Small heterodimer partner interacting leucine zipper protein (SMILE) ameliorates autoimmune arthritis via AMPK signaling pathway and the regulation of B cell activation.

Rheumatoid arthritis (RA) is an autoimmune disease that causes joint swelling and inflammation and can involve the entire body. RA is characterized by the increase of pro-inflammatory cytokines such as interleukin (IL) and tumor necrosis factor, and the over-activation of T lymphocytes and B lymphocytes, which may lead to severe chronic inflammation of joints. However, despite numerous studies the pathogenesis and treatment of RA remain unresolved. This study investigated the use of small heterodimer partner-interacting leucine zipper protein (SMILE) overexpression to treat a mouse model of RA. SMILE is an insulin-inducible corepressor through adenosine monophosphate-activated kinase (AMPK) signaling pathway. The injection of a SMILE overexpression vector to mice with collagen induced-arthritis resulted in a milder clinical pathology and a reduced incidence of arthritis, less joint tissue damage, and lower levels of Th17 cells and plasma B cells in the spleen. Immunohistochemistry of the joint tissue showed that SMILE decreased B-cell activating factor (BAFF) receptor (BAFF-R), mTOR, and STAT3 expression but increased AMPK expression. In SMILE-overexpressing transgenic mice with collagen antibody-induced arthritis (CAIA), a decrease in the arthritis score and reductions in tissue damage, the number of B cells, and antibody production were observed. The treatment of immune cells in vitro with curcumin, a known SMILE-inducing agent, led to decreases in plasma B cells, germinal center B cells, IL-17-producing B cells, and BAFF-R-positive B cells. Taken together, our findings demonstrate the therapeutic potential of SMILE in RA, based on its inhibition of B cell activation mediated by the AMPK/mTOR and STAT3 signaling pathway and BAFF-R expression. Video abstract.

Rebamipide treatment ameliorates obesity phenotype by regulation of immune cells and adipocytes.

Obesity is a medical term used to describe an over-accumulation of adipose tissue. It causes abnormal physiological and pathological processes in the body. Obesity is associated with systemic inflammation and abnormalities in immune cell function. Rebamipide, an amino acid derivative of 2-(1H)-quinolinone, has been used as a therapeutic for the protection from mucosal damage. Our previous studies have demonstrated that rebamipide treatment regulates lipid metabolism and inflammation, leading to prevention of weight gain in high-fat diet mice. In this study, mice were put on a high calorie diet for 11 weeks while receiving injections of rebamipide. Rebamipide treatment reduced the body weight, liver weight and blood glucose levels compared to control mice and reduced both glucose and insulin resistance. Fat accumulation has been shown to cause pro-inflammatory activity in mice. Treatment with rebamipide decreased the prevalence of inflammatory cells such as Th2, Th17 and M1 macrophages and increased anti-inflammatory Treg and M2 macrophages in epididymal fat tissue. Additionally, rebamipide addition inhibited adipocyte differentiation in 3T3-L1 cell lines. Taken together, our study demonstrates that rebamipide treatment is a novel and effective method to prevent diet-induced obesity.

Correction: The anti-arthritis effect of sulforaphane, an activator of Nrf2, is associated with inhibition of both B cell differentiation and the production of inflammatory cytokines.

[This corrects the article DOI: 10.1371/journal.pone.0245986.].

The anti-arthritis effect of sulforaphane, an activator of Nrf2, is associated with inhibition of both B cell differentiation and the production of inflammatory cytokines.

Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is an important transcription factor that plays a pivotal role in cellular defense against oxidative injury. Nrf2 signaling is involved in attenuating autoimmune disorders such as rheumatoid arthritis (RA). B cells play several roles in the pathogenesis of RA, such as in autoantibody production, antigen presentation, and T-cell activation. We investigated the anti-arthritic mechanisms of sulforaphane, an activator of Nrf2, in terms of its effect on B cells. To investigate the effect of sulforaphane on collagen-induced arthritis (CIA), sulforaphane was administered intraperitoneally after CIA induction. Hematoxylin and eosin-stained sections were scored for inflammation, pannus invasion, and bone and cartilage damage. We assessed the expression levels of inflammation-related factors by real-time PCR and the levels of various IgG subclasses by enzyme-linked immunosorbent assay. Sulforaphane treatment reduced the arthritis score and the severity of histologic inflammation in CIA mice. The joints from sulforaphane-treated CIA mice showed decreased expression of interleukin (IL)-6, IL-17, tumor necrosis factor (TNF)-α, receptor activator of NF-κB ligand, and tartrate-resistant acid phosphatase. Sulforaphane-treated mice showed lower circulating levels of type-II-collagen-specific IgG, IgG1, and IgG2a. In vitro, sulforaphane treatment significantly reduced the differentiation of lipopolysaccharide-stimulated murine splenocytes into plasma B cells and germinal-center B cells. Finally, sulforaphane significantly inhibited the production of IL-6, TNF-α, and IL-17 by human peripheral blood mononuclear cells stimulated with an anti-CD3 monoclonal antibody in a dose-dependent manner. Inhibition of differentiation into plasma B and Germinal Center B cells may be the mechanism underlying the anti-arthritic effect of sulforaphane.

Effectiveness and safety of biologic and targeted synthetic disease-modifying anti-rheumatic drugs in elderly patients with rheumatoid arthritis: real-world data from the KOBIO Registry.

OBJECTIVES: We aimed to evaluate the clinical outcomes and safety of biologic and targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs) and to identify predictors of treatment responses to b/tsDMARDs in elderly patients with rheumatoid arthritis (RA). METHODS: Data from the nationwide cohort of elderly (≥ 65 years) patients enrolled in the KOBIO Registry were analysed. Clinical outcomes were assessed, including changes in the Simplified Disease Activity Index, after treatment. Adverse events and reasons for drug discontinuation were assessed. Multivariable logistic regression analyses were performed to determine which baseline variables affected treatment responses and adverse events (AE). RESULTS: Elderly patients treated with b/tsDMARDs (n=355) or conventional synthetic DMARDs (csDMARDs) (n=104) were included. The median age was 70 years and 77% were female. After 1 year, 63% of patients in the b/tsDMARD group and 68% in the csDMARD group achieved remission or low disease activity (LDA). Overall, 27% of patients in the b/tsDMARDs group and 24% in the csDMARDs group experienced AE. A total of 43.4% of patients on b/tsDMARDs discontinued therapy due to lack of effectiveness (27%), AE (34%), or other reasons (35%). The estimated median retention of b/tsDMARDs was 2.5 years. Male sex and non-exposure to tobacco at baseline were independent factors associated with achieving remission or LDA after 1 year. Interstitial lung disease (ILD) was the most prominent comorbidity associated with AE. CONCLUSIONS: Treatment with b/tsDMARDs is effective and well tolerated in elderly patients with RA; nonetheless, ILD is a key comorbidity that should be monitored carefully.

Deep Neural Network-Based Prediction of the Risk of Advanced Colorectal Neoplasia.

Background/Aims: Risk prediction models using a deep neural network (DNN) have not been reported to predict the risk of advanced colorectal neoplasia (ACRN). The aim of this study was to compare DNN models with simple clinical score models to predict the risk of ACRN in colorectal cancer screening. Methods: Databases of screening colonoscopy from Kangbuk Samsung Hospital (n=121,794) and Kyung Hee University Hospital at Gangdong (n=3,728) were used to develop DNN-based prediction models. Two DNN models, the Asian-Pacific Colorectal Screening (APCS) model and the Korean Colorectal Screening (KCS) model, were developed and compared with two simple score models using logistic regression methods to predict the risk of ACRN. The areas under the receiver operating characteristic curves (AUCs) of the models were compared in internal and external validation databases. Results: In the internal validation set, the AUCs of DNN model 1 and the APCS score model were 0.713 and 0.662 (p<0.001), respectively, and the AUCs of DNN model 2 and the KCS score model were 0.730 and 0.667 (p<0.001), respectively. However, in the external validation set, the prediction performances were not significantly different between the two DNN models and the corresponding APCS and KCS score models (both p>0.1). Conclusions: Simple score models for the risk prediction of ACRN are as useful as DNN-based models when input variables are limited. However, further studies on this issue are warranted to predict the risk of ACRN in colorectal cancer screening because DNN-based models are currently under improvement.

Contribution of Personality Traits, Psychological Factors, and Health-Related Quality of Life to Medication Adherence in Patients with Rheumatoid Arthritis.

