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In addition to the shearing behavior of soil, the creep character is also considered crucial in determining the long-term shear strength. This especially holds true for the loess that possesses the metastable microstructure and is prone to landslide hazards. This study explored the potential application of straw reinforcement to enhance the shearing and creep properties of the Quaternary loess. The mechanism responsible for the straw reinforcement to elevate the peak shear strength was revealed. Furthermore, three creep characters, namely attenuating creep, non-attenuating creep, and viscous flow were identified in this study. The unreinforced and reinforced specimen behaved in a different manner under identical shear stress ratio condition. The reinforced specimen was superior in limiting the particle relative movement within the shear plane than the unreinforced specimen. The chain reaction of interparticle contact loss, accompanied with excessive viscous displacement, rapid weakening of creep resistance, and eventually accelerated creep displacement, provided an evidence for the formation mechanism of slow-moving landslide. The long-term shear strength using the isochronal stress–strain relationship may be used for optimising the design of high-fill embankment works.

Some methoxy-, hydroxyl-, pyridyl-, or fluoro-substituted 3,5-bis(arylidene)-4-piperidones (BAPs) could reduce inflammation and promote hepatoma cell apoptosis by inhibiting activation of NF-κB, especially after introduction of trifluoromethyl. Herein, a series of trifluoromethyl-substituted BAPs (4-30) were synthesised and the biological activities were evaluated. We successfully found the most potential 16, which contains three trifluoromethyl substituents and exhibits the best anti-tumour and anti-inflammatory activities. Preliminary mechanism research revealed that 16 could promote HepG2 cell apoptosis in a dose-dependent manner by down-regulating the expression of Bcl-2 and up-regulating the expression of Bax, C-caspase-3. Meanwhile, 16 inhibited activation of NF-κB by directly inhibiting the phosphorylation of p65 and IκBα induced by LPS, together with indirectly inhibiting MAPK pathway, thereby exhibiting both anti-hepatoma and anti-inflammatory activities. Molecular docking confirmed that 16 could bind to the active sites of Bcl-2, p65, and p38 reasonably. The above results suggested that 16 has enormous potential to be developed as a multifunctional agent for the clinical treatment of liver cancers and inflammatory diseases.

Objective: To analysis and summarize the imaging characteristics of the complications of hand-foot-mouth disease (HFMD) in Central Nervous System (CNS). Methods: 15 patients' CNS images were analyzed retrospectively, which included CT and MRI. And some correlative papers were reviewed. Results: There were 5 cases performed by CT. 2 patients' basal ganglion, 1 patient's centrum ovale, and 3 cases of brainstem were found slightly hypodense shadows with hazy border; 1 lesion was seen at right frontal and temporal lobe, which showed large sheet slightly hypodense shadow with hazy border and mass effect; There were 11 cases performed using MRI. 8 patients' brainstem, 3 patients’ basal ganglion, 1 patient's centrum ovale, 1 patient's corona radiate, and 2 patient’ cervical spinal cord were seen abnormal signals, which showed low or slightly low signals on T1WI, high or slightly high signals on T2WI, high signals on FLARI and DWI; and 1 patient's frontal and temporal lobe showed mass effect. Conclusions: The inflammation of the CNS in children with HFMD can be well displayed by MRI, especially enhanced MRI scanning. Besides, CT can also be employed when necessary. Keywords: Enterovirus 71, Hand-foot-mouth disease, Inflammation of the central nervous system, Children

The promyelocytic leukemia (PML) gene is a tumor suppressor gene. It was first identified in acute promyelocytic leukemia, in which it is fused to retinoic acid receptor α by the (15;17) chromosomal translocation. The function of the PML protein is frequently lost or aberrant in human solid tumors. In human ovarian carcinoma tissue, PML detected by immunohistochemistry was highly expressed. A PML-silencing vector, pSRG-shPml, was constructed and used to transfect human ovarian cancer cells. Cells were cultured and selected with puromycin for 10-15 days, and then the PML mRNA expression levels were detected by RT-qPCR and immunofluorescence. Proliferation and clone number of PML-depleted cells were detected using MTT assay and colony-forming assay. The protein expression associated with DNA damage and apoptosis was assessed in PML-depleted cells using western blot analysis and immunofluorescence. The results showed that PML was highly expressed in human ovarian tissue. The proliferation and colony formation of ovarian cancer cells were significantly inhibited after PML was depleted. Western blot analysis and immunofluorescence revealed that p-H2AX and cleaved caspase-3 expression significantly increased after PML silencing. PML was located in the nucleus, and it formed foci after X-ray irradiation. PML foci increased significantly with increasing irradiation doses.

Two fluorine-substituted 1,4,5,6-tetrahydrobenzo[h]quinazolin-2-amine (BQA) derivatives, namely 2-amino-4-(2-fluorophenyl)-9-methoxy-1,4,5,6-tetrahydrobenzo[h]quinazolin-3-ium chloride, (8), and 2-amino-4-(4-fluorophenyl)-9-methoxy-1,4,5,6-tetrahydrobenzo[h]quinazolin-3-ium chloride, (9), both C19H19FN3O+·Cl−, were generated by Michael addition reactions between guanidine hydrochloride and the α,β-unsaturated ketones (E)-2-(2-fluorobenzylidene)-7-methoxy-3,4-dihydronaphthalen-1(2H)-one, C18H15FO2, (6), and (E)-2-(4-fluorobenzylidene)-7-methoxy-3,4-dihydronaphthalen-1(2H)-one, (7). Because both sides of α,β-unsaturated ketones (6) or (7) can be attacked by guanidine, we obtained a pair of isomers in (8) and (9). Single-crystal X-ray diffraction indicates that each isomer has a chiral C atom and both (8) and (9) crystallize in the achiral space group P21/c. The chloride ion, as a hydrogen-bond acceptor, plays an important role in the formation of multiple hydrogen bonds. Thus, adjacent molecules are connected through intermolecular hydrogen bonds to generate a banded structure. Furthermore, these bands are linked into an interesting 3D network via hydrogen bonds and π–π interactions. Fortunately, the solubilities of (8) and (9) were distinctly improved and can exceed 50 mg ml−1 in water or PBS buffer system (pH 7.4) at room temperature. In addition, the results of an investigation of anti-inflammatory activity show that (8) and (9), with o- and p-fluoro substituents, respectively, display more potential for inhibitory effects on LPS-induced NO secretion than starting ketones (6) and (7).

