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ID PMID Title PublicationDate abstract
26330959 Delta Reverse Polarity Shoulder Replacement: Single Surgeon Experience with a Minimum 2-Ye 2015 Sep BACKGROUND: The delta reverse shoulder replacement system was developed for the treatment of rotator cuff arthropathy so that the deltoid can substitute for the deficient rotator cuff. To evaluate the results of delta reverse shoulder replacement for functional improvement and complications in a consecutive series by a single surgeon over a period of six years with a minimum follow-up of 2 years. METHODS: The data were collected retrospectively from electronic theatre records. Over a period of 6 years (2006-2012), 46 cases that fulfilled the inclusion criteria were identified. There were 34 females and 12 males. The average age of patients was 76.2 years (range, 58 to 87 years). A single surgeon performed all procedures using the anterosuperior approach. The mean follow-up time was 49 months (range, 24 to 91 months). All cases had preoperative and postoperative Constant scores. We collected the data on indications, hospital stay, and change in the Constant score, complications, and reoperation rates. RESULTS: The main indication for surgery was rotator cuff arthropathy (52.2%), followed by massive rotator cuff tear (28.3%), osteoarthritis (8.7%), fractures (6.5%), and rheumatoid arthritis (4.3%). Also, 65.2% of the cases were referred by general practitioners, 26% of the cases were referred by other consultants, and 8.8% of the cases were already under the care of a shoulder surgeon. The average preoperative Constant score was 23.5 (range, 8 to 59). The average Constant score at the final follow-up was 56 (range, 22 to 83). On average, there was an improvement of 33 points in the Constant score. The improvement in the Constant score was significant (p < 0.001). We observed complications in four patients (8.6%). Three of four patients (6.5%) needed reoperation. The first complication was pulmonary embolism in the early postoperative period. The other complications included dissociation of the glenosphere from the metaglene, deltoid detachment, and stitch abscess. CONCLUSIONS: This is a single-surgeon, single-approach series of 46 cases with a minimum follow-up of 2 years. At this stage, the results are encouraging with no cases of loosening, dislocation, or nerve injury.
26162403 Differential accumulation and function of proinflammatory 6-sulfo LacNAc dendritic cells i 2015 Oct Human Slan DCs have been studied in patients with psoriasis, rheumatoid arthritis, cancer, and autoimmune diseases. In this study, we investigated the frequency, phenotype, and function of Slan DCs in blood, colon, as well as mLNs of patients with IBD. We first show that the frequency of circulating CD14(dull)Slan DCs was reduced in CD patients refractory to immunosuppressive drugs or TNF-α blockers relative to untreated CD, UC, and healthy subjects. In blood of CD patients, Slan DCs expressed CD172a, as detected by CD47 fusion protein binding, when compared with its lack of expression in control subjects. Next, we demonstrate that CD172a(+)Slan DCs that produced IL-1β and TNF-α accumulated in mLNs and colons of CD patients. The CD172a(+)Slan DCs up-regulated their expression of CD14 in CD tissues and the proinflammatory cytokines were produced in CD14(bright)CD172a(+)Slan DCs. By contrast, no difference was noted in the frequency of Slan DCs between inflamed, noninflamed colonic mucosa of UC patients and control, non-IBD donors. Finally, the percentage of cytokine-producing Slan DCs also augmented in response to TLR2 and NOD2 in in vitro stimulation in PBMCs of CD, but not UC, patients. In conclusion, we propose that proinflammatory CD14(bright)CD172a(+)Slan DCs are a distinguishing feature between CD and UC, as these cells accumulate uniquely in mLNs and colonic mucosa of CD patients. Thus, Slan DCs may contribute to CD immunopathogenesis.
