few nm and an instrument response less than 100 fs. Using this technique we investigated the ultrafast electron dynamics at a hematite (α-Fe2O3) surface. Surface electron trapping and small polaron formation both occur in 660 fs following photoexcitation. These kinetics are independent of surface morphology indicating that electron trapping is not mediated by defects. Instead, small polaron formation is proposed as the likely driving force for surface electron trapping. We also show that in Fe2O3, Co3O4, and NiO, band gap excitation promotes electron transfer from O 2p valence band states to metal 3d conduction band states. In addition to detecting the photoexcited electron at the metal M2,3-edge, the valence band hole is directly observed as transient signal at the O L1-edge. The size of the resulting charge transfer exciton is on the order of a single metal-oxygen bond length. Spectral shifts at the O L1-edge correlate with metal-oxygen bond covalency, confirming the relationship between valence band hybridization and the overpotential for water oxidation. These examples demonstrate the unique ability to measure ultrafast electron dynamics with element and chemical state resolution using XUV-RA spectroscopy. Accordingly, this method is poised to play an important role to reveal chemical details of previously unseen surface electron dynamics.

Stability of the Rabbit Immunogenic Marker of RA 27/3 Rubella Vaccine Virus After Human Passage

PubMed Central

Linnemann, Calvin C.; Hutchinson, Leslie; Rotte, Thomas C.; Hegg, Marion E.; Schiff, Gilbert M.

1974-01-01

Rabbits were inoculated intravenously with “wild” rubella virus, RA 27/3 rubella vaccine virus, or rubella virus isolated from recipients of RA 27/3 vaccine. Rabbits receiving “wild” virus developed rubella hemagglutination inhibition antibody, and those receiving vaccine virus did not. One of the five reisolates tested produced a low transient antibody response in two of the five rabbits inoculated with this strain. The study indicates that the rabbit immunogenic marker after intravenous injection can be used to determine if a rubella virus isolated from a patient is of “wild” or vaccine origin. There was no significant change in the reduced immunogenicity characteristics of the RA 27/3 vaccine virus after human passage. PMID:4206028

Identification of compounds that modulate retinol signaling using a cell-based qHTS assay

PubMed Central

Chen, Yanling; Sakamuru, Srilatha; Huang, Ruili; Reese, David H.; Xia, Menghang

2016-01-01

In vertebrates, the retinol (vitamin A) signaling pathway (RSP) controls the biosynthesis and catabolism of all-trans retinoic acid (atRA), which regulates transcription of genes essential for embryonic development. Chemicals that interfere with the RSP to cause abnormal intracellular levels of atRA are potential developmental toxicants. To assess chemicals for the ability to interfere with retinol signaling, we have developed a cell-based RARE (Retinoic Acid Response Element) reporter gene assay to identify RSP disruptors. To validate this assay in a quantitative high-throughput screening (qHTS) platform, we screened the Library of Pharmacologically Active Compounds (LOPAC) in both agonist and antagonist modes. The screens detected known RSP agonists, demonstrating assay reliability, and also identified novel RSP agonists including kenpaullone, niclosamide, PD98059 and SU4312, and RSP antagonists including Bay 11-7085, LY294002, 3,4-Methylenedioxy-β-nitrostyrene, and topoisomerase inhibitors (camptothecin, topotecan, amsacrine hydrochloride, and idarubicin). When evaluated in the P19 pluripotent cell, these compounds were found to affect the expression of the Hoxa1 gene that is essential for embryo body patterning. These results show that the RARE assay is an effective qHTS approach for screening large compound libraries to identify chemicals that have the potential to adversely affect embryonic development through interference with retinol signaling. PMID:26820057

Retinoic acid reverses the airway hyperresponsiveness but not the parenchymal defect that is associated with vitamin A deficiency.

PubMed

McGowan, Stephen E; Holmes, Amey Jo; Smith, Jennifer

2004-02-01

Airway hyperresponsiveness (AHR) is influenced by structural components of the bronchial wall, including the smooth muscle and connective tissue elements and the neuromuscular function. AHR is also influenced by parenchymally derived tethering forces on the bronchial wall, which maintain airway caliber by producing outward radial traction. Our previous work has shown that vitamin A-deficient (VAD) rats exhibit cholinergic hyperresponsiveness and a decrease in the expression and function of the muscarinic-2 receptors (M2R). We hypothesized that if decreases in radial traction from airway or parenchymal structures contributed to the VAD-related increase in AHR, then the radial traction would normalize more slowly than VAD-related alterations in neurotransmitter signaling. Rats remained vitamin A sufficient (VAS) or were rendered VAD and then maintained on the VAD diet in the presence or absence of supplementation with all-trans retinoic acid (RA). VAD was associated with an approximately twofold increase in respiratory resistance and elastance compared with VAS rats. Exposure to RA for 12 days but not 4 days restored resistance and elastance to control (VAS) levels. In VAD rats, AHR was accompanied by decreases in bronchial M2R gene expression and function, which were restored after 12 days of RA supplementation. Subepithelial bronchial elastic fibers were decreased by approximately 50% in VAD rats and were significantly restored by RA. The increase in AHR that is associated with VAD is accompanied by decreases in M2R expression and function that can be restored by RA and a reduction in airway elastic fibers that can be partially restored by RA.

Prevention of cardiovascular disease in rheumatoid arthritis.

PubMed

Hollan, I; Dessein, P H; Ronda, N; Wasko, M C; Svenungsson, E; Agewall, S; Cohen-Tervaert, J W; Maki-Petaja, K; Grundtvig, M; Karpouzas, G A; Meroni, P L

2015-10-01

The increased risk of cardiovascular disease (CVD) in rheumatoid arthritis (RA) has been recognized for many years. However, although the characteristics of CVD and its burden resemble those in diabetes, the focus on cardiovascular (CV) prevention in RA has lagged behind, both in the clinical and research settings. Similar to diabetes, the clinical picture of CVD in RA may be atypical, even asymptomatic. Therefore, a proactive screening for subclinical CVD in RA is warranted. Because of the lack of clinical trials, the ideal CVD prevention (CVP) in RA has not yet been defined. In this article, we focus on challenges and controversies in the CVP in RA (such as thresholds for statin therapy), and propose recommendations based on the current evidence. Due to the significant contribution of non-traditional, RA-related CV risk factors, the CV risk calculators developed for the general population underestimate the true risk in RA. Thus, there is an enormous need to develop adequate CV risk stratification tools and to identify the optimal CVP strategies in RA. While awaiting results from randomized controlled trials in RA, clinicians are largely dependent on the use of common sense, and extrapolation of data from studies on other patient populations. The CVP in RA should be based on an individualized evaluation of a broad spectrum of risk factors, and include: 1) reduction of inflammation, preferably with drugs decreasing CV risk, 2) management of factors associated with increased CV risk (e.g., smoking, hypertension, hyperglycemia, dyslipidemia, kidney disease, depression, periodontitis, hypothyroidism, vitamin D deficiency and sleep apnea), and promotion of healthy life style (smoking cessation, healthy diet, adjusted physical activity, stress management, weight control), 3) aspirin and influenza and pneumococcus vaccines according to current guidelines, and 4) limiting use of drugs that increase CV risk. Rheumatologists should take responsibility for the education of health care providers and RA patients regarding CVP in RA. It is immensely important to incorporate CV outcomes in testing of anti-rheumatic drugs. Copyright © 2015 Elsevier B.V. All rights reserved.

Relationship between shift work and the onset of rheumatoid arthritis

PubMed Central

Hedström, Anna Karin; Åkerstedt, Torbjörn; Klareskog, Lars; Alfredsson, Lars

2017-01-01

Background Environmental factors play a prominent role in rheumatoid arthritis (RA) aetiology. Shift work has previously been associated with increased RA risk in females. The aim of this study was to investigate the potential association, including a dose–response association, between permanent night shift work, rotating shift work and day-oriented shift work and risk of developing anticitrullinated peptide antibodies (ACPA)-positive and ACPA-negative RA. Methods The present report is based on a population-based, case–control study with incident cases of RA (1951 cases and 2225 controls matched by age, gender and residential area). Using logistic regression, occurrence of RA among subjects who have been exposed to different kinds of shift work was compared with that among those who have never been exposed by calculating the OR with a 95% CI. Results Rotating shift work and day-oriented shift work increased the risk of developing ACPA-positive RA (OR 1.3, 95% CI 1.0 to 1.7 and OR 1.3, 95% CI 1.0 to 1.6), but not ACPA-negative RA. Permanent night shift work appeared to be a protective factor both against ACPA-positive RA (OR 0.7, 95% CI 0.6 to 0.9) and ACPA-negative RA (OR 0.8, 95% CI 0.6 to 1.0). For both subsets of RA, significant trends showed a lower risk of developing RA with increasing duration of permanent night shift work (p value for trend 0.002 vs 0.04). Conclusions Sleep restriction as a consequence of shift work is associated with several biological effects among which changes in melatonin production may be involved. The present epidemiological findings of a complex relationship between sleep patterns and different forms of RA may be of importance for increasing the understanding of the pathophysiology of RA. PMID:29225920

Removal of ash, sulfur, and trace elements of environmental concern from eight selected Illinois coals

USGS Publications Warehouse

Demir, I.

1998-01-01

Release analysis (RA) and float-sink (F-S) data were generated to assess the beneficiation potential of washed coals from selected Illinois coal preparation plants through the use of advanced physical cleaning at -60 mesh size. Generally, the F-S process removed greater amounts of ash, sulfur, and trace elements of environmental concern from the coals than the RA process, indicating that the cleanability of Illinois coals by advanced methods can be estimated best by F-S testing. At an 80%-combustibles recovery, the ash yield in the clean F-S products decreased by 47-75%, relative to the parent coals. Average decreases for the elements As(67%), Cd(78%), Hg(73%), Mn(71%), and P(66%) exceeded the average decrease for ash yield (55%). Average decreases for other elements were: Co(31%), Cr(27%), F(39%), Ni(25%), Pb(50%), S(28%), Sb(20%), Se(39), Th(32%), and U(8%). Only Be was enriched (up to 120%) in the clean products relative to the parent coals. These results suggested that the concentration of elements with relatively high atmospheric mobilities (As, Cd, F, Hg, Pb, and Se) during coal combustion can be reduced substantially in Illinois coals through the use of advanced physical cleaning. Advanced physical cleaning can be effective also for the removal of inorganic S. Environmental risks from the emission of other elements with enrichment or relatively low cleanabilities could be small because these elements generally have very low concentrations in Illinois coals or are largely retained in solid residues during coal combustion. ?? 1998 OPA (Overseas Publishers Association) N.V. Published by license under the Gordon and Breach Science Publishers imprint.

Ameliorative effect of rosmarinic acid on scopolamine-induced memory impairment in rats.

PubMed

Hasanein, Parisa; Mahtaj, Azam Kazemian

2015-01-12

Rosmarinic acid (RA) is a natural phenol that exerts different biological activities, such as antioxidant activity and neuroprotective effects. In this study, we hypothesized that administration of RA (8, 16, and 32 mg/kg, p.o.) for 7 days would effect on scopolamine-induced cognitive dysfunction as an extensively used model of cognitive impairment. The rats were divided into 10 groups. The acquisition trial was done 1h after the last administration of RA. Animals were divided into control, RA (8, 16, and 32 mg/kg) and donepezil (2 mg/kg) treated controls, scopolamine, RA (8, 16, and 32 mg/kg), and donepezil (2 mg/kg) treated scopolamine groups. Memory impairment was induced by scopolamine treatment (1 mg/kg, i.p.) 30 min after the administration of RA, donepezil, or saline. Scopolamine administration caused cognition deficits in the PAL and memory paradigm. While orally RA administration (16 and 32 mg/kg) improved learning and memory in control rats, it reversed learning and memory deficits of scopolamine received groups. Administration of RA at the dose of 8 mg/kg did not alter cognitive function in control and scopolamine treated groups. The combination of anticholinesterase, neuroprotective, and antioxidant properties of RA may all be responsible for the observed effects. These results indicate the beneficial effects of subchronic RA administration in passive avoidance learning and memory in control rats as well as in a pharmacological model of cholinergic deficit which continue to expand the knowledge base in creating new treatment strategies for cognition deficits and dementia. Of course, further studies are warranted for clinical use of RA in the management of demented subjects. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Rhythmic Diurnal Synthesis and Signaling of Retinoic Acid in the Rat Pineal Gland and Its Action to Rapidly Downregulate ERK Phosphorylation.

PubMed

Ashton, Anna; Stoney, Patrick N; Ransom, Jemma; McCaffery, Peter

2018-03-08

Vitamin A is important for the circadian timing system; deficiency disrupts daily rhythms in activity and clock gene expression, and reduces the nocturnal peak in melatonin in the pineal gland. However, it is currently unknown how these effects are mediated. Vitamin A primarily acts via the active metabolite, retinoic acid (RA), a transcriptional regulator with emerging non-genomic activities. We investigated whether RA is subject to diurnal variation in synthesis and signaling in the rat pineal gland. Its involvement in two key molecular rhythms in this gland was also examined: kinase activation and induction of Aanat, which encodes the rhythm-generating melatonin synthetic enzyme. We found diurnal changes in expression of several genes required for RA signaling, including a RA receptor and synthetic enzymes. The RA-responsive gene Cyp26a1 was found to change between day and night, suggesting diurnal changes in RA activity. This corresponded to changes in RA synthesis, suggesting rhythmic production of RA. Long-term RA treatment in vitro upregulated Aanat transcription, while short-term treatment had no effect. RA was also found to rapidly downregulate extracellular signal-regulated kinase (ERK) 1/2 phosphorylation, suggesting a rapid non-genomic action which may be involved in driving the molecular rhythm in ERK1/2 activation in this gland. These results demonstrate that there are diurnal changes in RA synthesis and activity in the rat pineal gland which are partially under circadian control. These may be key to the effects of vitamin A on circadian rhythms, therefore providing insight into the molecular link between this nutrient and the circadian system.

Dietary intake and risk of rheumatoid arthritis-a cross section multicenter study.

PubMed

He, Jing; Wang, Yu; Feng, Min; Zhang, Xia; Jin, Yue-Bo; Li, Xue; Su, Lin-Chong; Liu, Shuang; Wang, Ai-Xue; Chen, Xiao-Mei; Wu, Li-Jun; Yu, Xiao-Xia; Xu, Ning; Liu, Xiang-Yuan; Yan, Hui-Ming; Wang, Yong-Fu; Jia, Bin; Li, Jun-Fang; Tao, Jie-Mei; Zhang, Feng-Xiao; Yu, Ping; Cui, Liu-Fu; Yang, Jing; Li, Zhen-Bin; Xie, Jian-Li; Wei, Ping; Sun, Wen-Wen; Gong, Lu; Cheng, Yong-Jing; Huang, Ci-Bo; Wang, Xiao-Yuan; Wang, Yi; Guo, Hui-Fang; Jin, Hong-Tao; Liu, Xia; Wang, Guo-Chun; Wang, Yan-Hua; He, Lan; Zhao, Yi; Li, Xiao-Xia; Zhang, Yan; Guo, Jian-Ping; Li, Zhan-Guo

2016-12-01

Environmental factors play an important role in the development of rheumatoid arthritis (RA). Among these factors, smoking is generally considered to be an established risk factor for RA. Data regarding the impact of diet on risk of RA development is limited. This study assessed the impact of dietary patterns on RA susceptibility in Chinese populations. This was a large scale, case-control study composed of 968 patients with RA and 1037 matched healthy controls. Subjects were recruited from 18 teaching hospitals. Socio-demographic characteristics and dietary intakes 5 years prior to the onset of RA were reported by a self-administered questionnaire. Differences in quantity of consumption between cases and controls were analyzed by Student's t test. Multiple logistic regression analysis was applied to identify independent dietary risk factor(s) responsible for RA susceptibility. Compared to healthy individuals, RA patients had decreased consumption of mushrooms (P = 0.000), beans (P = 0.006), citrus (P = 0.000), poultry (P = 0.000), fish (P = 0.000), edible viscera (P = 0.018), and dairy products (P = 0.005). Multivariate analyses revealed that several dietary items may have protective effects on RA development, such as mushrooms (aOR = 0.669; 95%CI = 0.518-0.864, P = 0.002), citrus fruits (aOR = 0.990; 95%CI = 0.981-0.999, P = 0.04), and dairy products (aOR = 0.921; 95%CI 0.867-0.977, P = 0.006). Several dietary factors had independent effects on RA susceptibility. Dietary interventions may reduce the risk of RA.

Serum progranulin irrelated with Breg cell levels, but elevated in RA patients, reflecting high disease activity.

PubMed

Chen, Jiaxi; Li, Shuang; Shi, Jianfeng; Zhang, Lili; Li, Jun; Chen, Shiyong; Wu, Chunlong; Shen, Bo

2016-03-01

Soluble progranulin (PGRN) is known to directly regulate regulatory T cells; however, whether PGRN levels are elevated in patients with rheumatoid arthritis and affect the regulatory subsets of B cells remain unknown. In this study, a total of 80 RA patients and 60 healthy controls were studied. Serum progranulin levels were determined using enzyme-linked immune-sorbent assay. A receiver operating characteristic (ROC) curve was used to evaluate the feasibility of serum PGRN as a biomarker for distinguishing patients with RA. CD19(+)CD5(+)GrB(+) B cells were analyzed by flow cytometry in peripheral blood mononuclear cells (PBMCs). Serum progranulin levels in RA patients (median, 59.4 ng/mL) and in RA patients DAS28 > 5.1 (median, 71.98 ng/mL) were much higher than those in normal controls (median, 46.3 ng/mL; P < 0.001). The area under the ROC curve for progranulin levels was 0.705 for RA versus normal controls and the area under the ROC curve for progranulin levels in RA patients DAS28 > 5.1 was 0.977 versus normal controls (P < 0.001). Interestingly, serum progranulin and DAS28, CRP, ESR were all positively correlated in RA patients (P < 0.001). The number of CD19(+)CD5(+)GrB(+) B cells was significantly higher in RA patients (P < 0.05); however, the level of Breg cells was not related to PGRN (P > 0.05). Our findings indicated that induction of PGRN expression may play a role in RA immune reaction and PGRN levels could be a useful biomarker in RA inflammatory response, but irrelated with Breg cell levels.

Fibromyalgia remains a significant burden in rheumatoid arthritis patients in Australia.

PubMed

Gist, Anthea C; Guymer, Emma K; Eades, Laura E; Leech, Michelle; Littlejohn, Geoffrey O

2018-03-01

High rates of fibromyalgia (FM) are reported in rheumatoid arthritis (RA) patients. Advances in RA management have occurred, but information regarding current significance of FM in RA is limited. This investigation estimated the prevalence and health effects of concomitant FM in Australian RA patients. Participants were recruited from Australian rheumatology clinics. Subjects were assessed using the 1990 and 2011 American College of Rheumatology (ACR) FM criteria and the polysymptomatic distress score (PDS) was calculated. A medical history and a clinical examination were recorded. RA Disease Activity Score of 28 joints - erythrocyte sedimentation rate (DAS-28 ESR), and the Short Form-36 survey (SF-36) were completed. Of 117 RA patients, 33.3% (n = 39) met 1990 ACR FM criteria and 41.9% (n = 49) met 2011 ACR FM criteria. RA patients with comorbid FM had worse outcomes across all domains of health as defined by the SF-36 (P < 0.05). There was correlation between both physical and mental health outcomes and the PDS (P < 0.001). RA patients with FM on average took 1.18 extra ongoing prescribed medications (P < 0.05), despite comparable RA disease activity (DAS-28: 3.09 vs. 3.27, P = NS). Comorbid central sensitivity conditions were more common in patients with FM (P < 0.001). FM continues to demonstrate a high prevalence in a population of RA patients. RA patients with FM have more symptoms of other chronic sensitivity syndromes in addition to FM. They have a lower quality of life outcome and higher medication use. This has important clinical implications in terms of diagnosis, response to therapy, prescribing choices and clinical outcomes. © 2017 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.

9-Cis retinoic acid protects against methamphetamine-induced neurotoxicity in nigrostriatal dopamine neurons.

PubMed

Reiner, David J; Yu, Seong-Jin; Shen, Hui; He, Yi; Bae, Eunkyung; Wang, Yun

2014-04-01

Methamphetamine (MA) is a drug of abuse as well as a dopaminergic neurotoxin. 9-Cis retinoic acid (9cRA), a biologically active derivative of vitamin A, has protective effects against damage caused by H(2)O(2) and oxygen-glucose deprivation in vitro as well as infarction and terminal deoxynucleotidyl transferase-mediated dNTP nick-end labeling (TUNEL) labeling in ischemic brain. The purpose of this study was to examine if there was a protective role for 9cRA against MA toxicity in nigrostriatal dopaminergic neurons. Primary dopaminergic neurons, prepared from rat embryonic ventral mesencephalic tissue, were treated with MA. High doses of MA decreased tyrosine hydroxylase (TH) immunoreactivity while increasing TUNEL labeling. These toxicities were significantly reduced by 9cRA. 9cRA also inhibited the export of Nur77 from nucleus to cytosol, a response that activates apoptosis. The interaction of 9cRA and MA in vivo was next examined in adult rats. 9cRA was delivered intracerebroventricularly; MA was given (5 mg/kg, 4×) one day later. Locomotor behavior was measured 2 days after surgery for a period of 48 h. High doses of MA significantly reduced locomotor activity and TH immunoreactivity in striatum. Administration of 9cRA antagonized these changes. Previous studies have shown that 9cRA can induce bone morphogenetic protein-7 (BMP7) expression and that administration of BMP7 attenuates MA toxicity. We demonstrated that MA treatment significantly reduced BMP7 mRNA expression in nigra. Noggin (a BMP antagonist) antagonized 9cRA-induced behavioral recovery and 9cRA-induced normalization of striatal TH levels. Our data suggest that 9cRA has a protective effect against MA-mediated neurodegeneration in dopaminergic neurons via upregulation of BMP.

9-cis retinoic acid protects against methamphetamine-induced neurotoxicity in nigrostriatal dopamine neurons

PubMed Central

Reiner, David J; Yu, Seong-Jin; Shen, Hui; He, Yi; Bae, Eunkyung; Wang, Yun

2013-01-01

Methamphetamine (MA) is a drug of abuse as well as a dopaminergic neurotoxin. 9-cis retinoic acid (9cRA), a biologically active derivative of vitamin A, has protective effects against damage caused by H2O2 and oxygen-glucose deprivation in vitro as well as infarction and TUNEL labeling in ischemic brain. The purpose of this study was to examine if there was a protective role for 9cRA against MA toxicity in nigrostriatal dopaminergic neurons. Primary dopaminergic neurons, prepared from rat embryonic ventral mesencephalic tissue, were treated with MA. High doses of MA decreased tyrosine hydroxylase (TH) immunoreactivity while increasing TUNEL labeling. These toxicities were significantly reduced by 9cRA. 9cRA also inhibited the export of Nur77 from nucleus to cytosol, a response that activates apoptosis. The interaction of 9cRA and MA in vivo was next examined in adult rats. 9cRA was delivered intracerebroventricularly; MA was given (5 mg/kg, 4x) one day later. Locomotor behavior was measured two days after surgery for a period of 48 hours. High doses of MA significantly reduced locomotor activity and TH immunoreactivity in striatum. Administration of 9cRA antagonized these changes. Previous studies have shown that 9cRA can induce bone morphogenetic protein-7 (BMP7) expression and that administration of BMP7 attenuates MA toxicity. We demonstrated that MA treatment significantly reduced BMP7 mRNA expression in nigra. Noggin (a BMP antagonist) antagonized 9cRA-induced behavioral recovery and 9cRA-induced normalization of striatal TH levels. Our data suggest that 9cRA has a protective effect against MA -mediated neurodegeneration in dopaminergic neurons via upregulation of BMP. PMID:23884514

Retinoic acid-loaded polymeric nanoparticles enhance vascular regulation of neural stem cell survival and differentiation after ischaemia

NASA Astrophysics Data System (ADS)

Ferreira, R.; Fonseca, M. C.; Santos, T.; Sargento-Freitas, J.; Tjeng, R.; Paiva, F.; Castelo-Branco, M.; Ferreira, L. S.; Bernardino, L.

2016-04-01

Stroke is one of the leading causes of death and disability worldwide. However, current therapies only reach a small percentage of patients and may cause serious side effects. We propose the therapeutic use of retinoic acid-loaded nanoparticles (RA-NP) to safely and efficiently repair the ischaemic brain by creating a favourable pro-angiogenic environment that enhances neurogenesis and neuronal restitution. Our data showed that RA-NP enhanced endothelial cell proliferation and tubule network formation and protected against ischaemia-induced death. To evaluate the effect of RA-NP on vascular regulation of neural stem cell (NSC) survival and differentiation, endothelial cell-conditioned media (EC-CM) were collected. EC-CM from healthy RA-NP-treated cells reduced NSC death and promoted proliferation while EC-CM from ischaemic RA-NP-treated cells decreased cell death, increased proliferation and neuronal differentiation. In parallel, human endothelial progenitor cells (hEPC), which are part of the endogenous repair response to vascular injury, were collected from ischaemic stroke patients. hEPC treated with RA-NP had significantly higher proliferation, which further highlights the therapeutic potential of this formulation. To conclude, RA-NP protected endothelial cells from ischaemic death and stimulated the release of pro-survival, proliferation-stimulating factors and differentiation cues for NSC. RA-NP were shown to be up to 83-fold more efficient than free RA and to enhance hEPC proliferation. These data serve as a stepping stone to use RA-NP as vasculotrophic and neurogenic agents for vascular disorders and neurodegenerative diseases with compromised vasculature.

Strategic planning for MyRA performance: A causal loop diagram approach

NASA Astrophysics Data System (ADS)

Abidin, Norhaslinda Zainal; Zaibidi, Nerda Zura; Karim, Khairah Nazurah

2017-10-01

The nexus of research and innovation in higher education are continually receiving worldwide priority attention. Hence, Malaysia has taken its move to enhance public universities as a center of excellence by introducing the status of Research University (RU). To inspire all universities towards becoming a research university, The Ministry of Higher Education (MoHE) had revised an assessment called Malaysian Research Assessment Instrument (MyRA) to evaluate the performance of existence RUs, and other potential higher education institutions. The available spreadsheet tool to access MyRA performance is inadequate to support strategic planning. Since, higher education management is a complex system, in which components and their interactions are ever changing over time, there is a need to for an efficient approach to investigate system behavior and devise research management policies for the benefit of the institution itself and the higher education system. In this paper, we proposed a system dynamics simulation model to evaluate the impact of policies for obtaining the highest performance in MyRA assessment. Causal loop diagram is developed to investigate the relationship of various elements in research management, their inter-relationship that link together and their evolution of behavior over time.

Immune response profiling in early rheumatoid arthritis: discovery of a novel interaction of treatment response with viral immunity

PubMed Central

2013-01-01

Introduction It remains challenging to predict the outcomes of therapy in patients with rheumatoid arthritis (RA). The objective of this study was to identify immune response signatures that correlate with clinical treatment outcomes in patients with RA. Methods A cohort of 71 consecutive patients with early RA starting treatment with disease-modifying antirheumatic drugs (DMARDs) was recruited. Disease activity at baseline and after 21 to 24 weeks of follow-up was measured using the Disease Activity Score in 28 joints (DAS28). Immune response profiling was performed by analyzing multi-cytokine production from peripheral blood cells following incubation with a panel of stimuli, including a mixture of human cytomegalovirus (CMV) and Epstein-Barr virus (EBV) lysates. Profiles identified via principal components analysis (PCA) for each stimulus were then correlated with the ΔDAS28 from baseline to follow-up. A clinically meaningful improvement in the DAS28 was defined as a decrease of ≥1.2. Results A profile of T-cell cytokines (IL-13, IL-4, IL-5, IL-2, IL-12, and IFN-γ) produced in response to CMV/EBV was found to correlate with the ΔDAS28 from baseline to follow-up. At baseline, a higher magnitude of the CMV/EBV immune response profile predicted inadequate DAS28 improvement (mean PCA-1 scores: 65.6 versus 50.2; P = 0.029). The baseline CMV/EBV response was particularly driven by IFN-γ (P = 0.039) and IL-4 (P = 0.027). Among patients who attained clinically meaningful DAS28 improvement, the CMV/EBV PCA-1 score increased from baseline to follow-up (mean +11.6, SD 25.5), whereas among patients who responded inadequately to DMARD therapy, the CMV/EBV PCA-1 score decreased (mean -12.8, SD 25.4; P = 0.002). Irrespective of the ΔDAS28, methotrexate use was associated with up-regulation of the CMV/EBV response. The CMV/EBV profile was associated with positive CMV IgG (P <0.001), but not EBV IgG (P = 0.32), suggesting this response was related to CMV exposure. Conclusions A profile of T-cell immunity associated with CMV exposure influences the clinical response to DMARD therapy in patients with early RA. Because CMV latency is associated with greater joint destruction, our findings suggest that changes in T-cell immunity mediated by viral persistence may affect treatment response and possibly long-term outcomes of RA. PMID:24267267

Improving patient outlook in rheumatoid arthritis: experience with abatacept.

PubMed

Coughlin, Mary

2008-10-01

To examine the importance of improving patient outlook in rheumatoid arthritis (RA) and to discuss the role of the nurse practitioner (NP) who, through the assessment of patient-reported outcomes and in acting as an advocate for the patient with the wider healthcare team, has a crucial part to play in managing the overall well-being of the patient. This article will draw on the clinical experience to date with abatacept, a first-in-class therapy that has been approved for the treatment of RA in patients with an inadequate response to either traditional disease-modifying antirheumatic drugs (DMARDs), such as methotrexate, or biological DMARDs, such as tumor necrosis factor-alpha antagonists. A comprehensive literature search was performed using the National Library of Medicine (MEDLINE), EMBASE, and BIOSIS databases (restricted to articles posted between January 2000 and February 2007) with the search terms CTLA-4Ig, abatacept, and primary clinical trial publications in patients with RA. The clinical data are summarized in this review along with safety data presented in the prescribing information. Recent changes in the approach to RA treatment, particularly the advent of biological therapies, have impacted the role of the NP. The role of the NP is integral to the management of RA and in maximizing patient outcomes, through educating patients to make informed choices regarding their treatment, ensuring the safe administration of therapies and monitoring response to therapy, and in acting as an advocate for the patient within the wider healthcare team. The use of more patient-centered measures of response are gaining increasing importance both in clinical trials and in clinical practice, and as such the NP has an important role in ensuring that both the physical and the psychological needs of patients are met. Clinical trials to date have shown that abatacept provides significant and clinically meaningful improvements in patient-reported outcomes, as well as demonstrating significant clinical benefits and a consistent safety profile, thus representing a valuable treatment option within the RA treatment armamentarium.

Influence of the IL-1Ra gene polymorphism on in vivo synthesis of IL-1Ra and IL-1beta after live yellow fever vaccination.

PubMed

Hacker, U T; Erhardt, S; Tschöp, K; Jelinek, T; Endres, S

2001-09-01

The inflammatory response in infectious and autoimmune diseases is regulated by the balance between pro- and anti-inflammatory cytokines. The IL-1 complex contains polymorphic genes coding for IL-1alpha, IL-1beta and IL-1Ra. The IL-1Ra (variable number of tanden repeat) VNTR polymorphism has been shown to influence the capacity to produce IL-1beta and IL-1Ra after in vitro stimulation. Allele 2 of this polymorphism is associated with a number of inflammatory diseases. To determine the impact of the IL-1Ra polymorphism on in vivo human cytokine synthesis, we used a yellow fever vaccination model for the induction of cytokine synthesis in healthy volunteers. Two different yellow fever vaccines were used. After administration of the RKI vaccine (34 volunteers), plasma TNF-alpha concentration increased from 13.4 +/- 0.9 pg/ml to 23.3 +/- 1.1 pg/ml (P < 0.001), and plasma IL-1Ra concentration increased from 308 +/- 25 pg/ml to 1019 +/- 111 pg/ml (P < 0.001), on day 2. Using Stamaril vaccine, no increase in the plasma concentrations of either TNF-alpha or IL-1Ra could be detected (n = 17). Only the RKI vaccine induced TNF-alpha synthesis after in vitro stimulation of MNC. Carriers of allele 2 of the IL-1Ra polymorphism had increased baseline concentrations of IL-1Ra (350 +/- 32 pg/ml) compared with non-carriers (222 +/- 18 pg/ml, P < 0.001), and decreased concentrations of IL-1beta (0.9 +/- 0.2 pg/ml for carriers versus 2.8 +/- 0.7 pg/ml for non-carriers, P = 0.017). After yellow fever vaccination (RKI vaccine), no significant differences in the increase of IL-1Ra plasma levels were detected between carriers and non-carriers of allele 2 of the IL-1Ra gene polymorphism. This is the first study to examine the influence of this genetic polymorphism on in vivo-induced human IL-1beta and IL-1Ra synthesis. Baseline concentrations of IL-1Ra and IL-1beta were significantly influenced by the IL-1Ra polymorphism. No influence of the IL-1Ra polymorphism on the in vivo-induced production of IL-1Ra and IL-1beta could be detected.

Identification of the advanced glycation end products N -carboxymethyllysine in the synovial tissue of patients with rheumatoid arthritis

PubMed Central

Drinda, S; Franke, S; Canet, C; Petrow, P; Brauer, R; Huttich, C; Stein, G; Hein, G

2002-01-01

Background: Generation of advanced glycation end products (AGEs) is an inevitable process in vivo and can be accelerated under pathological conditions such as oxidative stress. In serum and synovial fluid of patients with rheumatoid arthritis (RA) raised AGE levels have been found. Objective: To determine the presence of N -carboxymethyllysine (CML; marker of oxidative stress) in RA synovial tissue by immunohistology. Methods: Frozen synovial tissue samples from 10 patients with RA and eight controls (four patients without joint disease and four patients with osteoarthritis (OA)) were treated with rabbit-anti-CML-IgG and goat-antirabbit-IgG. Immunostaining was visualised by streptavidine-alkaline phosphatase (chromogen fuchsin). Cell differentiation was performed with antibodies against CD68, CD45RO, and CD20. Results: CML was detected in the synovial lining, sublining, and endothelium in 10/10 RA and 4/4 OA synovial specimens. In RA some macrophages (CD68+) and T cells (CD45RO+) showed positive immunostaining for CML, whereas B cells were negative. Staining in OA synovial sublining was weak compared with RA. Conclusions: CML was detected for the first time in RA and OA synovial tissue. Different patterns of immunostaining in RA and OA and the presence of CML on macrophages and T cells, suggest a role for CML in the pathogenesis of RA. This might be due to presentation of new epitopes which can maintain or even trigger an autoimmune response. PMID:12006318

cDNA cloning of an intracellular form of the human interleukin 1 receptor antagonist associated with epithelium.

PubMed Central

Haskill, S; Martin, G; Van Le, L; Morris, J; Peace, A; Bigler, C F; Jaffe, G J; Hammerberg, C; Sporn, S A; Fong, S

1991-01-01

A cDNA encoding a receptor antagonist of interleukin 1 (IL-1ra), secreted from human monocytes, has recently been isolated and sequenced [Eisenberg, S. P., Evans, R. J., Arend, W. P., Verderber, E., Brewer, M. T., Hannum, C. H. & Thompson, R. C. (1990) Nature (London) 343, 341-346]. We have identified another version of this IL-1ra, which is predominantly expressed in epithelial cells. This IL-1ra lacks a leader sequence and, thus, is probably intracellular. Both proteins are derived from the same gene through use of an alternative transcriptional start site and internal splice-acceptor site. Expression of intracellular IL-1ra cDNA in COS cells demonstrated that the intracellular product specifically inhibited exogenous interleukin 1-dependent responses. Keratinocytes were shown to contain significant amounts of nonsecreted IL-1ra protein. Constitutive expression of the intracellular IL-1ra may be an intracellular defensive mechanism in exposed epithelial cells and/or may serve to regulate autocrine interleukin 1-mediated pathways of differentiation. Images PMID:1827201

Regulatory T cells and TH1/TH2 cytokines as immunodiagnosis keys in systemic autoimmune diseases.

PubMed

Ursaciuc, Cornel; Surcel, Mihaela; Ciotaru, Dan; Dobre, Maria; Pirvu, Ioana Ruxandra; Munteanu, Adriana Narcisa; Alecu, Mihail; Huică, Radu

2010-01-01

We assessed Helper T-cell involvement and possibilities to quantify the cell-based immune response in systemic autoimmune diseases (SAID) in 14 systemic lupus erythematosus (SLE) and 7 rheumatoid arthritis (RA) patients. The goals of investigation were T-CD4+/T-CD8+ ratio, regulatory T cells (Treg) status and TH1/TH2 serum cytokine profiles (IFN-gamma and IL-2, respectively IL-4 and IL-6). SLE group proved significant decreased average Treg value as compared to RA group and controls and showed significant low Treg incidence (86% patients). The distribution of high T-CD4+/T-CD8+ ratio registered no significant distinction among LES and RA groups. SAID patients presented low serum IFN-gamma (86% RA, 60% SLE), high IL-2 (57% RA) and high IL-6 (53% LES), but no significant IL-4 modification. We conclude that Treg percentage remains the only cellular criterion for SAID immune evaluation. In the same time, different secretion mechanisms seem to be involved in SAID, i.e. TH2 in SLE and TH1 in RA.

Allergic manifestations in patients with rheumatoid arthritis.

PubMed

Olsson, Asa Reckner; Wingren, Gun; Skogh, Thomas; Svernell, Olle; Ernerudh, Jan

2003-10-01

A functional dichotomy between Th1- and Th2-type immune responses has been suggested. This study was performed to investigate whether rheumatoid arthritis (RA), a disease with indications of Th1-deviated immune activation, is inversly related to atopic conditions which are Th2-mediated. Two hundred and sixty-three adult cases of RA, fulfilling the American Rheumatism Association (ARA) 1987 Revised Classification Criteria for RA, were identified in 1995 and compared with 541 randomly selected population referents. The presence of atopic manifestations was established through a postal questionnaire and by demonstrating circulating IgE antibodies to common allergens. RA was inversely associated with certain manifestations of rhinitis, which were regarded as the most reliable indicators of atopic disease in the present study. However, no negative association was seen between RA and asthma and eczema, respectively. The main results give some support for an inverse relationship between RA and rhinitis. The prevalence of circulating IgE antibodies was however similar in cases and controls, suggesting that the T-cell commitment mainly occurs in the affected organs.

Quantifying pretreatment degradation compounds in solution and accumulated by cells during solids and yeast recycling in the Rapid Bioconversion with Integrated recycling Technology process using AFEX™ corn stover.

PubMed

Sarks, Cory; Higbee, Alan; Piotrowski, Jeff; Xue, Saisi; Coon, Joshua J; Sato, Trey K; Jin, Mingjie; Balan, Venkatesh; Dale, Bruce E

2016-04-01

Effects of degradation products (low molecular weight compounds produced during pretreatment) on the microbes used in the RaBIT (Rapid Bioconversion with Integrated recycling Technology) process that reduces enzyme usage up to 40% by efficient enzyme recycling were studied. Chemical genomic profiling was performed, showing no yeast response differences in hydrolysates produced during RaBIT enzymatic hydrolysis. Concentrations of degradation products in solution were quantified after different enzymatic hydrolysis cycles and fermentation cycles. Intracellular degradation product concentrations were also measured following fermentation. Degradation product concentrations in hydrolysate did not change between RaBIT enzymatic hydrolysis cycles; the cell population retained its ability to oxidize/reduce (detoxify) aldehydes over five RaBIT fermentation cycles; and degradation products accumulated within or on the cells as RaBIT fermentation cycles increased. Synthetic hydrolysate was used to confirm that pretreatment degradation products are the sole cause of decreased xylose consumption during RaBIT fermentations. Copyright © 2016 Elsevier Ltd. All rights reserved.

Vocal exploration is locally regulated during song learning

PubMed Central

Ravbar, Primoz; Parra, Lucas C.; Lipkind, Dina; Tchernichovski, Ofer

2012-01-01

Exploratory variability is essential for sensory-motor learning, but it is not known how and at what time scales it is regulated. We manipulated song learning in zebra finches to experimentally control the requirements for vocal exploration in different parts of their song. We first trained birds to perform a one-syllable song, and once they mastered it we added a new syllable to the song model. Remarkably, when practicing the modified song, birds rapidly alternated between high and low acoustic variability to confine vocal exploration to the newly added syllable. Further, even within syllables, acoustic variability changed independently across song elements that were only milliseconds apart. Analysis of the entire vocal output during learning revealed that the variability of each song element decreased as it approached the target, correlating with momentary local distance from the target and less so with the overall distance. We conclude that vocal error is computed locally in sub-syllabic time scales and that song elements can be learned and crystalized independently. Songbirds have dedicated brain circuitry for vocal babbling in the anterior forebrain pathway (AFP), which generates exploratory song patterns that drive premotor neurons at the song nucleus RA (robust nucleus of the arcopallium). We hypothesize that either AFP adjusts the gain of vocal exploration in fine time scales, or that the sensitivity of RA premotor neurons to AFP/HVC inputs varies across song elements. PMID:22399765

MSFIA-LOV system for (226)Ra isolation and pre-concentration from water samples previous radiometric detection.

PubMed

Rodríguez, Rogelio; Borràs, Antoni; Leal, Luz; Cerdà, Víctor; Ferrer, Laura

2016-03-10

An automatic system based on multisyringe flow injection analysis (MSFIA) and lab-on-valve (LOV) flow techniques for separation and pre-concentration of (226)Ra from drinking and natural water samples has been developed. The analytical protocol combines two different procedures: the Ra adsorption on MnO2 and the BaSO4 co-precipitation, achieving more selectivity especially in water samples with low radium levels. Radium is adsorbed on MnO2 deposited on macroporous of bead cellulose. Then, it is eluted with hydroxylamine to transform insoluble MnO2 to soluble Mn(II) thus freeing Ra, which is then coprecipitated with BaSO4. The (226)Ra can be directly detected in off-line mode using a low background proportional counter (LBPC) or through a liquid scintillation counter (LSC), after performing an on-line coprecipitate dissolution. Thus, the versatility of the proposed system allows the selection of the radiometric detection technique depending on the detector availability or the required response efficiency (sample number vs. response time and limit of detection). The MSFIA-LOV system improves the precision (1.7% RSD), and the extraction frequency (up to 3 h(-1)). Besides, it has been satisfactorily applied to different types of water matrices (tap, mineral, well and sea water). The (226)Ra minimum detectable activities (LSC: 0.004 Bq L(-1); LBPC: 0.02 Bq L(-1)) attained by this system allow to reach the guidance values proposed by the relevant international agencies e.g. WHO, EPA and EC. Copyright © 2016 Elsevier B.V. All rights reserved.

Endothelial progenitor cells in active rheumatoid arthritis: effects of tumour necrosis factor and glucocorticoid therapy

PubMed Central

Grisar, Johannes; Aletaha, Daniel; Steiner, Carl W; Kapral, Theresa; Steiner, Sabine; Säemann, Marcus; Schwarzinger, Ilse; Buranyi, Barbara; Steiner, Günter; Smolen, Josef S

2007-01-01

Objectives To study the effects of short‐term intermediate dose glucocorticoid (GC) therapy in patients with active rheumatoid arthritis (RA) on circulating endothelial progenitor cells (EPC), which are known to influence cardiovascular risk, and to elucidate mechanisms potentially responsible for the reduction of EPCs in patients with active RA. Methods EPCs were quantified in 29 patients with active RA by flow cytometry, colony forming unit (CFU) and circulating angiogenic cell (CAC) assays before and after 7 days of intermediate dose GC therapy. CFU from patients with RA and from healthy referents (HR) were cultured in vitro in the absence or presence of dexamethasone (Dex) and/or TNF. Results After 1 week of GC therapy, EPC increased from 0.026 (SD 0.003)% to 0.053 (SD 0.010)% (p<0.01), and from 12 (SD 4) to 27 (SD 7) CFU/well (p<0.02); CAC also increased from 7 (SD 2) to 29 (SD 8) cells/high power field (p<0.05). In parallel, disease activity decreased significantly after GC treatment. TNF serum levels also decreased from 36 (SD 10) to 14 (SD 6) pg/ml (p<0.0001). Addition of Dex to the RA CFU led to a significant increase of mean CFU counts, whereas addition of TNF induced a decrease of CFU. Conclusions Our data indicate that TNF may be at least partly responsible for the reduction of EPC seen in patients with RA. Intermediate doses of GCs for a short period of time, apart from reducing disease activity, significantly increase circulating EPC. PMID:17293363

The systemic immune network in recent onset type 1 diabetes: central role of interleukin-1 receptor antagonist (DIATOR Trial).

