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Major Depression is the leading cause of disability worldwide. A cohort of patients do not respond adequately to available antidepressants, leading to treatment-resistant depression (TRD). We evaluated the antidepressant efficacy of an acute intravenous ketamine treatment (0.5 mg/kg) for patients with unipolar TRD, and measured peripheral blood-based biomarkers associated with response to treatment.Fifteen adults diagnosed with TRD completed an open label study of ten infusions of subanesthetic ketamine over four weeks. Out of fifteen patients, blood was collected from eleven patients at three timepoints to analyze peripheral biomarkers in isolated plasma, including IL-6, IL-10, TNF-α, BDNF, and irisin. Irisin analysis was completed using an ELISA assay, and the remaining biomarkers were analyzed together simultaneously using a multiplex immunoassay.Repeated ketamine infusions produced a significant decrease in total average depressive symptoms (MADRS) at all timepoints. Improvements in depressive symptoms were significant at one week, and continued to significantly decrease until two weeks, where it was maintained. Ketamine was generally well tolerated, and we observed improvements in functional impairment, anhedonia, and psychiatric symptoms, with no increases in manic symptoms. Levels of BDNF throughout treatment inversely correlated to decreases in MADRS scores, and higher levels of baseline BDNF predicted mood responses at one- and four weeks.The study was observational and uncontrolled, with a sample size of 15. Outpatients remained on their course of medications, unless they were pharmacological agents that have previously been identified to block ketamine's effects.Ketamine may be an efficacious and safe pharmacological option for the acute treatment of patients suffering from severe TRD. BDNF has the potential to function as a prognostic biomarker for predicting response to ketamine treatments.

Recent research on ketamine’s rapid antidepressant effect has been generating a growing interest on the best way to provide ketamine as a treatment option for resistant depression. However, the individual experiences of a mental health worker that aims to initiate a ketamine clinic can vary widely depending on the clinical setting. This chapter describes the process of developing a subanesthetic intravenous ketamine infusion service, combining the experiences of both academic and community public hospitals. We outline practical issues of setting up the service, funding, staffing, physical environment, protocols for patient assessment, responding to adverse events, and monitoring of outcomes. Establishing successful collaborative links between different healthcare departments such as nursing, anesthesiology, psychiatry, and hospital administration is discussed as being integral to the straightforward launching of a ketamine clinic. In addition, prompt dissemination of results and protocols, as well as sharing of data from each clinic would allow for similar services at other institutions to open. This would allow for the overall increased delivery of support for patients with depression. The protocols and processes included in this chapter should be continually adjusted and optimized depending on future research of ketamine, to practice the safest methods possible.

Background Despite advances in the field and new therapeutics being developed, heart disease remains the leading cause of mortality worldwide. Small extracellular vesicles (sEV) are 30–150 nm in diameter and ferry RNA and proteins to cells. sEV are a natural carrier of many signaling molecules and play an important role in heart disease. However, the high probability of off-target effects associated with these carriers is a major barrier to translation into clinical application. Purpose Our aim was to evaluate whether sEVs engineered to express potent cardiac targeting peptides (CTPs) could deliver siRNA to the heart and exert a therapeutic effect. Methods We use vectors encoding LAMP2B (sEV) or CTP-LAMP2B (PsEV) into HEK 293 cells expressing. sEVs were purified from culture media of HEK 293 cells by serial centrifugation followed by tangential flow filtration (TFF) system. sEV and PsEV were loaded with siRNAs by Exo-Fect™ exosome transfection reagent, and were treated into H9C2 rat cardiomyocyte. TNF-alpha were then added to the cells to induce inflammation. And sEVs were intravenously injected into myocarditis rat. Inflammation factors of in vitro and in vivo inflammation model were identified by western blot. Echocardiographic examination was also performed in rat. Results The successful development of PsEVs was analyzed by Western blot and TEM. We observed a 4 fold increase from that of the previously developed sEVs in H9C2 cells and a 200% increase in cardiac-specific delivery without toxicity in rat model. AGE is involved in proinflammatory/pro-apoptotic processes. To block RAGE, we loaded RAGE siRNA (siRAGE) in sEV that had high expression of PsEV. Characteristics of sEVs were maintained despite siRNA load.In inflammatory cell models and rat disease models, PsEV-treated groups significantly reduced molecular levels associated with inflammatory responses such as RAGE, IL-6, TNF-alpha, COX2, HMGB1, and p-p65 / p65. Conclusions Our results suggest that PsEV can potentially serve as a treatment delivery vehicle for heart disease. Scheme Funding Acknowledgement Type of funding source: None

Background Myocardial infarction (MI) is a public health problem and a leading cause of death worldwide. Due to insufficient current treatments, it is essential to develop effective alternatives for MI treatment. Curcumin is known to exhibit a variety of protective effects on the cardiovascular system such as MI, hypertension, and diabetic cardiomyopathy. However, due to its low solubility/stability and quick systemic elimination, curcumin has limited bioavailability. Extracellular vesicles (EVs) have lately emerged as a promising drug delivery vehicles by overcoming drug delivery hurdles. However, strategies are needed for delivery of EVs into the heart avoiding accumulation of other organs. Purpose The aim of this study is to investigate whether curcumin-loaded EVs functionalized with cardiac targeting peptide (CTP) may function as efficient heart-targeted delivery vehicles of curcumin, and further identify the molecular mechanisms underlying curcumin-mediated therapeutic effects in the MI. Methods EVs functionalized to express CTP (CTP-EVs) were isolated from culture medium of HEK293 cells transfected with mCherry-CD81–10 plasmid and CTP-LAMP2 plasmid by differential centrifugation, and then loaded with curcumin by coincubation, named CTP-EVs-Cur. The effect of CTP-EVs-Cur were evaluated H9C2 cardiomyocytes and mouse MI model. For the in vivo experiments, CTP-EVs-Cur (approximately 8–10 × 109 particles) were administered by intravenous injection into the tail vein and mice were subjected to the left anterior descending (LAD) artery ligation with a 6–0 silk suture. Results CTP-EVs were safely and successfully delivered curcumin to H9C2 cardiomyocytes and mouse hearts (4-fold; P Conclusion These findings suggest highly stable/effective ability of CTP-EVs for heart-targeted delivery and the novel mechanism of curcumin-mediated cardioprotective effects after MI, therefore, CTP-EVs-Cur are potentially powerful therapeutic strategy for MI treatment. Funding Acknowledgement Type of funding source: None

