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Summary Objective We investigated the effects of 29-kDa amino-terminal fibronectin fragment (29-kDa FN-f) on xylosyltransferase-1 (XT-1), an essential anabolic enzyme that catalyzes the initial and rate-determining step in glycosaminoglycan chain synthesis, in human primary chondrocytes. Methods Proteoglycan and XT-1 expression in cartilage tissue was analyzed using safranin O staining and immunohistochemistry. The effects of 29-kDa FN-f on XT-1 expression and its relevant signaling pathway were analyzed by quantitative real-time-PCR, immunoblotting, chromatin immunoprecipitation, and immunoprecipitation assays. The receptors for 29-kDa FN-f were investigated using small interference RNA and blocking antibodies. Results The expression of XT-1 was significantly lower in human osteoarthritis cartilage than in normal cartilage. Intra-articular injection of 29-kDa FN-f reduced proteoglycan levels and XT-1 expression in murine cartilage. In addition, in 29-kDa FN-f-treated cells, XT-1 expression was significantly suppressed at both the mRNA and protein levels, modulated by the transcription factors specificity protein 1 (Sp1), Sp3, and activator protein 1 (AP-1). The 29-kDa FN-f suppressed the binding of Sp1 to the promoter region of XT-1 and enhanced the binding of Sp3 and AP-1. Inhibition of mitogen-activated protein kinase and nuclear factor kappa B signaling pathways restored the 29-kDa FN-f-inhibited XT-1 expression, along with the altered expression of Sp1 and Sp3. Blockading toll-like receptor 2 (TLR-2) and integrin α5β1 via siRNA and blocking antibodies revealed that the effects of 29-kDa FN-f on XT-1 expression were mediated through the TLR-2 and integrin α5β1 signaling pathways. Conclusion These results demonstrate that 29-kDa FN-f negatively affects cartilage anabolism by regulating glycosaminoglycan formation through XT-1.

Summary Objective Osteoarthritic cartilage destruction can be regulated by the balance between proteases and anti-proteases. Here, we sought to identify novel cellular protease inhibitors associated with osteoarthritis (OA) pathogenesis. Methods Candidate molecules were screened from microarray data of chondrocytes treated with OA-associated catabolic factors. The functions of candidate molecules in OA pathogenesis were examined in primary-culture mouse articular chondrocytes and mouse models of OA, such as those stimulated by destabilization of the medial meniscus (DMM) or intra-articular (IA) injection of adenovirus expressing the candidate gene. The value of the selected candidate molecule as a biomarker of OA was examined by measuring its circulating levels in human and mouse blood. Results Bioinformatic analysis identified secretory leukocyte peptidase inhibitor (SLPI) as a highly upregulated cellular protease inhibitor in chondrocytes treated with pathogenic catabolic factors, including interleukin (IL)-1β, hypoxia-inducible factor (HIF)-2α, and zinc importer ZIP8. The adenovirus-mediated overexpression of SLPI in joint tissues did not cause any OA-like change or modulate DMM- or HIF-2α-induced experimental OA in mice. SLPI also did not markedly modulate the expression of OA-associated catabolic or anabolic factors in chondrocytes. However, SLPI was specifically upregulated in OA cartilage, and the serum SLPI levels were significantly elevated in human OA patients and experimental OA mice, suggesting that SLPI may be a biomarker of OA. Conclusion Although SLPI is upregulated in OA chondrocytes, it does not appear to per se modulate OA development in mice. However, it may be a potential biomarker of OA in humans and animal models.

Background In many countries, gastric cancer is not diagnosed until an advanced stage. An Internet-based e-learning system to improve the ability of endoscopists to diagnose gastric cancer at an early stage was developed and was evaluated for its effectiveness. Methods The study was designed as a randomized controlled trial. After receiving a pre-test, participants were randomly allocated to either an e-learning or non-e-learning group. Only those in the e-learning group gained access to the e-learning system. Two months after the pre-test, both groups received a post-test. The primary endpoint was the difference between the two groups regarding the rate of improvement of their test results. Findings 515 endoscopists from 35 countries were assessed for eligibility, and 332 were enrolled in the study, with 166 allocated to each group. Of these, 151 participants in the e-learning group and 144 in the non-e-learning group were included in the analysis. The mean improvement rate (standard deviation) in the e-learning and non-e-learning groups was 1·24 (0·26) and 1·00 (0·16), respectively (P, Highlights • This report establishes that an e-learning system on the Internet can improve the diagnostic ability of endoscopists. • Countless endoscopists worldwide can access the system to learn how to make an endoscopic diagnosis of early gastric cancer. • The e-learning system could be modified to provide education regarding endoscopic diagnosis in other organs. This is the first report to demonstrate how an e-learning system based on the Internet can improve the diagnostic ability of gastrointestinal endoscopists worldwide. There is no limit to the number of endoscopists who can access the system and benefit from this opportunity to learn how to make an endoscopic diagnosis of early gastric cancer. This e-learning system could be modified to provide education regarding endoscopic diagnosis in other organs such as the large intestine and the esophagus, as well as the stomach. It may contribute to human welfare and health by reducing the mortality from gastrointestinal cancer.

Background Although polymorphisms of the catechol-O-methyl transferase (COMT) gene have been implicated in altered pain sensitivity, results concerning the association between COMT gene polymorphisms and fibromyalgia (FM) are equivocal. We assessed the associations between COMT single-nucleotide polymorphisms (SNP) and FM risk and symptom severity. Methods In total, 409 FM patients and 423 controls were enrolled. Alleles and genotypes at five positions [rs6269 (A>G), rs4633 (C>T), rs4818 (C>G), rs4680 (C>G) and rs165599 (A>G)] in the COMT gene were genotyped from peripheral blood DNA. Results Alleles and genotypes of the rs4818 COMT gene polymorphism were significantly associated with increased susceptibility to FM. The rs4818 GG genotype was more strongly associated with FM compared to the CC genotype (OR = 1.680, 95% CI: 1.057, 2.672, p = 0.027). Although allele and genotype frequencies did not differ among groups, the rs4633 CT genotype was not associated with the presence of FM following adjustment for age and sex (OR = 0.745; 95% CI: 0.558, 0.995; p = 0.046). However, no association was observed between clinical measures and individual COMT SNPs. In haplotype analysis, there was a significant association between ACG haplotype and FM susceptibility sex (OR = 2.960, 95% CI: 1.447, 6.056, p = 0.003) and the number of tender points (p = 0.046). Conclusions This large-scale study suggests that polymorphisms of the COMT gene may be associated with FM risk and pain sensitivity in Korean FM patients. However, our results differed to those of previous studies, suggesting ethnic variation in COMT gene polymorphisms in FM. What does this study add By contrast to Caucasian and Latin-American populations, the COMT gene polymorphisms are associated with FM risk and pain sensitivity in Korean FM patients, suggesting ethnic variation in COMT gene polymorphisms.

