2,652 research outputs found
Intervening through Conversations: How Instructions Influence Conversational Valence and Binge Drinking Determinants
FcgammaR expression on macrophages is related to severity and chronicity of synovial inflammation and cartilage destruction during experimental immune-complex-mediated arthritis (ICA)
INTRODUCTION: FcÎł receptors (FcÎłRs) present on cells of the haematopoietic lineage communicate with IgG-containing immune complexes that are abundant in the synovial tissue of patients with rheumatoid arthritis (RA). In mice, three classes of FcÎłR (RI, RII, and RIII) have been described. Binding of these receptors leads to either activation (FcÎłRI and RIII) or deactivation (FcÎłRII) of intracellular transduction pathways. Together, the expression of activating and inhibitory receptors is thought to drive immune-complex-mediated diseases. Earlier studies in our laboratory showed that macrophages of the synovial lining are of utmost importance in the onset and propagation of immune-complex-driven arthritic diseases. Selective depletion of macrophages in the joint downregulated both inflammation and cartilage destruction. As all three classes of FcÎłR are expressed on synovial macrophages, these cells are among the first that come in contact with immune complexes deposited in the joint. Recently, we observed that when immune complexes were injected into the knee joints of mice, strains susceptible to collagen-type-II arthritis (DBA/1, B10.RIII) developed more severe arthritis than nonsusceptible strains did, or even developed chronic arthritis. One reason why these strains are more susceptible might be their higher levels of FcÎłRs on macrophage membranes. To test this hypothesis, we investigated the role of FcÎłRs in inflammation and cartilage damage during immune-complex-mediated arthritis (ICA). First, we studied arthritis and subsequent cartilage damage in mice lacking functional FcÎłRI and RIII (FcR Îł-chain(-/-) mice). Next, DBA/1 mice, which are prone to develop collagen-type-II arthritis (`collagen-induced arthritis'; CIA) and are hypersensitive to immune complexes, were compared with control C57BL/6 mice as regards cartilage damage and the expression and function of FcÎłRs on their macrophages. AIMS: To examine whether FcÎłR expression on macrophages is related to severity of synovial inflammation and cartilage destruction during immune-complex-mediated joint inflammation. METHODS: ICA was induced in three strains of mice (FcR Îł-chain(-/-), C57BL/6, and DBA/1, which have, respectively, no functional FcÎłRI and RIII, intermediate basal expression of FcÎłRs, and high basal expression of FcÎłRs) by passive immunisation using rabbit anti-lysozyme antibodies, followed by poly-L-lysine lysozyme injection into the right knee joint 1 day later. In other experiments, streptococcal-cell-wall (SCW)- or zymosan-induced arthritis was induced by injecting SCW (25 ÎŒg) or zymosan (180 ÎŒg) directly into the knee joint. At several time points after arthritis induction, knee joints were dissected and studied either histologically (using haematoxylin/eosin or safranin O staining) or immuno-histochemically. The arthritis severity and the cartilage damage were scored separately on an arbitrary scale of 0-3. FcÎłRs were immunohistochemically detected using the monoclonal antibody 2.4G2, which detects both FcÎłRII and RIII. Deposition of IgG and C3c in the arthritic joint tissue was also detected immunohistochemically. Expression of FcÎłRs by murine peritoneal macrophages was measured using a fluorescence-activated cell sorter (FACS). Peritoneal macrophages were stimulated using heat-aggregated gamma globulins (HAGGs), and production of IL-1 was measured using a bioassay. To assess the levels of IL-1 and its receptor antagonist (IL-1Ra) during arthritis, tissue was dissected and washed in RPMI medium. Washouts were tested for levels of IL-1 and IL-1Ra using radioimmunoassay and enzyme-linked immunosorbent assay. mRNA was isolated from the tissue, and levels of macrophage inflammatory protein (MIP)-2, monocyte chemoattractant protein (MCP)-1, IL-1, and IL-1Ra were determined using semiquantitative reverse-transcription polymerase chain reaction (RT-PCR). RESULTS: ICA induced in knee joints of C57BL/6 mice caused a florid inflammation at day 3 after induction. To investigate whether this arthritis was FcÎłR-mediated, ICA was induced in FcR Îł-chain(-/-) mice, which lack functional FcÎłRI and RIII. At day3, virtually no inflammatory cells were found in their knee joints. Levels of mRNA of IL-1, IL-1Ra, MCP-1, and MIP-2, which are involved in the onset of this arthritis, were significantly lower in FcR Îł-chain(-/-) mice than in control C57BL/6 mice. Levels of IL-1 protein were also measured. At 6 h after ICA induction, FcR Îł-chain(-/-) mice and control C57BL/6 mice showed similar IL-1 production as measured by protein level. By 