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ID PMID Title PublicationDate abstract
26842265 Molecular Actions of Glucocorticoids in Cartilage and Bone During Health, Disease, and Ste 2016 Apr Cartilage and bone are severely affected by glucocorticoids (GCs), steroid hormones that are frequently used to treat inflammatory diseases. Major complications associated with long-term steroid therapy include impairment of cartilaginous bone growth and GC-induced osteoporosis. Particularly in arthritis, GC application can increase joint and bone damage. Contrarily, endogenous GC release supports cartilage and bone integrity. In the last decade, substantial progress in the understanding of the molecular mechanisms of GC action has been gained through genome-wide binding studies of the GC receptor. These genomic approaches have revolutionized our understanding of gene regulation by ligand-induced transcription factors in general. Furthermore, specific inactivation of GC signaling and the GC receptor in bone and cartilage cells of rodent models has enabled the cell-specific effects of GCs in normal tissue homeostasis, inflammatory bone diseases, and GC-induced osteoporosis to be dissected. In this review, we summarize the current view of GC action in cartilage and bone. We further discuss future research directions in the context of new concepts for optimized steroid therapies with less detrimental effects on bone.
24255545 Inhibition of notch signalling ameliorates experimental inflammatory arthritis. 2015 Jan OBJECTIVE: To test the hypothesis that Notch signalling plays a role in the pathogenesis of rheumatoid arthritis (RA) and to determine whether pharmacological inhibition of Notch signalling with γ-secretase inhibitors can ameliorate the RA disease process in an animal model. METHODS: Collagen-induced arthritis was induced in C57BL/6 or Notch antisense transgenic mice by immunisation with chicken type II collagen (CII). C57BL/6 mice were administered with different doses of inhibitors of γ-secretase, an enzyme required for Notch activation, at disease onset or after onset of symptoms. Severity of arthritis was monitored by clinical and histological scores, and in vivo non-invasive near-infrared fluorescence (NIRF) images. Micro-CT was used to confirm joint destruction. The levels of CII antibodies and cytokines in serum were determined by ELISA and bead-based cytokine assay. The expression levels of cytokines were studied by quantitative PCR in rheumatoid synovial fibroblasts. RESULTS: The data show that Notch signalling stimulates synoviocytes and accelerates their production of proinflammatory cytokines and immune responses involving the upregulation of IgG1 and IgG2a. Pharmacological inhibition of γ-secretase and antisense-mediated knockdown of Notch attenuates the severity of inflammatory arthritis, including arthritis indices, paw thickness, tissue damage and neutrophil infiltration, and reduces the levels of active NF-κB, ICAM-1, proinflammatory cytokines and matrix metalloproteinase-3 activity in the mouse model of RA. CONCLUSIONS: These results suggest that Notch is involved in the pathogenesis of RA and that inhibition of Notch signalling is a novel approach for treating RA.
27038187 Relative expression and correlation of tumor necrosis factor-α, interferon-γ, and interl 2016 Jul Although tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), and interleukin-17 (IL-17) play important roles in RA, their relative expression and possible correlation in synovial tissues are not well understood. In this study, mRNA expression levels of IFN-γ, IL-17, and TNF-α were investigated in individual patients with RA and the correlations between pairs of these three pro-inflammatory cytokines were analyzed. Synovial tissues were obtained during arthroplasties from 24 joints of 24 RA patients. After harvesting synovial tissues, total RNA was isolated then quantitative real-time polymerase chain reaction (qRT-PCR) for IFN-γ, IL-17, and TNF-α was performed. Correlation of expression levels between them was also analyzed. Expression levels of TNF-α, IFN-γ, and IL-17 in patients receiving TNF inhibitors (TNFi) and those treated with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) alone were also compared between groups. Based on relative expression levels of the three pro-inflammatory cytokines, patients were classified into three major types; an IFN-γ plus TNF-α-dominant type, an IL-17-dominant type, and the other type. TNF-α expression levels were correlated with IFN-γ. In addition, there was a negative correlation between TNF-α and IL-17, and IFN-γ and IL-17. Median relative expression levels of TNF-α have no significant difference between the TNFi and the csDMARDs groups. In the rheumatoid synovial tissues, expression levels of TNF-α were modulated in parallel with IFN-γ, and TNF-α and IL-17, or IFN-γ and IL-17 did not co-express at high levels. This characteristic expression pattern of the three pro-inflammatory cytokines may be clinically useful information in the current cytokine-targeted treatment with biological DMARDs for RA.