Background CT-P13 is a biosimilar prescribed in a number of countries for indications approved for the reference infliximab (RINF), including ankylosing spondylitis (AS), rheumatoid arthritis, and inflammatory bowel diseases. Clinical data of CT-P13 have been analysed in previous clinical trials, demonstrating equivalence of efficacy and pharmacokinetic profile to RINF. However, there are few studies showing long-term data of its drug survival or safety. Objectives To investigate the drug retention rate and safety data of biosimilar CT-P13 in Korean AS patients. Methods Subjects were AS patients enrolled in the Korean College of Rheumatology biologics registry (KOBIO). Data from patients who received RINF and CT-P13 were included in the analysisDec 2012 ~ .Dec 2017 Discontinuation was defined as switching or stopping the biologic agent. Kaplan-Meier curve and Cox proportional hazard model were used for further analysis. Reason for RINF or CT-P13 discontinuation was also assessed. Results Data from 399 AS patients (CT-P13; 256, RINF; 143) were analysed. The mean age of patients was 39.0 in the CT-P13 group, and 73% were males. The mean disease duration was 4.1 years. Eighty percent of patients were first-time biologic users. Discontinuation of CT-P13 occurred in 30.9% (switching in 17.6%) of patients during follow-up. The drug retention rate of first-line users of CT-P13 was marginally higher compared with second or more (≥2)-line users of CT-P13, first-line users of RINF, and ≥2 line users of CT-P13 in Korean AS patients (p=0.0518). The reason of discontinuation was inefficacy (42.7%), adverse events (20.2%), clinical improvement (7.9%), and others (18.0%) in the CT-P13 group. The incidence of adverse events of CT-P13, including infusion reaction (n=10), mycobacterial infection (n=2), and skin eruption (n=1) was comparable to that of RINF. Conclusions Our study demonstrates that the drug retention rate of CT-P13, especially in first-line users was relatively higher than that of RINF,[H1] and CT-P13 showed a reasonable long-term safety profile in Korean AS patients. Disclosure of Interest None declared

Objectives Several lines of evidence suggest that brain-derived neurotrophic factor (BDNF) is involved in the pathophysiology of fibromyalgia (FM) and studies have found that FM patients have altered serum and plasma BDNF levels. However, it is not known whether polymorphisms of the BDNF gene are associated with FM. In this study, we explored the association between polymorphisms of the BDNF gene with FM susceptibility and the severity of symptoms. Methods The study enrolled 409 patients with FM and 423 controls from 10 medical centres that participated in the Korean nationwide FM survey study. Alleles at 10 positions in the BDNF gene were genotyped: rs2883187 (C>T), rs7103873 (G>C), rs7103411(C>T), rs10835210 (C>A), rs11030104 (A>G), rs12273539 (C>T), rs11030102(C>G), rs11030101 (A>T), rs6265 (G>A), and rs7124442(C>T). Results The allele and genotype frequencies of BDNF rs11030104 differed significantly between the FM patients and controls (p=0.031). The GG genotype of rs11030104 had a protective role against FM (p=0.016) and the G allele of rs11030104 was negatively associated with the presence of FM compared with the A allele (p=0.013). In comparison, although the allele and genotype frequencies of BDNF rs12273539 did not differ between the FM patients and controls, the TT genotype of BDNF rs12273539 was associated with susceptibility to FM (p=0.038). Haplotype analyses suggested that some BDNF haplotypes have a protective role against FM. Finally, we found that that some genotypes and haplotypes of the BDNF gene contribute to the specific symptoms of FM. Conclusions This study is the first to evaluate the associations of BDNF gene polymorphisms with FM. Our results suggest that some BDNF single-nucleotide polymorphisms and haplotypes are associated with susceptibility to, and contribute to the symptoms of, FM. Disclosure of Interest None declared

BACKGROUND: Acanthopanax divaricatus var. albeofructus (ADA) extract has been reported to have anti-oxidant, immunomodulatory, and anti-mutagenic activity. MATERIALS/METHODS: We investigated the effects of ADA extract on two mouse models of Alzheimer’s disease (AD); intracerebroventricular injection of β-amyloid peptide (Aβ) and amyloid precursor protein/presenilin 1 (APP/PS1)-transgenic mice. RESULTS: Intra-gastric administration of ADA stem extract (0.25 g/kg, every 12 hrs started from one day prior to injection of Aβ1-42 until evaluation) effectively blocked Aβ1-42-induced impairment in passive avoidance performance, and Aβ1-42-induced increase in immunoreactivities of glial fibrillary acidic protein and interleukin (IL)-1α in the hippocampus. In addition, it alleviated the Aβ1-42-induced decrease in acetylcholine and increase in malondialdehyde levels in the cortex. In APP/PS1-transgenic mice, chronic oral administration of ADA stem extract (0.1 or 0.5 g/kg/day for six months from the age of six to 12 months) resulted in significantly enhanced performance of the novel-object recognition task, and reduced amyloid deposition and IL-1β in the brain. CONCLUSIONS: The results of this study suggest that ADA stem extract may be useful for prevention and treatment of AD.

