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26809482 Familial autoimmunity and polyautoimmunity in 60 Brazilian Midwest patients with systemic 2016 Jan 13 INTRODUCTION: Systemic sclerosis (SSc) is a connective tissue disease of unknown etiology, characterized by a triad of vascular injury, autoimmunity and tissue fibrosis. It is known that a positive family history is the greatest risk factor already identified for the development of SSc in a given individual. Preliminary observation of a high prevalence of poliautoimmunity and of familial autoimmunity in SSc patients support the idea that different autoimmune phenotypes may share common susceptibility variants. OBJECTIVES: To describe the frequency of familial autoimmunity and poliautoimmunity in 60 SSc patients in the Midwest region of Brazil, as well as to report the main autoimmune diseases observed in this association of comorbidities. METHODS: A cross-sectional study with recruitment of 60 consecutive patients selected at the Rheumatology Department, University Hospital, Medicine School, Federal University of Mato Grosso do Sul (FMUFMS), as well as interviews of their relatives during the period from February 2013 to March 2014. RESULTS: A frequency of 43.3% of poliautoimmunity and of 51.7% of familial autoimmunity in SSc patients was found. Patients with presence of poliautoimmunity and familial autoimmunity presented primarily the diffuse form of SSc, but this indicator did not reach statistical significance. The autoimmune diseases most frequently observed in poliautoimmunity patients were: Hashimoto's thyroiditis (53.8%), Sjögren's syndrome (38.5%), and inflammatory myopathy (11.5%). The main autoimmune diseases observed in SSc patients' relatives were: Hashimoto's thyroiditis (32.3%), rheumatoid arthritis (22.6%), and SLE (22.6%). The presence of more than one autoimmune disease in SSc patients did not correlate with disease severity or activity. CONCLUSIONS: From the high prevalence of coexisting autoimmune diseases found in SSc patients, we stress the importance of the concept of shared autoimmunity, in order to promote a continued vigilance and promptly diagnose other possible autoimmune disease in patients, or in their kin.
26630011 Geometrical Frustration in Interleukin-33 Decouples the Dynamics of the Functional Element 2015 Interleukin-33 (IL-33) is currently the focus of multiple investigations into targeting pernicious inflammatory disorders. This mediator of inflammation plays a prevalent role in chronic disorders such as asthma, rheumatoid arthritis, and progressive heart disease. In order to better understand the possible link between the folding free energy landscape and functional regions in IL-33, a combined experimental and theoretical approach was applied. IL-33 is a pseudo- symmetrical protein composed of three distinct structural elements that complicate the folding mechanism due to competition for nucleation on the dominant folding route. Trefoil 1 constitutes the majority of the binding interface with the receptor whereas Trefoils 2 and 3 provide the stable scaffold to anchor Trefoil 1. We identified that IL-33 folds with a three-state mechanism, leading to a rollover in the refolding arm of its chevron plots in strongly native conditions. In addition, there is a second slower refolding phase that exhibits the same rollover suggesting similar limitations in folding along parallel routes. Characterization of the intermediate state and the rate limiting steps required for folding suggests that the rollover is attributable to a moving transition state, shifting from a post- to pre-intermediate transition state as you move from strongly native conditions to the midpoint of the transition. On a structural level, we found that initially, all independent Trefoil units fold equally well until a QCA of 0.35 when Trefoil 1 will backtrack in order to allow Trefoils 2 and 3 to fold in the intermediate state, creating a stable scaffold for Trefoil 1 to fold onto during the final folding transition. The formation of this intermediate state and subsequent moving transition state is a result of balancing the difficulty in folding the functionally important Trefoil 1 onto the remainder of the protein. Taken together our results indicate that the functional element of the protein is geometrically frustrated, requiring the more stable elements to fold first, acting as a scaffold for docking of the functional element to allow productive folding to the native state.
26264608 Inflammatory neuropathies: pathology, molecular markers and targets for specific therapeut 2015 Oct Inflammatory neuropathies encompass groups of heterogeneous disorders characterized by pathogenic immune-mediated hematogenous leukocyte infiltration of peripheral nerves, nerve roots or both, with resultant demyelination or axonal degeneration or both. Inflammatory neuropathies may be divided into three major disease categories: Guillain-Barré syndrome (particularly the acute inflammatory demyelinating polyradiculoneuropathy variant), chronic inflammatory demyelinating polyradiculoneuropathy and nonsystemic vasculitic neuropathy (or peripheral nerve vasculitis). Despite major advances in molecular biology, pathology and genetics, the pathogenesis of these disorders remains elusive. There is insufficient knowledge on the mechanisms of hematogenous leukocyte trafficking into the peripheral nervous system to guide the development of specific molecular therapies for immune-mediated inflammatory neuropathies compared to disorders such as psoriasis, inflammatory bowel disease, rheumatoid arthritis or multiple sclerosis. The recent isolation and characterization of human endoneurial endothelial cells that form the blood-nerve barrier provides an opportunity to elucidate leukocyte-endothelial cell interactions critical to the pathogenesis of inflammatory neuropathies at the interface between the systemic circulation and peripheral nerve endoneurium. This review discusses our current knowledge of the classic pathological features of inflammatory neuropathies, attempts at molecular classification and genetic determinants, the utilization of in vitro and in vivo animal models to determine pathogenic mechanisms at the interface between the systemic circulation and the peripheral nervous system relevant to these disorders and prospects for future potential molecular pathology biomarkers and targets for specific therapeutic intervention.
