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OBJECTIVE: To provide a single source for the best available estimates of the US prevalence of and number of individuals affected by arthritis overall, rheumatoid arthritis, juvenile arthritis, the spondylarthritides, systemic lupus erythematosus, systemic sclerosis, and Sjögren's syndrome. A companion article (part II) addresses additional conditions. METHODS: The National Arthritis Data Workgroup reviewed published analyses from available national surveys, such as the National Health and Nutrition Examination Survey and the National Health Interview Survey (NHIS). For analysis of overall arthritis, we used the NHIS. Because data based on national population samples are unavailable for most specific rheumatic conditions, we derived estimates from published studies of smaller, defined populations. For specific conditions, the best available prevalence estimates were applied to the corresponding 2005 US population estimates from the Census Bureau, to estimate the number affected with each condition. RESULTS: More than 21% of US adults (46.4 million persons) were found to have self-reported doctor-diagnosed arthritis. We estimated that rheumatoid arthritis affects 1.3 million adults (down from the estimate of 2.1 million for 1995), juvenile arthritis affects 294,000 children, spondylarthritides affect from 0.6 million to 2.4 million adults, systemic lupus erythematosus affects from 161,000 to 322,000 adults, systemic sclerosis affects 49,000 adults, and primary Sjögren's syndrome affects from 0.4 million to 3.1 million adults. CONCLUSION: Arthritis and other rheumatic conditions continue to be a large and growing public health problem. Estimates for many specific rheumatic conditions rely on a few, small studies of uncertain generalizability to the US population. This report provides the best available prevalence estimates for the US, but for most specific conditions, more studies generalizable to the US or addressing understudied populations are needed. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Several inflammatory rheumatic diseases are associated with accelerated atherosclerosis. Atherosclerosis may result from systemic and/or local vascular inflammation. The aim of this study was to evaluate the occurrence of chronic inflammatory infiltrates in the aortas of patients with and those without inflammatory rheumatic disease who had undergone coronary artery bypass graft (CABG) surgery, and to assess the relationship between the infiltrates and other factors thought to play a role in atherosclerosis, such as smoking. METHODS: Aortic specimens routinely removed during CABG surgery in 66 consecutive patients with inflammatory rheumatic disease and 51 control patients without inflammatory rheumatic disease were examined by light microscopy for the occurrence, location, and severity of chronic inflammatory infiltrates and atherosclerotic lesions. RESULTS: Mononuclear cell infiltrates in the inner adventitia (apart from those localized along the epicardium) were more frequent in the group of patients with inflammatory rheumatic disease (47% versus 20%; P = 0.002, odds ratio [OR] OR 3.6, 95% confidence interval [95% CI] 1.6-8.5), and the extent of these infiltrates was greater. Multivariate analyses revealed that the occurrence of mononuclear cell infiltrates was associated with inflammatory rheumatic disease (OR 2.99, P = 0.020) and current smoking (OR 3.93, P = 0.012), and they were observed in 6 of 7 patients with a history of aortic aneurysm. Inflammatory infiltrates in the media were seen only in patients with inflammatory rheumatic disease. The frequency of atherosclerotic lesions, inflammation within the plaques, and epicardial inflammatory infiltrates in the 2 groups was equal. CONCLUSION: Among aortic samples collected during CABG surgery, those obtained from patients with inflammatory rheumatic disease had more pronounced chronic inflammatory infiltration in the media and inner adventitia than those obtained from control patients. Current smoking was an independent predictor of chronic inner adventitial infiltrates. The infiltrates may represent an inflammatory process that promotes atherosclerosis and formation of aneurysms. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To compare the effectiveness of 3 therapeutic strategies in preventing progressive joint damage, in a population-based cohort. The 3 strategies were infliximab with concomitant disease-modifying antirheumatic drugs (DMARDs), etanercept with concomitant DMARDs, and etanercept alone. METHODS: We used sequential radiographs to assess all patients who were treated with infliximab or etanercept for >10 months. The rates of erosion progression and joint space narrowing (JSN) were analyzed using multivariate regression models for longitudinal data, with adjustment for potential confounders. RESULTS: A total of 372 patients treated with anti-tumor necrosis factor (TNF) therapies met the inclusion criteria. The baseline characteristics of the patients assigned to the 3 strategies were not significantly different, except that, as expected, more patients were receiving combination therapy with infliximab. The combination of infliximab plus DMARDs was significantly more effective than etanercept alone for controlling erosion progression (P < 0.001), but the effectiveness of the 2 combination-treatment strategies was similar (P = 0.07). The combination of infliximab plus DMARDs was also more effective at controlling progressive JSN compared with etanercept alone (P = 0.04) or etanercept plus DMARDs (P = 0.02). Treatment with anti-TNF agents (infliximab or etanercept) plus concomitant DMARDs was more effective than treatment with etanercept alone for controlling erosion progression (P = 0.045). CONCLUSION: When combined with traditional DMARDs, both etanercept and infliximab appear to offer similar protection against progressive structural joint damage, and combination therapy with either of these agents appears to be more effective than treatment with etanercept alone. [ABSTRACT FROM AUTHOR]

Non-typhoidal Salmonella serovars, such as Salmonella enterica serovar Typhimurium (STm), are a leading cause of inflammatory diarrhea in otherwise healthy individuals. Among children, the elderly, and immunocompromised individuals, STm can spread to systemic sites and cause potentially lethal bacteremia. Phagocytic cells and the immune complement system are pivotal to preventing the dissemination of STm. PgtE, an STm outer membrane protease, has been previously described to cleave over a dozen mammalian protein substrates in vitro , including complement protein C3. However, these activities have mostly been observed with mutant, avirulent strains with a truncated O-antigen that renders bacteria sensitive to complement killing. Here, we report that virulent STm utilizes PgtE to evade complement-mediated killing in vivo . The wild-type pathogen increases pgtE expression and PgtE proteolytic function within macrophages and in macrophage-like in vitro growth conditions, concomitant with physiologic O-antigen shortening in these environments. Furthermore, we found that wild-type STm's resistance to complement-mediated serum and neutrophil killing is PgtE-dependent. We propose that PgtE promotes the systemic spread of STm by acting as a second line of defense against complement when STm escapes from a macrophage.

This paper presents an equivalent source method (ESM) for analyzing sound propagation in small-scale acoustic structures with thermoviscous effects. The formulations that describe the thermal, viscous, and acoustic modes for thermoviscous acoustic problems are introduced. The concept of ESM is then applied to solve these formulations, resulting in an efficient numerical computation and implementation procedure. Based on two different strategies, the obtained ESM formulations are coupled at the boundary using the isothermal, non-slip, and null-divergence conditions. The coupling based on the first strategy is efficient for solving thermoviscous acoustic problems with few matrices required. However, this procedure faces the evaluation of the tangential derivatives of the boundary velocity. Coupling the ESM formulations directly for each component of the total particle velocity at the boundary has no such problem, which leads to the second strategy. However, it entails a larger memory usage compared to the former. Additionally, the coupled finite element method (FEM)-ESM formulations based on the above strategies are developed for acoustic-structural interaction. The validity of the presented ESM formulations is demonstrated through benchmark examples, and that of the coupled FEM-ESM formulation is illustrated by the numerical analysis of a simplified microphone., (© 2024 Acoustical Society of America.)

The study of acoustic radiation from spherical sound sources plays a crucial role in understanding the thermoviscous effects in practical acoustic problems. However, finding a general solution of acoustic radiation from spherical sound sources in thermoviscous fluids remains a formidable challenge. To advance this issue, an analytical method is developed in this paper to calculate the acoustic field radiated by spherical sound sources with the isothermal boundary condition and arbitrary velocity boundary condition. The developed method is utilized to present the solutions of the acoustic field generated by an oscillating sphere and a general spherical sound source, and the accuracy and validity of these solutions are verified through analytical and numerical methods., (© 2024 Acoustical Society of America.)