Background Patients with fibromyalgia (FM) exhibit significant clinical heterogeneity, in terms of physical, social and psychological functions, as well as therapeutic responses. Here, we examined FM patients in terms of pain, physical, social and psychological variables to identify clinical subgroups that may be predictive of treatment patterns. Methods A total of 313 FM patients were interviewed using a structured questionnaire that included sociodemographic data, current or past FM symptoms and current use of relevant medications. A K-means cluster analysis was conducted using variables reflecting tender points, the Fibromyalgia Impact Questionnaire, Beck Depression Inventory, State-Trait Anxiety Inventor and Social Support Scale. Results Four distinct clusters were identified in these patients. Group 1 was characterized by high pain levels, severe physical and mental impairment and low social support. Group 2 had moderate pain and physical impairment, mild mental impairment and moderate social support. Group 3 had moderate pain, low physical and moderate mental impairment and low social support. Group 4 had low pain levels, nearly normal physical and mental function and high social support. Group 1 was more often a current or past smoker, more likely to have a variety of symptoms, including swelling, cognitive dysfunction, dizziness, syncope, oesophageal dysmotility, dyspepsia, irritable bladder, vulvodynia and restless leg syndrome. Conclusions We identified four subgroups of FM patients based on pain, physical, social and psychological function. These subgroups had different clinical symptoms and medication profiles, suggesting that FM may be better managed using a more comprehensive assessment of an individual patient's symptoms. Significance FM patients can be clustered into four distinct subgroups based on clinically measurable variables – pain, physical involvement, psychological function and social support. These subgroups had different clinical symptoms and medication profiles.

We have investigated the effect of electron beam irradiation as well as insertion of a Ag layer on the electrical and optical properties of the ITO or IZO films. The results show that electron beam irradiation as well as inserting a very thin Ag layer can significantly reduce sheet resistance of the ITO/Ag/ITO and IZO/Ag/IZO films. The electron beam irradiation also increases light transmittance and optical band gap of the ITO/Ag/ITO multilayer films; meanwhile, it has not influence on the transmittance of the IZO/Ag/IZO films. These results can be explained by that In and Zn cation in IZO film have strong tendency to preserve their coordination with oxygen.

The aim of publishing the Korean Pharmaceutical Codex is to update and set specification of essential drugs for humane health. In accordance with speedy development of new drugs and improvement of science and technology, the need of revision of drug specification through the ICH guidelines and discussions between regulatory agency and pharmaceutical industry for the quality assurance of safer and efficient drugs is getting higher. The first edition of Korean Pharmaceutical Codex was published in 1983. Now, the third revision of the Codex is prepared because of the revision of domestic and foreign Pharmacopeias, changes of drug control environment, improvement of science and technology and so on. The aim of 3th edition is to improve the quality of essential drugs through the setting of the required specifications and discussions between the regulatory agency and pharmaceutical industry.

Uranium-adsorbed silica particles were prepared as a reference material for the fission track analysis (FTA) of swipe samples. A modified instrumental setup for particle generation, based on a commercial vibrating orifice aerosol generator to produce various sizes of droplets from a SiO 2 solution, is described. The droplets were transferred into a weak acidic solution bath to produce spherical solid silica particles. The classification of the silica particles in the range from 5 to 20 μm was carried out by the gravitational sedimentation method. The size distribution and morphology of the classified silica particles were investigated by scanning electron microscopy. The physicochemical properties of the classified silica particles such as the surface area, pore size and pore volume were measured. After an adsorption of 5% 235 U on the silica particles in a solution adjusted to pH 4.5, the uranium-adsorbed silica particles were calcined up to 950 °C in a furnace to fix the uranium strongly onto the silica particles. The various sizes of uranium-adsorbed silica particles were applied to the FTA for use as a reference material.

This study was designed to investigate the effect of Zen Meditation on serum nitric oxide activity (NO) and oxidative stress (lipid peroxidation). The experimental group included 20 subjects who had practiced the Zen Meditation program in Meditation Center located in Seoul, South Korea. The control group included 20 subjects who did not practice any formal stress management technique and were age and sex matched with experimental group. To provide an assessment of nitric oxide production, the serum level of nitrate/nitrite was determined using the Griess reagent. Malondialdehyde (MDA) concentration was measured as a convenient index of lipid peroxidation by thiobarbituric acid (TBA) method. Meditation group showed a significant higher level of serum nitrate+nitrite concentration and a significant reduced level of serum malondialdehyde (MDA) than control group. A comprehensive randomized controlled trial should be performed to prove the causal relationship between meditation and level of nitric oxide or oxidative stress in reducing cardiovascular risk factors.

This study investigated different physical properties of ZrC/Al2O3 imbedded heat storage woven fabrics. ZrC and Al2O3 imbedded heat storage PET filaments were spun on the pilot spinning equipment, respectively. Various physical properties of ceramic imbedded fabrics made of ZrC and Al2O3 imbedded filaments were measured and compared with those of the regular PET woven fabric. The surface temperatures of the ZrC and Al2O3 imbedded fabrics were higher than that of the regular fabric. Water absorption rate of ceramic imbedded fabrics was better than that of the regular fabric and drying property was inferior to that of regular fabric. Breathability by water vapour resistance(Ref) of ZrC imbedded fabric was superior to that of regular fabric. Heat keepability rates of the ceramic imbedded fabrics were higher than that of the regular fabrics, which revealed a good heat storage property of the ZrC/Al2O3 imbedded fabrics.

