Anti-TNF-α Therapies in Systemic Lupus Erythematosus

Tumor necrosis factor (TNF)-α is not just a proinflammatory cytokine. It has also been proposed to be an immunoregulatory molecule that can alter the balance of T regulatory cells. Anti-TNF-α therapies have been provided clinical benefit to many patients and introduced for treating moderate to severe rheumatoid arthritis, Crohn's disease, and other chronic inflammatory disorders. However, their use also is accompanied by new or aggravated forms of autoimmunity, such as formation of autoantibodies, including antinuclear antibodies (ANAs), antidouble-stranded DNA (dsDNA) antibodies, and anticardiolipin antibodies (ACL). Systemic lupus erythematosus (SLE) is a disease with autoimmune disturbance and inflammatory damage. The role of TNF-α in human SLE is controversial. Here we review the role of TNF-α in the pathophysiological processes of SLE and the likely effects of blocking TNF-α in treatment of SLE

A new convergence analysis for the Volterra series representation of nonlinear systems

The convergence of the Volterra series representation of nonlinear systems is the fundamental requirement for the analysis of nonlinear systems in the frequency domain. In the present study, a new criterion is derived to determine the convergence of the Volterra series representation of nonlinear systems described by a NARX (Nonlinear Auto Regressive with eXegenous input) model. The analysis is performed based on a new function known as Generalized Output Bound Characteristic Function (GOBCF), which is defined in terms of the input, output and parameters of the NARX model of nonlinear systems. Compared to the existing results, the new criterion provides a much more rigorous and effective approach to the analysis of the convergence conditions and properties of the Volterra series representation of nonlinear systems. Two case studies have been used to demonstrate the effectiveness of the new convergence analysis criterion and the advantages of the new analysis over those produced by existing approaches

The Effects of Linear and Nonlinear Characteristic Parameters on the Output Frequency Responses of Nonlinear Systems: The Associated Output Frequency Response Function

In the present study, a new concept known as the Associated Output Frequency Response Function (AOFRF) is introduced to facilitate the analysis of the effects of both linear and nonlinear characteristic parameters on the output frequency responses of nonlinear systems. Based on the AOFRF concept, the study has shown, for the first time, that the output frequency responses of a wide class of nonlinear systems that are described by the NARX (Nonlinear Auto Regressive with eXegenous input) model can be represented by a polynomial function of both the system linear and nonlinear characteristic parameters of interests to the system analysis. Moreover, an efficient algorithm is derived to determine the structure and coefficients of the AOFRF based representation for system output frequency responses. Finally, a case study is provided to demonstrate the effectiveness and advantages of the new AOFRF based representation and the implication of the result to the analysis and design of nonlinear systems in the frequency domain

Aspect construal in Mandarin: a usage-based constructionist perspective on LE

Despite extensive research efforts to explain the Mandarin Chinese particle le, confusion persists in the absence of a unitary theory and sufficient empirical evidence. This study provides a unitary account of le by adopting a usage-based constructionist approach, one that liberates grammatical aspect from, and is able to accommodate, lexical aspect. We argue that le participates in two distinct family resemblance constructions of aspect construal associated with two distinct sentential positions. The clause-internal le construction construes the closing or final boundary of an event and the clause-final le construction construes the opening or initial boundary of an event. Corpus analysis showed that the two aspect constructions have distinct patterns in natural language uses that are consistent with the proposed construals. Results from elicited response data showed that native speakers paid attention to construction-level formal and semantic cues in making family resemblance judgments about tokens of the two constructions. This study has both theoretical and methodological implications for crosslinguistic research on grammatical aspect in relation to lexical aspect and for usage-based constructionist approaches to grammatical categories beyond aspect.</p

Hypophosphatemia during continuous veno-venous hemofiltration is associated with mortality in critically ill patients with acute kidney injury