Background: Retrospective studies have shown that anti-citrullinated protein antibodies (ACPA) are a risk factor for the development of clinical arthritis. Objectives: We aimed to investigate in a prospective setting if ACPA and other biomarkers could predict development of ultrasound detected arthritis. Methods: Subjects with positive ACPA-test referred from primary care to the Rheumatology clinic that lacked arthritis in hands, feet and any other symptomatic joints by clinical and ultrasound examination (according to EULAR-OMERACT definition), were recruited into the Risk-RA research program during 2015-2016 and were followed up to the end of 2017. At inclusion a detailed clinical examination was performed and blood samples were analyzed for 13 specific ACPA reactivities (using a custom made peptide microarray) as well as 92 inflammation-associated protein biomarkers (using a multiplex immunoassay with Olink proximity extension technology). Presence of HLA-SE was analyzed using DR low-resolution kit. Univariate and multivariate analysis were used to investigate the association between clinical and laboratory parameters and development of ultrasound detected arthritis adjusting for the follow-up time. Results: 42% (27 out of 65) of the Risk RA subjects developed ultrasound detectable arthritis during a median follow up of 8 months. The remaining 58% (38 out of 65) were followed for a median of 25 months (range 12-44) without any signs of ultrasound detectable arthritis. Subjects developing arthritis had higher prevalence of HLA-SE (89% vs 56%) and increased occurrence of ultrasound detected tenosynovitis (44% vs 5%), as compared to those not developing arthritis. ACPA reactivities to citrullinated vimentin peptides (cit vim 2-17: 22% vs 6%; and cit vim 60-75: 70% vs 43%) and citrullinated histone peptides (cit H4 31-50: 89% vs 49%; and cit H3 21-44: 48% vs 23%) were a more common occurrence in subjects developing ultrasound detectable arthritis. Backward selection in a Cox regression model showed that ultrasound detectable arthritis could be predicted in a model including HLA-SE, tenosynovitis and ACPA reactivity to cit H4 31-50. Hazard ratio (HR) for arthritis development were 3.4 (95% CI 1.0-12, p 0.06) for HLA-SE carriers, 2.9 (95% CI 1.3-6.7, p 0.01) for tenosynovitis and 4.1 (95% CI 1.2-14, p 0.02) for Anti-citrullinated H4 31-50 positivity. Only modest differences were observed for few of the tested inflammatory markers in those developing as compared to those not developing ultrasound detectable arthritis: Interleukin- 6 (3.9 vs 3.3 AU/ML), Programmed death-ligand 1 (4.9 vs 5.2 AU/ML) and Chemokine (C-X-C motif) ligand 6 (9.2 vs 9.5 AU/ML). Conclusion: Certain ACPA fine specificities, HLA-SE and tenosynovitis predict the development of ultrasound detectable arthritis in seropositive individuals with musculoskeletal symptom who are at risk for RA. Disclosure of Interests: Aase Hensvold: None declared, Yogan Kisten: None declared, Alexandra Circiumaru: None declared, Monika Hansson: None declared, Meng Sun Grant/research support from: Yes, but not for presented project., Guozhong Fei: None declared, Nancy Vivar: None declared, Erik Af Klint: None declared, Hamed Rezaei: None declared, Lars Klareskog Grant/research support from: Yes, but not for the presented study., Aleksandra Antovic: None declared, Anca Catrina Grant/research support from: Yes, but not for the presented study.

This study aimed to investigate the periodontal health of patients with established rheumatoid arthritis (RA) in relation to oral microbiota, systemic and oral inflammatory mediators, and RA disease activity. Forty patients underwent full-mouth dental/periodontal and rheumatological examination, including collection of blood, saliva, gingival crevicular fluid (GCF) and subgingival plaque. Composition of plaque and saliva microbiota were analysed using 16S rRNA sequencing and levels of inflammatory mediators by multiplex-immunoassay. The majority of the patients (75%) had moderate or severe periodontitis and the rest had no/mild periodontitis. Anti-citrullinated protein antibody (ACPA) positivity was significantly more frequent in the moderate/severe periodontitis (86%) compared to the no/mild group (50%). No significance between groups was observed for RA disease duration or activity, or type of medication. Levels of sCD30/TNFRSF8, IFN-&alpha, 2, IL-19, IL-26, MMP-1, gp130/sIL-6R&szlig, and sTNF-R1 were significantly higher in serum or GCF, and April/TNFSF13 was significantly higher in serum and saliva samples in moderate/severe periodontitis. The microbial composition in plaque also differed significantly between the two groups. In conclusion, the majority of RA patients had moderate/severe periodontitis and that this severe form of the disease was significantly associated with ACPA positivity, an altered subgingival microbial profile, and increased levels of systemic and oral inflammatory mediators.