25721612 Lower PHQ-9 cutpoint accurately diagnosed depression in people with long-term conditions a 2015 May 1 BACKGROUND: Major Depressive Disorder (MDD) is frequent in the Accident and Emergency Department (AED) but is often unrecognized. We aimed to assess the prevalence of MDD and determine the psychometric properties of the PHQ-9 in diagnosing MDD in patients with long-term medical conditions attending an AED. METHODS: The PHQ-9 was administered to 349 patients with diabetes, COPD and chronic inflammatory rheumatic diseases, mainly rheumatoid arthritis and spondyloarthropathies, visiting an AED. The MINI interview was used as the criterion standard for MDD. Receiver operator characteristic (ROC) curve analysis was performed to determine the optimal PHQ-9 cutpoint for MDD. Construct validators included psychological distress (SCL-90-R), illness perceptions (B-IPQ) and Health-Related Quality of Life (WHOQOL-BREF). RESULTS: The prevalence of MDD was 27.2%. At an optimal cutpoint of 8, PHQ-9 had a sensitivity of 90.5% and specificity of 89.4%. The area under the curve (0.96) was excellent. Convergent validity was established by the strong associations between PHQ-9 scores and functional status, SCL-90-R depression, illness perceptions and AED visits during the previous year. LIMITATIONS: The sample consisted of multiple rather a single disease group, preventing us from accounting for illness severity using specific disease severity indices. CONCLUSION: MDD is frequent in patients with long-term medical conditions attending the AED and the PHQ-9, at a cutpoint of 8, is an accurate, reliable and valid measure for MDD screening in this patient population.
25556904 Rituximab-associated hypogammaglobulinemia: incidence, predictors and outcomes in patients 2015 Feb Rituximab is a B cell depleting monoclonal antibody used to treat lymphoma and autoimmune disease. Hypogammaglobulinemia has occurred after rituximab for lymphoma and rheumatoid arthritis but data are scarce for other autoimmune indications. This study describes the incidence and severity of hypogammaglobulinemia in patients receiving rituximab for small vessel vasculitis and other multi-system autoimmune diseases. Predictors for and clinical outcomes of hypogammaglobulinemia were explored. We conducted a retrospective study in a tertiary referral specialist clinic. The severity of hypogammaglobulinemia was categorized by the nadir serum IgG concentration measured during clinical care. We identified 288 patients who received rituximab; 243 were eligible for inclusion with median follow up of 42 months. 26% were IgG hypogammaglobulinemic at the time that rituximab was initiated and 56% had IgG hypogammaglobulinemia during follow-up (5-6.9 g/L in 30%, 3-4.9 g/L in 22% and <3 g/L in 4%); IgM ≤0.3 g/L in 58%. The nadir IgG was non-sustained in 50% of cases with moderate/severe hypogammaglobulinemia. A weak association was noted between prior cyclophosphamide exposure and nadir IgG concentration, but not cumulative rituximab dose. IgG concentrations prior to and at the time of rituximab correlated with the nadir IgG post rituximab. IgG replacement was initiated because of recurrent infection in 12 (4.2%) patients and a lower IgG increased the odds ratio of receiving IgG replacement. Rituximab is associated with an increased risk of hypogammaglobulinemia but recovery of IgG level can occur. IgG monitoring may be useful for patients receiving rituximab.
25496409 Pulmonary infections following immunosuppressive treatments during hospitalization worsen 2015 Jul OBJECTIVE: Connective tissue disease-associated interstitial pneumonia (CTD-IP) significantly affects the mortality of patients with CTD. The purpose of the present study is to identify causes and risk factors for death during hospitalization for immunosuppressive treatment of CTD-IP. METHODS: A multicenter, retrospective study was conducted that collected data from patients with CTD who had been hospitalized for commencing or intensifying immunosuppressive treatment of CTD-IP using a standardized case report form. Risk factors were identified using the Cox proportional hazard regression model. RESULTS: A total of 322 CTD-IP patients were enrolled with rheumatoid arthritis (n = 84), systemic lupus erythematosus (n = 13), polymyositis (n = 33), dermatomyositis (n = 69), systemic sclerosis (n = 55), mixed connective tissue disease (n = 21), microscopic polyangiitis (n = 19), and overlap syndrome (n = 28). Of the 42 patients who died during hospitalization, 22 died from CTD-IP, 15 from CTD-IP and pulmonary infection, 2 from pulmonary infection, and 3 from other causes. Age ≥ 65 years and development of pulmonary infections after commencing or intensifying immunosuppressive treatments were identified as risk factors for death during hospitalization after adjusting for covariates. CONCLUSION: Careful consideration of the benefit-risk balance of immunosuppressive treatment for CTD-IP is indispensable for improving the short-term vital prognosis of these patients.