PubMed

Kolb, Hubert; Lückemeyer, Kathrin; Heise, Tim; Herder, Christian; Schloot, Nanette C; Koenig, Wolfgang; Heinemann, Lutz; Martin, Stephan

2013-01-01

The hypothesis was tested that the systemic immune milieu in recent-onset type 1 diabetes is associated with residual beta cell function and other metabolic patient characteristics. All patients (n = 89, 40% female) of the Diabetes and Atorvastatin (DIATOR) Trial were analyzed at recruitment, i.e. prior to receiving the study medication. Inclusion criteria were insulin dependent diabetes for 2 weeks to 3 months, age range 18-39 years, and islet cell autoantibodies. Blood samples were analyzed for 14 immune mediators by standard methods. Concentrations of all mediators correlated with at least one other mediator (p<0.05, Spearman correlation) giving rise to a network. Interleukin 1 receptor antagonist (IL1-RA) held a central position and was associated with both pro- and anti-inflammatory mediators. Further central elements were the pro-inflammatory mediators CRP and IL-6, the soluble adhesion molecules sICAM-1 and E-selectin, and MCP-4 which held a central position in the chemokine network. The two Th1-associated mediators IFNγ and IP-10 remained outside the network but correlated with each other. All correlations were positive (r = 0.25-0.72), i.e., high levels of pro-inflammatory mediators were accompanied by increased levels of anti-inflammatory mediators. IL-1RA was the only mediator associated with fasting and liquid mixed meal stimulated C-peptide concentrations (r = 0.31 and 0.24, p = 0.003 and 0.025, after adjustment for age, sex, BMI). There were associations between the immune mediator network and BMI (IL-1RA, CRP, IL-6, MCP-4, MIP-1ß) but few or no associations with HbA1c, insulin dose, lipid parameters, age or sex. In patients with recent onset type 1 diabetes, systemic acute phase proteins, cytokines, chemokines and soluble adhesion molecules form a network. Among the few central elements IL-1RA has a dominant role. IL-1RA is associated with all other groups of mediators and is the only mediator which correlates (positively) with residual beta cell function. ClinicalTrials.gov registration number: NCT00974740.

The CpxRA two-component system contributes to Legionella pneumophila virulence.

PubMed

Tanner, Jennifer R; Li, Laam; Faucher, Sébastien P; Brassinga, Ann Karen C

2016-06-01

The bacterium Legionella pneumophila is capable of intracellular replication within freshwater protozoa as well as human macrophages, the latter of which results in the serious pneumonia Legionnaires' disease. A primary factor involved in these host cell interactions is the Dot/Icm Type IV secretion system responsible for translocating effector proteins needed to establish and maintain the bacterial replicative niche. Several regulatory factors have been identified to control the expression of the Dot/Icm system and effectors, one of which is the CpxRA two-component system, suggesting essentiality for virulence. In this study, we generated cpxR, cpxA and cpxRA in-frame null mutant strains to further delineate the role of the CpxRA system in bacterial survival and virulence. We found that cpxR is essential for intracellular replication within Acanthamoeba castellanii, but not in U937-derived macrophages. Transcriptome analysis revealed that CpxRA regulates a large number of virulence-associated proteins including Dot/Icm effectors as well as Type II secreted substrates. Furthermore, the cpxR and cpxRA mutant strains were more sodium resistant than the parental strain Lp02, and cpxRA expression reaches maximal levels during postexponential phase. Taken together, our findings suggest the CpxRA system is a key contributor to L. pneumophila virulence in protozoa via virulence factor regulation. © 2016 John Wiley & Sons Ltd.

Multiple Lava Types Erupted Over Short Spatial and Temporal Scales at the Southern East Pacific Rise: 17° 23'-17° 35'S

NASA Astrophysics Data System (ADS)

Bergmanis, E. C.; Sinton, J. M.; Rubin, K. H.

2003-12-01

Major, trace element and U-series disequilibria data reveal both short- and long-term compositional heterogeneity in lavas from the southern EPR 17° 23'-17° 35'S. Major-element compositional variation in the ˜18km-long Aldo-Kihi flow (MgO 7.7-8.4 wt %) is consistent with shallow-level fractional crystallization. (230Th)/(238U) disequilibria for samples from the Aldo-Kihi flow cover a narrow range of 1.85+/-0.15. However, the range of Th/U ratios (2.61-2.84) and (226Ra)/(230Th) disequilibria (2.26-2.65) are very broad for a single eruptive unit and cannot be a result of shallow-level fractional crystallization of a single magma composition. MgO contents, Th/U ratios, and (226Ra)/(230Th) disequilibria for Aldo-Kihi samples all peak at ˜17° 30.6'S and generally are greater for samples south of 17° 30'S implying that more than one magmatic component has contributed to this lava flow. This along-axis compositional diversity is hard to reconcile with propagation of a dike originating from a small area, and suggests vertical eruption from a magma chamber that is compositionally zoned along-axis. Along this ˜22km-long section of the southern EPR, major, trace element and U-series disequilibria data indicate that at least six compositionally distinct lava types are present within 1km of the axis. (210Pb)/(226Ra) deficits of ˜5 % for the Aldo-Kihi lava and two other compositionally distinct units suggest they are substantially younger than ˜100 yrs. Although geologic relationships demonstrate that Aldo-Kihi is the youngest of these, the range of (210Pb)/(230Ra) disequilibria for the individual units overlap making relative age determinations impossible using that criteria alone. Regional trends in major-element data show that twenty-three other samples older than Aldo-Kihi contain >8.0 wt % MgO; all but two occur south of 17° 28.4'S suggesting that the location of hottest sub-axial magma is a long-lived feature of this region. The distribution of rock types in this area requires a complex history of mantle melting, recharge, cooling, and eruption that varies considerably over along-axis distances of ˜22 kilometers and between successive eruptions.

Neurotoxic, inflammatory, and mucosecretory responses in the nasal airways of mice repeatedly exposed to the macrocyclic trichothecene mycotoxin roridin A: dose-response and persistence of injury.

PubMed

Corps, Kara N; Islam, Zahidul; Pestka, James J; Harkema, Jack R

2010-04-01

Macrocyclic trichothecene mycotoxins encountered in water-damaged buildings have been suggested to contribute to illnesses of the upper respiratory tract. Here, the authors characterized the adverse effects of repeated exposures to roridin A (RA), a representative macrocyclic trichothecene, on the nasal airways of mice and assessed the persistence of these effects. Young, adult, female C57BL/6 mice were exposed to single daily, intranasal, instillations of RA (0.4, 2, 10, or 50 microg/kg body weight [bw]) in saline (50 microl) or saline alone (controls) over 3 weeks or 250 microg/kg RA over 2 weeks. Histopathologic, immunohistochemical, and morphometric analyses of nasal airways conducted 24 hr after the last instillation revealed that the lowest-effect level was 10 microg/kg bw. RA exposure induced a dose-dependent, neutrophilic rhinitis with mucus hypersecretion, atrophy and exfoliation of nasal transitional and respiratory epithelium, olfactory epithelial atrophy and loss of olfactory sensory neurons (OSNs). In a second study, the persistence of lesions in mice instilled with 250 microg/kg bw RA was assessed. Nasal inflammation and excess luminal mucus were resolved after 3 weeks, but OSN loss was still evident in olfactory epithelium (OE). These results suggest that nasal inflammation, mucus hypersecretion, and olfactory neurotoxicity could be important adverse health effects associated with short-term, repeated, airborne exposures to macrocyclic trichothecenes.

Prevalence of rheumatoid arthritis in Dublin, Ireland: a population based survey.

PubMed

Power, D; Codd, M; Ivers, L; Sant, S; Barry, M

1999-01-01

The prevalence of Rheumatoid Arthritis (RA) in Ireland has never been established. Studies from different countries show varying rates, being almost 100 per cent greater in the highlands of Scotland (10/1,000) than in rural Lesotho (6/1,000). A recent study also suggests a fall in the prevalence of RA among women in the London urban area. Given these variations the validity of extrapolating prevalence rates established for other countries to Ireland is questionable. This study aimed to establish a prevalence rate for RA in a defined Dublin population. A self-administered questionnaire was sent to 2,500 people chosen at random from the electoral register. The questionnaire was designed to select out both undiagnosed patients and those with definite arthritis. Respondents whose replies indicated an arthritic process, but in whom no diagnosis had been made, were asked to attend for further assessment and investigations as appropriate. Those who responded that they had been diagnosed with arthritis were asked for consent to inspect their hospital or general practitioner records. A diagnosis of RA was based on American Rheumatism Association (ARA) criteria. Valid responses were received from 1,227 people surveyed (response rate = 49 per cent). Six cases of RA were identified including 2 previously undiagnosed cases. A prevalence rate of 5/1,000 has been estimated based on these findings.

Recent Progress in JAK Inhibitors for the Treatment of Rheumatoid Arthritis.

PubMed

Nakayamada, Shingo; Kubo, Satoshi; Iwata, Shigeru; Tanaka, Yoshiya

2016-10-01

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by synovial inflammation and joint destruction. Considerable advance in the treatment of RA has been made following the advent of biological disease-modifying anti-rheumatic drugs (DMARDs). However, these biologics require intravenous or subcutaneous injection and some patients fail to respond to biological DMARDs or lose their primary response. Various cytokines and cell surface molecules bind to receptors on the cell surface, resulting in the activation of various cell signaling pathways, including phosphorylation of kinase proteins. Among these kinases, the non-receptor tyrosine kinase family Janus kinase (JAK) plays a pivotal role in the pathological processes of RA. Several JAK inhibitors have been developed as new therapies for patients with RA. These are oral synthetic DMARDs that inhibit JAK1, 2, and 3. One JAK inhibitor, tofacitinib, has already been approved in many countries. Results of phase III clinical trials using a JAK1/2 inhibitor, baricitinib, have shown feasible efficacy and tolerable safety. Both drugs are effective in patients who showed inadequate response to biological DMARDs as well as synthetic DMARDs. In addition, clinical phase III trials using filgotinib and ABT-494, specific JAK1 inhibitors, are currently underway. JAK inhibitors are novel therapies for RA, but further studies are needed to determine their risk-benefit ratio and selection of the most appropriate patients for such therapy.

The rapid mode of calcium uptake into heart mitochondria (RaM): comparison to RaM in liver mitochondria.

PubMed

Buntinas, L; Gunter, K K; Sparagna, G C; Gunter, T E

2001-04-02

A mechanism of Ca(2+) uptake, capable of sequestering significant amounts of Ca(2+) from cytosolic Ca(2+) pulses, has previously been identified in liver mitochondria. This mechanism, the Rapid Mode of Ca(2+) uptake (RaM), was shown to sequester Ca(2+) very rapidly at the beginning of each pulse in a sequence [Sparagna et al. (1995) J. Biol. Chem. 270, 27510-27515]. The existence and properties of RaM in heart mitochondria, however, are unknown and are the basis for this study. We show that RaM functions in heart mitochondria with some of the characteristics of RaM in liver, but its activation and inhibition are quite different. It is feasible that these differences represent different physiological adaptations in these two tissues. In both tissues, RaM is highly conductive at the beginning of a Ca(2+) pulse, but is inhibited by the rising [Ca(2+)] of the pulse itself. In heart mitochondria, the time required at low [Ca(2+)] to reestablish high Ca(2+) conductivity via RaM i.e. the 'resetting time' of RaM is much longer than in liver. RaM in liver mitochondria is strongly activated by spermine, activated by ATP or GTP and unaffected by ADP and AMP. In heart, RaM is activated much less strongly by spermine and unaffected by ATP or GTP. RaM in heart is strongly inhibited by AMP and has a biphasic response to ADP; it is activated at low concentrations and inhibited at high concentrations. Finally, an hypothesis consistent with the data and characteristics of liver and heart is presented to explain how RaM may function to control the rate of oxidative phosphorylation in each tissue. Under this hypothesis, RaM functions to create a brief, high free Ca(2+) concentration inside mitochondria which may activate intramitochondrial metabolic reactions with relatively small amounts of Ca(2+) uptake. This hypothesis is consistent with the view that intramitochondrial [Ca(2+)] may be used to control the rate of ADP phosphorylation in such a way as to minimize the probability of activating the Ca(2+)-induced mitochondrial membrane permeability transition (MPT).

Retinoic acid plays an evolutionarily conserved and biphasic role in pancreas development

PubMed Central

Huang, Wei; Wang, Guangliang; Delaspre, Fabien; Vitery, Maria del Carmen; Beer, Rebecca L.

2015-01-01

As the developing zebrafish pancreas matures, hormone-producing endocrine cells differentiate from pancreatic Notch-responsive cells (PNCs) that reside within the ducts. These new endocrine cells form small clusters known as secondary (2°) islets. We use the formation of 2° islets in the pancreatic tail of the larval zebrafish as a model of β-cell neogenesis. Pharmacological inhibition of Notch signaling leads to precocious endocrine differentiation and the early appearance of 2° islets in the tail of the pancreas. Following a chemical screen, we discovered that blocking the retinoic acid (RA)-signaling pathway also leads to the induction of 2° islets. Conversely, the addition of exogenous RA blocks the differentiation caused by Notch inhibition. In this report we characterize the interaction of these two pathways. We first verified that signaling via both RA and Notch ligands act together to regulate pancreatic progenitor differentiation. We produced a transgenic RA reporter, which demonstrated that PNCs directly respond to RA signaling through the canonical transcriptional pathway. Next, using a genetic lineage tracing approach, we demonstrated these progenitors produce endocrine cells following inhibition of RA signaling. Lastly, inhibition of RA signaling using a cell-type specific inducible cre/lox system revealed that RA signaling acts cell-autonomously in PNCs to regulate their differentiation. Importantly, the action of RA inhibition on endocrine formation is evolutionarily conserved, as shown by the differentiation of human embryonic stem cells in a model of human pancreas development. Together, these results revealed a biphasic function for RA in pancreatogenesis. As previously shown by others, RA initially plays an essential role during embryogenesis as it patterns the endoderm and specifies the pancreatic field. We reveal here that later in development RA is involved in negatively regulating the further differentiation of pancreatic progenitors and expands upon the developmental mechanisms by which this occurs. PMID:25127993

The effect of infliximab and timing of vaccination on the humoral response to influenza vaccination in patients with rheumatoid arthritis and ankylosing spondylitis.

PubMed

Elkayam, Ori; Bashkin, Amir; Mandelboim, Michal; Litinsky, Irena; Comaheshter, Doron; Levartovsky, David; Mendelson, Ella; Wigler, Irena; Caspi, Dan; Paran, Daphna

2010-06-01

To assess the effect of the timing of vaccination in relation to administration of infliximab on the efficacy and safety of influenza vaccine in patients with rheumatoid arthritis (RA) and ankylosing spondylitis (AS). The study population comprised 38 patients treated with infliximab at a mean dosage of 3 mg/kg (20 RA patients; 18 AS patients; 23 RA controls (treated with disease modifying antirheumatic drugs other than anti-tumor necrosis factor-alpha; and 17 healthy controls). Split-virion inactivated vaccine containing 15 mug hemagglutinin/dose of each of A/New Caledionan/20/1999 (H1N1), A/Wisconsin/67/2005 (H3N2), and B/Malaysia/2506/2004 (M) was used. Patients treated with infliximab were divided into 2 groups: 22 were vaccinated on the day of administration of infliximab, while 16 received the vaccine 3 weeks after infliximab. Baseline and 4- to 6-week clinical assessment of disease activity included erythrocyte sedimentation rate and C-reactive protein for all patients, the 28-joint disease-activity score for RA patients, and Bath Ankylosing Spondylitis Disease Activity Index for AS patients. Hemagglutination inhibition (HI) antibodies were tested by a standard World Health Organization procedure. Response was defined as >or=4-fold rise in HI antibodies 4 to 6 weeks after vaccination, or seroconversion in patients with a nonprotective baseline level of antibodies (<1/40). Geometric mean titers (GMT) were calculated to assess the immunity of the whole group. At baseline, RA patients and controls had similar occurrence of protective levels of HI antibodies and GMT, while AS patients had lower levels reflecting lower rates of previous vaccination. Four weeks after vaccination, a significant and similar increase in GMT for each antigen was observed in all groups (P < 0.004) except in the RA-infliximab group, vaccinated 3 weeks after administration of infliximab, in whom the increase in GMT was not significant for H1N1 (P = 0.12) and H3 (P = 0.06). AS patients demonstrated an increase in GMT, independently of the time of vaccination. The percentage of responders was similar in all groups. The response was not affected by variables such as age, gender, methotrexate, or prednisone use. Parameters of disease activity remained unchanged. No adverse effects other than injection site pain were recorded. Influenza virus vaccine generated a good humoral response in RA and AS patients treated with infliximab. Copyright 2010 Elsevier Inc. All rights reserved.

The high sensitivity of the rabbit to the teratogenic effects of 13-cis-retinoic acid (isotretinoin) is a consequence of prolonged exposure of the embryo to 13-cis-retinoic acid and 13-cis-4-oxo-retinoic acid, and not of isomerization to all-trans-retinoic acid.

PubMed

Tzimas, G; Bürgin, H; Collins, M D; Hummler, H; Nau, H

1994-01-01

Previous studies suggested that the rabbit is much more susceptible to the teratogenic action of 13-cis-retinoic acid (13-cis-RA) than the mouse or the rat, while the teratogenicity of all-trans-RA was comparable in these species. In the present study we investigated if pharmacokinetics can explain these species- and structure-related differences. The embryotoxic and teratogenic potential of all-trans-retinoic acid (all-trans-RA) and 13-cis-RA were evaluated in the Swiss hare rabbit after oral administration of daily doses of the two drugs throughout organogenesis, from gestation day (GD) 6 to 18 (plug day = GD 0). All-trans-RA was given at dose levels of 0.7, 2 or 6 mg/kg body weight per day and 13-cis-RA at 3, 7.5 or 10 mg/kg per day. The doses needed to elicit a minimum teratogenic response were found to be 6 mg/kg per day for all-trans-RA and 10 mg/kg per day for 13-cis-RA. Using these doses, transplacental pharmacokinetics of all-trans- and 13-cis-RA were performed. Pregnant rabbits were treated once daily from GD 7 to 12 and plasma and embryo samples were collected for HPLC analysis at various time intervals after the final dose. The main plasma metabolites of all-trans- and 13-cis-RA were all-trans-beta-glucuronide (all-trans-RAG) and 13-cis-4-oxo-RA, respectively. The elimination of 13-cis-RA and its metabolites from maternal plasma were much slower than of all-trans-RA resulting in accumulation of the 13-cis-isomers in plasma. Marked differences in the placental transfer of the two drugs and their metabolites were observed. All-trans-RA and all-trans-4-oxo-RA were efficiently transferred to the rabbit embryo, reaching concentrations similar to the plasma levels. On the contrary, the 13-cis-isomers reached the embryo to a lesser extent. Despite its limited placental transfer, a considerable embryonic exposure to 13-cis-RA and 13-cis-4-oxo-RA was noticed after treatment with isotretinoin, as indicated by their area-under-the-concentration-time-curve (AUC) values in the embryo, which were in the same range as the corresponding AUC value of all-trans-RA after treatment with the all-trans-isomer.(ABSTRACT TRUNCATED AT 400 WORDS)

Ultrasound disease activity of bilateral wrist and finger joints at three months reflects the clinical response at six months of patients with rheumatoid arthritis treated with biologic disease-modifying anti-rheumatic drugs.

PubMed

Kawashiri, Shin-Ya; Nishino, Ayako; Shimizu, Toshimasa; Umeda, Masataka; Fukui, Shoichi; Nakashima, Yoshikazu; Suzuki, Takahisa; Koga, Tomohiro; Iwamoto, Naoki; Ichinose, Kunihiro; Tamai, Mami; Nakamura, Hideki; Origuchi, Tomoki; Aoyagi, Kiyoshi; Kawakami, Atsushi

2017-03-01

We evaluated whether the early responsiveness of ultrasound synovitis can predict the clinical response in rheumatoid arthritis (RA) patients treated with biologic disease-modifying anti-rheumatic drugs (bDMARDs). Articular synovitis was assessed by ultrasound at 22 bilateral wrist and finger joints in 39 RA patients treated with bDMARDs. Each joint was assigned a gray-scale (GS) and power Doppler (PD) score from 0 to 3, and the sum of the GS or PD scores was considered to represent the ultrasound disease activity. We investigated the correlation of the change in ultrasound disease activity at three months with the EULAR response criteria at six months. GS and PD scores were significantly decreased at three months (p < 0.0001). The % changes of the GS and PD scores at three months were significantly higher at six months in moderate and good responders compared with non-responders (p < 0.05). These tendencies were numerically more prominent if clinical response was set as good responder or Disease Activity Score 28 remission. Poor improvement of ultrasound synovitis scores had good predictive value for non-responders at six months. The responsiveness of ultrasound disease activity is considered to predict further clinical response in RA patients treated with bDMARDs.

Response to rituximab and timeframe to relapse in rheumatoid arthritis patients: association with B-cell markers.

PubMed

Pyrpasopoulou, Athina; Douma, Stella; Triantafyllou, Areti; Simoulidou, Elisavet; Samara, Magda; Parapanisiou, Efthymia; Aslanidis, Spyros

2010-02-01

Rituximab is used to deplete B cells and control disease activity, mainly in patients with rheumatoid arthritis (RA) who have not responded to anti-tumor necrosis factor (TNF) therapy. Response rates and time to relapse vary significantly among treated individuals. The objective of this study was to monitor the response of seropositive and seronegative RA patients to rituximab and correlate relapse with B-cell markers in the two groups. Seventeen RA patients (eight seropositive for rheumatoid factor [RF+] and nine seronegative [RF-]) were treated with two cycles of rituximab. After treatment, all patients were re-evaluated at the outpatient clinic, and rituximab was readministered when disease relapse was confirmed by clinical-laboratory measures (Disease Activity Score [DAS]-28). CD20+ cells and CD20 receptor expression levels were estimated at initiation, relapse, and re-evaluation timepoints, and were compared between the two groups. Seropositive patients responded favorably to treatment compared with the seronegative group. The mean time to relapse was 337.5 +/- 127.0 days for the RF+ patients versus 233.3 +/- 59.6 days for the RF- patients (p = 0.043), despite more aggressive concomitant treatment in the seronegative group. The DAS28 decrease 3 months after treatment was 1.695 +/- 1.076 in seropositive patients versus 0.94 +/- 1.62 in seronegative patients. At relapse, CD20 receptor expression (molecules/cell) was higher in RF+ patients than in their RF- counterparts, despite a significantly lower percentage of CD20+ cells. Rituximab treatment is efficient in both seropositive and seronegative RA. However, seropositive RA patients tend to respond favorably compared with seronegative patients. The differential CD20 receptor expression in the two groups at relapse potentially suggests a different pathogenetic mechanism of relapse and merits further investigation.

Combined epigenetic and differentiation-based treatment inhibits neuroblastoma tumor growth and links HIF2α to tumor suppression

PubMed Central

Westerlund, Isabelle; Shi, Yao; Toskas, Konstantinos; Fell, Stuart M.; Li, Shuijie; Surova, Olga; Södersten, Erik; Kogner, Per; Nyman, Ulrika; Schlisio, Susanne; Holmberg, Johan

2017-01-01

Neuroblastoma is a pediatric cancer characterized by variable outcomes ranging from spontaneous regression to life-threatening progression. High-risk neuroblastoma patients receive myeloablative chemotherapy with hematopoietic stem-cell transplant followed by adjuvant retinoid differentiation treatment. However, the overall survival remains low; hence, there is an urgent need for alternative therapeutic approaches. One feature of high-risk neuroblastoma is the high level of DNA methylation of putative tumor suppressors. Combining the reversibility of DNA methylation with the differentiation-promoting activity of retinoic acid (RA) could provide an alternative strategy to treat high-risk neuroblastoma. Here we show that treatment with the DNA-demethylating drug 5-Aza-deoxycytidine (AZA) restores high-risk neuroblastoma sensitivity to RA. Combined systemic distribution of AZA and RA impedes tumor growth and prolongs survival. Genome-wide analysis of treated tumors reveals that this combined treatment rapidly induces a HIF2α-associated hypoxia-like transcriptional response followed by an increase in neuronal gene expression and a decrease in cell-cycle gene expression. A small-molecule inhibitor of HIF2α activity diminishes the tumor response to AZA+RA treatment, indicating that the increase in HIF2α levels is a key component in tumor response to AZA+RA. The link between increased HIF2α levels and inhibited tumor growth is reflected in large neuroblastoma patient datasets. Therein, high levels of HIF2α, but not HIF1α, significantly correlate with expression of neuronal differentiation genes and better prognosis but negatively correlate with key features of high-risk tumors, such as MYCN amplification. Thus, contrary to previous studies, our findings indicate an unanticipated tumor-suppressive role for HIF2α in neuroblastoma. PMID:28696319

Combined epigenetic and differentiation-based treatment inhibits neuroblastoma tumor growth and links HIF2α to tumor suppression.

PubMed

Westerlund, Isabelle; Shi, Yao; Toskas, Konstantinos; Fell, Stuart M; Li, Shuijie; Surova, Olga; Södersten, Erik; Kogner, Per; Nyman, Ulrika; Schlisio, Susanne; Holmberg, Johan

2017-07-25

Neuroblastoma is a pediatric cancer characterized by variable outcomes ranging from spontaneous regression to life-threatening progression. High-risk neuroblastoma patients receive myeloablative chemotherapy with hematopoietic stem-cell transplant followed by adjuvant retinoid differentiation treatment. However, the overall survival remains low; hence, there is an urgent need for alternative therapeutic approaches. One feature of high-risk neuroblastoma is the high level of DNA methylation of putative tumor suppressors. Combining the reversibility of DNA methylation with the differentiation-promoting activity of retinoic acid (RA) could provide an alternative strategy to treat high-risk neuroblastoma. Here we show that treatment with the DNA-demethylating drug 5-Aza-deoxycytidine (AZA) restores high-risk neuroblastoma sensitivity to RA. Combined systemic distribution of AZA and RA impedes tumor growth and prolongs survival. Genome-wide analysis of treated tumors reveals that this combined treatment rapidly induces a HIF2α-associated hypoxia-like transcriptional response followed by an increase in neuronal gene expression and a decrease in cell-cycle gene expression. A small-molecule inhibitor of HIF2α activity diminishes the tumor response to AZA+RA treatment, indicating that the increase in HIF2α levels is a key component in tumor response to AZA+RA. The link between increased HIF2α levels and inhibited tumor growth is reflected in large neuroblastoma patient datasets. Therein, high levels of HIF2α, but not HIF1α, significantly correlate with expression of neuronal differentiation genes and better prognosis but negatively correlate with key features of high-risk tumors, such as MYCN amplification. Thus, contrary to previous studies, our findings indicate an unanticipated tumor-suppressive role for HIF2α in neuroblastoma.

Tofacitinib, an oral Janus kinase inhibitor, in patients from Mexico with rheumatoid arthritis: Pooled efficacy and safety analyses from Phase 3 and LTE studies.

PubMed

Burgos-Vargas, Ruben; Cardiel, Mario; Xibillé, Daniel; Pacheco-Tena, César; Pascual-Ramos, Virginia; Abud-Mendoza, Carlos; Mahgoub, Ehab; Rahman, Mahboob; Fan, Haiyun; Rojo, Ricardo; García, Erika; Santana, Karina

2017-05-25

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We characterized efficacy and safety of tofacitinib in Mexican patients from RA Phase 3 and long-term extension (LTE) studies. Data from Mexican patients with RA and an inadequate response to disease-modifying antirheumatic drugs (DMARDs) were taken from four Phase 3 studies (pooled across studies) and one open-label LTE study of tofacitinib. Patients received tofacitinib 5 or 10mg twice daily, adalimumab (one Phase 3 study) or placebo (four Phase 3 studies) as monotherapy or in combination with conventional synthetic DMARDs. Efficacy up to Month 12 (Phase 3) and Month 36 (LTE) was assessed by American College of Rheumatology 20/50/70 response rates, Disease Activity Score (erythrocyte sedimentation rate), and Health Assessment Questionnaire-Disability Index. Safety, including incidence rates (IRs; patients with events/100 patient-years) for adverse events (AEs) of special interest, was assessed throughout the studies. 119 and 212 Mexican patients were included in the Phase 3 and LTE analyses, respectively. Tofacitinib-treated patients in Phase 3 had numerically greater improvements in efficacy responses versus placebo at Month 3. Efficacy was sustained in Phase 3 and LTE studies. IRs for AEs of special interest were similar to those with tofacitinib in the global and Latin American RA populations. In Mexican patients from the tofacitinib global RA program, tofacitinib efficacy was demonstrated up to Month 12 in Phase 3 studies and Month 36 in the LTE study, with a safety profile consistent with tofacitinib global population. Copyright © 2017 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.

Current tobacco smoking, formal education, and the risk of rheumatoid arthritis.

PubMed

Uhlig, T; Hagen, K B; Kvien, T K

1999-01-01

To identify if tobacco smoking or sociodemographic characteristics are risk factors of rheumatoid arthritis (RA). From a county RA register 361 patients in the age range 20-79 years were recruited from incidence cohorts with recent disease onset (mean 3.4 years) and compared with 5851 randomly selected individuals from the same population area. Data on selected risk factors were collected by questionnaires (response rate 75 and 59%, respectively) and associations with smoking and risk factors were expressed as odds ratios (OR) with 95% confidence intervals (CI) in a multiple regression analysis. Age and female sex were, as expected, identified as risk factors of RA. In addition, current smoking was an overall risk factor (OR 1.46, 95% CI 1.10-1.94), in men (OR 2.38, 95% CI 1.45-3.92), especially in men with seropositive RA (OR 4.77, 95% CI 2.09-10.90). Separate analyses revealed no statistically significant risk in women (OR 1.14, 95% CI 0.80-1.62). Low level of formal education, body mass index, marital or employment status were not significantly associated with risk of RA. Current smoking in men was identified as an independent risk factor for RA, whereas surrogate markers of socioeconomic status were unrelated to the onset of RA.

NanoESI mass spectrometry of Rubisco and Rubisco activase structures and their interactions with nucleotides and sugar phosphates.

PubMed

Blayney, Michelle J; Whitney, Spencer M; Beck, Jennifer L

2011-09-01

Ribulose bisphosphate carboxylase/oxygenase (Rubisco) is the protein that is responsible for the fixation of carbon dioxide in photosynthesis. Inhibitory sugar phosphate molecules, which can include its substrate ribulose-1,5-bisphosphate (RuBP), can bind to Rubisco catalytic sites and inhibit catalysis. These are removed by interaction with Rubisco activase (RA) via an ATP hydrolytic reaction. Here we show the first nanoESI mass spectra of the hexadecameric Rubisco and of RA from a higher plant (tobacco). The spectra of recombinant, purified RA revealed polydispersity in its oligomeric forms (up to hexamer) and that ADP was bound. ADP was removed by dialysis against a high ionic strength solution and nucleotide binding experiments showed that ADP bound more tightly to RA than AMP-PNP (a non-hydrolysable ATP analog). There was evidence that there may be two nucleotide binding sites per RA monomer. The oligomerization capacity of mutant and wild-type tobacco RA up to hexamers is analogous to the subunit stoichiometry for other AAA+ enzymes. This suggests assembly of RA into hexamers is likely the most active conformation for removing inhibitory sugar phosphate molecules from Rubisco to enable its catalytic competency. Stoichiometric binding of RuBP or carboxyarabinitol bisphosphate (CABP) to each of the eight catalytic sites of Rubisco was observed.

15-Hydroxyprostaglandin dehydrogenase is upregulated by hydroxychloroquine in rheumatoid arthritis fibroblast-like synoviocytes

PubMed Central

KIM, HAK-JAE; LEE, SORA; LEE, HAW-YONG; WON, HANSOL; CHANG, SUNG-HAE; NAH, SEONG-SU

2015-01-01

15-Hydroxyprostaglandin dehydrogenase (HPGD) is the key enzyme responsible for the metabolic inactivation of prostaglandin E2 (PGE2) catabolism. PGE2 is one of the predominant catabolic factors involved in rheumatoid arthritis (RA). However, the expression and regulation of HPGD in RA fibroblast-like synoviocyte (FLS) remain to be elucidated. Disease-modifying anti-rheumatic drugs (DMARDs) are the most important anti-arthritic drugs, which reduce the effect of joint injury. The aim of the present study was to assess the expression of HPGD in RA tissues and cells, and normal synovial tissues and cells. The effect of the most popular DMARDs, hydroxychloroquine, on the expression of HPGD in RA-FLS was also investigated. Western blotting and immuno-histochemical analysis demonstrated that the expression levels of HPGD in human synovium were lower in RA synovium compared with the normal and OA synovium. In RA-FLS, the expression of HPGD was increased following treatment with several DMARDs, including sulfasalazine, methotrexate, and hydroxychloroquine. Hydroxychloroquine (10 µM) treatment induced the phosphorylation of ERK, SAPK/JNK and p38. Hydroxychloroquine induced a decrease in the release of PGE2, which was restored by mitogen-activated protein (MAP) kinase pathway inhibitors. Hydroxychloroquine may therefore, affect the pathogenesis of RA through the MAP kinase pathway by regulating the expression of HPGD. PMID:26082314

Role of UDP-glucuronosyltransferase isoforms in 13-cis retinoic acid metabolism in humans.

PubMed

Rowbotham, Sophie E; Illingworth, Nicola A; Daly, Ann K; Veal, Gareth J; Boddy, Alan V

2010-07-01

13-cis Retinoic acid (13cisRA, isotretinoin) is an important drug in both dermatology, and the treatment of high-risk neuroblastoma. 13cisRA is known to undergo cytochrome P450-mediated oxidation, mainly by CYP2C8, but phase II metabolic pathways have not been characterized. In the present study, the glucuronidation activities of human liver (HLM) and intestinal microsomes (HIM), as well as a panel of human UDP-glucuronosyltransferases (UGTs) toward both 13cisRA and the 4-oxo metabolite, 4-oxo 13cisRA, were compared using high-performance liquid chromatography. Both HLM and, to a greater extent, HIM catalyzed the glucuronidation of 13cisRA and 4-oxo 13cisRA. Based on the structures of 13cisRA and 4-oxo 13cisRA, the glucuronides formed are conjugated at the terminal carboxylic acid. Further analysis revealed that UGT1A1, UGT1A3, UGT1A7, UGT1A8, and UGT1A9 were the major isoforms responsible for the glucuronidation of both substrates. For 13cisRA, a pronounced substrate inhibition was observed with individual UGTs and with HIM. UGT1A3 exhibited the highest rate of activity toward both substrates, and a high rate of activity toward 13cisRA glucuronidation was also observed with UGT1A7. However, for both substrates, K(m) values were above concentrations reported in clinical studies. Therefore, UGT1A9 is likely to be the most important enzyme in the glucuronidation of both substrates as this enzyme had the lowest K(m) and is expressed in both the intestine and at high levels in the liver.

Role of Key TYMS Polymorphisms on Methotrexate Therapeutic Outcome in Portuguese Rheumatoid Arthritis Patients

PubMed Central

Lima, Aurea; Seabra, Vítor; Bernardes, Miguel; Azevedo, Rita; Sousa, Hugo; Medeiros, Rui

2014-01-01

Background Therapeutic outcome of rheumatoid arthritis (RA) patients treated with methotrexate (MTX) can be modulated by thymidylate synthase (TS) levels, which may be altered by genetic polymorphisms in TS gene (TYMS). This study aims to elucidate the influence of TYMS polymorphisms in MTX therapeutic outcome (regarding both clinical response and toxicity) in Portuguese RA patients. Methods Clinicopathological data from 233 Caucasian RA patients treated with MTX were collected, outcomes were defined and patients were genotyped for the following TYMS polymorphisms: 1) 28 base pairs (bp) variable number tandem repeat (rs34743033); 2) single nucleotide polymorphism C>G (rs2853542); and 3) 6 bp sequence deletion (1494del6, rs34489327). Chi-square and binary logistic regression analyses were performed, using genotype and haplotype-based approaches. Results Considering TYMS genotypes, 3R3R (p = 0.005, OR = 2.34), 3RC3RG (p = 0.016, OR = 3.52) and 6bp− carriers (p = 0.011, OR = 1.96) were associated with non-response to MTX. Multivariate analysis confirmed the increased risk for non-response to MTX in 6bp− carriers (p = 0.016, OR = 2.74). Data demonstrated that TYMS polymorphisms were in linkage disequilibrium (p<0.00001). Haplotype multivariate analysis revealed that haplotypes harboring both 3R and 6bp− alleles were associated with non-response to MTX. Regarding MTX-related toxicity, no statistically significant differences were observed in relation to TYMS genotypes and haplotypes. Conclusion Our study reveals that TYMS polymorphisms could be important to help predicting clinical response to MTX in RA patients. Despite the potential of these findings, translation into clinical practice needs larger studies to confirm these evidences. PMID:25279663

Epstein–Barr virus in bone marrow of rheumatoid arthritis patients predicts response to rituximab treatment

PubMed Central

Brisslert, Mikael; Zendjanchi, Kiandoht; Lindh, Magnus; Bokarewa, Maria I.

2010-01-01

Objectives. Viruses may contribute to RA. This prompted us to monitor viral load and response to anti-CD20 therapy in RA patients. Methods. Blood and bone marrow from 35 RA patients were analysed for CMV, EBV, HSV-1, HSV-2, parvovirus B19 and polyomavirus using real-time PCR before and 3 months after rituximab (RTX) treatment and related to the levels of autoantibodies and B-cell depletion. Clinical response to RTX was defined as decrease in the 28-joint disease activity score (DAS-28) >1.3 at 6 months. Results. Before RTX treatment, EBV was identified in 15 out of 35 patients (EBV-positive group), of which 4 expressed parvovirus. Parvovirus was further detected in eight patients (parvo-positive group). Twelve patients were negative for the analysed viruses. Following RTX, EBV was cleared, whereas parvovirus was unaffected. Eighteen patients were responders, of which 12 were EBV positive. The decrease in the DAS-28 was significantly higher in EBV-positive group compared with parvo-positive group (P = 0.002) and virus-negative patients (P = 0.04). Most of EBV-negative patients that responded to RTX (75%) required retreatment within the following 11 months compared with only 8% of responding EBV-positive patients. A decrease of RF, Ig-producing cells and CD19+ B cells was observed following RTX but did not distinguish between viral infections. However, EBV-infected patients had significantly higher levels of Fas-expressing B cells at baseline as compared with EBV-negative groups. Conclusions. EBV and parvovirus genomes are frequently found in bone marrow of RA patients. The presence of EBV genome was associated with a better clinical response to RTX. Thus, presence of EBV genome may predict clinical response to RTX. PMID:20547657

Efficacy and safety of the oral Janus kinase inhibitor peficitinib (ASP015K) monotherapy in patients with moderate to severe rheumatoid arthritis in Japan: a 12-week, randomised, double-blind, placebo-controlled phase IIb study

PubMed Central

Takeuchi, Tsutomu; Tanaka, Yoshiya; Iwasaki, Manabu; Ishikura, Hiroaki; Saeki, Satoshi; Kaneko, Yuichiro

2016-01-01

Objective To evaluate the efficacy, safety and dose response of a novel oral Janus kinase inhibitor, peficitinib (ASP015K), as monotherapy in Japanese patients with moderate to severe rheumatoid arthritis (RA). Methods In a 12-week, double-blind study, 281 adult patients with RA with active disease not on concomitant disease-modifying antirheumatic drug therapy were randomised equally to once-daily placebo or peficitinib 25, 50, 100 and 150 mg. The primary endpoint was American College of Rheumatology (ACR) 20 response in the peficitinib treatment groups versus placebo at week 12. Results Mean age was 53.0 years, 81.1% were female and 25.3% had previously used antitumour necrosis factor therapy. Peficitinib 50, 100 and 150 mg each showed statistically significantly higher ACR20 response rates compared with placebo, and response rates increased up to 150 mg with a statistically significant dose response. The total incidence of treatment-emergent adverse events (TEAEs) was similar between the placebo (64.3%) and peficitinib 25, 50, 100 and 150 mg groups (70.9%, 64.9%, 52.7% and 67.2%, respectively). TEAEs occurring more frequently in the peficitinib group compared with the placebo group included nasopharyngitis, increased blood creatine phosphokinase and diarrhoea. No cases of serious infections were reported. Herpes zoster occurred in four patients (two each in peficitinib 25 and 100 mg). Conclusions Treatment with peficitinib as monotherapy for 12 weeks in Japanese patients with moderate to severe RA is efficacious and showed acceptable safety profile. These findings support further developments of peficitinib for RA treatment. Trial registration number NCT01649999; Results. PMID:26672064

Association of the TYMS 3G/3G genotype with poor response and GGH 354GG genotype with the bone marrow toxicity of the methotrexate in RA patients.

PubMed

Jekic, Biljana; Lukovic, Ljiljana; Bunjevacki, Vera; Milic, Vera; Novakovic, Ivana; Damnjanovic, Tatjana; Milasin, Jelena; Popovic, Branka; Maksimovic, Nela; Damjanov, Nemanja; Radunovic, Goran; Kovacevic, Ljiljana; Krajinovic, Maja

2013-03-01

Gamma-glutamyl hydrolase (GGH), cyclin D1 (CCND1) and thymidylate synthase (TS) genes encode enzymes that are involved in methotrexate (MTX) action. In a group of 184 RA patients treated with MTX, we have investigated whether selected polymorphisms in these genes modulate MTX efficacy and/or have impact on adverse drug effects (ADEs). The efficacy of the MTX therapy has been estimated using the disease activity score in 28 joints (DAS28-ESR) based on EULAR criteria and relative DAS28 values (rDAS28). All adverse drug events were recorded. Patients were genotyped for selected polymorphisms of the GGH (-354 G > T and 452 C > T), CCND1 (870 A > G) and TYMS (variable number of tandem repeats, VNTR, and G to C substitution of triple repeat, 3R allele) gene. Association studies have been performed between obtained genotypes and the efficacy and toxicity of MTX. According to the EULAR response criteria, 146 RA patients (79.3 %) were classified as responders (good/moderate response) and 38 (20.7 %) as non-responders (poor response). Higher frequency of the TYMS 3 G/3 G genotype has been found among non-responders as compared to individuals with remaining genotypes (p = 0.02). ADEs were recorded in 53 patients. Among those patients eight experienced bone marrow toxicity, all of them carried GGH -354GG genotype (p = 0.003). No other significant association were observed. The 3 G/3 G genotype of the TYMS gene may indicate predisposition of poor response to MTX and GG genotype of GGH -354 T > G polymorphism may have high predictive value for myelosuppression in RA patients.

An Investigation of the Influence of Initial Roughness on the Friction and Wear Behavior of Ground Surfaces

PubMed Central

Liang, Guoxing; Schmauder, Siegfried; Lyu, Ming; Schneider, Yanling; Zhang, Cheng; Han, Yang

2018-01-01

Friction and wear tests were performed on AISI 1045 steel specimens with different initial roughness parameters, machined by a creep-feed dry grinding process, to study the friction and wear behavior on a pin-on-disc tester in dry sliding conditions. Average surface roughness (Ra), root mean square (Rq), skewness (Rsk) and kurtosis (Rku) were involved in order to analyse the influence of the friction and wear behavior. The observations reveal that a surface with initial roughness parameters of higher Ra, Rq and Rku will lead to a longer initial-steady transition period in the sliding tests. The plastic deformation mainly concentrates in the depth of 20–50 μm under the worn surface and the critical plastic deformation is generated on the rough surface. For surfaces with large Ra, Rq, low Rsk and high Rku values, it is easy to lose the C element in, the reciprocating extrusion. PMID:29401703

High levels of the soluble form of CD30 molecule in rheumatoid arthritis (RA) are expression of CD30+ T cell involvement in the inflamed joints.

PubMed Central

Gerli, R; Muscat, C; Bistoni, O; Falini, B; Tomassini, C; Agea, E; Tognellini, R; Biagini, P; Bertotto, A

1995-01-01

The CD30 is a surface molecule expressed by Th2-type lymphokine-producing T cells upon activation. CD30-expressing activated T cells release a soluble form of the molecule, which can be detectable both in vitro and in vivo. In the present study, high levels of soluble CD30 were found in peripheral blood and synovial fluid from patients with RA. However, CD30+ CD3+ cells, either CD4+ or CD8+, were significantly present in synovial fluid, but not in peripheral blood, of RA patients. Serum values of soluble CD30 were higher in active than inactive RA patients and directly correlated with rheumatoid factor serum titres. These data strongly support an involvement of CD30+ T cells in the immune processes of rheumatoid synovitis, and may suggest a relationship between Th2-type cytokine-secreting T cells and the pathological response in RA. PMID:8536371

Measurement of Erythrocyte Methotrexate Polyglutamate Levels: Ready for Clinical Use in Rheumatoid Arthritis?

PubMed Central

Danila, Maria I.; Hughes, Laura B.; Brown, Elizabeth E.; Morgan, Sarah L.; Baggott, Joseph E.; Arnett, Donna K.; Bridges, S. Louis

2013-01-01

Methotrexate (MTX) is one of the most commonly prescribed and most effective drugs for the treatment of rheumatoid arthritis (RA). Given the partial response of many patients and the side effect profile of the drug, there is considerable interest in identification of biomarkers to guide MTX therapy in RA. Upon entering cells, MTX is polyglutamated. Measuring methotrexate polyglutamates (MTX PGs) levels in circulating red blood cells (RBC) has been proposed as an objective measure that can help to optimize MTX therapy in RA. There is conflicting data with regard to the clinical utility of measurement of MTX PGs measurements as a predictor of the efficacy or toxicity of low-dose MTX effects in RA. Should large, randomized clinical trials of this assay show consistent, reproducible, long-term correlations between MTX PG levels and efficacy and toxicity, this test could become a prominent tool for clinicians to optimize the use of MTX in RA. PMID:20665136

Identification of rheumatoid arthritis biomarkers based on single nucleotide polymorphisms and haplotype blocks: A systematic review and meta-analysis

PubMed Central

Saad, Mohamed N.; Mabrouk, Mai S.; Eldeib, Ayman M.; Shaker, Olfat G.