PURPOSE: This study sought to investigate the associations between personality traits and medication adherence and to identify predictors of good medication adherence in rheumatoid arthritis (RA) patients. MATERIALS AND METHODS: A total of 207 RA patients using disease-modifying anti-rheumatic drugs were invited for an interview and questionnaire study. Medication adherence was measured using the Compliance Questionnaire for Rheumatology (CQR). Personality traits were analyzed with the five-factor model of the Korean version of the Big Five Inventory 10. Psychological factors were assessed with the Patient Health Questionnaire-9, Generalized Anxiety Disorder-7, and British Columbia Cognitive Inventory. Health-related Quality of Life (HRQoL) and functional disability were evaluated with the EuroQoL-5 dimension questionnaire and Health Assessment Questionnaire. Multivariate logistic regression analyses were performed to investigate predictors of good medication adherence. RESULTS: Nonadherence to medication was reported by 66.7%. The number of daily prescribed pills was higher in the medication adherence group than in the nonadherence group. Concomitant oral glucocorticoid doses were associated with medication adherence. A high level of conscientiousness and diabetes mellitus comorbidity were associated with better medication adherence [odds ratio (OR), 2.11; 95% confidence interval (CI), 1.01-4.38 and OR, 3.00; 95% CI, 1.12-8.07, respectively]. There were no significant differences in psychological factors or HRQoL between medication adherence and nonadherence groups. CONCLUSION: The personality trait of conscientiousness was associated with medication adherence among the five personality traits evaluated. Patients with diabetes mellitus also showed higher medication adherence than those without this comorbidity.

Direct Binding to NLRP3 Pyrin Domain as a Novel Strategy to Prevent NLRP3-Driven Inflammation and Gouty Arthritis.

OBJECTIVE: The NLRP3 inflammasome is closely linked to the pathophysiology of a wide range of inflammatory diseases. This study was undertaken to identify small molecules that directly bind to NLRP3 in order to develop pharmacologic interventions for NLRP3-related diseases. METHODS: A structure-based virtual screening analysis was performed with ~62,800 compounds to select efficient NLRP3 inhibitors. The production of caspase 1-p10 and interleukin-1ß (IL-1ß) was measured by immunoblotting and enzyme-linked immunosorbent assay to examine NLRP3 inflammasome activation. Two gouty arthritis models and an air pouch inflammation model induced by monosodium urate monohydrate (MSU) crystal injection were used for in vivo experiments. Primary synovial fluid cells from gout patients were used to determine the relevance of NLRP3 inflammasome inhibition in human gout. RESULTS: Beta-carotene (provitamin A) suppressed the NLRP3 inflammasome activation induced by various activators, including MSU crystals, in mouse bone marrow-derived primary macrophages (P < 0.05). Surface plasmon resonance analysis demonstrated the direct binding of ß-carotene to the pyrin domain (PYD) of NLRP3 (KD = 3.41 × 10-6 ). Molecular modeling and mutation assays revealed the interaction mode between ß-carotene and the NLRP3 PYD. Inflammatory symptoms induced by MSU crystals were attenuated by oral administration of ß-carotene in gouty arthritis mouse models (P < 0.05), correlating with its suppressive effects on the NLRP3 inflammasome in inflamed tissues. Furthermore, ß-carotene reduced IL-1ß secretion from human synovial fluid cells isolated from gout patients (P < 0.05), showing its inhibitory efficacy in human gout. CONCLUSION: Our results present ß-carotene as a selective and direct inhibitor of NLRP3, and the binding of ß-carotene to NLRP3 PYD as a novel pharmacologic strategy to combat NLRP3 inflammasome-driven diseases, including gouty arthritis.

Retinoic Acid Receptor-Related Receptor Alpha Ameliorates Autoimmune Arthritis via Inhibiting of Th17 Cells and Osteoclastogenesis.