Career situation of first and presenting author Post-doctoral fellow Introduction Anti-citrullinated protein antibodies (ACPA) are predictive markers with pathological effects in rheumatoid arthritis (RA). Previous prospective studies have used a clinical definition of arthritis. Thus, we aimed to investigate risk factors of developing arthritis in ACPA-positive subjects with musculoskeletal complaints who did not have any of clinical and ultrasound signs of arthritis. Methods Subjects with positive ACPA-test referred from primary care to rheumatology clinic, lacking arthritis in hands and feet by clinical and ultrasound examination (according to EULAR-OMERACT synovitis definition), were recruited into the Risk-RA research program. Patient included between years 2015–2016 with clinical data up to 2017 were analysed. Blood samples from inclusion were analysed for 13 specific ACPA reactivities using a custom made ImmunoCAP ISAC microarray. Presences of HLA-SE risk gene were analysed using DR low-resolution kit. Results 41% (27 out of 66) of the Risk RA subjects developed arthritis during a median follow up of 8 months. The rest was followed 25 months in median without any signs of arthritis. Subjects developing arthritis tended to have a higher concentration of anti-CCP, more tender joints and rheumatoid factor positivity at inclusion compared to those not developing arthritis. The number of ACPA-reactivities (mean 6 vs 3), the presence of HLA-SE (89% vs 56%) and the occurrence of ultrasound detected tenosynovitis (44% vs 5%) at inclusion were significantly increased in subjects developing arthritis compared to those not developing arthritis. Univariate cox proportional hazards regression showed a hazard ratio (HR) for arthritis development of 1.1 for every increase in number of ACPA reactivities (95% CI 0.99 to 1.2, p 0.07); HR: 4.4 (95% CI 2.0 to 9.5, p 0.0002) for tenosynovitis and for HR: 4.9 (95% CI 1.5 to 16, p 0.01) for HLA-SE carriers. All subjects with tenosynovitis (n=14) prior to arthritis development were carriers of HLA-SE, except for one subject but similar to the majority this HLA-SE no-carrier also progressed to arthritis. Conclusions Subjects with ACPA-positive musculoskeletal complaints lacking any clinical and ultrasound signs of arthritis are at high risk of developing arthritis, especially carriers of HLA-SE with tenosynovitis. The role of inflammatory spreading from tendons (synovial sheath) to synovial tissue within joints need to be further investigated. Disclosure of Interest None declared

NF-κB is a key signaling pathway molecule linking hepatoma and chronic inflammation. Inhibition of NF-κB activation can alleviate inflammation, and promote hepatoma cell apoptosis. In this study, a series of fluoro-substituted 1,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidines (PPMs, 31-57) were synthesized from 3,5-bis(arylidene)-4-piperidones (BAPs, 4-30) based on scaffold hopping. We successfully discovered the most potent 43 substituted by electron-withdrawing substitutes (3-F and 4-CF3) exhibited less toxicity and higher anti-inflammatory activity. Preliminary mechanistic studies revealed that 43 induced dose-dependent cell apoptosis at cell and protein level, while inhibited NF-κB activation by suppressing LPS-induced phosphorylation levels of p65, IκBα and Akt, and by indirectly suppressing MAPK signaling, and by inhibiting the nuclear translocation of NF-κB induced by TNF-α or LPS. Docking analysis verified simulated 43 could reasonably bind to the active site of Bcl-2, p65 and p38 proteins. This compound, as a novel NF-κB inhibitor, also demonstrated both anti-inflammatory and anti-hepatoma activities, warranting its further development as a potential multifunctional agent for the clinical treatment of liver cancers and inflammatory diseases.

Background The death-domain-associated protein (DAXX) was originally identified as a protein that binds to the transmembrane death receptor FAS and enhances both FAS-induced and transforming growth factor-β-dependent apoptosis. In a previous study, we found that nude mice injected with DAXX-overexpressing cells (ES-2-DAXX) accumulated large concentrations of first-generation ascites cells (I ascites cells). The role of DAXX in the development of ascites is unknown. The aim of this study was to analyze the effect of DAXX on proliferation and migration of ascites cells in ovarian cancer in vitro and in vivo. Methods Nude mice were housed in cages with a 14:10 h light:dark cycle; water and food were provided ad libitum. ES-2-DAXX cells (1×106) were injected intraperitoneally into athymic nude mice (8-week-old female mice). After 4 weeks, I ascites cells were collected. The I ascites cells were injected intraperitoneally into athymic nude mice (8-week-old female mice). After 4 weeks, II ascites cells were collected and cultured. Ascites cell survival, migration, and colony formation were measured using colony formation and cell growth assays. Immunofluorescent staining revealed the co-localization of DAXX and promyelocytic leukemia protein (PML) in ascites cell nuclei. Western blotting and immunohistochemistry showed that extracellular signal-related kinase (p-ERK) 1/2 and CEBP-β were highly expressed in tumor tissues formed by II ascites cells. Through immunoprecipitation, we also found that DAXX can interact with CEBP-β. Results DAXX enhanced ascites cell survival, migration, and colony formation. DAXX and PML nuclear foci dramatically increased in a passage-dependent manner in ascites cells, DAXX promoted the tumor growth of ascites cells in vivo, increased ascites cell proliferation in vivo, and enhanced ascites cell survival and migration by activating the ERK signalling pathway and integrating with CEBP-β. Conclusions DAXX can interact with CEBP-β. DAXX can induce ovarian cancer ascites formation by activating the ERK signal pathway and binding to CEBP-β.