2015-01-01

Genetics of autoimmune diseases represent a growing domain with surpassing biomarker results with rapid progress. The exact cause of Rheumatoid Arthritis (RA) is unknown, but it is thought to have both a genetic and an environmental bases. Genetic biomarkers are capable of changing the supervision of RA by allowing not only the detection of susceptible individuals, but also early diagnosis, evaluation of disease severity, selection of therapy, and monitoring of response to therapy. This review is concerned with not only the genetic biomarkers of RA but also the methods of identifying them. Many of the identified genetic biomarkers of RA were identified in populations of European and Asian ancestries. The study of additional human populations may yield novel results. Most of the researchers in the field of identifying RA biomarkers use single nucleotide polymorphism (SNP) approaches to express the significance of their results. Although, haplotype block methods are expected to play a complementary role in the future of that field. PMID:26843965

Epstein-Barr virus in autoimmune diseases.

PubMed

Toussirot, Eric; Roudier, Jean

2008-10-01

Autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and primary Sjögren's syndrome (pSS) are complex disorders with a genetic background and the involvement of environmental factors, including viruses. The Epstein-Barr virus (EBV) is a plausible candidate for playing a role in the pathophysiology of these diseases. Both SLE and RA are characterized by high titers of anti-EBV antibodies and impaired T-cell responses to EBV antigens. Compared with normal subjects, elevated EBV load in peripheral blood has been observed in SLE and RA. EBV DNA or RNA has been evidenced in target organs of RA (synovium) or pSS (salivary glands). Finally, molecular mimicry has been demonstrated between EBV proteins and self antigens in these three conditions. In addition, SLE, RA, and pSS are associated with an increased risk of lymphoma with a potential role for EBV. The influence of new and emergent treatments of these autoimmune diseases (biological therapies) on EBV load and the course of latent EBV infection requires further studies.

The relationship between adult reactive and proactive aggression, hostile interpretation bias, and antisocial personality disorder.

PubMed

Lobbestael, Jill; Cima, Maaike; Arntz, Arnoud

2013-02-01

Reactive aggression (RA) refers to angry responses to provocation or frustration, while proactive aggression (PA) denotes nonemotional, instrumental, and unprovoked aggression. The current study examined personality-related and cognitive correlates of both aggressive types. Respectively, the predictive values of antisocial personality disorder (ASPD), and of hostile interpretation bias, which is the tendency to interpret ambiguous stimuli in a hostile manner, were studied. The sample consisted of n = 37 male adult patients with mixed diagnoses and n = 29 male nonpatients that responded to vignettes and pictures of ambiguous situations, using both open and closed answer formats. ASPD was assessed by means of the Structured Clinical Interview for DSM-IV Axis II disorders (SCID-II), and the Reactive Proactive Questionnaire (RPQ) measured RA and PA. Results showed that although both RA and PA types were predicted by ASPD traits, RA was additionally predicted by a hostile interpretation bias. These findings suggest that reducing hostile bias is a promising avenue for clinical treatment of ASPD-patients high in RA.

Human skin levels of retinoic acid and cytochrome P-450-derived 4-hydroxyretinoic acid after topical application of retinoic acid in vivo compared to concentrations required to stimulate retinoic acid receptor-mediated transcription in vitro.

PubMed Central

Duell, E A; Aström, A; Griffiths, C E; Chambon, P; Voorhees, J J

1992-01-01

Metabolism of retinoic acid to a less active metabolite, 4-hydroxyretinoic acid, occurs via cytochrome P-450 isozyme(s). Effect of a pharmacological dose of retinoic acid on the level of retinoic acid in skin and on cytochrome P-450 activity was investigated. A cream containing 0.1% retinoic acid or cream alone was applied topically to adult human skin for four days under occlusion. Treated areas were removed by a keratome and a microsomal fraction was isolated from each biopsy. In vitro incubation of 3H-retinoic acid with microsomes from in vivo retinoic acid treated sites resulted in a 4.5-fold increase (P = 0.0001, n = 13) in its transformation to 4-hydroxyretinoic acid in comparison to in vitro incubations with microsomes from in vivo cream alone treated sites. This cytochrome P-450 mediated activity was oxygen- and NADPH-dependent and was inhibited 68% by 5 microM ketoconazole (P = 0.0035, n = 8) and 51% by carbon monoxide (P = 0.02, n = 6). Cotransfection of individual retinoic acid receptors (RARs) or retinoid X receptor-alpha (RXR-alpha) and a chloramphenicol acetyl transferase (CAT) reporter plasmid containing a retinoic acid responsive element into CV-1 cells was used to determine the ED50 values for stimulation of CAT activity by retinoic acid and its metabolites. Levels of all trans and 13-cis RA in RA-treated tissues were greater than the ED50 values determined for all three RARs with these compounds. Furthermore, the level of all trans RA was greater than the ED50 for RXR-alpha whereas the 4-OH RA level was greater than the ED50 for RAR-beta and RAR-gamma but less than for RAR-alpha and RXR-alpha. These data suggest that there are sufficient amounts of retinoic acid in treated skin to activate gene transcription over both RARs and RXR-alpha. PMID:1328295

Feasibility Studies of Optical Processing of Image Bandwidth Compression Schemes.

DTIC Science & Technology

1983-05-15

R.N. STRICKIAND AFOSR-81-O170 R.A. SCHOWENGERDT S. PERFORMING ORGANIZATION NAME AND ADDRESS 10. PROGRAM ELEMENT, PROJECT. TASK Ur,;t. o4 o . AREA & WORK...is the intent of research sponsored under this Grant to direct investi- gation into the following issues: () formulation of alternative architechtural

CD45RA, a specific marker for leukaemia stem cell sub-populations in acute myeloid leukaemia.

PubMed

Kersten, Bas; Valkering, Matthijs; Wouters, Rolf; van Amerongen, Rosa; Hanekamp, Diana; Kwidama, Zinia; Valk, Peter; Ossenkoppele, Gert; Zeijlemaker, Wendelien; Kaspers, Gertjan; Cloos, Jacqueline; Schuurhuis, Gerrit J

2016-04-01

Chemotherapy resistant leukaemic stem cells (LSC) are thought to be responsible for relapses after therapy in acute myeloid leukaemia (AML). Flow cytometry can discriminate CD34(+) CD38(-) LSC and normal haematopoietic stem cells (HSC) by using aberrant expression of markers and scatter properties. However, not all LSC can be identified using currently available markers, so new markers are needed. CD45RA is expressed on leukaemic cells in the majority of AML patients. We investigated the potency of CD45RA to specifically identify LSC and HSC and improve LSC quantification. Compared to our best other markers (CLL-1, also termed CLEC12A, CD33 and CD123), CD45RA was the most reliable marker. Patients with high percentages (>90%) of CD45RA on CD34(+) CD38(-) LSC have 1·69-fold higher scatter values compared to HSC (P < 0·001), indicating a more mature CD34(+) CD38(-) phenotype. Patients with low (<10%) or intermediate (10-90%) CD45RA expression on LSC showed no significant differences to HSC (1·12- and 1·15-fold higher, P = 0·31 and P = 0·44, respectively). CD45RA-positive LSC tended to represent more favourable cytogenetic/molecular markers. In conclusion, CD45RA contributes to more accurate LSC detection and is recommended for inclusion in stem cell tracking panels. CD45RA may contribute to define new LSC-specific therapies and to monitor effects of anti-LSC treatment. © 2016 John Wiley & Sons Ltd.

Elevated Expression of Immunoreceptor Tyrosine-Based Inhibitory Motif (TIGIT) on T Lymphocytes is Correlated with Disease Activity in Rheumatoid Arthritis.

PubMed

Luo, Qing; Deng, Zhen; Xu, Chuxin; Zeng, Lulu; Ye, Jianqing; Li, Xue; Guo, Yang; Huang, Zikun; Li, Junming

2017-03-10

BACKGROUND It is well known that lymphocytes play an important role in rheumatoid arthritis (RA). T cell immunoreceptors with immunoglobulin (Ig) and immunoreceptor tyrosine-based inhibitory motif (TIGIT) have immunosuppressive co-stimulatory molecules that mediate inhibitory effects, but their roles in RA are poorly understood. MATERIAL AND METHODS Were recruited 76 patients with RA and 33 healthy controls (HC). Clinical manifestations, laboratory measurements, physical examination, and medical history of RA patients were recorded. The expression of TIGIT on CD3+ T lymphocytes, B lymphocytes, monocytes, neutrophils, CD3+CD4+ T lymphocytes, and CD3+CD8+ T lymphocytes was determined using flow cytometry. The expression of TIGIT on T lymphocytes in patients with RA was further analyzed to investigate its correlations with markers of autoimmune response, inflammation, and disease activity in RA. RESULTS Compared with HC, the expression levels of TIGIT on CD3+CD4+ T lymphocytes and CD3+CD8+ T lymphocytes were significantly increased in patients with RA (P < 0.01). The frequency of TIGIT-expressing CD3+CD4+ T lymphocytes was positively correlated with RF, increased ACPA, ESR, and CRP levels. The frequency of TIGIT-expressing CD3+CD8+ T lymphocytes was positively correlated with RF and ESR levels. Furthermore, the expression level of TIGIT on CD3+CD4+ T lymphocytes was positively correlated with the DAS28 score in RA. CONCLUSIONS The expression levels of TIGIT on T lymphocytes were elevated and correlated with disease activity in RA.

Segmented all-electron Gaussian basis sets of double and triple zeta qualities for Fr, Ra, and Ac

NASA Astrophysics Data System (ADS)

Campos, C. T.; de Oliveira, A. Z.; Ferreira, I. B.; Jorge, F. E.; Martins, L. S. C.

2017-05-01

Segmented all-electron basis sets of valence double and triple zeta qualities plus polarization functions for the elements Fr, Ra, and Ac are generated using non-relativistic and Douglas-Kroll-Hess (DKH) Hamiltonians. The sets are augmented with diffuse functions with the purpose to describe appropriately the electrons far from the nuclei. At the DKH-B3LYP level, first atomic ionization energies and bond lengths, dissociation energies, and polarizabilities of a sample of diatomics are calculated. Comparison with theoretical and experimental data available in the literature is carried out. It is verified that despite the small sizes of the basis sets, they are yet reliable.

Periodontitis in early and chronic rheumatoid arthritis: a prospective follow-up study in Finnish population

PubMed Central

Äyräväinen, Leena; Leirisalo-Repo, Marjatta; Kuuliala, Antti; Ahola, Kirsi; Koivuniemi, Riitta; Meurman, Jukka H; Heikkinen, Anna Maria

2017-01-01

Objectives To investigate the association between rheumatoid arthritis (RA) and periodontitis with special emphasis on the role of antirheumatic drugs in periodontal health. Design Prospective follow-up study. Patients with early untreated RA and chronic active RA were examined at baseline and 16 months later. Controls were examined once. Settings and participants The study was conducted in Finland from September 2005 to May 2014 at the Helsinki University Hospital. Overall, 124 participants were recruited for dental and medical examinations: 53 were patients with early disease-modifying antirheumatic drug (DMARD) naїve RA (ERA), 28 were patients with chronic RA (CRA) with insufficient response to conventional DMARDs. After baseline examination, patients with ERA started treatment with synthetic DMARDs and patients with CRA with biological DMARDs. Controls were 43 age-matched, gender-matched and community-matched participants. Outcome measures Degree of periodontitis (defined according to the Center for Disease Control and Prevention and the American Academy of Periodontology). Prevalence of periodontal bacteria (analysed from plaque samples), clinical rheumatological status by Disease Activity Score, 28-joint count (DAS28), function by Health Assessment Questionnaire (HAQ) and treatment response by European League Against Rheumatism (EULAR) criteria. Results Moderate periodontitis was present in 67.3% of patients with ERA, 64.3% of patients with CRA and 39.5% of control participants (p=0.001). Further, patients with RA had significantly more periodontal findings compared with controls, recorded with common periodontal indexes. In the re-examination, patients with RA still showed poor periodontal health in spite of treatment with DMARDs after baseline examination. The prevalence of Porphyromonas gingivalis was higher in patients with ERA with periodontal probing depth ≥4 mm compared with patients with CRA and controls. Antirheumatic medication did not seem to affect the results. Conclusions Moderate periodontitis was more frequent in patients with RA than in controls. Patients with ERA and CRA exhibited poorer periodontal health parameters when compared with controls. There was no association between antirheumatic treatment and periodontal parameters. PMID:28143836

Periodontitis in early and chronic rheumatoid arthritis: a prospective follow-up study in Finnish population.

PubMed

Äyräväinen, Leena; Leirisalo-Repo, Marjatta; Kuuliala, Antti; Ahola, Kirsi; Koivuniemi, Riitta; Meurman, Jukka H; Heikkinen, Anna Maria

2017-01-31

To investigate the association between rheumatoid arthritis (RA) and periodontitis with special emphasis on the role of antirheumatic drugs in periodontal health. Prospective follow-up study. Patients with early untreated RA and chronic active RA were examined at baseline and 16 months later. Controls were examined once. The study was conducted in Finland from September 2005 to May 2014 at the Helsinki University Hospital. Overall, 124 participants were recruited for dental and medical examinations: 53 were patients with early disease-modifying antirheumatic drug (DMARD) naїve RA (ERA), 28 were patients with chronic RA (CRA) with insufficient response to conventional DMARDs. After baseline examination, patients with ERA started treatment with synthetic DMARDs and patients with CRA with biological DMARDs. Controls were 43 age-matched, gender-matched and community-matched participants. Degree of periodontitis (defined according to the Center for Disease Control and Prevention and the American Academy of Periodontology). Prevalence of periodontal bacteria (analysed from plaque samples), clinical rheumatological status by Disease Activity Score, 28-joint count (DAS28), function by Health Assessment Questionnaire (HAQ) and treatment response by European League Against Rheumatism (EULAR) criteria. Moderate periodontitis was present in 67.3% of patients with ERA, 64.3% of patients with CRA and 39.5% of control participants (p=0.001). Further, patients with RA had significantly more periodontal findings compared with controls, recorded with common periodontal indexes. In the re-examination, patients with RA still showed poor periodontal health in spite of treatment with DMARDs after baseline examination. The prevalence of Porphyromonas gingivalis was higher in patients with ERA with periodontal probing depth ≥4 mm compared with patients with CRA and controls. Antirheumatic medication did not seem to affect the results. Moderate periodontitis was more frequent in patients with RA than in controls. Patients with ERA and CRA exhibited poorer periodontal health parameters when compared with controls. There was no association between antirheumatic treatment and periodontal parameters. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Pesticide Exposure and Risk of Rheumatoid Arthritis among Licensed Male Pesticide Applicators in the Agricultural Health Study

PubMed Central

Meyer, Armando; Sandler, Dale P.; Beane Freeman, Laura E.; Hofmann, Jonathan N.

2017-01-01

Background: The occupation of farming has been associated with rheumatoid arthritis (RA); pesticides may account for this association, but there are few studies. Objectives: We investigated associations between RA and use of pesticides in the Agricultural Health Study. Methods: The study sample was drawn from male pesticide applicators enrolled in 1993–1997 who provided questionnaire data at baseline and at least once during follow-up (over a median 18 y; interquartile range 16–19). Incident RA cases (n=220), confirmed by physicians or by self-reported use of disease-modifying antirheumatic drugs, were compared with noncases (n=26,134) who did not report RA. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression, adjusting for enrollment age, state, smoking pack-years, and education. We evaluated the association of RA with the use of 46 pesticides and across 4 levels (never use and tertiles) of lifetime days of use for 16 pesticides with OR≥1.2 for ever use. Results: Incident RA was associated with ever use of fonofos (OR = 1.70; 95% CI: 1.22, 2.37), carbaryl (OR = 1.51; 95% CI: 1.03, 2.23), and chlorimuron ethyl (OR = 1.45; 95% CI: 1.01, 2.07) compared with never use. Statistically significant exposure–response trends in association with RA were observed for lifetime days of use of atrazine [ORtertile3= 1.62 (95% CI: 1.09, 2.40); ptrend=0.01] and toxaphene [ORtertile3= 2.42 (95% CI: 1.03, 5.68); ptrend=0.02]. Exposure–response was nonlinear for fonofos [ORtertile1= 2.27 (95% CI: 1.44, 3.57); ORtertile2= 0.98 (95% CI: 0.54, 1.80); ORtertile3= 2.10 (95% CI: 1.32, 3.36); ptrend=0.005] and suggestive for carbaryl (ptrend=0.053). Conclusions: Our results provide novel evidence of associations between exposure to some pesticides and RA in male farmers. https://doi.org/10.1289/EHP1013 PMID:28718769

Impact of adalimumab on work participation in rheumatoid arthritis: comparison of an open-label extension study and a registry-based control group.

PubMed

Halpern, M T; Cifaldi, M A; Kvien, T K

2009-06-01

Rheumatoid arthritis (RA) causes considerable disability and often results in loss of work capacity and productivity. This study evaluated the impact of adalimumab, a tumour necrosis factor antagonist with demonstrated efficacy in RA, on long-term employment. Data from an open-label extension study (DE033) of 486 RA patients receiving adalimumab monotherapy who previously did not respond to at least one disease-modifying antirheumatic drug (DMARD) and had baseline work status information were compared with data from 747 RA patients receiving DMARD treatment in a Norway-based longitudinal registry. Primary outcomes included the time patients continued working at least part time and the likelihood of stopping work. Secondary outcomes included American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) responses and disease remission. Outcomes were compared 6, 12 and 24 months after enrolment. During a 24-month period, the 158 patients who received adalimumab and were working at baseline worked 7.32 months longer (95% CI 4.8 to 9.1) than did the 180 patients treated with DMARDs, controlling for differences in baseline characteristics. Regardless of baseline work status, patients receiving adalimumab worked 2.0 months longer (95% CI 1.3 to 2.6) and were significantly less likely to stop working than those receiving DMARDs (HR 0.36 (95% CI -0.30 to 0.42) for all patients and 0.36 (95% CI 0.15 to 0.85) for patients working at baseline, respectively). The patients who received adalimumab were also considerably more likely to achieve ACR responses and disease remission than DMARD-treated patients. Patients who achieved EULAR good response and remission were less likely to stop working, but this relationship was only seen in patients receiving DMARDs. Patients with RA who received adalimumab experienced considerably longer periods of work and continuous employment, and greater rates of clinical responses, than patients receiving DMARDs. The mechanism by which adalimumab decreases likelihood of stopping work seems to be different from that of DMARD treatment and independent of clinical responses.

Downregulation of cardiac guanosine 5'-triphosphate-binding proteins in right atrium and left ventricle in pacing-induced congestive heart failure.

PubMed Central

Roth, D A; Urasawa, K; Helmer, G A; Hammond, H K

1993-01-01

The extent to which congestive heart failure (CHF) is dependent upon increased levels of the cardiac inhibitory GTP-binding protein (Gi), and the impact of CHF on the cardiac stimulatory GTP-binding protein (Gs) and mechanisms by which Gs may change remain unexplored. We have addressed these unsettled issues using pacing-induced CHF in pigs to examine physiological, biochemical, and molecular features of the right atrium (RA) and left ventricle (LV). CHF was associated with an 85 +/- 20% decrease in LV segment shortening (P < 0.001) and a 3.5-fold increase (P = 0.006) in the ED50 for isoproterenol-stimulated heart rate responsiveness. Myocardial beta-adrenergic receptor number was decreased 54% in RA (P = 0.004) and 57% in LV (P < 0.001), and multiple measures of adenylyl cyclase activity were depressed 49 +/- 8% in RA (P < 0.005), and 44 +/- 9% in LV (P < 0.001). Quantitative immunoblotting established that Gi and Gs were decreased in RA (Gi: 59% reduction; P < 0.0001; Gs: 28% reduction; P < 0.007) and LV (Gi: 35% reduction; P < 0.008; Gs: 28% reduction; P < 0.01) after onset of CHF. Reduced levels of Gi and Gs were confirmed by ADP ribosylation studies, and diminished function of Gs was established in reconstitution studies. Steady state levels for Gs alpha mRNA were increased in RA and unchanged in LV, and significantly more GS alpha was found in the supernatant (presumably cytosolic) fraction in RA and LV membrane homogenates after CHF, suggesting that increased Gs degradation, rather than decreased Gs synthesis, is the mechanism by which Gs is downregulated. We conclude that cardiac Gi content poorly predicts adrenergic responsiveness or contractile function, that decreased Gs is caused by increased degradation rather than decreased synthesis, and that alterations in beta-adrenergic receptors, adenylyl cyclase, and GTP-binding proteins are uniform in RA and LV in this model of congestive heart failure. Images PMID:8383705

K-RAS GTPase- and B-RAF kinase-mediated T-cell tolerance defects in rheumatoid arthritis.

PubMed

Singh, Karnail; Deshpande, Pratima; Li, Guangjin; Yu, Mingcan; Pryshchep, Sergey; Cavanagh, Mary; Weyand, Cornelia M; Goronzy, Jörg J

2012-06-19

Autoantibodies to common autoantigens and neoantigens, such as IgG Fc and citrullinated peptides, are immunological hallmarks of rheumatoid arthritis (RA). We examined whether a failure in maintaining tolerance is mediated by defects in T-cell receptor activation threshold settings. RA T cells responded to stimulation with significantly higher ERK phosphorylation (P < 0.001). Gene expression arrays of ERK pathway members suggested a higher expression of KRAS and BRAF, which was confirmed by quantitative PCR (P = 0.003), Western blot, and flow cytometry (P < 0.01). Partial silencing of KRAS and BRAF lowered activation-induced phosphorylated ERK levels (P < 0.01). In individual cells, levels of these signaling molecules correlated with ERK phosphorylation, attesting that their concentrations are functionally important. In confocal studies, B-RAF/K-RAS clustering was increased in RA T cells 2 min after T-cell receptor stimulation (P < 0.001). Overexpression of B-RAF and K-RAS in normal CD4 T cells amplified polyclonal T-cell proliferation and facilitated responses to citrullinated peptides. We propose that increased expression of B-RAF and K-RAS lowers T-cell activation thresholds in RA T cells, enabling responses to autoantigens.

Responsibility attribution of HIV infection and coping among injection drug users in Malaysia.

PubMed

Chou, Chih-Chin; Chronister, Julie; Chou, Chih-Hung; Tan, Sooyin; Macewicz, Thomas

2013-01-01

This study explored responsibility attribution (RA) of HIV/AIDS infection (i.e., how an individual perceives the cause of their HIV/AIDS infection) and its relationship to coping styles among injection drug users (IDUs) with HIV/AIDS. In addition, this study investigated whether self-esteem, social support, and religiosity mediate the relationship between RA and coping styles of IDUs with HIV/AIDS. Participants were 201 adult IDUs with HIV/AIDS participating in the National Drug Rehabilitation Center in Malaysia. Five measures were used to assess the above constructs. Cluster analysis, analysis of variance, and mediation analyses were conducted. Results of this study indicated that IDUs with HIV/AIDS in Malaysia can be classified into four homogenous attribution groups: external, fatalistic, internal, and indeterminate. Mediator analyses revealed that combination of self-esteem, social support, and religiosity mediate the relationship between RA and coping behaviors. Clinicians working with IDUs with HIV/AIDS need to address the role of RA, self-esteem, religiosity, and social support as these psychosocial constructs are linked to coping with HIV/AIDS. Future researchers should investigate whether enhancing self-esteem, social support, and religiosity can promote active problem-solving coping and reduce the use of avoidance coping behaviors.

Bronchoconstriction triggered by breathing hot humid air in patients with asthma: role of cholinergic reflex.

PubMed

Hayes, Don; Collins, Paul B; Khosravi, Mehdi; Lin, Ruei-Lung; Lee, Lu-Yuan

2012-06-01

Hyperventilation of hot humid air induces transient bronchoconstriction in patients with asthma; the underlying mechanism is not known. Recent studies showed that an increase in temperature activates vagal bronchopulmonary C-fiber sensory nerves, which upon activation can elicit reflex bronchoconstriction. This study was designed to test the hypothesis that the bronchoconstriction induced by increasing airway temperature in patients with asthma is mediated through cholinergic reflex resulting from activation of these airway sensory nerves. Specific airway resistance (SR(aw)) and pulmonary function were measured to determine the airway responses to isocapnic hyperventilation of humidified air at hot (49°C; HA) and room temperature (20-22°C; RA) for 4 minutes in six patients with mild asthma and six healthy subjects. A double-blind design was used to compare the effects between pretreatments with ipratropium bromide and placebo aerosols on the airway responses to HA challenge in these patients. SR(aw) increased by 112% immediately after hyperventilation of HA and by only 38% after RA in patients with asthma. Breathing HA, but not RA, triggered coughs in these patients. In contrast, hyperventilation of HA did not cause cough and increased SR(aw) by only 22% in healthy subjects; there was no difference between their SR(aw) responses to HA and RA challenges. More importantly, pretreatment with ipratropium completely prevented the HA-induced bronchoconstriction in patients with asthma. Bronchoconstriction induced by increasing airway temperature in patients with asthma is mediated through the cholinergic reflex pathway. The concomitant increase in cough response further indicates an involvement of airway sensory nerves, presumably the thermosensitive C-fiber afferents.

Prediction of Methotrexate Clinical Response in Portuguese Rheumatoid Arthritis Patients: Implication of MTHFR rs1801133 and ATIC rs4673993 Polymorphisms

PubMed Central

Lima, Aurea; Monteiro, Joaquim; Bernardes, Miguel; Sousa, Hugo; Azevedo, Rita; Seabra, Vitor; Medeiros, Rui

2014-01-01

Objective. Methotrexate (MTX), the most used drug in rheumatoid arthritis (RA) treatment, showing variability in clinical response, is often associated with genetic polymorphisms. This study aimed to elucidate the role of methylenetetrahydrofolate reductase (MTHFR) C677T and aminoimidazole carboxamide adenosine ribonucleotide transformylase (ATIC) T675C polymorphisms and clinicopathological variables in clinical response to MTX in Portuguese RA patients. Methods. Study included 233 RA patients treated with MTX for at least six months. MTHFR C677T and ATIC T675C polymorphisms were genotyped and clinicopathological variables were collected. Statistical analyses were performed and binary logistic regression method adjusted to possible confounding variables. Results. Multivariate analyses demonstrated that MTHFR 677TT (OR = 4.63; P = 0.013) and ATIC 675T carriers (OR = 5.16; P = 0.013) were associated with over 4-fold increased risk for nonresponse. For clinicopathological variables, noncurrent smokers (OR = 7.98; P = 0.001), patients positive to anti-cyclic citrullinated peptide (OR = 3.53; P = 0.004) and antinuclear antibodies (OR = 2.28; P = 0.045), with higher health assessment questionnaire score (OR = 2.42; P = 0.007), and nonsteroidal anti-inflammatory drug users (OR = 2.77; P = 0.018) were also associated with nonresponse. Contrarily, subcutaneous administration route (OR = 0.11; P < 0.001) was associated with response. Conclusion. Our study suggests that MTHFR C677T and ATIC T675C genotyping combined with clinicopathological data may help to identify patients whom will not benefit from MTX treatment and, therefore, assist clinicians in personalizing RA treatment. PMID:24967362

Practices and opinions on nitrous oxide/oxygen sedation from dentists licensed to perform relative analgesia in Brazil

PubMed Central

2012-01-01

Background Relative analgesia (RA), defined as the use of inhalation sedation with nitrous oxide and oxygen, is one of the most common pharmacological behavior management techniques used to provide sedation and analgesia for dental patients. This study aimed to assess RA licensed Brazilian dentists’ practices and opinions about nitrous oxide/oxygen sedation in the dental setting. Methods A cross sectional national survey was conducted with 281 dentists who were certified to perform RA, using an electronically mailed self-administered questionnaire containing closed questions about their practices and opinions regarding RA. Practice and opinion were individually analyzed by descriptive statistics. Non-parametric tests assessed the relationships between RA practice and independent variables. To test the interplay between practices and opinions, a k-means clusters analysis was used to divide the group for statistical comparisons. Results The response rate was 45.2%. Women made up 64.6% of the respondents, the mean age was 39.1 years (SD = 9.8), and the mean time since graduation in dentistry was 16 years (SD = 9.7). Seventy-seven percent of respondents reported the use of RA in clinical practice, most of them ‘sometimes’ (53.5%), and focusing more on adult patients. Patients with certain physical or mental deficiencies were indications associated with RA practice. ‘Equipment acquisition’ (p < 0.001) and ‘living in Southeast and South regions’ (p < 0.02) were also associated with RA practice. The scores for dentists’ opinions ranged from 15 to 41 points (mean 29.2, SD = 5.6), based on nine items scored from 1 to 5. Two clusters representing more favorable (n = 65) and less favorable (n = 55) opinions were established. Dentists who were women (p = 0.04), practiced RA in dental settings (p < 0.01) or practiced it frequently (p < 0.001), had more favorable opinions about RA. Conclusion Most of the RA licensed Brazilian dentists interviewed currently use RA. Current practice of RA and frequency of use determined the degree of favorable opinion about this inhalation sedation among this group of respondents. PMID:22808942

Policy-into-practice for rheumatoid arthritis: randomized controlled trial and cohort study of e-learning targeting improved physiotherapy management.

PubMed

Fary, Robyn E; Slater, Helen; Chua, Jason; Ranelli, Sonia; Chan, Madelynn; Briggs, Andrew M

2015-07-01

To examine the effectiveness of a physiotherapy-specific, web-based e-learning platform, "RAP-el," in best-practice management of rheumatoid arthritis (RA) using a single-blind, randomized controlled trial (RCT) and prospective cohort study. Australian-registered physiotherapists were electronically randomized into intervention and control groups. The intervention group accessed RAP-eL over 4 weeks. Change in self-reported confidence in knowledge and skills was compared between groups at the end of the RCT using linear regression conditioned for baseline scores by a blinded assessor, using intent-to-treat analysis. Secondary outcomes included physiotherapists' satisfaction with RA management and responses to RA-relevant clinical statements and practice-relevant vignettes. Retention was evaluated in a cohort study 8 weeks after the RCT. Eighty physiotherapists were randomized into the intervention and 79 into the control groups. Fifty-six and 48, respectively, provided baseline data. Significant between-group differences were observed for change in confidence in knowledge (mean difference 8.51; 95% confidence interval [95% CI] 6.29, 10.73; effect size 1.62) and skills (mean difference 7.26; 95% CI 5.1, 9.4; effect size 1.54), with the intervention group performing better. Satisfaction in ability to manage RA, 4 of the 6 clinical statements, and responses to vignettes demonstrated significant improvement in the intervention group. Although 8-week scores showed declines in most outcomes, their clinical significance remains uncertain. RAP-eL can improve self-reported confidence, likely practice behaviors and satisfaction in physiotherapists' ability to manage people with RA, and improve their clinical knowledge in several areas of best-practice RA management in the short term. © 2015, American College of Rheumatology.

The selective estrogen receptor alpha agonist Org 37663 induces estrogenic effects but lacks antirheumatic activity: a phase IIa trial investigating efficacy and safety of Org 37663 in postmenopausal female rheumatoid arthritis patients receiving stable background methotrexate or sulfasalazine.

PubMed

van Vollenhoven, Ronald F; Houbiers, Jos G A; Buttgereit, Frank; In 't Hout, Joanna; Boers, Maarten; Leij, Susanne; Kvien, Tore K; Dijkmans, Ben A C; Szczepański, Leszek; Szombati, Istvan; Sierakowski, Stanislaw; Miltenburg, André M M

2010-02-01

Multiple lines of evidence suggest that sex hormones may play a role in the pathogenesis or clinical expression of rheumatoid arthritis (RA). Studies on the effects of exogenous estrogens in RA patients have yielded contradictory results. We undertook this study to determine the effects of the selective estrogen receptor alpha (ERalpha) agonist Org 37663 in patients with RA, in terms of both its estrogenic effects and its ability to ameliorate disease activity. A 10-week, multicenter, randomized, double-blind, placebo-controlled, parallel group, dose-finding, proof-of-concept trial was initiated to obtain data on the efficacy and safety of Org 37663 in postmenopausal female patients with RA who were receiving background treatment with either methotrexate or sulfasalazine. Patients were randomized to receive placebo or Org 37663 at doses of 4 mg/day, 15 mg/day, or 50 mg/week. The primary efficacy variable was the Disease Activity Score in 28 joints (DAS28). Org 37663 induced a clear biologic, estrogenic response in several organ systems, including a dose-related increase in levels of sex hormone binding globulin. However, the DAS28 decreased similarly for all treatment groups including placebo, indicating lack of clinical efficacy of Org 37663 in this trial. The observed lack of clinical benefit in RA patients treated with an ERalpha agonist, in association with a clear biologic response to the study drug, provides evidence that a biologically relevant ERalpha-mediated estrogenic effect is not associated with a clinically relevant effect on RA symptoms and signs.

A study on single lane-change manoeuvres for determining rearward amplification of multi-trailer articulated heavy vehicles with active trailer steering systems

NASA Astrophysics Data System (ADS)

Wang, Qiushi; He, Yuping

2016-01-01

The Society of Automotive Engineers issued a test procedure, SAE-J2179, to determine the rearward amplification (RA) of multi-trailer articulated heavy vehicles (MTAHVs). Built upon the procedure, the International Organization for Standardization released the test manoeuvres, ISO-14791, for evaluating directional performance of MTAHVs. For the RA measures, ISO-14791 recommends two single lane-change manoeuvres: (1) an open-loop procedure with a single sine-wave steering input; and (2) a closed-loop manoeuvre with a single sine-wave lateral acceleration input. For an articulated vehicle with active trailer steering (ATS), the RA measure in lateral acceleration under the open-loop manoeuvre was not in good agreement with that under the closed-loop manoeuvre. This observation motivates the research on the applicability of the two manoeuvres for the RA measures of MTAHVs with ATS. It is reported that transient response under the open-loop manoeuvre often leads to asymmetric curve of tractor lateral acceleration [Winkler CB, Fancher PS, Bareket Z, Bogard S, Johnson G, Karamihas S, Mink C. Heavy vehicle size and weight - test procedures for minimum safety performance standards. Final technical report, NHTSA, US DOT, contract DTNH22-87-D-17174, University of Michigan Transportation Research Institute, Report No. UMTRI-92-13; 1992]. To explore the effect of the transient response, a multiple cycle sine-wave steering input (MCSSI) manoeuvre is proposed. Simulation demonstrates that the steady-state RA measures of an MTAHV with and without ATS under the MCSSI manoeuvre are in excellent agreement with those under the closed-loop manoeuvre. It is indicated that between the two manoeuvres by ISO-14791, the closed-loop manoeuvre is more applicable for determining the RA measures of MTAHVs with ATS.

The response of various muscle types to a restriction -re-alimentation feeding strategy in growing pigs.

PubMed

Lebret, B; Heyer, A; Gondret, F; Louveau, I

2007-07-01

Muscle lipid concentration is known to influence pork eating quality. This study aimed at evaluating the effect of a restriction-re-alimentation feeding strategy on intramuscular fat deposition in pigs. A total of 70 Duroc × (Large White × Landrace) pigs (castrated males and females) were used. Ten pigs were first slaughtered at 30 kg live weight (LW) to determine initial body and muscle composition. From 30 to 80 kg LW (growing period), pigs were either fed ad libitum (AL) or restricted to 70% of the ad libitum intake of AL pigs (RA). From 80 to 110 kg LW (finishing period), both AL and RA pigs were fed ad libitum. In each group, pigs were slaughtered at 80 kg (n = 10) and at 110 kg (n = 20) LW. During the growing period, the growth rate of RA pigs was reduced by 30% (P < 0.001) compared with AL pigs. During the finishing period, RA pigs had a 7% (P = 0.09) higher growth rate than AL pigs due to compensatory feed intake (+14%). Plasma insulin-like growth factor-1 concentration was lower in RA pigs at 80 kg LW, but markedly increased after re-alimentation up to the level observed in AL pigs (P < 0.001). At 80 kg, the leaner carcasses of RA pigs resulted from a more pronounced reduction in fat than in lean tissue deposition rates. Re-alimentation of RA pigs increased fat tissue deposition (+160% for females, P < 0.01) but not lean deposition in the carcass, leading to limited differences in carcass composition between RA and AL pigs at 110 kg LW. Regarding tissue deposition rates, the response to feeding strategy differs between muscles. In the m. biceps femoris (BF), restriction affected lipid (-50%, P < 0.001) and protein (-25%, P < 0.001) deposition, whereas re-alimentation increased lipid (+62%, P < 0.05) but not protein deposition rates. At market weight, the extent of the difference in BF lipid concentration between RA and AL pigs was strongly reduced, but still significant. By contrast, in the m. longissimus, restriction decreased protein but not lipid deposition, whereas neither of them was modified during re-alimentation. Therefore, an increased muscle lipid concentration at 110 kg LW could not be reached in RA pigs. Modifications of onset and/or duration of restriction and re-alimentation periods should be tested to optimise effects on muscle lipid deposition and thereby achieve improved pork quality.

Surface disposal of produced waters in western and southwestern Pennsylvania: potential for accumulation of alkali-earth elements in sediments

USGS Publications Warehouse

Skalak, Katherine J.; Engle, Mark A.; Rowan, Elisabeth L.; Jolly, Glenn D.; Conko, Kathryn M.; Benthem, Adam J.; Kraemer, Thomas F.

2014-01-01

Waters co-produced with hydrocarbons in the Appalachian Basin are of notably poor quality (concentrations of total dissolved solids (TDS) and total radium up to and exceeding 300,000 mg/L and 10,000 pCi/L, respectively). Since 2008, a rapid increase in Marcellus Shale gas production has led to a commensurate rise in associated wastewater while generation of produced water from conventional oil and gas activities has continued. In this study, we assess whether disposal practices from treatment of produced waters from both shale gas and conventional operations in Pennsylvania could result in the accumulation of associated alkali earth elements. The results from our 5 study sites indicate that there was no increase in concentrations of total Ra (Ra-226) and extractable Ba, Ca, Na, or Sr in fluvial sediments downstream of the discharge outfalls (p > 0.05) of publicly owned treatment works (POTWs) and centralized waste treatment facilities (CWTs). However, the use of road spreading of brines from conventional oil and gas wells for deicing resulted in accumulation of Ra-226 (1.2 ×), and extractable Sr (3.0 ×), Ca (5.3 ×), and Na (6.2 ×) in soil and sediment proximal to roads (p < 0.05). Although this study is an important initial assessment of the impacts of these disposal practices, more work is needed to consider the environmental consequences of produced waters management.

Characterization of Rheumatoid Arthritis Subtypes Using Symptom Profiles, Clinical Chemistry and Metabolomics Measurements

PubMed Central

van der Kooij, Anita J.; Reijmers, Theo H.; Schroën, Yan; Wang, Mei; Xu, Zhiliang; Wang, Xinchang; Kong, Hongwei; Xu, Guowang; Hankemeier, Thomas; Meulman, Jacqueline J.; van der Greef, Jan

2012-01-01

Objective The aim is to characterize subgroups or phenotypes of rheumatoid arthritis (RA) patients using a systems biology approach. The discovery of subtypes of rheumatoid arthritis patients is an essential research area for the improvement of response to therapy and the development of personalized medicine strategies. Methods In this study, 39 RA patients are phenotyped using clinical chemistry measurements, urine and plasma metabolomics analysis and symptom profiles. In addition, a Chinese medicine expert classified each RA patient as a Cold or Heat type according to Chinese medicine theory. Multivariate data analysis techniques are employed to detect and validate biochemical and symptom relationships with the classification. Results The questionnaire items ‘Red joints’, ‘Swollen joints’, ‘Warm joints’ suggest differences in the level of inflammation between the groups although c-reactive protein (CRP) and rheumatoid factor (RHF) levels were equal. Multivariate analysis of the urine metabolomics data revealed that the levels of 11 acylcarnitines were lower in the Cold RA than in the Heat RA patients, suggesting differences in muscle breakdown. Additionally, higher dehydroepiandrosterone sulfate (DHEAS) levels in Heat patients compared to Cold patients were found suggesting that the Cold RA group has a more suppressed hypothalamic-pituitary-adrenal (HPA) axis function. Conclusion Significant and relevant biochemical differences are found between Cold and Heat RA patients. Differences in immune function, HPA axis involvement and muscle breakdown point towards opportunities to tailor disease management strategies to each of the subgroups RA patient. PMID:22984493

PER2 is downregulated by the LPS-induced inflammatory response in synoviocytes in rheumatoid arthritis and is implicated in disease susceptibility.

PubMed

Lee, Hwayoung; Nah, Seong-Su; Chang, Sung-Hae; Kim, Hyung-Ki; Kwon, Jun-Tack; Lee, Sanghyun; Cho, Ik-Hyun; Lee, Sang Won; Kim, Young Ock; Hong, Seung-Jae; Kim, Hak-Jae

2017-07-01

The clinical symptoms of rheumatoid arthritis (RA) present with circadian variation, with joint stiffness and pain more prominent in the early morning. The mammalian clock genes, which include circadian locomotor output cycles kaput, brain and muscle Arnt-like protein 1, period and cryptochrome, regulate circadian rhythms. In order to identify the association between genetic polymorphisms in the circadian clock gene period 2 (PER2) and RA, the present study genotyped three PER2 single nucleotide polymorphisms (SNPs), rs934945, rs6754875, and rs2304674, using genetic information from 256 RA patients and 499 control subjects. Primary cultured rheumatoid synovial cells were stimulated with 10 µM lipopolysaccharide (LPS). Total protein was then extracted from the synovial cells following 12 and 24 h, and PER2 protein expression was assayed by immunoblotting. The rs2304674 SNP demonstrated a significant association with susceptibility to RA following Bonferroni correction. However, statistical analysis indicated that the SNPs were not associated with any clinical features of patients with RA. Immunoblotting analysis demonstrated that PER2 protein expression was decreased by LPS‑induced inflammation in RA synovial cells; however, this was not observed in normal synovial cells. The results suggest that the PER2 gene may be a risk factor for RA, and expression of the PER2 protein may be affected by inflammation. Therefore, PER2 may contribute to the pathogenesis of RA.

Response of soil microorganisms to radioactive oil waste: results from a leaching experiment

NASA Astrophysics Data System (ADS)

Galitskaya, P.; Biktasheva, L.; Saveliev, A.; Ratering, S.; Schnell, S.; Selivanovskaya, S.

2015-01-01

Oil wastes produced in large amounts in the processes of oil extraction, refining, and transportation are of great environmental concern because of their mutagenicity, toxicity, high fire hazardousness, and other properties. About 40% of these wastes contain radionuclides; however, the effects of oil products and radionuclides on soil microorganisms are frequently studied separately. The toxicity and effects on various microbial parameters of raw waste (H) containing 575 g of total petroleum hydrocarbons (TPH) kg-1 waste, 4.4 kBq kg-1 of 226Ra, 2.8 kBq kg-1 of 232Th, and 1.3 kBq kg-1 of 40K and its treated variant (R) (1.6 g kg-1 of TPH, 7.9 kBq kg-1 of 226Ra, 3.9 kBq kg-1 of 232Th, and 183 kBq kg-1 of 40K) were estimated in a leaching column experiment to separate the effects of hydrocarbons from those of radioactive elements. The disposal of H waste samples on the soil surface led to an increase of the TPH content in soil: it became 3.5, 2.8, and 2.2 times higher in the upper (0-20 cm), middle (20-40 cm), and lower (40-60 cm) layers respectively. Activity concentrations of 226Ra and 232Th increased in soil sampled from both H- and R-columns in comparison to their concentrations in control soil. The activity concentrations of these two elements in samples taken from the upper and middle layers were much higher for the R-column compared to the H-column, despite the fact that the amount of waste added to the columns was equalized with respect to the activity concentrations of radionuclides. The H waste containing both TPH and radionuclides affected the functioning of the soil microbial community, and the effect was more pronounced in the upper layer of the column. Metabolic quotient and cellulase activity were the most sensitive microbial parameters as their levels were changed 5-1.4 times in comparison to control ones. Changes of soil functional characteristics caused by the treated waste containing mainly radionuclides were not observed. PCR-SSCP (polymerase chain reaction - single strand conformation polymorphism) analysis followed by MDS (metric multidimensional scaling) and clustering analysis revealed that the shifts in microbial community structure were affected by both hydrocarbons and radioactivity.

“RaMassays”: Synergistic Enhancement of Plasmon-Free Raman Scattering and Mass Spectrometry for Multimodal Analysis of Small Molecules

NASA Astrophysics Data System (ADS)

Alessandri, Ivano; Vassalini, Irene; Bertuzzi, Michela; Bontempi, Nicolò; Memo, Maurizio; Gianoncelli, Alessandra

2016-10-01

SiO2/TiO2 core/shell (T-rex) beads were exploited as “all-in-one” building-block materials to create analytical assays that combine plasmon-free surface enhanced Raman scattering (SERS) and surface assisted laser desorption/ionization (SALDI) mass spectrometry (RaMassays). Such a multi-modal approach relies on the unique optical properties of T-rex beads, which are able to harvest and manage light in both UV and Vis range, making ionization and Raman scattering more efficient. RaMassays were successfully applied to the detection of small (molecular weight, M.W. <400 Da) molecules with a key relevance in biochemistry and pharmaceutical analysis. Caffeine and cocaine were utilized as molecular probes to test the combined SERS/SALDI response of RaMassays, showing excellent sensitivity and reproducibility. The differentiation between amphetamine/ephedrine and theophylline/theobromine couples demonstrated the synergistic reciprocal reinforcement of SERS and SALDI. Finally, the conversion of L-tyrosine in L-DOPA was utilized to probe RaMassays as analytical tools for characterizing reaction intermediates without introducing any spurious effects. RaMassays exhibit important advantages over plasmonic nanoparticles in terms of reproducibility, absence of interference and potential integration in multiplexed devices.