25587188 Extensive glycosylation of ACPA-IgG variable domains modulates binding to citrullinated an 2016 Mar OBJECTIVES: To understand the molecular features distinguishing anti-citrullinated protein antibodies (ACPA) from 'conventional' antibodies in rheumatoid arthritis (RA). METHODS: Serum of ACPA-positive RA patients was fractionated by size exclusion chromatography and analysed for the presence of ACPA-IgG by ELISA. ACPA-IgG and non-citrulline-specific IgG were affinity purified from serum, plasma and/or synovial fluid and analysed by gel electrophoresis. Electrophoresis bands were excised, enzymatically digested and analysed by mass spectrometry. Binding affinity to citrullinated antigens was measured by ELISA and imaging surface plasmon resonance using recombinant monoclonal ACPA with molecular modifications. RESULTS: In all donor samples studied (n=24), ACPA-IgG exhibited a 10-20 kDa higher molecular weight compared with non-autoreactive IgG. This feature also distinguished ACPA-IgG from antibodies against recall antigens or other disease-specific autoantibodies. Structural analysis revealed that a high frequency of N-glycans in the (hyper)variable domains of ACPA is responsible for this observation. In line with their localisation, these N-glycans were found to modulate binding avidity of ACPA to citrullinated antigens. CONCLUSIONS: The vast majority of ACPA-IgG harbour N-glycans in their variable domains. As N-linked glycosylation requires glycosylation consensus sites in the protein sequence and as these are lacking in the 'germline-counterparts' of identified variable domains, our data indicate that the N-glycosylation sites in ACPA variable domains have been introduced by somatic hypermutation. This finding also suggests that ACPA-hyperglycosylation confers a selective advantage to ACPA-producing B cells. This unique and completely novel feature of the citrulline-specific immune response in RA elucidates our understanding of the underlying B cell response.
27376373 Efficacy and Treatment Costs of Monotherapy with bDMARDs in the Treatment of Rheumatoid Ar 2016 Aug INTRODUCTION: Only limited information is available on cost efficacy of the various biological agents used to treat patients with rheumatoid arthritis with intolerance or for whom it would be inappropriate to continue treatment with conventional agents. We estimated the efficacy and treatment costs of monotherapy with biological agents in the treatment of this group of patients. METHODS: Data from two previous meta-analyses in the treatment of patients who are intolerant to methotrexate (MTX), or for whom it would be inappropriate to continue treatment with MTX was used. Pharmacoeconomic comparison between biological agents was carried out to estimate the respective cost for the number needed to treat (NNT) compared to placebo using both American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) criteria. The analysis involved the four agents approved in Italy: adalimumab (ADA), etanercept (ETN), certolizumab pegol (CTZ), and tocilizumab (TCZ). A six-month period was considered sufficient to understand the most important differences in efficacy and treatment costs. Direct medical costs, including pharmacological therapy, administration and monitoring were considered. RESULTS: Using both ACR and EULAR criteria, TCZ (intravenous [iv]/subcutaneous [sc]) had a lower NNT than the other agents. The difference in NNT observed for ETN was more pronounced with EULAR criteria, whereas in the comparison with ADA, the most sensitive differences were observed with ACR criteria. ETN had the lowest treatment cost (€6402.19), followed by ADA (€6698.84), TCZ sc (€6887.61), and TCZ iv (€7130.83). TCZ sc had the lowest cost for NNT with both ACR and EULAR criteria. The differences compared to ETN and ADA were significant and related with the level of efficacy. Sensitivity analysis confirmed these results. CONCLUSION: TCZ is a cost-effective therapeutic option compared to other tumor necrosis factor-α inhibitors (ADA, ETA, CTZ) as first-line monotherapy for patients who are intolerant to MTX, or for whom it is inappropriate to continue treatment with MTX. FUNDING: Roche SpA.