INTRODUCTION: The primary aim of this study was to determine whether hypophosphatemia during continuous veno-venous hemofiltration (CVVH) is associated with the global outcome of critically ill patients with acute kidney injury (AKI). METHODS: 760 patients diagnosed with AKI and had received CVVH therapy were retrospectively recruited. Death during the 28-day period and survival at 28 days after initiation of CVVH were used as endpoints. Demographic and clinical data including serum phosphorus levels were recorded along with clinical outcome. Hypophosphatemia was defined according to the colorimetric method as serum phosphorus levels < 0.81 mmol/L (2.5 mg/dL), and severe hypophosphatemia was defined as serum phosphorus levels < 0.32 mmol/L (1 mg/dL). The ratio of CVVH therapy days with hypophosphatemia over total CVVH therapy days was calculated to reflect the persistence of hypophosphatemia. RESULTS: The Cox proportional hazard survival model analysis indicated that the incidence of hypophosphatemia or even severe hypophosphatemia was not associated with 28-day mortality independently (p = 0.700). Further analysis with the sub-cohort of patients who had developed hypophosphatemia during the CVVH therapy period indicated that the mean ratio of CVVH therapy days with hypophosphatemia over total CVVH therapy days was 0.58, and the ratio independently associated with the global outcome. Compared with the patients with low ratio (< 0.58), those with high ratio (≥ 0.58) conferred a 1.451-fold increase in 28-day mortality rate (95% CI 1.103–1.910, p = 0.008). CONCLUSIONS: Hypophosphatemia during CVVH associated with the global clinical outcome of critically ill patients with AKI. The ratio of CVVH therapy days with hypophosphatemia over total CVVH therapy days was independently associated with the 28-day mortality, and high ratio conferred higher mortality rate

Elevated magmatic sulfur and chlorine contents in ore-forming magmas at the Red Chris porphyry Cu-Au deposit, Northern British Columbia, Canada

The Red Chris porphyry Cu-Au deposit is located in the Stikinia island-arc terrane in northwest British Columbia. It is hosted by the Red Stock, which has four phases of porphyry intrusions: P1, P2E, P2L, and P3. New U-Pb dating of zircon shows that these intrusions were emplaced at 211.6 ± 1.3 Ma (MSWD = 0.85), 206.0 ± 1.2 Ma (MSWD = 1.5), 203.6 ± 1.8 Ma (MSWD = 1.5), and 201.7 ± 1.2 Ma (MSWD = 1.05), respectively. The ore-forming event at Red Chris was a short-lived event at 206.1 ± 0.5 Ma (MSWD = 0.96; weighted average age of three Re-Os analyses), implying a duration of <1 m.y., as defined by the uncertainty range. This mineralization age coincides with the emplacement age of the P2E porphyry, and is consistent with crosscutting relationships that suggest P2E was the main syn-mineralization intrusion. Zircons from P1 to P3 porphyry rocks have consistently high EuN/EuN* ratios (mostly > 0.4), indicating that their associated magmas were moderately oxidized. The magmatic water contents estimated from plagioclase and amphibole compositions suggest H2O contents of ~5 wt. %. Taken together, the P1 to P3 porphyries are interpreted to be moderately oxidized and hydrous. The four phases of porphyries are differentiated by sulfur and chlorine contents. The SO3 contents of igneous apatite microphenocrysts from the mineralization-related P2 porphyries are higher (P2E: 0.30 ± 0.13 wt. %, n = 34; P2L: 0.29 ± 0.18 wt. %, n = 100) than those from the pre-mineralization P1 (0.11 ± 0.03 wt. %, n = 34) and postmineralization P3 porphyries (0.03 ± 0.01 wt. %, n = 13). The chlorine contents in apatite grains from the P2E and P2L porphyries are 1.18 ± 0.37 (n = 34) and 1.47 ± 0.28 wt. % (n = 100), also higher than those from P1 (0.51 ± 0.3 wt. % Cl, n = 34) and P3 (0.02 ± 0.02 wt. % Cl, n = 17). These results imply that the sulfur and chlorine contents of the P2E and P2L magmas were higher than in the P1 and P3 magmas, suggesting that elevated magmatic S-Cl contents in the P2 porphyries may have been important for ore-formation. Although the process that caused the increase in sulfur and chlorine is not clear, reverse zoning seen in plagioclase phenocrysts from the P2 porphyry, and the occurrence of more mafic compositions in P2L suggest that recharge of the deeper magma chamber by a relatively S-Cl-rich mafic magma may have triggered the ore-forming hydrothermal event

Higher Carbohydrate Antigen 125 Levels Are Associated with Increased Risk of Coronary Heart Disease in Elderly Chinese: A Population-Based Case-Control Study