25465161 2-Methoxyestradiol inhibits bleomycin-induced systemic sclerosis through suppression of fi 2015 Jan BACKGROUND: The most dominant feature of systemic sclerosis (SSc) is fibrosis, which is caused by overproduction of collagen by fibroblasts. 2-Methoxyestradiol (2-ME) has exhibited disease-modifying activity in animal models of rheumatoid arthritis and autoimmune encephalomyelitis and inhibitory effect in cell proliferation and collagen synthesis. Therefore, we hypothesized that 2-ME may exhibit antifibrotic effect in SSc. OBJECTIVE: To investigate the antifibrotic effect of 2-ME in SSc. METHODS: We established a bleomycin-induced SSc mice model by injection with bleomycin daily for 21 days. 2-ME (100mg/kg/d) was simultaneously administered for 14 days. On the end of Week1 (W1), W2, W3 and W4, skins and lungs were collected for histological examination and analysis of hydroxyproline content and mRNA level of α1(I) procollagen (COL1A1) and COL1A2. In skin fibroblasts derived from SSc patients and healthy subjects treated with 2-ME (1, 5, or 25 μM), we examined cell proliferation, expression of α-smooth muscle actin (SMA) and mRNA level of COL1A1, COL1A2, COL3A1, matrix metalloproteinase(MMP)-1 and tissue inhibitors of MMP (TIMP)-1. RESULTS: We found reduced dermal thickness and lung fibrosis and decreased hydroxyproline content and mRNA level of COL1A1 and COL1A2 in skin and lung in SSc mice treated with 2-ME. In cell study, we observed a dose- and time-dependent inhibitory effect on proliferation of SSc fibroblasts by 2-ME. We also detected reduced α-SMA expression, decreased mRNA level of COL1A1, COL1A2, COL3A1 and TIMP-1, and increased mRNA level of MMP-1 in SSc fibroblasts treated with 2-ME. CONCLUSION: 2-ME could suppress SSc tissue fibrosis, which may be attributable to its inhibitory effect on the excessive proliferation, differentiation and production of collagen in fibroblasts. 2-ME is rising as a prospective agent for control of fibrosis in SSc.
27183593 RBP-J-Regulated miR-182 Promotes TNF-α-Induced Osteoclastogenesis. 2016 Jun 15 Increased osteoclastogenesis is responsible for osteolysis, which is a severe consequence of inflammatory diseases associated with bone destruction, such as rheumatoid arthritis and periodontitis. The mechanisms that limit osteoclastogenesis under inflammatory conditions are largely unknown. We previously identified transcription factor RBP-J as a key negative regulator that restrains TNF-α-induced osteoclastogenesis and inflammatory bone resorption. In this study, we tested whether RBP-J suppresses inflammatory osteoclastogenesis by regulating the expression of microRNAs (miRNAs) important for this process. Using high-throughput sequencing of miRNAs, we obtained the first, to our knowledge, genome-wide profile of miRNA expression induced by TNF-α in mouse bone marrow-derived macrophages/osteoclast precursors during inflammatory osteoclastogenesis. Furthermore, we identified miR-182 as a novel miRNA that promotes inflammatory osteoclastogenesis driven by TNF-α and whose expression is suppressed by RBP-J. Downregulation of miR-182 dramatically suppressed the enhanced osteoclastogenesis program induced by TNF-α in RBP-J-deficient cells. Complementary loss- and gain-of-function approaches showed that miR-182 is a positive regulator of osteoclastogenic transcription factors NFATc1 and B lymphocyte-induced maturation protein-1. Moreover, we identified that direct miR-182 targets, Foxo3 and Maml1, play important inhibitory roles in TNF-α-mediated osteoclastogenesis. Thus, RBP-J-regulated miR-182 promotes TNF-α-induced osteoclastogenesis via inhibition of Foxo3 and Maml1. Suppression of miR-182 by RBP-J serves as an important mechanism that restrains TNF-α-induced osteoclastogenesis. Our results provide a novel miRNA-mediated mechanism by which RBP-J inhibits osteoclastogenesis and suggest that targeting of the newly described RBP-J-miR-182-Foxo3/Maml1 axis may represent an effective therapeutic approach to suppress inflammatory osteoclastogenesis and bone resorption.