Breathing hot humid air induces airway irritation and cough in patients with allergic rhinitis.

PubMed

Khosravi, Mehdi; Collins, Paul B; Lin, Ruei-Lung; Hayes, Don; Smith, Jaclyn A; Lee, Lu-Yuan

2014-07-01

We studied the respiratory responses to an increase in airway temperature in patients with allergic rhinitis (AR). Responses to isocapnic hyperventilation (40% of maximal voluntary ventilation) for 4min of humidified hot air (HA; 49°C) and room air (RA; 21°C) were compared between AR patients (n=7) and healthy subjects (n=6). In AR patients, cough frequency increased pronouncedly from 0.10±0.07 before to 2.37±0.73 during, and 1.80±0.79coughs/min for the first 8min after the HA challenge, but not during the RA challenge. In contrast, neither HA nor RA had any significant tussive effect in healthy subjects. The HA challenge also caused respiratory discomfort (mainly throat irritation) measured by the handgrip dynamometry in AR patients, but not in healthy subjects. Bronchoconstriction was not detected after the HA challenge in either group of subjects. In conclusion, hyperventilation of HA triggered vigorous cough response and throat irritation in AR patients, indicating the involvement of sensory nerves innervating upper airways. Copyright © 2014 Elsevier B.V. All rights reserved.

An Overview of Quantitative Risk Assessment of Space Shuttle Propulsion Elements

NASA Technical Reports Server (NTRS)

Safie, Fayssal M.

1998-01-01

Since the Space Shuttle Challenger accident in 1986, NASA has been working to incorporate quantitative risk assessment (QRA) in decisions concerning the Space Shuttle and other NASA projects. One current major NASA QRA study is the creation of a risk model for the overall Space Shuttle system. The model is intended to provide a tool to estimate Space Shuttle risk and to perform sensitivity analyses/trade studies, including the evaluation of upgrades. Marshall Space Flight Center (MSFC) is a part of the NASA team conducting the QRA study; MSFC responsibility involves modeling the propulsion elements of the Space Shuttle, namely: the External Tank (ET), the Solid Rocket Booster (SRB), the Reusable Solid Rocket Motor (RSRM), and the Space Shuttle Main Engine (SSME). This paper discusses the approach that MSFC has used to model its Space Shuttle elements, including insights obtained from this experience in modeling large scale, highly complex systems with a varying availability of success/failure data. Insights, which are applicable to any QRA study, pertain to organizing the modeling effort, obtaining customer buy-in, preparing documentation, and using varied modeling methods and data sources. Also provided is an overall evaluation of the study results, including the strengths and the limitations of the MSFC QRA approach and of qRA technology in general.

Cyr61 induces IL-6 production by fibroblast-like synoviocytes promoting Th17 differentiation in rheumatoid arthritis.

PubMed

Lin, Jinpiao; Zhou, Zhou; Huo, Rongfen; Xiao, Lianbo; Ouyang, Guilin; Wang, Li; Sun, Yue; Shen, Baihua; Li, Dangsheng; Li, Ningli

2012-06-01

Cysteine-rich protein 61 (Cyr61)/CCN1 is a product of an immediate early gene and functions in mediating cell adhesion and inducing cell migration. We previously showed that increased production of Cyr61 by fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA) promotes FLS proliferation and participates in RA pathogenesis with the IL-17-dependent pathway. However, whether Cyr61 in turn regulates Th17 cell differentiation and further enhances inflammation of RA remained unknown. In the current study, we explored the potential role of Cyr61 as a proinflammatory factor in RA pathogenesis. We found that Cyr61 treatment dramatically induced IL-6 production in FLS isolated from RA patients. Moreover, IL-6 production was attenuated by Cyr61 knockdown in FLS. Mechanistically, we showed that Cyr61 activated IL-6 production via the αvβ5/Akt/NF-κB signaling pathway. Further, using a coculture system consisting of purified CD4(+) T cells and RA FLS, we found that RA FLS stimulated Th17 differentiation, and the pro-Th17 differentiation effect of RA FLS can be attenuated or stimulated by Cyr61 RNA interference or addition of exogenous Cyr61, respectively. Finally, using the collagen-induced arthritis animal model, we showed that treatment with the anti-Cyr61 mAb led to reduction of IL-6 levels, decrease of Th17 response, and attenuation of inflammation and disease progression in vivo. Taken together, our results reveal a novel role of Cyr61 in promoting Th17 development in RA via upregulation of IL-6 production by FLS, thus adding a new layer into the functional interplay between FLS and Th17 in RA pathogenesis. Our study also suggests that targeting of Cyr61 may represent a novel strategy in RA treatment.

Protease-degradable PEG-maleimide coating with on-demand release of IL-1Ra to improve tissue response to neural electrodes

PubMed Central

Gutowski, Stacie M.; Shoemaker, James T.; Templeman, Kellie L.; Wei, Yang; Latour, Robert A.; Bellamkonda, Ravi V.; LaPlaca, Michelle C.; García, Andrés J.

2015-01-01

Neural electrodes are an important part of brain-machine interface devices that can restore functionality to patients with sensory and movement disorders. Chronically implanted neural electrodes induce an unfavorable tissue response which includes inflammation, scar formation, and neuronal cell death, eventually causing loss of electrode function. We developed a poly(ethylene glycol) hydrogel coating for neural electrodes with non-fouling characteristics, incorporated an anti-inflammatory agent, and engineered a stimulus-responsive degradable portion for on-demand release of the anti-inflammatory agent in response to inflammatory stimuli. This coating reduces in vitro glial cell adhesion, cell spreading, and cytokine release compared to uncoated controls. We also analyzed the in vivo tissue response using immunohistochemistry and microarray qRT-PCR. Although no differences were observed among coated and uncoated electrodes for inflammatory cell markers, lower IgG penetration into the tissue around PEG+IL-1Ra coated electrodes indicates an improvement in blood-brain barrier integrity. Gene expression analysis showed higher expression of IL-6 and MMP-2 around PEG+IL-1Ra samples, as well as an increase in CNTF expression, an important marker for neuronal survival. Importantly, increased neuronal survival around coated electrodes compared to uncoated controls was observed. Collectively, these results indicate promising findings for an engineered coating to increase neuronal survival and improve tissue response around implanted neural electrodes. PMID:25617126

Two main and a new type rare earth elements in Mg alloys: A review

NASA Astrophysics Data System (ADS)

Kong, Linghang

2017-09-01

Magnesium (Mg) alloys stand for the lightest structure engineering materials. Moreover, the strengthening of Mg alloys in ductility, toughness and corrosion predominates their wide applications. With adding rare earth elements in Mg, the mechanical properties will be improved remarkably, especially their plasticity and strength. A brief overview of the addition of rare earth elements for Mg alloys is shown. The basic mechanisms of strengthening Mg alloys with rare earth elements are reviewed, including the solid solution strengthening, grain refinement and long period stacking ordered (LPSO) phase. Furthermore, the available rare earth elements are summarized by type, chemical or physical effects and other unique properties. Finally, some challenge problems that the research is facing and future expectations of ra-re-earth Mg alloys are stated and discussed.

Combining airborne thermal infrared images, radium isotopes and radon to study Submarine Groundwater Discharge along the French Mediterranean coastline (Côte Bleue)}

NASA Astrophysics Data System (ADS)

Bejannin, Simon; Tamborski, Joseph; Souhaut, Marc; Radakovitch, Olivier; Claude, Christelle; Stieglitz, Thomas; Crispi, Olivier; Pujo-Pay, Mireille; Conan, Pascal; Caparros, Jocelyne; Heimburger, Lars-Eric; Petrova, Macha; Le Roy, Emilie; Lacan, François; van Beek, Pieter

2017-04-01

Submarine Groundwater Discharge (SGD) is now recognized as an important vector for many chemical elements that may impact the quality of the coastal environment and marine ecosystems. Although these fluxes have been investigated in many places of the world, few studies have been conducted along the French Mediterranean coastline. In this study, we report airborne thermal infrared (TIR) images that allowed us to locate several freshwater inputs along the "Côte Bleue" located west of the city of Marseille. We used salinity, radon and radium isotopes to confirm that the TIR signal could be related to SGD. Radon was analyzed in situ along the coastline on board a rubber boat. The four radium isotopes (223Ra, 224Ra, 226Ra, 228Ra) were analyzed in samples collected in the coastal waters characterized by a strong TIR signal, as well as along transects conducted on board RV Antedon II between the coast and offshore (between 200 m and 8 km). We also analyzed nutrient (nitrates, phosphates and silicates) and mercury concentrations in the water samples. Radium isotopes were thus used to quantify SGD fluxes and to determine the fluxes of nutrients and mercury associated with SGD along this coastline.

RARα-PLZF overcomes PLZF-mediated repression of CRABPI, contributing to retinoid resistance in t(11;17) acute promyelocytic leukemia

PubMed Central

Guidez, Fabien; Parks, Sarah; Wong, Henna; Jovanovic, Jelena V.; Mays, Ashley; Gilkes, Amanda F.; Mills, Kenneth I.; Guillemin, Marie-Claude; Hobbs, Robin M.; Pandolfi, Pier Paolo; de Thé, Hugues; Solomon, Ellen; Grimwade, David

2007-01-01

Leukemia-associated chimeric oncoproteins often act as transcriptional repressors, targeting promoters of master genes involved in hematopoiesis. We show that CRABPI (encoding cellular retinoic acid binding protein I) is a target of PLZF, which is fused to RARα by the t(11;17)(q23;q21) translocation associated with retinoic acid (RA)-resistant acute promyelocytic leukemia (APL). PLZF represses the CRABPI locus through propagation of chromatin condensation from a remote intronic binding element culminating in silencing of the promoter. Although the canonical, PLZF-RARα oncoprotein has no impact on PLZF-mediated repression, the reciprocal translocation product RARα-PLZF binds to this remote binding site, recruiting p300, inducing promoter hypomethylation and CRABPI gene up-regulation. In line with these observations, RA-resistant murine PLZF/RARα+RARα/PLZF APL blasts express much higher levels of CRABPI than standard RA-sensitive PML/RARα APL. RARα-PLZF confers RA resistance to a retinoid-sensitive acute myeloid leukemia (AML) cell line in a CRABPI-dependent fashion. This study supports an active role for PLZF and RARα-PLZF in leukemogenesis, identifies up-regulation of CRABPI as a mechanism contributing to retinoid resistance, and reveals the ability of the reciprocal fusion gene products to mediate distinct epigenetic effects contributing to the leukemic phenotype. PMID:18000064

Aging of the Immune System. Mechanisms and Therapeutic Targets.

PubMed

Weyand, Cornelia M; Goronzy, Jörg J

2016-12-01

Beginning with the sixth decade of life, the human immune system undergoes dramatic aging-related changes, which continuously progress to a state of immunosenescence. The aging immune system loses the ability to protect against infections and cancer and fails to support appropriate wound healing. Vaccine responses are typically impaired in older individuals. Conversely, inflammatory responses mediated by the innate immune system gain in intensity and duration, rendering older individuals susceptible to tissue-damaging immunity and inflammatory disease. Immune system aging functions as an accelerator for other age-related pathologies. It occurs prematurely in some clinical conditions, most prominently in patients with the autoimmune syndrome rheumatoid arthritis (RA); and such patients serve as an informative model system to study molecular mechanisms of immune aging. T cells from patients with RA are prone to differentiate into proinflammatory effector cells, sustaining chronic-persistent inflammatory lesions in the joints and many other organ systems. RA T cells have several hallmarks of cellular aging; most importantly, they accumulate damaged DNA. Because of deficiency of the DNA repair kinase ataxia telangiectasia mutated, RA T cells carry a higher burden of DNA double-strand breaks, triggering cell-indigenous stress signals that shift the cell's survival potential and differentiation pattern. Immune aging in RA T cells is also associated with metabolic reprogramming; specifically, with reduced glycolytic flux and diminished ATP production. Chronic energy stress affects the longevity and the functional differentiation of older T cells. Altered metabolic patterns provide opportunities to therapeutically target the immune aging process through metabolic interference.

Development of Fractal Dimension and Characteristic Roughness Models for Turned Surface of Carbon Steels

NASA Astrophysics Data System (ADS)

Zuo, Xue; Zhu, Hua; Zhou, Yuankai; Ding, Cong; Sun, Guodong

2016-08-01

Relationships between material hardness, turning parameters (spindle speed and feed rate) and surface parameters (surface roughness Ra, fractal dimension D and characteristic roughness τ∗) are studied and modeled using response surface methodology (RSM). The experiments are carried out on a CNC lathe for six carbon steel material AISI 1010, AISI 1020, AISI 1030, AISI 1045, AISI 1050 and AISI 1060. The profile of turned surface and the surface roughness value are measured by a JB-5C profilometer. Based on the profile data, D and τ∗ are computed through the root-mean-square method. The analysis of variance (ANOVA) reveals that spindle speed is the most significant factors affecting Ra, while material hardness is the most dominant parameter affecting τ∗. Material hardness and spindle speed have the same influence on D. Feed rate has less effect on three surface parameters than spindle speed and material hardness. The second-order models of RSM are established for estimating Ra, D and τ∗. The validity of the developed models is approximately 80%. The response surfaces show that a surface with small Ra and large D and τ∗ can be obtained by selecting a high speed and a large hardness material. According to the established models, Ra, D and τ∗ of six carbon steels surfaces can be predicted under cutting conditions studied in this paper. The results have an instructive meaning to estimate the surface quality before turning.

Niclosamide as an adjuvant to etanercept in treatment patients with active rheumatoid arthritis: an 8-week randomized controlled pilot study.

PubMed

Al-Gareeb, Ali Ismail A; Gorial, Faiq Isho; Mahmood, Ahmed S

2018-06-07

This study designed to identify the therapeutic efficacy of niclosamide (NCL) in Iraqi patients suffering from active rheumatoid arthritis (RA) who were using etanercept (ETN) for more than 3 months and still had high or moderate active RA. One hundred ten patients suffering from active rheumatoid arthritis (RA) who were using etanercept (ETN) for more than 3 months and still had high or moderate active RA were allocated randomly into two equal groups: one of them treated with 1000 mg/day NCL and the other treated with 1000 mg/day lactose in capsule dosage form. The study duration was 8 weeks. Clinical efficacy of the NCL was measured depending on scoring of the 28-joint Disease Activity Score (DAS28), simple disease activity index (SDAI), clinical disease activity index (CDAI), and Health Assessment Questionnaire Disability Index (HAQ-DI) at the baseline and at the end of the 8-week treatment period. Moreover, blood sample were taken from the patients at baseline and at after 8 weeks of treatment for measurement of the erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), interleukin 1β (IL-1 β), interleukin-6, tumor necrosis factor (TNF-α), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin. At the end of the clinical study, patients had good response to NCL when added to the ETN with a high significant improvement in the SJC, TJC, DAS-28, CDAI, SDAI, and HAQ-DI compared to patients who were received placebo drug. In addition to that, 33% of patients achieved an ACR 20% response (ACR20) on NCL and ETN. Of these, 4% achieved ACR50 and another 4% achieved ACR70 response. While those group treated by placebo + ETN, 5% achieved ACR20 response and no one reached to ACR50 or ACR70 response. Twenty-seven percent of RA patients who have taken the NCL achieved moderate EULAR score while only 17% from the group that taken placebo with ETN achieved moderate response. On the other hand, no significant reduction was found in CRP, ESR, TNF-α, and IL-6, while IL-1 β reduced significantly after treatment with NCL. Treatment with NCL also exerts a significant lowering in the serum level of the E-selectin, ICAM1, and VCAM1 when compared to their value in baseline level. In RA disease, the use of NCL as adjuvant with ETN has resulted in a marked reduction in clinical assessment scoring indices and significantly decreased the E-selectin, ICAM-1, and VCAM-1 with marked improvement in the quality of life of patients.

Response of soil microorganisms to radioactive oil waste: results from a leaching experiment

NASA Astrophysics Data System (ADS)

Galitskaya, P.; Biktasheva, L.; Saveliev, A.; Ratering, S.; Schnell, S.; Selivanovskaya, S.

2015-06-01

Oil wastes produced in large amounts in the processes of oil extraction, refining, and transportation are of great environmental concern because of their mutagenicity, toxicity, high fire hazardousness, and hydrophobicity. About 40% of these wastes contain radionuclides; however, the effects of oil products and radionuclides on soil microorganisms are frequently studied separately. The effects on various microbial parameters of raw waste containing 575 g of total petroleum hydrocarbons (TPH) kg-1 waste, 4.4 of 226Ra, 2.8 of 232Th, and 1.3 kBq kg-1 of 40K and its treated variant (1.6 g kg-1 of TPH, 7.9 of 226Ra, 3.9 of 232Th, and 183 kBq kg-1 of 40K) were examined in a leaching column experiment to separate the effects of hydrocarbons from those of radioactive elements. The raw waste sample (H) was collected from tanks during cleaning and maintenance, and a treated waste sample (R) was obtained from equipment for oil waste treatment. Thermal steam treatment is used in the production yard to reduce the oil content. The disposal of H waste samples on the soil surface led to an increase in the TPH content in soil: it became 3.5, 2.8, and 2.2 times higher in the upper (0-20 cm), middle (20-40 cm), and lower (40-60cm) layers, respectively. Activity concentrations of 226Ra and 232Th increased in soil sampled from both H- and R- columns in comparison to their concentrations in control soil. The activity concentrations of these two elements in samples taken from the upper and middle layers were much higher for the R-column compared to the H-column, despite the fact that the amount of waste added to the columns was equalized with respect to the activity concentrations of radionuclides. The H waste containing both TPH and radionuclides affected the functioning of the soil microbial community, and the effect was more pronounced in the upper layer of the column. Metabolic quotient and cellulase activity were the most sensitive microbial parameters as their levels were changed 5-1.4 times in comparison to control ones. Changes in soil functional characteristics caused by the treated waste containing mainly radionuclides were not observed. PCR-SSCP (polymerase chain reaction - single strand conformation polymorphism) analysis followed by MDS (metric multidimensional scaling) and clustering analysis revealed that the shifts in microbial community structure were affected by both hydrocarbons and radioactivity. Thus, molecular methods permitted to reveal the effects on soil microbial community not only from hydrocarbons, which significantly altered functional characteristics of soil microbiome, but also from radioactive elements.

68Ga-PSMA-11 PET Represents the Tumoricidal Effect of 223Ra in a Patient With Castrate-Resistant Metastatic Prostate Cancer.

PubMed

Ahmadzadehfar, Hojjat; Schlenkhoff, Carl Diedrich; Rogenhofer, Sebastian; Yordanova, Anna; Essler, Markus

2016-09-01

A 64-year-old man with prostate cancer and an increasing prostate-specific antigen (PSA) level under therapy with abiraterone acetate underwent a therapy with Ra. Before the first therapy and 4 weeks after the last cycle, the patient underwent Ga-PSMA PET, which showed a clear response of bone metastases.

Comparison of Cognitive Behavioral and Mindfulness Meditation Interventions on Adaptation to Rheumatoid Arthritis for Patients with and without History of Recurrent Depression

ERIC Educational Resources Information Center

Zautra, Alex J.; Davis, Mary C.; Reich, John W.; Nicassio, Perry; Tennen, Howard; Finan, Patrick; Kratz, Anna; Parrish, Brendt; Irwin, Michael R.

2008-01-01

This research examined whether cognitive behavioral therapy and mindfulness interventions that target responses to chronic stress, pain, and depression reduce pain and improve the quality of everyday life for adults with rheumatoid arthritis (RA). The 144 RA participants were clustered into groups of 6-10 participants and randomly assigned to 1 of…

Influence of CD94 and NKG2A variants on susceptibility to rheumatoid arthritis and efficacy of anti-TNF treatment.

PubMed

Iwaszko, Milena; Świerkot, Jerzy; Kolossa, Katarzyna; Jeka, Sławomir; Wiland, Piotr; Bogunia-Kubik, Katarzyna

2016-01-01

The present study aimed to investigate relationships between the CD94 and NKG2A gene polymorphisms and the risk of rheumatoid arthritis (RA) development as well as their association with the response to anti-TNF therapy. A total of 284 patients with RA receiving anti-TNF therapy and 124 healthy subjects were enrolled to the study. Genotypings for CD94 (rs2302489) and NKG2A (rs7301582, rs2734440, rs2734414) polymorphisms were performed using a polymerase chain reaction (PCR) amplification employing LightSNiP assays (TIB-MolBiol, Berlin, Germany). Clinical response was evaluated at 12th and 24th week after initiation of the therapy according to the EULAR response criteria. The frequency of the CD94 AA genotype was significantly decreased in RA patients compared to controls (OR=0.44; P=0.016). The CD94 AA homozygotes were also more common among patients negative to anti-cyclic citrullinated peptide (anti-CCP) antibodies (OR=11.28; P=0.001) as compared to anti-CCP-positive patients and the presence of the CD94 allele A was associated with lack of anti-CCP antibodies (OR=5.00; P=0.0005). The CD94 rs2302489 TT genotype was over-represented in patients exhibiting worse EULAR response at 12th week (OR=3.33; P=0.017). Furthermore, the lack of response after 12 weeks was more frequent among patients carrying the NKG2A rs7301582C allele (OR=3.68; P=0.019) or the CC genotype (OR=3.58; P=0.035) in comparison to allele T or CT/TT genotypes, respectively. These results indicate that CD94 and NKG2A polymorphisms may contribute to genetic susceptibility to RA or affect the response to anti-TNF therapy in patients of Caucasian origin. Copyright © 2015 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.

Identification of a transitional fibroblast function in very early rheumatoid arthritis

PubMed Central

Filer, Andrew; Ward, Lewis S C; Kemble, Samuel; Davies, Christopher S; Munir, Hafsa; Rogers, Rebekah; Raza, Karim; Buckley, Christopher Dominic; Nash, Gerard B; McGettrick, Helen M

2017-01-01

Objectives Synovial fibroblasts actively regulate the inflammatory infiltrate by communicating with neighbouring endothelial cells (EC). Surprisingly, little is known about how the development of rheumatoid arthritis (RA) alters these immunomodulatory properties. We examined the effects of phase of RA and disease outcome (resolving vs persistence) on fibroblast crosstalk with EC and regulation of lymphocyte recruitment. Methods Fibroblasts were isolated from patients without synovitis, with resolving arthritis, very early RA (VeRA; symptom ≤12 weeks) and established RA undergoing joint replacement (JRep) surgery. Endothelial-fibroblast cocultures were formed on opposite sides of porous filters. Lymphocyte adhesion from flow, secretion of soluble mediators and interleukin 6 (IL-6) signalling were assessed. Results Fibroblasts from non-inflamed and resolving arthritis were immunosuppressive, inhibiting lymphocyte recruitment to cytokine-treated endothelium. This effect was lost very early in the development of RA, such that fibroblasts no longer suppressed recruitment. Changes in IL-6 and transforming growth factor beta 1 (TGF-β1) signalling appeared critical for the loss of the immunosuppressive phenotype. In the absence of exogenous cytokines, JRep, but not VeRA, fibroblasts activated endothelium to support lymphocyte. Conclusions In RA, fibroblasts undergo two distinct changes in function: first a loss of immunosuppressive responses early in disease development, followed by the later acquisition of a stimulatory phenotype. Fibroblasts exhibit a transitional functional phenotype during the first 3 months of symptoms that contributes to the accumulation of persistent infiltrates. Finally, the role of IL-6 and TGF-β1 changes from immunosuppressive in resolving arthritis to stimulatory very early in the development of RA. Early interventions targeting ‘pathogenic’ fibroblasts may be required in order to restore protective regulatory processes. PMID:28847766

Do spouses know how much fatigue, pain, and physical limitation their partners with rheumatoid arthritis experience? Implications for social support.

PubMed

Lehman, Allen J; Pratt, Daniel D; DeLongis, Anita; Collins, John B; Shojania, Kam; Koehler, Barry; Offer, Robert; Esdaile, John M

2011-01-01

To determine whether perceptions of clinical manifestations (fatigue, pain, and physical limitation) of rheumatoid arthritis (RA) differ between spouses and their partners with RA, and to determine whether the differences are associated with the perception of beneficial and problematic spousal social support. English-speaking adults with RA of ≥ 6 months' duration and their spouses (n = 222 couples) completed standardized questionnaires for fatigue, pain, physical limitation, beneficial spousal support, and problematic spousal support. Spouses completed questionnaires based on their perception of their partner with RA. Agreement scores for fatigue, pain, and physical limitation were calculated by subtracting spouse scores from the scores of the partner with RA. Agreement levels were defined a priori: agreement (within ± one-half of a minimum clinically important difference [MCID] unit), overestimator (< one-half an MCID), and underestimator (> one-half an MCID). Separate hierarchical linear regression models were used to measure the association between beneficial support and problematic support after adjusting for RA duration, physical health, sex, educational level, relationship duration, and satisfaction. Response rate for couples was 82%. Relative to participants with RA, spouses overestimated fatigue (26%), pain (29%), and physical limitation (39%), and underestimated fatigue (11%), pain (17%), and physical limitation (34%). After statistically controlling for demographic, disease, and psychosocial variables, participants with RA whose spouses underestimated fatigue received more problematic support (R(2) = 3.7%, P = 0.002), as did those whose spouses underestimated or overestimated physical limitation (R(2) = 3.4%, P = 0.017). Persons with RA perceived more problematic spousal support when their spouse underestimated fatigue, or underestimated or overestimated physical limitation levels. Copyright © 2011 by the American College of Rheumatology.

[Intra-articular injections of triamcinolone hexacetonide in rheumatoid arthritis: short and long-term improvement predictors].

PubMed

Furtado, Rita Nely Vilar; Machado, Flavia Soares; Luz, Karine Rodrigues da; Santos, Marla Francisca dos; Konai, Monique Sayuri; Lopes, Roberta Vilela; Natour, Jamil

2015-01-01

Identify good response predictors to intra-articular injection (IAI) with triamcinolone hexacetonide (TH). This study was carried out in rheumatoid arthritis (RA) patients (American College of Rheumatology criteria) submitted to IAI (mono, pauci or polyarticular injection). A "blinded" observer prospectively evaluated joints at one week (T1), four weeks (T4), twelve weeks (T12) and 24 weeks (T24) after IAI. Outcome measurements included Visual Analogue Scale (0-10 cm) at rest, in movement and for swollen joints. Clinical, demographic and variables related to injection at baseline were analyzed according to IAI response. We studied 289 patients with RA (635 joints) with a mean age of 48.7 years (±10.68), 48.5% of them Caucasians, VAS for global pain=6.52 (±1.73). Under univariate analysis, the variables relating the best responses following IAI (improvement > 70%) were: "elbow and metacarpophalangeal (MCP) IAI, and functional class II". Under multivariate analysis, "males" and "non-whites" were the predictors with the best response to IAI at T4, while "elbow and MCP IAI", "polyarticular injection", "use of methotrexate" and "higher total dose of TH" obtained the best response at T24. Several predictors of good response to IAI in patients with RA were identified. The best-response predictors for TH IAI of long term were "apply elbow and MCP IAI" and "apply polyarticular injection". Copyright © 2014 Elsevier Editora Ltda. All rights reserved.

Publications - AR 2011-C | Alaska Division of Geological & Geophysical

Science.gov Websites

Alaska's Mineral Industry Reports AKGeology.info Rare Earth Elements WebGeochem Engineering Geology Alaska content DGGS AR 2011-C Publication Details Title: Engineering Geology FY12 project descriptions Authors Combellick, R.A., 2012, Engineering Geology FY12 project descriptions, in DGGS Staff, Alaska Division of

Concentrations of the naturally occurring radionucleides Pb-210, Po-210, and Ra-226 in aquatic fauna

NASA Technical Reports Server (NTRS)

Holtzman, R. B.

1969-01-01

Study reveals naturally occurring radionuclides are ubiquitous and contribute a substantial fraction of the natural radiation dose to humans and various biota. Measurements may be useful in ecological and other biological problems such as tracing food chains of animals and study of the metabolism of these elements.

ICPMS analysis of proteins separated by Native-PAGE: Evaluation of metaloprotein profiles in human synovial fluid with acute and chronic arthritis.

PubMed

Moyano, Mario F; Mariño-Repizo, Leonardo; Tamashiro, Héctor; Villegas, Liliana; Acosta, Mariano; Gil, Raúl A

2016-07-01

The role of trace elements bound to proteins in the etiology and pathogenesis of rheumatoid arthritis (RA) remains unclear. In this sense, the identification and detection of metalloproteins has a strong and growing interest. Metalloprotein studies are currently carried out by polyacrylamide gel electrophoresis (PAGE) associated to inductively coupled plasma mass spectrometry (ICPMS), and despite that complete information can be obtained for metals such as Fe, Cu and Zn, difficulties due to poor sensitivity for other trace elements such as Sn, As, etc, are currently faced. In the present work, a simple and fast method for the determination of trace metals bound to synovial fluid (SF) proteins was optimized. Proteins from SF (long and short-term RA) were separated in ten fractions by native PAGE, then dissolved in nitric acid and peroxide hydrogen, and analyzed by ICPMS. Fifteen metals were determined in each separated protein fraction (band). Adequate calibration of proteins molecular weight allowed stablishing which protein type were bound to different metals. Copyright © 2016 Elsevier GmbH. All rights reserved.

Potential of (18)F-FDG-PET as a valuable adjunct to clinical and response assessment in rheumatoid arthritis and seronegative spondyloarthropathies.

PubMed

Vijayant, Vishu; Sarma, Manjit; Aurangabadkar, Hrushikesh; Bichile, Lata; Basu, Sandip

2012-12-28

To evaluate the role of fluorine-18-labeled fluorodeoxyglucose positron emission tomography ((18)F-FDG PET) in various rheumatic diseases and its potential in the early assessment of treatment response in a limited number of patients. This study involved 28 newly diagnosed patients, of these 17 had rheumatoid arthritis (RA) and 11 had seronegative spondyloarthropathy (SSA). In the SSA group, 7 patients had ankylosing spondylitis, 3 had psoriatic arthritis, and one had non-specific SSA. Patients with RA were selected as per the American College of Rheumatology criteria. One hour after FDG injection, a whole body PET scan was performed from the skull vertex to below the knee joints using a GE Advance dedicated PET scanner. Separate scans were acquired for both upper and lower limbs. Post-treatment scans were performed in 9 patients in the RA group (at 6-9 wk from baseline) and in 1 patient with psoriatic arthropathy. The pattern of FDG uptake was analysed visually and quantified as maximum standardized uptake value (SUVmax) in a standard region of interest. Metabolic response on the scan was assessed qualitatively and quantitatively and was correlated with clinical assessment. The qualitative FDG uptake was in agreement with the clinically involved joints, erythrocyte sedimentation rate, C-reactive protein values and the clinical assessment by the rheumatologist. All 17 patients in the RA group showed the highest FDG avidity in painful/swollen/tender joints. The uptake pattern was homogeneous, intense and poly-articular in distribution. Hypermetabolism in the regional nodes (axillary nodes in the case of upper limb joint involvement and inguinal nodes in lower limb joints) was a constant feature in patients with RA. Multiple other extra-articular lesions were also observed including thyroid glands (in associated thyroiditis) and in the subcutaneous nodules. Treatment response was better appreciated using SUVmax values than visual interpretation, when compared with clinical evaluation. Four patients showed a favourable response, while 3 had stable disease and 2 showed disease progression. The resolution of regional nodal uptake (axillary or inguinal nodes based on site of joint involvement) in RA following disease modifying anti-rheumatoid drugs was noteworthy, which could be regarded as an additional parameter for identifying responding patients. In the SSA group, uptake in the affected joint was heterogeneous, low grade and non-symmetrical. In particular, there was intense tendon and muscular uptake corresponding to symptomatic joints. The patients with psoriatic arthritis showed intense FDG uptake in the joints and soft tissue. (18)F-FDG PET accurately delineates the ongoing inflammatory activity in various rheumatic diseases (both at articular and extra-articular sites) and relates well to clinical symptoms. Different metabolic patterns on FDG-PET scanning in RA and SSA can have important implications for their diagnosis and management in the future with the support of larger studies. FDG-PET molecular imaging is also a sensitive tool in the early assessment of treatment response, especially when using quantitative information. With these benefits, FDG-PET could play a pivotal clinical role in the management of inflammatory joint disorders in the future.

Systematic review and meta-analysis of serious infections with tofacitinib and biologic disease-modifying antirheumatic drug treatment in rheumatoid arthritis clinical trials.

PubMed

Strand, Vibeke; Ahadieh, Sima; French, Jonathan; Geier, Jamie; Krishnaswami, Sriram; Menon, Sujatha; Checchio, Tina; Tensfeldt, Thomas G; Hoffman, Elaine; Riese, Richard; Boy, Mary; Gómez-Reino, Juan J

2015-12-15

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Tofacitinib modulates the signaling of cytokines that are integral to lymphocyte activation, proliferation, and function. Thus, tofacitinib therapy may result in suppression of multiple elements of the immune response. Serious infections have been reported in tofacitinib RA trials. However, limited head-to-head comparator data were available within the tofacitinib RA development program to directly compare rates of serious infections with tofacitinib relative to biologic agents, and specifically adalimumab (employed as an active control agent in two randomized controlled trials of tofacitinib). A systematic literature search of data from interventional randomized controlled trials and long-term extension studies with biologics in RA was carried out. Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) consensus was followed for reporting results of the review and meta-analysis. Incidence rates (unique patients with events/100 patient-years) for each therapy were estimated based on data from randomized controlled trials and long-term extension studies using a random-effects model. Relative and absolute risk comparisons versus placebo used Mantel-Haenszel methods. The search produced 657 hits. In total, 66 randomized controlled trials and 22 long-term extension studies met the selection criteria. Estimated incidence rates (95% confidence intervals [CIs]) for abatacept, rituximab, tocilizumab, and tumor necrosis factor inhibitors were 3.04 (2.49, 3.72), 3.72 (2.99, 4.62), 5.45 (4.26, 6.96), and 4.90 (4.41, 5.44), respectively. Incidence rates (95% CIs) for tofacitinib 5 and 10 mg twice daily (BID) in phase 3 trials were 3.02 (2.25, 4.05) and 3.00 (2.24, 4.02), respectively. Corresponding incidence rates in long-term extension studies were 2.50 (2.05, 3.04) and 3.19 (2.74, 3.72). The risk ratios (95% CIs) versus placebo for tofacitinib 5 and 10 mg BID were 2.21 (0.60, 8.14) and 2.02 (0.56, 7.28), respectively. Risk differences (95% CIs) versus placebo for tofacitinib 5 and 10 mg BID were 0.38% (-0.24%, 0.99%) and 0.40% (-0.22%, 1.02%), respectively. In interventional studies, the risk of serious infections with tofacitinib is comparable to published rates for biologic disease-modifying antirheumatic drugs in patients with moderate to severely active RA.

Association of the -1082 G/A promoter polymorphism of interleukin-10 gene with the autoantibodies production in patients with rheumatoid arthritis.

PubMed

Nemec, Petr; Pavkova-Goldbergova, Monika; Gatterova, Jindra; Fojtik, Zdenek; Vasku, Anna; Soucek, Miroslav

2009-08-01

Interleukin-10 (IL-10) is an immunoregulatory cytokine, usually considered to mediate the downregulation of the inflammatory response in rheumatoid arthritis (RA). Some effects of IL-10 are not anti-inflammatory; for example, the activation of B cells to promote autoantibody production. Allelic polymorphisms located in the promoter region of the IL-10 gene may contribute to the regulation of autoantibodies production. To examine the putative association between the -1082 G/A polymorphism in the promoter region of the IL-10 gene and the susceptibility to disease onset and severity of RA, a total of 144 patients with RA diagnosed according to the revised criteria of the American College of Rheumatology for RA were consecutively recruited into the study. Radiographic progression of RA was scored according to the Sharp/van der Heijde method. Serum levels of rheumatoid factors (RFs) were measured by enzyme-linked immunosorbent assay. Polymerase chain reaction amplification was used for the analysis of the promoter polymorphism of the IL-10 gene. We observed significant differences in genotype distribution of the -1082 G/A polymorphism between IgM RF, IgA RF, and IgG RF positive/negative subgroups of RA patients, with higher prevalence of the GG genotype within IgM RF (Pg = 0.006), IgA RF (Pg = 0.05), and IgG RF (Pg = 0.007) negative RA patients. Results obtained in this study provide the evidence of an association between the -1082 G/A polymorphism in the IL-10 gene promoter and the production of RFs in RA patients.

Integrating toxicogenomics into human health risk assessment: lessons learned from the benzo[a]pyrene case study.

PubMed

Chepelev, Nikolai L; Moffat, Ivy D; Labib, Sarah; Bourdon-Lacombe, Julie; Kuo, Byron; Buick, Julie K; Lemieux, France; Malik, Amal I; Halappanavar, Sabina; Williams, Andrew; Yauk, Carole L

2015-01-01

The use of short-term toxicogenomic tests to predict cancer (or other health effects) offers considerable advantages relative to traditional toxicity testing methods. The advantages include increased throughput, increased mechanistic data, and significantly reduced costs. However, precisely how toxicogenomics data can be used to support human health risk assessment (RA) is unclear. In a companion paper ( Moffat et al. 2014 ), we present a case study evaluating the utility of toxicogenomics in the RA of benzo[a]pyrene (BaP), a known human carcinogen. The case study is meant as a proof-of-principle exercise using a well-established mode of action (MOA) that impacts multiple tissues, which should provide a best case example. We found that toxicogenomics provided rich mechanistic data applicable to hazard identification, dose-response analysis, and quantitative RA of BaP. Based on this work, here we share some useful lessons for both research and RA, and outline our perspective on how toxicogenomics can benefit RA in the short- and long-term. Specifically, we focus on (1) obtaining biologically relevant data that are readily suitable for establishing an MOA for toxicants, (2) examining the human relevance of an MOA from animal testing, and (3) proposing appropriate quantitative values for RA. We describe our envisioned strategy on how toxicogenomics can become a tool in RA, especially when anchored to other short-term toxicity tests (apical endpoints) to increase confidence in the proposed MOA, and emphasize the need for additional studies on other MOAs to define the best practices in the application of toxicogenomics in RA.

Impact of morning stiffness on working behaviour and performance in people with rheumatoid arthritis.

PubMed

Mattila, Kalle; Buttgereit, Frank; Tuominen, Risto

2014-12-01

Work disability remains a considerable problem for many patients with rheumatoid arthritis (RA). Morning stiffness is a symptom of RA associated with early retirement from work and with impaired functional ability. We aimed to explore the patient's perception of the impact of morning stiffness on the working life of patients with RA. A survey was conducted in 11 European countries. Patients of working age, with RA for ≥6 months and morning stiffness ≥3 mornings a week, were interviewed by telephone using a structured questionnaire. Responses were assessed in the total sample and in subgroups defined by severity and duration of morning stiffness and by country. A total of 1,061 respondents completed the survey, 534 were working, 224 were retired and the rest were, i.e. homemakers and unemployed. Among the 534 working respondents, RA-related morning stiffness affected work performance (47 %), resulted in late arrival at work (33 %) and required sick leave in the past month (15 %). Of the 224 retired respondents, 159 (71 %) stopped working earlier than their expected retirement age, with 64 % giving RA-related morning stiffness as a reason. There was a differential impact of increasing severity and increasing duration of morning stiffness on the various parameters studied. There were notable inter-country differences in the impact of RA-related morning stiffness on ability to work and on retirement. This large survey showed that from the patient's perspective, morning stiffness reduces the ability to work in patients with RA and contributes to early retirement.

Interleukin-17 receptor A maintains and protects the skin barrier to prevent allergic skin inflammation1

PubMed Central

Floudas, Achilleas; Saunders, Sean P.; Moran, Tara; Schwartz, Christian; Hams, Emily; Fitzgerald, Denise C.; Johnston, James A.; Ogg, Graham S.; McKenzie, Andrew N.; Walsh, Patrick T.; Fallon, Padraic G.

2017-01-01

Atopic dermatitis (AD) is a common inflammatory skin disease affecting up to 20% of children and 3% of adults worldwide and is associated with dysregulation of the skin barrier. While type 2 responses are implicated in AD, emerging evidence indicates potential role for the IL-17A signalling axis in AD pathogenesis. In this study we show that in the filaggrin mutant mouse model of spontaneous AD, IL-17RA deficiency (Il17ra-/-) resulted in severe exacerbation of skin inflammation. Interestingly, Il17ra-/- mice without the filaggrin mutation also developed spontaneous progressive skin inflammation with eosinophilia, increased levels of thymic stromal lymphopoietin (TSLP) and IL-5 in the skin. Il17ra-/- mice have a defective skin barrier with altered filaggrin expression. The barrier dysregulation and spontaneous skin inflammation in Il17ra-/- mice was dependent on TSLP, but not the other alarmins IL-25 and IL-33. The associated skin inflammation was mediated by IL-5 expressing pathogenic effector (pe) Th2 cells and was independent of TCRγδ T cells and IL-22. An absence of IL-17RA in non-hematopoietic cells, but not in the hematopoietic cells, was required for the development of spontaneous skin inflammation. Skin microbiome dysbiosis developed in the absence of IL-17RA, with antibiotic intervention resulting in significant amelioration of skin inflammation and reductions in skin infiltrating peTh2 cells and TSLP. This study describes a previously unappreciated protective role for IL-17RA signalling in regulation of the skin barrier and maintenance of skin immune homeostasis. PMID:28615416

Patient-centred care in established rheumatoid arthritis.

PubMed

Voshaar, M J H; Nota, I; van de Laar, M A F J; van den Bemt, B J F

2015-01-01

Review of the evidence on patient-centred care (PCC) in rheumatoid arthritis (RA) shows that involving the patient as an individual - with unique needs, concerns and preferences - has a relevant impact on treatment outcomes (safety, effectiveness and costs). This approach empowers patients to take personal responsibility for their treatment. Because clinicians are only able to interact personally with their patients just a few hours per year, patients with a chronic condition such as RA should be actively involved in the management of their disease. To stimulate this active role, five different PCC activities can be distinguished: (1) patient education, (2) patient involvement/shared decision-making, (3) patient empowerment/self-management, (4) involvement of family and friends and (5) physical and emotional support. This article reviews the existing knowledge on these five PCC activities in the context of established RA management, especially focused on opportunities to increase medication adherence in established RA. Copyright © 2015 Elsevier Ltd. All rights reserved.

[New therapies for rheumatoid arthritis].

PubMed

Salgado, Eva; Maneiro, José Ramón

2014-11-18

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease characterized by inflammation of the synovial membrane and progressive destruction of the articular cartilage and bone. Advances in the knowledge of disease pathogenesis allowed the identification of novel therapeutic targets such as tumor necrosis factor (TNF), interleukin (IL)-1, IL-6 or the system JAK/STAT phosphorylation. At present there are 5 TNF antagonists approved for RA. Tocilizumab blocks the pathway of IL-6 and is the only biological with proven efficacy in monotherapy. Rituximab modulates B cell response in RA. Abatacept provided new data on T cell involvement in the pathogenesis of RA. Tofacitinib is the first kinase inhibitor approved for this disease. Biologic drugs have proven efficacy, almost always in combination with methotrexate, and even halt radiographic progression. Monitoring infection is the main precaution in handling these patients. Copyright © 2013 Elsevier España, S.L.U. All rights reserved.

Measuring patients' experiences with rheumatic care: the consumer quality index rheumatoid arthritis.

PubMed

Zuidgeest, Marloes; Sixma, Herman; Rademakers, Jany

2009-12-01

Rheumatologists and other caregivers can learn from patients’ experiences with the quality of care that can be measured with the CQ-index Rheumatoid Arthritis (CQ-index RA) survey. Patients with RA (n = 590) received this survey were they rated their actual experiences and what they find important in rheumatic healthcare. Descriptive analyses and psychometric methods were used to test the reliability. The response rate was 69%. The items in the pilot instrument could be grouped into 10 scales (α ranged from 0.77 to 0.94). The most important quality aspects according to patients concerned the alertness when prescribing medication. Providing patients with information on a special website of the hospital about RA was the highest quality improvement aspect. The results of this study show that the CQ-index RA is a reliable instrument for quality assessment from the patients’ perspective. The instrument provides rheumatologists and other caregivers with feedback for service improvement initiatives.

Effect of anti-TNF treatment on body composition and serum adiponectin levels of women with rheumatoid arthritis.

PubMed

Serelis, John; Kontogianni, Meropi D; Katsiougiannis, Stergios; Bletsa, Maria; Tektonidou, Maria G; Skopouli, Fotini N

2008-06-01

The aim of this study was to investigate the effect of anti-tumor necrosis factor alpha (anti-TNF) treatment on body composition and serum adiponectin levels of women with rheumatoid arthritis (RA). Nineteen women with RA starting anti-TNF treatment were included in the study. Disease activity, body composition, lumbar spine bone mineral density (BMD) and serum adiponectin concentrations were measured at baseline and after 1 year of follow-up. No important changes on body composition and lumbar spine BMD were observed, while the serum levels of adiponectin levels increased after 1 year of anti-TNF treatment (p = 0.02). Anti-TNF treatment in women with RA does not have any significant effect on body composition; however, it is associated with increase in adiponectin levels which may ameliorate the systemic inflammatory response state associated with RA.