The creep characteristics of an aged Mg–4Zn–0.5Ca (wt%) were investigated using impression creep tests in the temperature range of 423–523 K and under punch stresses in the range of 225–750 MPa for dwell times up to 3600 s. The creep behaviour of the alloy was found to be associated with a threshold stress and well-described by the Garofalo hyperbolic sine equation modified for the threshold stress concept. The stress exponent of 5 and the activation energy for creep close to that of pipe diffusion in Mg, i.e. 97 kJ mol −1 , implies that dislocation climb controlled by diffusion through dislocation cores is the dominant rate-controlling mechanism. However, fitting the Garofalo equation to the experimental data showed that power-law breakdown (PLB) occurred in the material at high stress levels, especially at low temperatures. The threshold stress, appeared at low stress levels and low temperatures, was attributed to the nano-precipitates formed in the microstructure during aging treatment. The threshold stress was temperature-dependent, decreasing with increasing testing temperature and disappearing at about 575 K.

Introduction: Insomnia in Major Depressive Disorder (MDD) is highly prevalent and associated with increased suffering and functional impairment. Effective, evidence-based treatments for insomnia in MDD are an unmet need in clinical practice.Areas covered: Herein, the authors provide a review of the clinical correlates, putative neurobiological mechanisms and treatment options for the management of insomnia in individuals with MDD.Expert opinion: Sleep disturbances in MDD should be recognized as at least one of the following: (1) a domain of depressive psychopathology; (2) a consequence of rhythm disruptions; (3) a manifestation of comorbidities of sleep disturbances; (4) a manifestation of the influence of sex hormones in the brain in MDD; (5) a general medical comorbidity; and (6) a side effect of antidepressant medications. Assessment of insomnia in clinical practices is routinely performed with the use of non-structured interviews. Other methods such as standardized questionnaires and sleep diaries, along with complementary methods such as actigraphy and polysomnography are more scarcely applied. Smartphones and personal devices offer a promising strategy with the use of passive, long lasting, and ecologically valid assessments despite the lack of studies specifically targeting insomnia in individuals with MDD. New therapeutic approaches are essential, including novel targets such as orexins/hypocretins and the endocannabinoid system.

This paper describes a study and experimental demonstration on a magnetron operating at 2.45 GHz. We checked the characteristics of the 1 kW magnetron. There were two noise sources of magnetron at frequencies of 0.5 Hz and 75 kHz. In order to suppress these noises, we used an external injection locking method. Measurement results showed that the frequency noise suppression was down up to 30 dBc and the phase fluctuation is reduced to 4 degrees when injection input power was 7 W. Power combining experiments were performed using two identical magnetrons. An initial result showed an output power of 2 kW, corresponding to combining efficiency $\pmb{ > 93\%}$ .

We evaluated the effects of repeated subanesthetic ketamine infusions on suicidal ideation (SI) in patients with major depression. 82 subjects with treatment-resistant unipolar and bipolar depression completed a two-site open-label case-series of repeated (up to four weeks) infusions of ketamine (0.5 mg/kg). Ketamine produced a significant reduction in SI as early as one hour (71.1%) and up to 1-week post-infusion (60.4%), accompanied by a reduction in overall depressive symptoms which were maintained until the 4th week. The observed anti-suicidal effect was independent of mood changes, as patients whose mood did not respond still exhibited significantly less SI than baseline.

Shear punch test (SPT) was employed to study the high temperature mechanical properties of an Mg–4Zn–0.5Ca (wt%) alloy in the as-cast and aged conditions in the temperature range 150–250 °C. The microstructure of the as-cast alloy consisted of α-Mg matrix with some Ca 2 Mg 6 Zn 3 and MgZn second phase particles distributed in the interdendritic regions. Aging treatment resulted in the formation of equiaxed α-Mg grains together with coarse Ca 2 Mg 6 Zn 3 phase in the form of a semi-continuous network at the grain boundaries and triple points, while nano-sized Mg 4 Zn 7 , MgZn 2, and Ca 2 Mg 6 Zn 3 precipitates formed in the grain interiors. These phases have high thermal stabilities that could improve the high-temperature mechanical properties of the tested alloy after aging treatment.

The shear deformation behaviour of an extruded Mg–4Zn–0.5Ca alloy was studied using shear punch testing at room temperature. The extrusion process effectively refined the microstructure, leading to a grain size of 4.6 ± 1.4 μm. Contributions of different strengthening mechanisms to the room temperature shear yield stress, and overall flow stress of the material, were calculated. These mechanisms include dislocation strengthening, grain boundary strengthening, solid solution hardening and strengthening resulting from second-phase particles. Grain boundary strengthening and solid solution hardening made significant contributions to the overall strength of the material, while the contributions of second-phase particles and dislocations were trivial. The observed differences between calculated and experimental strength values were discussed based on the textural softening of the material.

We here report the use of thin layers of graphene oxide (GO) as a protective coating that inhibits corrosion of underlying magnesium (Mg) metal. In order to coat the GO layer, Mg surfaces were hydroxylated with NaOH solution followed by silanization with dipping in 3-aminopropyltriethoxysilane (APTES) solution and subsequent coating with GO. Here, electrochemical methods were employed to study the corrosion behavior of Mg by coating graphene on it using multi-step coatings. Potentiodynamic polarization measurement determined that the graphene coating effectively inhibited the metal from corrosion. Electrochemical impedance spectroscopy (EIS) measurements suggested that graphene film on metal surface protect the metal from oxidation. This was as a result of impermeability of GO coatings to ions diffuse of oxidizing gas and corrosive liquid solution.