27338297 Expression of Long Interspersed Nuclear Element 1 Retroelements and Induction of Type I In 2016 Nov OBJECTIVE: Increased expression of type I interferon (IFN) and a broad signature of type I IFN-induced gene transcripts are observed in patients with systemic lupus erythematosus (SLE) and other systemic autoimmune diseases. To identify disease-relevant triggers of the type I IFN pathway, this study sought to investigate whether endogenous virus-like genomic repeat elements, normally silent, are expressed in patients with systemic autoimmune disease, and whether these retroelements could activate an innate immune response and induce type I IFN. METHODS: Expression of type I IFN and long interspersed nuclear element 1 (LINE-1; L1) was studied by polymerase chain reaction, Western blotting, and immunohistochemistry in samples of kidney tissue from patients with lupus nephritis and minor salivary gland (MSG) tissue from patients with primary Sjögren's syndrome (SS). Induction of type I IFN by L1 was investigated by transfection of plasmacytoid dendritic cells (PDCs) or monocytes with an L1-encoding plasmid or L1 RNA. Involvement of innate immune pathways and altered L1 methylation were assessed. RESULTS: Levels of L1 messenger RNA transcripts were increased in lupus nephritis kidneys and in MSG tissue from patients with SS. Transcript expression correlated with the expression of type I IFN and L1 DNA demethylation. L1 open-reading frame 1/p40 protein and IFNβ were expressed in MSG ductal epithelial cells and in lupus nephritis kidneys, and IFNα was detected in infiltrating PDCs. Transfection of PDCs or monocytes with L1-encoding DNA or RNA induced type I IFN. Inhibition of Toll-like receptor 7 (TLR-7)/TLR-8 reduced the induction of IFNα by L1 in PDCs, and an inhibitor of IKKε/TANK-binding kinase 1 abrogated the induction of type I IFN by L1 RNA in monocytes. CONCLUSION: L1 genomic repeat elements represent endogenous nucleic acid triggers of the type I IFN pathway in SLE and SS and may contribute to initiation or amplification of autoimmune disease.
27900509 Conversion of hip fusion to total hip arthroplasty: clinical, radiological outcomes and co 2017 Jan OBJECTIVE: The purpose of this retrospective study is to report the clinical and radiological outcome of total hip arthroplasty in patients with previous hip arthrodesis. PATIENTS AND METHODS: We retrospectively reviewed 28 (40 hips) prospectively followed patients in whom ankylosed hips were converted to total hip arthroplasty (THA) between 2010 and 2014 in our institution. The average age at the time of the conversion operation was 40.8 ± 9.8 years (range 24-62). The ankylosis had lasted 20.4 ± 13.0 years (range 3-56) before conversion surgery. The etiology of the ankylosis was septic arthritis in 10 (25%), post-traumatic hip osteoarthritis in 8 (20%), developmental hip dysplasia in 6 (15%), rheumatoid arthritis in 6 (15%), primary osteoarthritis in 5 (12.5%) and ankylosing spondylitis in 5 (12.5%) hips. The indications for arthroplasty were intractable low back pain in 14 (50%), hip pain in 24 (85.7%), and ipsilateral knee pain in 19 (67.8%) patients. Harris Hip Score (HHS) was used to rate the clinical results before and after the surgery. Radiographic evaluations included component malposition and loosening. All complications during the study period were recorded. RESULTS: The mean follow-up period was 39.9 ± 10.6 months (range 24-60). The mean preoperative HHS was 33.3 ± 8.6 (range 18-50) and the mean HHS at the final follow-up was 74.9 ± 8.6 (range 52-97). There was a statistically significant increase in HHS (p = 0.0001). HHS was excellent in 1, good in 6, fair in 14 and poor in 7 patients. Increase in HHS was lower than 20 points in one patient (18 points), and one patient required two-staged exchange procedure due to deep infection. Thus, according to our success criteria (increase in HHS more than 20 points, radiographically stable implant, and no further surgical reconstruction), 92.8% (26/28) of patients had benefit from the surgery. Trendelenburg sign was positive in 12 hips. There was limb length inequality in 11 patients (mean 0.5 cm, range 1-3 cm). No patients had heterotopic ossification, sciatic nerve palsy or dislocation. There were five intra-operative fractures of the greater trochanter that were treated with cable wiring. One patient had trochanteric avulsion injury and was treated with trochanteric grip and cables. One patient (2.5%) had deep infection one year after the conversion THA and was treated with two-staged exchange procedure. CONCLUSION: Conversion hip arthroplasty is an effective treatment method which provides functional recovery and patient satisfaction. However, a proper surgical technique and planning is necessary to minimize the complications.