Rheumatoid arthritis (RA) is a chronic inflammatory polyarthritis characterized by progressive joint destruction. IL-17-producing CD4+ T (Th17) cells play pivotal roles in RA development and progression. Retinoic acid receptor-related orphan receptor alpha (RORα) is a negative regulator of inflammatory responses, whereas RORγt, another member of the ROR family, is a Th17 lineage-specific transcription factor. Here, we investigated the immunoregulatory potential of RORα in collagen-induced arthritis (CIA) mice, an experimental model of RA. Cholesterol sulfate (CS) or SR1078, a ligand of RORα, inhibited RORγt expression and Th17 differentiation in vitro. In addition, fortification of RORα in T cells inhibited the expression levels of glycolysis-associated genes. We found that RORα overexpression in CIA mice attenuated the clinical and histological severities of inflammatory arthritis. The anti-arthritic effect of RORα was associated with suppressed Th17 differentiation and attenuated mTOR-STAT3 signaling in T cells. Furthermore, altered RORα activity could directly affect osteoclastogenesis implicated in progressive bone destruction in human RA. Our findings defined a critical role of RORα in the pathogenesis of RA. These data suggest that RORα may have novel therapeutic uses in the treatment of RA.

Quality Indicators and Outcome Measures of Endoscopy in the National Cancer Screening Program.

PURPOSE: Quality indicators of the National Endoscopy Quality Improvement Program (NEQIP) and outcome measures of endoscopy in the National Cancer Screening Program (NCSP) in Korea are not clear. We evaluated the quality indicators of the revised NEQIP and outcome measures of endoscopy at different types of healthcare facilities participating in the NCSP. MATERIALS AND METHODS: This study was conducted between March and August 2018 in primary, secondary, and tertiary healthcare facilities that perform endoscopy as a part of the NCSP. Representative endoscopists completed a questionnaire for quality indicators of the NEQIP and provided data on outcome measures for endoscopy. RESULTS: Quality indicators of the NEQIP were mostly acceptable. However, the quality indicators for annual volume of esophagogastroduodenoscopy (EGD) and colonoscopy, training for endoscopy quality improvement by endoscopy nursing staff, colonoscopy reports, documentation of pathologic lesions, quality of endoscopy reprocessing areas, and completion of endoscopy reprocessing education programs were suboptimal. For outcome measures of EGD, the number of photo-documentations and total procedure time were higher at tertiary healthcare facilities than at other facilities (p<0.001 and p=0.023, respectively). For the outcome measures of colonoscopy, colonoscopy completion rate and waiting times for colonoscopy were significantly higher at tertiary healthcare facilities than at other facilities (both p<0.001). CONCLUSION: Outcome measures of endoscopy should be included as quality indicators of NCSP. However, universal outcome measures for all types of healthcare facilities should be established because performance levels of some outcome measures differ among individual healthcare facility types.

Daurinol Attenuates Autoimmune Arthritis via Stabilization of Nrp1-PTEN-Foxp3 Signaling in Regulatory T Cells.

Optimizing Treg function and improving Treg stability are attractive treatment strategies for treating autoimmune rheumatoid arthritis (RA). However, the limited number of circulating Tregs and questions about the functional stability of in vitro-expanded Tregs are potential limitations of Treg-based cell therapy. The aim of this study was to analyze the regulatory effect of daurinol, a catalytic inhibitor of topoisomerase IIα, on Th cell differentiation and to evaluate their therapeutic potential in a preclinical experimental model of RA. We investigated the effect of daurinol on T cell differentiation by flow cytometry. Foxp3 stability and methylation were analyzed by suppression assays and bisulfite pyrosequencing. Daurinol was treated in the collagen-induced arthritis (CIA) model, and the effects in vivo were determined. We found that daurinol can promote Treg differentiation and reciprocally inhibit Th17 differentiation. This Treg-inducing property of daurinol was associated with decreased activity of Akt-mTOR and reciprocally increased activity of neuropilin-1 (Nrp1)-PTEN. Daurinol treatment inhibited aerobic glycolysis in Th17 conditions, indicating the metabolic changes by daurinol. We found that the daurinol increase the Treg stability was achieved by Foxp3 hypomethylation. In vivo daurinol treatment in CIA mice reduced the clinical arthritis severity and histological inflammation. The Treg population frequency increased and the Th17 cells decreased in the spleens of arthritis mice treated with daurinol. These results showed the anti-arthritic and immunoregulating properties of daurinol is achieved by increased differentiation and stabilization of Tregs. Our study provides first evidence for daurinol as a treatment for RA.

Metformin Augments Anti-Inflammatory and Chondroprotective Properties of Mesenchymal Stem Cells in Experimental Osteoarthritis.