26259585 IL-17A Contributes to the Pathogenesis of Endometriosis by Triggering Proinflammatory Cyto 2015 Sep 15 Endometriosis is a chronic, inflammatory disease characterized by the growth of endometrial tissue in aberrant locations outside the uterus. Neoangiogenesis or establishment of new blood supply is one of the fundamental requirements of endometriotic lesion survival in the peritoneal cavity. IL-17A is emerging as a potent angiogenic and proinflammatory cytokine involved in the pathophysiology of several chronic inflammatory diseases such as rheumatoid arthritis and psoriasis. However, sparse information is available in the context of endometriosis. In this study, we demonstrate the potential importance of IL-17A in the pathogenesis and pathophysiology of endometriosis. The data show a differential expression of IL-17A in human ectopic endometriotic lesions and matched eutopic endometrium from women with endometriosis. Importantly, surgical removal of lesions resulted in significantly reduced plasma IL-17A concentrations. Immunohistochemistry revealed localization of IL-17A primarily in the stroma of matched ectopic and eutopic tissue samples. In vitro stimulation of endometrial epithelial carcinoma cells, Ishikawa cells, and HUVECs with IL-17A revealed significant increase in angiogenic (vascular endothelial growth factor and IL-8), proinflammatory (IL-6 and IL-1β), and chemotactic cytokines (G-CSF, CXCL12, CXCL1, and CX3CL1). Furthermore, IL-17A promoted tubulogenesis of HUVECs plated on Matrigel in a dose-dependent manner. Thus, we provide the first evidence, to our knowledge, that endometriotic lesions produce IL-17A and that the removal of the lesion via laparoscopic surgery leads to the significant reduction in the systemic levels of IL-17A. Taken together, our data show a likely important role of IL-17A in promoting angiogenesis and proinflammatory environment in the peritoneal cavity for the establishment and maintenance of endometriosis lesions.
26215452 Whipple's disease diagnosed during anti-tumor necrosis factor alpha treatment: two case re 2015 Jul 28 INTRODUCTION: Whipple's disease is a rare infectious disease caused by Tropheryma whipplei with protean clinical manifestations. This infection may mimic chronic inflammatory rheumatisms. CASE PRESENTATION: We report two cases of Whipple's disease diagnosed in the context of an inflammatory disease with anti-tumor necrosis factor alpha failure. The first patient was a 58-year-old white man with psoriatic spondylarthritis, who was treated with adalimumab, etanercept, infliximab, tocilizumab and golimumab. The second was a 73-year-old white man with rheumatoid arthritis, who received treatment with infliximab, then etanercept and rituximab. CONCLUSIONS: Whipple's disease should be suspected in all patients diagnosed with chronic inflammatory rheumatism, partially controlled or not controlled by treatment with tumor necrosis factor alpha blockers, whose condition worsens after treatment.
26071216 The tumor necrosis factor receptor superfamily member 1B polymorphisms predict response to 2015 Sep Numerous published data on the tumor necrosis factor receptor superfamily member 1B (TNFRSF1B) gene polymorphisms are shown to be associated with response or non-response to anti-TNF therapy in autoimmune diseases such as rheumatoid arthritis (RA), psoriasis and Crohn's Disease (CD). The aim of this study is to investigate whether the TNFRSF1B rs1061622 T/G or TNFRSF1A A/G rs767455 polymorphisms can predict the response to anti-TNF-based therapy in patients with autoimmune diseases. We conducted a meta-analysis of studies on the association between TNFRSF1B rs1061622 T/G polymorphism or TNFRSF1A A/G rs767455 polymorphism and non-responsiveness to anti-TNF therapy in autoimmune diseases. A total of 8 studies involving 929 subjects for TNFRSF1B rs1061622 and 564 subjects for TNFRSF1A rs767455 were finally considered. These studies consisted of seven studies on the TNFRSF1B polymorphism and four studies on the TNFRSF1A polymorphism. Meta-analysis showed significant association between the TNFRSF1B rs1061622 allele and non-responders to anti-TNF therapy [T/G odds ratio (OR) 0.72, 95% confidence interval (CI) 0.57-0.93, p=0.01]. Stratification by disease type indicated an association between the TNFRSF1B rs1061622 allele and non-responders to TNF antagonist in RA (T/G OR 0.69, 95% CI 0.48-0.99, p<0.05) and psoriasis (T/G OR 0.39, 95% CI 0.23-0.67, p<0.001), but not in CD (T/G OR 1.14, 95% CI 0.57-0.93, p=0.57). And there was no association between TNFRSF1A rs767455 genotype and non-responders to the anti-TNF therapy (A/G OR 0.93, 95% CI 0.70-1.23, p=0.59). This meta-analysis demonstrates that TNFRSF1B T allele carriers show a better response to anti-TNF therapy, and individuals carrying TNFRSF1A A allele have no relationship with the response to anti-TNF therapy for autoimmune diseases. The genotyping of this polymorphism could help to optimize the treatment by identifying patients with a likely poor response to biological drugs.