NiTi alloys have exhibited significant potential as a matrix of wear resistant composites. In this study, in order to examine the effect of starting materials on the wear performance of NiTi-based composites, both elemental Ni/Ti and prealloyed NiTi powders were used to fabricate NiTi–6 wt% nano-Al 2 O 3 composites using hot isostatic pressing (HIP). Nanoindentation and microhardness test results indicate that the composite samples produced from the elemental Ni/Ti powders exhibited higher hardness and lower pseudoelasticity properties than those of the samples fabricated from the prealloyed NiTi powders; this is attributed to the higher amount of Ni 3 Ti/NiTi 2 phases in the samples from the elemental powders. The wear test results also confirm the superior performance of the composite samples produced from the elemental powders. The high-resolution transmission electron microscopy studies of the wear debris demonstrate that the heavy local plastic deformation induced during the wear test appeared to inhibit the pseudoelasticity during the wear process. Hence, it can be deduced that the role of the hardness enhancement is more pronounced than that of the pseudoelasticity reduction in the wear performance of NiTi-based composite samples.

Significance and Impact of the Study: Based on the biochemical characteristics, the phylogenetic prop- erty of the 16S rRNA gene and PFGE types of Edwardsiella tarda, we could identify the intraspecific diversity of isolates from Japanese eel, Anguilla japonica in Korea. In addition, this study describes the strong congruence of virulence-related genes and pathogenicity, suggesting that the virulence profile may be useful tool for prediction of pathogenicity. Abstract Edwardsiella tarda is the predominant bacterium in farm-cultured eel in Korea. Here, we evaluated the heterogeneity of 37 E. tarda isolates derived from Japanese eel with various origins (olive flounder, common carp and ornamental fish) between 2003 and 2010. Regardless of origins, the biochemical characteristics of E. tarda isolates were homogenous except hydrogen sulfide production, citrate utilization and mannitol fermentation. Based on the phylogenetic analysis of 16S rRNA, E. tarda isolates could be classified into two subgroups and displayed a close relation with Edwardsiella ictaluri and Edwardsiella hosinae lineages, suggesting that the subgroup I has been a predominant type in the Jeonnam and Jeonbuk provinces. I-CeuI-based pulsed-field gel electrophoresis (PFGE) typing showed that the isolates from Japanese eels belonged to 11 pulsotypes, indicating that the presence of highly genomic diversity. Additionally, two isolates, ET-060 and ET-191, showed a high frequency of virulence genes (100%) and caused 90% and 60% mortality in Japanese eel, respectively. This finding suggests a substantial congruence of virulence gene profiles and pathogenicity. Our results demonstrate that the intraspecific diversity within E. tarda strains from Japanese eel has been in prior existence.

In this paper we construct a new type of q-Bernstein polyno- mials related to q-Euler numbers and polynomials with weak weight ; E ( ) n;q , E ( ) n;q (x) respectively. Some interesting results and relationships are obtained.

Observation and Control of Interfacial Defects in ZnO/ZnSe Coaxial Nanowires W.A. Bhutto, Z.M. Wu∗, Y.Y. Cao, W.P. Wang and J.Y. Kang∗ Fujian Key Laboratory of Semiconductor Materials and Applications, Department of Physics, Xiamen University Xiamen 361005, P.R. China ZnO/ZnSe coaxial nanowires with di erent ZnO core diameters were synthesized by using a two-step chemical vapor deposition. The scanning electron microscopy images demonstrated that the coaxial nanowires with small ZnO core diameter had the smoother surface than that with large ZnO core diameter. A coherent ZnSe layer with wurtzite structure was observed in the nanowire interface between the ZnO core and the ZnSe shell by high resolution transmission electron microscopy. This coherent layer is bene cial to reduce the defect density and improve the crystal quality by suppressing the phase transition. It was found that the coherent thickness was signi cantly related to the ZnO core diameter. For the nanowire with large ZnO core, a thin critical thickness of 2 3 nm was obtained. As a result, a layer of zinc blende ZnSe appeared outside the nanowire, and a lot of defects existed in the interface between the ZnSe layers with di erent phase structures. For the nanowire with small ZnO core, however, the critical thickness increased and a coherent coaxial structure was observed with the same lattice spacing in the ZnO core and the ZnSe shell. To obtain defect-free coaxial nanowire, an optimal structure was also proposed by theoretical calculation.

A Mobile Harbor is a new transportation platform which can load and unload has containers to and from very large container ships on the sea. Currently designed Mobile Harbor a catamaran type which is equipped with precisely controlled gantry crane on the deck, and can transport 250 TEUs at a time. Loading and unloading works by crane require very small motion of Mobile Harbor in waves, because it may be operated outside of harbors. In this project, applicability of both tuned-type anti-rolling tank and maglev-type active mass driver is studied as anti-rolling systems.

This paper reports a light guide plate based flexible optical cuff for optogenetic stimulation of motor units. We propose the optical cuff based on a single-sheet PDMS light guide plate (LGP). It has good flexibility, and can be improved the efficiency of the light source by distributing the light globally through the LGP. Moreover, the possibility of cell necrosis due to heat can help to reduce by preventing direct contact between the µ-LED and neurons.