Mesenchymal stem cells (MSCs) can protect against cartilage breakdown in osteoarthritis (OA) via their immunomodulatory capacities. However, the optimization strategy for using MSCs remains challenging. This study's objective was to identify the in vivo effects of metformin-stimulated adipose tissue-derived human MSCs (Ad-hMSCs) in OA. An animal model of OA was established by intra-articular injection of monosodium iodoacetate into rats. OA rats were divided into a control group and two therapy groups (treated with Ad-hMSCs or metformin-stimulated Ad-hMSCs). Limb nociception was assessed by measuring the paw withdrawal latency and threshold. Our data show that metformin increased IL-10 and IDO expression in Ad-hMSCs and decreased high-mobility group box 1 protein, IL-1ß, and IL-6 expression. Metformin increased the migration capacity of Ad-hMSCs with upregulation of chemokine expression. In cocultures, metformin-stimulated Ad-hMSCs inhibited the mRNA expression of RUNX2, COL X, VEGF, MMP1, MMP3, and MMP13 in IL-1ß-stimulated OA chondrocytes and increased the expression of TIMP1 and TIMP3. The antinociceptive activity and chondroprotective effects were greater in OA rats treated with metformin-stimulated Ad-hMSCs than in those treated with unstimulated Ad-hMSCs. TGF-ß expression in subchondral bone of OA joints was attenuated more in OA rats treated with metformin-stimulated Ad-hMSCs. Our findings suggest that metformin offers a promising option for the clinical application of Ad-hMSCs as a cell therapy for OA.

RIPK1 inhibition attenuates experimental autoimmune arthritis via suppression of osteoclastogenesis.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic and systemic inflammatory disease characterized by upregulation of inflammatory cell death and osteoclastogenesis. Necrostatin (NST)-1s is a chemical inhibitor of receptor-interacting serine/threonine-protein kinase (RIPK)1, which plays a role in necroptosis. METHODS: We investigated whether NST-1s decreases inflammatory cell death and inflammatory responses in a mouse model of collagen-induced arthritis (CIA). RESULTS: NST-1s decreased the progression of CIA and the synovial expression of proinflammatory cytokines. Moreover, NST-1s treatment decreased the expression of necroptosis mediators such as RIPK1, RIPK3, and mixed lineage kinase domain-like (MLKL). In addition, NST-1s decreased osteoclastogenesis in vitro and in vivo. NST-1s downregulated T helper (Th)1 and Th17 cell expression, but promoted Th2 and regulatory T (Treg) cell expression in CIA mice. CONCLUSIONS: These results suggest that NST-1s attenuates CIA progression via the inhibition of osteoclastogenesis and might be a potential therapeutic agent for RA therapy.

Overview of Deep Learning in Gastrointestinal Endoscopy.

Artificial intelligence is likely to perform several roles currently performed by humans, and the adoption of artificial intelligence-based medicine in gastroenterology practice is expected in the near future. Medical image-based diagnoses, such as pathology, radiology, and endoscopy, are expected to be the first in the medical field to be affected by artificial intelligence. A convolutional neural network, a kind of deep-learning method with multilayer perceptrons designed to use minimal preprocessing, was recently reported as being highly beneficial in the field of endoscopy, including esophagogastroduodenoscopy, colonoscopy, and capsule endoscopy. A convolutional neural network-based diagnostic program was challenged to recognize anatomical locations in esophagogastroduodenoscopy images, Helicobacter pylori infection, and gastric cancer for esophagogastroduodenoscopy; to detect and classify colorectal polyps; to recognize celiac disease and hookworm; and to perform small intestine motility characterization of capsule endoscopy images. Artificial intelligence is expected to help endoscopists provide a more accurate diagnosis by automatically detecting and classifying lesions; therefore, it is essential that endoscopists focus on this novel technology. In this review, we describe the effects of artificial intelligence on gastroenterology with a special focus on automatic diagnosis, based on endoscopic findings.

Notoginseng Radix and Rehmanniae Radix Preparata Extract Combination (YH23537) Reduces Pain and Cartilage Degeneration in Rats with Monosodium Iodoacetate-Induced Osteoarthritis.