27255462 Standardizing disease-specific quality of life measures across multiple chronic conditions 2016 Jun 2 BACKGROUND: To document the development and evaluation of the Quality of life Disease Impact Scale (QDIS®), a measure that standardizes item content and scoring across chronic conditions and provides a summary, norm-based QOL impact score for each disease. METHODS: A bank of 49 disease impact items was constructed from previously-used descriptions of health impact to represent ten frequently-measured quality of life (QOL) content areas and operational definitions successfully utilized in generic QOL surveys. In contrast to health in general, all items were administered with attribution to a specific disease (osteoarthritis, rheumatoid arthritis, angina, myocardial infarction, congestive heart failure, chronic kidney disease (CKD), diabetes, asthma, or COPD). Responses from 5418 adults were analyzed as five disease groups: arthritis, cardiovascular, CKD, diabetes, and respiratory. Unidimensionality, item parameter and scale-level invariance, reliability, validity and responsiveness to change during 9-month follow-up were evaluated by disease group and for all groups combined using multi-group confirmatory factor analysis (MGCFA), item response theory (IRT) and analysis of variance methods. QDIS was normed in an independent chronically ill US population sample (N = 4120). RESULTS: MGCFA confirmed a 1-factor model, justifying a summary score estimated using equal parameters for each item across disease groups. In support of standardized IRT-based scoring, correlations were very high between disease-specific and standardized IRT item slopes (r = 0.88-0.96), thresholds (r = 0.93-0.99) and person-level scores (r ≥ 0.99). Internal consistency, test-retest and person-level IRT reliability were consistently satisfactory across groups. In support of interpreting QDIS as a disease-specific measure, in comparison with generic measures, QDIS consistently discriminated markedly better across disease severity levels, correlated higher with other disease-specific measures in cross-sectional tests, and was more responsive in comparisons of groups with better, same or worse evaluations of disease-specific outcomes at the 9-month follow-up. CONCLUSIONS: Standardization of content and scoring across diseases was shown to be justified psychometrically and enabled the first summary measure of disease-specific QOL impact normed in the chronically ill population. This disease-specific approach substantially improves discriminant validity and responsiveness over generic measures and provides a basis for better understanding the relative QOL impact of multiple chronic conditions in research and clinical practice.
26932562 Anti-TNF certolizumab pegol induces antioxidant response in human monocytes via reverse si 2016 Mar 1 BACKGROUND: Anti TNF drugs have been widely used in rheumatoid arthritis (RA) but only 70 to 80 % of patients respond to this therapy. Exploring the mode of action of anti-TNF drugs remains important in order to improve the efficiency of the treatment and enhance our knowledge of inflammation. TNF-α exists as classical soluble cytokine as well as transmembrane protein (tmTNF-α). Evidence suggests that tmTNF-α can induce reverse signaling. In the present study, we have explored consequences of reverse signaling in human monocytes using certolizumab pegol (CZP). METHODS: Monocytes were purified from healthy blood donors and were incubated with CZP. Nuclear translocation of Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) was evaluated by wide-field microscopy and cell fractionation. Heme oxygenase 1 (HO-1) was assessed by RT-qPCR and western blot. Monocytes were stimulated with lipopolysaccharide (LPS). IL-1β was quantitated by RT-qPCR. Reactive oxygen species (ROS) were evaluated by flow cytometry using the H2DCFDA fluorescent marker. RESULTS: CZP induced rapid minimal ROS production and Nrf2 nuclear translocation. This was followed by HO-1 mRNA and protein production. IL-1β induction by LPS was inhibited at the mRNA and protein level. At a later time-point, CZP was able to counteract the strong production of ROS induced by LPS. Reverse signaling was suggested by short kinetics of Nrf2 translocation, extensive washing of CZP and the use of anti-TNF-Rs antibodies. CONCLUSION: Our data suggest a novel mechanism of ROS modulation by CZP. This observation sheds new light on the function of reverse signaling and on potential mechanisms of action of anti-TNF drugs.
27865216 Establishing the Role of Unlinked Total Elbow Arthroplasty in Low Demand Patients: A Long- 2016 Jun INTRODUCTION: Experience with total elbow arthroplasty is scarce in most centers. It seems to have a significant rate of associated complications. Most studies are based on non-validated outcome measures and short-term results. MATERIAL AND METHODS: We selected patients undergoing unlinked total elbow arthroplasty, with a resultant sample of thirteen cases, with a mean postoperative follow-up of 72 months. We applied the Mayo Elbow Score and all patients underwent an X-ray study, prior to surgery and during the follow-up period. RESULTS: All patients have a systemic inflammatory condition. The mean Mayo score increased from 43 points preoperatively to 70 and 80 points at the intermediate follow-up period (with a mean of 15 months after the operation) and at the time of the latest follow-up evaluation (with a mean of 72 months after the operation). There was an increase in range of motion in all cases. There was one case of mechanical failure and two cases of transient ulnar neuropathy. DISCUSSION: Elbow dysfunction causes great loss in patient´s quality of life, incapacitating them for the simplest activities. Small improvements in range of motion and pain relief result in significant changes in the patient's functional ability. There is a demand to clarify the performance of total elbow arthroplasty in selected patient groups in order to throw more light on the relative roles of the available implants. CONCLUSIONS: The results obtained in this study seem to confirm the long-term benefit of the unlinked arthroplasty in severe joint dysfunction in patients with low physical demand, particularly in rheumatoid arthritis, a common and limiting condition in our population.