Emulsified meat products contain high animal fat content, and excessive intake of animal fat is not good for health, so people are paying more and more attention to reduced-fat meat products. This study investigated the impact of varying proportions of pork back-fat and/or resistant starch on the proximate composition, water and fat retention, texture properties, color, and rheology characteristic of pork batter. The results found that replacing pork back-fat with resistant starch and ice water significantly decreased the total lipid and energy contents of cooked pork batter ( p < 0.05) while improving emulsion stability, cooking yield, texture, and rheology properties. Additionally, when the pork back-fat replacement ratio was no more than 50%, there was a significant increase in emulsion stability, cooking yield, hardiness, springiness, cohesiveness, chewiness, and L* and G' values ( p < 0.05). Furthermore, resistant starch and ice water enhanced myosin head and tail thermal stability and increased G' value at 80 °C. However, the initial relaxation times significantly decreased ( p < 0.05) and the peak ratio of P 21 significantly increased from 84.62% to 94.03%, suggesting reduced fluidity of water. In conclusion, it is feasible to use resistant starch and ice water as a substitute for pork back-fat in order to produce reduced-fat pork batter with favorable gel and rheology properties.

Objective: This study was undertaken to examine the relationship between alcohol consumption and hip osteoarthritis in women. Alcohol has been associated with both adverse and beneficial health effects generally; however, the relationship between alcohol consumption and hip osteoarthritis has been minimally studied., Methods: Among women in the Nurses' Health Study cohort in the US, alcohol consumption was assessed every 4 years, starting in 1980. Intake was computed as cumulative averages and simple updates with latency periods of 0-4 through 20-24 years. We followed 83,383 women without diagnosed osteoarthritis in 1988 to June 2012. We identified 1,796 cases of total hip replacement due to hip osteoarthritis defined by self-report of osteoarthritis with hip replacement., Results: Alcohol consumption was positively associated with hip osteoarthritis risk. Compared with nondrinkers, multivariable hazard ratios (HRs) and 95% confidence intervals (95% CIs) were HR 1.04 (95% CI 0.90, 1.19) for drinkers of >0 to <5 grams/day, HR 1.12 (95% CI 0.94, 1.33) for 5 to <10 grams/day, HR 1.31 (95% CI 1.10, 1.56) for 10 to <20 grams/day, and HR 1.34 (95% CI 1.09, 1.64) for ≥20 grams/day (P for trend < 0.0001). This association held in latency analyses of up to 16-20 years, and for alcohol consumption between 35-40 years of age. Independent of other alcoholic beverages, the multivariable HRs (per 10 grams of alcohol) were similar for individual types of alcohol intake (wine, liquor, and beer; P = 0.57 for heterogeneity among alcohol types)., Conclusion: Higher alcohol consumption was associated with greater incidence of total hip replacement due to hip osteoarthritis in a dose-dependent manner in women., (© 2023 American College of Rheumatology.)

Phytoene synthase (PSY) is a key enzyme in carotenoid metabolism and often regulated by orange protein. However, few studies have focused on the functional differentiation of the two PSYs and their regulation by protein interaction in the β-carotene-accumulating Dunaliella salina CCAP 19/18. In this study, we confirmed that DsPSY1 from D. salina possessed high PSY catalytic activity, whereas DsPSY2 almost had no activity. Two amino acid residues at positions 144 and 285 responsible for substrate binding were associated with the functional variance between DsPSY1 and DsPSY2. Moreover, orange protein from D. salina (DsOR) could interact with DsPSY1/2. DbPSY from Dunaliella sp. FACHB-847 also had high PSY activity, but DbOR could not interact with DbPSY, which might be one reason why it could not highly accumulate β-carotene. Overexpression of DsOR , especially the mutant DsOR His , could significantly improve the single-cell carotenoid content and change cell morphology (with larger cell size, bigger plastoglobuli, and fragmented starch granules) of D. salina . Overall, DsPSY1 played a dominant role in carotenoid biosynthesis in D. salina , and DsOR promoted carotenoid accumulation, especially β-carotene via interacting with DsPSY1/2 and regulating the plastid development. Our study provides a new clue for the regulatory mechanism of carotenoid metabolism in Dunaliella . IMPORTANCE Phytoene synthase (PSY) as the key rate-limiting enzyme in carotenoid metabolism can be regulated by various regulators and factors. We found that DsPSY1 played a dominant role in carotenogenesis in the β-carotene-accumulating Dunaliella salina , and two amino acid residues critical in the substrate binding were associated with the functional variance between DsPSY1 and DsPSY2. Orange protein from D. salina (DsOR) can promote carotenoid accumulation via interacting with DsPSY1/2 and regulating the plastid development, which provides new insights into the molecular mechanism of massive accumulation of β-carotene in D. salina ., Competing Interests: The authors declare no conflict of interest.

Dunaliella salina is the most salt-tolerant eukaryote and has the highest β-carotene content, but its carotenoid synthesis pathway is still unclear, especially the synthesis of lycopene, the upstream product of β-carotene. In this study, DsGGPS , DsPSY , DsPDS , DsZISO , DsZDS , DsCRTISO , and DsLYCB genes were cloned from D. salina and expressed in Escherichia coli. A series of carotenoid engineering E. coli strains from phytoene to β-carotene were obtained. ZISO was first identified from Chlorophyta , while CRTISO was first isolated from algae. It was found that DsZISO and DsCRTISO were essential for isomerization of carotenoids in photosynthetic organisms and could not be replaced by photoisomerization, unlike some plants. DsZDS was found to have weak beta cyclization abilities, and DsLYCB was able to catalyze 7,7',9,9'-tetra- cis -lycopene to generate 7,7',9,9'-tetra- cis -β-carotene, which had not been reported before. A new carotenoid 7,7',9,9'-tetra- cis -β-carotene, the beta cyclization product of prolycopene, was discovered. Compared with the bacterial-derived carotenoid synthesis pathway, there is higher specificity and greater efficiency of the carotenoid synthesis pathway in algae. This research experimentally confirmed that the conversion of phytoene to lycopene in D. salina was similar to that of plants and different from bacteria and provided a new possibility for the metabolic engineering of β-carotene. IMPORTANCE The synthesis mode of all trans -lycopene in bacteria and plants is clear, but there are still doubts in microalgae. Dunaliella is the organism with the highest β-carotene content, and plant-type and bacterial-type enzyme genes have been found in its carotenoid metabolism pathway. In this study, the entire plant-type enzyme gene was completely cloned into Escherichia coli, and high-efficiency expression was obtained, which proved that carotenoid synthesis of algae is similar to that of plants. In bacteria, CRT can directly catalyze 4-step continuous dehydrogenation to produce all trans -lycopene. In plants, four enzymes (PDS, ZISO, ZDS, and CRTISO) are involved in this process. Although a carotenoid synthetase similar to that of bacteria has been found in algae, it does not play a major role. This research reveals the evolutionary relationship of carotenoid metabolism in bacteria, algae, and plants and is of methodologically innovative significance for molecular evolution research.