Notoginseng Radix and Rehmanniae Radix Preparata have been widely used traditionally for treating inflammatory diseases. This research studies the therapeutic effects of YH23537, the extracts of Notoginseng Radix and Rehmanniae Radix Preparata, on pain and cartilage degeneration in an experimental osteoarthritis (OA) model. Male Wistar rats were inoculated intra-articularly with 3 mg of monosodium iodoacetate (MIA) in the right intra-articular. Four days later, the animals were administrated orally with YH23537 daily for 24 days. Tactile allodynia and weight bearing were measured. Macroscopic and microscopic observations for articular cartilage were performed at the end of the experiment. Protein expression in the joint was determined by immunohistochemistry. The effects of YH23537 on mRNA levels in chondrocytes stimulated with interleukin (IL)-1ß were analyzed using random polymerase chain reaction. OA induction was confirmed by significant decrease of paw withdrawal latency, paw withdrawal threshold, and weight bearing compared with the normal group at 3 days after MIA injection. The YH23537-treated groups displayed significant increases in pain thresholds and weight bearing throughout the observation period. The damage to articular cartilage was significantly lessened visually and histopathologically by YH23537 treatment. YH23537 suppressed the expression of metalloproteinase-3, nitrotyrosine, IL-1ß and IL-6 increased in OA joints. YH23537 upregulated tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-3 in IL-1ß-stimulated human OA chondrocytes. The protein levels of the NF-κBp65 and HIF-2α in the joint tissues were reduced by YH23537. YH23537 exerted antinociceptive effects and cartilage protective effects in experimental OA rats by suppressing oxidative injury, inflammatory mediators, and inducing anabolic factors. We suggest that YH23537 may have efficacy for treating OA in humans.

IL-1-IL-17 Signaling Axis Contributes to Fibrosis and Inflammation in Two Different Murine Models of Systemic Sclerosis.

OBJECTIVE: Systemic sclerosis (SSc) is a progressive fibrotic disease that affects the skin and internal organs. Despite evidence implicating increased interleukin-17 (IL-17) activity in SSc, the role of IL-17 in SSc remains uncertain. The purpose of this study was to investigate whether IL-17 plays a pathophysiological role in SSc in two different murine models of SSc. METHODS: Bleomycin (BLM)-induced fibrosis and chronic graft-versus-host disease (cGVHD) models were used. Histological analysis was performed using Masson's trichrome and immunohistochemical staining. Quantitative reverse transcription-polymerase chain reaction and enzyme-linked immunoassays were used to quantify the messenger RNA and protein levels of inflammatory mediators in dermal fibroblasts. RESULTS: IL-1 receptor antagonist-deficient (IL-1Ra-KO) mice were more severely affected by BLM injection, as shown by dermal and pulmonary fibrosis, compared with wild-type (WT) mice. Increased tissue fibrosis was reversed by knocking down IL-17. In vitro experiments showed that IL-1 and IL-17 exerted synergistic effects on the expression of profibrotic and inflammatory mediators. In the cGVHD model, C57BL/6 mice receiving splenocytes of IL-1Ra-KO BALB/c mice developed more severe cGVHD than did those receiving cells from WT mice. Knockdown of IL-17 in IL-1Ra-KO donor mice significantly attenuated the IL-1-induced acceleration of cGVHD severity. CONCLUSION: Targeting IL-1 and its downstream IL-17 activity may be a novel treatment strategy for inhibiting inflammation and tissue fibrosis in SSc.

Revision of Quality Indicators for the Endoscopy Quality Improvement Program of the National Cancer Screening Program in Korea.

Gastroscopy and colonoscopy are widely used for the early diagnosis of stomach and colorectal cancer. The present revision integrates recent data regarding previous quality indicators and novel indicators suggested for gastroscopy and colonoscopy procedures for the National Cancer Screening Program in Korea. The new indicators, developed by the Quality Improvement Committee of the Korean Society for Gastrointestinal Endoscopy, vary in the level of supporting evidence, and most are based solely on expert opinion. Updated indicators validated by clinical research were prioritized, but were chosen by expert consensus when such studies were absent. The resultant quality indicators were graded according to the levels of consensus and recommendations. The updated indicators will provide a relevant guideline for high-quality endoscopy. The future direction of quality indicator development should include relevant outcome measures and an evidence-based approach to support proposed performance targets.

Differences in quality of life determinants according to the presence of fibromyalgia in middle-aged female patients with systemic lupus erythematosus: a multicenter, cross-sectional, single-ethnicity cohort.