Background The pathophysiological processes leading from musculoskeletal (MSK) complaints to clinically manifest rheumatoid arthritis (RA) are not fully understood. The urgency for imaging and serological markers that predict arthritis development in individuals at risk of RA is of clinical importance. Objectives To identify ultrasound (US) markers that can predict arthritis development. Methods Patients presenting with MSK complaints and a positive Anti-Citrullinated Protein Antibody (ACPA) test were referred from primary care units to the Rheumatology Unit. Those lacking clinical signs of arthritis, confirmed by absence of synovial hypertrophy with Doppler activity on US examination, were recruited into the Risk-RA prospective program. A total of 66 patients with complete US records were included between years 2015 up to December 2016. Hands and feet, including symptomatic joints were US-evaluated for synovitis, hyperemia and bone erosions. The presence of wrist (compartments 1–6) and finger (flexor and extensor) tenosynovitis, according to OMERACT guidelines were also recorded in all patients. Serum samples from inclusion were analysed on a multiplex immunoassay Results 66 Risk-RA patients (85% female, median age 50 years, range 22–82) were included and followed up to arthritis onset (median 8 months, range 1–27), or to the end of year 2017 (median 25 months, range 11–43). 27 patients (41%, 86% female, median age 52 years, range 22–74) developed arthritis. Of these 7 had tenosynovitis detected by US at inclusion and 7 more developed tenosynovitis at follow-up visits (in total n=14). At the time of diagnosis, 20 out of 27 patients presented with both tenosynovitis and synovitis. A large majority of patients with tenosynovitis (12 out of 14, 86%) and a minority without tenosynovitis (15 out of 52, 29%) developed arthritis, resulting in an increased relative risk of 3.0 (95% CI 1.8–4.8) to develop arthritis for patients presenting with tenosynovitis at baseline or follow-up visits (p=0.001). Concentrations of the anti-CCP antibodies, anti-CEP antibodies and anti-citrullinated vimentin 60–75 antibodies tended to be higher in patients with tenosynovitis developing arthritis (n=12, median of 70 AU/ml, range 2–175 for anti-CCP, median of 68 AU/ml, range 0–673 for anti-CEP, median of 53, range 0–644 for anti-vim) than those without tenosynovitis developing arthritis (n=15, median of 35 AU/ml, range 1–100 for anti CCP, median of 12, range of 0–1179 for anti-CEP, median of 29, range 0–332 for anti-vimentin). Same trend was observed when comparing patients with tenosynovitis developing arthritis to those without-tenosynovitis not-developing arthritis. The 2 patients with tenosynovitis not developing arthritis, had lower levels of the antibodies as compared to those with tenosynovitis developing arthritis. No significant differences in other patient baseline characteristics were seen between those with, and those without tenosynovitis (86 vs 85% female, median (range) 54 years 29–71 vs 50 years, 22–82 mean visual analogue scale pain 34 vs 31, mean c-reactive protein 2.7 vs 3.2; tender joint count 1.2 vs 0.7). Conclusions Ultrasound detected tenosynovitis in the context of ACPA positivity is a good clinical predictor of rapid arthritis onset in individuals at risk of developing RA. Disclosure of Interest None declared

Diabetic cardiomyopathy (DCM) is a kind of disease caused by metabolic disorders and microangiopathy. The main pathophysiological changes of DCM include fibrosis, myocardial cell apoptosis and autonomic neuropathy. Therefore, treatment aimed at these processes may benefit patients with DCM. We designed an experiment with the peroxisome proliferator-activated receptor-gamma (PPARγ) agonist GW 1929 to detect whether the activation of PPARγ could alleviate the degree of DCM. To further detect the mechanism of PPARγ in DCM, we used the PPARγ antagonist GW 9662 and ERK antagonist PD 098059 both in vitro and in vivo and found that PPARγ functioned by inhibiting ERK. We also performed Western blot, PCR, ELISA, immunohistochemistry, TUNEL assay, Sirius red staining and gelatin zymography to investigate inflammation, apoptosis, MMP activity and epithelial-to-mesenchymal transition (EMT). The results showed that the activation of PPARγ inhibited these reactions and inhibiting ERK also simulated this phenomenon. In conclusion, these results demonstrated that PPARγ activation in the diabetic myocardium of mice reduces myocardial fibrosis via regulation of the TGF-β/ERK pathway and EMT.

Introduction Prospective studies of individuals at increased risk of developing rheumatoid arthritis (RA) will further improve the understanding of disease development. Ultrasound emerges clinically useful in detecting subtle inflammatory changes in rheumatic diseases. Objectives To investigate ultrasound (US) detected changes as markers for future arthritis development. Methods Patients presenting with musculoskeletal complaints and a positive Anti-Citrullinated Protein Antibody (ACPA) test at primary care, were referred to Karolinska rheumatology clinic for further rheumatic joint disease assessments. Those lacking arthritis by clinical and US examination (defined as synovial hypertrophy with Doppler activity) were recruited into the Risk-RA clinical research program, and followed-up by our multidisciplinary rheumatology team. A total of 64 patients with complete US records were included between years 2015→2016. Our patient demographics were 84% (n 54/64) females, mean age 49 (range 22–82) years, median relative ACPA (times cut-off) 26 (range 1–174) titer, median visual analogue scale (VAS) pain 30, median VAS patient global 28 and median C-reactive protein was 1 (0–20) at inclusion. Hand (Wrists, MCP’s, PIP’s, DIP’s) and feet joints were US-evaluated for synovial hypertrophy, hyperemia and bone erosions. The presence of wrist (compartments 1–6) and finger (flexor and extensor) tenosynovitis were assessed. Data from inclusion→follow-up visits until September 2017 were analysed. SPSS software version 25 was used (Univariate, Chi-square, T-test and Mann Whitney U-test) for comparisons. Results At inclusion, none of the 64 patients had any signs of active joint inflammation. However, ultrasound changes for tenosynovitis were seen in 7 out of 64 patients, 3 of who also presented with mild hypertrophy without Doppler activity and one patient with mild Doppler hyperemia (without hypertrophy), and none with bone erosions at inclusion. Among all tendons evaluated bilaterally, tenosynovitis of the Extensor Carpi Ulnaris (ECU) wrist tendons (4 of 7 patients) and the 2nd finger flexor-tendons (3 of 7 patients) were most commonly affected. Of the 57 patients without US-tendon changes, one had mild Doppler hyperemia (without hypertrophy). Patients with US-tendon changes were 86% (n 6/7) females, had mean age 56 years, median VAS pain 42, median VAS global health 20, mean 2.7 mg/L CRP, median relative ACPA titer 70 in comparison to patients without US-tendon changes, 75% females, mean age of 48 years, median VAS pain 24, median VAS global health 28, mean 2.7 mg/L CRP and median ACPA titer of 23. The numerical difference in pain and relative ACPA titer were non-significant (p>0.05). After follow up for mean 18 months (range 1–18), 7 out of 7 (100%) with US-tendon changes at inclusion and 18 out of 57 (32%) without US-tendon changes developed arthritis. Patients with US-tendon changes compared to those without tenosynovitis at inclusion, developed arthritis within 12 and 11 mean months follow-up, respectively. Conclusions Our study shows that tenosynovitis is a specific marker for arthritis development in ACPA-positive patients with musculoskeletal symptoms. The role of inflammatory spreading from tendons (synovial sheath) to synovial tissue within joints need to be further investigated. Disclosure of interest None declared