We previously reported that p-synephrine has antidepressant-like activity in the murine models of forced swimming and tail suspension. In the present study, we characterized antidepressant-like effects of p-synephrine stereoisomers in both in vivo and in vitro systems. In the tail suspension test, S-(+)-p-synephrine (3 mg/kg, p.o.) reduced the duration of immobility, while R-(-)-p-synephrine (0.3-3 mg/kg, p.o.) had no effect. S-(+)-p-synephrine (0.3, 1 and 3 mg/kg, p.o.) and R-(-)-p-synephrine (1 mg/ kg and 3 mg/kg, p.o.) significantly reversed the reserpine (2.5 mg/kg, i.p.)-induced hypothermia. S-(+)-p-synephrine was more effective than R-(-)-p-synephrine in inhibition of both [3H]noradrenaline uptake in rat cerebral cortical slices (maximal inhibition 85.7 +/- 7.8% vs. 59.8 +/- 4.3%; EC50 5.8 +/- 0.7 microM vs. 13.5 +/- 1.2 microM) and [3H]nisoxetine binding (Ki 4.5 +/- 0.5 microM vs. 8.2 +/- 0.7 microM). In contrast, R-(-)-p-synephrine was more effective than S-(+)-p-synephrine in stimulation of [3H]noradrenaline release from rat cerebral cortical slices (maximal stimulation 23.9 +/- 1.8% vs. 20.1 +/- 1.7%; EC50 8.2 +/- 0.6 microM vs. EC50 12.3 +/- 0.9 microM). The stimulatory effect of R-(-)-p-synephrine on [3H]noradrenaline release was inhibited by nisoxetine (100 nM), but tetrodotoxin (1 microM) and elimination of extracellular calcium had no effect. It is suggested that S-(+)-p-synephrine has more effective antidepressant-like activity than R-(-)-p-synephrine.

1. beta-Amyloid peptide (A beta), a 39 -- 43 amino acid peptide, is believed to induce oxidative stress and inflammation in the brain, which are postulated to play important roles in the pathogenesis of Alzheimer's disease. Ferulic acid is an antioxidant and anti-inflammatory agent derived from plants; therefore, the potential protective activity of ferulic acid against A beta toxicity in vivo was examined. 2. Mice were allowed free access to drinking water (control) or water containing ferulic acid (0.006%). After 4 weeks, A beta 1-42 (410 pmol) was administered via intracerebroventricular injection. 3. Injection of control mice with A beta 1-42 impaired performance on the passive avoidance test (35% decrease in step-through latency), the Y-maze test (19% decrease in alternation behaviour), and the water maze test (32% decrease in percentage time in platform-quadrant). In contrast, mice treated with ferulic acid prior to A beta 1-42 administration were protected from these changes (9% decrease in step-through latency; no decrease in alternation behaviour; 14% decrease in percentage time in platform-quadrant). A beta 1-42 induced 31% decrease in acetylcholine level in the cortex, which was tended to be ameliorated by ferulic acid. 4. In addition, A beta 1-42 increased immunoreactivities of the astrocyte marker glial fibrillary acidic protein (GFAP) and interleukin-1 beta (IL-1 beta) in the hippocampus, effects also suppressed by pretreatment with ferulic acid. 5. Administration of ferulic acid per se unexpectedly induced a transient and slight increase in GFAP and IL-1 beta immunoreactivity in the hippocampus on day 14, which returned to basal levels on day 28. A slight (8%) decrease in alternation behaviour was observed on day 14. 6. These results demonstrate that long-term administration of ferulic acid induces resistance to A beta 1-42 toxicity in the brain, and suggest that ferulic acid may be a useful chemopreventive agent against Alzheimer's disease.

To evaluate the involvement of brain protein kinase C (PKC) in the stress-induced activation of hypothalamic-pituitary-adrenal (HPA) axis, we examined the effects of PKC inhibitors administered intracerebroventricularly (i.c.v.) on the immobilization stress-induced plasma corticosterone levels in mice. Calphostin C (a pan-specific PKC inhibitor) injected i.c.v. decreased the immobilization stress-induced plasma corticosterone level: maximal inhibition of 35% was attained at a dose of 100 pmol. Gö 6976 (an alpha and beta1 PKC isotype-selective inhibitor) was less effective than Calphostin C: maximal inhibition of 17% was attained at a dose of 30 pmol. Phorbol 12-myristate 13-acetate (a general PKC activator) injected i.c.v. at doses of 16 and 48 pmol increased the plasma corticosterone levels in a dose-dependent manner. The present study demonstrates the involvement of PKC in the brain in the regulation of the immobilization stress-induced stimulation of HPA axis in vivo.

Objectives Although polymorphisms of the catechol-O-methyl transferase (COMT) gene have been implicated in altered pain sensitivity, results concerning the association between COMT gene polymorphisms and FM are equivocal. We assessed the associations between COMT single-nucleotide polymorphisms (SNP) and FM risk and symptom severity. Methods In total, 409 FM patients and 423 controls were enrolled. Alleles and genotypes at five positions [rs6269 (A>G), rs4633 (C>T), rs4818 (C>G), rs4680 (C>G) and rs165599 (A>G)] in the COMT gene were genotyped from peripheral blood DNA. Results Alleles and genotypes of the rs4818 COMT gene polymorphism were significantly associated with increased susceptibility to FM. The rs4818 GG genotype was more strongly associated with FM compared to the CC genotype (OR =1.680, 95% CI: 1.057, 2.672, P=0.027). Although allele and genotype frequencies did not differ among groups, the rs4633 CT genotype was not associated with the presence of FM following adjustment for age and sex (OR =0.745; 95% CI: 0.558, 0.995; P=0.046). However, no association was observed between clinical measures and individual COMT SNPs. In haplotype analysis, there was a significant association between ACG haplotype and FM susceptibility sex (OR =2.960, 95% CI: 1.447, 6.056, P=0.003) and the number of tender points (P=0.046). Conclusions This large-scale study suggests that polymorphisms of the COMT gene may be associated with FM risk and pain sensitivity in Korean FM patients. However, our results differed to those of previous studies, suggesting ethnic variation in COMT gene polymorphisms in FM. Disclosure of Interest None declared