26703449 Niclosamide induces apoptosis in human rheumatoid arthritis fibroblast-like synoviocytes. 2016 Feb To explore the effects of niclosamide on the viability and apoptosis of rheumatoid arthritis of fibroblast-like synoviocytes (rheumatoid arthritis (RA)fibroblast-like synoviocytes (FLS)), FLS obtained from RA patients were treated with niclosamide. Niclosamide significantly inhibited the viability of RA FLS in a concentration-dependent manner. Niclosamide treated FLS showed a significant increase in the percentage of apoptosis and higher intracellular ROS levels. N-acetyl-l-cysteine (NAC) pretreatment significantly attenuated niclosamide-induced apoptosis. The apoptotic response was due to the up-regulation of pro-apoptotic protein, Bax, and down-regulation of antiapoptotic protein, B cell lymphoma 2 (Bcl-2). The activation of mitochondrial pathway in niclosamide-treated RA FLS induced the cytochrome C, cleavage of caspase-9 and caspase-3. Additionally, niclosamide inhibited the phosphorylation of Akt. Collectively, our results reveal that niclosamide inhibits cell proliferation and induces mitochondrial apoptosis of RAFLSs, which is associated with the modulation of Akt signaling pathways.
26488775 Outcomes of a Newer-Generation Cementless Total Knee Arthroplasty Design. 2015 Oct Newer-generation cementless total knee arthroplasties (TKAs) aim to improve durability, function, and longevity. In a large series of cementless TKAs at a mean 4-year follow-up, the authors evaluated (1) survivorship, (2) range of motion, (3) patient-reported outcomes, and (4) complications. Mean age was 66 years (range, 34-88 years) and mean body mass index was 32.5 kg/m(2) (range, 20-54 kg/m(2)). Aseptic and septic implant survivorships were 99.6% and 99.5%, respectively. Mean extension, flexion, and Knee Society scores improved significantly. There were 3 septic failures. Aseptic failures included 3 aseptic loosenings, 1 polyethylene revision, and 1 revision to a cemented patella. This study showed excellent clinical and patient-reported outcomes of cementless TKA.
27999943 Long-term use of biologic agents does not increase the risk of serious infections in elder 2017 Mar This study aimed to determine whether the long-term use of biologic agents increases serious infections in elderly patients with rheumatoid arthritis (RA) and to determine the risk factors of serious infections in biologics-treated elderly RA patients. We retrospectively analyzed the incidence rate of serious infections that required hospitalization between biologics-treated and non-biologic disease-modifying antirheumatic drug (DMARD)-treated elderly RA patients (aged over 65 years). We examined the risk factors for serious infections in biologics-treated elderly RA patients. We found that, during a 3-year observation period, the incidence rate of serious infections was not significantly different between biologics-treated and non-biologic DMARD-treated elderly RA patients [8.0 (95% CI 4.7-13.5) and 6.3 (95% CI 4.1-9.5) events per 100 person-years of follow-up, respectively, P = 0.78]. The time to the first serious infection did not significantly differ between the two groups by the analysis of the Kaplan-Meier curves, either (P = 0.46). We then found that prednisolone doses alone were significantly associated with serious infections in biologics-treated elderly RA patients. Furthermore, we found that prednisolone at 1-4 mg/day was associated with serious infections in biologics-treated patients, but not non-biologic DMARD-treated patients. On the other hand, prednisolone at greater than 5 mg/day was associated with serious infections in both biologics-treated and non-biologics-treated patients. We show that there is not a significant difference between the incidence of serious infections between biologics group and non-biologics group in elderly RA patients (≧65 years) and that even very low-dose glucocorticoid use (prednisolone 1-4 mg/day) is a risk factor for serious infections in biologics-treated elderly RA patients.