24 h after induction, however, IL-1 production in the FcR Îł-chain(-/-) mice was below the detection limit, whereas the controls were still producing a significant amount. To investigate whether the difference in reaction to immune complexes between the DBA/1 and C57BL/6 mice might be due to variable expression of FcÎłRs in the knee joint, expression in situ of FcÎłRs in naĂŻve knee joints of these mice was determined. The monoclonal antibody 2.4G2, which detects both FcÎłRII and RIII, stained macrophages from the synovial lining of DBA/1 mice more intensely than those from C57BL/6 mice. This finding suggests a higher constitutive expression of FcÎłRs by macrophages of the autoimmune-prone DBA/1 mice. To quantify the difference in FcÎłR expression on macrophages of the two strains, we determined the occurrence of FcÎłRs on peritoneal macrophages by FACS analysis. The levels of FcÎłR expressed by macrophages were twice as high in the DBA/1 mice as in the C57BL/6 mice (mean fluorescence, respectively, 440 ± 50 and 240 ± 30 intensity per cell). When peritoneal macrophages of both strains were stimulated with immune complexes (HAGGs), we found that the difference in basal FcÎłR expression was functional. The stimulated macrophages from DBA/1 mice had significantly higher IL-1α levels (120 and 135 pg/ml at 24 and 48 h, respectively) than cells from C57BL/6 mice (45 and 50 pg/ml, respectively). When arthritis was induced using other arthritogenic triggers than immune complexes (zymosan, SCW), all the mouse strains tested (DBA/1, FcR Îł-chain(-/-), and C57BL/6) showed similar inflammation, indicating that the differences described above are found only when immune complexes are used to elicit arthritis. We next compared articular cartilage damage in arthritic joints of the three mouse strains FcR Îł-chain(-/-), C57BL/6 (intermediate basal expression of FcÎłRs), and DBA/1 (high basal expression of FcÎłRs). Three indicators of cartilage damage were investigated: depletion of PGs, chondrocyte death, and erosion of the cartilage matrix. At day 3 after induction of ICA, there was no PG depletion in FcR Îł-chain(-/-) mice, whereas PG depletion in the matrix of the C57BL/6 mice was marked and that in the arthritic DBA/1 mice was even greater. PG depletion was still massive at days 7 and 14 in the DBA/1 mice, whereas by day 14 the PG content was almost completely restored in knee joints of the C57BL/6 mice. Chondrocyte death and erosion of cartilage matrix, two indicators of more severe cartilage destruction, were significantly higher in the DBA/1 than in the C57BL/6 mice, while both indicators were completely absent in the FcR Îł-chain(-/-) mice. Again, when arthritis was induced using other triggers (SCW, zymosan), all strains showed similar PG depletion and no chondrocyte death or matrix erosion. These findings underline the important role of immune complexes and FcÎłRs in irreversible cartilage damage. DISCUSSION: Our findings indicate that inflammation and subsequent cartilage damage caused by immune complexes may be related to the occurrence of FcÎłRs on macrophages. The absence of functional FcÎłRI and RIII prevented inflammation and cartilage destruction after induction of ICA, whereas high basal expression of FcÎłRs on resident joint macrophages of similarly treated mice susceptible to autoimmune arthritis was correlated with markedly more synovial inflammation and cartilage destruction. The difference in joint inflammation between the three strains was not due to different susceptibilities to inflammation per se, since intra-articular injection of zymosan or SCW caused comparable inflammation. Although extensive inflammatory cell mass was found in the synovium of all strains after intra-articular injection of zymosan, no irreversible cartilage damage (chondrocyte death or matrix erosion) was found. ICA induced in C57BL/6 and DBA/1 mice did cause irreversible cartilage damage at later time points, indicating that immune complexes and FcÎłRs play an important role in inducing irreversible cartilage damage. Macrophages communicate with immune complexes via FcÎł receptors. Absence of functional activating receptors completely abrogates the synovial inflammation, as was shown after ICA induction in FcR Îł-chain(-/-) mice. However, the Îł-chain is essential not only in FcÎłRI and RIII but also for FcΔRI (found on mast cells) and the T cell receptor (TcR)-CD3 (Tcells) complex of γΎT cells. However, T, B, or mast cells do not play a role in this arthritis that is induced by passive immunisation. Furthermore, this effect was not caused by a difference in clearance of IgG or complement deposition in the tissue. In this study, DBA/1 mice, which are susceptible to collagen-induced autoimmune arthritis and in a recent study have been shown to react hypersensitively to immune complexes, are shown to express higher levels of FcÎłRs on both synovial and