Rupture of an intracranial aneurysm is a life-threatening acute cerebrovascular event. The purpose of this study was to investigate whether aneurysmal subarachnoid haemorrhage (SAH) incidence rate is higher or lower in elderly population than in middle aged population.Aneurysmal SAH cases were collected retrospectively from the archives of 21 hospitals in Mainland China. All the cases were collected from September 2016 and backward consecutively for a period of time up to 8 years. SAH was initially diagnosed by brain computed tomography (CT). CT angiography (CTA) or digital subtraction angiography (DSA) was followed and SAH was confirmed to be due to cerebral aneurysm rupture. For cases when multiple bleeding occurred, the age of the first SAH was used in this study. The total incidence from all hospitals at each age group were summed together for females and males respectively; then adjusted by the total population number at each age group for females and males which was from the 2010 population census of the People's Republic of China.In total there were 8,144 cases of intracranial aneurysmal SAH, with 4,861 females and 3,283 males. For females the relative aneurysmal SAH incidence rate started to decrease after around 65 years old, while for males the relative aneurysmal SAH incidence rate started to decrease after around 53 years old.Our data tentatively suggest elderly patients may be at a reduced risk of rupture compared with patients who are younger while have similar other risk factors.

Background There is today a paucity of prospective studies to describe the natural longitudinal history of anti-ccp positive individuals developing RA or not developing RA. Further no study to investigate the detailed ACPA reactivities in such a setting is currently available. Methods Individuals at risk of developing RA were included in a cohort at Karolinska University Hospital, Stockholm. Examinations of peripheral joints was repeated at one year follow-up visit or at any time the patients experienced worsening of their symptoms. Peripheral blood samples were available at inclusion (n=70). Serum was run on a microarray based on the ImmuoCAP ISAC system testing for ACPA reactivities toward 13 different citrullinated peptides (fillagrin, fibrinogen, alpha-enolase, vimentin, histone) (1). Results Individuals referred from primary care with musculoskeletal complaints and positive anti-ccp test were systematically investigated as part of routine care at our rheumatology clinic. Individuals lacking self-reported history of suspect arthritis, clinical arthritis according to rheumatologist and signs of synovitis on ultrasound examination were included in a clinical Risk-RA program with life-style coaching and personalized information on the risk of developing RA. Seventy individuals, with a mean age of 48 years (SD 15) and 86% females, were included in the program. Twenty (29%) individuals developed arthritis during a medium follow up time of 7 months (range 1–25 months). Number of ACPA reactivities at baseline was significant higher among those developing (in mean 6 reactivities) as compared to those not developing arthritis (in mean 4 reactivities). A increased proportion of individuals were showing reactivity towards citrullinated (cit) vimentin (vim) 60–75, fibrinogen (fib) 573 and enolase (eno) (CEP-1) among those developing arthritis (80% for anti-cit-vim 45% for anti-cit-fib and 60% for anti-cit eno) as compared to those not developing arthritis (41% for anti-cit-vim, 30% for anti-cit-fib and 52% for anti-cit-eno). Increased level of anti-cit-vim and anti-cit-eno antibodies was also observed at inclusion for those individuals developing arthritis as compared to those not developing arthritis. Conclusions We describe here the pattern of ACPA reactivities in anti-CCP positive individuals with non-specific musculoskeletal symptoms at risk of developing RA and without clinical and ultrasonograph signs of synovitis and report that 30% of these patients will develop arthritis during a short follow-up. Number, frequency and titers of specific ACPA reactivities appear to be enriched already at inclusion among those patients that developed arthritis during follow-up. References Hansson et al Arthritis Res Ther 2012. Disclosure of Interest None declared

The cover is one of the key components of carding machine and its structural parameters play an important role for the carding quality and yield. In this paper, the force of the designed cover is analyzed when the cover into the carding zone, to obtain the stress and strain distribution of the cover in the whole carding process, based on the finite element analysis software ANSYS Workbench. The research not only examines the stiffness and strength properties of the cover, but also provides a theoretical guidance for the future structure design and parameter optimization.

In this paper, a cured door structure of mine rescue capsule is proposed, and compared with ordinary flat panel doors. Firstly two kind of three-dimensional solid models of mine removable protective airtight doors are established by the Pro/e software. And then take the advantage of the strength analysis of ANSYS finite element software to draw the stress and strain diagrams. The analysis results show that the strength and stiffness of the curved door is better than ordinary flat panel doors, which provide important theoretical basis and reference value on the design, research and dynamic analysis of the life-saving door.

To evaluate the immune activation and reactive oxygen species scavenging activity of Cordyceps militaris polysaccharides (CMP) in vivo, 90 male BALB/c mice were randomly divided into six groups. The mice in the three experimental groups were given cyclophosphamide at 80 mg/kg/d via intraperitoneal injection and 17.5, 35, or 70 mg/kg body weight CMP via gavage. The lymphocyte proliferation, phagocytic index, and biochemical parameters were measured. The results show that the administration of CMP was able to overcome the CY-induced immunosuppression, significantly increased the spleen and thymus indices, and enhanced the spleen lymphocyte activity and macrophage function. CMP can also improve the antioxidation activity in immunosuppressed mice, significantly increase the superoxidase dismutase, catalase, and glutathione peroxidase levels and the total antioxidant capacity, and decrease the malondialdehyde levels in vivo.

Seven new cucurbitane glucosides, hemslepensides J-P ( 1 – 7 ), and two known compounds, 16,25- O -diacetyl-cucurbitane F ( 8 ) and 25- O -acetyl-23,24-dihydrocucurbitacin F ( 9 ), were isolated from the tubers of Hemsleya pengxianensis var. jinfushanensis . The structures of 1 – 7 were elucidated using infrared absorption spectroscopy, nuclear magnetic resonance spectroscopy and high-resolution electrospray ionization mass spectrometry. The treatment of HT29 cells, human colon cancer cells, with compounds 8 and 9 inhibited cell proliferation. Further study demonstrated that compounds 8 and 9 induced F-actin aggregation, G 2 /M phase cell cycle arrest and cell apoptosis in HT29 cells. In summary, the present study enriched the chemical composition research of H. pengxianensis , and suggested that the compounds 8 / 9 treatment may be a potentially useful therapeutic option for colon cancer.