Background Several pro-inflammatory cytokines such as TNF-α, IL-1, IL-6, IL-8 and IL-15 are known to be critical in synovial inflammatory process in RA and successful results have been obtained in RA treatment with targeting pro-inflammatory cytokines including TNF-α, IL-1 and IL-6. Objectives This study sought to investigate the role of IL-33 and IL-6 in RA patients receiving IL-6 receptor inhibition therapy. Methods We analyzed the association of the IL-33 and IL-6 level with disease activity and serologic features in 83 patients with RA. We also measured the serum level of IL-33 and IL-6 before and after the administration of tocilizumab for 24 weeks in 40 patients. Results Serum IL-33 level showed significant correlation with RF (rho =0.660, p Serum IL-33 level significantly decreased after 24 weeks of IL-6 receptor inhibition in patients with RA (p Serum IL-6 levels were not significantly changed after 24 weeks of IL-6 receptor inhibition therapy (median 7.1 to 8.9 pg/mL, p=0.503). Changes of IL-6 levels were insignificant both in ACR20 responders and non-responders after 24 weeks of IL-6 receptor inhibition therapy. Baseline IL-6 levels were not different between ACR20 responders and non-responders. Conclusions The use of IL-6 receptor inhibitor decreased the serum level of IL-33 and this effect seems to be led by the responder group. IL-33 could be a useful indicator to monitor the response in IL-6 receptor inhibition therapy. Disclosure of Interest None declared

Background In recently, with development of biologic agents, RA patients increased the change of reaching remission. But some patients with normalization of inflammatory sign didn9t reach to clinical remission state after optimization of treatment. Objectives This study was performed to investigate the contribution of the more subjective versus the objective component of the DAS28 to response to treatment in RA patient. The secondary aim was to examine the factors associated with 6 month change in pain and EULAR response. Methods The DAS28-P was calculated (Subjective components of DAS28 relative to the total DAS28: DAS28-P=0.56*sqrt(TJC28) + 0.014*(VAS-GH)/0.56*sqrt(TJC28) + 0.28*sqrt(SJC28) + 0.78 In(ESR) + 0.014*(VAS-GH)). From September 2011 to 2013, 462 new patients were included in this study. EULAR response was assessed after 6month of treatment. Results The mean age of the included patient was 54 years, and 79% were female. The mean DAS28 at baseline was 4.91±1.07 (range 3.21–8.56) and that at after 6 months of treatment was 3.29±1.28 (range 0.49–8.47). Good responders according to the EULAR criteria were 180 (38.9%), moderate responders 150 (32.4%) and none responders 96 (22.5%). The change of DAS28-P score at baseline and 6 month was significant only for good responders (0.43±0.11 versus 0.3±0.25, p Conclusions Our study showed that there are distinct RA patients with high DAS28-P, an index derived from subjective measures, who fails to respond adequately to treatment despite normalization of objective measures. Disclosure of Interest None declared

Objectives Endothelial PAS domain protein-1 (EPAS-1/HIF-2α), encoded by EPAS1 gene, is a catabolic transcription factor to regulate osteoarthritis (OA) cartilage destruction. In this study we examined whether microRNA-365 (miR-365) can regulate interleukin (IL)-1β-induced expression of catabolic factors in SW1353 cells and human articular chondrocytes via regulation of EPAS-1. Methods Total RNA was isolated from normal and OA cartilage tissues, human chondrocytes, and SW1353 cells. The level of miR-365 was quantified by TaqMan assay. The effects of miR-365 on expression of EPAS-1 and EPAS-1-modulated genes were measured by quantitative real-time polymerase chain reaction (qRT PCR), Western blot analysis, and enzyme-linked immunosorbent assay (ELISA). To examine the direct interaction of miR-365 with 39 untranslated region (UTR) of EPAS-1 mRNA, luciferase reporter assay was performed. Results The level of miR-365 in human OA cartilage was significantly decreased compared to normal cartilage. The overexpression of miR-365 significantly suppressed IL-1β-induced expression of EPAS-1 in both SW1353 cells and human articular chondrocytes. QRT PCR analysis using pharmacological inhibitors revealed that mitogen activated protein kinase and nuclear factor-κB signaling pathway was involved in IL-1β-induced miR-365 decrease and subsequent increase of EPAS-1 expression. Luciferase reporter assay using DNA construct containing binding site of miR-365 within 39UTR of human EPAS-1 mRNA demonstrated that the overexpression of miR-365 significantly suppressed IL-1β-induced up-regulation of EPAS-1. Furthermore, miR-365 overexpression significantly suppressed IL-1β-induced expression of catabolic factors, including cyclooxygenase-2, inducible nitric oxide synthase, and matrix metalloproteinase-1, -3 and -13, in SW1353 cells and human chondrocytes. Conclusions MiR-365 regulates IL-1β-stimulated catabolic effects in SW1353 cells and human chondrocytes via modulating the expression of EPAS-1. Disclosure of Interest None declared

Objectives Researchers continue to gather evidence that transient receptor potential vanilloid ( TRPV ) channels contribute towards pain signaling pathways. However, it is unknown whether polymorphisms of the TRPV gene are associated with fibromyalgia (FM). For the first time, we investigated the association between the polymorphisms of the TRPV2 and TRPV3 genes with FM susceptibility and the severity of the symptoms. Methods A total of 409 patients with FM and 423 controls were enrolled from 10 medical centers that participated in the Korean nationwide FM survey. The alleles and genotypes at three positions [rs3813768 (C>G), rs8121 (C>T), and rs1129235 (C>A)] in the TRPV2 gene, and two positions [rs7216486 (G>A) and rs395357 (C>T)] in the TRPV3 gene, were genotyped. Results The frequencies of the alleles and genotypes of individual TRPV2 and TRPV3 genes were not significantly associated with FM susceptibility. However, the GTA haplotype of TRPV2 showed a defense against FM susceptibility ( P =0.035). In addition, polymorphisms of TRPV3 were associated with symptom severity in FM patients. The single nucleotide polymorphism (SNP) rs395357 of TRPV3 was associated with the scores of the Brief Fatigue Inventory (BFI) ( P =0.017) in FM patients. Furthermore, haplotypes of TRPV3 were associated with the BFI and the SF-36 mental health summary scores ( P =0.036, respectively) Conclusions This study was the first to evaluate the associations of TRPV gene polymorphisms with FM. Our results suggest that certain TRPV2 haplotypes may have a protective role against FM, and also that some genotypes and haplotypes of TRPV3 contribute towards the symptoms of FM. Disclosure of Interest None declared