25997745 TANK-binding kinase 1 (TBK1) modulates inflammatory hyperalgesia by regulating MAP kinases 2015 May 23 BACKGROUND: TANK-binding kinase (TBK1) is a non-canonical IκB kinase (IKK) involved in the regulation of type I interferons and of NF-κB signal transduction. It is activated by viral infections and inflammatory mediators and has therefore been associated with viral diseases, obesity, and rheumatoid arthritis. Its role in pain has not been investigated so far. Due to the important roles of NF-κB, classical IκB Kinases and the IKK-related kinase, IKKε, in inflammatory nociception, we hypothesized that TBK1, which is suggested to form a complex with IKKε under certain conditions, might also alter the inflammatory nociceptive response. METHODS: We investigated TBK1 expression and regulation in "pain-relevant" tissues of C57BL/6 mice by immunofluorescence, quantitative PCR, and Western blot analysis. Furthermore, nociceptive responses and the underlying signal transduction pathways were assessed using TBK1(-/-) mice in two models of inflammatory nociception. RESULTS: Our data show that TBK1 is expressed and regulated in the spinal cord after peripheral nociceptive stimulation and that a deletion of TBK1 alleviated the inflammatory hyperalgesia in mice while motor function and acute nociception were not altered. TBK1-mediated effects are at least partially mediated by regulation of NF-κB dependent COX-2 induction but also by alteration of expression of c-fos via modulation of MAP kinases as shown in the spinal cord of mice and in cell culture experiments. CONCLUSION: We suggest that TBK1 exerts pronociceptive effects in inflammatory nociception which are due to both modulation of NF-κB dependent genes and regulation of MAPKs and c-fos. Inhibition of TBK1 might therefore constitute a novel effective tool for analgesic therapy.
25996152 Online training on skin cancer diagnosis in rheumatologists: results from a nationwide ran 2015 Patients with inflammatory rheumatisms, such as rheumatoid arthritis, are more prone to develop skin cancers than the general population, with an additional increased incidence when receiving TNF blockers. There is therefore a need that physicians treating patients affected with inflammatory rheumatisms with TNF blockers recognize malignant skin lesions, requiring an urgent referral to the dermatologist and a potential withdrawal or modification of the immunomodulatory treatment. We aimed to demonstrate that an online training dedicated to skin tumors increase the abilities of rheumatologists to discriminate skin cancers from benign skin tumors. A nationwide randomized web-based survey involving 141 French rheumatologists was conducted. The baseline evaluation included short cases with skin lesion pictures and multiple choice questions assessing basic knowledge on skin cancers. For each case, rheumatologists had to indicate the nature of skin lesion (benign; premalignant/malignant), their level of confidence in this diagnosis (10-points Likert scale), and the precise dermatological diagnosis among 5 propositions. Different scores were established. After randomization, only one group had access to the online formation consisting in 4 e-learning modules on skin tumors, of 15 minutes each (online training group). After reevaluation, the trained and the non-trained group (control group) were compared. The primary end-point was the number of adequate diagnoses of the nature of the skin lesions. The mean number of adequate diagnosis for the benign versus premalignant/malignant nature of the lesions was higher in the online training group (13.4 vs. 11.2 points; p value <0.0001). While the other knowledge scores were also significantly higher, no statistical difference was observed on the level of self-confidence between the 2 groups. In conclusion, the online formation was effective to improve the rheumatologists' ability to diagnose skin cancer.