26292180 Total glucosides of paeony can reduce the hepatotoxicity caused by Methotrexate and Leflun 2015 Sep OBJECTIVE: Total glucosides of paeony (TGP) have been confirmed to exert anti-inflammatory and hepatoprotective effects. Methotrexate (MTX) and Leflunomide (LEF) combination has a better efficacy in the treatment of active rheumatoid arthritis (RA), but hepatotoxicity was observed. In this study, we investigated the effect of TGP on hepatic dysfunction caused by MTX and LEF in patients with active RA. METHODS: A total of 268 patients with active RA (disease activity score in 28 joints, DAS28>3.2) were enrolled in this study. All patients were randomly assigned to two groups, the therapeutic group in which patients were treated with TGP (1.8 g/day) combined with MTX and LEF (MTX 10mg/week plus LEF 20mg/day) while in the control group, patients were treated without TGP up to 12 weeks. The efficacy and liver abnormalities were observed. RESULTS: The incidence of abnormal liver function within 12 weeks in TGP group was significantly lower than that in control group (11.38% vs 23.26%, P=0.013). The proportion of patients with ALT/AST >3 times ULN (upper limits of normal) was significantly lower in TGP group than control group (1.63% vs 7.75%, P=0.022). More patients achieved remission, good and moderate response in TGP group than control group at 4, 8 and 12 weeks, but the difference was not significant (P>0.05). The proportions of all adverse events were comparable in the two groups except for diarrhea. CONCLUSIONS: Our study demonstrates that TGP can significantly reduce the incidence and severity of liver damage caused by MTX+LEF in the treatment of active RA patients.
26414243 Breg Cells Are Numerically Decreased and Functionally Impaired in Patients With Systemic S 2016 Feb OBJECTIVE: Breg cells, a regulatory cell subset that produces interleukin-10 (IL-10), play a significant role in suppressing autoimmune responses and preventing autoimmunity. This study was undertaken to examine the number and function of Breg cells in patients with systemic sclerosis (SSc), a disease with many autoantibodies. METHODS: Forty-five patients with SSc (12 with early SSc, 33 with established disease including 16 with SSc-associated pulmonary fibrosis [PF]), 12 healthy control subjects, and 10 patients with rheumatoid arthritis (RA)-associated PF were studied. The phenotypes of immature/transitional Breg cells (CD19+CD24(high) CD38(high) ) and memory Breg cells (CD19+CD27+CD24(high) ) were evaluated by flow cytometry. The function of Breg cells was assessed by measuring the production of IL-10 after B cell activation. In addition, activation of p38 MAPK and STAT-3 was measured following stimulation of the cells with B cell receptor (BCR) and Toll-like receptor 9 (TLR-9). RESULTS: Percentages of memory Breg cells were decreased in patients with early SSc (mean ± SEM 1.85 ± 0.38%), those with established SSc (1.6 ± 0.88%), those with SSc-associated PF (1.52 ± 0.17%), and those with RA-associated PF (1.58 ± 0.26%), compared to healthy controls (6.3 ± 0.49%; each P < 0.001). Percentages of transitional Breg cells were also decreased. Expression of IL-10 by Breg cells after stimulation with TLR-9 was impaired in patients with SSc, particularly those with SSc-associated PF. Activation of STAT-3 and p38 MAPK was impaired in naive and memory B cells from patients with SSc after stimulation with BCR and TLR-9. Expression of the stimulatory CD19 receptor was increased in B cells and also increased, to a lesser extent, in Breg cells from patients with SSc compared to healthy controls. Percentages of memory B cells were decreased in patients with SSc, particularly in those with SSc-associated PF. CONCLUSION: This is the first study to demonstrate that Breg cells are phenotypically and functionally impaired in patients with SSc. Furthermore, in SSc, B cells exhibit impaired p38 MAPK and STAT-3 activation upon stimulation with BCR and TLR-9. The findings of decreased numbers of Breg cells along with increased expression of CD19 support the idea of B cell autoaggression acting as an immunopathogenic mediator in SSc.
27311191 [Prevention of surgical site infection for orthopaedic surgery in rheumatoid arthritis]. 2016 Jun Rheumatoid arthritis (RA) is considered to be a risk factor of surgical site infection(SSI). RA patients have higher rates of nasal and oral carriage, which can cause endogenous infections. The decolonization strategy and good oral care may decrease the rate of SSI in RA patients. In the perioperative management of medications, methotrexate can be used continuously during the perioperative period. Biological agents should be withheld for an appropriate period considering the half-lives of each agent. If possible, withholding them for at least a week prior to and after surgery is preferred. Whether biological agents increase the rate of SSI in orthopaedic surgery is unclear. Several reports have indicated that biological agents can increase the risk of SSI in total joint replacements. This warrants attention.