Polymyxin A1 was a rarely investigated member in the polymyxins family produced by Bacillus aerosporus . As a cyclic non-ribosomal lipopeptide, it was purified from Paenibacillus thiaminolyticus for the first time. The producing strain SY20 was screened from Chinese natural fermented bamboo shoots and identified as P. thiaminolyticus SY20 using 16S rRNA homology along with whole genome sequencing. The optimum incubation time was 32 h by the growth kinetics of antimicrobial agent production. The proteinaceous nature of antimicrobial agents was characterized according to the physicochemical properties of the cell-free supernatant. Subsequently, the active antimicrobial agent was purified from the supernatant using ammonium sulfate-graded precipitation, ion-exchange chromatography, and C 18 -H chromatography. The active agent was identified as polymyxin A1 with a molecular weight 1156.7 Da and antimicrobial activity mainly against Gram-negative bacteria. The molecular structure, a cyclic heptapeptide and a tripeptide side chain acylated by a fatty acid at the amino terminus, was elucidated using the combination of liquid chromatography-tandem mass spectrometry (LC-MS/MS), matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS), amino acid analysis, and whole genome mining tool. Meanwhile, the biosynthetic gene cluster of polymyxin A1 including five open reading frames (ORFs) was demonstrated in the genome. The compound should be further explored for its efficacy and toxicity in vivo to develop its application., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wu, Liu, Liang, Huang, Lin and Xiao.)

Microalgae are considered to be a very promising class of raw material for carotenoid production. In this study, melatonin (MLT), a widely used plant growth regulator, was added to the autotrophic medium of Dunaliella bardawil to explore its effects on the growth and pigment accumulation of Dunaliella bardawil. The results showed that the induction of exogenous MLT alone was not beneficial to the growth and pigment accumulation of Dunaliella bardawil, and the higher the concentration, the more obvious the inhibitory effect on the algal cells. Therefore, a strategy to promote carotenoid accumulation in Dunaliella bardawil by combining exogenous MLT and light induction was carried out. Under 4500 LUX light intensity, the content of zeaxanthin was significantly increased under exogenous MLT induction. In the 200 μg/mL, 300 μg/mL, and 400 μg/mL MLT-treated groups, the zeaxanthin single-cell content in the 300 μg/mL-treated group was as high as 0.38 ng/mL (0.17 ng/mL in the control group), which was 1.24-fold higher compared to the control. Under 9500 LUX light intensity, all carotenoids showed an increasing trend in all experimental groups, except for zeaxanthin, which showed a decreasing trend. The effect of 300 μg/mL showed the most obvious in the 200 μg/mL,300 μg/mL, and 400 μg/mL MLT treatment groups, where the lutein, α-carotene and β-carotene contents were 1.24, 1.14 and 1.31 times higher than those of the control group, respectively. Overall, exogenous MLT at high light intensities had a significant effect on pigment accumulation in Dunaliella bardawil., Competing Interests: Conflicts of interest The authors declare no conflict of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Cold stress is one of the abiotic stress conditions that severely limit plant growth and development and productivity. Triacylglycerol lipases are important metabolic enzymes for the catabolism of triacylglycerols and, therefore, play important roles in cellular activities including seed germination and early seedling establishment. However, whether they play a role in cold stress responses remains unknown. In this study, we characterized two Arabidopsis triacylglycerol lipases, MPL1 and LIP1 and defined their role in cold stress. The expression of MPL1 and LIP1 is reduced by cold stress, suggesting that they may be negative factors related to cold stress. Indeed, we found that loss-of-function of MPL1 and LIP1 resulted in increased cold tolerance and that the mpl1lip1 double mutant displayed an additive effect on cold tolerance. We performed RNA-seq analysis to reveal the global effect of the mpl1 and lip1 mutations on gene expression under cold stress. The mpl1 mutation had a small effect on gene expression under both under control and cold stress conditions whereas the lip1 mutation caused a much stronger effect on gene expression under control and cold stress conditions. The mpl1lip1 double mutant had a moderate effect on gene expression under control and cold stress conditions. Together, our results indicate that MPL1 and LIP1 triacylglycerol lipases are negative regulators of cold tolerance without any side effects on growth in Arabidopsis and that they might be ideal candidates for breeding cold-tolerant crops through genome editing technology.

Dunaliella bardawil, a unicellular green alga, can accumulate a large amount of lutein and β-carotene under stresses. Using chemical inducers combined with abiotic stress to promote the accumulation of high value-added products such as lipids and carotenoids in microalgae has attracted more and more attention. In this study, creatinine was added into autotrophic medium to investigate its effects on the growth, chlorophyll content, and the ingredients and content of carotenoids in D. bardawil. The results showed that creatinine alone could significantly increase the biomass, chlorophyll and carotenoid contents of D. bardawil, among which the contents of lutein and β-carotene were further increased, while the content of zeaxanthin was decreased. In order to further improve the content of the two carotenoids, different light intensities combined with creatinine have been adopted. Under 6.589 W/m 2 light intensity, creatinine could effectively increase the production of lutein, zeaxanthin, α-carotene and β-carotene. Compared with the control, the content of lutein increased by 46 % and the content of β-carotene increased by 77 % when the concentration of creatinine was 500 μg/mL. In conclusion, creatinine can effectively improve the production lutein and β-carotene in D. bardawil, which is more conducive under lower light intensity., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Despite promising candidates for new therapeutic options in the treatment of systemic lupus erythematosus (SLE), many clinical trials have failed in the past few years. The disappointing results have been at least partly be attributed to trial designs. With the aim of stimulating new developments in SLE trial design, an international open space meeting was held on occasion of the European Lupus Meeting 2018 in Duesseldorf, Germany about 'What are the topics you care about for making trials in lupus more effective?'. The Open Space is a participant-driven technology, where the discussion topics and schedule are selected during the meeting by all participants and discussion rounds are led by the people attending encouraging active contributions. Eleven topics were selected for further discussion, of which 6 were voted to be more intensively discussed in two consecutive rounds. Major topics were the optimal handling of glucocorticoids in clinical trials, the improvement of outcome measures, reducing or controlling the placebo response and the identification of biomarkers and stratification parameters. Further, the importance of local and international networks was emphasised. By networking, collaborations are facilitated, patient recruitment is more efficient and treatment can be harmonised thus lead to more successful SLE trials. Further discussions are needed to substantiate the results and develop new trial designs., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Biological remediation of toxic oxygen-containing anions such as nitrate that are common in the environment is of great significance. Therefore, it is necessary to understand the specific role of nitrate and nitrite reductase in the bioremediation process. Bacillus cereus LJ01, which was isolated from traditional Chinese soybean paste, effectively degraded nitrite (such as NaNO 2 ) at 0-15 mmol L -1 in LB medium. Moreover, the nitrite-degrading active substance (ASDN) was isolated and purified from B. cereus LJ01. The nitrite-degrading activity of nitrite reductase (named LJ01-NiR) was 4004.89 U mg -1 . The gene encoding the assimilation of nitrite reductase in B. cereus LJ01 was cloned and overexpressed in E. coli. The purified recombinant LJ01-NiR has a wide range of activities under temperature (20-60 °C), pH (6.5-8.0) and metal ions (Fe 3+ , Fe 2+ , Cu 2+ , Mn 2+ , and Al 3+ ). Kinetic parameters of LJ01-NiR, including the values of K m and V max were 1.38 mM and 2.00 μmol g -1 min -1 , respectively. The results showed that LJ01-NiR could degrade nitrite with or without an electron donor. In addition, sequence analysis revealed that LJ01-NiR was a ferredoxin-dependent nitrite reductase given the presence of conserved [Fe4-S4] cluster and heme-binding domain. The nitrite ion binds to the LJ01-NiR active site by forming three hydrogen bonds with the residues ASN72, ALA133 and ASN140. Due to its high nitrite-degrading activity, LJ01-NiR could potentially be used for environmental pollution treatment., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Lactarius volemus Fr. has been regarded as a great edible medicinal fungal resource in China. In this study, L. volemus Fr. polysaccharide (LVP) with an average molecular weight of 16.842 kDa was obtained by water extraction. The structure of LVP was characterized to be mannan, and the linkages in the mannan were found to comprise the Man p , (1→4)-α-Man and (1→4,6)-α-Man. Furthermore, intraperitoneal administration of LVP increased the thymus, spleen and liver indices, dose-dependently. Additionally, LVP enhanced the immune response and the phagocytic activities. Pathological evaluations showed that LVP in mice increased the proliferation of red medullary lymphocytes (60-70%). Collectively, these results indicated that LVP might be a potential resource of raw material for further investigations of functional foods., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

