Increasing levels of circulating Th17 cells and interleukin-17 in rheumatoid arthritis patients with an inadequate response to anti-TNF-α therapy

Introduction: The objective of this study was to investigate the effects of tumor necrosis factor (TNF)-alpha inhibitors on circulating T helper-type 17 (Th17) cells and Th17-related cytokines in patients with rheumatoid arthritis (RA). Methods: The frequencies of circulating Th17 cells and serum levels of Th17-related cytokines were determined using flow cytometry analysis and ELISA, respectively, in 48 RA patients both before (baseline) and six months after anti-TNF-alpha therapy. Therapeutic response was evaluated using European League Against Rheumatism (EULAR) response criteria. Results: Significantly higher baseline frequencies of circulating Th17 cells and serum levels of interleukin (IL)-6, IL17, IL-21, IL-23 and TNF-alpha were observed in active RA patients than in 12 healthy controls (all P < 0.001). After anti-TNF-alpha therapy, 36 patients (75%) were EULAR responders (20 good responders and 16 moderate responders) and 12 (25.0%) were non-responders. The mean levels of circulating Th17 cells and IL-17 significantly decreased (1.13% vs. 0.79%; 43.1 pg/ml vs. 27.8 pg/ml; respectively, both P < 0.001) in parallel with clinical remission in responders. Levels of IL-6, IL-21, IL-23 and TNF-alpha were significantly decreased after anti-TNF-alpha therapy in responders. In contrast, the mean levels of circulating Th17 cells and IL-17 significantly increased after anti-TNF-alpha therapy (2.94% vs. 4.23%; 92.1 pg/ml vs. 148.6 pg/ml; respectively, both P < 0.05) in non-responders. Logistic regression analysis identified a high baseline level of IL-17 as a significant predictor of poor therapeutic response. Conclusions: The beneficial effect of anti-TNF-alpha therapy might involve a decrease in Th17-related cytokines in responders, whereas rising levels of circulating Th17-cells and IL-17 were observed in patients with an inadequate response to anti-TNF-alpha therapy

Probing structure-function relationships of serine hydrolases and proteases with carbamate and thiocarbamate inhibitors

Benzene-1,3-di-N-n-octylcarbamate (1), benzene-1-hydroxyl-3-N-n-octylcarbamate (2), benzene-1,3-di-N-n-ocztylthiocarbamate (3), and benzene-1-hydroxyl-3-N-n-octylthiocarbamate (4) are synthesized from 1,3-benzene-diol and are characterized as the pseudo-substrate inhibitors of acetylcholinesterase, butyrylcholinesterase, cholesterol esterase, lipase, trypsin, and chymotrypsin. For these six enzyme inhibitions by 1-4, the pK(i) values are linearly correlated with their log k(i) values - Bronsted plots. Therefore, 1-4 inhibit these enzymes through a common mechanism. Moreover, both pK(i) and log k(i) values for the inhibitions by 1,3, and 4 are linearly correlated with both pK(i) and log k(i) values for the inhibitions by 2, respectively. Thus, the pK(i) values for the inhibitions by 2 are defined as the nucleophilicity constants of these enzymes (n(enzyme)). The log k(2) values for the inhibitions by 1-4 are also linearly correlated with the n(enzyme) values. Therefore, the nucleophilicity for serine hydrolases and proteases toward 1-4 also applies the Swain-Scott correlations

Combination of transverse myelitis and arachnoiditis in cauda equina syndrome of long-standing ankylosing spondylitis: MRI features and its role in clinical management

The cauda equina syndrome (CES) is a rare neurological complication of ankylosing spondylitis (AS). Imaging diagnosis of CES in long-standing AS patients (CES-AS) using myelography, computed tomography (CT), and magnetic resonance imaging (MRI) were reported in the literature. They, however, demonstrate only the chronic abnormalities of CES-AS, i.e., dural ectasia, dorsal dural diverticula, and selective bone erosion at the posterior elements of the vertebrae. To our knowledge, imaging features of acute intradural inflammation in CES-AS were not described. We report a patient of CES-AS in whom MRI disclosed acute transverse myelitis and arachnoiditis along the lower spinal cord, and discuss the pathogenesis of CES-AS and the role of MRI in clinical management

Quenched chiral logarithms in lattice QCD with exact chiral symmetry

We examine quenched chiral logarithms in lattice QCD with overlap Dirac quark. For 100 gauge configurations generated with the Wilson gauge action at $\beta = 5.8$ on the $8^3 \times 24$ lattice, we compute quenched quark propagators for 12 bare quark masses. The pion decay constant is extracted from the pion propagator, and from which the lattice spacing is determined to be 0.147 fm. The presence of quenched chiral logarithm in the pion mass is confirmed, and its coefficient is determined to be $\delta = 0.203 \pm 0.014$, in agreement with the theoretical estimate in quenched chiral perturbation theory. Further, we obtain the topological susceptibility of these 100 gauge configurations by measuring the index of the overlap Dirac operator. Using a formula due to exact chiral symmetry, we obtain the $\eta'$ mass in quenched chiral perturbation theory, $m_{\eta'} = (901 \pm 64)$ Mev, and an estimate of $\delta = 0.197 \pm 0.027$, which is in good agreement with that determined from the pion mass.Comment: 24 pages, 6 EPS figures; v2: some clarifications added, to appear in Physical Review