27824862 Delayed-Type Hypersensitivity to Metals of Environmental Burden in Patients with Takotsubo 2016 OBJECTIVE: Takotsubo syndrome (TS) is a heart condition characterised by a sudden transient left ventricular dysfunction; its pathophysiology is probably associated with elevated levels of catecholamines but the exact mechanism is not known as yet. Literature and clinical experience suggest that TS affects persons with various comorbidities. This pilot work aims to evaluate the frequency of comorbidities with potential pathological immune reactivity, and to evaluate the potential association between TS and hypersensitivity to metals assessed by LTT-MELISA®. METHODOLOGY, RESULTS: A total of 24 patients (23 women, 1 man) with a history of TS attack and 27 healthy controls were evaluated. Hypersensitivity was evaluated by a lymphocyte transformation test (LTT-MELISA®); a questionnaire of environmental burden was used to select evaluated metals. A total of 19 patients (79%) had at least one condition that might potentially be associated with pathological immune reactivity (autoimmune thyroid disease, drug allergy, bronchial asthma, cancer, contact dermatitis, rheumatoid arthritis). Hypersensitivity to metals was identified significantly more frequently in TS patients than in healthy controls (positive reaction to at least one metal was identified in 95.8% of TS patients and in 59.3% of controls; p = 0.003); the difference was statistically significant for mercury (45.8% and 14.8%, respectively; p = 0.029). CONCLUSION: Our work shows that conditions with pathological immune reactivity occur frequently in TS patients, and our data suggest a possible association between TS and hypersensitivity to metals (mercury in particular) evaluated by LTT-MELISA®. We also suggest that apart from the triggering stress factor, potential existence of other serious conditions should be considered when taking medical history of TS patients.
26648084 Pharmacokinetics and safety of single doses of tabalumab in subjects with rheumatoid arthr 2016 May AIMS: Two phase 1 studies evaluated the pharmacokinetics (PK), safety and biological activity of tabalumab, a human monoclonal antibody against B-cell activating factor (BAFF), administered intravenously (i.v.) or subcutaneously (s.c.) in subjects with rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE). METHODS: In study A, subjects with RA (n = 23) or SLE (n = 6) received a single i.v. dose of tabalumab (RA 0.01, 0.04, 0.125, 0.5, 2.0, and 8.0 mg kg(-1) and SLE 0.125 or 2.0 mg kg(-1) ) or placebo. In study B, subjects with RA received a single tabalumab dose i.v. (10 mg) (n = 12) or s.c. (20 mg) (n = 12). Serum tabalumab and CD20+ B cells were evaluated and safety was assessed throughout both studies. RESULTS: Tabalumab PK were non-linear across the 0.01 to 8.0 mg kg(-1) dose range. Clearance (CL) decreased from 2.9 to 0.1 l day(-1) and terminal half-life (t1/2 ) increased from about 1.6 to 25 days. Subjects with RA or SLE had similar PK. After s.c. dosing, tabalumab time to maximal concentration (tmax ) was 5.5 days. Absolute bioavailability (F) was approximately 62%. Following tabalumab dosing, CD20+ B cells transiently increased from baseline followed by a progressive decrease below baseline. CONCLUSION: A single tabalumab dose administered i.v. or s.c. was well tolerated and had non-linear CL over the dose range investigated in subjects with RA and SLE. The non-linearity likely reflects target-mediated CL due to binding to BAFF. Tabalumab showed biological activity based on changes in peripheral CD20+ lymphocyte numbers in both subjects with RA and SLE.