The halophilic green alga Dunaliella bardawil has been used for commercial production of natural β-carotene by large-scale outdoor cultivation, which often suffers from heat stress especially at noon in hot summers. In this study, the effects of heat stress on cell growth, pigment contents, and activities of antioxidant system in D. bardawil were studied, and RNA-seq experiment was conducted to analyze the transcriptional response to heat stress (42 °C for 2 h) in D. bardawil. High temperature (42 °C) for short time treatment (≤3 h) did not severely affect the cell growth and pigment accumulation of D. bardawil. Multiple genes encoding heat shock proteins for protein folding and antioxidant enzymes against toxic reactive oxygen species were substantially up-regulated significantly under heat stress. D. bardawil cells tended to shift from aerobic to glycolytic metabolism for energy production to increase survival chances under heat stress. Furthermore, the enrichment of ascorbate-glutathione cycle, up-regulation of genes responsible for chloroplast membranes, and changes in lipid characteristics like carbon chain length and unsaturation degree could play a vital role in achieving thermotolerance of D. bardawil. Taken together, this study improved our understanding of the molecular mechanisms of heat stress responses in D. bardawil., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The halophilic green alga Dunaliella bardawil FACHB-847 is rich in lutein and α-carotene, which has great potential for carotenoid production in open ponds. In this study, genes encoding lycopene β- and ε-cyclases (DbLcyB and DbLcyE) from D. bardawil FACHB-847 were functionally identified by genetic complementation in E. coli. The bifunctional DbLcyB not only catalyzed the formation of both mono- and bi-cyclic β-rings with a major β-cyclase activity, but also possessed a weak ε-cyclase activity. In contrast, DbLcyE preferred to convert lycopene into monocyclic δ-carotene, and possessed a weak β-monocyclase activity. Lutein and α-carotene were the prominent carotenoids in D. bardawil FACHB-847, which was in agreement with the result of genetic complementation of co-expression of DbLcyB and DbLcyE in E. coli with α-carotene as the prominent product. The bifunctional DbLcyB and DbLcyE may contribute to the high accumulation of α-carotene in D. bardawil FACHB-847. Interestingly, the accumulation of lutein in D. bardawil FACHB-847 was more sensitive to salt stress, while the accumulation of β-carotene in D. salina CCAP 19/18 was induced by salt stress. In brief, the production of different carotenoid compositions from these two Dunaliella species can be induced by different growth conditions., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Glycerol-3-phosphate (G3P) is the important precursors for triacylglycerol synthesis, while glycerol-3-phosphate dehydrogenase (GPDH) determines the formation of G3P. In this study, two GDPH genes, Dtgdp1 and Dtgdp2 were isolated and identified from Dunaliella tertiolecta. The full-length Dtgdp1 and Dtgdp2 CDS were 2016 bp and 2094 bp, which encoded two putative protein sequences of 671 and 697 amino acids with predicted molecular weights of 73.64 kDa and 76.73 kDa, respectively. DtGDP1 and DtGDP2 both had a close relationship with those of algal and higher plants. DtGDP1 shared two conserved superfamily (A1 and A2) and four signature motifs (I-IV), and the DtGDP2 showed six signature domains (from motif I to VI) and DAO&#95;C conserved family. Our previous work showed that the triethylamine intervention could greatly increase the triacylglycerol content (up to 80%) of D. tertiolecta. This study aims to investigate the effect of triethylamine on GPDH expression. Results showed that, when treated by triethylamine at 100 ppm and 150 ppm, the expression levels of Dtgdp1 and Dtgpd2 were increased to 5.121- and 56.964-fold compared with the control, respectively. Triethylamine seemed to enhance lipid metabolic flow by inducing the expressions of Dtgdp1 and Dtgdp2 to increase the lipid content, which provides a new insight into the desired pathway of lipid synthesis in algae through genetic engineering., (Copyright © 2019 Elsevier Inc. All rights reserved.)

A two-step strategy was employed to culture Dunaliella tertiolecta, an oleaginous unicellular green alga, combined by the salt stress and sodium azide intervention, to observe their effects on its lipid accumulation. When the algae cultured at different salt concentrations reached the logarithmic growth phase, sodium azide was added. The results showed that the addition of sodium azide significantly increased the lipid content and had no significant effect on cell biomass. The lipid yield and single cell lipid content under 50 μM sodium azide increased by 10.4% and 21.7%. Under the two-step culture condition, combining of the treatment of 50 μM sodium azide and 2.5 M salt stress, the total lipid productivity and single-cell lipid content were 10% and 70.5% higher than that of the control. It seemed that sodium azide and salinity might have a synergistic effect on the lipid accumulation of D. tertiolecta. It can be concluded that sodium azide is an effective inducer of lipid accumulation in D. tertiolecta, and two-stage cultivation is a feasible way to improve lipid accumulation in microalgae., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Microalgae are promising alternatives for sustainable biodiesel production. Previously, it was found that 100 ppm triethylamine greatly enhanced lipid production and lipid content per cell of Dunaliella tertiolecta by 20% and 80%, respectively. However, triethylamine notably reduced biomass production and pigment contents. In this study, a two-stage cultivation with glycerol and triethylamine was attempted to improve cell biomass and lipid accumulation. At the first stage with 1.0 g/liter glycerol addition, D. tertiolecta cells reached the late log phase in a shorter time due to rapid cell growth, leading to the highest cell biomass (1.296 g/liter) for 16 days. However, the increased glycerol concentrations with glycerol addition decreased the lipid content. At the second-stage cultivation with 100 ppm triethylamine, the highest lipid concentration and lipid weight content were 383.60 mg/liter and 37.7% of dry cell weight (DCW), respectively, in the presence of 1.0 g/liter glycerol, which were 27.36% and 72.51% higher than those of the control group, respectively. Besides, the addition of glycerol alleviated the inhibitory effect of triethylamine on cell morphology, algal growth, and pigment accumulation in D. tertiolecta The results indicated that two-stage cultivation is a viable way to improve lipid yield in microalgae. IMPORTANCE Microalgae are promising alternatives for sustainable biodiesel production. Two-stage cultivation with glycerol and triethylamine enhanced the lipid productivity of Dunaliella tertiolecta , indicating that two-stage cultivation is an efficient strategy for biodiesel production from microalgae. It was found that glycerol significantly enhanced cell biomass of D. tertiolecta , and the presence of glycerol alleviated the inhibitory effect of triethylamine on algal growth. Glycerol, the major byproduct from biodiesel production, was used for the biomass accumulation of D. tertiolecta at the first stage of cultivation. Triethylamine, as a lipid inducer, was used for lipid accumulation at the second stage of cultivation. Two-stage cultivation with glycerol and triethylamine enhanced lipid productivity and alleviated the inhibitory effect of triethylamine on the algal growth of D. tertiolecta , which is an efficient strategy for lipid production from D. tertiolecta ., (Copyright © 2019 American Society for Microbiology.)