26189496 Intravenous Immunoglobulin (IVIG) Attenuates TNF-Induced Pathologic Bone Resorption and Su 2016 Feb Investigations on the therapeutic effects of intravenous immunoglobulin (IVIG) have focused on the suppression of autoantibody and immune complex-mediated inflammatory pathogenesis. Inflammatory diseases such as rheumatoid arthritis are often accompanied by excessive bone erosion but the effect of IVIG on osteoclasts, bone-resorbing cells, has not been studied. Here, we investigate whether IVIG directly regulates osteoclast differentiation and has therapeutic potential for suppressing osteoclast-mediated pathologic bone resorption. IVIG or cross-linking of Fcγ receptors with plate-bound IgG suppressed receptor activator of nuclear factor-κ B ligand (RANKL)-induced osteoclastogenesis and expression of osteoclast-related genes such as integrin β3 and cathepsin K in a dose-dependent manner. Mechanistically, IVIG or plate-bound IgG suppressed osteoclastogenesis by downregulating RANKL-induced expression of NFATC1, the master regulator of osteoclastogenesis. IVIG suppressed NFATC1 expression by attenuating RANKL-induced NF-κB signaling, explained in part by induction of the inflammatory signaling inhibitor A20. IVIG administration attenuated in vivo osteoclastogenesis and suppressed bone resorption in the tumor necrosis factor (TNF)-induced calvarial osteolysis model. Our findings show that, in addition to suppressing inflammation, IVIG directly inhibits osteoclastogenesis through a mechanism involving suppression of RANK signaling. Direct suppression of osteoclast differentiation may provide beneficial effects on preserving bone mass when IVIG is used to treat rheumatic disorders.
25636035 Systems pharmacology dissection of the anti-inflammatory mechanism for the medicinal herb 2015 Jan 28 Inflammation is a hallmark of many diseases like diabetes, cancers, atherosclerosis and arthritis. Thus, lots of concerns have been raised toward developing novel anti-inflammatory agents. Many alternative herbal medicines possess excellent anti-inflammatory properties, yet their precise mechanisms of action are yet to be elucidated. Here, a novel systems pharmacology approach based on a large number of chemical, biological and pharmacological data was developed and exemplified by a probe herb Folium Eriobotryae, a widely used clinical anti-inflammatory botanic drug. The results show that 11 ingredients of this herb with favorable pharmacokinetic properties are predicted as active compounds for anti-inflammatory treatment. In addition, via systematic network analyses, their targets are identified to be 43 inflammation-associated proteins including especially COX2, ALOX5, PPARG, TNF and RELA that are mainly involved in the mitogen-activated protein kinase (MAPK) signaling pathway, the rheumatoid arthritis pathway and NF-κB signaling pathway. All these demonstrate that the integrated systems pharmacology method provides not only an effective tool to illustrate the anti-inflammatory mechanisms of herbs, but also a new systems-based approach for drug discovery from, but not limited to, herbs, especially when combined with further experimental validations.