26246004 IgG Subclass Specificity Discriminates Restricted IgM Rheumatoid Factor Responses From Mor 2015 Dec OBJECTIVE: To investigate the presence and patterns of specific IgG subclass recognition by IgM rheumatoid factor (IgM-RF) and IgA-RF with a newly developed enzyme-linked immunosorbent assay (ELISA), which can discriminate between polyspecific and restricted RF responses. METHODS: Polyspecific and restricted RF responses were determined with our ELISA, which uses individually coated recombinant IgG subclasses instead of polyclonal IgG as target antibodies. Fine specificity was determined using target antibodies with single amino acid mutations in the Fc region. RESULTS: In a screening panel of 93 sera that were previously found to be IgM-RF positive in a conventional RF assay, we were able to discriminate between sera with polyspecific IgM-RF responses (i.e., RF responses directed against all 4 IgG subclasses) and those with restricted IgM-RF responses, with low or absent relative reactivity against IgG2, IgG3, or IgG4. We found the largest variation for anti-IgG3 reactivity. Samples without detectable anti-IgG4 reactivity formed an independent group from the other restricted RF responses and the polyspecific RF responses. The specificity of these anti-IgG4-negative sera could be pinpointed to single amino acid differences between IgG1 and IgG4. Polyspecific RF responses more often showed signs of RF response maturation, with more isotype switching to IgA-RF, as compared to restricted RF responses. In a cohort of IgM-RF+ and/or anti-citrullinated protein antibody (ACPA)-positive arthralgia patients, we found restricted RF responses in 35% (49 of 140) of RF+/ACPA- patients, while RF+/ACPA+ patients, who have a much higher risk of developing rheumatoid arthritis, virtually always (123 of 128 [96%]) showed a polyspecific RF response. CONCLUSION: IgG subclass-specific RF distinguishes between immature restricted RF responses and potentially more pathogenic, ACPA-associated polyspecific responses.
25557658 The effect of tocilizumab on bone mineral density, serum levels of Dickkopf-1 and bone rem 2015 Mar Previous studies showed that the control of inflammation by biological therapies has a positive effect on bone in inflammatory diseases. The objective of this study was to assess the effects on bone mineral density (BMD) and bone remodeling of an anti-IL-6 monoclonal antibody (tocilizumab (TCZ)) in patients with rheumatoid arthritis (RA). METHODS: One hundred and three patients (75% women, 52±12years) with active RA were treated with TCZ 8mg/kg + methotrexate (MTX) every 4 weeks during 48 weeks. Hip and lumbar spine BMDs were measured at baseline and after 48 weeks by dual energy X-ray absorptiometry (DXA). Pro-collagen serum type I N-terminal propeptide (PINP), serum C-terminal cross-linked telopeptide of type I collagen (CTX-I), and serum levels of total Dickkopf-1 (Dkk-1) and sclerostin were assessed at baseline, 12 and 48 weeks. RESULTS: BMD was available for 76 patients at baseline and at the end of the study. There was no change in lumbar spine and hip BMD over 48 weeks. Serum PINP increased from baseline by 22% (P≤0.001) and 19% (P≤0.001) at week 12 and week 48, whereas serum CTX-I remained stable. Serum DKK-1 significantly decreased from baseline by -31% (P≤0.001) and -25% (P=0.025) at week 12 and 48. Similar results were observed in the patients receiving low doses of oral corticosteroids. CONCLUSION: In this 1-year prospective open study, patients with active RA receiving TCZ and MTX had no change in BMD, a decrease in serum DKK-1 and an increase in bone formation marker.
27511630 Inhibition of CDK9 as a therapeutic strategy for inflammatory arthritis. 2016 Aug 11 Rheumatoid arthritis is characterised by synovial inflammation and proliferation of fibroblast-like synoviocytes. The induction of apoptosis has long been proposed as a target for proliferative autoimmune diseases, and has further been shown to act as a successful treatment of experimental models of arthritis, such as collagen-induced arthritis. Here we examined the effects of specific oral small-molecule inhibitors of the transcription regulating cyclin-dependent kinase 9 on the development and progression of collagen-induced arthritis. DBA/1 mice were immunised with bovine collagen type II and treated orally with specific CDK9 inhibitors. The effects of CDK9 inhibition on RNA levels and protein expression, apoptosis induction, caspase activation and lymphocyte phenotype were further analysed. Mice showed a significant delay in disease onset and a reduction in disease severity following treatment with CDK9 inhibitors. Inhibiting CDK9 activity in peripheral blood mononuclear cells resulted in the loss of Mcl-1 expression at both the protein and RNA levels, along with a subsequent increase in apoptosis. CDK9 specific inhibitors may be a potential alternative treatment not only of cancer, but also for autoimmune- and inflammatory diseases. Taken together, these results show that transient inhibition of CDK9 induces apoptosis in leukocyte subsets and modulates the immune response.