Several lifestyle and dietary factors are commonly cited as risk factors for gastro-oesophageal reflux disease (GORD) and modification of these factors has been advocated as first-line measures for the management of GORD. We performed a systematic review of the literature from 2005 to the present relating to the effect of these factors and their modification on GORD symptoms, physiological parameters of reflux as well as endoscopic appearances. Conflicting results existed for the association between smoking, alcohol and various dietary factors in the development of GORD. These equivocal findings are partly due to methodology problems. There is recent good evidence that weight reduction and smoking cessation are beneficial in reducing GORD symptoms. Clinical and physiological studies also suggest that some physical measures as well as modification of meal size and timing can also be beneficial. However, there is limited evidence for the role of avoiding alcohol and certain dietary ingredients including carbonated drinks, caffeine, fat, spicy foods, chocolate and mint.

Hepatocellular carcinoma (HCC) has a poor prognosis once it becomes symptomatic. Attempts have been made to screen high risk populations in order to detect asymptomatic HCC, some of which may be amena

Belotecan (Camtobell, CKD602) is a new camptothecin derivative antitumor agent that belongs to the topoisomerase inhibitors. The aim of this phase II study was to evaluate the efficacy and safety of single agent belotecan in patients with small cell lung cancer (SCLC). Patients with previously untreated extensive stage disease (ED) SCLC were entered into the study. Belotecan was given by daily intravenous infusion at 0.5mg/m(2)/day for 5 consecutive days, every 3 weeks. 62 patients were enrolled in this study. The overall response rate to chemotherapy on an intention-to-treat basis was 53.2%. The median overall survival was 10.4 months, the median time to progression 4.6 months, and the 1-year survival rate 49.9%. The most common toxicity was hematologic. Grade 3/4 neutropenia occurred in 71.0% of patients and grade 3/4 thrombocytopenia 12.9%. Non-hematologic toxicity of grade 3 or 4 was low. The results suggest that belotecan is relatively active and well tolerable as single agent in patients with ED SCLC. Further investigations with platinum or other active agents are needed.

We present a mimicking methodology to describe device-level endurance in a 1T1C, 64 Mb FRAM (ferroelectric random access memory). Device-level endurance of FRAM must clarify all the issues raised from destructive read-out READ/WRITE. To explore endurance properties in a real-time operational situation, we have established a measurement set-up that covers asymmetric pulse chains corresponding to Data 1 (D1) and Data 0 (D0) READ/RESTORE over a frequency range from 1.0 to 7.7 MHz. The cycle-to-failure of 5.9 × 1024 cycles in an operational condition of 7.7 MHz and 85 °C, has been obtained from extrapolation to VDD = 2.0 V in a voltage acceleration. We compare testing results with those of D1?D0 populations of bit-line potential.

This paper proposes a Reed-Solomon (RS) decoder for applications that require high-speed data communication and reliability. The proposed architecture can support variable n and k values (37

With the increasing importance of EC (Electronic Commerce) across the Internet, the need for agents to support both customers and suppliers is growing rapidly. But the lack of standard on product ontology, message and negotiation protocol between agents and brokering makes full automation of EC infeasible. In this paper, we describe an open infrastructure for agent-based EC and design a virtual market server. As an open infrastructure, we propose a complete architecture and message protocol for inter-agent negotiation. We designed and partially implemented a virtual marker server, named ICOMA (Intelligent electronic COmmerce system based on Multi-Agent) based on the advanced agent technologies. The goal of ICOMA is to construct the decentralized, dynamic, and diverse EC environment.

This paper proposes a low power and area efficient FIR filter chip for partial-response maximum likelihood (PRML) disk drive read channels, which is a 6-b, 8-tap digital FIR filter. The proposed filter employs a parallel processing architecture and consists of four pipeline stages. It uses the modified Booth algorithm for multiplication and compressor logic for addition. CMOS pass-transistor logic is used for low power consumption and single-rail logic is used to reduce the chip area. The proposed filter chip, using the 0.65 /spl mu/m technology, dissipates 120 mW at 100 Hz, uses the 3.3 V power supply and occupies 1.88/spl times/1.38 mm/sup 2/. The chip shows about 11% power reduction and about 15% area reduction compared with existing architectures. This chip was fabricated by Hyundai Semiconductor.

This paper proposes a low power and area efficient FIR filter chip for a partial-response maximum likelihood (PRML) disk drive read channel, which is a 6-b, 8-tap FIR filter. The proposed filter employs a parallel processing pipelined architecture. It uses the modified Booth algorithm for multiplication and the compressor logic for addition. The CMOS pass-transistor logic is used for the low power consumption and the single-rail logic is used to reduce the chip area. The proposed filter chip dissipates 120 mW at 100 Hz, 3.3 V power supply and occupies 1.88/spl times/1.38 mm/sup 2/. The proposed filter shows about 11% power reduction and about 15% area reduction compared with existing architectures. This chip was fabricated by Hyundai Semiconductor.

Background Systemic lupus erythematosus (SLE) is an autoimmune disease in which various organs and tissues are damaged through abnormal immune responses mediated by tissue-binding autoantibodies and immune complex deposition. As the majority of SLE patients are women of child-bearing age, estrogen has been suggested to play an important role in the pathogenesis of SLE. One of the proposed roles of estrogen is to increase autoantibody production. IL-21, a common-γ chain cytokine, has been shown to be crucial in the differentiation of activated B cells into plasma cells. Objectives Based on these concepts, we investigated the effect of estrogen on the production of IL-21 by T cells and subsequent B cell activation in SLE patients. Methods Peripheral blood mononuclear cells (PBMCs) were obtained from peripheral blood of 23 SLE patients and 16 healthy controls. CD4+ T cells, non CD4+ T cells and B cells were isolated using microbeads. Isolated cells were treated with 17-β estradiol at various concentrations for 48hrs. The expression of IL-21 and its receptor was assessed by measuring the level of protein and mRNA using ELISA and RT-PCR, respectively. The level of immunoglobulin G was measured with specific ELISA. Results The expression of IL-21 and its receptor in serum, PBMCs, and CD4+ T cells were higher in the patients with SLE compared to healthy controls. Exposure of CD4+ T cells from SLE patients to 17-β estradiol leads to a dose-and time-dependent increase in the IL-21 expression. The increase was abolished in the presence of MAP kinase (MEK, p38, JNK) inhibitors. B cells of healthy controls showed an increased antibody production when they were co-cultured with estrogen treated CD4+ T cells of patients with SLE. Treatment with anti-IL-21 antibody abrogated the increased antibody production of the co-culture systems, suggesting the increase was mediated by IL-21 dependent manner. Conclusions Estrogen upregulates IL-21 expression of CD4+ T cells via MAPK dependent pathways in SLE patients, which in turn induces increased antibody production by B cells. Disclosure of Interest : None declared DOI 10.1136/annrheumdis-2014-eular.3160