25981373 Nrf2 deficiency causes lipid oxidation, inflammation, and matrix-protease expression in DH 2015 Nov Fish oil rich in docosahexaenoic acid (DHA) has beneficial effects on human health. Omega-3 polyunsaturated fatty acids are precursors of eicosanoids and docosanoids, signaling molecules that control inflammation and immunity, and their dietary uptake improves a range of disorders including cardiovascular diseases, ulcerative colitis, rheumatoid arthritis, and psoriasis. The unsaturated nature of these fatty acids, however, makes them prone to oxidation, especially when they are incorporated into (membrane) phospholipids. The skin is an organ strongly exposed to oxidative stress, mainly due to solar ultraviolet radiation. Thus, increased levels of PUFA in combination with oxidative stress could cause increased local generation of oxidized lipids, whose action spectrum reaches from signaling molecules to reactive carbonyl compounds that can crosslink biomolecules. Here, we investigated whether PUFA supplements to fibroblasts are incorporated into membrane phospholipids and whether an increase of PUFA within phospholipids affects the responses of the cells to UV exposure. The redox-sensitive transcription factor Nrf2 is the major regulator of the fibroblast stress response to ultraviolet radiation or exposure to oxidized lipids. Here we addressed how Nrf2 signaling would be affected in PUFA-supplemented human dermal fibroblasts and mouse dermal fibroblasts from Nrf2-deficient and wild type mice. We found, using HPLC-tandem MS, that DHA supplements to culture media of human and murine fibroblasts were readily incorporated into phospholipids and that subsequent irradiation of the supplemented cells with UVA resulted in an increase in 1-palmitoyl-2-(epoxyisoprostane-E2)-sn-glycero-3-phosphorylcholine and Oxo-DHA esterified to phospholipid, both of which are Nrf2 agonists. Also, induction of Nrf2 target genes was enhanced in the DHA-supplemented fibroblasts after UVA irradiation. In Nrf2-deficient murine fibroblasts, the expression of the target genes was, as expected, decreased, but surprisingly, expression of TNFα and MMP13 was strongly induced in DHA-supplemented, UVA-irradiated cells. Also, Nrf2-deficient cells had increased levels of oxidized phospholipids relative to the unoxidized precursors after UVA irradiation. Our data suggest that under ultraviolet stress a functioning Nrf2 system is required to prevent DHA-induced inflammation and matrix degradation in dermal fibroblasts.
25941933 Quantitative Real-Time PCR Analysis of YKL-40 and Its Comparison with Mammalian Chitinase 2015 Apr 30 YKL-40 (YKL for the first three N-terminal residues of a 40 kDa protein) belongs to a group of human chitinase-like proteins (CLPs), which are similar to chitinases but lack chitinolytic activity. YKL-40 mRNA and its protein levels have been reported elevated in multiple disorders including asthma, cystic fibrosis, rheumatoid arthritis and malignant tumors. Here, we quantified the YKL-40 mRNA levels and compared them with chitinases and housekeeping genes in normal human tissues. To establish the quantitative real-time PCR (qPCR) system for evaluation of relative YKL-40 mRNA levels, we constructed a human standard DNA molecule by ligating cDNAs of YKL-40, two mammalian chitinases and two housekeeping genes in a one-to-one ratio. We generated cDNAs from various normal human tissues and analyzed the YKL-40 mRNA expression levels using a qPCR system with the standard DNA. We found that YKL-40 mRNA is present widely in human tissues while its expression patterns exhibit clear tissue specificity. Highest YKL-40 mRNA levels were detected in the liver, followed by kidney, trachea and lung. The levels of YKL-40 mRNA in the kidney and liver were more than 100-times higher than those of chitotriosidase mRNA. Our study provides for the first time a comprehensive analysis of the relative expression levels of YKL-40 mRNA versus mammalian chitinases in normal human tissues.
25733803 Antidrug antibodies against TNF-blocking agents: correlations between disease activity, hy 2015 Although anti-TNF drugs have changed the clinical course of rheumatoid arthritis (RA), survival rates and resistance-to-therapy data confirm that about 30% of RA patients fail to respond. The aim of this study was to evaluate the correlations between the development of antidrug antibodies, specific IgG4 antibodies against TNF inhibitors, and resistance to therapy in RA patients. This retrospective study involved 129 patients with established RA naïve to biological agents (98 females and 32 males, mean age 56.7±12.3 years, disease duration 6.3±1.2 years, baseline Disease Activity Score [DAS]-28 3.2-5.6) who received treatment with anti-TNF agents after the failure of conventional disease-modifying antirheumatic drugs (32 received infliximab [IFX], 58 etanercept [ETN], and 39 adalimumab [ADA]). After 6 months of treatment, the patients were classified as being in remission (DAS28 <2.6), having low disease activity (LDA; DAS28 2.6-3.2), or not responding (NR: DAS28 >3.2). The patients were also tested for serum antidrug antibodies and IgG4 antibodies against TNF inhibitors. After 24 weeks of treatment, 38% of the ETN-treated patients and 28% of those treated with ADA had injection-site reactions; the rate of systemic reactions in the IFX group was 25%. The differences among the three groups were not statistically significant (P=0.382; ETN versus ADA P=0.319). The percentages of patients with adverse events stratified by drug response were: LDA 8% and NR 18% in the ADA group; in remission 3%, LDA 22%, and NR 10% in the ETN group; and LDA 6% and NR 16% in the IFX group (P=0.051). The percentages of patients with antidrug antibodies were: ADA 33.3%, ETN 11.5%, and IFX 10.3% (P=0.025; ADA versus ETN P=0.015). The percentages of patients with IgG4 antibodies were: ADA 6%, ETN 13%, and IFX 26% (P=0.017; ADA versus ETN P=0.437). Associations between antidrug antibodies, specific IgG4 antibodies, and adverse reactions were not significant for any of the three drugs. IgG4 levels were higher in the ADA group than in the other two groups, and higher in the patients with worse DAS28 (NR) and in those experiencing adverse events. These data suggest a possible association between IgG4 levels and worse DAS28 (r (2)=5.8%, P=0.011). The presence of specific IgG4 antibodies against TNF blockers in patients with RA might affect the drugs' activity. Patients with injection-site reactions and IgG4 against ETN may show a decreased response.