25252121 Mechanisms of tumor necrosis factor α antagonist-induced lupus in a murine model. 2015 Jan OBJECTIVE: Tumor necrosis factor α (TNFα) antagonists are effective for treating rheumatoid arthritis and other inflammatory diseases, but their use can be complicated by the development of lupus-like phenomena. This study was undertaken to investigate the role of TNFα in a murine model of lupus. METHODS: Toll-like receptor 7 (TLR-7) ligand-driven lupus was induced by injection of pristane into C57BL/6 (B6) mice deficient in TNFα (TNFα(-/-) ) or TNFα-intact B6 mice as wild-type controls. Autoantibody and type I interferon (IFN) production was measured in each group of mice, and the effects of the presence or absence of TNFα on type I IFN-producing plasmacytoid dendritic cells (PDCs), Ly-6C(high) monocytes, and TNFα-producing neutrophils were determined. RESULTS: TNFα(-/-) mice did not spontaneously develop autoantibodies or clinical manifestations of lupus, suggesting that TNFα deficiency alone is insufficient to cause lupus. Although the levels of type I IFN were comparable between untreated TNFα(-/-) and wild-type control mice, untreated TNFα(-/-) mice had increased circulating levels of PDCs and PDC-like cells, which enhanced the potential for production of type I IFN. When treated with pristane, TNFα(-/-) mice developed more severe lupus compared to pristane-treated controls, characterized by increased levels of anti-Sm/RNP autoantibodies, type I IFN, PDCs, and peritoneal inflammatory (Ly-6C(high) ) monocytes. In pristane-treated TNFα(-/-) mice, the numbers of neutrophils, a cell type that promotes resolution of inflammation, were decreased considerably, whereas the responses of inflammatory monocytes and PDCs and the production of type I IFN were increased and prolonged. CONCLUSION: Low levels of TNFα will increase the number of circulating PDCs in mice, thereby enhancing the potential to produce type I IFN. However, this does not necessarily lead to type I IFN production or autoimmunity unless there is concomitant exposure to endogenous TLR-7 ligands, which are released from dead cells following pristane treatment. In humans, the rate of clearance of dead cells, along with the levels of TNFα, may influence who will develop lupus following treatment with TNFα inhibitors.
27050433 Smoking and Subclinical ILD in RA versus the Multi-Ethnic Study of Atherosclerosis. 2016 A population-based cohort showed an association between cigarette smoking and subclinical parenchymal lung disease defined as regions of increased computed tomography (CT) lung densitometry. This technique has not been applied to the rheumatoid arthritis (RA) population where associated ILD is highly prevalent. The association between cumulative cigarette smoking and volume of areas of high attenuation (HAA: >-600 and <-250 Hounsfield Units) on full inspiratory CT was compared in 172 RA participants and 3,969 controls in a general population sample. Multivariable regression models were used to adjust for demography, anthropometrics, percent emphysema, and CT parameters. The mean cumulative cigarette smoking exposure was 25 (IQR 10-42) and 15(IQR 5-31) pack-years for the RA and non-RA cohorts, respectively. Mean HAA was 153(±57) cm3 and 129(±50) cm3 in the RA and non-RA cohorts, respectively. Each 10 cigarette pack-year increment was associated with a higher HAA by 0.03% (95% CI, 0.007-0.05%) in RA patients and by 0.008% (95% CI, 0.003-0.01%) in those without RA (interaction p = 0.001). Cigarette smoking was associated with higher lung attenuation; with a magnitude of association more pronounced in those with RA than in the general population. These data suggest that cigarette smoking may be a more potent ILD risk factor for RA patients than in the general population.
26566388 IL7R gene expression network associates with human healthy ageing. 2015 BACKGROUND: The level of expression of the interleukin 7 receptor (IL7R) gene in blood has recently been found to be associated with familial longevity and healthy ageing. IL7R is crucial for T cell development and important for immune competence. To further investigate the IL7R pathway in ageing, we identified the closest interacting genes to construct an IL7R gene network that consisted of IL7R and six interacting genes: IL2RG, IL7, TSLP, CRLF2, JAK1 and JAK3. This network was explored for association with chronological age, familial longevity and immune-related diseases (type 2 diabetes, chronic obstructive pulmonary disease and rheumatoid arthritis) in 87 nonagenarians, 337 of their middle-aged offspring and 321 middle-aged controls from the Leiden Longevity Study (LLS). RESULTS: We observed that expression levels within the IL7R gene network were significantly different between the nonagenarians and middle-aged controls (P = 4.6 × 10(-4)), being driven by significantly lower levels of expression in the elderly of IL7, IL2RG and IL7R. After adjustment for multiple testing and white blood cell composition and in comparison with similarly aged controls, middle-aged offspring of nonagenarian siblings exhibit a lower expression level of IL7R only (P = 0.006). Higher IL7R gene expression in the combined group of middle-aged offspring and controls is associated with a higher prevalence of immune-related disease (P = 0.001). On the one hand, our results indicate that lower IL7R expression levels, as exhibited by the members of long-lived families that can be considered as 'healthy agers', are beneficial in middle age. This is augmented by the observation that higher IL7R gene expression associates with immune-related disease. On the other hand, IL7R gene expression in blood is lower in older individuals, indicating that low IL7R gene expression might associate with reduced health. Interestingly, this contradictory result is supported by the observation that a higher IL7R gene expression level is associated with better prospective survival, both in the nonagenarians (Hazard ratio (HR) = 0.63, P = 0.037) and the middle-aged individuals (HR = 0.33, P = 1.9 × 10(-4)). CONCLUSIONS: Overall, we conclude that the IL7R network reflected by gene expression levels in blood may be involved in the rate of ageing and health status of elderly individuals.