Efficacy of VX-509 (decernotinib) in combination with a disease-modifying antirheumatic drug in patients with rheumatoid arthritis: clinical and MRI findings.

PubMed

Genovese, Mark C; Yang, Fang; Østergaard, Mikkel; Kinnman, Nils

2016-11-01

To assess early effects on joint structures of VX-509 in combination with stable disease-modifying antirheumatic drug (DMARD) therapy using MRI in adults with rheumatoid arthritis (RA). This phase II, placebo-controlled, double-blind, dose-ranging study randomised patients with RA and inadequate DMARD response to VX-509 100 mg (n=11), 200 mg (n=10) or 300 mg (n=10) or placebo (n=12) once daily for 12 weeks. Outcome measures included American College of Rheumatology score (ACR20; improvement of ≥20%) and disease activity score (DAS28) using C reactive protein (CRP), and the RA MRI scoring (RAMRIS) system. ACR20 response at week 12 was 63.6%, 60.0% and 60.0% in the VX-509 100-mg, 200-mg and 300-mg groups, respectively, compared with 25.0% in the placebo group. DAS28-CRP scores decreased in a dose-dependent manner with increasing VX-509 doses. Decreases in RAMRIS synovitis scores were significantly different from placebo for all VX-509 doses (p<0.01) and for RAMRIS osteitis scores (p<0.01) for VX-509 300 mg. Treatment was generally well tolerated. VX-509 plus a DMARD reduced the signs and symptoms of RA in patients with an inadequate response to a DMARD alone. MRI responses were detected at week 12. Treatment was generally well tolerated. NCT01754935; results. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Effects of centrally acting analgesics on spinal segmental reflexes and wind-up.

PubMed

Mazo, I; Roza, C; Zamanillo, D; Merlos, M; Vela, J M; Lopez-Garcia, J A

2015-08-01

The spinal cord is a prime site of action for analgesia. Here we characterize the effects of established analgesics on segmental spinal reflexes. The aim of the study was to look for the pattern of action or signature of analgesic effects on these reflexes. We used a spinal cord in vitro preparation of neonate mice to record ventral root responses to dorsal root stimulation. Pregabalin, clonidine, morphine and duloxetine and an experimental sigma-1 receptor antagonist (S1RA) were applied to the preparation in a cumulative concentration protocol. Drug effects on the wind-up produced by repetitive stimulation of C-fibres and on responses to single A- and C-fibre intensity stimuli were analysed. All compounds produced a concentration-dependent inhibition of total spikes elicited by repetitive stimulation. Concentrations producing ∼50% reduction in this parameter were (in μM) clonidine (0.01), morphine (0.1), pregabalin (1), duloxetine (10) and S1RA (30). At these concentrations clonidine, pregabalin and S1RA had significant effects on the wind-up index and little depressant effects on responses to single stimuli. Morphine and duloxetine did not depress wind-up index and showed large effects on responses to single stimuli. None of the compounds had strong effects on the amplitude of the non-nociceptive monosynaptic reflex. morphine and duloxetine had general depressant effects on spinal reflexes, whereas the effects of clonidine, pregabalin and S1RA appeared to be restricted to signals originated by strong repetitive activation of C-fibres. Results are discussed in the context of reported behavioural effects of the compounds studied. © 2014 European Pain Federation - EFIC®

The yellow fever virus vaccine induces a broad and polyfunctional human memory CD8+ T cell response.

PubMed

Akondy, Rama S; Monson, Nathan D; Miller, Joseph D; Edupuganti, Srilatha; Teuwen, Dirk; Wu, Hong; Quyyumi, Farah; Garg, Seema; Altman, John D; Del Rio, Carlos; Keyserling, Harry L; Ploss, Alexander; Rice, Charles M; Orenstein, Walter A; Mulligan, Mark J; Ahmed, Rafi

2009-12-15

The live yellow fever vaccine (YF-17D) offers a unique opportunity to study memory CD8(+) T cell differentiation in humans following an acute viral infection. We have performed a comprehensive analysis of the virus-specific CD8(+) T cell response using overlapping peptides spanning the entire viral genome. Our results showed that the YF-17D vaccine induces a broad CD8(+) T cell response targeting several epitopes within each viral protein. We identified a dominant HLA-A2-restricted epitope in the NS4B protein and used tetramers specific for this epitope to track the CD8(+) T cell response over a 2 year period. This longitudinal analysis showed the following. 1) Memory CD8(+) T cells appear to pass through an effector phase and then gradually down-regulate expression of activation markers and effector molecules. 2) This effector phase was characterized by down-regulation of CD127, Bcl-2, CCR7, and CD45RA and was followed by a substantial contraction resulting in a pool of memory T cells that re-expressed CD127, Bcl-2, and CD45RA. 3) These memory cells were polyfunctional in terms of degranulation and production of the cytokines IFN-gamma, TNF-alpha, IL-2, and MIP-1beta. 4) The YF-17D-specific memory CD8(+) T cells had a phenotype (CCR7(-)CD45RA(+)) that is typically associated with terminally differentiated cells with limited proliferative capacity (T(EMRA)). However, these cells exhibited robust proliferative potential showing that expression of CD45RA may not always associate with terminal differentiation and, in fact, may be an indicator of highly functional memory CD8(+) T cells generated after acute viral infections.

Bronchoconstriction Triggered by Breathing Hot Humid Air in Patients with Asthma

PubMed Central

Hayes, Don; Collins, Paul B.; Khosravi, Mehdi

2012-01-01

Rationale: Hyperventilation of hot humid air induces transient bronchoconstriction in patients with asthma; the underlying mechanism is not known. Recent studies showed that an increase in temperature activates vagal bronchopulmonary C-fiber sensory nerves, which upon activation can elicit reflex bronchoconstriction. Objectives: This study was designed to test the hypothesis that the bronchoconstriction induced by increasing airway temperature in patients with asthma is mediated through cholinergic reflex resulting from activation of these airway sensory nerves. Methods: Specific airway resistance (SRaw) and pulmonary function were measured to determine the airway responses to isocapnic hyperventilation of humidified air at hot (49°C; HA) and room temperature (20–22°C; RA) for 4 minutes in six patients with mild asthma and six healthy subjects. A double-blind design was used to compare the effects between pretreatments with ipratropium bromide and placebo aerosols on the airway responses to HA challenge in these patients. Measurements and Main Results: SRaw increased by 112% immediately after hyperventilation of HA and by only 38% after RA in patients with asthma. Breathing HA, but not RA, triggered coughs in these patients. In contrast, hyperventilation of HA did not cause cough and increased SRaw by only 22% in healthy subjects; there was no difference between their SRaw responses to HA and RA challenges. More importantly, pretreatment with ipratropium completely prevented the HA-induced bronchoconstriction in patients with asthma. Conclusions: Bronchoconstriction induced by increasing airway temperature in patients with asthma is mediated through the cholinergic reflex pathway. The concomitant increase in cough response further indicates an involvement of airway sensory nerves, presumably the thermosensitive C-fiber afferents. PMID:22505744

Hypotonic stress promotes ATP release, reactive oxygen species production and cell proliferation via TRPV4 activation in rheumatoid arthritis rat synovial fibroblasts

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hu, Fen; Hui, Zhenhai; Wei, Wei

Rheumatoid arthritis (RA) is a chronic and systemic autoimmune-disease with complex and unclear etiology. Hypotonicity of synovial fluid is a typical characteristic of RA, which may play pivotal roles in RA pathogenesis. In this work, we studied the responses of RA synovial fibroblasts to hypotonic stress in vitro and further explored the underlying mechanisms. Data showed that hyposmotic solutions significantly triggered increases in cytosolic calcium concentration ([Ca{sup 2+}]{sub c}) of synoviocytes. Subsequently, it caused rapid release of ATP, as well as remarkable production of intracellular reactive oxygen species (ROS). Meanwhile, hypotonic stimulus promoted the proliferation of synovial fibroblasts. These effects weremore » almost abolished by calcium-free buffer and significantly inhibited by gadolinium (III) chloride (a mechanosensitive Ca{sup 2+} channel blocker) and ruthenium red (a transient receptor potential vanilloid 4 (TRPV4) blocker). 4α-phorbol 12,13-didecanoate, a specific agonist of TRPV4, also mimicked hypotonic shock-induced responses shown above. In contrast, voltage-gated channel inhibitors verapamil and nifedipine had little influences on these responses. Furthermore, RT-PCR and western blotting evidently detected TRPV4 expression at mRNA and protein level in isolated synoviocytes. Taken together, our results indicated that hypotonic stimulus resulted in ATP release, ROS production, and cell proliferation depending on Ca{sup 2+} entry through activation of TRPV4 channel in synoviocytes. - Highlights: • Hypotonic stress evokes Ca{sup 2+} entry in rheumatoid arthritis synovial fibroblasts. • Hypotonic stress induces rapid ATP release and ROS production in synoviocytes. • Hypotonic stimulation promotes the proliferation of synovial fibroblasts. • TRPV4 controls hypotonic-induced responses in synoviocytes.« less

Effects of human-induced alteration of groundwater flow on concentrations of naturally-occurring trace elements at water-supply wells

USGS Publications Warehouse

Ayotte, J.D.; Szabo, Z.; Focazio, M.J.; Eberts, S.M.

2011-01-01

The effects of human-induced alteration of groundwater flow patterns on concentrations of naturally-occurring trace elements were examined in five hydrologically distinct aquifer systems in the USA. Although naturally occurring, these trace elements can exceed concentrations that are considered harmful to human health. The results show that pumping-induced hydraulic gradient changes and artificial connection of aquifers by well screens can mix chemically distinct groundwater. Chemical reactions between these mixed groundwaters and solid aquifer materials can result in the mobilization of trace elements such as U, As and Ra, with subsequent transport to water-supply wells. For example, in the High Plains aquifer near York, Nebraska, mixing of shallow, oxygenated, lower-pH water from an unconfined aquifer with deeper, confined, anoxic, higher-pH water is facilitated by wells screened across both aquifers. The resulting higher-O2, lower-pH mixed groundwater facilitated the mobilization of U from solid aquifer materials, and dissolved U concentrations were observed to increase significantly in nearby supply wells. Similar instances of trace element mobilization due to human-induced mixing of groundwaters were documented in: (1) the Floridan aquifer system near Tampa, Florida (As and U), (2) Paleozoic sedimentary aquifers in eastern Wisconsin (As), (3) the basin-fill aquifer underlying the California Central Valley near Modesto (U), and (4) Coastal Plain aquifers of New Jersey (Ra). Adverse water-quality impacts attributed to human activities are commonly assumed to be related solely to the release of the various anthropogenic contaminants to the environment. The results show that human activities including various land uses, well drilling, and pumping rates and volumes can adversely impact the quality of water in supply wells, when associated with naturally-occurring trace elements in aquifer materials. This occurs by causing subtle but significant changes in geochemistry and associated trace element mobilization as well as enhancing advective transport processes.

Btk inhibition suppresses agonist-induced human macrophage activation and inflammatory gene expression in RA synovial tissue explants.

PubMed

Hartkamp, Linda M; Fine, Jay S; van Es, Inge E; Tang, Man Wai; Smith, Michael; Woods, John; Narula, Satwant; DeMartino, Julie; Tak, Paul P; Reedquist, Kris A

2015-08-01

Bruton's tyrosine kinase (Btk) is required for B lymphocyte and myeloid cell contributions to pathology in murine models of arthritis. Here, we examined the potential contributions of synovial Btk expression and activation to inflammation in rheumatoid arthritis (RA). Btk was detected by immunohistochemistry and digital image analysis in synovial tissue from biologically naive RA (n=16) and psoriatic arthritis (PsA) (n=12) patients. Cell populations expressing Btk were identified by immunofluorescent double labelling confocal microscopy, quantitative (q-) PCR and immunoblotting. The effects of a Btk-specific inhibitor, RN486, on gene expression in human macrophages and RA synovial tissue explants (n=8) were assessed by qPCR, ELISA and single-plex assays. Btk was expressed at equivalent levels in RA and PsA synovial tissue, restricted to B lymphocytes, monocytes, macrophages and mast cells. RN486 significantly inhibited macrophage IL-6 production induced by Fc receptor and CD40 ligation. RN486 also reduced mRNA expression of overlapping gene sets induced by IgG, CD40 ligand (CD40L) and RA synovial fluid, and significantly suppressed macrophage production of CD40L-induced IL-8, TNF, MMP-1 and MMP-10, LPS-induced MMP-1, MMP-7 and MMP-10 production, and spontaneous production of IL-6, PDGF, CXCL-9 and MMP-1 by RA synovial explants. Btk is expressed equivalently in RA and PsA synovial tissue, primarily in macrophages. Btk activity is needed to drive macrophage activation in response to multiple agonists relevant to inflammatory arthritis, and promotes RA synovial tissue cytokine and MMP production. Pharmacological targeting of Btk may be of therapeutic benefit in the treatment of RA and other inflammatory diseases. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Osteoarthritis and rheumatoid arthritis pannus have similar qualitative metabolic characteristics and pro-inflammatory cytokine response.

PubMed

Furuzawa-Carballeda, J; Macip-Rodríguez, P M; Cabral, A R

2008-01-01

Pannus in osteoarthritis (OA) has only recently been characterized. Little is known, however, regarding the behavior of OA pannus in vitro compared to rheumatoid arthritis (RA) pannus. The purpose of our study was to compare OA with RA pannus. Pannus and synovial tissue co-cultures from 5 patients with OA and 5 patients with RA obtained during arthroplasty were studied. Pannus was defined as the microscopic invasive granulation tissue covering the articular surface. Tissues were cultured for 7 days and stained with Alcian Blue technique. Interleukin-1beta (IL-1beta), IL-8, IL-10, IL-12, tumor necrosis factor-alpha (TNF-alpha), and interferon gamma (IFN-gamma) were also determined in supernatants by ELISA. Cartilage oligomeric matrix protein (COMP), type II collagen, TNF-alpha, IL-10 and Ki-67 expression were also detected by immunohistochemistry. All patients had vascular or fibrous pannus. Synovial proliferation, inflammatory infiltrates and a decrease of extracellular matrix proteins were observed in all tissue samples. Chondrocyte proliferation was lower in OA than RA cartilage. OA synovial tissue expressed lower levels of proteoglycans than RA synoyium. Type II collagen levels were lower in OA than in RA cartilage. Significantly higher levels of IL-1beta were found in the supernatants of RA pannus compared to OA pannus (p<0.05). High but similar levels of TNF-alpha, IL-8 and TIMP-1 were detected in OA and RA pannus supernatants. IL-10, IL-12 and IFN-gamma were undetectable. RA and OA pannus had similar pro-inflammatory and anti-inflammatory cytokine profile expression. OA cartilage, synovial tissue and pannus had lower production of proteoglycans, type II collagen and IL-1beta. It remains to be elucidated why OA pannus invades the cartilage surface but does not cause the marginal erosions typically seen in RA.

Stratum corneum cytokines and skin irritation response to sodium lauryl sulfate.

PubMed

De Jongh, Cindy M; Verberk, Maarten M; Withagen, Carien E T; Jacobs, John J L; Rustemeyer, Thomas; Kezic, Sanja

2006-06-01

Little is known about cytokines involved in chronic irritant contact dermatitis. Individual cytokine profiles might explain at least part of the differences in the individual response to irritation. Our objective was to investigate the relation between baseline stratum corneum (SC) cytokine levels and the skin response to a single and a repeated irritation test. This study also aimed to determine changes in SC cytokine levels after repeated irritation. Transepidermal water loss (TEWL) and erythema were measured in 20 volunteers after single 24-hr exposure to 1% sodium lauryl sulfate (SLS), and during and after repeated exposure to 0.1% SLS over a 3-week period. SC cytokine levels were measured from an unexposed skin site and from the repeatedly exposed site. Interleukin (IL)-1alpha decreased by 30% after repeated exposure, while IL-1RA increased 10-fold and IL-8 increased fourfold. Baseline IL-1RA and IL-8 values were predictors of TEWL and erythema after single exposure (r = 0.55-0.61). 6 subjects showed barrier recovery during repeated exposure. Baseline IL-1RA and IL-8 levels are likely to be indicators of higher skin irritability after single exposure to SLS. Barrier repair in some of the subjects might explain the lack of agreement between the TEWL response after single and repeated irritation.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, Young Il; Chung, Jin Wook, E-mail: chungjw@snu.ac.kr; Kim, Hyun Beom

PurposeThis study was designed to investigate the effects of stenting across the branching arteries on the patency and stent-tissue responses over the branching arterial orifices. Methods: Thirteen dogs were observed after placing aortic stents across the celiac arteries (CA), superior mesenteric arteries (SMA), and renal arteries (RA). The animals were grouped according to stent types: large-cell group (n = 6) and small-cell group (n = 7). Angiography was performed to evaluate the branching artery patency at 2, 6, and 12 months after stent insertion, and the stent-tissue responses covering the orifices were evaluated on histopathologic examination. Results: All branching arteriesmore » were patent on follow-up angiography; however, three patterns of stent-tissue responses over the orifices were observed: neointimal layering, bridging septa, and papillary hyperplasia. Although neointimal layering and bridging septa were evenly observed, severe papillary hyperplasia was more frequent at SMA and CA than RA. Four RA showed less than 50% ostial patency, and localized infarct was observed in six kidneys (24%). The ostial patency tended to decrease with small-cell stent during the follow-up period. Conclusions: Various stent-tissue responses over the branching artery orifices are induced by the aortic stent covering the branching arteries and may not be easily detected by conventional angiography. Subclinical renal infarct also may occur despite patent renal angiography.« less

Delayed hypersensitivity and neutrophil chemotaxis: effect of trauma.

PubMed

Meakins, J L; McLean, A P; Kelly, R; Bubenik, O; Pietsch, J B; MacLean, L D

1978-04-01

To investigate alterations in host defense produced by trauma, skin testing with five standard recall antigens was done on admission and weekly on 53 patients with blunt trauma and seven with penetrating missile injuries, who then were classified as normal (N), 2 or more positive responses; relatively anergic (RA), one positive response; or anergic (A), no response. Neutrophil chemotaxis was tested 145 times in 32 patients. Degree of injury was assessed by assigning one point to pelvic fracture, long-bone fracture, head, chest, or abdominal injury, to a maximum of five. The A and RA patients had greater trauma, 3 vs. 1.6 for N, and a significantly increased rate of sepsis (p less than 0.005) and mortality (p less than 0.05). Incidence of anergy depended upon age and extent of trauma. Neutrophil chemotaxis in A and RA patients was significantly (p less than 0.001) worse at 96.7 +/- 2.4 mu and 99.8 +/- 1.7 mu compared to N, 113.2 +/- 1.7 mu, and controls 121 +/- 4 mu. With recovery, chemotaxis returned to normal. It is concluded that failure of delayed hypersensitivity responses follows trauma, is related to the severity of injury and age of patient, and is associated with an abnormality of neutrophil chemotaxis and increased rate of sepsis.

Plant/soil concentration ratios of SSWRa for contrasting sites around an active U mine-mill

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ibrahim, S.A.; Whicker, F.W.

Concentrations of 226Ra were determined in native vegetation and underlying substrate (soil and tailings) at various sites around a conventional open-pit, acid leach U production operation in Wyoming. Plant/soil concentration ratios (CRs) for 226Ra were estimated for various sites, including weathered tailings; a tailings impoundment shoreline; downwind from exposed tailings; a mine overburden reclamation area; and several background locations. Radium-226 concentrations for vegetation and substrate and CR values from the perturbed sites were elevated above background. The highest vegetation concentration (1.3 Bq g-1) was found in a grass which had invaded exposed, weathered tailings. Levels of 226Ra in soil andmore » vegetation and CR values decreased with distance from the tailings impoundment edge. CR values varied significantly among sites, but few differences were found between plant species groups. The observed CR values ranged from 0.07 at the background and reclamation areas to 0.4 downwind from the tailings area. Average CR values for plants growing on exposed tailings and within one meter from the impoundment edge were 0.15 and 0.3, respectively. CR values of 226Ra for plants on tailings substrates were comparatively low in contrast to other radionuclides in the U chain. We speculate that in the case of sulfuric acid leached tailings-derived material, 226Ra is sequestered as sulfate, which is highly insoluble relative to the sulfates of the other elements (e.g., U and Th) resulting in reduced availability for plant uptake.« less

The Systemic Immune Network in Recent Onset Type 1 Diabetes: Central Role of Interleukin-1 Receptor Antagonist (DIATOR Trial)

PubMed Central

Kolb, Hubert; Lückemeyer, Kathrin; Heise, Tim; Herder, Christian; Schloot, Nanette C.; Koenig, Wolfgang; Heinemann, Lutz; Martin, Stephan

2013-01-01

Background The hypothesis was tested that the systemic immune milieu in recent-onset type 1 diabetes is associated with residual beta cell function and other metabolic patient characteristics. Methods and Findings All patients (n = 89, 40% female) of the Diabetes and Atorvastatin (DIATOR) Trial were analyzed at recruitment, i.e. prior to receiving the study medication. Inclusion criteria were insulin dependent diabetes for 2 weeks to 3 months, age range 18–39 years, and islet cell autoantibodies. Blood samples were analyzed for 14 immune mediators by standard methods. Concentrations of all mediators correlated with at least one other mediator (p<0.05, Spearman correlation) giving rise to a network. Interleukin 1 receptor antagonist (IL1-RA) held a central position and was associated with both pro- and anti-inflammatory mediators. Further central elements were the pro-inflammatory mediators CRP and IL-6, the soluble adhesion molecules sICAM-1 and E-selectin, and MCP-4 which held a central position in the chemokine network. The two Th1-associated mediators IFNγ and IP-10 remained outside the network but correlated with each other. All correlations were positive (r = 0.25–0.72), i.e., high levels of pro-inflammatory mediators were accompanied by increased levels of anti-inflammatory mediators. IL-1RA was the only mediator associated with fasting and liquid mixed meal stimulated C-peptide concentrations (r = 0.31 and 0.24, p = 0.003 and 0.025, after adjustment for age, sex, BMI). There were associations between the immune mediator network and BMI (IL-1RA, CRP, IL-6, MCP-4, MIP-1ß) but few or no associations with HbA1c, insulin dose, lipid parameters, age or sex. Conclusions In patients with recent onset type 1 diabetes, systemic acute phase proteins, cytokines, chemokines and soluble adhesion molecules form a network. Among the few central elements IL-1RA has a dominant role. IL-1RA is associated with all other groups of mediators and is the only mediator which correlates (positively) with residual beta cell function. Trial registration ClinicalTrials.gov registration number: NCT00974740 PMID:23991111

Buffer layers and articles for electronic devices

DOEpatents

Paranthaman, Mariappan P.; Aytug, Tolga; Christen, David K.; Feenstra, Roeland; Goyal, Amit

2004-07-20

Materials for depositing buffer layers on biaxially textured and untextured metallic and metal oxide substrates for use in the manufacture of superconducting and other electronic articles comprise RMnO.sub.3, R.sub.1-x A.sub.x MnO.sub.3, and combinations thereof; wherein R includes an element selected from the group consisting of La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, and Y, and A includes an element selected from the group consisting of Be, Mg, Ca, Sr, Ba, and Ra.

Alkaline earth filled nickel skutterudite antimonide thermoelectrics

DOEpatents

Singh, David Joseph

2013-07-16

A thermoelectric material including a body centered cubic filled skutterudite having the formula A.sub.xFe.sub.yNi.sub.zSb.sub.12, where A is an alkaline earth element, x is no more than approximately 1.0, and the sum of y and z is approximately equal to 4.0. The alkaline earth element includes guest atoms selected from the group consisting of Be, Mb, Ca, Sr, Ba, Ra and combinations thereof. The filled skutterudite is shown to have properties suitable for a wide variety of thermoelectric applications.

Atrioventricular nonuniformity of pericardial constraint.

PubMed

Hamilton, Douglas R; Sas, Rozsa; Tyberg, John V

2004-10-01

Physiologists and clinicians commonly refer to "pressure" as a measure of the constraining effects of the pericardium; however, "pericardial pressure" is really a local measurement of epicardial radial stress. During diastole, from the bottom of the y descent to the beginning of the a wave, pericardial pressure over the right atrium (P(pRA)) is approximately equal to that over the right ventricle (P(pRV)). However, in systole, during the interval between the bottom of the x descent and the peak of the v wave, these two pericardial pressures appear to be completely decoupled in that P(pRV) decreases, whereas P(pRA) remains constant or increases. This decoupling indicates considerable mechanical independence between the RA and RV during systole. That is, RV systolic emptying lowers P(pRV), but P(pRA) continues to increase, suggesting that the relation of the pericardium to the RA must allow effective constraint, even though the pericardium over the RV is simultaneously slack. In conclusion, we measured the pericardial pressure responsible for the previously reported nonuniformity of pericardial strain. P(pRA) and P(pRV) are closely coupled during diastole, but during systole they become decoupled. Systolic nonuniformity of pericardial constraint may augment the atrioventricular valve-opening pressure gradient in early diastole and, so, affect ventricular filling.

Increased dietary intake of vitamin A promotes aortic valve calcification in vivo.

PubMed

Huk, Danielle J; Hammond, Harriet L; Kegechika, Hiroyuki; Lincoln, Joy

2013-02-01

Calcific aortic valve disease (CAVD) is a major public health problem with no effective treatment available other than surgery. We previously showed that mature heart valves calcify in response to retinoic acid (RA) treatment through downregulation of the SRY transcription factor Sox9. In this study, we investigated the effects of excess vitamin A and its metabolite RA on heart valve structure and function in vivo and examined the molecular mechanisms of RA signaling during the calcification process in vitro. Using a combination of approaches, we defined calcific aortic valve disease pathogenesis in mice fed 200 IU/g and 20 IU/g of retinyl palmitate for 12 months at molecular, cellular, and functional levels. We show that mice fed excess vitamin A develop aortic valve stenosis and leaflet calcification associated with increased expression of osteogenic genes and decreased expression of cartilaginous markers. Using a pharmacological approach, we show that RA-mediated Sox9 repression and calcification is regulated by classical RA signaling and requires both RA and retinoid X receptors. Our studies demonstrate that excess vitamin A dietary intake promotes heart valve calcification in vivo. Therefore suggesting that hypervitaminosis A could serve as a new risk factor of calcific aortic valve disease in the human population.

“RaMassays”: Synergistic Enhancement of Plasmon-Free Raman Scattering and Mass Spectrometry for Multimodal Analysis of Small Molecules

PubMed Central

Alessandri, Ivano; Vassalini, Irene; Bertuzzi, Michela; Bontempi, Nicolò; Memo, Maurizio; Gianoncelli, Alessandra

2016-01-01

SiO2/TiO2 core/shell (T-rex) beads were exploited as “all-in-one” building-block materials to create analytical assays that combine plasmon-free surface enhanced Raman scattering (SERS) and surface assisted laser desorption/ionization (SALDI) mass spectrometry (RaMassays). Such a multi-modal approach relies on the unique optical properties of T-rex beads, which are able to harvest and manage light in both UV and Vis range, making ionization and Raman scattering more efficient. RaMassays were successfully applied to the detection of small (molecular weight, M.W. <400 Da) molecules with a key relevance in biochemistry and pharmaceutical analysis. Caffeine and cocaine were utilized as molecular probes to test the combined SERS/SALDI response of RaMassays, showing excellent sensitivity and reproducibility. The differentiation between amphetamine/ephedrine and theophylline/theobromine couples demonstrated the synergistic reciprocal reinforcement of SERS and SALDI. Finally, the conversion of L-tyrosine in L-DOPA was utilized to probe RaMassays as analytical tools for characterizing reaction intermediates without introducing any spurious effects. RaMassays exhibit important advantages over plasmonic nanoparticles in terms of reproducibility, absence of interference and potential integration in multiplexed devices. PMID:27698368

The role of autoantibodies in the pathophysiology of rheumatoid arthritis.

PubMed

Derksen, V F A M; Huizinga, T W J; van der Woude, D

2017-06-01

Rheumatoid arthritis (RA) is an autoimmune disease characterized by joint inflammation. The presence of autoantibodies in the sera of RA patients has provided many clues to the underlying disease pathophysiology. Based on the presence of several autoantibodies like rheumatoid factor (RF), anti-citrullinated protein antibodies (ACPA), anti-carbamylated protein antibodies (anti-CarP), and more recently anti-acetylated protein antibodies RA can be subdivided into seropositive and seronegative disease. The formation of these autoantibodies is associated with both genetic and environmental risk factors for RA, like specific human leukocyte antigen (HLA) alleles and smoking. Autoantibodies can be detected many years before disease onset in a subset of patients, suggesting a sequence of events in which the first autoantibodies develop in predisposed hosts, before an inflammatory response ensues leading to clinically apparent arthritis. Research on the characteristics and effector functions of these autoantibodies might provide more insight in pathophysiological processes underlying arthritis in RA. Recent data suggests that ACPA might play a role in perpetuating inflammation once it has developed. Furthermore, pathophysiological mechanisms have been discovered supporting a direct link between the presence of ACPA and both bone erosions and pain in RA patients. In conclusion, investigating the possible pathogenic potential of autoantibodies might lead to improved understanding of the underlying pathophysiological processes in rheumatoid arthritis.

Optimal responses in disease activity scores to treatment in rheumatoid arthritis: Is a DAS28 reduction of >1.2 sufficient?

PubMed

Mian, Aneela N; Ibrahim, Fowzia; Scott, David L; Galloway, James

2016-06-16

The overall benefit of intensive treatment strategies in rheumatoid arthritis (RA) remains uncertain. We explored how reductions in disability and improvements in quality of life scores are affected by alternative assessments of reductions in disease activity scores for 28 joints (DAS28) in two trials of intensive treatment strategies in active RA. One trial (CARDERA) studied 467 patients with early active RA receiving 24 months of methotrexate monotherapy or steroid and disease-modifying anti-rheumatic drug (DMARD) combinations. The other trial (TACIT) studied 205 patients with established active RA; they received 12 months of treatment with DMARD combinations or biologic agents. We compared changes in the health assessment questionnaire (HAQ) and Euroqol-5D (EQ5D) at trial endpoints in European League Against Rheumatism (EULAR) good and moderate EULAR responders in patients in whom complete endpoint data were available. In the CARDERA trial 98 patients (26 %) were good EULAR responders and 160 (32 %) were EULAR moderate responders; comparable data in TACIT were 66 (35 %) and 86 (46 %) patients. The magnitude of change in the HAQ and EQ5D was greater in both trials in EULAR good responders than in EULAR moderate responders. HAQ scores had a difference in of -0.49 (95 % CI -0.66, -0.32) in the CARDERA and -0.31 (95 % CI -0.47, -0.13) in the TACIT trial. With the EQ5D comparable differences were 0.12 (95 % CI 0.04, 0.19) and 0.15 (95 % CI 0.05, 0.25). Both exceeded minimum clinically important differences in HAQ and EQ5D scores. We conclude that achieving a good EULAR response with DMARDs and biologic agents in active RA results in substantially improved mean HAQ and EQ5D scores. Patients who achieve such responses should continue on treatment. However, continuing such treatment strategies is more challenging when only a moderate EULAR response is achieved. In these patients evidence of additional clinically important benefits in measures such as the HAQ should also be sought.

Local fibroblast proliferation but not influx is responsible for synovial hyperplasia in a murine model of rheumatoid arthritis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Matsuo, Yusuke; Mizoguchi, Fumitaka; Saito, Tetsuya

Synovial fibroblasts play crucial roles in inflammation and joint destruction in rheumatoid arthritis (RA). How they accumulate in the RA joints remains unclear. This study was conducted to discern whether cellular influx from the outside of the joints and local proliferation are responsible for synovial fibroblast accumulation in an animal model of RA. We found that synovial fibroblasts were identified as GFP+ cells using collagen type I alpha 2 (Col1a2)-GFP transgenic reporter mice. Then, bone marrow transplantation and parabiosis techniques were utilized to study the cellular influx. Irradiated wild-type mice were transplanted with bone marrow from Col1a2-GFP mice. Col1a2-GFP andmore » wild-type mice were conjoined for parabiosis. The transplanted mice and the parabionts were subjected to collagen antibody-induced arthritis (CAIA). We found no GFP+ cells in the hyperplastic synovial tissues from the transplanted mice with CAIA and from the wild-type parabionts with CAIA. Furthermore, normal and CAIA synovial tissues from Col1a2-GFP mice and from fluorescent ubiquitination-based cell cycle indicator (Fucci) transgenic mice, in which cells in S/G{sub 2}/M phases of the cell cycle express Azami-Green, were studied for Ki67, a cellular proliferation marker, and vimentin, a fibroblast marker, expression. The percentages of Ki67+/GFP+ and Azami-Green+/vimentin+ cells in the CAIA synovial tissues were higher than those in the untreated synovial tissues (34% vs. 0.40% and 19% vs. 0.26%, respectively). These findings indicate that local fibroblast proliferation but not cellular influx is responsible for the synovial hyperplasia in CAIA. Suppression of proliferation of the local synovial fibroblasts should be a promising treatment for RA. - Highlights: • We studied how synovial fibroblasts accumulate in joints in a murine model of RA. • Bone marrow-derived cells did not accumulate in arthritic joints. • Synovial fibroblasts did not accumulate in arthritic joints via circulation. • Local proliferation was responsible for the synovial fibroblast accumulation.« less

Effects of retinoids on ultraviolet-induced carcinogenesis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Epstein, J.H.

The evidence for effects of the retinoids on UV-induced carcinogenesis is sparse. Clinical observations indicate that topical RA can cause significant regression of premalignant actinic keratoses. Also there is some evidence that this agent can cause dissolution of some basal cell epitheliomas. However this latter effect does not appear to be of therapeutic value. Systemic retinoids are of little value in the treatment of premalignant and malignant cutaneous lesions though 13-cis-retinoic acid might be of use in the basal cell nevus syndrome. Examination of the influence of the retinoids on photocarcinogenesis essentially has been confined to RA and animal experimentation.more » RA in nontoxic concentrations can both stimulate and inhibit photocarcinogenesis depending upon the circumstances of the study. The mechanisms of these responses are not clear. Influences on DNA synthesis directly and/or indirectly or on immune responses may be involved in both effects. Preliminary studies with oral 13-cis-retinoic acid have not demonstrated any effects to date on UV-induced skin cancer formation.« less

Crowdsourced assessment of common genetic contribution to predicting anti-TNF treatment response in rheumatoid arthritis.

PubMed

Sieberts, Solveig K; Zhu, Fan; García-García, Javier; Stahl, Eli; Pratap, Abhishek; Pandey, Gaurav; Pappas, Dimitrios; Aguilar, Daniel; Anton, Bernat; Bonet, Jaume; Eksi, Ridvan; Fornés, Oriol; Guney, Emre; Li, Hongdong; Marín, Manuel Alejandro; Panwar, Bharat; Planas-Iglesias, Joan; Poglayen, Daniel; Cui, Jing; Falcao, Andre O; Suver, Christine; Hoff, Bruce; Balagurusamy, Venkat S K; Dillenberger, Donna; Neto, Elias Chaibub; Norman, Thea; Aittokallio, Tero; Ammad-Ud-Din, Muhammad; Azencott, Chloe-Agathe; Bellón, Víctor; Boeva, Valentina; Bunte, Kerstin; Chheda, Himanshu; Cheng, Lu; Corander, Jukka; Dumontier, Michel; Goldenberg, Anna; Gopalacharyulu, Peddinti; Hajiloo, Mohsen; Hidru, Daniel; Jaiswal, Alok; Kaski, Samuel; Khalfaoui, Beyrem; Khan, Suleiman Ali; Kramer, Eric R; Marttinen, Pekka; Mezlini, Aziz M; Molparia, Bhuvan; Pirinen, Matti; Saarela, Janna; Samwald, Matthias; Stoven, Véronique; Tang, Hao; Tang, Jing; Torkamani, Ali; Vert, Jean-Phillipe; Wang, Bo; Wang, Tao; Wennerberg, Krister; Wineinger, Nathan E; Xiao, Guanghua; Xie, Yang; Yeung, Rae; Zhan, Xiaowei; Zhao, Cheng; Greenberg, Jeff; Kremer, Joel; Michaud, Kaleb; Barton, Anne; Coenen, Marieke; Mariette, Xavier; Miceli, Corinne; Shadick, Nancy; Weinblatt, Michael; de Vries, Niek; Tak, Paul P; Gerlag, Danielle; Huizinga, Tom W J; Kurreeman, Fina; Allaart, Cornelia F; Louis Bridges, S; Criswell, Lindsey; Moreland, Larry; Klareskog, Lars; Saevarsdottir, Saedis; Padyukov, Leonid; Gregersen, Peter K; Friend, Stephen; Plenge, Robert; Stolovitzky, Gustavo; Oliva, Baldo; Guan, Yuanfang; Mangravite, Lara M; Bridges, S Louis; Criswell, Lindsey; Moreland, Larry; Klareskog, Lars; Saevarsdottir, Saedis; Padyukov, Leonid; Gregersen, Peter K; Friend, Stephen; Plenge, Robert; Stolovitzky, Gustavo; Oliva, Baldo; Guan, Yuanfang; Mangravite, Lara M

2016-08-23

Rheumatoid arthritis (RA) affects millions world-wide. While anti-TNF treatment is widely used to reduce disease progression, treatment fails in ∼one-third of patients. No biomarker currently exists that identifies non-responders before treatment. A rigorous community-based assessment of the utility of SNP data for predicting anti-TNF treatment efficacy in RA patients was performed in the context of a DREAM Challenge (http://www.synapse.org/RA_Challenge). An open challenge framework enabled the comparative evaluation of predictions developed by 73 research groups using the most comprehensive available data and covering a wide range of state-of-the-art modelling methodologies. Despite a significant genetic heritability estimate of treatment non-response trait (h(2)=0.18, P value=0.02), no significant genetic contribution to prediction accuracy is observed. Results formally confirm the expectations of the rheumatology community that SNP information does not significantly improve predictive performance relative to standard clinical traits, thereby justifying a refocusing of future efforts on collection of other data.

Selective tyrosine kinase inhibition by imatinib mesylate for the treatment of autoimmune arthritis

PubMed Central

Paniagua, Ricardo T.; Sharpe, Orr; Ho, Peggy P.; Chan, Steven M.; Chang, Anna; Higgins, John P.; Tomooka, Beren H.; Thomas, Fiona M.; Song, Jason J.; Goodman, Stuart B.; Lee, David M.; Genovese, Mark C.; Utz, Paul J.; Steinman, Lawrence; Robinson, William H.

2006-01-01

Tyrosine kinases play a central role in the activation of signal transduction pathways and cellular responses that mediate the pathogenesis of rheumatoid arthritis. Imatinib mesylate (imatinib) is a tyrosine kinase inhibitor developed to treat Bcr/Abl-expressing leukemias and subsequently found to treat c-Kit–expressing gastrointestinal stromal tumors. We demonstrate that imatinib potently prevents and treats murine collagen-induced arthritis (CIA). We further show that micromolar concentrations of imatinib abrogate multiple signal transduction pathways implicated in RA pathogenesis, including mast cell c-Kit signaling and TNF-α release, macrophage c-Fms activation and cytokine production, and fibroblast PDGFR signaling and proliferation. In our studies, imatinib attenuated PDGFR signaling in fibroblast-like synoviocytes (FLSs) and TNF-α production in synovial fluid mononuclear cells (SFMCs) derived from human RA patients. Imatinib-mediated inhibition of a spectrum of signal transduction pathways and the downstream pathogenic cellular responses may provide a powerful approach to treat RA and other inflammatory diseases. PMID:16981009

The multi-faceted assessment of independence in patients with rheumatoid arthritis: preliminary validation from the ATTAIN study.

PubMed

Hassett, Afton L; Li, Tracy; Buyske, Steven; Savage, Shantal V; Gignac, Monique A M

2008-05-01

To consider the feasibility of assessing multiple facets of independence in rheumatoid arthritis (RA) using a measure developed from existing items and examining its face validity, construct validity and responsiveness to change. The ATTAIN (Abatacept Trial in Treatment of Anti-tumor necrosis factor [TNF] Inadequate responders) database was used. Patients with RA were randomized 2:1, abatacept (n = 258) and placebo (n = 133). A multi-faceted scale to measure physical and psychosocial independence was constructed using items from the Health Assessment Questionnaire (HAQ) and Short Form 36 Health Survey (SF-36). Questions assessing activity limitations and need for outside caregiver help were also examined. Interviews with 20 RA patients assessed face validity. Item Response Theory analysis yielded two traits - 'Psychosocial Independence', derived from the number of days with activity limitations plus the Role Emotional, Social Functioning and Role Physical subscale items from the SF-36; and 'Physical Independence', derived from 15 HAQ items assessing need for help from another. The two traits showed no significant differential item functioning for age or gender and demonstrated good face validity. Changes over 169 days on Psychosocial Independence were greater (mean 0.46 units, 95% confidence interval [CI]: 0.17-0.75) for the abatacept group than for placebo (p = 0.002). Changes in Physical Independence were greater (mean 0.59 units, 95% CI: 0.35-0.82) for the abatacept group than for placebo (p < 0.001). The multi-faceted assessment of independence in RA based on items from commonly used instruments is feasible suggesting promise for evaluating independence in future clinical trials. This approach demonstrated good face and construct validity and responsiveness in RA patients who had previously failed anti-TNF therapy. However, we caution against an interpretation that these data suggest that abatacept improves independence because the component parts of this assessment came from instruments used in the ATTAIN trial where data had been previously analyzed.

European perspective on the management of rheumatoid arthritis: clinical utility of tofacitinib.

PubMed

Kawalec, Paweł; Śladowska, Katarzyna; Malinowska-Lipień, Iwona; Brzostek, Tomasz; Kózka, Maria

2018-01-01

Xeljanz ® (tofacitinib) is an oral small-molecule inhibitor that reversibly inhibits Janus-activated kinase (JAK)-dependent cytokine signaling, thus reducing inflammation. As a result of these mechanisms, effects on the immune system such as a moderate decrease in the total lymphocyte count, a dose-dependent decrease in natural killer (NK) cell count, and an increase in B-cell count have been observed. Therefore, tofacitinib provides an innovative approach to modulating the immune and inflammatory responses in patients with rheumatoid arthritis (RA), which is especially important in individuals who do not respond to tumor necrosis factor inhibitors or show a loss of response over time. The aim of this article was to review studies on the pharmacology, mode of action, pharmacokinetics, efficacy, and safety of tofacitinib in patients with RA. Tofacitinib has been shown to reduce symptoms of RA and improve the quality of life in the analyzed groups of patients. Moreover, it showed high efficacy and an acceptable safety profile in Phase III randomized clinical trials on RA and was the first JAK inhibitor approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) in the RA therapy, thus providing a useful alternative treatment strategy. Randomized controlled studies revealed a significant benefit over placebo in efficacy outcomes (American College of Rheumatology [ACR] 20 and ACR50 response rates); accordingly, clinically meaningful improvements in patient-related outcomes compared with placebo have been reported. The safety profile seems acceptable, although some severe adverse effects have been observed, including serious infections, opportunistic infections (including tuberculosis and herpes zoster), malignancies, and cardiovascular events, which require strict monitoring irrespective of the duration of tofacitinib administration. As an oral drug, tofacitinib offers an alternative to subcutaneous or intravenous biologic drugs and should be recognized as a more convenient way of drug administration.

European perspective on the management of rheumatoid arthritis: clinical utility of tofacitinib

PubMed Central

Kawalec, Paweł; Śladowska, Katarzyna; Malinowska-Lipień, Iwona; Brzostek, Tomasz; Kózka, Maria

2018-01-01

Xeljanz® (tofacitinib) is an oral small-molecule inhibitor that reversibly inhibits Janus-activated kinase (JAK)-dependent cytokine signaling, thus reducing inflammation. As a result of these mechanisms, effects on the immune system such as a moderate decrease in the total lymphocyte count, a dose-dependent decrease in natural killer (NK) cell count, and an increase in B-cell count have been observed. Therefore, tofacitinib provides an innovative approach to modulating the immune and inflammatory responses in patients with rheumatoid arthritis (RA), which is especially important in individuals who do not respond to tumor necrosis factor inhibitors or show a loss of response over time. The aim of this article was to review studies on the pharmacology, mode of action, pharmacokinetics, efficacy, and safety of tofacitinib in patients with RA. Tofacitinib has been shown to reduce symptoms of RA and improve the quality of life in the analyzed groups of patients. Moreover, it showed high efficacy and an acceptable safety profile in Phase III randomized clinical trials on RA and was the first JAK inhibitor approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) in the RA therapy, thus providing a useful alternative treatment strategy. Randomized controlled studies revealed a significant benefit over placebo in efficacy outcomes (American College of Rheumatology [ACR] 20 and ACR50 response rates); accordingly, clinically meaningful improvements in patient-related outcomes compared with placebo have been reported. The safety profile seems acceptable, although some severe adverse effects have been observed, including serious infections, opportunistic infections (including tuberculosis and herpes zoster), malignancies, and cardiovascular events, which require strict monitoring irrespective of the duration of tofacitinib administration. As an oral drug, tofacitinib offers an alternative to subcutaneous or intravenous biologic drugs and should be recognized as a more convenient way of drug administration. PMID:29317823

Clinical and serological predictors of remission in rheumatoid arthritis are dependent on treatment regimen.