peritoneal macrophages. Because antibodies directed against the different subclasses of FcÎłR are not available, no distinction could be made between FcÎłRII and RIII. Genetic differences in DBA/1 mice in genes coding for or regulating FcÎłRs may be responsible for altered FcÎłR expression. If so, these mouse strains would have a heightened risk for immune-complex-mediated diseases. To provide conclusive evidence for the roles of the various classes of FcÎłR during ICA, experiments are needed in which FcÎłRs are blocked with specific antibodies, or in which knockout mice lacking one specific class of FcÎłR are used. The only available specific antibody to FcÎłR (2.4G2) has a stimulatory effect on cells once bound to the receptor, and therefore cannot be used in blocking experiments. Experiments using specific knockout mice are now being done in our laboratory. Macrophages are the dominant type of cell present in chronic inflammation during RA and their number has been shown to correlate well with severe cartilage destruction. Apart from that, in humans, these synovial tissue macrophages express activating FcRs, mainly FcÎłIIIa, which may lead to activation of these macrophages by IgG-containing immune complexes. The expression of FcRs on the surface of these cells may have important implications for joint inflammation and severe cartilage destruction and therefore FCRs may constitute a new target for therapeutic intervention
EFFECT OF METHOTREXATE ALONE OR IN COMBINATION WITH SULPHASALAZINE ON THE PRODUCTION AND CIRCULATING CONCENTRATIONS OF CYTOKINES AND THEIR ANTAGONISTS. LONGITUDINAL EVALUATION IN PATIENTS WITH RHEUMATOID ARTHRITIS
Fatigue In Teenagers on the interNET - The FITNET Trial. A randomized clinical trial of web-based cognitive behavioural therapy for adolescents with chronic fatigue syndrome: study protocol. [ISRCTN59878666]
Contains fulltext :
97913.pdf (publisher's version ) (Open Access)BACKGROUND: Chronic Fatigue Syndrome (CFS) is increasingly recognized as a cause of disability and inactivity in adolescents in the Netherlands. CFS is characterized by unexplained fatigue lasting more than 6 months. Cognitive Behavioural Therapy (CBT) has proven to be effective. However, CBT availability for adolescents with CFS is limited and requires special therapeutic skills not always readily available. An alternative to the face-to-face CBT is FITNET, a web-based therapeutic program designed specifically for adolescents diagnosed with CFS, and their parents. This new CBT approach appeals to the modern youth, who grow up with internet as their main source of information. A web-based program offers the opportunity to lower thresholds for the acceptance and realization of healthcare. This treatment can be activated at any chosen time. The communication between patient and therapist can elapse asynchronously. If effective, this web-based program would greatly increase the therapeutic accessibility. METHODS/DESIGN: A randomized clinical trial is currently conducted. One-hundred-forty adolescents aged 12-18 years diagnosed with CFS will be recruited and randomized to one of two groups: FITNET or usual care. After 6 months, the usual care group will have access to the FITNET program. Outcomes will be assessed at baseline, post intervention, and at 6 months follow-up. Primary outcome measures are school presence, fatigue severity, and physical functioning. DISCUSSION: The FITNET study is the first randomized clinical trial which evaluates the effect of web-based CBT versus usual care in adolescents with CFS. The intervention is based on a theoretical existing model of CBT for patients with CFS. The results of this study will provide information about the possibility and efficacy of web-based CBT for adolescents with CFS and will reveal predictors of efficacy. TRIAL REGISTRATION: ISRCTN: ISRCTN59878666 and ClinicalTrials.gov: NCT00893438
The origin and orbit of the old, metal-rich, open cluster NGC 6791: Insights from kinematics
NGC 6791 is a unique stellar system among Galactic open clusters being at the
same time one of the oldest open clusters and the most metal rich. Combination
of its properties is puzzling and poses question of its origin. One possible
scenario is that the cluster formed close to the Galactic Center and later
migrated outwards to its current location. In this work we study the cluster's
orbit and investigate the possible migration processes which might have
displaced NGC 6791 to its present-day position, under the assumption that it
actually formed in the inner disk. To this aim we performed integrations of NGC
6791's orbit in a potential consistent with the main Milky Way parameters. In
addition to analytical expressions for halo, bulge and disk, we also consider
the effect of bar and spiral arm perturbations, which are expected to be very
important for the disk dynamical evolution, especially inside the solar circle.