Background Xylosyltransferase-1 (XT-1), encoded by xylt1 gene, is an essential anabolic enzyme to catalyze the initial and rate-determining step in glycosaminoglycan chain synthesis. The effect of fibronectin fragments (FN-fs), generated by proteolytic cleavage of FN and known as damage-associated molecular pattern (DAMP) molecules, on cartilage metabolism was poorly characterized. Objectives In this study we examined 29-kDa amino-terminal fibronectin fragment (29-kDa FN-f)-mediated XT-1 expression mechanism and its signaling pathway, determining the role of 29-kDa FN-f in cartilage matrix synthesis. Methods Human articular chondrocytes were enzymatically isolated from articular cartilage and cultured in monolayer. In 29-kDa FN-f-stimulated chondrocytes, the relative levels of mRNA and protein for XT-1 were analyzed by real-time quantitative reverse transcription-polymerase chain reaction and Western blot analysis, respectively. In order to investigate the effects of 29-kDa FN-f on XT-1, human chondrocytes were transfected with small interfering RNAs (siRNAs) targeting TLR-2. Results The level of aggrecan and XT-1 in human osteoarthritis cartilage was significantly decreased compared to normal cartilage. XT-1 expression in cultured primary articluar chondrocytes showed a periodic oscillation in both mRNA and protein level. 29-kDa FN-f significantly suppressed the mRNA and protein levels of XT-1 at 14 h and 24 h, respectively. Knockdown of toll like receptor-2 (TLR-2) using small interference RNA revealed that the decrease of XT-1 expression by 29-kDa FN-f is mediated by TLR-2 signaling pathway. Inhibition of mitogen activated protein kinase (MAPK) and nuclear factor-κB (NF- κB) signaling pathway restored 29-kDa FN-f-inhibited XT-1 expression. In addition, reduction of XT-1 expression by 29-kDa FN-f- was associated with activation of activator protein 1 (AP-1) signaling pathway. Finally, 29-kDa FN-f enhanced the expression of Sp3 and inhibited the expression of Sp1. Knockdown and overexpression experiments confirmed that XT-1 expression was modulated by Sp3 and Sp1, which are ubiquitous transcriptional proteins and compete for the same DNA binding site. Conclusions These results demonstrated that 29-kDa FN-f plays a detrimental role in the regulation of cartilage extracellular matrix formation including XT-1 expression. Disclosure of Interest None declared

Background The disease activity scored based on 28 joints (DAS28) has been widely used in clinical practice and research studies of rheumatoid arthritis (RA). Objectives The objective of this study was to evaluate discordance between DAS28 based on erythrocyte sedimentation rate (ESR) versus C-reactive protein (CRP) in patients with RA. Methods From August to December 2011, 540 RA patients who visited 2 rheumatology clinics affiliated to Hallym University and had at least one DAS28 evaluation were examined. Results The mean age of the included patients was 53 years, and 82% were female. The mean duration of disease was 32.9±41.2 months. The mean DAS28-ESR was higher than DAS28-CRP (3.65 vs 3.44; p Conclusions There was discordance between the ESR based and CRP based DAS28, a situation that could affect clinical treatment decisions for RA patients. Disclosure of Interest None declared

Background Osteoarthritis (OA) is a degenerative disease characterized by the death of chondrocytes and the gradual loss of articular cartilage. Recently, transfer of a therapeutic protein into cells by the use of protein transduction domain (PTD) that targets the lipid bilayer directly has been tested in terms of therapeutic applications. The FK506-binding protein 12 kDa (FK506BP12) binds immunosuppressive drugs such as FK506 and modulates T cell activation via calcineurin inhibition. The anti-inflammatory properties of and immunomodulatory role played by FK506BP12, independent of FK506, have been demonstrated in several disease models Objectives In this study, we investigated the ability of PEP-1-FK506BP12, consisting of FK506BP12 fused to the PTD PEP-1 peptide, to suppress catabolic responses in primary human chondrocytes and in a mouse carrageenan-induced paw arthritis model. Methods Western blotting and immunofluorescence analysis showed that PEP-1-FK506BP12 efficiently penetrated chondrocytes and cartilage explants. Results In interleukin-1β (IL-1β)-treated chondrocytes, PEP-1-FK506BP12 significantly suppressed the expression of catabolic enzymes, including matrix metalloproteinases (MMPs)-1, -3, and -13; and cyclooxygenase-2, at both the mRNA and protein levels, whereas FK506BP12 alone did not. In addition, PEP-1-FK506BP12 decreased IL-1β-induced phosphorylation of the mitogen-activated protein kinase (MAPK) complex (p38, JNK, and ERK) and the inhibitor kappa B alpha. In the mouse model of carrageenan-induced paw arthritis, PEP-1-FK506BP12 suppressed both carrageenan-induced MMP-13 production and paw inflammation. Conclusions Thus, PEP-1-FK506BP12 may have therapeutic potential in the alleviation of OA progression. References S.R. Goldring, M.B. Goldring, The role of cytokines in cartilage matrix degeneration in osteoarthritis, Clin. Orthop. Relat. Res. (2004) S27-36. D.W. Kim, S.H. Lee, S.K. Ku, et al., Transduced PEP-1-FK506BP ameliorates corneal injury in Botulinum toxin A-induced dry eye mouse model, BMB Rep. 46 (2013) 124-129. S.Y. Kim, E.J. Sohn, D.W. Kim, et al., Transduced PEP-1-FK506BP ameliorates atopic dermatitis in NC/Nga mice, J. Invest. Dermatol. 131 (2013) 1477-1485. Acknowledgements This research was supported by a grant (A120960) from the Korean Health Technology RD Mid-career Research program grant (NRF-2009-0084569), and by Hallym University Research Fund. Disclosure of Interest None declared

Background Loss to follow-up can occur with many reasons, which influenced the outcomes of longitudinal cohort studies. Objectives To compare the characteristics of patients who lost to follow-up and patients who completed the 2 years of follow-up, and examine the associated factors for early loss to follow-up (ELTF). Methods The study subjects consisted of the KORONA cohort which is a multicenter longitudinal RA cohort. After excluding 1,119 patients who did not complete the 2 years of follow-up but still are actively participating, we divided the patients (n=4,257) into two groups; patients who lost to follow-up within 2 years (ELTF group), and patients who completed the 2 years of follow-up (FU group). Multivariate analysis was performed using the variables significant in univariate analyses and institutional factor. Institutions were divided in 3 groups based on the number of patients enrolled; A (largest) and C (smallest). Results ELTF group patients (n=1,674, 39%) were older (p=0.04) and less educated (p