Objective: To develop and validate new classification criteria for adult and juvenile idiopathic inflammatory myopathies (IIM) and their major subgroups., Methods: Candidate variables were assembled from published criteria and expert opinion using consensus methodology. Data were collected from 47 rheumatology, dermatology, neurology, and pediatric clinics worldwide. Several statistical methods were utilized to derive the classification criteria., Results: Based on data from 976 IIM patients (74% adults; 26% children) and 624 non-IIM patients with mimicking conditions (82% adults; 18% children), new criteria were derived. Each item is assigned a weighted score. The total score corresponds to a probability of having IIM. Subclassification is performed using a classification tree. A probability cutoff of 55%, corresponding to a score of 5.5 (6.7 with muscle biopsy) "probable IIM," had best sensitivity/specificity (87%/82% without biopsies, 93%/88% with biopsies) and is recommended as a minimum to classify a patient as having IIM. A probability of ≥90%, corresponding to a score of ≥7.5 (≥8.7 with muscle biopsy), corresponds to "definite IIM." A probability of <50%, corresponding to a score of <5.3 (<6.5 with muscle biopsy), rules out IIM, leaving a probability of ≥50-<55% as "possible IIM.", Conclusion: The European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) classification criteria for IIM have been endorsed by international rheumatology, dermatology, neurology, and pediatric groups. They employ easily accessible and operationally defined elements, and have been partially validated. They allow classification of "definite," "probable," and "possible" IIM, in addition to the major subgroups of IIM, including juvenile IIM. They generally perform better than existing criteria., (© 2017, American College of Rheumatology.)

Objective: To describe the methodology used to develop new classification criteria for adult and juvenile idiopathic inflammatory myopathies (IIMs) and their major subgroups., Methods: An international, multidisciplinary group of myositis experts produced a set of 93 potentially relevant variables to be tested for inclusion in the criteria. Rheumatology, dermatology, neurology and paediatric clinics worldwide collected data on 976 IIM cases (74% adults, 26% children) and 624 non-IIM comparator cases with mimicking conditions (82% adults, 18% children). The participating clinicians classified each case as IIM or non-IIM. Generally, the classification of any given patient was based on few variables, leaving remaining variables unmeasured. We investigated the strength of the association between all variables and between these and the disease status as determined by the physician. We considered three approaches: (1) a probability-score approach, (2) a sum-of-items approach criteria and (3) a classification-tree approach., Results: The approaches yielded several candidate models that were scrutinised with respect to statistical performance and clinical relevance. The probability-score approach showed superior statistical performance and clinical practicability and was therefore preferred over the others. We developed a classification tree for subclassification of patients with IIM. A calculator for electronic devices, such as computers and smartphones, facilitates the use of the European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) classification criteria., Conclusions: The new EULAR/ACR classification criteria provide a patient's probability of having IIM for use in clinical and research settings. The probability is based on a score obtained by summing the weights associated with a set of criteria items., Competing Interests: Competing interests: JAS has received research grants from Takeda and Savient and consultant fees from Savient, Takeda, Regeneron, Merz, Bioiberica, Crealta and Allergan. JAS serves as the principal investigator for an investigator-initiated study funded by Horizon pharmaceuticals through a grant to DINORA, Inc., a 501 (c)(3) entity. JAS is a member of the executive of OMERACT, an organisation that develops outcome measures in rheumatology and receives arms-length funding from 36 companies; a member of the American College of Rheumatology’s (ACR) Annual Meeting Planning Committee (AMPC); Chair of the ACR Meet-the-Professor, Workshop and Study Group Subcommittee; and a member of the Veterans Affairs Rheumatology Field Advisory Committee. HC and RGC’s work in myositis is partly funded by grants from Arthritis Research UK (18474) and the Medical Research Council (MR/N003322/1). JV’s work in myositis is supported by the Project (Ministry of Health, Czech Republic) for Conceptual Development of Research Organization 00023728.

Three kinds of π-conjugated perylenetetracarboxylic diimide (PTCDI)-based organic functional derivatives, i.e., N,N'-di(2-ethylhexyl)-3,4,9,10-perylene diimide (molecule 1), N,N'-di(2-ethylhexyl)-1,7-dithien-2-yl-3,4,9,10-perylene diimide (molecule 2), N,N'-di(2-ethylhexyl)-1,7-di(2-bromothien-5-yl)-perylene-3,4,9,10-perylene diimide (molecule 3), have been prepared and investigated by using a scanning tunneling microscopy under ambient conditions. All of them can form long-ranged ordered self-assembled monolayer (SAM) with two different phase structures on highly oriented pyrolitic graphite (HOPG) surface. Coexistence of the two phases in the formed SAMs depends strongly on cooperation of various interactions including the molecule-substrate and molecule-molecule. Orientation of the molecular perylene cores primarily governs the molecular orientation in the SAMs by π-π interaction of the molecule-substrate through uttermost matching the graphite surface lattice. At the same time, the branched alkyl-chain substituents at N-sites can adjust intermolecular distances through conformation change while cyclic π-conjugated substituents at bay-positions lead to molecular rotation movement on HOPG, driven by the decreased molecule-substrate interaction caused by distortion of the perylene cores and the intermolecular interaction among the adjacent bay-substituents with rotation conformation change. In addition, the lateral forces from rotation conformation change of the bay-position substituents can also be strong enough to keep the orientation of the perylene cores unchanged. DFT calculation results further reveal the formation mechanisms for the three molecular self-assembly systems. These findings distinctly show that the SAM structures based on the π-conjugated PTCDI-based organic functional derivative molecules can be precisely modulated through introducing suitable substituents at both N- and bay-positions on the PTCDI core., (Copyright © 2017 Elsevier Inc. All rights reserved.)

HBscFv-IFNγ, a fusion protein constructed by fusing γ-interferon (IFNγ) with an antibody fragment HBscFv for the purpose of targeted delivery of the cytokine IFNγ, was designed in order to enhance its therapeutic efficacy through increasing its hepatoma localization. HBscFv and IFNγ were connected into HBscFv-IFNγ by the linker (Gly 4 Ser) 3 , and then the multicopy recombinant plasmids pPICZαA/(HBscFv-IFNγ) 1,2,4 were constructed and transformed into Komagatella (Pichia) pastoris X33. The engineering strain X4, which had much higher copy number and could secretively express HBscFv-IFNγ, was screened from transformed X33 by qPCR. Results from SDS-PAGE, Western blotting and ELISA indicated that HBscFv-IFNγ displayed an excellent immunoreaction against HBsAg. The culture supernatant of X4 was purified by 14F7 affinity chromatography to obtain the fusion protein HBscFv-IFNγ in a purity of 95-98%. The HBscFv-IFNγ was able to bind 27.9% HBsAg in the serum of HBV transgenic mice, showing that the antibody of HBscFv-IFNγ has high binding affinity against HBsAg. The expressing of the recombinant HBscFv-IFNγ in P. pastoris provides a promising and inexpensive diagnostic reagent for preventing HBV infection., (Copyright © 2017. Published by Elsevier Inc.)

The unicellular alga Dunaliella bardawil is a highly salt-tolerant organism, capable of accumulating glycerol, glycine betaine and β-carotene under salt stress, and has been considered as an excellent model organism to investigate the molecular mechanisms of salt stress responses. In this study, several carotenogenic genes (DbCRTISO, DbZISO, DbLycE and DbChyB), DbBADH genes involved in glycine betaine synthesis and genes encoding probable WRKY transcription factors from D. bardawil were isolated, and promoters of DbCRTISO and DbChyB were cloned. The promoters of DbPSY, DbLycB, DbGGPS, DbCRTISO and DbChyB contained the salt-regulated element (SRE), GT1GMSCAM4, while the DbGGPS promoter has another SRE, DRECRTCOREAT. All promoters of the carotenogenic genes had light-regulated elements and W-box cis-acting elements. Most WRKY transcription factors can bind to the W-box, and play roles in abiotic stress. qRT-PCR analysis showed that salt stress up-regulated both carotenogenic genes and WRKY transcription factors. In contrast, the transcription levels of DbBADH showed minor changes. In D. bardawil, it appears that carotenoid over-accumulation allows for the long-term adaptation to salt stress, while the rapid modulation of glycine betaine biosynthesis provides an initial response., Competing Interests: The authors declare no competing financial interests.