Background Previous studies found a range of prognostic factors but no consensus about the proper staging system for multiple myeloma has been achieved. This study explored the prognostic factors to find a staging system for multiple myeloma most suitable for Chinese patients. Methods Between February 1990 to August 2004, 206 patients (138 men and 68 women, mean aged (59 +/- 11) years) who were initially diagnosed as multiple myeloma in Changzheng Hospital (Shanghai, China) and had followup records were enrolled in this study. Potential prognostic factors were evaluated by univariate and multivariate analyses. Four staging systems were applied to compare their suitability for the patients. Results The median survival time of the patients was 33 months. The 1-, 3- and 5-year survival rates were 80.18%, 48.08% and 33.7% respectively. Factors identified as adversely affecting survival were older age, severe bone lesions, low haemoglobin, low platelet, low serum calcium, low serum albumin, high proportion of plasma cells in marrow, high serum creatinine, high serum beta(2) microglobulin and high C-reactive protein. Among these, only C-reactive protein, beta(2) microglobulin, albumin and age were the independent prognostic factors. There were statistically significant survival differences among the three groups in Durie Salmon staging system and Bataille staging system, but not in British Medical Research Council staging system or International Staging System. Conclusions High beta(2) microglobulin, high C-reactive protein, low albumin and old age are independent prognostic factors of multiple myeloma. Bataille staging system appears to be optimal for Chinese multiple myeloma patients.

Thalidomide (Thal) has been used for a few years as salvage treatment for patients with multiple myeloma (MM). However, the response rate in Chinese patients treated with Thal has not been determined and the prognostic factors for response rate (RR), progression-free survival (PFS) and overall survival (OS) not yet well identified. This study enrolled 110 Chinese patients with MM who received either Thal alone, Thal plus dexamethasone (Thal + Dex) or Thal plus conventional chemotherapy (Thal + CC). Their laboratory and clinical parameters were retrospectively analysed. The overall RR was 63.6% (complete response rate 6.4%, partial response rate 57.3%). Patients aged65 years, time from diagnosis to the start of Thal treatment6 months or combined therapy had a significantly higher RR (p0.05). In univariate analysis, age65years predicted a longer PFS (p = 0.008). Age65 years, serum creatinine176.8 micromol L-1 and serum beta 2 microglobulin (beta2M)3.5 mg L-1 were associated with longer OS (p = 0.028, 0.045 and 0.019, respectively). Multi-factor analysis suggested that serum beta2M was the only independent prognostic factor for OS (p = 0.025).

Objective. There is an important inflammatory component to atherosclerosis and cardiovascular disease (CVD). It is therefore interesting that the risk of CVD is high in inflammatory diseases such as systemic lupus erythematosus (SLE). In this study, we investigated nontraditional risk factors for the development of CVD in patients with SLE. Methods. Twenty-six women (mean age 52 years) with SLE and a history of CVD were compared with 26 age-matched women with SLE and no clinical manifestations of CVD (SLE controls) and 26 age-matched healthy women (population controls). Serum levels of several novel nontraditional risk and protective factors were determined: heat-shock protein (HSP)–related factors (Hsp60, Hsp70, anti–human Hsp60, anti–human Hsp70, and anti–mycobacterial Hsp65), plateletactivating factor–acetylhydrolase (PAF-AH) activity, secretory phospholipase A2 GIIA (sPLA2), and anti– endothelial cell antibody (AECA). The intima-media thickness and the presence of plaques in the common carotid arteries were determined by B-mode ultrasound as a surrogate measure of atherosclerosis. Results. Levels of PAF-AH, but not HSP-related factors, AECA, or sPLA2, were significantly increased in SLE cases. Only PAF-AH discriminated between SLE cases and SLE controls (P 0.005). PAF-AH was significantly associated with low-density lipoprotein (LDL) cholesterol and total cholesterol in the SLE cases (r 0.50, P 0.0093 and r 0.54, P 0.0045), but not in either control group. Conclusion. The increased levels of PAF-AH in SLE cases and the association between PAF-AH and LDL cholesterol adds support to the notion that PAF-AH may promote atherothrombosis in SLE. The role of HSPs in CVD is complex, since anti-Hsp65 appears to be associated with the presence of CVD, whereas Hsp70 might protect against it. In this crosssectional study, levels of HSP-related factors, AECA, and sPLA 2 were not associated with CVD in SLE.

Objective To investigate how blood lipid levels are related to disease activity, clinical characteristics, and serum levels of tumor necrosis factor α (TNFα) and its soluble type 1 and 2 receptors, sTNFR1 and sTNFR2, in systemic lupus erythematosus (SLE). Methods Fasting blood samples were obtained from an unselected cohort of SLE patients at Karolinska Hospital (n = 208, mean ± SD age 45.7 ± 14.2 years). Disease activity was estimated using the SLE Disease Activity Measure (SLAM). Levels of circulating TNFα, sTNFR1, and sTNFR2 were determined by enzyme-linked immunosorbent assay. Blood lipid levels obtained after overnight fasting were analyzed by routine chemistry. Results Triglyceride (TG) levels were associated with the SLAM score (r = 0.48, P < 0.0001) and with the activities of TNFα (r = 0.29, P = 0.0001), sTNFR1 (r = 0.38, P < 0.0001), and sTNFR2 (r = 0.40, P < 0.0001). High-density lipoprotein (HDL) levels were negatively associated with the SLAM score (r = −0.27, P = 0.0003) and with the activities of TNFα (r = −0.15, P = 0.04) and sTNFR2 (r = −0.19, P = 0.01). High levels of TGs, total cholesterol, TNFα, sTNFR1, and sTNFR2 all showed close correlations with the presence of nephritis and arterial disease (P < 0.05). In multiple logistic regression models, the TNFα activity and TG levels were independent determinants (P = 0.003 for both) of active disease (SLAM score ≥7). Conclusion Dyslipoproteinemia with high TG/low HDL levels correlates with disease activity in SLE, and enhanced activity in the TNFα/sTNFR system seems to be an important underlying factor. Both dyslipoproteinemia and enhanced activity of the TNFα system are closely related to cardiovascular and renal manifestations in SLE, and thus both may serve as markers of more severe disease.