Background: Gastric cancer is the second highest cause of cancer deaths worldwide. Apart from Japan and Korea where screening programs are implemented, most gastric cancer patients worldwide are diagnosed at an advanced stage because of limited knowledge and experience of endoscopists. An internet-based e-learning system to teach detection of early gastric cancer using standard endoscopy has been developed and this study evaluated its effectiveness. Methods: The study was designed as a randomized controlled trial. Participants worldwide signed a consent form before first undertaking a pre-test via the internet, after which they were randomly allocated to the e-learning and non-e-learning groups. Pre-adjustment strata were the pre-test score, experience of endoscopy, being a nurse endoscopist or a medical practitioner, and medical institution and country. Only the participants in the e-learning group were allowed to access the e-learning system, which consisted of video lectures on basic knowledge and self-exercise tests to accumulate experience. A post-test in both groups was conducted 2 months after the pre-test. The pre-determined primary endpoint was the difference in the rate of improvement of the test result (post-test score/pre-test score) between groups. After completion of the post-test, the e-learning system was opened for all participants. Results: Among the 515 endoscopists from 35 countries assessed for eligibility, 322 participants who met the study’s inclusion criteria completed the pre-test and were enrolled: 166 were allocated to the e-learning group and 166 to the non-e-learning. Of these, 151 participants in the e-learning group and 144 in the non-e-learning group completed the post-test, and were included in the analysis. The mean rate of improvement (standard deviation) of the test result in the e-learning and non-elearning groups was 1.24 (0.26) and. 1.00 (0.16), respectively (P!0.001, Student’s ttest). Conclusion: This global study clearly demonstrated the efficacy of an e-learning system to improve knowledge and experience on endoscopic detection of early gastric cancer. Its effectiveness will be further evaluated in a study of improvements in the rate of early gastric cancer detection by all participants in actual clinical practice (UMIN: R000012039).

Accumulating evidence indicates that glial cells are actively involved in the pathogenesis of Alzheimer's disease. We recently reported protective effects of long-term administration of ferulic acid against learning and memory deficit induced by centrally administered beta-amyloid peptide (Abeta)1-42 in mice. In that report, we found that the Abeta1-42-induced increases in immunoreactivities of glial fibrillary acidic protein, the astrocyte marker, and interleukin(IL)-1beta in the hippocampus are also suppressed by pretreatment with ferulic acid. In the present study, we aimed to further characterize the effect of long-term administration of ferulic acid on the centrally administered Abeta1-42-induced activation of glial cells in mice. Mice were allowed free access to drinking water (control) or water containing ferulic acid (0.006%) for 4 weeks, and then Abeta1-42 (410 pmol) was administered via intracerebroventricular injection. Intracerebroventricularly injected Abeta1-42 induced an increase in immunoreactivities of endothelial nitric oxide synthase (eNOS) and 3-nitrotyrosine (3-NT) in the activated astrocytes in the hippocampus. Pretreatment of ferulic acid for 4 weeks prevented the Abeta1-42-induced increase in eNOS and 3-NT immunoreactivities. Administration of ferulic acid per se induced a transient and slight increase in eNOS immunoreactivity in the hippocampus on day 14, which returned to basal levels on day 28. Intracerebroventricularly injected Abeta1-42 also increased interleukin-1alpha(IL-1alpha) immunoreactivity in the hippocampus, which was also suppressed by pretreatment with ferulic acid. These results demonstrate that long-term administration of ferulic acid induces suppression of the centrallly injected Abeta1-42-induced activation of astrocytes which is suggested to underlie the protective effect of ferulic acid against Abeta1-42 toxicity in vivo.

Flavonoids and monophenolic compounds have been well described in recent years as antioxidants and scavengers of reactive oxygen and nitrogen species. In the present study, we aimed to characterize the effects of long-term administration of ferulic acid on the centrally administered beta-amyloid peptide (Abeta)(1-42)-induced activation of microglial cells in mice. Abeta(1-42) increased the immunoreactivity of OX-42, a microglial marker, and interferon-gamma in the hippocampus at 8 h after the intracerebroventricular injection. The effects were suppressed by long-term (4-week) pretreatment with ferulic acid. This inhibition of microglial cell activation may underlie the beneficial effects of long-term administration of ferulic acid on Abeta(1-42)-induced toxicity in vivo.

A phosphatase and tensin homolog (PTEN) has been known to play multiple biological roles. However, role of PTEN in astrocyte activation is not clear yet. In the present study, the expression pattern of PTEN in the process of reactive gliosis was immunohistochemically examined in intracerebroventricular (i.c.v.) injected kainic acid mouse hippocampus. Mice were grouped into three; 30 min, 1 day and 7 days after kainic acid i.c.v. injection. Thirty minutes after kainic acid i.c.v. injection, astrocytes were activated and PTEN was weakly expressed in immature astrocytes. Seven days after kainic acid i.c.v. injection, PTEN expression was decreased in highly activated astrocytes showing extensively spindled shape. Immunofluorescence double labeling experiment showed that PTEN was expressed in glial fibrillary acidic protein-positive astrocytes. These findings suggest that PTEN might have a role in early stage of reactive astrogliosis in vivo.