Background Leg muscle mass is related to development and progression of knee OA, and some studies suggested low leg muscle mass quantified by cross-sectional images of CT or MRI was related to knee symptoms [1,2]. However, this direct method of quantification is hard to apply to clinical practices, and it can be affected by total body mass which can confound the relationship of leg muscle mass and knee symptoms. Objectives We sought to examine if the ratio of leg to whole body muscle or fat mass by DXA relates to knee symptoms in radiographic knee OA. Methods We performed a cross-sectional study using data from the Fifth Korean National Health and Nutrition Examination Survey. We included subjects with radiographic knee OA (Kellgren-Lawrence grade≥2) and obtained degree of symptoms, body composition of both legs and the whole body using DXA and calculated the ratios of leg to whole body for muscle and fat mass. Analysis of covariance and multivariable logistic regression models were used to examine the associations of leg to whole body mass with knee symptoms adjusting for possible confounders. Results 1664 subjects were eligible for analysis. The ratio of leg to whole body muscle mass (LTWBM) was significantly lower in the group with knee pain or stiffness (30.27±0.10 vs. 30.92±0.08, p Conclusions Symptomatic knee OA was associated with reduced leg muscle mass. Local sarcopenia indicated by low leg to whole body muscle mass could be an important and useful clinical marker for symptomatic knee OA. Strategies to increase leg muscle mass might counteract having symptomatic knee OA. References Sattler, M., et al., Side differences of thigh muscle cross-sectional areas and maximal isometric muscle force in bilateral knees with the same radiographic disease stage, but unilateral frequent pain - data from the osteoarthritis initiative. Osteoarthritis Cartilage, 2012. 20(6): p. 532-40. Wang, Y., et al., Increase in vastus medialis cross-sectional area is associated with reduced pain, cartilage loss, and joint replacement risk in knee osteoarthritis. Arthritis Rheum, 2012. 64(12): p. 3917-25. Disclosure of Interest : None declared DOI 10.1136/annrheumdis-2014-eular.2422

Background Ursolic acid (UA) is a pentacytclic triterpenoid compound which is ubiquitously present in plants. Objectives Based on its known anti-inflammatory and anti-oxidative effect, this study was undertaken to investigate the effect of UA on collagen-induced arthritis (CIA) and to delineate the underlying mechanism. Methods UA (150mg/kg) or 10% dimethyl sulfoxide was injected intraperitoneally three times a week to mice with CIA from the day 14 after immunization. The expressions of proinflammatory cytokines and molecules associated with oxidative stress in arthritic joints were measured by immunohistochemical staining. The number of CD4+IL-17+ cells or CD4+CD25+Foxp3+ cells or phosphorylated (p) STAT3 + cells was determined by confocal immunostaining of the spleen or flow cytometry analysis of splenocytes. The level of mRNA expression and immunoglobulin was analyzed by real time RT-PCR and ELISA, respectively. Results UA injection prevented clinical arthritis incidence and joint inflammation in mice with CIA. A significant reduction in pSTAT3 and resultant decrease in the number of Th17 was observed with UA treatment. Consistently, the expression of IL-17 and retinoic acid orphan receptor (ROR)γt was markedly reduced with UA. Although the expression of Foxp3 was unaffected, the number of Treg cells was increased with UA treatment. There was a marked reduction in type II collagen-specific immunoglobulin G production. When IL-21-or LPS-stimulated CD19+ B cells were cultured in the presence or absence of UA, the mRNA expression of markers associated with B cell activation (Bcl-6), plasma cell differentiation (Blimp-1) and isotype switching (activation-induced deaminase) was markedly reduced with UA treatment. Conclusions Our findings suggest that UA can regulate Th17 and reciprocally promote Treg cells by inhibiting expression of ROR γt and pSTAT3. UA also inhibits plasma cell differentiation, resulting in a reduction of immunoglobulin production. By targeting pathogenic Th17 and immunoglobulin production, UA may be a novel therapeutic for treatment of autoimmune arthritis and other Th17-related diseases. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.3181