Background: High carbohydrate antigen 125 (CA-125) level was reported to be associated with some cardiac dysfunctions, such as chronic heart failure, but the relationship between CA-125 level and coronary heart disease (CHD) risk remains unclear. The aim of this study was to explore the potential association in a Chinese older population. Methods: In a population-based case-control study conducted in a Chinese older population, serum CA-125 levels were measured in 1177 diagnosed CHD patients and 3531 age and sex matched control subjects without CHD. Results: Serum CA-125 level was significantly higher in CHD patients than controls (P < 0.001) with adjustment for age, gender, smoking, drinking, BMI, physical activity, hypertension, dyslipidemia, diabetes mellitus, medication history and family history of CHD and myocardial infarction. CHD risk was doubled (OR: 2.10, 95%CI: 1.69-2.60) among subjects in the highest quartile compared to those in the lowest quartile of CA-125 level (Ptrend < 0.001). Furthermore, CA-125 levels were associated with CHD risks in subjects with age over 60 years (OR: 2.19, 95%CI: 1.75-2.73), current smokers (OR: 2.29, 95%CI: 1.50-3.49), current drinkers (OR: 2.35, 95%CI: 1.57-3.53) and subjects with hypertension (OR: 2.04, 95%CI: 1.71-2.43). Conclusions: Elevated serum CA-125 level might be associated with increased risk of coronary heart disease in the Chinese older population. Further investigations are needed to identify the possible biological role of CA-125 in CHD development in the future

Novel norcantharidin-loaded liver targeting chitosan nanoparticles to enhance intestinal absorption

In this paper, two novel liver-targeting nanoparticles, norcantharidin-loaded chitosan nanoparticles (NCTD-CS-NPs) and norcantharidin-associated galactosylated chitosan nanoparticles (NCTD-GC-NPs), were prepared using ionic cross-linkage. The physical properties, particle size, encapsulation efficiency, and drug release characteristics of the nanoparticles were investigated in vitro. To investigate the intestinal absorption mechanisms of the two preparations, a series of experiments was carried out, including in situ circulation method, in vitro everted gut sacs, and Ussing chamber perfusion technique. The absorption rate constants (Ka) of NCTD at different segments were found to be duodenum > jejunum > ileum > colon. The concentration had no distinctive effect on absorption kinetics, suggesting that drug absorption is not dose-dependent. The transport of NCTD was found to be inhibited by P-glycoprotein (P-gp) inhibitor, indicating that NCTD might be the substrate of P-gp. The order of the absorption enhancer effects were as follows: low molecular weight chitosan (CS-8kDa) > high molecular weight chitosan (CS-30kDa) > Poloxamer > sodium dodecyl sulfate (SDS) > sodium deoxycholate (SDCh). The results indicate that the chitosan nanoparticles can improve intestinal absorption of NCTD

Genome-wide association study on serum alkaline phosphatase levels in a Chinese population

Background: Serum alkaline phosphatase (ALP) is a complex phenotype influenced by both genetic and environmental factors. Recent Genome-Wide Association Studies (GWAS) have identified several loci affecting ALP levels; however, such studies in Chinese populations are limited. We performed a GWAS analyzing the association between 658,288 autosomal SNPs and serum ALP in 1,461 subjects, and replicated the top SNPs in an additional 8,830 healthy Chinese Han individuals. The interactions between significant locus and environmental factors on serum ALP levels were further investigated. Results: The association between ABO locus and serum ALP levels was replicated (P = 2.50 × 10-21, 1.12 × 10-56 and 2.82 × 10-27 for SNP rs8176720, rs651007 and rs7025162 on ABO locus, respectively). SNP rs651007 accounted for 2.15% of the total variance of serum ALP levels independently of the other 2 SNPs. When comparing our findings with previously published studies, ethnic differences were observed across populations. A significant interaction between ABO rs651007 and overweight and obesity was observed (FDR for interaction was 0.036); for individuals with GG genotype, those with normal weight and those who were overweight or obese have similar serum ALP concentrations; minor allele A of rs651007 remarkably reduced serum ALP levels, but this effect was attenuated in overweight and obese individuals. Conclusions: Our findings indicate that ABO locus is a major determinant for serum ALP levels in Chinese Han population. Overweight and obesity modifies the effect of ABO locus on serum ALP concentrations