25585627 AA amyloidosis treated with tocilizumab: case series and updated literature review. 2015 BACKGROUND: In published case reports, tocilizumab (TCZ) has shown good efficacy for AA amyloidosis in almost all patients. We investigated the efficacy and safety of TCZ in AA amyloidosis in a multicentre study of unselected cases. METHODS: We e-mailed rheumatology and internal medicine departments in France, Switzerland and North Africa by using the Club Rhumatismes Inflammation (CRI) network and the French TCZ registry, Registry RoAcTEmra (REGATE), to gather data on consecutive patients with histologically proven AA amyloidosis who had received at least one TCZ infusion. Efficacy was defined as a sustained decrease in proteinuria level and/or stable or improved glomerular filtration rate (GFR) and by TCZ maintenance. RESULTS: We collected 12 cases of AA amyloidosis treated with TCZ as monotherapy (mean age of patients 63 ± 16.2 years, amyloidosis duration 20.6 ± 31.3 months): eight patients had rheumatoid arthritis (RA), six with previous failure of anti-tumor necrosis factor α (anti-TNF-α) therapy. In total, 11 patients had renal involvement, with two already on hemodialysis (not included in the renal efficacy assessment). For the nine other patients, baseline GFR and proteinuria level were 53.6 ± 32.8 mL/min and 5 ± 3.3 g/24 h, respectively. The mean follow-up was 13.1 ± 11 months. TCZ was effective for six of the eight RA patients (87.5%) according to European League Against Rheumatism response criteria (four good and two moderate responders). As expected, C-reactive protein (CRP) level decreased with treatment for 11 patients. Renal amyloidosis (n = 9) progressed in three patients and was stabilized in three. Overall, three patients showed improvement, with sustained decrease in proteinuria level (42%, 82% and 96%). Baseline CRP level was higher in subsequent responders to TCZ than other patients (p = 0.02). Among the six RA patients with previous anti-TNF-α therapy, amyloidosis was ameliorated in one and stabilized in three. Three serious adverse events occurred (two diverticulitis and one major calciphylaxia due to renal failure). Finally, 7 of 12 (58%) patients continued TCZ. CONCLUSIONS: The efficacy of TCZ for AA amyloidosis varies depending on the inflammatory status at treatment onset. Discrepancies between our study of unselected consecutive patients and reported cases may be due to publication bias. These results support further prospective trials of TCZ for AA amyloidosis.
26435264 Complications and revisions after semi-constrained total elbow arthroplasty: a mono-centre 2016 Jan BACKGROUND: The complication rate after total elbow arthroplasties is higher than for other arthroplasties. PURPOSE: The purpose of this study was to evaluate the complications and revision rate after 100 semi-constrained total elbow arthroplasties from various types of aetiologies performed in our university hospital. METHODS: One hundred linked semiconstrained total elbow arthroplasties were performed and were reviewed with 24-months minimum follow-up. Indications were rheumatoid arthritis (45), trauma (33), revisions (16) and others (6). RESULTS: At five years average follow-up (range, 2-11), the complication rate was 37 %. Most frequent complications were ulnar nerve involvement (9 %) and triceps insufficiency (7 %). Five implants were aseptically loosed. The infection rate was 4 % with loosening of the implant in two. Four fractures were observed, including three at the ulna and one at the humerus proximal or distal to the stem. The radial nerve was injured in two cases. Failure of the locking system of the prosthesis was noted in one case and a fracture of the ulnar component was found in another patient. A revision surgery was performed in 13 cases (13 %). At follow-up 94 prostheses were still in place and the survival rate was 98 % at five years and 86 % at ten years. CONCLUSION: Total elbow arthroplasty remains a difficult procedure with sometimes a high rate of complications necessitating revision procedures. Selection of the patients, a rigorous surgical technique, and a systematic follow-up are prerequisite to limit this incidence. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.