Background The lupus flare rate during pregnancy was reduced with pre-pregnancy counseling and effective strategies. However, limitation of using immunosuppressant, the outcome of the lupus pregnancies with renal flare can be worse than the lupus patients without pregnancy. Objectives The aims of this study were to compare clinical manifestations of pregnancy complications in lupus mothers with and without LN and to identify predictors for LN flares during pregnancy. In the case of renal flare during pregnancy, the long term prognosis has not been established. Therefore, we assessed the change in proteinuria and glomerular filtration rate (GFR) during a year after delivery. Methods We performed a retrospective analysis of 183 pregnancies in 132 SLE patients managed in Catholic University Medical Center, Korea. Demographic data, SLE clinical manifestations and treatment, and obstetric outcomes were recorded from medical charts. Laboratory data included blood chemistry, urinalysis, spot urine protein to creatinine ratio or protein level from 24 hours urine collection, C3 and C4 level were collected from before pregnancy, during pregnancy, after 1 month, 6 months and 1 year after delivery. Results 76 pregnancies had history of LN before conception. Pregnancies with history of LN had more adverse obstetric outcomes. Most of LN flare cases were reactivated and 4 cases (5.3%) became inactive during pregnancy. LN flare was predicted by high serum uric acid level (OR 1.843; 95% CI, 0.991-3.426; P =0.053). Twelve patients achieved a complete remission within 3 months after delivery but 15 patients showed persistent proteinuria or decreased GFR after 1 year from delivery. The peak level of proteinuria was not different between remission and persistent LN, but pregnancies who had attained a ≥50% reduction in urine protein at 6 months were significantly low in persistent after 1 year group. A ≥50% reduction in urine protein at 6 months predicts a favorable longterm outcome in renal flares during pregnancies (OR 0.132; 95% CI, 0.034-0.525; P =0.004). Conclusions Lupus mothers with LN gave successful living births, but still there were more maternal and fetal comorbidity including LN flares. Baseline uric acid level was the only predictor for LN flare during pregnancy among the pregnancies with history of LN. The long-term renal outcome of LN during pregnancy was not inferior comparing with non-pregnant lupus patients. To reduce proteinuria to a level more than 50% within 6 months is important. References 1. Stojan G and Baer AN. Flares of systemic lupus erythematosus during pregnancy and the puerperium: prevention, diagnosis and management. Expert review of clinical immunology. 2012; 8: 439-53. 2. Stanhope TJ, White WM, Moder KG, Smyth A and Garovic VD. Obstetric nephrology: lupus and lupus nephritis in pregnancy. Clinical journal of the American Society of Nephrology: CJASN. 2012; 7: 2089-99. 3. Imbasciati E, Tincani A, Gregorini G, et al. Pregnancy in women with pre-existing lupus nephritis: predictors of fetal and maternal outcome. Nephrol Dial Transplant. 2009; 24: 519-25. 4. Moroni G, Quaglini S, Gallelli B, Banfi G, Messa P and Ponticelli C. The long-term outcome of 93 patients with proliferative lupus nephritis. Nephrol Dial Transplant. 2007; 22: 2531-9. Disclosure of Interest : None declared DOI 10.1136/annrheumdis-2014-eular.2494

Background Since the concept of reprogramming mature somatic cells to generate induced pluripotent stem cells (iPSCs) was demonstrated in 2006, iPSCs have become a potential substitute for embryonic stem cells (ESCs) given their pluripotency and “stemness” characteristics, which resemble those of ESCs. Objectives We investigated to reprogram fibroblast-like synoviocytes (FLSs) from patients with rheumatoid arthritis (RA) and osteoarthritis (OA) to generate iPSCs using a 4-in-1 lentiviral vector system. Methods A 4-in-1 lentiviral vector containing Oct4, Sox2, Klf4, and c-Myc was transduced into RA and OA FLSs isolated from the synovia of two RA patients and two OA patients. Immunohistochemical staining and real-time PCR studies were performed to demonstrate the pluripotency of iPSCs. Chromosomal abnormalities were determined based on the karyotype. SCID-biege mice were injected with iPSCs and sacrificed to test for teratoma formation. Results After 14 days of transduction using the 4-in-1 lentiviral vector, RA FLSs and OA FLSs were transformed into spherical shapes that resembled embryonic stem cell colonies. Colonies were picked and cultivated on matrigel plates to produce iPSC lines. Real-time PCR of RA and OA iPSCs detected positive markers of pluripotency. Immunohistochemical staining tests with Nanog, Oct4, Sox2, Tra-1-80, Tra-1-60, and SSEA-4 were also positive. Teratomas that comprised three compartments of ectoderm, mesoderm, and endoderm were formed at the injection sites of iPSCs. Established iPSCs were shown to be compatible by karyotyping. Finally, we confirmed that the patient-derived iPSCs were able to differentiate into osteoblast, which was shown by an osteoimage mineralization assay. Conclusions FLSs derived from RA and OA could be cell resources for iPSC reprogramming. Disease- and patient-specific iPSCs have the potential to be applied in clinical settings as source materials for molecular diagnosis and regenerative therapy. References Takahashi K, Yamanaka S: Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006, 126:663-76. Tiscornia G, Vivas EL, Izpisua Belmonte JC: Diseases in a dish: modeling human genetic disorders using induced pluripotent cells. Nat Med 2011, 17:1570-6. Grskovic M, Javaherian A, Strulovici B, Daley GQ: Induced pluripotent stem cells–opportunities for disease modelling and drug discovery. Nat Rev Drug Discov 2011, 10:915-29. Acknowledgements This work was supported by a grant from the Korea Healthcare Technology R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea (A092258). Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.4862

Background Gout is a chronic inflammatory disease of which the development is associated with metabolic abnormality caused by obesity. However, there are a substantial number of non-obese patients (body mass index (BMI) 100cm2 was defined as visceral fat obesity (VFO). The frequency of VFO was compared in patients and control groups. The frequency of metabolic syndrome as well as its components was investigated. Results The prevalence of metabolic syndrome in patients with gout was 31.7% (33/104) according to modified ATP III criteria. BMI (26.3±3.8 vs. 23.4±2.4 kg/m2, P