The objective of this study was to assess the role performance among KOSPEN community health volunteer in Kuching district and its associated factors. This was a cross-sectional study, conducted in 21 localities in Kuching with a total of 210 respondents. Data were collected using validated interviewer-administered questionnaires and analyzed using SPSS version 22.0. The respondents comprised 55.2% females, 81.9% married, and 41.4% aged above 45 and above and 72.4% completed their education up to secondary school. The result revealed that 59.0% of the respondents agreed and understood their role performances. Multiple Logistics analysis revealed that factors associated with role performance were age group ( p = 0.003), education level ( p < 0.001), marital status ( p = 0.025), prestige and respect ( p = 0.012), being seen as "doctor" in community ( p = 0.003), job aids ( p = 0.009), training location ( p = 0.001), and supervision by community ( p < 0.001). To increase and maintain the work performance of CHVs, commitment from the government, policy makers, stakeholders, and the communities is required., Competing Interests: The authors declare that there is no conflict of interests. This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Background: The estimation of an effect size is an important step in designing an adequately powered, feasible clinical trial intended to change clinical practice. During the planning phase of VA Cooperative Study #590, "Double-Blind Placebo-Controlled Study of Lithium for Preventing Repeated Suicidal Self-Directed Violence in Patients with Depression or Bipolar Disorder (Li+)," it was not clear what effect size would be considered large enough to influence prescribing behavior among practicing clinicians., Methods: We conducted an online survey of VA psychiatrists to assess their interest in the study question, their clinical experience with lithium, and their opinion about what suicide reduction rate would change their prescribing habits. The 9-item survey was hosted on SurveyMonkey © and VA psychiatrists were individually emailed an invitation to complete an anonymous online survey. Three email waves were sent over three weeks., Results: Overall, 862 of 2713 VA psychiatrists (response rate = 31.8%) responded to the anonymous survey. 74% of the respondents would refer a patient to the proposed trial, 9% would not, and 17% were unsure. Presented with suicide reduction rates in 10% increments ranging from 10 to 100%, 61% of respondents indicated that they would use lithium if suicide attempts were reduced by at least 40%; 83% would use lithium if it reduced attempts by at least 50%., Conclusions: Even with the limitations of response bias and the reliability of responses on future prescribing behavior, a survey of potential users of a clinical trial's results offers a convenient, empirical method for determining and justifying clinically relevant effect sizes.

AMP-forming acetyl-CoA synthetase (ACS) catalyzes the formation of acetyl-CoA. Here, a cDNA of ACS from Dunaliella tertiolecta (DtACS) was isolated using RACEs. The full-length DtACS cDNA (GenBank: KT692941) is 2,464 bp with a putative ORF of 2,184 bp, which encodes 727 amino acids with a predicted molecular weight of 79.72 kDa. DtACS has a close relationship with Chlamydomonas reinhardtii and Volvox carteri f. nagariensis. ACSs existing in Bacteria, Archaea and Eukaryota share ten conserved motifs (A1-A10) and three signature motifs (I-III) of the acyl-adenylate/thioester forming enzyme superfamily. DtACS was expressed in E. coli BL21 as Trx-His-tagged fusion protein (~100 kDa) and the enzymatic activity was detected. The recombinant DtACS was purified by HisTrap(TM) HP affinity chromatography to obtain a specific activity of 52.873 U/mg with a yield of 56.26%, which approached the specific activity of ACS isolated from other eukaryotes. Kinetic analysis indicated that the Km of DtACS was 3.59 mM for potassium acetate, and the purified DtACS exhibited a temperature optimum of 37 °C and a pH optimum of 8.0. In addition, the expression levels of DtACS were increased after nitrogen starvation cultivation, indicating that ACS activity may be related to the lipid accumulation under nitrogen deficient condition.

Since the 2002 Dusseldorf meeting, one new agent, Benlysta, has been approved by the US Food and Drug Administration for systemic lupus erythematosus. Experiences from the field in conducting trials of all the agents tested during this period have provided valuable practical insights. There has been incremental progress in defining the minimal clinically important difference (MCID) of key disease manifestations and the view is largely that of the health care providers and not that of the person suffering the disease. This basic methodological work on the MCID should improve the efficiency and the clinical relevance of future trials and their design.

Group sequential designs are used to potentially shorten randomized clinical trials and thereby reduce subject burden, improve safety, and save time and resources. Clinical trials comparing treatments for systemic lupus erythematosus (SLE) might adopt such designs if the ordinal outcome scales for SLE, such as the Systemic Lupus Activity Measure and Systemic Lupus Erythematosus Disease Activity Index, were more like continuous outcome scales with interval properties. After describing the basic features of sequential trials and highlighting some major issues in their design, we propose approaches that mitigate these issues. In particular, high-speed computing has accelerated advances in sequential design, making available a variety of designs that can be implemented with minimal technical support. The challenge now is to understand the concepts behind such flexible designs and then to apply them to improve studies of SLE.

Snake venom protein from Deinagkistrodon acutus (DA protein), one of the major venomous species in Taiwan, causes hemorrhagic symptoms that can lead to death. Although horse-derived antivenin is a major treatment, relatively strong and detrimental side effects are seen occasionally. In our study, yolk immunoglobulin (IgY) was purified from eggs, and DA protein was recognized using Western blotting and an enzyme-linked immunosorbent assay (ELISA), similar to therapeutic horse antivenin. The ELISA also indicated that specific IgY antibodies were elicited after the fifth booster, plateaued, and lasted for at least 3 months. To generate monoclonal single-chain variable fragment (scFv) antibodies, we used phage display technology to construct two libraries with short or long linkers, containing 6.24 × 10(8) and 5.28 × 10(8) transformants, respectively. After four rounds of biopanning, the eluted phage titer increased, and the phage-based ELISA indicated that the specific clones were enriched. Nucleotide sequences of 30 individual clones expressing scFv were analyzed and classified into four groups that all specifically recognized the DA venom protein. Furthermore, based on mass spectrometry, the scFv-bound protein was deduced to be snake venom metalloproteinase proteins. Most importantly, both IgY and mixed scFv inhibited the lethal effect in mice injected with the minimum lethal dosage of the DA protein. We suggest that together, these antibodies could be applied to the development of diagnostic agents or treatments for snakebite envenomation in the future., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

Objective: To investigate the determinants of health care utilization and costs with use of glucocorticoid (GC) drugs among adult systemic lupus erythematosus (SLE) patients., Methods: This cross-sectional study analyzed established SLE patients identified by International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes from a large US insurance claims database in 2007-2011. Five patient groups were defined by their oral GC use during a 1-year period: non-GC users, <60 days of GC use, and ≥60 days of GC use in low dosage (≤7.5 mg/day), medium dosage (>7.5 to ≤15 mg/day), or higher dosage (>15 mg/day). Annual health care utilization and costs were compared across these groups. Incremental costs of GC groups, calculated as the difference in total health care costs compared with those of the non-GC group, were estimated from multivariable regressions adjusting for demographic/clinical characteristics and stratified by concomitant immunosuppressant use., Results: A total of 50,230 SLE patients were identified (52% non-GC users, 20% <60 days of GC use, and 10% low dose, 10% medium dose, and 8% higher dose of ≥60 days of GC use). GC users had higher health care utilization and costs. Incremental costs were significant (all P < 0.01) for medium-dose ($5,319 and $6,913) and higher-dose ($12,517 and $15,019) GC groups, regardless of concomitant immunosuppressant use. The incremental costs for the low-dose GC group with concomitant immunosuppressants ($1,285; P = 0.04) were smaller than the incremental costs for the low-dose GC group without concomitant immunosuppressants ($2,514; P < 0.01)., Conclusion: GC use, especially at higher doses, was associated with higher health care utilization and costs. Findings in users with concomitant immunosuppressants suggest that therapies with a GC-sparing effect may be associated with lower economic burden in SLE treatment., (© 2015, American College of Rheumatology.)