Alzheimer’s disease (AD) is an age-related neurodegenerative disorder characterized by intelligence decline, behavioral disorders and cognitive disability. The purpose of this study was to investigate gene expression in AD, based on published microarray data on Tg2576 mice. Hierarchical Cluster Analysis and Gene Ontology were employed to group genes together on the basis of their product characteristics and annotation data. Genes with prominent alterations were clustered into apoptosis and axon guidance pathways. Based on our findings and those of previous studies, we propose that the mitochondria-mediated apoptotic pathway plays a crucial role in the neuronal loss and synaptic dysfunction associated with AD. Furthermore, based on the findings of Positional Gene Enrichment analysis and Gene Set Enrichment analysis, we propose that the regulation of transcription of AD genes may be an important pathogenic factor in this neurodegenerative disease. Our results highlight the importance of genes that could subsequently be examined for their potential as prognostic markers for AD.

Hyperhomocysteinemia (Hhcy) may induce memory deficits with β-amyloid (Aβ) accumulation and tau hyperphosphorylation. Simultaneous supplement of folate and vitamin B12 partially restored the plasma homocysteine level and attenuated tau hyperphosphorylation, Aβ accumulation and memory impairments induced by Hhcy. However, folate and vitamin B12 treatment have no effects on Hhcy which has the methylenetetrahydrofolate reductase genotype mutation. In this study, we investigated the effects of simultaneous supplement of betaine on Alzheimer-like pathological changes and memory deficits in hyperhomocysteinemic rats after a 2-week induction by vena caudalis injection of homocysteine (Hcy). We found that supplementation of betaine could ameliorate the Hcy-induced memory deficits, enhance long-term potentiation (LTP) and increase dendritic branches numbers and the density of the dendritic spines, with up-regulation of NR1, NR2A, synaptotagmin, synaptophysin, and phosphorylated synapsin I protein levels. Supplementation of betaine also attenuated the Hcy-induced tau hyperphosphorylation at multiple AD-related sites through activation protein phosphatase-2A (PP2A) with decreased inhibitory demethylated PP2A(C) at Leu309 and phosphorylated PP2A(C) at Tyr307. In addition, supplementation of betaine also decreased Aβ production with decreased presenilin-1 protein levels. Our data suggest that betaine could be a promising candidate for arresting Hcy-induced AD-like pathological changes and memory deficits.

Objective— The cause of the exceedingly high risk of atherothrombosis in systemic lupus erythematosus (SLE) is not clear but antiphospholipid antibodies (aPL) and potentially antithrombotic annexin V have been implicated. Methods and Results— Twenty-six women (52±8.2 years) with SLE and a history of cardiovascular disease (CVD) (SLE cases) were compared with 26 women with SLE but no CVD (SLE controls) and 26 healthy women (population controls). Common carotid intima-media thickness (IMT) was determined by B-mode ultrasound as a surrogate measure of atherosclerosis. Annexin V binding to human umbilical vein endothelial cells (HUVECs) as determined by flow cytometry after 24-hour culture with plasma was decreased when plasma from SLE cases was used (SLE cases versus population controls: P =0.002; SLE cases versus SLE controls P =0.02). Antibodies against cardiolipin were among IgG antibodies causing decreased binding. There was a positive association between annexin V binding and IMT ( R =0.73; P Conclusions— Decreased annexin V binding to endothelium caused by antibodies may represent a novel mechanism of atherothrombosis. We hypothesize that even though annexin V may promote plaque growth at some disease stages, it may also stabilize plaque.

The risk of cardiovascular disease (CVD) in SLE patients is very high. It is therefore surprising that IL-10 has been discussed both as pathogenic in SLE and as an atheroprotective cytokine. In contrast, TNF is believed to be atherogenic and we recently reported that raised activity in the TNF-system is implicated in SLE-related CVD. Twenty-six (aged 52 +/- 8 years) female patients with SLE and a history of CVD (myocardial infarction, angina, stroke or claudication) were compared with 26 age-matched SLE patients without CVD (SLE controls) or 26 age-matched population controls. The -1087IL-10 gene polymorphism was determined by PCR with restriction endonuclease mapping. Serum IL-10 and TNF-levels were determined by ELISA. The A allele frequency of -1087IL-10 gene in SLE/CVD was higher than in SLE controls (0.62 versus 0.42, p0.05). Ten (38%) of 26 SLE/CVD exhibited IL-10 AA genotype compared with five (19%) of 26 SLE controls. Serum IL-10 and TNF-levels were raised in SLE/CVD compared with SLE controls or population controls (p0.001). Furthermore, in SLE/CVD, a significantly reduced IL-10:TNF ratio was observed in patients with IL-10 AA genotype compared with AG or GG genotype (0.56 versus 0.77 versus 1.24, p0.05). In SLE controls and population controls, individuals with IL-10 GG genotype tended to have higher IL-10:TNF ratio. In conclusion, the A-1087IL-10 allele which has been reported to cause a lower capacity for IL-10 production could contribute to CVD in SLE. Furthermore, the IL-10 AA genotype is associated with reduced ratio of atheroprotective to atherogenic cytokines in SLE patients with CVD.