Background Anti-TNF therapy was known to increase the risk of certain infection. There are no sufficient data about the reactivation of hepatitis B virus (HBV) after anti-TNF therapy. Objectives The study was aimed to investigate the clinical course of hepatitis B in patients with rheumatoid arthritis (RA) and ankylosing spondylitis (AS) after the introduction of anti-TNF therapy. Methods We retrospectively reviewed to identify patients infected with HBV treated with TNF inhibitors between October, 2004 and September, 2013. For patients with HBV infection, the liver enzyme and the viral status were monitored. The HBV reactivation was defined according to the Korean guideline by hepatology. Results Of 983 patients (RA, n=536; AS, n=447) who were treated with TNF inhibitors, 23 patients (RA, n=17; AS, n=6) had comorbidities of HBV infection. Eighteen patients were treated with etanercept, three with adalimumab, and two with infliximab. Seven patients received pre-emptive antiviral prophylaxis before anti-TNF therapy: 4 with entecavir, 1 with telbivudine, 1 with tenofovir, and 1 with lamivudine. Among 23 patients with HBV infection, 4 (17.4%) patients experienced the reactivation of HBV, which occurred in 3 patients without prophylaxis and 1 patient with lamivudine prophylaxis. In the latter case, YMDD mutation was identified and addition of adefovir resulted in virological response. The other three patients were treated successfully with entecavir or tenofovir. There was no subsequent events associated with HBV infection. Conclusions This study indicates the risk of HBV reactivation after anti-TNF therapy. Careful management is mandatory for patients who planned to be treated with TNF inhibitors. References Vassilopoulos D, Calabrese LH. Management of rheumatic disease with comorbid HBV or HCV infection. Nature reviews Rheumatology. 2012 Jun;8(6):348-57 Oketani M, Ido A, Uto H, Tsubouchi H. Prevention of hepatitis B virus reactivation in patients receiving immunosuppressive therapy or chemotherapy. Hepatology research: the official journal of the Japan Society of Hepatology. 2012 Jul;42(7):627-36 Korean Association for the Study of the L. KASL Clinical Practice Guidelines: Management of chronic hepatitis B. Clinical and molecular hepatology. 2012 Jun;18(2):109-62 Acknowledgements This study was supported by a grant from the Korea Healthcare Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (HI10C2020). Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.5251

Background IL-33 and its receptor, ST2, are associated with many inflammatory disorders. However, the data on IL-33/ST2 in Sjogren9s syndrome (SS) is very limited. Objectives To evaluate the expression of IL-33 and its receptor in sera and salivary tissues obtained from patients with primary Sjogren9s syndrome (pSS) and to investigate the possible relationship with clinical profiles. Methods Serum IL-33 and soluble ST2 (sST2) of 55 patients with pSS and 48 controls were determined using ELISA, and assessed for correlation with clinical profiles. The expression of IL-33/ST2 in salivary tissues was investigated by immunohistochemical (IHC) staining, and was further characterized by confocal microscopy. We also measured ST2 expression in peripheral blood mononuclear cells (PBMCs) of pSS patients, and IL-33 production in salivary glandular epithelial cell by pro-inflammatory stimuli. Results The serum levels of IL-33 and sST2 were higher in pSS patients compared to healthy controls ( P =0.018 and P P =0.029) and duration of disease ( p =0.013). Contrary to sST2, ST2 was downregulated in PBMCs obtained from pSS patients. The expression of IL-33 and ST2 was elevated in salivary gland of pSS patients with grade 2 inflammation, and decreased as inflammation progresses. In pSS patients, IL-33 was mainly observed in epithelial cells and endothelial cells of gland tissue. The production of IL-33 mRNA by salivary gland epithelial cell line was increased under stimulation with interferon-γ. Conclusions IL-33 and sST2 concentrations were elevated in sera of pSS patients, whereas ST2 in salivary gland and PBMC of pSS patients showed downregulated expression. This result suggests that IL-33/ST2 axis might have a role in the pathogenesis of pSS. References Schmitz, J., et al., IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity, 2005. 23(5): p. 479-90. Palmer, G. and C. Gabay, Interleukin-33 biology with potential insights into human diseases. Nat Rev Rheumatol, 2011. 7(6): p. 321-9. Moussion, C., N. Ortega, and J.P. Girard, The IL-1-like cytokine IL-33 is constitutively expressed in the nucleus of endothelial cells and epithelial cells in vivo: a novel `9alarmin”? PLoS One, 2008. 3(10): p. e3331. Acknowledgements This study was supported by a grant from the Korea Healthcare Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (HI13C0016). Disclosure of Interest : None declared DOI 10.1136/annrheumdis-2014-eular.4921

Background Systemic lupus erytematosus (SLE) is a multi-organ autoimmune disease that affects women of childbearing age. SLE and lupus nephritis have more maternal and fetal complications than the general population. However, the impact of pregnancy on SLE activity is controversial in the literature, some studies reporting increased risk of lupus flare, while others indicate no increased risk. Objectives The aims of this study were to investigate the effect of the pregnancy on disease status, both during the pregnancy and puerparium and the predictors for lupus flare. In addition, we examine lupus activity and pregnancy outcomes in lupus pregnancies continued, discontinued or not treated with Hydroxychloroquine (HCQ) during pregnancy. Methods We performed a retrospective analysis of 183 pregnancies in 132 SLE patients managed in Catholic University Medical Center, Korea, between 1998 and 2012. Clinical profiles and maternal and fetal outcomes were assessed for this study population. Lupus flare was assessed with SLEDAI score. Discontinued HCQ group was defined as cessation of HCQ treatment within the 3 months prior to pregnancy. Not treated with HCQ from pre-pregnancy was defined cessation of HCQ treatment beyond 3 months prior to pregnancy. Results The pregnancies were divided into 2 groups: experienced lupus flare (84 pregnancies) and not experienced lupus flare (99 pregnancies). 87.4% of pregnancies had successful delivery. There were significantly more preeclampsias (27.4% vs. 7.1%, with and without lupus flare, respectively, P P =0.01), low birth weight (2.42±0.60 kg vs. 2.85±0.54 kg, P P =0.004) in pregnancies with lupus flare. Lupus flares were predicted by discontinuation of HCQ (OR=4.968, 95% CI, 1.114-22.145; p=0.036), history of lupus nephritis (OR, 4.417; 95% CI 1.253-15.575, p=0.021), active disease status at conception (OR, 4.526; 95% CI, 1.276-16.049; p=0.019), high serum uric acid level (OR, 2.624; 95% CI, 1.414-4.868; p=0.002) and C4 level at pre-pregnancy (OR 0.858, 95% CI 0.762-0.966; p=0.011). Conclusions Our study indicates that achieving remission before pregnancy and continuing HCQ treatment during pregnancy are important to prevent lupus flare during pregnancy. References Stojan G and Baer AN. Flares of systemic lupus erythematosus during pregnancy and the puerperium: prevention, diagnosis and management. Expert review of clinical immunology. 2012; 8: 439-53. Lateef A and Petri M. Management of pregnancy in systemic lupus erythematosus. Nature reviews Rheumatology. 2012; 8: 710-8. Stanhope TJ, White WM, Moder KG, Smyth A and Garovic VD. Obstetric nephrology: lupus and lupus nephritis in pregnancy. Clinical journal of the American Society of Nephrology: CJASN. 2012; 7: 2089-99. Ateka-Barrutia O and Khamashta M. The challenge of pregnancy for patients with SLE. Lupus. 2013; 22: 1295-308. Clowse ME. Lupus activity in pregnancy. Rheumatic diseases clinics of North America. 2007; 33: 237-52, v. Petri M. Sex hormones and systemic lupus erythematosus. Lupus. 2008; 17: 412-5. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.2483