Objective: To assess the epidemiology, clinical features, and outcomes of systemic lupus erythematosus (SLE) in the predominantly African Caribbean population of Barbados., Methods: A national registry of all patients diagnosed with SLE was established in 2007. Complete case ascertainment was facilitated by collaboration with the island's sole rheumatology service, medical practitioners, and the lupus advocacy group. Informed consent was required for inclusion., Results: Between January 1, 2000 and December 31, 2009, there were 183 new cases of SLE (98% African Caribbean) affecting 172 women and 11 men for unadjusted annual incidence rates of 12.21 (95% confidence interval [95% CI] 10.46-14.18) and 0.84 (95% CI 0.42-1.51) per 100,000 person-years, respectively. Excluding pediatric cases (ages <18 years), the unadjusted incidence rate among women was 15.14 per 100,000 person-years. The principal presenting manifestations were arthritis (84%), nephritis (47%), pleuritis (41.5%), malar rash (36.4%), and discoid lesions (33.1%). Antinuclear antibody positivity was 95%. The overall 5-year survival rate was 79.9% (95% CI 69.6-87.1), decreasing to 68% in patients with nephritis. A total of 226 persons with SLE were alive at the end of the study for point prevalences of 152.6 (95% CI 132.8-174.5) and 10.1 (95% CI 5.4-17.2) per 100,000 among women and men, respectively., Conclusion: Rates of SLE in Barbadian women are among the highest reported to date, with clinical manifestations similar to African American women and high mortality. Further study of this population and similar populations of West African descent might assist our understanding of environmental, genetic, and health care issues underpinning disparities in SLE., (Copyright © 2012 by the American College of Rheumatology.)

Background: Length of stay (LOS) is one of the most important quantitative indexes that measures health service utilization within a hospital. Many studies have examined the association of three major stroke categories with LOS. Our aim is to investigate the differences of LOS among ischemic stroke subtypes, results from which are helpful to healthcare providers and government agencies to improve health care delivery efficiency., Methodology/principal Findings: Using the Beijing Municipal Health Bureau's hospitalization summary reports, we performed a retrospective study among first-ever in-hospital patients with ischemic stroke (ICD-10 I63) in three general teaching hospitals in Beijing, China, from 2006 to 2010 with generalized linear model. In our study, 5,559 patients (female, 36.0%; age, 64.4 ± 12.9 years) were included. The estimated mean LOS of ischemic stroke was 17.4 ± 1.8 days. After adjusting for confounders, LOS of lacunar infarction (14.7 days; p<0.001) and LOS of small cerebral infarction (17.0 days; p=0.393) were shorter than that of single cerebral infarction (17.9 days, p<0.001). LOS of multi-infarct (19.0 days; p=0.028), brainstem infarction (19.3 days; p=0.045), basal ganglia infarction (18.5 days; p=0.452) and other subtypes of ischemic stroke (18.9 days; p=0.327) were longer than that of single cerebral infarction., Conclusions: LOS of ischemic stroke patient differes across single cerebral infarction, lacunar infarction, multi-infarct and brainstem infarction patients. The ascending order of LOS was lacunar infarction, small cerebral infarction, single cerebral infarction, basal ganglia infarction, other subtypes of ischemic stroke, multi-infarct and brainstem infarction.

Disparities in health outcomes occur in systemic lupus erythematosus (SLE) especially in economically disadvantaged populations. At the 9th International Congress on SLE, June 24-27, 2010, held in Vancouver, British Columbia, a symposium "Narrowing the Gap in the Treatment and Study of SLE worldwide" was held. Participating physicians from the Caribbean, Central and South America, Asia, Portugal, Africa and impoverished areas of the United States detailed their constraints and desires. These were remarkably consistent. Out of these discussions, a statement on minimum best practice was put forth aimed at the cost-effective management of SLE focusing on the critical factors that make a difference and are feasible even in the most challenging environments. Approaches to designing studies and establishing research and mentoring collaborations was also discussed. The ultimate aim was to provide an avenue for the improvement of care and outcomes for patients with SLE worldwide.

Objective: To investigate the influence of cumulative lifetime hip joint force on the risk of self-reported medically-diagnosed hip osteoarthritis (OA)., Design: Prospective cohort., Setting: General population., Participants: Members of Canadian Association of Retired Persons, community-dwelling., Main Outcome: Health-professional diagnosed hip OA, self-reported., Methods: Exposure data on lifetime physical activity type (occupational, household, sport) and dose (frequency, intensity, duration) was collected in 2005. Subjects were ranked in terms of a 'cumulative peak force index' (CFPI), a measure of lifetime mechanical hip joint force. Multivariable survival analyses were performed to obtain adjusted effects for mean lifetime exposure and during 5-year age periods., Results: Of 2918 subjects aged 45-85, 176 (6.03%) developed hip OA during the 2-year follow up (43 men, 133 women). The highest quintile of mean lifetime hip CPFI (HR 2.32; 95% CI 1.31-4.12), and high hip force in three age periods (35-39, 40-44, 45-49) were independently associated with hip OA. Previous hip injury was an approximate five-fold risk for development of hip OA across all models. In analysis by activity domain (occupation, sport, household), there was a trend (non-significant) for the highest quintile of occupational force, but not sport or household, to be associated with hip OA., Conclusions: A newly proposed measure of lifetime mechanical hip force was used to estimate the risk of self-reported, medically-diagnosed hip OA. While there are important limitations, this prospective study suggests that lifelong physical activity is generally safe. Very high levels of lifetime force from all domains combined, and in particular from occupational forces, may be important in the etiology of hip OA., (Copyright © 2011 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objective: This study examines the determinants of patients' side effects from arthritis medication. Proposed predictors were patients' beliefs about medications, objective disease activity, treatment regimen, and psychiatric and rheumatoid arthritis symptoms., Methods: In a longitudinal design, 100 rheumatoid arthritis outpatients were investigated at baseline and again at 6 months after receiving both pharmacologic and psychosocial treatment., Results: Multivariate analyses showed no influence of disease status, type of treatment, or psychiatric or arthritis symptoms on side effects. Heightened concerns about arthritis medication at baseline predicted side effects at baseline (partial correlation r = 0.37, P < 0.001) and at 6 months (partial correlation r = 0.25, P < 0.001) after controlling for relevant disease- and treatment-related variables. In a cross-lagged panel analysis, prior experience with side effects from arthritis medication was ruled out as a cause of heightened concerns, indicating that negative beliefs genuinely contribute to side effects. A comparison of patients who did and did not start new medications showed no difference in side effects in patients with positive beliefs about medications, but led to significantly more side effects in patients with negative beliefs., Conclusion: Patients' beliefs about arthritis medications were stable and consistently associated with side effects. Patients with greater concerns about their arthritis medications are at higher risk for developing side effects, especially when starting new drugs. Identifying those patients is important to avoid premature drug discontinuation. Research into cause and preventability of negative attitudes to prescribed medicines is needed.

