Water transport model during CAPD: Determination of parameters

Water transport model during CAPD: Determination of parameters. To minimize the total amount of glucose required for removing the same volume of water as a bolus, a continuous infusion of glucose during CAPD was proposed and studied. Both a computer simulation of water transport through the peritoneal membrane and in vivo assessment with rats were carried out to evaluate the feasibility of the newly proposed mathematical model in which lymphatic drainage of dialysate from the peritoneal cavity to lymphatic system was considered in addition to conventional water transport. Mass transport area coefficients (KA) of 0.041 to 0.063 ml/min/100 g body wt and 0.045 to 0.066 ml/min/100 g body wt were measured for glucose and urea during CAPD with male Wistar rats. Hydraulic conductivity of peritoneal membrane (Lc) was 7.9 × 10-5 to 1.5 × 10-4 ml/min/mm Hg/100 g body wt, which was calculated by a linear relationship between volume and osmotic pressure. Simulated water transport model using determined parameters indicated that the ratio of lymphatic transport to convective transport would be changeable in CAPD with glucose infusion at varying infusion rates, while up to 16% of the glucose uptake could be reduced compared with that of the common CAPD at the same dwell time

A Possible Anticancer Agent, Type III Interferon, Activates Cell Death Pathways and Produces Antitumor Effects

Recently identified interleukin-28 and -29 belong to a novel type III interferon (IFN) family, which could have distinct biological properties from type I and II IFNs. Type I IFNs, IFN-α/β, have been clinically applied for treating a certain kind of malignancies for over 30 years, but a wide range of the adverse effects hampered the further clinical applications. Type III IFNs, IFN-λs, have similar signaling pathways as IFN-α/β and inhibits proliferation of tumor cells through cell cycle arrest or apoptosis. Restricted patterns of type III IFN receptor expression in contrast to ubiquitously expressed IFN-α/β receptors suggest that type III IFNs have limited cytotoxicity to normal cells and can be a possible anticancer agent. In this paper, we summarize the current knowledge on the IFN-λs-mediated tumor cell death and discuss the functional difference between type I and III IFNs

Conventional versus Rapid Glucocorticoid Tapering in Severe Systemic Lupus Erythematosus Patients: A Non-Blind, Randomized Controlled Trial

Glucocorticoids (GCs) have long played a central role in the treatment of systemic lupus erythematosus (SLE), but these drugs have many adverse effects. We will determine whether rapid weekly GC tapering is non-inferior to conventional biweekly tapering in patients with severe SLE. This is a randomized, open-label, multicenter controlled trial. The primary outcome is the relapse-free survival rate at 52 weeks. The main secondary outcome is the prevalence of the Lupus Low Disease Activity State at 52 weeks. The trial will determine the optimal method of tapering GCs in patients with severe SLE

Conventional-dose Versus Half-dose Sulfamethoxazole-trimethoprim for the Prophylaxis of Pneumocystis Pneumonia in Patients with Systemic Rheumatic Disease: A Non-blind, Randomized Controlled Trial

Pneumocystis pneumonia (PCP) due to Pneumocystis jirovecii infection is the leading cause of fatal opportunistic infections in immunocompromised patients. We will determine whether a daily sulfamethoxazole-trimethoprim (SMX/TMP) dose of 200/40 mg was non-inferior to 400/80 mg for PCP prevention in patients with systemic rheumatic disease under immunosuppressive therapy. This is a randomized, open-label, multicenter controlled trial. The primary outcome is the rate of PCP prevention at 52 weeks. The secondary outcome is the discontinuation rate of SMX/TMP. The trial will evaluate the optimal dose of SMX/TMP for PCP prevention in patients with systemic rheumatic disease under immunosuppressive therapy

Porphyromonas gingivalis Outer Membrane Vesicles Stimulate Gingival Epithelial Cells to Induce Pro-Inflammatory Cytokines via the MAPK and STING Pathways