26413459 Persisting Racial Disparities in Total Shoulder Arthroplasty Utilization and Outcomes. 2015 OBJECTIVE: The purpose was to study whether racial disparities in total shoulder arthroplasty (TSA) utilization and outcomes have declined over time. METHODS: We used the US Nationwide Inpatient Sample from 1998 to 2011.We used chi-squared test to compare characteristics, Cochran-Armitage test to compare utilization rates, and Cochran-Armitage test and logistic regression to compare time-trends in outcomes by race. RESULTS: From 1998 to 2011, 176,141 Whites and 7694 Blacks underwent TSA. Compared to Whites, Blacks who underwent TSA were younger (69.1 vs. 64.2 years; p<0.0001), more likely to be female (54.9 vs. 71.0 %; p<0.0001), and have rheumatoid arthritis or avascular necrosis as the underlying diagnosis (1.7 vs. 3.0%and 1.7 vs. 6.1 %; p<0.0001 for both) and a Deyo-Charlson index of 2 or higher (8.5 vs. 16.7 %; p<0.0001). Compared to Whites, Blacks had much lower TSA utilization rate/100,000 in 1998 (2.97 vs. 0.83; p<0.0001) and in 2011 (12.27 vs. 3.33; p<0.0001); racial disparities increased from 1998 to 2011 (p<0.0001). A higher proportion of Blacks than Whites had a hospital stay greater than median in 1998-2000, 62 vs. 51.4 % (p=0.02), and in 2009-2011, 34.4 vs. 27.3 % (p<0.0001); disparities did not change over time (p=0.31). These disparities in utilization were borderline significant in adjusted analyses. There were no racial differences in proportion discharged to inpatient medical facility in 1998-2000, 15.2 vs. 15.0 % (p=0.95), and in 2009-2011, 12.3 vs. 11.1%(p=0.37), respectively. CONCLUSIONS: We found increasing racial disparities in TSA utilization. Some disparities in outcomes exist as well. Patients, surgeons, and policy-makes should be aware of these findings and take action to reduce racial disparities.
26406469 Changes in the Prevalence of Rheumatic Diseases in Shantou, China, in the Past Three Decad 2015 This study aimed to clarify changes in the prevalence of rheumatic diseases in Shantou, China, in the past 3 decades and validate whether stair-climbing is a risk factor for knee pain and knee osteoarthritis (KOA). The World Health Organization-International League Against Rheumatism Community Oriented Program for Control of Rheumatic Diseases (COPCORD) protocol was implemented. In all, 2337 adults living in buildings without elevators and 1719 adults living in buildings with elevators were surveyed. The prevalence of rheumatic pain at any site and in the knee was 15.7% and 10.2%, respectively; both types of pain had a significantly higher incidence in residents of buildings without elevators than was reported by people who lived in buildings with elevators (14.9% vs. 10.6% and 11.32% vs. 8.82%, respectively) (both P < 0.0001). The prevalence of rheumatic pain in the neck, lumbar spine, shoulder, elbow, and foot was 5.6%, 4.5%, 3.1%, 1.4%, and 1.8%, respectively; these findings were similar to the data from the 1987 rural survey, but were somewhat lower than data reported in the urban and suburban surveys of the 1990s, with the exception of neck and lumbar pain. The prevalence of KOA, gout, and fibromyalgia was 7.10%, 1.08%, and 0.07%, respectively, and their prevalence increased significantly compared with those in previous studies from the 20th century. There were no significant differences in the prevalence of rheumatoid arthritis (RA) (0.35%) or ankylosing spondylitis (AS) (0.31%) compared to that reported in prior surveys. The prevalence of KOA was higher in for residents of buildings without elevators than that in those who had access to elevators (16-64 years, 5.89% vs. 3.95%, P = 0.004; 16->85 years, 7.64% vs. 6.26%, P = 0.162). The prevalence of RA and AS remained stable, whereas that of KOA, gout, and fibromyalgia has increased significantly in Shantou, China, during the past 3 decades. Stair-climbing might be an important risk factor for knee pain and KOA.