Haplotyping the human leukocyte antigen system from single chromosomes

We describe a method for determining the parental HLA haplotypes of a single individual without recourse to conventional segregation genetics. Blood samples were cultured to identify and sort chromosome 6 by bivariate flow cytometry. Single chromosome 6 amplification products were confirmed with a single nucleotide polymorphism (SNP) array and verified by deep sequencing to enable assignment of both alleles at the HLA loci, defining the two haplotypes. This study exemplifies a rapid and efficient method of haplotyping that can be applied to any chromosome pair, or indeed all chromosome pairs, using a single sorting operation. The method represents a cost-effective approach to complete phasing of SNPs, which will facilitate a deeper understanding of the links between SNPs, gene regulation and protein function

Chlamydia trachomatis ompA Variants in Trachoma: What Do They Tell Us?

Trachoma is an important cause of blindness resulting from transmission of the bacterium Chlamydia trachomatis. One way to understand better how this infection is transmitted and how the human immune system controls it is to study the strains of bacteria associated with infection. Comparing strains before and after treatment might help us learn if someone has a new infection or the same one as before. Identifying differences between disease-causing strains should help us understand how infection leads to disease and how the human host defences work. We chose to study variation in the chlamydial gene ompA because it determines the protein MOMP, one of the leading candidates for inclusion in a vaccine to prevent trachoma. If immunity to MOMP is important in natural trachoma infections, we would expect to find evidence of this in the way the strains varied. We did not find this, but instead found that two common strains seemed to cause different types of disease. Although their MOMPs were very slightly different, this did not really explain the differences. We conclude that methods of typing strains going beyond the ompA gene will be needed to help us understand the interaction between Chlamydia and its human host

Identification of alpha-enolase as an autoantigen in lung cancer: Its overexpression is associated with clinical outcomes

Purpose: Although existence of humoral immunity has been previously shown in malignant pleural effusions, only a limited number of immunogenic tumor-associated antigens (TAA) have been identified and associated with lung cancer. In this study, we intended to identify more TAAs in pleural effusion-derived tumor cells. Experimental Design: Using morphologically normal lung tissues as a control lysate in Western blotting analyses, 54 tumor samples were screened with autologous effusion antibodies. Biochemical purification and mass spectrometric identification of TAAs were done using established effusion tumor cell lines as antigen sources. We identified a p48 antigen as of-enolase (ENO1). Semiquantitative immunohistochemistry was used to evaluate expression status of ENO1 in the tissue samples of 80 patients with non-small cell lung cancer (NSCLC) and then correlated with clinical variables. Results: Using ENO1-specifc antiserum, up-regulation of ENO1 expression in effusion tumor cells from 11 of 17 patients was clearly observed compared with human normal lung primary epithelial and non-cancer-associated effusion cells. Immunohistochemical studies consistently showed high level of ENO1 expression in all the tumors we have examined thus far. Log-rank and Cox's analyses of ENO1 expression status revealed that its expression level in primary tumors was a key factor contributing to overall- and progression-free survivals of patients (P < 0.05). The same result was also obtained in the early stage of NSCLC patients, showing that tumors expressing relatively higher ENO1 level were tightly correlated with poorer survival outcomes. Conclusions: Our data strongly support a prognostic role of ENO1 in determining tumor malignancy of patients with NSCLC

The Cancer Genome Atlas Comprehensive Molecular Characterization of Renal Cell Carcinoma

Renal cell carcinoma(RCC) is not a single disease, but several histologically defined cancers with different genetic drivers, clinical courses, and therapeutic responses. The current study evaluated 843 RCC from the three major histologic subtypes, including 488 clear cell RCC, 274 papillary RCC, and 81 chromophobe RCC. Comprehensive genomic and phenotypic analysis of the RCC subtypes reveals distinctive features of each subtype that provide the foundation for the development of subtype-specific therapeutic and management strategies for patients affected with these cancers. Somatic alteration of BAP1, PBRM1, and PTEN and altered metabolic pathways correlated with subtype-specific decreased survival, while CDKN2A alteration, increased DNA hypermethylation, and increases in the immune-related Th2 gene expression signature correlated with decreased survival within all major histologic subtypes. CIMP-RCC demonstrated an increased immune signature, and a uniform and distinct metabolic expression pattern identified a subset of metabolically divergent (MD) ChRCC that associated with extremely poor survival

A Networked Sketching Environment for Supporting Collective Creativity

In the early conceptual design, individual designers often make extensive use of sketches to explore design problems. Moreover, within the collaborative design sessions, designers communicate and discuss with each other by sharing their temporary sketches. These private design artifacts are used to externalize ideas and share them with other designers in order to facilitate the performance of design sessions. During such social interaction performance, some abstraction behaviours behind social activities like collective creativity are synchronized. However, the existent tele-communication tools proposed for separated design groups, slightly hold back the activities of collective creativity. It makes designers dedicated just in the table discussion, and negatively influenced on collective creativity sharing. Thus, some private design artifacts became isolated in tele-communicative environments. In order to respect this, we propose an approach that uses the notion of Digital Backchannel to realize the sub-channel communications. In this paper, we also present the implementation of a working prototype of groupware application. Finally, we discussed some points from our studies