PubMed

Ma, Margaret H Y; Scott, Ian C; Dahanayake, Chanaka; Cope, Andrew P; Scott, David L

2014-07-01

Early intensive treatment is now the cornerstone for the management of rheumatoid arthritis (RA). In the era of personalized medicine, when treatment is becoming more individualized, it is unclear from the current literature whether all patients with RA benefit equally from such intensive therapies. We investigated the benefit of different treatment regimens on remission rates when stratified to clinical and serological factors. The Combination Anti-rheumatic Drugs in Early Rheumatoid Arthritis (CARDERA) trial recruited patients with RA of less than 2 years' duration who had active disease. The trial compared 4 treatment regimens: methotrexate monotherapy, 2 different double therapy regimens (methotrexate and cyclosporine or methotrexate and prednisolone) and 3-drug therapy. Clinical predictors included age, male sex, and tender joint count (TJC) and serological biomarkers included rheumatoid factor (RF) and anticitrullinated protein antibodies (ACPA). Patients who were male, over 50 years, had ≥ 6 TJC, were RF-IgM-positive, or ACPA-positive were more likely to achieve remission at 24 months using 3-drug therapy compared to monotherapy (OR 2.99, 4.95, 2.71, 2.54, and 3.52, respectively). There were no differences in response to monotherapy and 3-drug therapy if patients were female, under 50 years, had < 6 TJC, or were seronegative. Early intensive regimens have become the gold standard in the treatment of early RA. Our study suggests that this intensive approach is only superior to monotherapy in certain subsets of patients. Although these are unlikely to be the only predictors of treatment response, our study brings us a step closer to achieving personalized medicine in RA.

Initial validation and results of the Symptoms in Persons At Risk of Rheumatoid Arthritis (SPARRA) questionnaire: a EULAR project

PubMed Central

van Beers-Tas, Marian H; ter Wee, Marieke M; van Tuyl, Lilian H; Maat, Bertha; Hoogland, Wijnanda; Hensvold, Aase H; Catrina, Anca I; Mosor, Erika; Finckh, Axel; Courvoisier, Delphine S; Filer, Andrew; Sahbudin, Ilfita; Stack, Rebecca J; Raza, Karim; van Schaardenburg, Dirkjan

2018-01-01

Objectives To describe the development and assess the psychometric properties of the novel ‘Symptoms in Persons At Risk of Rheumatoid Arthritis’ (SPARRA) questionnaire in individuals at risk of rheumatoid arthritis (RA) and to quantify their symptoms. Methods The questionnaire items were derived from a qualitative study in patients with seropositive arthralgia. The questionnaire was administered to 219 individuals at risk of RA on the basis of symptoms or autoantibody positivity: 74% rheumatoid factor and/or anticitrullinated protein antibodies positive, 26% seronegative. Validity, reliability and responsiveness were assessed. Eighteen first degree relatives (FDR) of patients with RA were used for comparison. Results Face and content validity were high. The test-retest showed good agreement and reliability (1 week and 6 months). Overall, construct validity was low to moderate, with higher values for concurrent validity, suggesting that some questions reflect symptom content not captured with regular Visual Analogue Scale pain/well-being. Responsiveness was low (small subgroup). Finally, the burden of symptoms in both seronegative and seropositive at risk individuals was high, with pain, stiffness and fatigue being the most common ones with a major impact on daily functioning. The FDR cohort (mostly healthy individuals) showed a lower burden of symptoms; however, the distribution of symptoms was similar. Conclusions The SPARRA questionnaire has good psychometric properties and can add information to currently available clinical measures in individuals at risk of RA. The studied group had a high burden and impact of symptoms. Future studies should evaluate whether SPARRA data can improve the prediction of RA in at risk individuals.

The behavior of the uranium decay chain nuclides and thorium during the flank eruptions of Kilauea (Hawaii) between 1983 and 1985

DOE Office of Scientific and Technical Information (OSTI.GOV)

Reinitz, I.M.; Turekian, K.K.

1991-12-01

The concentrations of members of the {sup 238}U decay chain and {sup 232}Th have been determined for the lavas that erupted on the East Rift Zone of Kilauea Volcano, Hawaii (Puu Oo) between January 1983 and January 1985. There was a decrease during the first 180 days in the abundances of all nuclides, following the behavior of the incompatible elements. ({sup 230}Th/{sup 238}U) varies with ({sup 232}Th/{sup 238}U) yielding a batch process age for the source magma of 127,800 {plus minus} 28,500 (2{omega}) y, similar to East Pacific Rise basalts. No ({sup 226}Ra/{sup 230}Th) disequilibrium was evident at Puu Oomore » although Haleakala and Loihi show significant excesses of ({sup 226}Ra) over ({sup 230}Th). The initial ({sup 210}Pb) excess relative to ({sup 226}Ra) implies strong incompatibility of {sup 210}Pb probably with the help of chloride complexing, and the deficiency in later episodes indicates volatilization from the melt mediated by the formation of volatile chloride compounds.« less

Geochemistry of radioactive elements in bituminous sands and sandstones of Permian bitumen deposits of Tatarstan (east of the Russian plate)

NASA Astrophysics Data System (ADS)

Mullakaev, A. I.; Khasanov, R. R.; Badrutdinov, O. R.; Kamaletdinov, I. R.

2018-05-01

The article investigates geochemical features of Permian (Cisuralian, Ufimian Stage and Biarmian, Kazanian Stage of the General Stratigraphic Scale of Russia) bituminous sands and sandstones located on the territory of the Volga-Ural oil and gas province (Republic of Tatarstan). Natural bitumens are extracted using thermal methods as deposits of high-viscosity oils. In the samples studied, the specific activity of natural radionuclides from the 238U (226Ra), 232Th, and 40K series was measured using gamma spectrometry. As a result of the precipitation of uranium and thorium and their subsequent decay, the accumulation of radium (226Ra and 228Ra) has been shown to occur in the bituminous substance. In the process of exploitation of bitumen-bearing rock deposits (as an oil fields) radium in the composition of a water-oil mixture can be extracted to the surface or deposited on sulfate barriers, while being concentrated on the walls of pipes and other equipment. This process requires increased attention to monitoring and inspection the environmental safety of the exploitation procedure.

Brine Spills Associated with Unconventional Oil Development in North Dakota.

PubMed

Lauer, Nancy E; Harkness, Jennifer S; Vengosh, Avner

2016-05-17

The rapid rise of unconventional oil production during the past decade in the Bakken region of North Dakota raises concerns related to water contamination associated with the accidental release of oil and gas wastewater to the environment. Here, we characterize the major and trace element chemistry and isotopic ratios ((87)Sr/(86)Sr, δ(18)O, δ(2)H) of surface waters (n = 29) in areas impacted by oil and gas wastewater spills in the Bakken region of North Dakota. We establish geochemical and isotopic tracers that can identify Bakken brine spills in the environment. In addition to elevated concentrations of dissolved salts (Na, Cl, Br), spill waters also consisted of elevated concentrations of other contaminants (Se, V, Pb, NH4) compared to background waters, and soil and sediment in spill sites had elevated total radium activities ((228)Ra + (226)Ra) relative to background, indicating accumulation of Ra in impacted soil and sediment. We observed that inorganic contamination associated with brine spills in North Dakota is remarkably persistent, with elevated levels of contaminants observed in spills sites up to 4 years following the spill events.

Optimization of cutting parameters in CNC turning of stainless steel 304 with TiAlN nano coated carbide cutting tool

NASA Astrophysics Data System (ADS)

Durga Prasada Rao, V.; Harsha, N.; Raghu Ram, N. S.; Navya Geethika, V.

2018-02-01

In this work, turning was performed to optimize the surface finish or roughness (Ra) of stainless steel 304 with uncoated and coated carbide tools under dry conditions. The carbide tools were coated with Titanium Aluminium Nitride (TiAlN) nano coating using Physical Vapour Deposition (PVD) method. The machining parameters, viz., cutting speed, depth of cut and feed rate which show major impact on Ra are considered during turning. The experiments are designed as per Taguchi orthogonal array and machining process is done accordingly. Then second-order regression equations have been developed on the basis of experimental results for Ra in terms of machining parameters used. Regarding the effect of machining parameters, an upward trend is observed in Ra with respect to feed rate, and as cutting speed increases the Ra value increased slightly due to chatter and vibrations. The adequacy of response variable (Ra) is tested by conducting additional experiments. The predicted Ra values are found to be a close match of their corresponding experimental values of uncoated and coated tools. The corresponding average % errors are found to be within the acceptable limits. Then the surface roughness equations of uncoated and coated tools are set as the objectives of optimization problem and are solved by using Differential Evolution (DE) algorithm. Also the tool lives of uncoated and coated tools are predicted by using Taylor’s tool life equation.

IL-1 receptor-antagonist (IL-1Ra) knockout mice show anxiety-like behavior by aging.

PubMed

Wakabayashi, Chisato; Numakawa, Tadahiro; Odaka, Haruki; Ooshima, Yoshiko; Kiyama, Yuji; Manabe, Toshiya; Kunugi, Hiroshi; Iwakura, Yoichiro

2015-07-10

Interleukin 1 (IL-1) plays a critical role in stress responses, and its mRNA is induced in the brain by restraint stress. Previously, we reported that IL-1 receptor antagonist (IL-1Ra) knockout (KO) mice, which lacked IL-1Ra molecules that antagonize the IL-1 receptor, showed anti-depression-like behavior via adrenergic modulation at the age of 8 weeks. Here, we report that IL-1Ra KO mice display an anxiety-like phenotype that is induced spontaneously by aging in the elevated plus-maze (EPM) test. This anxiety-like phenotype was improved by the administration of diazepam. The expression of the anxiety-related molecule glucocorticoid receptor (GR) was significantly reduced in 20-week-old but not in 11-week-old IL-1Ra KO mice compared to wild-type (WT) littermates. The expression of the mineralocorticoid receptor (MR) was not altered between IL-1Ra KO mice and WT littermates at either 11 or 20 weeks old. Analysis of monoamine concentration in the hippocampus revealed that tryptophan, the serotonin metabolite 5-hydroxyindole acetic acid (5-HIAA), and the dopamine metabolite homovanillic acid (HVA) were significantly increased in 20-week-old IL-1Ra KO mice compared to littermate WT mice. These findings strongly suggest that the anxiety-like behavior observed in older mice was caused by the complicated alteration of monoamine metabolism and/or GR expression in the hippocampus. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Nociceptive Afferent Activity Alters the SI RA Neuron Response to Mechanical Skin Stimulation

PubMed Central

Favorov, O.V.; Li, Y.; Lee, J.; Quibrera, P.M.; Tommerdahl, M.

2010-01-01

Procedures that reliably evoke cutaneous pain in humans (i.e., 5–7 s skin contact with a 47–51 °C probe, intradermal algogen injection) are shown to decrease the mean spike firing rate (MFR) and degree to which the rapidly adapting (RA) neurons in areas 3b/1 of squirrel monkey primary somatosensory cortex (SI) entrain to a 25-Hz stimulus to the receptive field center (RFcenter) when stimulus amplitude is “near-threshold” (i.e., 10–50 μm). In contrast, RA neuron MFR and entrainment are either unaffected or enhanced by 47–51 °C contact or intradermal algogen injection when the amplitude of 25-Hz stimulation is 100–200 μm (suprathreshold). The results are attributed to an “activity dependence” of γ-aminobutyric acid (GABA) action on the GABAA receptors of RA neurons. The nociceptive afferent drive triggered by skin contact with a 47–51 °C probe or intradermal algogen is proposed to activate nociresponsive neurons in area 3a which, via corticocortical connections, leads to the release of GABA in areas 3b/1. It is hypothesized that GABA is hyperpolarizing/inhibitory and suppresses stimulus-evoked RA neuron MFR and entrainment whenever RA neuron activity is low (as when the RFcenter stimulus is weak/near-threshold) but is depolarizing/excitatory and augments MFR and entrainment when RA neuron activity is high (when the stimulus is strong/suprathreshold). PMID:20308203

Possible rheumatoid arthritis subtypes in terms of rheumatoid factor, depression, diagnostic delay and emotional expression: an exploratory case-control study

PubMed Central

2013-01-01

Introduction Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the pathology of rheumatoid arthritis (RA), particularly as vulnerable personality types are exposed to chronic stress. Emotions are powerful modulators of stress responses. However, little is known about whether patients with RA process emotions differently to matched controls. In this study we: 1) assessed whether the trait emotional intelligence (trait EI) scores of patients with RA differ from healthy controls at the facet level; 2) explored any subgroups in RA, in terms of trait EI and common risk factors. Methods A total of 637 patients with RA were compared to 496 controls on the trait EI Questionnaire (TEIQue). RA subgroups were explored in terms of trait EI, rheumatoid factor status (RF+/-), depression and time from onset of symptoms until diagnosis (diagnostic delay). Results The RA group rated themselves lower on Adaptability, Stress-management, Emotion management, Self-esteem, Sociability, Assertiveness, Impulsiveness and Well-being, and higher on Empathy and Relationships than healthy controls. The RF- subtype reported more time with depression (25.2 vs. 11.3 months), a longer diagnostic delay (3.0 vs. 1.7 years), and greater emotional expression (5.15 vs. 4.72), than the RF+ subtype. These differences were significant at the P <0.05 level, but not following strict Bonferroni corrections and should therefore be treated as indicative only. RF- patients with a longer diagnostic delay reported depression lasting three times longer (42.7 months), when compared to three other subtypes (11.0 to 12.7 months). Conclusions RA patients and controls differ in their emotion-related personality traits, as operationalized by trait EI. These differences may make people with RA more susceptible to chronic stress and HPA-axis dysregulation. RA may be a highly heterogeneous illness where at least two subtypes may be characterized by personality, psychiatric and immunological differences. RF- status, as well as diagnostic delay and emotional expression, may predict future risk of depression. Research on the causes of RA could benefit from a systems science approach. PMID:23517876

SCIL-STROKE (Subcutaneous Interleukin-1 Receptor Antagonist in Ischemic Stroke): A Randomized Controlled Phase 2 Trial.

PubMed

Smith, Craig J; Hulme, Sharon; Vail, Andy; Heal, Calvin; Parry-Jones, Adrian R; Scarth, Sylvia; Hopkins, Karen; Hoadley, Margaret; Allan, Stuart M; Rothwell, Nancy J; Hopkins, Stephen J; Tyrrell, Pippa J

2018-05-01

The proinflammatory cytokine IL-1 (interleukin-1) has a deleterious role in cerebral ischemia, which is attenuated by IL-1 receptor antagonist (IL-1Ra). IL-1 induces peripheral inflammatory mediators, such as interleukin-6, which are associated with worse prognosis after ischemic stroke. We investigated whether subcutaneous IL-1Ra reduces the peripheral inflammatory response in acute ischemic stroke. SCIL-STROKE (Subcutaneous Interleukin-1 Receptor Antagonist in Ischemic Stroke) was a single-center, double-blind, randomized, placebo-controlled phase 2 trial of subcutaneous IL-1Ra (100 mg administered twice daily for 3 days) in patients presenting within 5 hours of ischemic stroke onset. Randomization was stratified for baseline National Institutes of Health Stroke Scale score and thrombolysis. Measurement of plasma interleukin-6 and other peripheral inflammatory markers was undertaken at 5 time points. The primary outcome was difference in concentration of log(interleukin-6) as area under the curve to day 3. Secondary outcomes included exploratory effect of IL-1Ra on 3-month outcome with the modified Rankin Scale. We recruited 80 patients (mean age, 72 years; median National Institutes of Health Stroke Scale, 12) of whom 73% received intravenous thrombolysis with alteplase. IL-1Ra significantly reduced plasma interleukin-6 ( P <0.001) and plasma C-reactive protein ( P <0.001). IL-1Ra was well tolerated with no safety concerns. Allocation to IL-1Ra was not associated with a favorable outcome on modified Rankin Scale: odds ratio (95% confidence interval)=0.67 (0.29-1.52), P =0.34. Exploratory mediation analysis suggested that IL-1Ra improved clinical outcome by reducing inflammation, but there was a statistically significant, alternative mechanism countering this benefit. IL-1Ra reduced plasma inflammatory markers which are known to be associated with worse clinical outcome in ischemic stroke. Subcutaneous IL-1Ra is safe and well tolerated. Further experimental studies are required to investigate efficacy and possible interactions of IL-1Ra with thrombolysis. URL: http://www.clinicaltrials.gov. Unique identifier: ISRCTN74236229. © 2018 American Heart Association, Inc.

Respiratory responses of the air-breathing fish Hoplosternum littorale to hypoxia and hydrogen sulfide.

PubMed

Affonso, E G; Rantin, F T

2005-07-01

The present study analyzes the respiratory responses of the neotropical air-breathing fish Hoplosternum littorale to graded hypoxia and increased sulfide concentrations. The oxygen uptake (VO2), critical O2 tension (PcO2), respiratory (fR) and air-breathing (fRA) frequencies in response to graded hypoxia were determined for fish acclimated to 28 degrees C. H. littorale was able to maintain a constant VO2 down to a PcO2 of 50 mm Hg, below which fish became dependent on the environmental O2 even with significant increases in fR. The fRA was kept constant around 1 breath h(-1) above 50 mm Hg and increased significantly below 40 mm Hg, reaching maximum values (about 4.5 breaths h(-1)) at 10 mm Hg. The lethality to sulfide concentrations under normoxic and hypoxic conditions were also determined along with the fRA. For the normoxic fish the sulfide lethal limit was about 70 microM, while in the hypoxic ones this limit increased to 87 muM. The high sulfide tolerance of H. littorale may be attributed to the air-breathing capability, which is stimulated by this compound.

Baricitinib for the treatment of rheumatoid arthritis.

PubMed

Kubo, Satoshi; Nakayamada, Shingo; Tanaka, Yoshiya

2016-09-01

Rheumatoid arthritis (RA) is characterized by systemic synovitis causing joint destruction. With the development of biological disease-modifying anti-rheumatic drugs (bDMARDs) and combination of conventional DMARDs, clinical remission is perceived as an appropriate and realistic goal in many patients. However, bDMARDs require intravenous or subcutaneous injection and some patients fail to respond to bDMARDs or lose their primary response. Under the circumstances, targeted synthetic DMARDs (tsDMARDs), which are orally available low-molecular weight products, have been emerging. Five phase 3 trials of Baricitinib, a JAK1 and JAK2 inhibitor, have been performed and showed high clinical efficacy in patients with active RA and naïve to sDMARDs or an inadequate response to sDMARDs, MTX or bDMARDs. There was a favorable response for clinical and functional parameters in studies with placebo, MTX and adalimumab as comparator. It is also reported that safety was tolerable within the limited study period. We here review the recent progress in the development of baricitinib and its potential for the treatment of RA. Expert commentary: Although baricitinib is only one of the highly effective DMARDs that has a new mode of action, it will bring new concepts for rheumatology in the future.

Addition of the Neurokinin-1-Receptor Antagonist (RA) Aprepitant to a 5-Hydroxytryptamine-RA and Dexamethasone in the Prophylaxis of Nausea and Vomiting Due to Radiation Therapy With Concomitant Cisplatin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jahn, Franziska, E-mail: franziska.jahn@uk-halle.de; Riesner, Anica; Jahn, Patrick

Purpose: To assess, in a prospective, observational study, the safety and efficacy of the addition of the neurokinin-1-receptor antagonist (NK1-RA) aprepitant to concomitant radiochemotherapy, for the prophylaxis of radiation therapy–induced nausea and vomiting. Patients and Methods: This prospective observational study compared the antiemetic efficacy of an NK1-RA (aprepitant), a 5-hydroxytryptamine-RA, and dexamethasone (aprepitant regimen) versus a 5-hydroxytryptamine-RA and dexamethasone (control regimen) in patients receiving concomitant radiochemotherapy with cisplatin at the Department of Radiation Oncology, University Hospital Halle (Saale), Germany. The primary endpoint was complete response in the overall phase, defined as no vomiting and no use of rescue therapy in thismore » period. Results: Fifty-nine patients treated with concomitant radiochemotherapy with cisplatin were included in this study. Thirty-one patients received the aprepitant regimen and 29 the control regimen. The overall complete response rates for cycles 1 and 2 were 75.9% and 64.5% for the aprepitant group and 60.7% and 54.2% for the control group, respectively. Although a 15.2% absolute difference was reached in cycle 1, a statistical significance was not detected (P=.22). Furthermore maximum nausea was 1.58 ± 1.91 in the control group and 0.73 ± 1.79 in the aprepitant group (P=.084); for the head-and-neck subset, 2.23 ± 2.13 in the control group and 0.64 ± 1.77 in the aprepitant group, respectively (P=.03). Conclusion: This is the first study of an NK1-RA–containing antiemetic prophylaxis regimen in patients receiving concomitant radiochemotherapy. Although the primary endpoint was not obtained, the absolute difference of 10% in efficacy was reached, which is defined as clinically meaningful for patients by international guidelines groups. Randomized phase 3 studies are necessary to further define the potential role of an NK1-RA in this setting.« less

Regulation of Metastasis and DNA Damage Resistance Pathways by Transposable Elements

DTIC Science & Technology

2014-10-01

Innes AM, Boycott KM, Moreau LA, Moilanen JS, Greenberg RA: Biallelic Mutations in BRCA1 Cause a New Fanconi Anemia Subtype. Cancer Discov 2014 in...corresponding authors. Highlighted in Cancer Discovery 2013: D’Andrea AD. BRCA1: A Missing Link in the Fanconi /BRCA Pathway. 5. Tang J, Cho NW, Cui G, Manion EM

Millennials: Rendezvous with Destiny?

DTIC Science & Technology

2008-03-05

St ra te gy R es ea rc h Pr oj ec t MILLENNIALS : RENDEZVOUS WITH DESTINY? BY COLONEL FREDERICK L. FAHLBUSCH United States Air Force...AND SUBTITLE Millennials Rendezvou with Destiny? 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Frederick...PROJECT MILLENNIALS : RENDEZVOUS WITH DESTINY? by Colonel Frederick L. Fahlbusch United States Air Force

Impact of Friction Reduction Technologies on Fuel Economy for Ground Vehicles

DTIC Science & Technology

2009-08-13

UNCLAS: Dist A. Approved for public release IMPACT OF FRICTION REDUCTION TECHNOLOGIES ON FUEL ECONOMY FOR GROUND VEHICLES G. R. Fenske , R. A. Erck...PROGRAM ELEMENT NUMBER 6. AUTHOR(S) G.R. Fenske ; R.A. Erck; O.O. Ajayi; A. Masoner’ A.S. Confort 5d. PROJECT NUMBER 5e. TASK NUMBER 5f. WORK UNIT

Rheumatoid arthritis: Recent advances on its etiology, role of cytokines and pharmacotherapy.

PubMed

Alam, Javaid; Jantan, Ibrahim; Bukhari, Syed Nasir Abbas

2017-08-01

An autoimmune disease is defined as a clinical syndrome resulted from an instigation of both T cell and B cell or individually, in the absence of any present infection or any sort of distinguishable cause. Clonal deletion of auto reactive cells remains the central canon of immunology for decades, keeping the role of T cell and B cell aside, which are actually the guards to recognize the entry of foreign body. According to NIH, 23.5 million Americans are all together affected by these diseases. They are rare, but with the exception of RA. Rheumatoid arthritis is chronic and systemic autoimmune response to the multiple joints with unknown ethology, progressive disability, systemic complications, early death and high socioeconomic costs. Its ancient disease with an old history found in North American tribes since 1500 BCE, but its etiology is yet to be explored. Current conventional and biological therapies used for RA are not fulfilling the need of the patients but give only partial responses. There is a lack of consistent and liable biomarkers of prognosis therapeutic response, and toxicity. Rheumatoid arthritis is characterized by hyperplasic synovium, production of cytokines, chemokines, autoantibodies like rheumatoid factor (RF) and anticitrullinated protein antibody (ACPA), osteoclastogensis, angiogenesis and systemic consequences like cardiovascular, pulmonary, psychological, and skeletal disorders. Cytokines, a diverse group of polypeptides, play critical role in the pathogenesis of RA. Their involvement in autoimmune diseases is a rapidly growing area of biological and clinical research. Among the proinflammatory cytokines, IL-1α/β and TNF-α trigger the intracellular molecular signalling pathway responsible for the pathogenesis of RA that leads to the activation of mesenchymal cell, recruitment of innate and adaptive immune system cells, activation of synoviocytes which in term activates various mediators including tumour necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), interleukin-6 (IL-6) and interleukin-8 (IL-8), resulting in inflamed synovium, increase angiogenesis and decrease lymphangiogensis. Their current pharmacotherapy should focus on their three phases of progression i.e. prearthritis phase, transition phase and clinical phase. In this way we will be able to find a way to keep the balance between the pro and anti-inflammatory cytokines that is believe to be the dogma of pathogenesis of RA. For this we need to explore new agents, whether from synthetic or natural source to find the answers for unresolved etiology of autoimmune diseases and to provide a quality of life to the patients suffering from these diseases specifically RA. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Radiological and hydrochemical study of thermal and fresh groundwater samples of northern Euboea and Sperchios areas, Greece: insights into groundwater natural radioactivity and geology.

PubMed

Kanellopoulos, C; Mitropoulos, P; Argyraki, A

2018-04-04

A radiological and hydrochemical study has been conducted on thermal and fresh groundwater samples of northern Euboea Island and eastern central Greece. Both areas are characterized by complex geology and are renowned since antiquity for their hot springs, that are exploited for therapeutic spa purposes until today. The aim of the study was to combine radiological and hydrochemical data in order to achieve a holistic water quality assessment with insights into the geology of the study areas. All samples were characterized with respect to their major and trace ion and element composition, as well as activity concentrations of 222 Rn, 226 Ra, 228 Ra, 228 Th, and 40 K. The samples demonstrated elevated natural radioactivity and U concentrations, especially in some locations of the Kamena Vourla area, reaching 179 Bq/L 222 Rn, 2.2 Bq/L 226 Ra, 2.9 Bq/L 228 Ra, and 17 μg/L U. The estimated circulation depth of thermal groundwater ranges between 250 m in central Greece and 1240 m in north Euboea study area, whereas the calculated water residence times range between 27 and 555 years. Our data suggest the possible presence of an unknown until know U-rich plutonic rock formation in Kamena Vourla area and immiscibility of the fresh and thermal groundwaters in the studied areas.

Radionuclides as tracer for submarine groundwater discharge (SGD) research at Dapeng Bay in Southern Taiwan

NASA Astrophysics Data System (ADS)

Huang, Jun-Chen; Su, Chih-Chieh

2017-04-01

Conventionally, river is the most important source for delivering nutrients, such as nitrogen, phosphorus and silicon, and trace elements into the ocean. The issues of land-sea interaction by rivers have been long-tern concerned and studied, on contrary, the pathway and impact through submarine groundwater discharge (SGD) is still unclear and the relevant researches need to be strengthened. The research site, Dapeng Bay, is located at Pingtung County in Southern Taiwan. Dapeng Bay is an bag-shape lagoon with a sand spit serving as the single outlet of the bay. The longshore currents transport sediments which delivered by Donggang and Linbian Rivers deposited at the nearshore and eventually form the semi-enclosed shallow bay. In the Dapeng Bay, there is no river poured into the lagoon and the main sources of freshwater are rainwater, domestic wastewater and fish ponds etc. The tidal driven water exchange between lagoon and ocean is through the sand spit outlet. The purpose of this study is to evaluate the weighting and seasonal change between SGD and riverine input in the Dapeng Bay. The radium isotopes, 223Ra (11.4d), 224Ra (3.7d), 226Ra (1600y), 228Ra (5.7y), were used as tracers for assessing SGD and riverine inputs. Samples were collected by using MnO2-coated fibers for radium isotopes adsorption.

CoCoRaHS: A Community Science Program Providing Valuable Precipitation Data to Guide Decision Making

NASA Astrophysics Data System (ADS)

Robinson, D. A.; Doesken, N.

2017-12-01

CoCoRaHS is an acronym for the Community Collaborative Rain, Hail and Snow Network. It is long-running, community-based network of volunteers working together to measure and map precipitation (rain, hail and snow). Precipitation is an ideal element for public engagement because it affects everyone, it is so variable in time and space and it impacts so many things. By using a standard precipitation gauge, stressing training and education, utilizing an interactive website, and having observations undergo quality assurance, the CoCoRaHS program provides high-quality data for natural resource, education and research applications. The program currently operates in all states, Canada and the Bahamas. It originated with the Colorado Climate Center at Colorado State University in 1998 due in part to the Fort Collins flood a year prior. Upwards of 12,000 observers submit observations each day. Observations meet federal guidelines and are archived at the U.S. National Centers for Environmental Information. Because of excellent spatial coverage, data quality, practical relevance, and accessibility, CoCoRaHS observations are used by a wide variety of organizations and individuals. The U.S. National Weather Service, hydrologists, emergency managers, city utilities (water supply, storm water), insurance adjusters, the U.S. Department of Agriculture, engineers, mosquito control commissions, ranchers and farmers, outdoor and recreation interests, teachers and students are just some examples of those who use CoCoRaHS data in making well-informed, meaningful decisions. Some examples of community applications and the science utility of CoCoRaHS observations include storm warnings, water supply and demand forecasts, disaster declarations (drought, winter storm, etc.), drought and food production assessments, calibration/validation of remote sensing, infrastructure evaluation and potential redesign (ice and snow loading, bridge, storm and sewer design), recreation planning, and environmental education. This presentation will demonstrate a growing trust in volunteered data and that the CoCoRaHS program succeeds in striking a balance between education, local interest, community service and service to science.

Low expression of CD39 on regulatory T cells as a biomarker for resistance to methotrexate therapy in rheumatoid arthritis

PubMed Central

Peres, Raphael Sanches; Liew, Foo Y.; Talbot, Jhimmy; Carregaro, Vanessa; Oliveira, Rene D.; Almeida, Sergio L.; França, Rafael F. O.; Donate, Paula B.; Pinto, Larissa G.; Ferreira, Flavia I. S.; Costa, Diego L.; Demarque, Daniel P.; Gouvea, Dayana Rubio; Lopes, Norberto P.; Queiroz, Regina Helena C.; Silva, Joao Santana; Figueiredo, Florencio; Alves-Filho, Jose Carlos; Cunha, Thiago M.; Ferreira, Sérgio H.; Louzada-Junior, Paulo; Cunha, Fernando Q.

2015-01-01

Rheumatoid arthritis (RA) is an inflammatory autoimmune disease characterized by joint destruction and severe morbidity. Methotrexate (MTX) is the standard first-line therapy of RA. However, about 40% of RA patients are unresponsive to MTX treatment. Regulatory T cells (Tregs, CD4+CD25+FoxP3+) are thought to play an important role in attenuating RA. To investigate the role of Tregs in MTX resistance, we recruited 122 RA patients (53 responsive, R-MTX; 69 unresponsive, UR-MTX) and 33 healthy controls. Three months after MTX treatment, R-MTX but not UR-MTX showed higher frequency of peripheral blood CD39+CD4+CD25+FoxP3+ Tregs than the healthy controls. Tregs produce adenosine (ADO) through ATP degradation by sequential actions of two cell surface ectonucleotidases: CD39 and CD73. Tregs from UR-MTX expressed a lower density of CD39, produced less ADO, and had reduced suppressive activity than Tregs from R-MTX. In a prospective study, before MTX treatment, UR-MTX expressed a lower density of CD39 on Tregs than those of R-MTX or control (P < 0.01). In a murine model of arthritis, CD39 blockade reversed the antiarthritic effects of MTX treatment. Our results demonstrate that MTX unresponsiveness in RA is associated with low expression of CD39 on Tregs and the decreased suppressive activity of these cells through reduced ADO production. Our findings thus provide hitherto unrecognized mechanism of immune regulation in RA and on mode of action of MTX. Furthermore, our data suggest that low expression of CD39 on Tregs could be a noninvasive biomarker for identifying MTX-resistant RA patients. PMID:25675517

Low expression of CD39 on regulatory T cells as a biomarker for resistance to methotrexate therapy in rheumatoid arthritis.

PubMed

Peres, Raphael Sanches; Liew, Foo Y; Talbot, Jhimmy; Carregaro, Vanessa; Oliveira, Rene D; Almeida, Sergio L; França, Rafael F O; Donate, Paula B; Pinto, Larissa G; Ferreira, Flavia I S; Costa, Diego L; Demarque, Daniel P; Gouvea, Dayana Rubio; Lopes, Norberto P; Queiroz, Regina Helena C; Silva, Joao Santana; Figueiredo, Florencio; Alves-Filho, Jose Carlos; Cunha, Thiago M; Ferreira, Sérgio H; Louzada-Junior, Paulo; Cunha, Fernando Q

2015-02-24

Rheumatoid arthritis (RA) is an inflammatory autoimmune disease characterized by joint destruction and severe morbidity. Methotrexate (MTX) is the standard first-line therapy of RA. However, about 40% of RA patients are unresponsive to MTX treatment. Regulatory T cells (Tregs, CD4(+)CD25(+)FoxP3(+)) are thought to play an important role in attenuating RA. To investigate the role of Tregs in MTX resistance, we recruited 122 RA patients (53 responsive, R-MTX; 69 unresponsive, UR-MTX) and 33 healthy controls. Three months after MTX treatment, R-MTX but not UR-MTX showed higher frequency of peripheral blood CD39(+)CD4(+)CD25(+)FoxP3(+) Tregs than the healthy controls. Tregs produce adenosine (ADO) through ATP degradation by sequential actions of two cell surface ectonucleotidases: CD39 and CD73. Tregs from UR-MTX expressed a lower density of CD39, produced less ADO, and had reduced suppressive activity than Tregs from R-MTX. In a prospective study, before MTX treatment, UR-MTX expressed a lower density of CD39 on Tregs than those of R-MTX or control (P < 0.01). In a murine model of arthritis, CD39 blockade reversed the antiarthritic effects of MTX treatment. Our results demonstrate that MTX unresponsiveness in RA is associated with low expression of CD39 on Tregs and the decreased suppressive activity of these cells through reduced ADO production. Our findings thus provide hitherto unrecognized mechanism of immune regulation in RA and on mode of action of MTX. Furthermore, our data suggest that low expression of CD39 on Tregs could be a noninvasive biomarker for identifying MTX-resistant RA patients.

Updated consensus statement on the use of rituximab in patients with rheumatoid arthritis

PubMed Central

Buch, Maya H; Smolen, Josef S; Betteridge, Neil; Breedveld, Ferdinand C; Burmester, Gerd; Dörner, Thomas; Ferraccioli, Gianfranco; Gottenberg, Jacques-Eric; Isaacs, John; Kvien, Tore K; Mariette, Xavier; Martin-Mola, Emilio; Pavelka, Karel; Tak, Paul P; van der Heijde, Desiree; van Vollenhoven, Ronald F; Emery, Paul

2011-01-01

Background Since initial approval for the treatment of rheumatoid arthritis (RA), rituximab has been evaluated in clinical trials involving various populations with RA. Information has also been gathered from registries. This report therefore updates the 2007 consensus document on the use of rituximab in the treatment of RA. Methods Preparation of this new document involved many international experts experienced in the treatment of RA. Following a meeting to agree upon the core agenda, a systematic literature review was undertaken to identify all relevant data. Data were then interrogated by a drafting committee, with subsequent review and discussion by a wider expert committee leading to the formulation of an updated consensus statement. These committees also included patients with RA. Results The new statement covers wide-ranging issues including the use of rituximab in earlier RA and impact on structural progression, and aspects particularly pertinent to rituximab such as co-medication, optimal dosage regimens, repeat treatment cycles and how to manage non-response. Biological therapy following rituximab usage is also addressed, and safety concerns including appropriate screening for hepatitis, immunoglobulin levels and infection risk. This consensus statement will support clinicians and inform patients when using B-cell depletion in the management of RA, providing up-to-date information and highlighting areas for further research. Conclusion New therapeutic strategies and treatment options for RA, a chronic destructive and disabling disease, have expanded over recent years. These have been summarised in general strategic suggestions and specific management recommendations, emphasising the importance of expedient disease-modifying antirheumatic drug implementation and tight disease control. This consensus statement is in line with these fundamental principles of management. PMID:21378402

Association of rheumatoid arthritis with allergic diseases: A nationwide population-based cohort study.

PubMed

Lai, Ning-Sheng; Tsai, Tzung-Yi; Koo, Malcolm; Lu, Ming-Chi

2015-01-01

Low-grade inflammation conditions, e.g., type 2 diabetes, have been shown to be associated with an increased risk of rheumatoid arthritis (RA). However, the association between other chronic inflammatory conditions, e.g., asthma, allergic rhinitis, and atopic dermatitis, is still unclear. To investigate the risk of RA in patients with allergic diseases, including asthma, allergic rhinitis, and atopic dermatitis, by using a nationwide health claims database. The Taiwan National Health Insurance Research Database was used to assemble a cohort of 170,570 patients ages 20 years old and older diagnosed with allergic diseases, including asthma, allergic rhinitis, or atopic dermatitis. A comparison cohort of 170,238 patients was constructed from the same data base, with frequency matching for sex, 10-year age group, and year of insurance enrollment. Cox proportional hazards regression analyses were conducted to assess the association between the allergic diseases and incident RA. Asthma (adjusted hazard ratio [AHR] 1.67, [95% confidence interval {CI}], 1.32-2.62) and allergic rhinitis (AHR 1.62 [95% CI, 1.33-1.98]) were significantly associated with the incident RA. These associations remained significant even after excluding patients who had concurrent diagnoses of asthma and allergic rhinitis. Patients with more than one allergic disease had an increased risk of developing RA (AHR 1.98 [95% CI, 1.50-2.62]). Subgroup analysis further indicated that middle-aged and elderly female patients with more than one allergic disease exhibited a high risk of developing RA. Significant associations between common allergic diseases and incident RA was found in this population-based cohort study. Our findings provided support to the hypothesis that allergic diseases and RA might share a similar underlying etiologic pathway related to chronic inflammatory responses.

Pro-apoptotic signaling induced by Retinoic acid and dsRNA is under the control of Interferon Regulatory Factor-3 in breast cancer cells.

PubMed

Bernardo, Ana R; Cosgaya, José M; Aranda, Ana; Jiménez-Lara, Ana M

2017-07-01

Breast cancer is one of the most lethal malignancies for women. Retinoic acid (RA) and double-stranded RNA (dsRNA) are considered signaling molecules with potential anticancer activity. RA, co-administered with the dsRNA mimic polyinosinic-polycytidylic acid (poly(I:C)), synergizes to induce a TRAIL (Tumor-Necrosis-Factor Related Apoptosis-Inducing Ligand)- dependent apoptotic program in breast cancer cells. Here, we report that RA/poly(I:C) co-treatment, synergically, induce the activation of Interferon Regulatory Factor-3 (IRF3) in breast cancer cells. IRF3 activation is mediated by a member of the pathogen recognition receptors, Toll-like receptor-3 (TLR3), since its depletion abrogates IRF3 activation by RA/poly(I:C) co-treatment. Besides induction of TRAIL, apoptosis induced by RA/poly(I:C) correlates with the increased expression of pro-apoptotic TRAIL receptors, TRAIL-R1/2, and the inhibition of the antagonistic receptors TRAIL-R3/4. IRF3 plays an important role in RA/poly(I:C)-induced apoptosis since IRF3 depletion suppresses caspase-8 and caspase-3 activation, TRAIL expression upregulation and apoptosis. Interestingly, RA/poly(I:C) combination synergizes to induce a bioactive autocrine/paracrine loop of type-I Interferons (IFNs) which is ultimately responsible for TRAIL and TRAIL-R1/2 expression upregulation, while inhibition of TRAIL-R3/4 expression is type-I IFN-independent. Our results highlight the importance of IRF3 and type-I IFNs signaling for the pro-apoptotic effects induced by RA and synthetic dsRNA in breast cancer cells.

Retinoic Acid Signaling Is Essential for Valvulogenesis by Affecting Endocardial Cushions Formation in Zebrafish Embryos.

PubMed

Li, Junbo; Yue, Yunyun; Zhao, Qingshun

2016-02-01

Retinoic acid (RA) plays important roles in many stages of heart morphogenesis. Zebrafish embryos treated with exogenous RA display defective atrio-ventricular canal (AVC) specification. However, whether endogenous RA signaling takes part in cardiac valve formation remains unknown. Herein, we investigated the role of RA signaling in cardiac valve development by knocking down aldh1a2, the gene encoding an enzyme that is mainly responsible for RA synthesis during early development, in zebrafish embryos. The results showed that partially knocking down aldh1a2 caused defective formation of primitive cardiac valve leaflets at 108 hpf (hour post-fertilization). Inhibiting endogenous RA signaling by 4-diethylaminobenzal-dehyde revealed that 16-26 hpf was a key time window when RA signaling affects the valvulogenesis. The aldh1a2 morphants had defective formation of endocardial cushion (EC) at 76 hpf though they had almost normal hemodynamics and cardiac chamber specification at early development. Examining the expression patterns of AVC marker genes including bmp4, bmp2b, nppa, notch1b, and has2, we found the morphants displayed abnormal development of endocardial AVC but almost normal development of myocardial AVC at 50 hpf. Being consistent with the reduced expression of notch1b in endocardial AVC, the VE-cadherin gene cdh5, the downstream gene of Notch signaling, was ectopically expressed in AVC of aldh1a2 morphants at 50 hpf, and overexpression of cdh5 greatly affected the formation of EC in the embryos at 76 hpf. Taken together, our results suggest that RA signaling plays essential roles in zebrafish cardiac valvulogenesis.

A Polysaccharide Virulence Factor from Aspergillus fumigatus Elicits Anti-inflammatory Effects through Induction of Interleukin-1 Receptor Antagonist

PubMed Central

Gresnigt, Mark S.; Bozza, Silvia; Becker, Katharina L.; Joosten, Leo A. B.; Abdollahi-Roodsaz, Shahla; van der Berg, Wim B.; Dinarello, Charles A.; Netea, Mihai G.; Fontaine, Thierry; De Luca, Antonella; Moretti, Silvia; Romani, Luigina; Latge, Jean-Paul; van de Veerdonk, Frank L.

2014-01-01

The galactosaminogalactan (GAG) is a cell wall component of Aspergillus fumigatus that has potent anti-inflammatory effects in mice. However, the mechanisms responsible for the anti-inflammatory property of GAG remain to be elucidated. In the present study we used in vitro PBMC stimulation assays to demonstrate, that GAG inhibits proinflammatory T-helper (Th)1 and Th17 cytokine production in human PBMCs by inducing Interleukin-1 receptor antagonist (IL-1Ra), a potent anti-inflammatory cytokine that blocks IL-1 signalling. GAG cannot suppress human T-helper cytokine production in the presence of neutralizing antibodies against IL-1Ra. In a mouse model of invasive aspergillosis, GAG induces IL-1Ra in vivo, and the increased susceptibility to invasive aspergillosis in the presence of GAG in wild type mice is not observed in mice deficient for IL-1Ra. Additionally, we demonstrate that the capacity of GAG to induce IL-1Ra could also be used for treatment of inflammatory diseases, as GAG was able to reduce severity of an experimental model of allergic aspergillosis, and in a murine DSS-induced colitis model. In the setting of invasive aspergillosis, GAG has a significant immunomodulatory function by inducing IL-1Ra and notably IL-1Ra knockout mice are completely protected to invasive pulmonary aspergillosis. This opens new treatment strategies that target IL-1Ra in the setting of acute invasive fungal infection. However, the observation that GAG can also protect mice from allergy and colitis makes GAG or a derivative structure of GAG a potential treatment compound for IL-1 driven inflammatory diseases. PMID:24603878

Genetics of Rheumatoid Arthritis — A Comprehensive Review

PubMed Central

Kurkó, Júlia; Besenyei, Timea; Laki, Judit; Glant, Tibor T.; Mikecz, Katalin

2013-01-01

The “Bermuda triangle” of genetics, environment and autoimmunity is involved in the pathogenesis of rheumatoid arthritis (RA). Various aspects of genetic contribution to the etiology, pathogenesis and outcome of RA are discussed in this review. The heritability of RA has been estimated to be about 60 %, while the contribution of HLA to heritability has been estimated to be 11–37 %. Apart from known shared epitope (SE) alleles, such as HLA-DRB1*01 and DRB1*04, other HLA alleles, such as HLA-DRB1*13 and DRB1*15 have been linked to RA susceptibility. A novel SE classification divides SE alleles into S1, S2, S3P and S3D groups, where primarily S2 and S3P groups have been associated with predisposition to seropositive RA. The most relevant non-HLA gene single nucleotide polymorphisms (SNPs) associated with RA include PTPN22, IL23R, TRAF1, CTLA4, IRF5, STAT4, CCR6, PADI4. Large genome-wide association studies (GWAS) have identified more than 30 loci involved in RA pathogenesis. HLA and some non-HLA genes may differentiate between anti-citrullinated protein antibody (ACPA) seropositive and seronegative RA. Genetic susceptibility has also been associated with environmental factors, primarily smoking. Some GWAS studies carried out in rodent models of arthritis have confirmed the role of human genes. For example, in the collagen-induced (CIA) and proteoglycan-induced arthritis (PgIA) models, two important loci — Pgia26/Cia5 and Pgia2/Cia2/Cia3, corresponding the human PTPN22/CD2 and TRAF1/C5 loci, respectively — have been identified. Finally, pharmacogenomics identified SNPs or multiple genetic signatures that may be associated with responses to traditional disease-modifying drugs and biologics. PMID:23288628

Genetics of rheumatoid arthritis - a comprehensive review.