Objective: Several studies show that the inflammatory component in atherosclerosis may contribute to increased risk for cardiovascular disease (CVD). Interleukin-6 (IL-6) is a key pro-inflammatory and immune-stimulatory cytokine of presumed importance for CVD and the metabolic syndrome. Methods and results: In this case–control study, 1179 surviving myocardial infarction (MI) cases and 1528 healthy controls were genotyped for three IL-6 promoter SNPs, and serum concentrations of IL-6 and C-reactive protein (CRP) were measured. In men, MI risk assessed as odds ratios (OR) was higher with increasing IL-6 levels, with the highest compared to the lowest IL-6 quartiles giving an OR of 2.7 [95% CI 1.7–4.4]. The ORs were independent from the effects of elevated CRP which were associated with modest MI risks (OR=1.6 [95% CI 1.0–2.5]). Also, synergistic interactions between high IL-6 levels and hypercholesterolaemia further increased MI risk estimates. The −174C allele was associated with lower serum-insulin levels among male controls but did not significantly influence MI risk or IL-6 levels. Conclusions: Elevated IL-6 levels are important risk markers for MI in men, the risk being further enhanced through synergistic interaction with hypercholesterolaemia. The data provide no clear evidence that polymorphisms in the IL-6 promotor region play a significant role in the pathogenesis of MI, and it remains to be further evaluated whether or not the −174C allele is of relevance for insulin resistance.

Patients with systemic lupus erythematosus (SLE) are at high risk of cardiovascular disease (CVD). Tumour necrosis factor-alpha (TNF-alpha) has been implicated in the pathophysiological processes of both SLE and CVD. This study focuses on the role of TNF-alpha and its soluble receptors in SLE-related CVD. In summary, 26 women (52 +/- 8.2 years) with SLE and a history of CVD (SLE cases) we compared with 26 age-matched women with SLE and no clinical manifestations of CVD (SLE controls) and 26 age-matched population-based control women (population controls). Plasma concentrations of circulating TNF-alpha, TNF-alpha receptor 1 (sTNFR1) and TNF-a receptor 2 (sTNFR2) were determined by ELISA. TNF-alpha, sTNFR1 and sTNFR2 were raised in SLE cases as compared to SLE controls (P = 0.009; P = 0.001; P = 0.001, respectively), and SLE controls had higher levels than population controls (P = 0.001; P = 0.02; P = 0.001, respectively). Exclusively in the SLE case group there was a striking positive correlation between TNF-alpha and plasma triglycerides (r = 0.57, P < 0.002), VLDL triglycerides (r = 0.54, P = 0.004) and VLDL cholesterol (r = 0.58, P = 0.002). Furthermore, TNF-alpha correlated with the waist-hip ratio but not with estimated insulin resistance. TNF-alpha may thus be a major factor in SLE-related CVD acting both by contributing to hypertriglyceridaemia and by promoting atherosclerosis-related inflammation. sTNFR1 and sTNFR2 are strongly associated with CVD in SLE but their exact roles in disease development remain to be elucidated.

Oxidised low density lipoprotein (oxLDL) is one factor that may cause the immune reaction in the artery wall characteristic of atherosclerosis. OxLDL can promote immune activation as determined by enhanced secretion of IFN-gamma and TNF by immune competent cells. We previously demonstrated that Platelet-activating factor (PAF)-like lipids and/or lysophosphatidylcholine (LPC) in OxLDL contribute significantly to this immune activation, but these factors may also inhibit immune activation, at higher concentrations. We here demonstrate that IL-12 induces enhanced IFN-gamma secretion in peripheral blood mononuclear cells (PBMC), with no addition of a specific antigen, as determined by ELISPOT. Antibodies to IL-12 and to MHC class II inhibited both IL-12- and oxLDL-induced IFN-gamma secretion. OxLDL induced IL-12 production in PBMC. In the presence of IL-10, a T helper 2 cytokine, oxLDL induced a decreased IFN-gamma secretion, indicating that the local cytokine-milieu may determine the immunological properties of oxLDL. IL-10 could also be induced by OxLDL. Mononuclear leukocytes were prepared directly from human atherosclerotic plaques obtained at carotid operations. OxLDL had the capacity to induce IL-12, IL-10 and TNF from plaque cells using ELISPOT. Taken together, our data indicate that oxLDL can modulate immune reactivity in atherosclerosis by a nonspecific mechanism. OxLDL can be inhibitory, especially at higher concentrations. However, oxLDL can also promote immune activation by functioning as an adjuvant, potentiating and/or modulating immune-reactions via IL-12 and other cytokines including IL-10. This suggests that a specific T cell epitope in oxLDL is not necessary for oxLDL-induced T cell activation.

A direct binding enzyme-linked immunosorbent assay (ELISA) was established for quantitative determination of serum IgM antibodies towards a synthetic peptide corresponding to a selected segment (14-21) of the preS2-gene product containing an immunodominant linear B-cell epitope. The prevalence of IgM anti-preS2 (14-21) antibody titers > 1,000 for hepatitis B e antigen (HBeAg)-positive patients with chronic hepatitis B virus (HBV) infection was 38% (22/58) and 10% (2/21) for HBeAg-negative subjects (P < 0.005). IgM anti-preS2 (14-21) reactivity was detected during the clinical course of chronic HBV infection and IgM anti-peptide antibody titers declined and disappeared before spontaneous HBe/anti-HBe seroconversion. Recombinant interferon (IFN)-alpha 2b with an antecedent short course of corticosteroids was administered to eight Chinese patients with chronic HBV infection. The IgM anti-preS2 (14-21) reactivity was monitored consecutively during treatment and patients were followed for more than 1 year. A close association between the presence of pretreatment IgM anti-preS2 (14-21) in serum and the capacity to respond favorably to the combined prednisone/IFN-alpha 2b therapy was detected. The IgM anti-preS2 (14-21) titers decreased during treatment with subsequent loss of detectable antibodies 8-16 weeks after the initiation of therapy. This decrease was concomitant with an alanine aminotransferase (ALT) augmentation preceding the disappearance of HBV-DNA and anti-HBe seroconversion. Long-term remission was not observed in treated patients who lacked detectable levels of pretreatment IgM anti-preS2 (14-21) in the circulation.(ABSTRACT TRUNCATED AT 250 WORDS)