Starting from state-of-the art initial conditions for NGC 6791, we calculate
1000 orbits back in time for about 1 Gyr turning on and off different
non-axisymmetric components of the global potential. We then compare
statistical estimates of the cluster's recent orbital parameters with the
orbital parameters of 10^4 test-particles originating close to the Galactic
Center (having initial galocentric radii in the range of 3-5 kpc) and
undergoing radial migration during 8 Gyr of forward integration. We find that a
model which incorporates a strong bar and spiral arm perturbations can indeed
be responsible for the migration of NGC 6791 from the inner disk (galocentric
radii of 3-5 kpc) to its present-day location. Such a model can provide orbital
parameters which are close enough to the observed ones. However, the
probability of this scenario as it results from our investigations is very low.Comment: 11 pages, 9 figures, 7 tables, accepted for publication in A&A || v2:
minor changes to match the published versio
Incidence, Characteristics and Implications of Thromboembolic Events in Patients with Muscle Invasive Urothelial Carcinoma of the Bladder Undergoing Neoadjuvant Chemotherapy
Purpose: Neoadjuvant chemotherapy and pelvic surgery are significant risk factors for thromboembolic events. Our study objectives were to investigate the timing, incidence and characteristics of thromboembolic events during and after neoadjuvant chemotherapy and subsequent radical cystectomy in patients with muscle invasive bladder cancer. Materials and Methods: We performed a multi-institutional retrospective analysis of 761 patients who underwent neoadjuvant chemotherapy and radical cystectomy for muscle invasive bladder cancer from 2002 to 2014. Median followup from diagnosis was 21.4 months (range 3 to 272). Patient characteristics included the Khorana score, and the incidence and timing of thromboembolic events (before vs after radical cystectomy). Survival was calculated using the Kaplan-Meier method. The log rank test and multivariable Cox proportional hazards regression were used to compare survival between patients with vs without thromboembolic events. Results: The Khorana score indicated an intermediate thromboembolic event risk in 88% of patients. The overall incidence of thromboembolic events in patients undergoing neoadjuvant chemotherapy was 14% with a wide variation of 5% to 32% among institutions. Patients with thromboembolic events were older (67.6 vs 64.6 years, p = 0.02) and received a longer neoadjuvant chemotherapy course (10.9 vs 9.7 weeks, p = 0.01) compared to patients without a thromboembolic event. Of the thromboembolic events 58% developed preoperatively and 72% were symptomatic. On multivariable regression analysis the development of a thromboembolic event was not significantly associated with decreased overall survival. However, pathological stage and a high Khorana score were adverse risk factors for overall survival. Conclusions: Thromboembolic events are common in patients with muscle invasive bladder cancer who undergo neoadjuvant chemotherapy before and after radical cystectomy. Our results suggest that a prospective trial of thromboembolic event prophylaxis during neoadjuvant chemotherapy is warranted.Peer reviewe
Uninvited Guests: Traditional Insect Repellents in Estonia used Against the Clothes Moth Tineola bisselliella, Human Flea Pulex irritons and Bedbug Cimex lectularius
Extensive folklore records from pre-modern Estonia give us an excellent opportunity to study a variety of local plant knowledge and plant use among the peasantry in various parts of the country. One important biocultural domain where plant knowledge has been crucial was in the various methods of combating different ectoparasites that cohabited and coexisted with humans and their domestic animals. Some of these methods were widely known (world-wide, Eurasia, Europe, Baltic Rim), while others were more local. Here we discuss ways of reducing clothes moths Tineola bisselliella (Hummel) (Lepidoptera: Tineidae), human fleas Pulex irritons L. (Siphonaptera: Pulicidae) and bedbugs Cimex lectularius L. (Hemiptera: Cimicidae) with the help of plants. Various taxa used as traditional repellents have been identified. The use of plants as repellents and their toxic principles are also discussed from a comparative perspective
Search for new neutral Higgs bosons through the H â ZAâ â+ââb b ÂŻ process in pp collisions at âs = 13 TeV
This paper reports on a search for an extension to the scalar sector of the standard model, where a new CP-even (odd) boson decays to a Z boson and a lighter CP-odd (even) boson, and the latter further decays to a b quark pair. The Z boson is reconstructed via its decays to electron or muon pairs. The analysed data were recorded in proton-proton collisions at a center-of-mass energy s = 13 TeV, collected by the CMS experiment at the LHC during 2016, corresponding to an integrated luminosity of 35.9 fbâ1. Data and predictions from the standard model are in agreement within the uncertainties. Upper limits at 95% confidence level are set on the production cross section times branching fraction, with masses of the new bosons up to 1000 GeV. The results are interpreted in the context of the two-Higgs-doublet model. [Figure not available: see fulltext.]
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