27212252 The joint synovium: A critical determinant of articular cartilage fate in inflammatory joi 2017 Feb The synovium constitutes the envelope of articular joints and is a critical provider of synovial fluid components and articular cartilage nutrients. Its inflammation is a predominant feature and cause of joint degeneration in diseases as diverse as rheumatoid, psoriatic, juvenile and idiopathic arthritis, and lupus, gout and lyme disease. These inflammatory joint diseases (IJDs) are due to a wide variety of genetic, epigenetic and environmental factors that trigger, promote, and perpetuate joint destabilization. In spite of this variety of causes, IJDs share main pathological features, namely inflammation of the joint synovium (synovitis) and progressive degeneration of articular cartilage. In addition to being a driving force behind the destruction of articular cartilage in IJD, synovitis is also increasingly being recognized as a significant contributor of articular cartilage degeneration in osteoarthritis, a disease primarily due to aging- or trauma-related wear and tear of cartilage surfaces. In view of this important role of the synovium in determining the fate of articular cartilage, this review focuses on its underlying mechanisms in the pathology of IJD. We address the roles of synovial fibroblasts, macrophages and endothelial cells in the maintenance of joint health and in the destruction of articular cartilage integrity during IJD. Molecular mechanisms that have been recently shown to govern the pathological activities of the resident synovial cells are highlighted. Finally, advantages and disadvantages of targeting these new molecular mechanisms for preventing cartilage degeneration due to chronic inflammation are also discussed.
26659335 Group Medical Visits Using an Empowerment-based Model as Treatment for Women With Chronic 2015 Nov BACKGROUND: Over the past decade, group medical visits have become more prevalent. Group medical visits may have some advantages in treating chronic illnesses such as chronic pain as they can be more patient centered. The empowerment model is a novel approach used to provide support, education, and healthy activities guided by participants. OBJECTIVE: To evaluate the early stages of a chronic pain group medical visit program based on the empowerment model. METHODS: This prospective cohort study recruited 60 female participants to participate between October 2004 and May 2005. All enrolled participants completed the SF-36 questionnaire, which was administered at baseline and again after 6 months of participation. Data from chart review included age, race, weight, height, chronic illness, chronic pain diagnosis, and degree of participation. Chronic pain diagnoses included back pain, osteoarthritis, fibromyalgia, rheumatoid/inflammatory arthritis, and other/unknown. RESULTS: Forty-two participants were enrolled in the program for 6 months. Their average Charleson Comorbidity Index score was 3.1 (SD=1.5). Statistically significant changes (P<.05) were seen in the following SF-36 categories: Role-Physical, Bodily Pain, General Health, Social Function, and Mental Health. All factors trended toward improvement, with the largest improvements seen in Role-Physical and Role-Emotional. CONCLUSION: Participants in the chronic pain group medical visit program had a high degree of comorbidity and poor health related quality of life in regards to functioning. There was improvement in many domains of health-related quality of life.
26258277 Bilateral Iritis after Vaccine for Bladder Cancer. 2015 Oct PURPOSE: Bacille Calmette-Guérin (BCG) is a vaccine that can be instilled into the urinary bladder as immunotherapy against superficial bladder cancer. Several case reports have implicated intravesical BCG in the development of uveitis. Patients treated with BCG therapy may present with systemic symptoms resembling reactive arthritis and, less frequently, have ocular adverse effects including bilateral panuveitis or chorioretinitis. In all but three previously reported cases of uveitis associated with BCG treatment, HLA-B27 has been positive. No patients have been reported to be positive for rheumatoid factor or antinuclear antibody (ANA). CASE REPORT: An HLA-B27-negative and low-positive ANA patient presented with bilateral uveitis after treatment with BCG therapy for superficial bladder cancer. CONCLUSIONS: There is a need for greater awareness among urologists, primary care physicians, and optometrists of the potential for BCG to cause uveitis. These doctors should look for indicators of uveitis, such as circumlimbal conjunctival injection, photophobia, irregular pupils, and keratic precipitates. Together with appropriate treatment or prompt referral, this could prevent unnecessary morbidity. Future studies are needed to further elucidate the possible reasons for ANA positivity in these patients and the future role of the test in diagnosis and management.