25571844 Anti-inflammatory effects of Crataeva nurvala Buch. Ham. are mediated via inactivation of 2015 Mar 13 ETHNOPHARMACOLOGICAL RELEVANCE: Crataeva nurvala Buch. Ham. is an important medicinal plant in India, and its extracts and components were used to treat various inflammatory diseases, such as urinary tract infection, rheumatoid arthritis, and colitis. However, no systemic studies about anti-inflammatory effects of Crataeva nurvala Buch. Ham. and its underlying mechanisms of action have been reported. This study aimed to explore the anti-inflammatory effects of ethanol extracts of Crataeva nurvala Buch. Ham. (ECN). MATERIALS AND METHODS: The non-cytotoxic and maximal effective concentration of ECN was determined by measuring the formation of formazan from water-soluble tetrazolium salt in living cells. The inhibitory effect of ECN on nitric oxide (NO) synthesis was measured using Griess reagent, and Enzyme-linked immunosorbent assay (ELISA) was used to measure secreted tumor necrosis factor (TNF)-α and interleukin (IL)-6 protein levels. Furthermore, reverse transcription polymerase chain reaction (RT-PCR) and Western blotting analysis were used to assess the mRNA and protein expression of each inflammatory mediator or relating signaling protein, respectively. RESULTS: A non-cytotoxic concentration of ECN (≤200 μg/ml) significantly reduced the production of NO and IL-6, but not TNF-α, in lipopolysaccharides (LPS)-stimulated RAW 264.7 macrophages. Decreased production of NO by ECN was correlated with reduced expression of iNOS at the mRNA and protein levels. However, cyclooxygenase (COX)-2 expressions at mRNA and protein level were not regulated by ECN. The mRNA expression of IL-6 and IL-1β, but not TNF-α, was also inhibited by ECN treatment in LPS-stimulated RAW 264.7 macrophages. Reduced production of inflammatory mediators by ECN was followed by decreased activity of mitogen-activated protein kinases (MAPKs), especially extracellular signal-regulated kinase (ERK), but not nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). CONCLUSIONS: These results indicate that ECN inhibits LPS-induced inflammatory responses via negative regulation of ERK in murine macrophages, suggesting that ECN is a candidate for alleviating severe inflammation.
25125385 Hydroxychloroquine's Efficacy as an Antiplatelet Agent Study in Healthy Volunteers: A Proo 2015 Mar BACKGROUND: With the inflammatory model of atherosclerosis taking center stage, anti-inflammatory drugs hold a promising place in the therapy of cardiovascular disease (CVD). Recent studies showed that hydroxychloroquine (HCQ) was protective against thrombovascular events in lupus erythematosus and traditional cardiovascular risk factors in patients with rheumatoid arthritis. Some preliminary experimental data have shown that it may prevent platelet activation too. OBJECTIVE: To evaluate the antiplatelet activity of HCQ when given alone and in combination with aspirin (ASA) and compare it with ASA alone and ASA plus clopidogrel (CLOP) in healthy human volunteers. METHODS: In part 1 of the study, 8 volunteers were given HCQ for 7 days. In part 2, 12 volunteers were randomly assigned in a 1:1:1 ratio to the 3 groups in which 2 of the 3 treatments, ASA, ASA plus CLOP, and ASA plus HCQ, were given in the 2 treatment periods separated by a 14-day washout period using the incomplete block design. Inhibition of platelet aggregation (IPA) was measured by light transmission aggregometry. RESULTS: When arachidonic acid (AA) was used as agonist, HCQ given alone showed a significant reduction in platelet aggregation (11.0% ± 4.2%, P = .03). The IPA was significantly increased when ASA plus HCQ was compared with ASA alone (31.2% ± 8.1%, P = .002). This synergistic effect was not seen with adenosine diphosphate and collagen as agonists. Levels of serum 11-dehydrothromboxane B2, a stable marker of thromboxane A2 production, were not significantly different between the groups. There was also a significant decrease in fibrinogen and erythrocyte sedimentation rate values when HCQ was used alone or in combination with ASA. CONCLUSION: This study suggests that HCQ has antiplatelet properties possibly through the AA pathway (downstream to thromboxane A2 production). With possible additional beneficial effects over the traditional CVD risk factors, larger studies in the future might explore HCQ's potential as an antiplatelet agent.
27721430 USP15 regulates type I interferon response and is required for pathogenesis of neuroinflam 2017 Jan Genes and pathways in which inactivation dampens tissue inflammation present new opportunities for understanding the pathogenesis of common human inflammatory diseases, including inflammatory bowel disease, rheumatoid arthritis and multiple sclerosis. We identified a mutation in the gene encoding the deubiquitination enzyme USP15 (Usp15(L749R)) that protected mice against both experimental cerebral malaria (ECM) induced by Plasmodium berghei and experimental autoimmune encephalomyelitis (EAE). Combining immunophenotyping and RNA sequencing in brain (ECM) and spinal cord (EAE) revealed that Usp15(L749R)-associated resistance to neuroinflammation was linked to dampened type I interferon responses in situ. In hematopoietic cells and in resident brain cells, USP15 was coexpressed with, and functionally acted together with the E3 ubiquitin ligase TRIM25 to positively regulate type I interferon responses and to promote pathogenesis during neuroinflammation. The USP15-TRIM25 dyad might be a potential target for intervention in acute or chronic states of neuroinflammation.