27895040 The role of non-invasive cardiovascular imaging in the assessment of cardiovascular risk i 2017 Jul This review assesses the risk assessment of cardiovascular disease (CVD) in rheumatoid arthritis (RA) and how non-invasive imaging modalities may improve risk stratification in future. RA is common and patients are at greater risk of CVD than the general population. Cardiovascular (CV) risk stratification is recommended in European guidelines for patients at high and very high CV risk in order to commence preventative therapy. Ideally, such an assessment should be carried out immediately after diagnosis and as part of ongoing long-term patient care in order to improve patient outcomes. The risk profile in RA is different from the general population and is not well estimated using conventional clinical CVD risk algorithms, particularly in patients estimated as intermediate CVD risk. Non-invasive imaging techniques may therefore play an important role in improving risk assessment. However, there are currently very limited prognostic data specific to patients with RA to guide clinicians in risk stratification using these imaging techniques. RA is associated with increased risk of CV mortality, mainly attributable to atherosclerotic disease, though in addition, RA is associated with many other disease processes which further contribute to increased CV mortality. There is reasonable evidence for using carotid ultrasound in patients estimated to be at intermediate risk of CV mortality using clinical CVD risk algorithms. Newer imaging techniques such as cardiovascular magnetic resonance and CT offer the potential to improve risk stratification further; however, longitudinal data with hard CVD outcomes are currently lacking.
27712663 Whole- and partial-body cryostimulation/cryotherapy: Current technologies and practical ap 2016 Oct Cold therapy is commonly used as a method to relieve pain and inflammation. This review focuses primarily on two methods of cold therapy that have received recent attention: whole-body cryotherapy and partial-body cryotherapy. These methods are used to induce physiological and psychological benefits in humans in the context of medicine, health and sports. The subjects experiencing cryotherapy are dressed in minimal clothing and are exposed to very cold air (at -110°C or less) for 1-4min. Despite the increasing scientific interest in these methods, there is a lack of information about the technologies used. Moreover, there is no existing reference concerning exposure protocols and the relationship between temperature, duration, number of repetitions and the treatments' desired effects. The aim of this review is to compare whole- and partial-body cryotherapy effects (especially on skin temperature) and to classify the protocols for exposure according to the desired effects. This review emphasises 1) the lack of information concerning the actual temperatures inside the cabin or chamber during exposure and 2) the heterogeneity among the exposure protocols that have been reported in the scientific literature. This review will be valuable and relevant to health professionals endeavouring to optimize the cold treatments offered to patients and producers of cryotherapy apparatus striving to create more efficient devices that meet market requirements.
25262152 Enlight: web-based integration of GWAS results with biological annotations. 2015 Jan 15 Identifying causal variants remains a key challenge in post-GWAS (genome-wide association study) era, as many GWAS single-nucleotide polymorphisms (SNPs) (including imputed ones) fall into non-coding regions, making it difficult to associate statistical significance with predicted functionality. Therefore, we created a web-based tool, Enlight, which overlays functional annotation information, such as histone modification states, methylation patterns, transcription factor binding sites, eQTL and higher-order chromosomal structure, to GWAS results. AVAILABILITY AND IMPLEMENTATION: Accessible by a Web browser at http://enlight.usc.edu.
25851105 On the interactions of leflunomide and teriflunomide within receptor cavity--NMR studies a 2015 May Leflunomide is a disease-modifying antirheumatic drug with antiinflammatory and immunosuppressive activity used for the treatment of psoriatic and rheumatoid arthritis. It undergoes rapid metabolization to teriflunomide, a metabolite that is responsible for the biological activity of leflunomide. Continuing our investigations on the interactions of biologically important azahetarenes with the environment, we focused on leflunomide and its active metabolite, teriflunomide, considering the interactions teriflunomide-amino acid within the target protein (dihydroorotate dehydrogenase) using density functional theory, as well as ONIOM techniques. The results of theoretical studies have shown that the interactions of teriflunomide with tyrosine and arginine involve principally the amide fragment of teriflunomide. The presence of the internal hydrogen bond between (Z)-teriflunomide carbonyl oxygen and enolic hydroxyl decreases the interaction strength between teriflunomide and tyrosine or arginine. Even the E isomer of teriflunomide would usually provide a stronger interaction teriflunomide-amino acid than the Z isomer with the internal hydrogen bond.