Background Rheumatoid arthritis (RA) is a systemic inflammatory disease and is commonly associated with osteoporosis. To prevent osteoporotic fractures in patients with RA, it is important to identify the high risk groups with a low bone mineral density (BMD) as well as other clinical risk factors and to apply an early pharmacological intervention for osteoporosis. The standard of pharmacological intervention for osteoporosis in patients with RA is based on the T-score measured by dual-energy X-ray absorptiometry (DEXA) similar to the general population. However, it may not be the proper standard to measure the high-risk group of patients with RA. To overcome the limitations of T-score, the fracture risk assessment tool (FRAX) was developed by the World Health Organization (WHO). Objectives To identify patients without osteoporosis who met the criteria of the FRAX criteria of the National Osteoporosis Foundation (NOF) only and to compare patients who met only the FRAX criteria of the NOF and patients who presented osteoporosis in the incidence of fractures. Methods Five hundred and forty five patients with rheumatoid arthritis who visited a single center were recruited in South Korea. The candidates for a pharmacological osteoporosis intervention were identified using the World Health Organization (WHO) criteria and the Korean FRAX model. In the follow-up period during median 30 months were investigated the new onset of fractures. Results Of 223 patients who have no osteoporosis, 39 (17.4%) satisfied the FRAX criteria for pharmacological intervention. The discordance between the BMD and FRAX criteria for pharmacological intervention was remarkable in men, 11/29 (37.9%) vs. 19/29 (65.5%). During the follow up period occurred 2 new onset fractures in patients who met only the FRAX criteria and 22 new onset fractures in patients with osteoporosis by BMD. The incidence rate for new onset fractures of patients who met only the FRAX criteria was with 295.93 per 10,000 person-years higher than in the general population with 114.99 per 10,000 person-years. Conclusions Patients who met the FRAX criteria of the NOF only need pharmacological intervention because their numbers of incidences for new onset fractures are similar to those of patients with osteoporosis by BMD. References Sinigaglia L, Nervetti A, Mela Q, Bianchi G, Del Puente A, Di Munno O et al. A multicenter cross sectional study on bone mineral density in rheumatoid arthritis. Italian Study Group on Bone Mass in Rheumatoid Arthritis. J Rheumatol 2000;27:2582-9. van Staa TP, Geusens P, Bijlsma JW, Leufkens HG, Cooper C. Clinical assessment of long-term risk of fracture in patients with rheumatoid arthritis. Arthritis Rheum 2006;54:3104-12. Kim SY, Schneeweiss S, Liu J, Daniel GW, Chang CL, Garneau K et al. Risk of osteoporotic fracture in a large population-based cohort of patients with rheumatoid arthritis. Arthritis Res Ther 2010;12:R154. Baskan BM, Sivas F, Alemdaroglu E, Duran S, Ozoran K. Association of bone mineral density and vertebral deformity patients with rheumatoid arthritis. Rheumatol Int 2007;27:579-84. Silverman SL. The clinical consequences of vertebral compression fracture. Bone 1992;13:S27–31. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.2501

Background Recent studies demonstrated that sodium chloride (NaCl) can be a risk factor for autoimmune disease through the induction of pathogenic IL-17 producing T helper (Th17) cells. Objectives This study was aimed to evaluate the potential effect of NaCl on Th17 differentiation in patients with rheumatoid arthritis (RA) and on the inflammation in collagen induced arthritis (CIA) model. Methods Peripheral blood mononuclear cells (PBMC) obtained from RA patients were cultured under high salt condition, and analyzed using flowcytometry to determine Th17 population. For evaluation of in vivo effect, CIA mice were fed with normal diet (control group) or high salt diet ad libitum (high salt group). Clinical assessment was performed daily based on visual scoring of paw swelling. The arthrogenic differentiation of mouse bone marrow derived cells and mouse splenocytes were evaluated with tartrate-resistant acid phosphatase (TRAP) staining and flowcytometry, respectively. Results NaCl promoted the induction of Th17 cells from PBMC in RA patients. Th17 differentiation was progressively upregulated as NaCl concentration increased upto 60 mM. Correspondingly, high salt diet exacerbated the arthritis of CIA mice. The arthritis score was considerably elevated in high salt group compared with control group. In high salt group, osteoclast differentiation represented by TRAP activity was more prominent. We also observed the increased expression of CD4+ RORrt+ cells in spleen of high salt fed mice. Conclusions This study suggests that NaCl can aggravate arthritis via Th17 differentiation. High salt condition can contribute to the development and progression of RA. References Kleinewietfeld, M., et al., Sodium chloride drives autoimmune disease by the induction of pathogenic T17 cells. Nature, 2013. Wu, C., et al., Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1. Nature, 2013. 496(7446): p. 513-7. Acknowledgements This work was supported by a grant from the Korea Healthcare Technology R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea (A092258). Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.5138