27723820 Development of Novel Methods to Define Deficits in Appendicular Lean Mass Relative to Fat 2016 BACKGROUND: Recent studies suggest that adjustment of measures of lean mass for adiposity improves associations with physical function. Our objective was to develop and test a method to adjust appendicular lean mass for adiposity. METHODS: Whole-body DXA data in 14,850 adults in the National Health and Nutrition Examination Survey were used to generate sex-, and race-specific standard deviation scores (Z-Scores relative to age and T-scores relative to 25 year-olds) for appendicular lean mass index (ALMI, kg/m2) and fat mass index (FMI, kg/m2). Correlations between ALMI and FMI Z- and T-Scores were assessed within demographic categories. Fat-adjusted ALMI (ALMIFMI) scores were determined using residual methods. Sarcopenia was defined as a T-Score <-2.0 and low lean for age as a Z-Score <-1.0. Correlations with physical function were assessed in an at-risk population. RESULTS: Positive associations between ALMI and FMI Z- and T-Scores were significant (R >0.50; p<0.001) within all demographic categories. The impact of a unit greater FMI Z-score on ALMI Z-score was less in the elderly, men, white subjects, and among individuals with lower FMI (all tests for interaction p<0.001). There was fair agreement between ALMI and ALMIFMI estimates of sarcopenia and low lean for age [Kappa: 0.46, 0.52, respectively (p<0.0001)]. Elderly subjects were likely to be re-classified as sarcopenic while young subjects were likely to be re-classified as normal using ALMIFMI. ALMIFMI T-scores resulted in approximately twice the number of subjects defined as sarcopenic, compared with ALMI T-Scores. (1299 v. 534). Among rheumatoid arthritis patients, ALMIFMI Z-scores correlated with physical function (Health Assessment Questionnaire: rho = -0.22, p = 0.04; Short Physical Performance Battery: rho = 0.27, p = 0.01); however, the ALMI Z-Score did not. CONCLUSIONS: Adjustment of ALMI for the confounding association with FMI impacts the definition of lean mass deficits. These methods provide a practical tool for investigators and clinicians based on population-based reference data.
27654604 Timing of Allergenic Food Introduction to the Infant Diet and Risk of Allergic or Autoimmu 2016 Sep 20 IMPORTANCE: Timing of introduction of allergenic foods to the infant diet may influence the risk of allergic or autoimmune disease, but the evidence for this has not been comprehensively synthesized. OBJECTIVE: To systematically review and meta-analyze evidence that timing of allergenic food introduction during infancy influences risk of allergic or autoimmune disease. DATA SOURCES: MEDLINE, EMBASE, Web of Science, CENTRAL, and LILACS databases were searched between January 1946 and March 2016. STUDY SELECTION: Intervention trials and observational studies that evaluated timing of allergenic food introduction during the first year of life and reported allergic or autoimmune disease or allergic sensitization were included. DATA EXTRACTION AND SYNTHESIS: Data were extracted in duplicate and synthesized for meta-analysis using generic inverse variance or Mantel-Haenszel methods with a random-effects model. GRADE was used to assess the certainty of evidence. MAIN OUTCOMES AND MEASURES: Wheeze, eczema, allergic rhinitis, food allergy, allergic sensitization, type 1 diabetes mellitus, celiac disease, inflammatory bowel disease, autoimmune thyroid disease, and juvenile rheumatoid arthritis. RESULTS: Of 16 289 original titles screened, data were extracted from 204 titles reporting 146 studies. There was moderate-certainty evidence from 5 trials (1915 participants) that early egg introduction at 4 to 6 months was associated with reduced egg allergy (risk ratio [RR], 0.56; 95% CI, 0.36-0.87; I2 = 36%; P = .009). Absolute risk reduction for a population with 5.4% incidence of egg allergy was 24 cases (95% CI, 7-35 cases) per 1000 population. There was moderate-certainty evidence from 2 trials (1550 participants) that early peanut introduction at 4 to 11 months was associated with reduced peanut allergy (RR, 0.29; 95% CI, 0.11-0.74; I2 = 66%; P = .009). Absolute risk reduction for a population with 2.5% incidence of peanut allergy was 18 cases (95% CI, 6-22 cases) per 1000 population. Certainty of evidence was downgraded because of imprecision of effect estimates and indirectness of the populations and interventions studied. Timing of egg or peanut introduction was not associated with risk of allergy to other foods. There was low- to very low-certainty evidence that early fish introduction was associated with reduced allergic sensitization and rhinitis. There was high-certainty evidence that timing of gluten introduction was not associated with celiac disease risk, and timing of allergenic food introduction was not associated with other outcomes. CONCLUSIONS AND RELEVANCE: In this systematic review, early egg or peanut introduction to the infant diet was associated with lower risk of developing egg or peanut allergy. These findings must be considered in the context of limitations in the primary studies.