OBJECTIVE: The purpose of this study was to identify whether determinants of health-related quality of life (HRQoL) in middle-aged female patients with systemic lupus erythematosus (SLE) differed according to the presence or absence of fibromyalgia. METHODS: One hundred and fifty-two patients with SLE and 139 healthy controls (HCs) completed the Medical Outcomes Study 36-Item Short Form (SF-36) and EuroQol EQ-5D questionnaires about HRQoL. Disease activity and cumulative disease damage were assessed with standard indices. Sleep quality was assessed using the Korean version of the Pittsburgh Sleep Quality Index (K-PSQI). RESULT: The mean EQ-5D and physical and mental components of SF-36 were lower in SLE patients with fibromyalgia (n = 41) than in those without fibromyalgia (n = 111) and HCs. The scores in all eight domains of the SF-36 were lower in SLE patients with fibromyalgia than in patients without fibromyalgia and HCs. Poor sleep (defined as a K-PSQI > 5) was reported by 85% of SLE patients with fibromyalgia, by 51% of patients without fibromyalgia, and by 33% of HCs. Multivariate logistic regression analysis showed that lower educational level, cumulative organ damage severity and poor sleep quality were independent determinants of HRQoL in SLE patients with fibromyalgia, whereas disease activity, sleep quality and depressive mood were independent determinants of HRQoL in those without fibromyalgia. CONCLUSION: Poor sleep quality is the common independent risk factor for poor HRQoL in both middle-aged SLE patients with fibromyalgia and without fibromyalgia. Sleep quality improvement may improve HRQoL in female SLE patients, even in those without fibromyalgia.

[Revision of Quality Indicators for the Endoscopy Quality Improvement Program of the National Cancer Screening Program in Korea].

Gastroscopy and colonoscopy are widely used for the early diagnosis of stomach and colorectal cancer. The present revision integrates recent data regarding previous quality indicators and novel indicators suggested for gastroscopy and colonoscopy procedures for the National Cancer Screening Program in Korea. The new indicators, developed by the Quality Improvement Committee of the Korean Society for Gastrointestinal Endoscopy, vary in the level of supporting evidence, and most are based solely on expert opinion. Updated indicators validated by clinical research were prioritized, but were chosen by expert consensus when such studies were absent. The resultant quality indicators were graded according to the levels of consensus and recommendations. The updated indicators will provide a relevant guideline for high-quality endoscopy. The future direction of quality indicator development should include relevant outcome measures and an evidence-based approach to support proposed performance targets.

Kaempferol targeting on the fibroblast growth factor receptor 3-ribosomal S6 kinase 2 signaling axis prevents the development of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a systemic inflammatory disease that mainly affects the synovial joints. Although involvement of the fibroblast growth factor (FGF) signaling pathway has been suggested as an important modulator in RA development, no clear evidence has been provided. In this study, we found that synovial fluid basic FGF (bFGF) concentration was significantly higher in RA than in osteoarthritis (OA) patients. bFGF stimulates proliferation and migration of human fibroblast-like synoviocytes (FLSs) by activation of the bFGF-FGF receptor 3 (FGFR3)-ribosomal S6 kinase 2 (RSK2) signaling axis. Moreover, a molecular docking study revealed that kaempferol inhibited FGFR3 activity by binding to the active pocket of the FGFR3 kinase domain. Kaempferol forms hydrogen bonds with the FGFR3 backbone oxygen of Glu555 and Ala558 and the side chain of Lys508. Notably, the inhibition of bFGF-FGFR3-RSK2 signaling by kaempferol suppresses the proliferation and migration of RA FLSs and the release of activated T-cell-mediated inflammatory cytokines, such as IL-17, IL-21, and TNF-α. We further found that activated phospho-FGFR3 and -RSK2 were more highly observed in RA than in OA synovium. The hyperplastic lining and sublining lymphoid aggregate layers of RA synovium showed p-RSK2-expressing CD68+ macrophages with high frequency, while pRSK2-expressing CD4+ T-cells was observed at a lower frequency. Notably, kaempferol administration in collagen-induced arthritis mice relieved the frequency and severity of arthritis. Kaempferol reduced osteoclast differentiation in vitro and in vivo relative to the controls and was associated with the inhibition of osteoclast markers, such as tartrate-resistant acid phosphatase, integrin ß3, and MMP9. Conclusively, our data suggest that bFGF-induced FGFR3-RSK2 signaling may play a critical role during the initiation and progression of RA in terms of FLS proliferation and enhanced osteoclastogenesis, and that kaempferol may be effective as a new treatment for RA.