Background Tocilizumab (TCZ) has been developed and investigated in several clinical trials for efficacy and adverse events in RA patients. But it remains to be investigated which biomarkers have early predictive values. Objectives To investigate predictive cytokines of TCZ therapy in rheumatoid arthritis (RA) patients with an inadequate response to disease-modifying antirheumatic drugs (DMARDs). Methods We collected sera as part of CWP-TCZ301, a 24-week, randomized, double–blinded trial of TCZ in RA patients with an inadequate response to DMARDs. Serum levels of cytokines including tumor necrosis factor (TNF)-α, interleukin (IL)-17A, IL-21 and IL-23 were determined by luminex multiplex analysis at baseline and after treatment (4, 12 and 24 weeks). IL-6 and soluble IL-6 receptor (sIL-6R) were measured by ELISA. Therapeutic response was evaluated by American College of Rheumatology 20% improvement (ACR20) in the TCZ group (n=47) and placebo group (n=48) after 24 weeks. Results Early withdrawal patients from the study were excluded in the evaluation. In TCZ group (n=40), 29 patients were ACR20 responders and 11 patients were non-responders after 24 weeks of treatment. Baseline serum levels of IL-17A were significantly lower in responders than in non-responders ( p

Background Although recent imaging studies of fibromyalgia (FM) have converged on a dysfunction of central pain processing as a primary pathophysiology of the disorder, microstructural alteration suggestive of abnormal synaptic transmission or functional activation has not been extensively examined. Objectives We aimed to investigate white matter integrity and its possible relationship with pain symptoms in female subjects with FM. Methods Nineteen FM patients and age-, and gender-, and education-matched 21 healthy controls (HCs) were included and underwent diffusion-weighted imaging. Group difference in white matter integrity, assessed via fractional anisotropy (FA), was investigated by applying tract-based spatial statistics. Results FM group showed a single cluster with lower FA in the left body of corpus callosum, which was found to be connected with the bilateral sensorimotor cortices, compared with HCs corrected for multiple comparisons ( P Conclusions In summary, the current study demonstrated that patients with FM had disrupted white matter microstructure in the body of corpus callosum associated with clinical pain intensity. Our results suggest that abnormal interhemispheric transfer might contribute to heightened pain perception and further strengthen the hypothesis of centrally augmented pain processing in FM. Disclosure of Interest : None declared DOI 10.1136/annrheumdis-2014-eular.4736

Background Fibromyalgia (FM) is characterized by chronic widespread pain. Patients are more sensitive to sensory stimulation regardless of type and modality, suggesting generalized dysfunction in sensory processing. Mismatch Negativity (MMN) is an event-related potential measuring pre-attentive auditory processing. Objectives The present study aimed to explore pre-attentive auditory processing, which might be affected as a part of generalized sensory processing dysfunction in FM by measuring MMN in FM patients and healthy controls (HC). Also we tried to find an association between MMN parameters and pain sensitivity in FM patients. Methods Auditory evoked fields were recorded using magnetoencephalography in 18 right-handed female FM patients and 21 age-, sex- and education-matched right handed HC during a duration-deviant auditory oddball paradigm (50-ms standard and 100-ms deviant tones). The magnetic counterpart of the MMN (MMNm) was obtained by subtracting the response to standard stimuli from the response to deviant stimuli. Peak latencies, amplitudes and directional asymmetry coefficient (AC) of the MMNm source were compared between two groups. Pressure pain threshold over the thenar and trapezius muscle was assessed for measuring pain sensitivity. Results FM patients exhibited reduced MMNm amplitude in the right hemisphere. Rightward asymmetry of MMNm was altered in FM patients indexed by lower AC values. Also, smaller right MMNm amplitude was associated with lower pressure pain threshold of thenar muscle in FM patients. Conclusions Pre-attentive auditory processing was compromised in FM indexed by reduced MMNm amplitude. This result suggests likelihood of generalized sensory processing dysfunction in FM. Disclosure of Interest : None declared DOI 10.1136/annrheumdis-2014-eular.4728

Transcatheter arterial radioembolization (TARE) with Yttrium-90 ((90)Y)-labeled microspheres has an emerging role in treatment of patients with unresectable hepatocellular carcinoma. Although complication of TARE can be minimized by aggressive pre-evaluation angiography and preventive coiling of aberrant vessels, radioembolization-induced gastroduodenal ulcer can be irreversible and can be life-threatening. Treatment of radioembolization-induced gastric ulcer is challenging because there is a few reported cases and no consensus for management. We report a case of severe gastric ulceration with bleeding that eventually required surgery due to aberrant deposition of microspheres after TARE.

Background Interleukin-6 (IL-6), a proinflammatory cytokine, is thought to play a major pathological role in rheumatoid arthritis (RA). Tocilizumab is humanized anti IL-6 receptor monoclonal antibody which has been shown to improve signs and symptoms of RA. Objectives To investigate the efficacy and safety of tocilizumab in a Korean population. Methods This clinical trial was a 24-week phase III, randomized, double-blind, placebo-controlled, multicenter trial with two treatments arms and conducted from October, 2009 to October, 2010. The eligible patients had moderate to severe active RA, inadequately responding to MTX (or DMARDs). Tocilizumab at a dose of 8mg/kg or placebo were administered in a blinded manner, intravenously every 4 weeks, with stable dose of methotrexate (MTX) or other DMARDs. Results Total of 80 patients completed 24 week’s treatment with 40 patients in each treatment arm. At week 24, proportions of ACR 20, ACR 50, DAS28 remission and EULAR response were significantly higher in Tocilizumab group than in placebo group ( p p =0.0002, p =0.0002 and p p =0.0002, p =0.0055, respectively). Adverse drug reactions were more frequent in Tocilizumab group than in placebo group as follows; increased SGPT (21%), granulocytopenia (17%), leukocytopenia (15%), hypercholesterolemia (13%), pharyngitis (13%), and increased SGOT (10%). There were more incidences of serious adverse drug reactions in Tocilizumab group than in placebo group, but it was not significant ( p =0.0548). Conclusions In Korean population, administration of tocilizumab 8 mg/kg in combination with MTX (with or without other DMARDs) reduced RA activity significantly. Most of RA activity parameters including ACR 20, ACR 50, DAS 28 remission and EULAR response were achieved more frequently in Tocilizumab group than in placebo group. Tocilizumab was generally well tolerated since no safety issue was observed during the study. This study was financially supported by JW Pharmaceutical Co. (KFDA clinical trial-146). References Maini RN, et al. Arthritis Rheum. 2006;54(9):2817-29. Jones G, et al. Ann Rheum Dis. 2010;69(1):88-96. Disclosure of Interest None Declared