PubMed

Kurkó, Júlia; Besenyei, Timea; Laki, Judit; Glant, Tibor T; Mikecz, Katalin; Szekanecz, Zoltán

2013-10-01

The "Bermuda triangle" of genetics, environment and autoimmunity is involved in the pathogenesis of rheumatoid arthritis (RA). Various aspects of genetic contribution to the etiology, pathogenesis and outcome of RA are discussed in this review. The heritability of RA has been estimated to be about 60 %, while the contribution of HLA to heritability has been estimated to be 11-37 %. Apart from known shared epitope (SE) alleles, such as HLA-DRB1*01 and DRB1*04, other HLA alleles, such as HLA-DRB1*13 and DRB1*15 have been linked to RA susceptibility. A novel SE classification divides SE alleles into S1, S2, S3P and S3D groups, where primarily S2 and S3P groups have been associated with predisposition to seropositive RA. The most relevant non-HLA gene single nucleotide polymorphisms (SNPs) associated with RA include PTPN22, IL23R, TRAF1, CTLA4, IRF5, STAT4, CCR6, PADI4. Large genome-wide association studies (GWAS) have identified more than 30 loci involved in RA pathogenesis. HLA and some non-HLA genes may differentiate between anti-citrullinated protein antibody (ACPA) seropositive and seronegative RA. Genetic susceptibility has also been associated with environmental factors, primarily smoking. Some GWAS studies carried out in rodent models of arthritis have confirmed the role of human genes. For example, in the collagen-induced (CIA) and proteoglycan-induced arthritis (PgIA) models, two important loci - Pgia26/Cia5 and Pgia2/Cia2/Cia3, corresponding the human PTPN22/CD2 and TRAF1/C5 loci, respectively - have been identified. Finally, pharmacogenomics identified SNPs or multiple genetic signatures that may be associated with responses to traditional disease-modifying drugs and biologics.

[Correlation of DNase I in serum and synovial fluid with inflammatory activity in patients with rheumatoid arthritis].

PubMed

Xu, Xia-Yu; Yang, Wen-Fang; Zhang, Si-Gong; Zhao, Qin; Linag, Li-Jun; Wang, Xin; Shen, Hai-Li

2016-08-20

To investigate the potential role of deoxyribonuclease I (DNase I) in the pathogenesis of rheumatoid arthritis (RA). DNase I activity was measured by radial enzyme-diffusion method in serum samples from 83 RA patients and 60 healthy volunteers and in the synovial fluid (SF) from 27 RA patients and 38 patients with other inflammatory arthritis. SF cfDNA level was measured with Pico Green Kit, and the correlation among DNase I activity, cfDNA level and clinical parameters of RA patients was analyzed. Serum DNase I activity was significantly lower in RA patients than in the healthy control subjects (0.3065∓0.1436 vs 0.4289∓0.1976 U/mL, P<0.001), and was negatively correlated with ESR (r=-0.2862, P=0.0122), CRP (r=-0.2790, P=0.0184) and neutrophil cell counts (r=-0.287, P=0.011). SF DNase I activity was almost negative in patients with RA, ankylosing spondylitis (AS) and gouty arthritis (GA). SF cfDNA level in RA patients was significantly higher than that in patients with osteoarthritis (100.81∓142.98 vs 18.98∓31.40 µg/mL, P=0.002), but similar to that in patients with AS (45.85∓47.67 µg/mL, P=0.428) and GA (162.95∓97.49 µg/mL, P=0.132). In patients with inflammatory arthritis, SF cfDNA level was positively correlated with ESR (r=0.4106, P=0.0116) and CRP (r=0.5747, P=0.0002). Impairment of DNase I activity may be responsible for the enhanced NETs generation and plays a role in the pathogenesis of RA.

Smoking is associated with an increased risk of developing ACPA-positive but not ACPA-negative rheumatoid arthritis in Asian populations: evidence from the Malaysian MyEIRA case-control study.

PubMed

Yahya, Abqariyah; Bengtsson, Camilla; Lai, Too Chun; Larsson, Per T; Mustafa, Amal Nasir; Abdullah, Nor Aini; Muhamad, Norasiah; Hussein, Heselynn; Klareskog, Lars; Alfredsson, Lars; Murad, Shahnaz

2012-08-01

We investigated the association between cigarette smoking and the risk of developing rheumatoid arthritis (RA) in the Malaysian population. A total of 1,056 RA patients and 1,416 matched controls aged 18-70 years within a defined area of Peninsular Malaysia were evaluated in a case-control study between August 2005 and December 2009. A case was defined as a person with early diagnosed RA using the 1987 American College of Rheumatology criteria for RA. Controls were randomly selected matched for sex, age, and residential area. Cases and controls answered a questionnaire on a broad range of issues, including lifestyle factors and smoking habits wherein current and former smoking was classified as ever-smoking. The presence of anti-citrullinated peptide antibodies (ACPA) was determined for cases and controls. We found that ever-smokers had an increased risk of developing ACPA-positive RA [odds ratio (OR) = 4.1, 95% confidence interval (CI) 1.9-9.2] but not ACPA-negative RA (OR = 0.7, 95% CI 0.3-2.0), compared with never-smokers. A significant dose-response relationship between cumulative dose of smoking and risk of ACPA-positive RA was observed (<20 pack-years OR = 3.3, 95% CI 1.1-9.8; at least 20 pack-years OR = 5.2, 95% CI 1.6-17.6). Hence, smoking is associated with an increased risk of ACPA-positive RA in the Malaysian population, in which the genetic context is similar to several other Asian countries.

Association Between Genetic Variation in FOXO3 and Reductions in Inflammation and Disease Activity in Inflammatory Polyarthritis

PubMed Central

Viatte, Sebastien; Lee, James C.; Fu, Bo; Espéli, Marion; Lunt, Mark; De Wolf, Jack N. E.; Wheeler, Lily; Reynolds, John A.; Castelino, Madhura; Symmons, Deborah P. M.; Lyons, Paul A.

2016-01-01

Objective Genetic variation in FOXO3 (tagged by rs12212067) has been associated with a milder course of rheumatoid arthritis (RA) and shown to limit monocyte‐driven inflammation through a transforming growth factor β1–dependent pathway. This genetic association, however, has not been consistently observed in other RA cohorts. We sought to clarify the contribution of FOXO3 to prognosis in RA by combining detailed analysis of nonradiographic disease severity measures with an in vivo model of arthritis. Methods Collagen‐induced arthritis, the most commonly used mouse model of RA, was used to assess how Foxo3 contributes to arthritis severity. Using clinical, serologic, and biochemical methods, the arthritis that developed in mice carrying a loss‐of‐function mutation in Foxo3 was compared with that which occurred in littermate controls. The association of rs12212067 with nonradiographic measures of RA severity, including the C‐reactive protein level, the swollen joint count, the tender joint count, the Disease Activity Score in 28 joints, and the Health Assessment Questionnaire score, were modeled longitudinally in a large prospective cohort of patients with early RA. Results Loss of Foxo3 function resulted in more severe arthritis in vivo (both clinically and histologically) and was associated with higher titers of anticollagen antibodies and interleukin‐6 in the blood. Similarly, rs12212067 (a single‐nucleotide polymorphism that increases FOXO3 transcription) was associated with reduced inflammation, both biochemically and clinically, and with lower RA activity scores. Conclusion Consistent with its known role in restraining inflammatory responses, FOXO3 limits the severity of in vivo arthritis and, through genetic variation that increases its transcription, is associated with reduced inflammation and disease activity in RA patients, effects that result in less radiographic damage. PMID:27214848

Parasite-specific IL-17-type cytokine responses and soluble IL-17 receptor levels in Alveolar Echinococcosis patients.

PubMed

Lechner, Christian J; Grüner, Beate; Huang, Xiangsheng; Hoffmann, Wolfgang H; Kern, Peter; Soboslay, Peter T

2012-01-01

Alveolar Echinococcosis (AE) caused by the cestode Echinococcus multilocularis, is a severe helminth infection of man, where unrestricted parasite growth will ultimately result in organ failure and fatality. The tissue-infiltrative growth of the larval metacestode and the limited efficacy of available drugs complicate successful intervention in AE; patients often need life-long medication, and if possible, surgical resection of affected tissues and organs. Resistance to AE has been reported, but the determinants which confer protection are not known. ln this study, we analyzed in patients at distinct stages of Alveolar Echirococcosis, that is cured, stable and progressive AE, as well as in infection-free controls, the cellular production and plasma levels of pro-inflammatory cytokines lL-17A, lL-17B, lL-17F and their soluble receptors lL-17RA (slL-17RA) and IL-17RB (sIL-17RB). Significantly elevated levels of IL-17B and slL-17RB were observed, whilst lL-17F and slL-17RA were reduced in patients with AE. Similarly, the cellular production of lL-17F and slL-L7RA in response to E. multilocularis antigens was low in AE patients, while levels of slL-17RB were highly enhanced. These observations suggest immune-modulating properties of E. multitocularis on lL-17 cytokine-mediated pro-inflammatory immune responses; this may facilitate the tissue infiltrative growth of the parasite and its persistence in the human host.

Both retinoic-acid-receptor- and retinoid-X-receptor-dependent signalling pathways mediate the induction of the brown-adipose-tissue-uncoupling-protein-1 gene by retinoids.

PubMed Central

Alvarez, R; Checa, M; Brun, S; Viñas, O; Mampel, T; Iglesias, R; Giralt, M; Villarroya, F

2000-01-01

The intracellular pathways and receptors mediating the effects of retinoic acid (RA) on the brown-fat-uncoupling-protein-1 gene (ucp-1) have been analysed. RA activates transcription of ucp-1 and the RA receptor (RAR) is known to be involved in this effect. However, co-transfection of an expression vector for retinoid-X receptor (RXR) increases the action of 9-cis RA but not the effects of all-trans RA on the ucp-1 promoter in brown adipocytes. Either RAR-specific ¿p-[(E)-2-(5,6,7,8,-tetrahydro-5,5,8, 8-tetramethyl-2-naphthalenyl)-1-propenyl]benzoic acid¿ or RXR-specific [isopropyl-(E,E)-(R,S)-11-methoxy-3,7, 11-trimethyldodeca-2,4-dienoate, or methoprene] synthetic compounds increase the expression of UCP-1 mRNA and the activity of chloramphenicol acetyltransferase expression vectors driven by the ucp-1 promoter. The RXR-mediated action of 9-cis RA requires the upstream enhancer region at -2469/-2318 in ucp-1. During brown-adipocyte differentiation RXRalpha and RXRgamma mRNA expression is induced in parallel with UCP-1 mRNA, whereas the mRNA for the three RAR subtypes, alpha, beta and gamma, decreases. Co-transfection of murine expression vectors for the different RAR and RXR subtypes indicates that RARalpha and RARbeta as well as RXRalpha are the major retinoid-receptor subtypes capable of mediating the responsiveness of ucp-1 to retinoids. It is concluded that the effects of retinoids on ucp-1 transcription involve both RAR- and RXR-dependent signalling pathways. The responsiveness of brown adipose tissue to retinoids in vivo relies on a complex combination of the capacity of RAR and RXR subtypes to mediate ucp-1 induction and their distinct expression in the differentiated brown adipocyte. PMID:10600643

Validity and measurement precision of the PROMIS physical function item bank and a content validity-driven 20-item short form in rheumatoid arthritis compared with traditional measures.

PubMed

Oude Voshaar, Martijn A H; Ten Klooster, Peter M; Glas, Cees A W; Vonkeman, Harald E; Taal, Erik; Krishnan, Eswar; Bernelot Moens, Hein J; Boers, Maarten; Terwee, Caroline B; van Riel, Piet L C M; van de Laar, Mart A F J

2015-12-01

To evaluate the content validity and measurement properties of the Patient-Reported Outcome Measurement Information System (PROMIS) physical function item bank and a 20-item short form in patients with RA in comparison with the HAQ disability index (HAQ-DI) and 36-item Short Form Health Survey (SF-36) physical functioning scale (PF-10). The content validity of the instruments was evaluated by linking their items to the International Classification of Functioning, Disability and Health (ICF) core set for RA. The measures were administered to 690 RA patients enrolled in the Dutch Rheumatoid Arthritis Monitoring registry. Measurement precision was evaluated using item response theory methods and construct validity was evaluated by correlating physical function scores with other clinical and patient-reported outcome measures. All 207 health concepts identified in the physical function measures referred to activities that are featured in the ICF. Twenty-three of 26 ICF RA core set domains are featured in the full PROMIS physical function item bank compared with 13 and 8 for the HAQ-DI and PF-10, respectively. As hypothesized, all three physical function instruments were highly intercorrelated (r 0.74-0.84), moderately correlated with disease activity measures (r 0.44-0.63) and weakly correlated with age (rs 0.07-0.14). Item response theory-based analysis revealed that a 20-item PROMIS physical function short form covered a wider range of physical function levels than the HAQ-DI or PF-10. The PROMIS physical function item bank demonstrated excellent measurement properties in RA. A content-driven 20-item short form may be a useful tool for assessing physical function in RA. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Prenatal caffeine exposure induced a lower level of fetal blood leptin mainly via placental mechanism

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wu, Yi-meng; Luo, Han-wen; Kou, Hao

It's known that blood leptin level is reduced in intrauterine growth retardation (IUGR) fetus, and placental leptin is the major source of fetal blood leptin. This study aimed to investigate the decreased fetal blood leptin level by prenatal caffeine exposure (PCE) and its underlying placental mechanisms. Pregnant Wistar rats were intragastrically administered caffeine (30–120 mg/kg day) from gestational day 9 to 20. The level of fetal serum leptin and the expression of placental leptin-related genes were analyzed. Furthermore, we investigated the molecular mechanism of the reduced placental leptin's expression by treatment with caffeine (0.8–20 μM) in the BeWo cells. Inmore » vivo, PCE significantly decreased fetal serum leptin level in caffeine dose-dependent manner. Meanwhile, placental mRNA expression of adenosine A2a receptor (Adora2a), cAMP-response element binding protein (CREB), a short-type leptin receptor (Ob-Ra) and leptin was reduced in the PCE groups. In vitro, caffeine significantly decreased the mRNA expression of leptin, CREB and ADORA2A in concentration and time-dependent manners. The addition of ADORA2A agonist or adenylyl cyclase (AC) agonist reversed the inhibition of leptin expression induced by caffeine. PCE induced a lower level of fetal blood leptin, which the primary mechanism is that caffeine inhibited antagonized Adora2a and AC activities to decreased cAMP synthesis, thus inhibited the expression of the transcription factor CREB and target gene leptin in the placenta. Meantime, the reduced transportation of maternal leptin by placental Ob-Ra also contributed to the reduced fetal blood leptin. Together, PCE decreased fetal blood leptin mainly via reducing the expression and transportation of leptin in the placenta. - Highlights: • Caffeine reduced fetal blood leptin level. • Caffeine inhibited placental leptin production and transport. • Caffeine down-regulated placental leptin expression via antagonizing ADORA2. • Caffeine inhibited placental leptin transport via decreased OB-Ra expression.« less

Targeted delivery of human iPS-ECs overexpressing IL-8 receptors inhibits neointimal and inflammatory responses to vascular injury in the rat.

PubMed

Giordano, Samantha; Zhao, Xiangmin; Xing, Daisy; Hage, Fadi; Oparil, Suzanne; Cooke, John P; Lee, Jieun; Nakayama, Karina H; Huang, Ngan F; Chen, Yiu-Fai

2016-03-15

Interleukin-8 (IL8) is highly expressed by injured arteries in a variety of diseases and is a chemoattractant for neutrophils which express IL8 receptors IL8RA and RB (IL8RA/B) on their membranes. Neutrophils interact with the damaged endothelium and initiate an inflammatory cascade at the site of injury. We have generated a novel translational targeted cell therapy for acute vascular injury using adenoviral vectors to overexpress IL8RA/B and green fluorescent protein (GFP) on the surface of endothelial cells (ECs) derived from human induced pluripotent stem cells (HiPS-IL8RA/B-ECs). We hypothesize that HiPS-IL8RA/B-ECs transfused intravenously into rats with balloon injury of the carotid artery will target to the injured site and compete with neutrophils, thus inhibiting inflammation and neointima formation. Young adult male Sprague-Dawley rats underwent balloon injury of the right carotid artery and received intravenous transfusion of saline vehicle, 1.5 × 10(6) HiPS-ECs, 1.5 × 10(6) HiPS-Null-ECs, or 1.5 × 10(6) HiPS-IL8RA/B-ECs immediately after endoluminal injury. Tissue distribution of HiPS-IL8RA/B-ECs was analyzed by a novel GFP DNA qPCR method. Cytokine and chemokine expression and leukocyte infiltration were measured in injured and uninjured arteries at 24 h postinjury by ELISA and immunohistochemistry, respectively. Neointimal, medial areas, and reendothelialization were measured 14 days postinjury. HiPS-IL8RA/B-ECs homed to injured arteries, inhibited inflammatory mediator expression and inflammatory cell infiltration, accelerated reendothelialization, and attenuated neointima formation after endoluminal injury while control HiPS-ECs and HiPS-Null-ECs did not. HiPS-IL8RA/B-ECs transfused into rats with endoluminal carotid artery injury target to the injured artery and provide a novel strategy to treat vascular injury.

Targeted delivery of human iPS-ECs overexpressing IL-8 receptors inhibits neointimal and inflammatory responses to vascular injury in the rat

PubMed Central

Giordano, Samantha; Zhao, Xiangmin; Xing, Daisy; Hage, Fadi; Oparil, Suzanne; Cooke, John P.; Lee, Jieun; Nakayama, Karina H.; Huang, Ngan F.

2016-01-01

Interleukin-8 (IL8) is highly expressed by injured arteries in a variety of diseases and is a chemoattractant for neutrophils which express IL8 receptors IL8RA and RB (IL8RA/B) on their membranes. Neutrophils interact with the damaged endothelium and initiate an inflammatory cascade at the site of injury. We have generated a novel translational targeted cell therapy for acute vascular injury using adenoviral vectors to overexpress IL8RA/B and green fluorescent protein (GFP) on the surface of endothelial cells (ECs) derived from human induced pluripotent stem cells (HiPS-IL8RA/B-ECs). We hypothesize that HiPS-IL8RA/B-ECs transfused intravenously into rats with balloon injury of the carotid artery will target to the injured site and compete with neutrophils, thus inhibiting inflammation and neointima formation. Young adult male Sprague-Dawley rats underwent balloon injury of the right carotid artery and received intravenous transfusion of saline vehicle, 1.5 × 106 HiPS-ECs, 1.5 × 106 HiPS-Null-ECs, or 1.5 × 106 HiPS-IL8RA/B-ECs immediately after endoluminal injury. Tissue distribution of HiPS-IL8RA/B-ECs was analyzed by a novel GFP DNA qPCR method. Cytokine and chemokine expression and leukocyte infiltration were measured in injured and uninjured arteries at 24 h postinjury by ELISA and immunohistochemistry, respectively. Neointimal, medial areas, and reendothelialization were measured 14 days postinjury. HiPS-IL8RA/B-ECs homed to injured arteries, inhibited inflammatory mediator expression and inflammatory cell infiltration, accelerated reendothelialization, and attenuated neointima formation after endoluminal injury while control HiPS-ECs and HiPS-Null-ECs did not. HiPS-IL8RA/B-ECs transfused into rats with endoluminal carotid artery injury target to the injured artery and provide a novel strategy to treat vascular injury. PMID:26801304

Natural radioactivity in soils of the state of Rio de Janeiro (Brazil): Radiological characterization and relationships to geological formation, soil types and soil properties.

PubMed

Ribeiro, F C A; Silva, J I R; Lima, E S A; do Amaral Sobrinho, N M B; Perez, D V; Lauria, D C

2018-02-01

Located in the south-western part of Brazil, the state of Rio de Janeiro is geotectonically contained within a complex structural province that resulted in the amalgamation of the Western Gondwana Paleocontinent. To undertake an extensive radiological characterization of this complex geological province and investigate the influence of bedrock, soil type and soil chemical-physical characteristics on natural radionuclide levels in soils, 259 surface soil samples were collected that encompassed the main soil types and geological formations throughout the state. Gamma spectrometry analysis of the samples resulted in median values of 114 Bq.kg -1 for 40 K, 32 Bq.kg -1 for 226 Ra and 74 Bq.kg -1 for 228 Ra. The median value for 226 Ra was similar to the world median value for soils, the 40 K value was well below the worldwide value, and that for 228 Ra exceeded the world median value. The intense weathering caused by the high rainfall rates and high temperatures may be responsible for the low levels of 40 K in the soils, of which the strongly acidic and clayey soils are markedly K-depleted. A soil from a high-grade metamorphic rock (granulite) presented the lowest 226 Ra (18 Bq.kg -1 ) content, whereas the highest levels for 226 Ra (92 Bq.kg -1 ) and 228 Ra (139 Bq.kg - 1) were observed in a young soil enriched in primary minerals (Leptsol). A lowland soil (Gleysol) showed the highest median of 40 K (301 Bq.kg -1 ). Strongly acidic soils tended to present high amounts of 226 Ra, and sandy soils tended to contain low levels of 228 Ra. The external radiation dose indicates that the state has a background radiation level within the natural range. Copyright © 2017 Elsevier Ltd. All rights reserved.

PhosphoLipid transfer protein (PLTP) exerts a direct pro-inflammatory effect on rheumatoid arthritis (RA) fibroblasts-like-synoviocytes (FLS) independently of its lipid transfer activity

PubMed Central

Deckert, Valérie; Daien, Claire I.; Che, Hélène; Elhmioui, Jamila; Lemaire, Stéphanie; Pais de Barros, Jean-Paul; Desrumaux, Catherine; Combe, Bernard; Hahne, Michael; Lagrost, Laurent; Morel, Jacques

2018-01-01

Rheumatoid arthritis (RA) is a chronic inflammatory rheumatic disease with modification of lipids profile and an increased risk of cardiovascular events related to inflammation. Plasma phospholipid transfer protein (PLTP) exerts a lipid transfer activity through its active form. PLTP can also bind to receptors such as ATP-binding cassette transporter A1 (ABCA1). In addition to its role in lipoprotein metabolism and atherosclerosis, the latest advances came in support of a complex role of PLTP in the regulation of the inflammatory response, both with pro-inflammatory or anti-inflammatory properties. The aim of the present study was to decipher the role of PLTP in joint inflammation and to assess its relevance in the context of RA. PLTP expression was examined by western-blot and by immunochemistry. ABCA1 expression was analyzed by flow cytometry. Lipid transfer activity of PLTP and pro-inflammatory cytokines were measured in sera and synovial fluid (SF) from RA patients and controls (healthy subjects or osteoarthritis patients [OA]). FLS were treated with both lipid-transfer active form and inactive form of recombinant human PLTP. IL-8, IL-6, VEGF and MMP3 produced by FLS were assessed by ELISA, and proliferation by measuring 3H-Thymidine incorporation. RA synovial tissues showed higher PLTP staining than OA and PLTP protein levels were also significantly higher in RA-FLS. In addition, RA, unlike OA patients, displayed elevated levels of PLTP activity in SF, which correlated with pro-inflammatory cytokines. Both lipid-transfer active and inactive forms of PLTP significantly increased the production of cytokines and proliferation of FLS. ABCA1 was expressed on RAFLS and PLTP activated STAT3 pathway. To conclude, PLTP is highly expressed in the joints of RA patients and may directly trigger inflammation and FLS proliferation, independently of its lipid transfer activity. These results suggest a pro-inflammatory role for PLTP in RA. PMID:29565987

Glycosylation of random IgG distinguishes seropositive and seronegative rheumatoid arthritis.

PubMed

Magorivska, I; Döncző, B; Dumych, T; Karmash, A; Boichuk, M; Hychka, K; Mihalj, M; Szabó, M; Csánky, E; Rech, J; Guttman, A; Vari, S G; Bilyy, R

2018-05-01

The N-glycosylation of human immunoglobulins, especially IgGs, plays a critical role in determining affinity of IgGs towards their effector (pro- and anti-inflammatory) receptors. However, it is still not clear whether altered glycosylation is involved in only antibody-dependent disorders like seropositive rheumatoid arthritis (RA) or also in pathologies with similar clinical manifestations, but no specific autoantibodies like seronegative RA. The clarification of that uncertainty was the aim of the current study. Another study aim was the detection of specific glycan forms responsible for altered exposure of native glycoepitopes. We studied sera from seropositive RA (n = 15) and seronegative RA (n = 12) patients for exposure of glycans in native IgG molecules, followed by determination of specific glycans by capillary electrophoresis with laser-induced fluorescent detection (CE-LIF). Aged-matched groups of normal healthy donors (NHD) and samples of intravenous immunoglobulin IgG preparations (IVIG) served as controls. There was significantly stronger binding of Lens culinaris agglutinin (LCA) and Aleuria aurantia lectin (AAL) lectins towards IgG from seropositive RA compared to seronegative RA or NHD. CE-LIF analysis revealed statistically significant increases in bisecting glycans FA2BG2 (p = .006) and FABG2S1 (p = .005) seropositive RA, accompanied by decrease of bisecting monogalactosylated glycan FA2(6)G1 (p = .074) and non-bisecting monosialylated glycan FA2(3)G1S1 (p = .055). The results suggest that seropositive RA is distinct from seronegative RA in terms of IgG glycan moieties, attributable to specific immunoglobulin molecules present in seropositive disease. These glycans were determined to be bisecting GlcNAc-bearing forms FA2BG2 and FABG2S1, and their appearance increased the availability of LCA and AAL lectin-binding sites in native IgG glycoepitopes.

Retinoic Acid Excess Impairs Amelogenesis Inducing Enamel Defects

PubMed Central

Morkmued, Supawich; Laugel-Haushalter, Virginie; Mathieu, Eric; Schuhbaur, Brigitte; Hemmerlé, Joseph; Dollé, Pascal; Bloch-Zupan, Agnès; Niederreither, Karen

2017-01-01

Abnormalities of enamel matrix proteins deposition, mineralization, or degradation during tooth development are responsible for a spectrum of either genetic diseases termed Amelogenesis imperfecta or acquired enamel defects. To assess if environmental/nutritional factors can exacerbate enamel defects, we investigated the role of the active form of vitamin A, retinoic acid (RA). Robust expression of RA-degrading enzymes Cyp26b1 and Cyp26c1 in developing murine teeth suggested RA excess would reduce tooth hard tissue mineralization, adversely affecting enamel. We employed a protocol where RA was supplied to pregnant mice as a food supplement, at a concentration estimated to result in moderate elevations in serum RA levels. This supplementation led to severe enamel defects in adult mice born from pregnant dams, with most severe alterations observed for treatments from embryonic day (E)12.5 to E16.5. We identified the enamel matrix proteins enamelin (Enam), ameloblastin (Ambn), and odontogenic ameloblast-associated protein (Odam) as target genes affected by excess RA, exhibiting mRNA reductions of over 20-fold in lower incisors at E16.5. RA treatments also affected bone formation, reducing mineralization. Accordingly, craniofacial ossification was drastically reduced after 2 days of treatment (E14.5). Massive RNA-sequencing (RNA-seq) was performed on E14.5 and E16.5 lower incisors. Reductions in Runx2 (a key transcriptional regulator of bone and enamel differentiation) and its targets were observed at E14.5 in RA-exposed embryos. RNA-seq analysis further indicated that bone growth factors, extracellular matrix, and calcium homeostasis were perturbed. Genes mutated in human AI (ENAM, AMBN, AMELX, AMTN, KLK4) were reduced in expression at E16.5. Our observations support a model in which elevated RA signaling at fetal stages affects dental cell lineages. Thereafter enamel protein production is impaired, leading to permanent enamel alterations. PMID:28111553

Impairment in immuno-modulatory function of Flk1(+)CD31(-)CD34(-) MSCs from MDS-RA patients.

PubMed

Han, Qin; Sun, Zhao; Liu, Lihui; Chen, Bin; Cao, Ying; Li, Kanghua; Zhao, Robert Chunhua

2007-11-01

Myelodysplastic syndromes are a group of hematopoietic disorders characterized by hematopoietic stem cell dysregulation and abnormalities in the immune system. Mesenchymal stem cells (MSCs) and their derived stromal cells constitute a bone marrow microenvironment, which is the niche for hematopoiesis and a key compartment for immune development and regulation. Existing evidence has shown that MSCs from MDS patients have impaired capacity in supporting hematopoiesis. Here, we conducted an investigation to determine whether the immuno-modulatory function of MSCs is also impaired in MDS-RA (refractory anemia) patients. Flk1(+)CD31(-)CD34(-) MSCs were isolated from 15 MDS-RA patients and cultured for testing biological and immunological characteristics. MDS-RA patient-derived Flk1(+)CD31(-)CD34(-) MSCs showed normal morphology, phenotype and karyotype but appeared impaired in immuno-modulatory function. The capacity of patient Flk1(+)CD31(-)CD34(-) MSCs to inhibit T lymphocyte activation and proliferation was impaired in vitro. In conclusion, MDS-RA patient-derived MSCs have impaired immuno-modulatory functions, suggesting that the dysregulation of hematopoiesis and immune response may originate from MSCs rather than HSCs. MSCs might be a potential target for developing efficacious cures for MDS.

Tracing anti-cancer and cancer-promoting actions of all-trans retinoic acid in breast cancer to a RARα epigenetic mechanism of mammary epithelial cell fate.

PubMed

Rossetti, Stefano; Ren, MingQiang; Visconti, Nicolo; Corlazzoli, Francesca; Gagliostro, Vincenzo; Somenzi, Giulia; Yao, Jin; Sun, Yijun; Sacchi, Nicoletta

2016-12-27

A hallmark of cancer cells is the ability to evade the growth inhibitory/pro-apoptotic action of physiological all-trans retinoic acid (RA) signal, the bioactive derivative of Vitamin A. However, as we and others reported, RA can also promote cancer cell growth and invasion. Here we show that anticancer and cancer-promoting RA actions in breast cancer have roots in a mechanism of mammary epithelial cell morphogenesis that involves both transcriptional (epigenetic) and non-transcriptional RARα (RARA) functions. We found that the mammary epithelial cell-context specific degree of functionality of the RARA transcriptional (epigenetic) component of this mechanism, by tuning the effects of the non-transcriptional RARA component, determines different cell fate decisions during mammary morphogenesis. Indeed, factors that hamper the RARA epigenetic function make physiological RA drive aberrant morphogenesis via non-transcriptional RARA, thus leading to cell transformation. Remarkably, also the cell context-specific degree of functionality of the RARA epigenetic component retained by breast cancer cells is critical to determine cell fate decisions in response to physiological as well as supraphysiological RA variation. Overall this study supports the proof of principle that the epigenetic functional plasticity of the mammary epithelial cell RARA mechanism, which is essential for normal morphogenetic processes, is necessary to deter breast cancer onset/progression consequent to the insidious action of physiological RA.

Infliximab Biosimilar (CT-P13; Infliximab-dyyb): A Review in Autoimmune Inflammatory Diseases.

PubMed

Blair, Hannah A; Deeks, Emma D

2016-10-01

Infliximab biosimilar (CT-P13/infliximab-dyyb; Remsima ® , Inflectra ® ) is approved in several countries for use in all indications for which reference infliximab (Remicade ® ) is approved, including rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriatic arthritis, psoriasis, Crohn's disease, and ulcerative colitis. Clinical data contributing to the EU approval of infliximab biosimilar were obtained from two pivotal double-blind clinical trials in patients with AS (PLANETAS) or RA (PLANETRA). Infliximab biosimilar demonstrated equivalence to reference infliximab in terms of its pharmacokinetic profile in patients with AS, patients with RA, and in healthy volunteers, and in terms of its efficacy in patients with RA. Clinical response rates in patients with RA or AS were maintained over the longer term (up to 102 weeks). In addition, the efficacy of infliximab biosimilar in patients with RA or Crohn's disease and ulcerative colitis [i.e. inflammatory bowel disease (IBD)] has been demonstrated in the real-world setting. Infliximab biosimilar was generally well tolerated, with a tolerability profile similar to that of reference infliximab. Switching from reference infliximab to infliximab biosimilar had no detrimental effect on efficacy, safety, or immunogenicity compared with continuous infliximab biosimilar therapy, according to the extensions of PLANETAS and PLANETRA, and real-world data in IBD. Current evidence therefore suggests that infliximab biosimilar is a useful alternative to reference infliximab in patients with autoimmune inflammatory diseases.

Work ability of Dutch employees with rheumatoid arthritis.

PubMed

de Croon, E M; Sluiter, J K; Nijssen, T F; Kammeijer, M; Dijkmans, B A C; Lankhorst, G J; Frings-Dresen, M H W

2005-01-01

To (i) examine the association between fatigue, psychosocial work characteristics (job control, support, participation in decision making, psychological job demands), and physical work requirements on the one hand and work ability of employees with rheumatoid arthritis (RA) on the other, and (ii) determine the advice that health care professionals give to employees with RA on how to maintain their work ability. Data were gathered from 78 employees with early RA (response = 99%) by telephone interviews and self-report questionnaires. Fatigue, lack of autonomy, low coworker/supervisor support, low participation in decision making, and high physical work requirements (i.e. using manual force) predicted low work ability. High psychological job demands, however, did not predict low work ability. The rheumatologist, occupational physician, occupational therapist, physiotherapist, and psychologist gave advice on how to cope with RA at work to 36, 30, 27, 26, and 17% of the employees, respectively. Advice was directed mainly at factors intrinsic to the employee. Employees expressed a positive attitude towards this advice. Fatigue, lack of support, lack of autonomy, lack of participation in decision making, and using manual force at work (e.g. pushing and pulling) threaten the work ability of employees with RA. According to the employees with RA, involvement of health care professionals from different disciplines and the implementation of organizational and technical interventions would help them to tackle these threats.

Aberrant methylation patterns affect the molecular pathogenesis of rheumatoid arthritis.

PubMed

Lin, Yang; Luo, Zhengqiang

2017-05-01

This study aims to investigate DNA methylation signatures in fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA), and to explore the relationship with transcription factors (TFs) that help to distinguish RA from osteoarthritis (OA). Microarray dataset of GSE46346, including six FLS samples from patients with RA and five FLS samples from patients with OA, was downloaded from the Gene Expression Omnibus database. RA and OA samples were screened for differentially methylated loci (DMLs). The corresponding differentially methylated genes (DMGs) were identified, followed by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) enrichment analysis. A transcriptional regulatory network was built with TFs and their corresponding DMGs. Overall, 280 hypomethylated loci and 561 hypermethylated loci were screened. Genes containing hypermethylated loci were enriched in pathways in cancer, ECM-receptor interaction, focal adhesion and neurotrophin signaling pathways. Genes containing hypomethylated loci were enriched in the neurotrophin signaling pathway. Moreover, we found that CCCTC-binding factor (CTCF), Yin Yang 1 (YY1), v-myc avian myelocytomatosis viral oncogene homolog (c-MYC), and early growth response 1 (EGR1) were important TFs in the transcriptional regulatory network. Therefore, DMGs might participate in the neurotrophin signaling pathway, pathways in cancer, ECM-receptor interaction and focal adhesion pathways in RA. Furthermore, CTCF, c-MYC, YY1, and EGR1 may play important roles in RA through regulating DMGs. Copyright © 2017 Elsevier B.V. All rights reserved.

Retinoic Acid Is Involved in the Metamorphosis of the Anal Fin into an Intromittent Organ, the Gonopodium, in the Green Swordtail (Xiphophorus hellerii)

PubMed Central

Meyer, Axel; Begemann, Gerrit

2013-01-01

In poeciliid fish the male anal fin has been transformed into a gonopodium, an intromittent organ required for internal fertilization. Elevated testosterone levels induce metamorphosis of a subset of anal fin rays to grow and form the specialized terminal structures of the gonopodium. The molecular mechanisms underlying these processes are largely unknown. Here, we investigated whether retinoic acid (RA) signaling is involved in gonopodium development in the swordtail Xiphophorus hellerii. We showed that aldh1a2, a RA synthesizing enzyme, and the RA receptors, rar-ga and rar-gb, are expressed in anal fins during metamorphosis. aldh1a2 expression is regulated by testosterone in a concentration-dependent manner and is up-regulated in both hormone-induced and naturally developing gonopodia. Androgen receptor (ar), a putative regulator of gonopodial development, is co-expressed with aldh1a2 and the RA receptors in gonopodial rays. Importantly, experimental increase of RA signaling promoted growth of the gonopodium and increased the number of new segments. Based on gene expression analyses and pharmacological manipulation of gonopodium development, we show that the RA signaling pathway is activated in response to androgen signaling and promotes fin ray growth and development during the metamorphosis of the anal fin into the gonopodium. PMID:24204880

A step-by-step approach to study the influence of N-acetylation on the adjuvanticity of N,N,N-trimethyl chitosan (TMC) in an intranasal nanoparticulate influenza virus vaccine.

PubMed

Verheul, Rolf J; Hagenaars, Niels; van Es, Thomas; van Gaal, Ethlinn V B; de Jong, Pascal H J L F; Bruijns, Sven; Mastrobattista, Enrico; Slütter, Bram; Que, Ivo; Heldens, Jacco G M; van den Bosch, Han; Glansbeek, Harrie L; Hennink, Wim E; Jiskoot, Wim

2012-03-12

Recently we reported that reacetylation of N,N,N-trimethyl chitosan (TMC) reduced the adjuvant effect of TMC in mice after intranasal (i.n.) administration of whole inactivated influenza virus (WIV) vaccine. The aim of the present study was to elucidate the mechanism of this lack of adjuvanticity. Reacetylated TMC (TMC-RA, degree of acetylation 54%) was compared with TMC (degree of acetylation 17%) at six potentially critical steps in the induction of an immune response after i.n. administration in mice. TMC-RA was degraded in a nasal wash to a slightly larger extent than TMC. The local i.n. distribution and nasal clearance of WIV were similar for both TMC types. Fluorescently labeled WIV was taken up more efficiently by Calu-3 cells when formulated with TMC-RA compared to TMC and both TMCs significantly reduced transport of WIV over a Calu-3 monolayer. Murine bone-marrow derived dendritic cell activation was similar for plain WIV, and WIV formulated with TMC-RA or TMC. The inferior adjuvant effect in mice of TMC-RA over that of TMC might be caused by a slightly lower stability of TMC-RA-WIV in the nasal cavity, rather than by any of the other factors studied in this paper. Copyright © 2011 Elsevier B.V. All rights reserved.

Increased prevalence of preeclampsia among women undergoing procedural intervention for renal artery fibromuscular dysplasia.

PubMed

Vance, Chardonnay J; Taylor, Robert N; Craven, Timothy E; Edwards, Matthew S; Corriere, Matthew A

2015-08-01

Renal artery fibromuscular dysplasia (RA-FMD) has a higher prevalence among women and a presumed hormonal etiology. Although preeclampsia has a clinical presentation similar to symptomatic RA-FMD and occurs exclusively in women, associations between these 2 diseases have not been characterized. To explore epidemiologic associations between RA-FMD and preeclampsia, we administered a validated screening instrument for preeclampsia to a cohort of women with a history of pregnancy who had previously been treated with procedural intervention for symptomatic RA stenosis. Women with a history of pregnancy who had previously undergone procedural intervention (including angioplasty and/or bypass) for symptomatic RA stenosis were identified from a prospectively maintained operative registry and screened for remote history of preeclampsia using a validated survey instrument. Univariable associations between RA-FMD and preeclampsia among participants with a history of pregnancy were evaluated using t-tests for continuous factors and chi-squared tests for dichotomous factors. Multivariable associations were evaluated using logistic regression models. A total of 144 women were identified who met the study inclusion criteria, including 94 with atherosclerotic RA stenosis and 50 with RA-FMD. Sixty-nine patients were contacted, 59 consented to participate, and 52 had a history of pregnancy (and therefore were at risk for preeclampsia). Participants completed the survey instrument at a mean of 7.1 ± 3.1 vs. 6.9 ± 3.6 years after RA procedural intervention, respectively. Survey responses indicated a history of preeclampsia in 19/52 (36.5%) of participants overall, including 14/27 (51.9%) with RA-FMD versus 5/20 (20.0%) with RA atherosclerosis (P = 0.02). Preeclampsia remained associated with FMD in a multivariable model adjusting for smoking status, age at time of surgery, and estimated glomerular filtration rate (odds ratio [OR] 9.51, 95% confidence interval [CI] 1.49-60.6, P = 0.017); age at the time of surgery (OR 2.78, 95% CI 1.04-7.42, P = 0.041) and estimated glomerular filtration rate (OR 3.31, 95% CI 1.29-8.52, P = 0.013) were also associated with FMD in the multivariable model. Women with a history of procedural intervention for symptomatic RA stenosis have an overall prevalence of preeclampsia which greatly exceeds that expected in the general population, and our results suggest that preeclampsia is specifically associated with RA-FMD. Further investigation is needed to characterize the mechanistic relationships between FMD and preeclampsia and may have potential to decrease related cardiovascular morbidity and mortality. Copyright © 2015 Elsevier Inc. All rights reserved.

Environmental impact assessment of radionuclides and trace elements at the Kurday U mining site, Kazakhstan.

PubMed

Salbu, B; Burkitbaev, M; Strømman, G; Shishkov, I; Kayukov, P; Uralbekov, B; Rosseland, B O

2013-09-01

The Kurday uranium mining site in Kazakhstan operated from 1954 to 1965 as part of the USSR nuclear weapon programme. To assess the environmental impact of radionuclides and trace elements associated with the Kurday mining site, field expeditions were performed in 2006. In addition to in situ gamma and (220)Rn dose rate measurements, sampling included at site fractionation of water as well as sampling of water, fish, sediment, soils and vegetation. The concentrations of U and associated trace metals were enriched in the Pit Lake and in the artesian water (U exceeding the WHO guideline value for drinking water), and decreased downstream from the mining area. Uranium, As, Mo and Ni were predominantly present as mobile low molecular mass species in waters, while a significant proportion of Cr, Mn and Fe were associated with colloids and particles. Due to oxidation of divalent iron in the artesian ground water upon contact with air, Fe served as scavenger for other elements, and peak concentrations of U-, Ra-isotopes, As and Mn were seen. Most radionuclides and trace elements were contained in minerals in soils and sediments, and good correlations were obtained between U and As, Cd, Mo and (226)Ra. Based on sequential extractions, a significant fraction of U, Pb and Cd could be considered mobile. Radioactive particles carrying significant amount of trace metals may represent a hazard during strong wind events. The transfer of radionuclides and metals from soils or sediments to water was in general low. The Kd levels varied with the element in question, ranging from 0.5 to 3 × 10(2) L/kg d.w. for (238)U being relatively mobile, 10(3) for (226)Ra, As, Cd, Ni, to 10(4) L/kg d.w. for Cu, Cr and Pb being rather inert The transfer of radionuclides and metals from soils to vegetation (TF) was low, while higher if the transfer to vegetation, especially underwater mosses, occurred via water (e.g., BCF 37 L/kg w.w. for (238)U and 3 × 10(3) L/kg w.w. for (226)Ra). The transfer of Cd, Pb and As from water to fish liver (BCF) was rather high, showing BCFs in the range of 10(2)-10(3) L/kg w.w., and may, if eaten, represent a health risk. Furthermore, the high Hg level in fish filet reaching 0.3 mg/kg w.w. muscle and the tendency of biomagnification call for dietary restrictions. Total gamma and Rn dose rate to man amounted to about 6 mSv/y, while the highest calculated dose rate for non-human species based on the ERICA Assessment Tool were obtained in aquatic plants, with calculated mean doses of 700 μGy/hr, mostly due to the U exposure. Overall, it is concluded that measures such as restricted access to the Pit Lake as well as dietary restrictions with respect to drinking water and intake of fish should be taken to reduce the environmental risk to man and biota. Copyright © 2012. Published by Elsevier Ltd.

Measurements of natural radioactivity concentration in drinking water samples of Shiraz city and springs of the Fars province, Iran, and dose estimation.

PubMed

Mehdizadeh, Simin; Faghihi, Reza; Sina, Sedigheh; Derakhshan, Shahrzad

2013-11-01

The Fars province is located in the south-west region of Iran where different nuclear sites has been established, such as Bushehr Nuclear Power Plant. In this research, 92 water samples from the water supplies of Shiraz city and springs of the Fars province were investigated with regard to the concentrations of natural radioactive elements, total uranium, (226)Ra, gross alpha and gross beta. (226)Ra concentration was determined by the (222)Rn emanation method. To measure the total uranium concentration, a laser fluorimetry analyzer (UA-3) was used. The mean concentration of (226)Ra in Shiraz's water resources was 23.9 mBq l(-1), while 93 % of spring waters have a concentration <2 mBq l(-1). The results of uranium concentration measurements show the mean concentrations of 7.6 and 6 μg l(-1) in the water of Shiraz and springs of Fars, respectively. The gross alpha and beta concentrations measured by the evaporation method were lower than the limit of detection of the measuring instruments used in this survey. The mean annual effective doses of infants, children and adults from (238)U and (226)Ra content of Shiraz's water and spring waters were estimated. According to the results of this study, the activity concentration in water samples were below the maximum permissible concentrations determined by the World Health Organization and the US Environmental Protection Agency. Finally, the correlation between (226)Ra and total U activity concentrations and geochemical properties of water samples, i.e. pH, total dissolve solids and SO4(-2), were estimated.