Objectives: The objectives of the study were 1) to assess the effect of cash lottery on participation rates in a web-based study of physical activity and joint health and 2) to compare recruitment via direct e-mail versus advertisement in an online newsletter., Methods: A sample of 1,150 individuals, randomly selected from a database of members of the Canadian Association of Retired Persons (CARP), was e-mailed a request to participate in an online survey, with follow-up e-mails after 1 and 2 weeks. The sample was randomly split into two groups. Half the sample was offered entry into a cash draw with a $500 grand prize and five $100 prizes, whereas the other half was not offered any incentive. In addition, a brief advertisement about the survey (without an incentive) was placed in an online newsletter that was circulated to 14,000 randomly selected CARP members., Results: In the incentive group, 305 (53.0%) clicked on the hyperlink and visited the website and 84 (14.6%) completed the survey. In the group who received no incentive, 280 (48.7%) clicked on the link and 59 (10.3%) completed the survey. Of those who received the online newsletter, 492 (3.5%) visited the website and 106 (0.76%) completed the survey., Conclusion: A relatively modest financial incentive in the form of a cash lottery significantly increased participation rates in an online health survey. Recruitment through a newsletter advertisement had a very low yield compared to direct e-mail.

Where risk factors have been identified in knee and hip osteoarthritis (OA), with few exceptions, no prevention strategies have proven beneficial. The major risk factors for knee OA are advanced age, injury and obesity. However, there is limited or no evidence that they are modifiable or to what degree modifying them is effective in preventing development of knee OA or in preventing symptoms and progressive disease in persons with early OA. The notable exception is the growing epidemic of (sports) injury related knee OA. This review details the biological and clinical data indicating the efficacy of interventions targeting neuromuscular and biomechanical factors that make this subset of OA an attractive public health target, and highlights research opportunities for the future.

Skin maintenance and healing after wounding requires complex epithelial-mesenchymal interactions purportedly mediated by growth factors and cytokines. We show here that, for wound healing, transforming growth factor-beta-activated kinase 1 (TAK1) in keratinocytes activates von Hippel-Lindau tumor suppressor expression, which in turn represses the expression of platelet-derived growth factor-B (PDGF-B), integrin beta1, and integrin beta5 via inhibition of the Sp1-mediated signaling pathway in the keratinocytes. The reduced production of PDGF-B leads to a paracrine-decreased expression of hepatocyte growth factor in the underlying fibroblasts. This TAK1 regulation of the double paracrine PDGF/hepatocyte growth factor signaling can regulate keratinocyte cell proliferation and is required for proper wound healing. Strikingly, TAK1 deficiency enhances cell migration. TAK1-deficient keratinocytes displayed lamellipodia formation with distinct microspike protrusion, associated with an elevated expression of integrins beta1 and beta5 and sustained activation of cdc42, Rac1, and RhoA. Our findings provide evidence for a novel homeostatic control of keratinocyte proliferation and migration mediated via TAK1 regulation of von Hippel-Lindau tumor suppressor. Dysfunctional regulation of TAK1 may contribute to the pathology of non-healing chronic inflammatory wounds and psoriasis.

Brain-derived neurotrophic factor (BDNF) has been strongly implicated in the synaptic plasticity, neuronal survival and pathophysiology of depression. Lithium and valproic acid (VPA) are two primary mood-stabilizing drugs used to treat bipolar disorder. Treatment of cultured rat cortical neurons with therapeutic concentrations of LiCl or VPA selectively increased the levels of exon IV (formerly rat exon III)-containing BDNF mRNA, and the activity of BDNF promoter IV. Surprisingly, lithium- or VPA-responsive element(s) in promoter IV resides in a region upstream from the calcium-responsive elements (CaREs) responsible for depolarization-induced BDNF induction. Moreover, activation of BDNF promoter IV by lithium or VPA occurred in cortical neurons depolarized with KCl, and deletion of these three CaREs did not abolish lithium- or VPA-induced activation. Lithium and VPA are direct inhibitors of glycogen synthase kinase-3 (GSK-3) and histone deacetylase (HDAC), respectively. We showed that lithium-induced activation of promoter IV was mimicked by pharmacological inhibition of GSK-3 or short interfering RNA (siRNA)-mediated gene silencing of GSK-3alpha or GSK-3beta isoforms. Furthermore, treatment with other HDAC inhibitors, sodium butyrate and trichostatin A, or transfection with an HDAC1-specific siRNA also activated BDNF promoter IV. Our study demonstrates for the first time that GSK-3 and HDAC are respective initial targets for lithium and VPA to activate BDNF promoter IV, and that this BDNF induction involves a novel responsive region in promoter IV of the BDNF gene. Our results have strong implications for the therapeutic actions of these two mood stabilizers.

Background: The main aim of the present study was to compare the occurrence of inflammatory cell infiltrates in the aorta, a vessel with a high occurrence of atherosclerosis, with that in the saphenous vein (SV) and internal mammary artery (IMA), which are protected from atherosclerosis., Methods and Results: Samples from the aorta, SV, and IMA of 65 patients with inflammatory rheumatic diseases (IRD) and from 51 control patients undergoing coronary artery bypass graft surgery were examined for the presence and location of inflammatory cell infiltrates and atherosclerotic lesions. Mononuclear cell infiltrates (MCIs) in the media or adventitia were observed in 2% IMAs, 17% SVs, and 35% aortic specimens (SV vs IMA: p=0.006; SV vs aorta: p=0.001). Atherosclerotic lesions were present in none IMA, 3% SVs and 18% aortic specimens. IRD and smoking increased the odds of MCI in the aorta (odds ratio (OR)=3.6, 95% confidence interval (CI): 1.6-8.5 and OR=4.0, 95% CI: 1.5-10.9), but not in the SV or IMA., Conclusions: The occurrence of medial and adventitial MCI in the aorta, SV, and IMA paralleled each vessel's susceptibility to atherosclerosis: it was highest in the aorta and lowest in IMA. Local vascular inflammation may be involved in atherogenesis, and influence the patency of vascular grafts.

Objective: Some evidence suggests that perinatal factors, including birth weight and breastfeeding, may influence the occurrence of autoimmune rheumatic diseases. However, few studies have investigated these factors in patients with systemic lupus erythematosus (SLE). Therefore, we evaluated the role of birth weight, being breastfed, and preterm birth on the incidence of SLE in participants in the Nurses' Health Study (NHS) and the Nurses' Health Study II (NHSII)., Methods: We studied 87,411 NHS participants and 98,413 NHSII participants without SLE at baseline who provided information on perinatal exposures. Among these women, during 26 (NHS) and 14 (NHSII) years of followup, 222 incident SLE cases were confirmed (136 NHS and 86 NHSII) by medical record review using American College of Rheumatology criteria. We used stratified Cox models to estimate the association of perinatal factors with SLE, adjusting for race, early passive cigarette smoke exposure, and parents' occupation. A random-effects meta-analysis was used to compute combined estimates across the 2 cohorts., Results: After adjustment for multiple potential confounders, high birth weight (> or =10 pounds) was associated with increased rates of SLE compared with normal birth weight (7-8.5 pounds; rate ratio [RR] 2.7, 95% confidence interval [95% CI] 1.2-5.9), as was being born > or =2 weeks preterm (RR 1.9, 95% CI 1.2-3.0); however, being breastfed was not (RR 0.8, 95% CI 0.6-1.1)., Conclusion: Birth weight > or =10 pounds and preterm birth were both positively associated with incident SLE among women.