Groundwater-saline lakes interaction - The contribution of saline groundwater circulation to solute budget of saline lakes: a lesson from the Dead Sea

NASA Astrophysics Data System (ADS)

Kiro, Yael; Weinstein, Yishai; Starinsky, Abraham; Yechieli, Yoseph

2013-04-01

Saline lakes act as base level for both surface water and groundwater. Thus, a change in lake levels is expected to result in changes in the hydrogeological system in its vicinity, exhibited in groundwater levels, location of the fresh-saline water interface, sub-lacustrine groundwater discharge (SGD) and saline water circulation. All these processes were observed in the declining Dead Sea system, whose water level dropped by ~35 meters in the last 50 years. This work focuses mainly on the effect of circulation of Dead Sea water in the aquifer, which continues even in this very rapid base level drop. In general, seawater circulation in coastal aquifers is now recognized as a major process affecting trace element mass balances in coastal areas. Estimates of submarine groundwater discharge (SGD) vary over several orders of magnitude (1-1000000 m3/yr per meter shoreline). These estimates are sensitive to fresh-saline SGD ratios and to the temporal and spatial scales of the circulation. The Dead Sea system is an excellent natural field lab for studying seawater-groundwater interaction and large-scale circulation due to the absence of tides and to the minor role played by waves. During Dead Sea water circulation in the aquifer several geochemical reactions occur, ranging from short-term adsorption-desorption reactions and up to long-term precipitation and dissolution reactions. These processes affect the trace element distribution in the saline groundwater. Barite and celestine, which are supersaturated in the lake water, precipitate during circulation in the aquifer, reducing barium (from 5 to 1.5 mg/L), strontium (from 350 to 300 mg/L) and the long-lived 226Ra (from 145 to 60 dpm/L) in the saline groundwater. Redox-controlled reactions cause a decrease in uranium from 2.4 to 0.1 μg/L, and an increase in iron from 1 to 13 mg/L. 228Ra (t1/2=5.75 yr) activity in the Dead Sea is ~1 dpm/L and increase gradually as the saline water flows further inland until reaching steady-state activities (~27 dpm/L) with the aquifer sediments. The decrease in 226Ra and increase in 228Ra in the circulation process provide a robust method for calculating the amount of Dead Sea water circulating in the aquifer. This process can affect trace element concentrations in the Dead Sea and emphasize the potential of long-term seawater circulation in mass balances of saline water bodies.

Retrospective clinical study on the notable efficacy and related factors of infliximab therapy in a rheumatoid arthritis management group in Japan: one-year clinical outcomes (RECONFIRM-2)

PubMed Central

Takeuchi, Tsutomu; Inoue, Eisuke; Saito, Kazuyoshi; Sekiguchi, Naoya; Sato, Eri; Nawata, Masao; Kameda, Hideto; Iwata, Shigeru; Amano, Kouichi; Yamanaka, Hisashi

2008-01-01

Biologics targeting TNF have brought about a paradigm shift in the treatment of rheumatoid arthritis (RA) and infliximab, anti-TNF-α chimeric monoclonal antibody, was marketed in 2003 in Japan. We previously reported on the RECONFIRM study, a retrospective clinical study on the efficacy of infliximab therapy in a RA management group in Japan, where we evaluated the clinical response after 22 weeks of the therapy in 258 patients. The study reported here was aimed at reconfirming the clinical efficacy of the infliximab therapy and demographic factors related to the efficacy over a 54-week study period in 410 RA patients in the same study group. Infliximab was infused according to the domestically approved method, and the clinical response was evaluated following 54 weeks of infliximab therapy using the European League Against Rheumatism (EULAR) response criteria. Disease activity was assessed by DAS28-CRP (Disease Activity Score including a 28-joint count/C-reactive protein). Infliximab was discontinued in 24.4% of the 410 patients at 54 weeks and 9.3% and 8.1% discontinued the therapy due to adverse events and inefficiency, respectively. Average DAS28-CRP decreased from 5.5 at week 0 to 3.1 at week 54 after the therapy. Patients in remission and those showing low-, moderate-, and high-disease activity changed from 0.0, 1.0, 9.0 and 90.0%, respectively, at the start of the study to 27.6, 11.7, 34.4 and 26.3%, respectively, at week 54. Younger age, RF-negativity and low scores of DAS28-CRP showed significant correlations with remission at week 54. EULAR response criteria—good, moderate, and no response to infliximab—were 37.0, 41.7 and 21.2%, respectively. In conclusion, we reconfirmed the clinical efficacy of infliximab and demographic factors related to the efficacy over a 54-week study period in 410 Japanese patients with RA using DAS28-CRP and EULAR response criteria. PMID:18283523

High Frequency Bottom Interaction in Range Dependent Biot Media

DTIC Science & Technology

1999-09-30

acoust . Soc. Am. Stephen, R.A. Benchmark models for propagation and scattering in Biot media. Fall ASA, Norfolk, VA, October...1998, J. Acoust . Soc. Am., 104, 1808. X. Zhu and G. A. McMechan, “Numerical simulation of seismic responses of poroelastic reservoirs using Biot...reverberation from rough and heterogeneous seafloors. J. acoust . Soc. Am. Stephen, R.A., in press. Optimum and standard beam widths for numerical modeling of interface scattering problems. J. acoust . Soc. Am.

Receptor-selective retinoids implicate retinoic acid receptor alpha and gamma in the regulation of bmp-2 and bmp-4 in F9 embryonal carcinoma cells.

PubMed

Rogers, M B

1996-01-01

The effect of retinoids on malignant cells and embryos indicates that retinoids influence the expression of growth factors or alter the response of cells to growth factors. The bone morphogenetic proteins, Bmp-2 and Bmp-4, are candidates for such growth factors because retinoic acid (RA) treatment of F9 embryonal carcinoma cells induced Bmp-2 mRNA, while simultaneously repressing Bmp-4 levels. Also, recombinant Bmp-2 affected the growth and differentiation of these cells. Regulation of each gene was concentration dependent and required continuous RA treatment. The short half-lives of the Bmp-2 (75 +/- 11 min) and Bmp-4 (70 +/- 4 min) mRNAs suggest that their abundance is primarily controlled at the transcriptional level. To determine which RA receptor (RAR) controls bmp-2 and bmp-4 expression, F9 cells were exposed to various receptor-selective retinoids. RAR alpha- and gamma-selective retinoids induced Bmp-2 and repressed Bmp-4 equally as well as all-trans RA. In contrast, a RAR beta-selective retinoid had little effect on Bmp-2 induction but repressed Bmp-4. A RAR alpha-selective antagonist inhibited all-trans RA stimulation of Bmp-2, although not as dramatically as a RAR beta gamma-selective antagonist. No differences were observed between Bmp levels in all-trans RA and 9-cis RA-treated cells, indicating that the RXRs play little part in controlling these genes. The results are consistent with RAR alpha and gamma-controlled Bmp-2 and Bmp-4 regulation.

Anti-TNF-alpha therapy does not modulate leptin in patients with severe rheumatoid arthritis.

PubMed

Gonzalez-Gay, M A; Garcia-Unzueta, M T; Berja, A; Gonzalez-Juanatey, C; Miranda-Filloy, J A; Vazquez-Rodriguez, T R; de Matias, J M; Martin, J; Dessein, P H; Llorca, J

2009-01-01

The adipocytokine leptin regulates weight centrally and participates in the regulation of the immune and inflammatory responses. Chronic systemic inflammation is of major importance in the development of atherosclerosis in rheumatoid arthritis (RA). In the present study we investigated whether inflammation, obesity or both of these characteristics are potential determinants of circulating leptin concentrations in a group of RA patients on periodical treatment with the TNF-alpha-blocker-infliximab due to severe disease. We also assessed whether the infusion of infliximab may alter circulating leptin concentrations in patients with severe RA. We investigated 33 patients with RA on periodical treatment with infliximab. Serum leptin levels were determined immediately prior to and after infliximab infusion. There was a positive correlation between body mass index of RA patients and baseline serum level of leptin (rho=0.665, p<0.001). Apart from a significant correlation with VCAM-1 (rho=0.349, p=0.04), no significant correlations between baseline leptin levels and the age at the time of the study or at the onset of the disease, disease duration, ESR and CRP levels, DAS28, lipids, insulin sensitivity, adhesion molecules, resistin, adiponectin, ghrelin or the cumulative prednisone dose at the time of the study were found. Leptin levels did not change upon infliximab infusion (p=0.48). In RA patients on TNF-alpha blocker treatment, circulating leptin levels are unrelated to disease activity but constitute a manifestation of adiposity. The beneficial effect of anti-TNF-alpha therapy on cardiovascular mortality in RA does not seem to be mediated by reduction in serum levels of leptin.

Integrative analysis for identification of shared markers from various functional cells/tissues for rheumatoid arthritis.

PubMed

Xia, Wei; Wu, Jian; Deng, Fei-Yan; Wu, Long-Fei; Zhang, Yong-Hong; Guo, Yu-Fan; Lei, Shu-Feng

2017-02-01

Rheumatoid arthritis (RA) is a systemic autoimmune disease. So far, it is unclear whether there exist common RA-related genes shared in different tissues/cells. In this study, we conducted an integrative analysis on multiple datasets to identify potential shared genes that are significant in multiple tissues/cells for RA. Seven microarray gene expression datasets representing various RA-related tissues/cells were downloaded from the Gene Expression Omnibus (GEO). Statistical analyses, testing both marginal and joint effects, were conducted to identify significant genes shared in various samples. Followed-up analyses were conducted on functional annotation clustering analysis, protein-protein interaction (PPI) analysis, gene-based association analysis, and ELISA validation analysis in in-house samples. We identified 18 shared significant genes, which were mainly involved in the immune response and chemokine signaling pathway. Among the 18 genes, eight genes (PPBP, PF4, HLA-F, S100A8, RNASEH2A, P2RY6, JAG2, and PCBP1) interact with known RA genes. Two genes (HLA-F and PCBP1) are significant in gene-based association analysis (P = 1.03E-31, P = 1.30E-2, respectively). Additionally, PCBP1 also showed differential protein expression levels in in-house case-control plasma samples (P = 2.60E-2). This study represented the first effort to identify shared RA markers from different functional cells or tissues. The results suggested that one of the shared genes, i.e., PCBP1, is a promising biomarker for RA.

Consensus statement on blocking the effects of interleukin-6 and in particular by interleukin-6 receptor inhibition in rheumatoid arthritis and other inflammatory conditions

PubMed Central

Smolen, Josef S; Schoels, Monika M; Nishimoto, Norihiro; Breedveld, Ferdinand C; Burmester, Gerd R; Dougados, Maxime; Emery, Paul; Ferraccioli, Gianfranco; Gabay, Cem; Gibofsky, Allan; Gomez-Reino, Juan Jesus; Jones, Graeme; Kvien, Tore K; Murakami, Miho; Betteridge, Neil; Bingham, Clifton O; Bykerk, Vivian; Choy, Ernest H; Combe, Bernard; Cutolo, Maurizio; Graninger, Winfried; Lanas, Angel; Martin-Mola, Emilio; Montecucco, Carlomaurizio; Ostergaard, Mikkel; Pavelka, Karel; Rubbert-Roth, Andrea; Sattar, Naveed; Scholte-Voshaar, Marieke; Tanaka, Yoshiya; Trauner, Michael; Valentini, Gabriele; Winthrop, Kevin L; de Wit, Maarten; van der Heijde, Désirée

2013-01-01

Background Since approval of tocilizumab (TCZ) for treatment of rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA), interleukin 6 (IL-6) pathway inhibition was evaluated in trials of TCZ and other agents targeting the IL-6 receptor and ligand in various RA populations and other inflammatory diseases. This consensus document informs on interference with the IL-6 pathway based on evidence and expert opinion. Methods Preparation of this document involved international experts in RA treatment and RA patients. A systematic literature search was performed that focused on TCZ and other IL6-pathway inhibitors in RA and other diseases. Subsequently, incorporating available published evidence and expert opinion, the steering committee and a broader expert committee (both including RA patients) formulated the current consensus statement. Results The consensus statement covers use of TCZ as combination- or monotherapy in various RA populations and includes clinical, functional and structural aspects. The statement also addresses the second approved indication in Europe JIA and non-approved indications. Also early phase trials involving additional agents that target the IL-6 receptor or IL-6 were evaluated. Safety concerns, including haematological, hepatic and metabolic issues as well as infections, are addressed likewise. Conclusions The consensus statement identifies points to consider when using TCZ, regarding indications, contraindications, screening, dose, comedication, response evaluation and safety. The document is aimed at supporting clinicians and informing patients, administrators and payers on opportunities and limitations of IL-6 pathway inhibition. PMID:23172750

Rheumatoid arthritis phenotype at presentation differs depending on the number of autoantibodies present.

PubMed

Derksen, V F A M; Ajeganova, S; Trouw, L A; van der Helm-van Mil, A H M; Hafström, I; Huizinga, T W J; Toes, R E M; Svensson, B; van der Woude, D

2017-04-01

In rheumatoid arthritis (RA), seropositive and seronegative disease may be two entities with different underlying pathophysiological mechanisms, long-term outcomes and disease presentations. However, the effect of the conjoint presence of multiple autoantibodies, as proxy for a more pronounced humoral autoimmune response, on clinical phenotype remains unclear. Therefore, this study investigates the association between the number of autoantibodies and initial clinical presentation in two independent cohorts of patients with early RA. Autoantibody status (rheumatoid factor, anticitrullinated protein antibodies and anticarbamylated protein antibodies) was determined at baseline in the Leiden Early Arthritis Cohort (n=828) and the Swedish BARFOT (Better Anti-Rheumatic Farmaco-Therapy, n=802) study. The association between the number of autoantibodies and baseline clinical characteristics was investigated using univariable and multivariable ordinal regression. In both cohorts, the following independent associations were found in multivariable analysis: patients with a higher number of RA-associated antibodies were younger, more often smokers, had a longer symptom duration and a higher erythrocyte sedimentation rate at presentation compared with patients with few autoantibodies. The number of autoantibodies, reflecting the breadth of the humoral autoimmune response, is associated with the clinical presentation of RA. Predisease pathophysiology is thus reflected by the initial clinical phenotype. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Retinoic Acid Is Essential for Th1 Cell Lineage Stability and Prevents Transition to a Th17 Cell Program

PubMed Central

Brown, Chrysothemis C.; Esterhazy, Daria; Sarde, Aurelien; London, Mariya; Pullabhatla, Venu; Osma-Garcia, Ines; al-Bader, Raya; Ortiz, Carla; Elgueta, Raul; Arno, Matthew; de Rinaldis, Emanuele; Mucida, Daniel; Lord, Graham M.; Noelle, Randolph J.

2015-01-01

Summary CD4+ T cells differentiate into phenotypically distinct T helper cells upon antigenic stimulation. Regulation of plasticity between these CD4+ T-cell lineages is critical for immune homeostasis and prevention of autoimmune disease. However, the factors that regulate lineage stability are largely unknown. Here we investigate a role for retinoic acid (RA) in the regulation of lineage stability using T helper 1 (Th1) cells, traditionally considered the most phenotypically stable Th subset. We found that RA, through its receptor RARα, sustains stable expression of Th1 lineage specifying genes, as well as repressing genes that instruct Th17-cell fate. RA signaling is essential for limiting Th1-cell conversion into Th17 effectors and for preventing pathogenic Th17 responses in vivo. Our study identifies RA-RARα as a key component of the regulatory network governing maintenance and plasticity of Th1-cell fate and defines an additional pathway for the development of Th17 cells. PMID:25769610

Nonassociation of homocysteine gene polymorphisms with treatment outcome in South Indian Tamil Rheumatoid Arthritis patients.

PubMed

Muralidharan, Niveditha; Gulati, Reena; Misra, Durga Prasanna; Negi, Vir S

2018-02-01

The aim of the study was to look for any association of MTR 2756A>G and MTRR 66A>G gene polymorphisms with clinical phenotype, methotrexate (MTX) treatment response, and MTX-induced adverse events in South Indian Tamil patients with rheumatoid arthritis (RA). A total of 335 patients with RA were investigated. MTR 2756A>G gene polymorphism was analyzed by PCR-RFLP, and MTRR 66A>G SNP was analyzed by TaqMan 5' nuclease assay. The allele frequencies were compared with HapMap groups. MTR 2756G allele was found to be associated with risk of developing RA. The allele frequencies of MTR 2756A>G and MTRR 66A>G SNPs in controls differed significantly when compared with HapMap groups. Neither of the SNPs influenced the MTX treatment outcome and adverse effects. Neither of the SNPs seems to be associated with MTX treatment outcome and adverse events in South Indian Tamil patients with RA.

The relationships of a rationality/antiemotionality personality scale to mortalities of cancer and cardiovascular disease in a community population in Japan.

PubMed

Hirokawa, Kumi; Nagata, Chisato; Takatsuka, Naoyoshi; Shimizu, Hiroyuki

2004-01-01

Grossarth-Maticek et al. reported that an individual's level on a rationality/antiemotionality (R/A) personality was strongly predictive of cancer, ischemic heart disease and stroke mortality. To investigate the relationships of an individual's level on the R/A personality to cancer and cardiovascular disease mortality in Japan, we conducted a population-based cohort study. A self-administered questionnaire was distributed to 36990 Japanese residents in September 1992. The response rate was 90.3%. Data from 13226 males and 14880 females were analyzed. Dates and causes of death through December 31, 1999 were obtained for deceased participants. The results from multivariate hazard ratios (HRs) revealed that males scoring in the middle level compared to those scoring in the lower level of the R/A personality scale decreased their risk of death from cancer and cardiovascular diseases after controlling for covariates. The level on the R/A personality scale may affect mortality from cancer and cardiovascular diseases differently in Japan.

Positron emission tomography/computed tomography imaging and rheumatoid arthritis.

PubMed

Wang, Shi-Cun; Xie, Qiang; Lv, Wei-Fu

2014-03-01

Rheumatoid arthritis (RA) is a phenotypically heterogeneous, chronic, destructive inflammatory disease of the synovial joints. A number of imaging tools are currently available for evaluation of inflammatory conditions. By targeting the upgraded glucose uptake of infiltrating granulocytes and tissue macrophages, positron emission tomography/computed tomography with fluorine-18 fluorodeoxyglucose ((18) F-FDG PET/CT) is available to delineate inflammation with high sensitivity. Recently, several studies have indicated that FDG uptake in affected joints reflects the disease activity of RA. In addition, usage of FDG PET for the sensitive detection and monitoring of the response to treatment has been reported. Combined FDG PET/CT enables the detailed assessment of disease in large joints throughout the whole body. These unique capabilities of FDG PET/CT imaging are also able to detect RA-complicated diseases. Therefore, PET/CT has become an excellent ancillary tool to assess disease activity and prognosis in RA. © 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.

Spin-orbit effects on reflectance anisotropy spectroscopy of aclean CdTe(001) surface

NASA Astrophysics Data System (ADS)

Vázquez-Nava, Raül A.

2005-03-01

The spectroscopical reflectance anisotropy (RA) response of a clean (001) surface of CdTe, which exhibits a c(2 x2) surface reconstruction, is studied using a microscopic formulation based on a semi-empirical tight binding approach (SETB) which includes the spin-orbit (SO) interaction. Following Ref. 1, we apply an unitary transformation to the usual SETB sp^3s^* basis to describe the electronic states in terms of a set of atomic states which are eigenstates of the total angular momentum (TAM). These states are better suited to treat the SO interaction in this model, and their use in the computation of the RA signal is straightforward [1]. We show how the RA changes when SO is taken into account and compare our theoretical results with experimental measurements of Ref. 2. [1] R.A. V'azquez-Nava, B.S. Mendoza and C. Castillo, Phys. Rev. B 70, 165306 (2004). [2] J. R. Molina and R. Espinosa-Luna, J. Phys. D: Appl. Phys. (2004), accepted.

EULAR recommendations for terminology and research in individuals at risk of rheumatoid arthritis: report from the Study Group for Risk Factors for Rheumatoid Arthritis

PubMed Central

Gerlag, Danielle M; Raza, Karim; van Baarsen, Lisa G M; Brouwer, Elisabeth; Buckley, Christopher D; Burmester, Gerd R; Gabay, Cem; Catrina, Anca I; Cope, Andrew P; Cornelis, François; Dahlqvist, Solbritt Rantapää; Emery, Paul; Eyre, Stephen; Finckh, Axel; Gay, Steffen; Hazes, Johanna M; van der Helm-van Mil, Annette; Huizinga, Tom W J; Klareskog, Lars; Kvien, Tore K; Lewis, Cathryn; Machold, Klaus P; Rönnelid, Johan; van Schaardenburg, Dirkjan; Schett, Georg; Smolen, Josef S; Thomas, Sue; Worthington, Jane; Tak, Paul P

2012-01-01

The Study Group for Risk Factors for Rheumatoid Arthritis was established by the EULAR Standing Committee on Investigative Rheumatology to facilitate research into the preclinical and earliest clinically apparent phases of rheumatoid arthritis (RA). This report describes the recommendation for terminology to be used to define specific subgroups during different phases of disease, and defines the priorities for research in this area. Terminology was discussed by way of a three-stage structured process: A provisional list of descriptors for each of the possible phases preceding the diagnosis of RA were circulated to members of the study group for review and feedback. Anonymised comments from the members on this list were fed back to participants before a 2-day meeting. 18 participants met to discuss these data, agree terminologies and prioritise important research questions. The study group recommended that, in prospective studies, individuals without RA are described as having: genetic risk factors for RA; environmental risk factors for RA; systemic autoimmunity associated with RA; symptoms without clinical arthritis; unclassified arthritis; which may be used in a combinatorial manner. It was recommended that the prefix ‘pre-RA with:’ could be used before any/any combination of the five points above but only to describe retrospectively a phase that an individual had progressed through once it was known that they have developed RA. An approach to dating disease onset was recommended. In addition, important areas for research were proposed, including research of other tissues in which an adaptive immune response may be initiated, and the identification of additional risk factors and biomarkers for the development of RA, its progression and the development of extra-articular features. These recommendations provide guidance on approaches to describe phases before the development of RA that will facilitate communication between researchers and comparisons between studies. A number of research questions have been defined, requiring new cohorts to be established and new techniques to be developed to image and collect material from different sites. PMID:22387728

Translocator protein as an imaging marker of macrophage and stromal activation in RA pannus.

PubMed

Narayan, Nehal; Owen, David; Mandhair, Harpreet; Smyth, Erica; Carlucci, Francesco; Saleem, Azeem; Gunn, Roger; Rabiner, Eugenii Ilan A; Wells, Lisa; Dakin, Stephanie; Sabokbar, Afsie; Taylor, Peter

2018-01-04

Positron Emission Tomography (PET) radioligands targeted to Translocator protein (TSPO), offer a highly sensitive and specific means of imaging joint inflammation in rheumatoid arthritis (RA). Through high expression of TSPO on activated macrophages, TSPO PET has been widely reported in several studies of RA as a means of imaging synovial macrophages in vivo. However, this premise does not take into account the ubiquitous expression of TSPO. This study aimed to investigate TSPO expression in major cellular constituents of RA pannus; monocytes, macrophages, fibroblast-like synoviocytes (FLS) and CD4+ T lymphocytes, to more accurately interpret TSPO PET signal from RA synovium. Methods: 3 RA patients and 3 healthy volunteers underwent PET both knees using the TSPO radioligand 11 C-PBR28. Through synovial tissue 3H-PBR28 autoradiography and immunostaining of 6 RA patients and 6 healthy volunteers, cellular expression of TSPO in synovial tissue was evaluated. TSPO mRNA expression and 3H-PBR28 radioligand binding was assessed using in vitro monocytes, macrophages, FLS and CD4+ T-lymphocytes. Results: 11 C-PBR28 PET signal was significantly higher in RA compared to healthy joints (average SUV 0.82± 0.12 compared to 0.03± 0.004 respectively, p<0.01). Further, 3H-PBR28 specific binding in synovial tissue was approximately 10-fold higher in RA compared to healthy controls. Immunofluorescence revealed TSPO expression on macrophages, FLS and CD4+ T cells. In vitro study demonstrated highest TSPO mRNA expression and 3H-PBR28 specific binding, in activated FLS, non-activated and activated 'M2' reparative macrophages, with least TSPO expression in activated and non-activated CD4+ T lymphocytes. Conclusion: This study is the first evaluation of cellular TSPO expression in synovium, finding highest TSPO expression and PBR28 binding on activated synovial FLS and M2 phenotype macrophages. TSPO targeted PET may therefore have unique sensitivity to detect FLS and macrophage predominant inflammation in RA, with potential utility to assess treatment response in trials using novel FLS-targeted therapies. Copyright © 2018 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

EULAR recommendations for terminology and research in individuals at risk of rheumatoid arthritis: report from the Study Group for Risk Factors for Rheumatoid Arthritis.

PubMed

Gerlag, Danielle M; Raza, Karim; van Baarsen, Lisa G M; Brouwer, Elisabeth; Buckley, Christopher D; Burmester, Gerd R; Gabay, Cem; Catrina, Anca I; Cope, Andrew P; Cornelis, François; Dahlqvist, Solbritt Rantapää; Emery, Paul; Eyre, Stephen; Finckh, Axel; Gay, Steffen; Hazes, Johanna M; van der Helm-van Mil, Annette; Huizinga, Tom W J; Klareskog, Lars; Kvien, Tore K; Lewis, Cathryn; Machold, Klaus P; Rönnelid, Johan; van Schaardenburg, Dirkjan; Schett, Georg; Smolen, Josef S; Thomas, Sue; Worthington, Jane; Tak, Paul P

2012-05-01

The Study Group for Risk Factors for Rheumatoid Arthritis was established by the EULAR Standing Committee on Investigative Rheumatology to facilitate research into the preclinical and earliest clinically apparent phases of rheumatoid arthritis (RA). This report describes the recommendation for terminology to be used to define specific subgroups during different phases of disease, and defines the priorities for research in this area. Terminology was discussed by way of a three-stage structured process: A provisional list of descriptors for each of the possible phases preceding the diagnosis of RA were circulated to members of the study group for review and feedback. Anonymised comments from the members on this list were fed back to participants before a 2-day meeting. 18 participants met to discuss these data, agree terminologies and prioritise important research questions. The study group recommended that, in prospective studies, individuals without RA are described as having: genetic risk factors for RA; environmental risk factors for RA; systemic autoimmunity associated with RA; symptoms without clinical arthritis; unclassified arthritis; which may be used in a combinatorial manner. It was recommended that the prefix 'pre-RA with:' could be used before any/any combination of the five points above but only to describe retrospectively a phase that an individual had progressed through once it was known that they have developed RA. An approach to dating disease onset was recommended. In addition, important areas for research were proposed, including research of other tissues in which an adaptive immune response may be initiated, and the identification of additional risk factors and biomarkers for the development of RA, its progression and the development of extra-articular features. These recommendations provide guidance on approaches to describe phases before the development of RA that will facilitate communication between researchers and comparisons between studies. A number of research questions have been defined, requiring new cohorts to be established and new techniques to be developed to image and collect material from different sites.

Prioritizing the patient: optimizing therapy in rheumatoid arthritis. Results of a patient questionnaire in northern Germany.

PubMed

Wollenhaupt, Jürgen; Ehlebracht-Koenig, Inge; Groenewegen, André; Fricke, Dieter

2013-01-01

A 40-question postal survey was developed to gain insight into the nature of difficulties experienced by patients due to rheumatoid arthritis (RA), as well as patient perceptions and priorities regarding their RA treatment. A total of 3000 Lower Saxony, Germany members of Rheuma-Liga (RL), a patient support group for people with RA, were invited to participate between July 1, and August 20, 2009. The questionnaire was divided into four sections: (1) patient demographics, (2) quality of life (QOL), (3) treatment expectations and, (4) patient perceptions of RL. The questionnaire could be completed in writing or via the internet. Of 959 respondents (response rate = 32.0%), 318 had diagnosed RA and were included in the analysis. The respondents were mostly retired (71.2%), female (83.3%), and >60 years of age (63.5%). Members' responses indicated that most were generally satisfied with their current treatment (67.3%), considered it efficacious (84.0%), and reported minimal (none or little) side-effects (61.2%). Patient involvement in treatment decisions, however, was reportedly low (49.6% felt insufficiently involved). Patients' primary impairments were reflected in their treatment priorities: mobility (97.0%), ability to run errands/do shopping (97.1%), do the housework (95.6%), and be independent of others (94.2%). The primary service provided by RL and used by respondents was physiotherapy (70.6%), which was reported to benefit physical function and mood by over 90.0% of respondents. RA had a detrimental effect upon respondents' quality of life, specifically impairing their ability to perform daily tasks and causing pain/emotional distress. Independence and mobility were strong priorities for respondents. Physical therapy, provided by RL, was felt to help both physical and mental/emotional health.

Repository corticotropin injection in a patient presenting with focal segmental glomerulosclerosis, rheumatoid arthritis, and optic neuritis: a case report.

PubMed

Madan, Arvind

2015-01-01

Focal segmental glomerulosclerosis (FSGS) causes scarring or sclerosis of glomeruli that act as tiny filters in the kidneys, damage to which results in diminished ability to properly filter blood, resulting in the urinary loss of plasma proteins and subsequent proteinuria. A 60-year-old, white female with a history of intermittent proteinuria was referred by her primary care physician for renal dysfunction. Biopsy confirmed FSGS and she was treated with an angiotensin-converting enzyme inhibitor. She also had rheumatoid arthritis (RA) but no active synovitis and was maintained on prednisone 5 mg/d. She also complained of worsening vision in her right eye and was diagnosed with optic neuritis (ON). She remained stable for about 8 months when examination indicated FSGS relapse, and she reported painful RA flares. She was treated with Acthar(®) Gel (40 mg biweekly) for 6 months, after which proteinuria and urine protein-to-creatinine ratio decreased to about half. Her ON improved, and she reported that she had fewer RA flares and pain improved by 50%. This case of confirmed FSGS showed an improved response to treatment with Acthar Gel for FSGS with concomitant RA and ON. This referral case is relevant to primary care practitioners who treat disorders that may be responsive to corticosteroid therapy. The antiproteinuric effects and ancillary improvement in RA and ON symptoms during treatment with Acthar Gel are not entirely explained by its steroidogenic actions. ACTH is a bioactive peptide that, together with α-melanocyte-stimulating hormone, exhibits biologic efficacy by modulating proinflammatory cytokines and subsequent leukocyte extravasation and may have autocrine/paracrine effects in joints. While Acthar Gel was primarily administered in this case to treat proteinuria, it also showed ancillary benefits in patients with concomitant inflammatory disease states.

Baicalin reduces blood lipids and inflammation in patients with coronary artery disease and rheumatoid arthritis: a randomized, double-blind, placebo-controlled trial.

PubMed

Hang, Yuanxing; Qin, Xian; Ren, Tianli; Cao, Jianing

2018-06-23

Patients with rheumatoid arthritis (RA) have an increased risk of coronary artery disease (CAD) above the baseline. Baicalin possesses beneficial effects against both RA and CAD, but little is know on its clincial efficacy among patients manifesting both CAD and RA. Three hundred seventy four patients with CAD and RA were randomized to receive either 500 mg baicalin or placebo orally everyday for 12 weeks. Lipid profile, cardiotrophin-1 (CT-1), high sensitivity C-reactive protein (hs-CRP), European League Against Rheumatism (EULAR) response were analyzed at the end of study period. After 12 week treatment, levels of triglycerides, total cholesterol, LDL-cholesterol and apolipoproteins, as well as CT-1 and hs-CRP, were all significantly improved in the baicalin group compared to the placebo group (1.12 ± 0.36 vs 1.87 ± 0.46 mmol/L, 2.87 ± 1.23 vs 3.22 ± 1.07 mmol/L, 1.38 ± 0.41 vs 1.16 ± 0.32 mmol/L, 1.31 ± 0.41 vs 1.23 ± 0.29 g/L, 42.9 ± 13.7 vs 128.4 ± 24.3 ng/mL, 1.64 ± 0.38 vs 3.9 ± 1.4 mg/dL, respectively). Significantly higher proportion of patients in the baicalin group (71%) reported good/moderate EULAR response than the placebo group (53%). Baicalin reduces blood lipids and inflammation in patients with both CAD and RA, supporting its further clinical application.

Whole-Exome Sequencing in a South American Cohort Links ALDH1A3, FOXN1 and Retinoic Acid Regulation Pathways to Autism Spectrum Disorders.

PubMed

Moreno-Ramos, Oscar A; Olivares, Ana María; Haider, Neena B; de Autismo, Liga Colombiana; Lattig, María Claudia

2015-01-01

Autism spectrum disorders (ASDs) are a range of complex neurodevelopmental conditions principally characterized by dysfunctions linked to mental development. Previous studies have shown that there are more than 1000 genes likely involved in ASD, expressed mainly in brain and highly interconnected among them. We applied whole exome sequencing in Colombian-South American trios. Two missense novel SNVs were found in the same child: ALDH1A3 (RefSeq NM_000693: c.1514T>C (p.I505T)) and FOXN1 (RefSeq NM_003593: c.146C>T (p.S49L)). Gene expression studies reveal that Aldh1a3 and Foxn1 are expressed in ~E13.5 mouse embryonic brain, as well as in adult piriform cortex (PC; ~P30). Conserved Retinoic Acid Response Elements (RAREs) upstream of human ALDH1A3 and FOXN1 and in mouse Aldh1a3 and Foxn1 genes were revealed using bioinformatic approximation. Chromatin immunoprecipitation (ChIP) assay using Retinoid Acid Receptor B (Rarb) as the immunoprecipitation target suggests RA regulation of Aldh1a3 and Foxn1 in mice. Our results frame a possible link of RA regulation in brain to ASD etiology, and a feasible non-additive effect of two apparently unrelated variants in ALDH1A3 and FOXN1 recognizing that every result given by next generation sequencing should be cautiously analyzed, as it might be an incidental finding.

Gene expression profile predicting the response to anti-TNF treatment in patients with rheumatoid arthritis; analysis of GEO datasets.

PubMed

Kim, Tae-Hwan; Choi, Sung Jae; Lee, Young Ho; Song, Gwan Gyu; Ji, Jong Dae

2014-07-01

Anti-tumor necrosis factor (TNF) therapy is the treatment of choice for rheumatoid arthritis (RA) patients in whom standard disease-modifying anti-rheumatic drugs are ineffective. However, a substantial proportion of RA patients treated with anti-TNF agents do not show a significant clinical response. Therefore, biomarkers predicting response to anti-TNF agents are needed. Recently, gene expression profiling has been applied in research for developing such biomarkers. We compared gene expression profiles reported by previous studies dealing with the responsiveness of anti-TNF therapy in RA patients and attempted to identify differentially expressed genes (DEGs) that discriminated between responders and non-responders to anti-TNF therapy. We used microarray datasets available at the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO). This analysis included 6 studies and 5 sets of microarray data that used peripheral blood samples for identification of DEGs predicting response to anti-TNF therapy. We found little overlap in the DEGs that were highly ranked in each study. Three DEGs including IL2RB, SH2D2A and G0S2 appeared in more than 1 study. In addition, a meta-analysis designed to increase statistical power found one DEG, G0S2 by the Fisher's method. Our finding suggests the possibility that G0S2 plays as a biomarker to predict response to anti-TNF therapy in patients with rheumatoid arthritis. Further investigations based on larger studies are therefore needed to confirm the significance of G0S2 in predicting response to anti-TNF therapy. Copyright © 2014 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.

A Novel Pan-Negative-Gating Modulator of KCa2/3 Channels, Fluoro-Di-Benzoate, RA-2, Inhibits Endothelium-Derived Hyperpolarization–Type Relaxation in Coronary Artery and Produces Bradycardia In Vivo

PubMed Central

Oliván-Viguera, Aida; Valero, Marta Sofía; Coleman, Nicole; Brown, Brandon M.; Laría, Celia; Divina Murillo, María; Gálvez, José A.; Díaz-de-Villegas, María D.; Wulff, Heike; Badorrey, Ramón

2015-01-01

Small/intermediate conductance KCa channels (KCa2/3) are Ca2+/calmodulin regulated K+ channels that produce membrane hyperpolarization and shape neurologic, epithelial, cardiovascular, and immunologic functions. Moreover, they emerged as therapeutic targets to treat cardiovascular disease, chronic inflammation, and some cancers. Here, we aimed to generate a new pharmacophore for negative-gating modulation of KCa2/3 channels. We synthesized a series of mono- and dibenzoates and identified three dibenzoates [1,3-phenylenebis(methylene) bis(3-fluoro-4-hydroxybenzoate) (RA-2), 1,2-phenylenebis(methylene) bis(3-fluoro-4-hydroxybenzoate), and 1,4-phenylenebis(methylene) bis(3-fluoro-4-hydroxybenzoate)] with inhibitory efficacy as determined by patch clamp. Among them, RA-2 was the most drug-like and inhibited human KCa3.1 with an IC50 of 17 nM and all three human KCa2 subtypes with similar potencies. RA-2 at 100 nM right-shifted the KCa3.1 concentration-response curve for Ca2+ activation. The positive-gating modulator naphtho[1,2-d]thiazol-2-ylamine (SKA-31) reversed channel inhibition at nanomolar RA-2 concentrations. RA-2 had no considerable blocking effects on distantly related large-conductance KCa1.1, Kv1.2/1.3, Kv7.4, hERG, or inwardly rectifying K+ channels. In isometric myography on porcine coronary arteries, RA-2 inhibited bradykinin-induced endothelium-derived hyperpolarization (EDH)–type relaxation in U46619-precontracted rings. Blood pressure telemetry in mice showed that intraperitoneal application of RA-2 (≤100 mg/kg) did not increase blood pressure or cause gross behavioral deficits. However, RA-2 decreased heart rate by ≈145 beats per minute, which was not seen in KCa3.1−/− mice. In conclusion, we identified the KCa2/3–negative-gating modulator, RA-2, as a new pharmacophore with nanomolar potency. RA-2 may be of use to generate structurally new types of negative-gating modulators that could help to define the physiologic and pathomechanistic roles of KCa2/3 in the vasculature, central nervous system, and during inflammation in vivo. PMID:25468883

Crowdsourced assessment of common genetic contribution to predicting anti-TNF treatment response in rheumatoid arthritis

PubMed Central

Sieberts, Solveig K.; Zhu, Fan; García-García, Javier; Stahl, Eli; Pratap, Abhishek; Pandey, Gaurav; Pappas, Dimitrios; Aguilar, Daniel; Anton, Bernat; Bonet, Jaume; Eksi, Ridvan; Fornés, Oriol; Guney, Emre; Li, Hongdong; Marín, Manuel Alejandro; Panwar, Bharat; Planas-Iglesias, Joan; Poglayen, Daniel; Cui, Jing; Falcao, Andre O.; Suver, Christine; Hoff, Bruce; Balagurusamy, Venkat S. K.; Dillenberger, Donna; Neto, Elias Chaibub; Norman, Thea; Aittokallio, Tero; Ammad-ud-din, Muhammad; Azencott, Chloe-Agathe; Bellón, Víctor; Boeva, Valentina; Bunte, Kerstin; Chheda, Himanshu; Cheng, Lu; Corander, Jukka; Dumontier, Michel; Goldenberg, Anna; Gopalacharyulu, Peddinti; Hajiloo, Mohsen; Hidru, Daniel; Jaiswal, Alok; Kaski, Samuel; Khalfaoui, Beyrem; Khan, Suleiman Ali; Kramer, Eric R.; Marttinen, Pekka; Mezlini, Aziz M.; Molparia, Bhuvan; Pirinen, Matti; Saarela, Janna; Samwald, Matthias; Stoven, Véronique; Tang, Hao; Tang, Jing; Torkamani, Ali; Vert, Jean-Phillipe; Wang, Bo; Wang, Tao; Wennerberg, Krister; Wineinger, Nathan E.; Xiao, Guanghua; Xie, Yang; Yeung, Rae; Zhan, Xiaowei; Zhao, Cheng; Calaza, Manuel; Elmarakeby, Haitham; Heath, Lenwood S.; Long, Quan; Moore, Jonathan D.; Opiyo, Stephen Obol; Savage, Richard S.; Zhu, Jun; Greenberg, Jeff; Kremer, Joel; Michaud, Kaleb; Barton, Anne; Coenen, Marieke; Mariette, Xavier; Miceli, Corinne; Shadick, Nancy; Weinblatt, Michael; de Vries, Niek; Tak, Paul P.; Gerlag, Danielle; Huizinga, Tom W. J.; Kurreeman, Fina; Allaart, Cornelia F.; Louis Bridges Jr., S.; Criswell, Lindsey; Moreland, Larry; Klareskog, Lars; Saevarsdottir, Saedis; Padyukov, Leonid; Gregersen, Peter K.; Friend, Stephen; Plenge, Robert; Stolovitzky, Gustavo; Oliva, Baldo; Guan, Yuanfang; Mangravite, Lara M.

2016-01-01

Rheumatoid arthritis (RA) affects millions world-wide. While anti-TNF treatment is widely used to reduce disease progression, treatment fails in ∼one-third of patients. No biomarker currently exists that identifies non-responders before treatment. A rigorous community-based assessment of the utility of SNP data for predicting anti-TNF treatment efficacy in RA patients was performed in the context of a DREAM Challenge (http://www.synapse.org/RA_Challenge). An open challenge framework enabled the comparative evaluation of predictions developed by 73 research groups using the most comprehensive available data and covering a wide range of state-of-the-art modelling methodologies. Despite a significant genetic heritability estimate of treatment non-response trait (h2=0.18, P value=0.02), no significant genetic contribution to prediction accuracy is observed. Results formally confirm the expectations of the rheumatology community that SNP information does not significantly improve predictive performance relative to standard clinical traits, thereby justifying a refocusing of future efforts on collection of other data. PMID:27549343

An Update on the NASA Planetary Science Division Research and Analysis Program

NASA Astrophysics Data System (ADS)

Bernstein, Max; Richey, Christina; Rall, Jonathan

2015-11-01

Introduction: NASA’s Planetary Science Division (PSD) solicits its research and analysis (R&A) programs each year in Research Opportunities in Space and Earth Sciences (ROSES). Beginning with the 2014 ROSES solicitation, PSD changed the structure of the program elements under which the majority of planetary science R&A is done. Major changes included the creation of five core research program elements aligned with PSD’s strategic science questions, the introduction of several new R&A opportunities, new submission requirements, and a new timeline for proposal submission.ROSES and NSPIRES: ROSES contains the research announcements for all of SMD. Submission of ROSES proposals is done electronically via NSPIRES: http://nspires.nasaprs.com. We will present further details on the proposal submission process to help guide younger scientists. Statistical trends, including the average award size within the PSD programs, selections rates, and lessons learned, will be presented. Information on new programs will also be presented, if available.Review Process and Volunteering: The SARA website (http://sara.nasa.gov) contains information on all ROSES solicitations. There is an email address (SARA@nasa.gov) for inquiries and an area for volunteer reviewers to sign up. The peer review process is based on Scientific/Technical Merit, Relevance, and Level of Effort, and will be detailed within this presentation.ROSES 2015 submission changes: All PSD programs will continue to use a two-step proposal submission process. A Step-1 proposal is required and must be submitted electronically by the Step-1 due date. The Step-1 proposal should include a description of the science goals and objectives to be addressed by the proposal, a brief description of the methodology to be used to address the science goals and objectives, and the relevance of the proposed research to the call submitted to.

The Gulf of Mexico Coastal Ocean Observing System: A Decade of Data Aggregation and Services.

NASA Astrophysics Data System (ADS)

Howard, M.; Gayanilo, F.; Kobara, S.; Baum, S. K.; Currier, R. D.; Stoessel, M. M.

2016-02-01

The Gulf of Mexico Coastal Ocean Observing System Regional Association (GCOOS-RA) celebrated its 10-year anniversary in 2015. GCOOS-RA is one of 11 RAs organized under the NOAA-led U.S. Integrated Ocean Observing System (IOOS) Program Office to aggregate regional data and make these data publicly-available in preferred forms and formats via standards-based web services. Initial development of GCOOS focused on building elements of the IOOS Data Management and Communications Plan which is a framework for end-to-end interoperability. These elements included: data discovery, catalog, metadata, online-browse, data access and transport. Initial data types aggregated included near real-time physical oceanographic, marine meteorological and satellite data. Our focus in the middle of the past decade was on the production of basic products such as maps of current oceanographic conditions and quasi-static datasets such as bathymetry and climatologies. In the latter part of the decade we incorporated historical physical oceanographic datasets and historical coastal and offshore water quality data into our holdings and added our first biological dataset. We also developed web environments and products to support Citizen Scientists and stakeholder groups such as recreational boaters. Current efforts are directed towards applying data quality assurance (testing and flagging) to non-federal data, data archiving at national repositories, serving and visualizing numerical model output, providing data services for glider operators, and supporting marine biodiversity observing networks. GCOOS Data Management works closely with the Gulf of Mexico Research Initiative Information and Data Cooperative and various groups involved with Gulf Restoration. GCOOS-RA has influenced attitudes and behaviors associated with good data stewardship and data management practices across the Gulf and will to continue to do so into the next decade.