Porphyromonas gingivalis (Pg) is a keystone pathogen associated with chronic periodontitis and produces outer membrane vesicles (OMVs) that contain lipopolysaccharide (LPS), gingipains, and pathogen-derived DNA and RNA. Pg-OMVs are involved in the pathogenesis of periodontitis. Pg-OMV-activated pathways that induce the production of the pro-inflammatory cytokines, interleukin (IL)-6, and IL-8 in the human gingival epithelial cell line, OBA-9, were investigated. The role of mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-κB in levels of Pg-OMV-induced pro-inflammatory cytokines was investigated using Western blot analysis and specific pathway inhibitors. Pg-OMVs induced IL-6 and IL-8 production via the extracellular signal-regulated kinase (Erk) 1/2, c-Jun N-terminal kinase (JNK), p38 MAPK, and NF-κB signaling pathways in OBA-9 cells. In addition, the stimulator of interferon genes (STING), an essential innate immune signaling molecule, was triggered by a cytosolic pathogen DNA. Pg-OMV-induced IL-6 and IL-8 mRNA expression and production were significantly suppressed by STING-specific small interfering RNA. Taken together, these results demonstrated that Pg-OMV-activated Erk1/2, JNK, p38 MAPK, STING, and NF-κB signaling pathways resulting in increased IL-6 and IL-8 expression in human gingival epithelial cells. These results suggest that Pg-OMVs may play important roles in periodontitis exacerbation by stimulating various pathways

Augmented expression of cardiac ankyrin repeat protein is induced by pemetrexed and a possible marker for the pemetrexed resistance in mesothelioma cells

BackgroundPemetrexed (PEM) is an anti-cancer agent targeting DNA and RNA synthesis, and clinically in use for mesothelioma and non-small cell lung carcinoma. A mechanism of resistance to PEM is associated with elevated activities of several enzymes involved in nucleic acid metabolism.MethodsWe established two kinds of PEM-resistant mesothelioma cells which did not show any increase of the relevant enzyme activities. We screened genes enhanced in the PEM-resistant cells with a microarray analysis and confirmed the expression levels with Western blot analysis. A possible involvement of the candidates in the PEM-resistance was examined with a WST assay after knocking down the expression with si-RNA. We also analyzed a mechanism of the up-regulated expression with agents influencing AMP-activated protein kinase (AMPK) and p53.ResultsWe found that expression of cardiac ankyrin repeat protein (CARP) was elevated in the PEM-resistant cells with a microarray and Western blot analysis. Down-regulation of CARP expression with si-RNA did not however influence the PEM resistance. Parent and PEM-resistant cells treated with PEM increased expression of CARP, AMPK, p53 and histone H2AX. The CARP up-regulation was however irrelevant to the p53 genotypes and not induced by an AMPK activator. Augmented p53 levels with nutlin-3a, an inhibitor for p53 degradation, and DNA damages were not always associated with the enhanced CARP expression.ConclusionsThese data collectively suggest that up-regulated CARP expression is a potential marker for development of PEM-resistance in mesothelioma and that the PEM-mediated enhanced expression is not directly linked with immediate cellular responses to PEM

An image cytometric technique is a concise method to detect adenoviruses and host cell proteins and to monitor the infection and cellular responses induced

BackgroundGenetically modified adenoviruses (Ad) with preferential replications in tumor cells have been examined for a possible clinical applicability as an anti-cancer agent. A simple method to detect viral and cellular proteins is valuable to monitor the viral infections and to predict the Ad-mediated cytotoxicity.MethodsWe used type 5 Ad in which the expression of E1A gene was activated by 5′-regulatory sequences of genes that were augmented in the expression in human tumors. The Ad were further modified to have the fiber-knob region replaced with that derived from type 35 Ad. We infected human mesothelioma cells with the fiber-replaced Ad, and sequentially examined cytotoxic processes together with an expression level of the viral E1A, hexon, and cellular cleaved caspase-3 with image cytometric and Western blot analyses.ResultsThe replication-competent Ad produced cytotoxicity on mesothelioma cells. The infected cells expressed E1A and hexon 24 h after the infection and then showed cleavage of caspase-3, all of which were detected with image cytometry and Western blot analysis. Image cytometry furthermore demonstrated that increased Ad doses did not enhance an expression level of E1A and hexon in an individual cell and that caspase-3-cleaved cells were found more frequently in hexon-positive cells than in E1A-positive cells. Image cytometry thus detected these molecular changes in a sensitive manner and at a single cell level. We also showed that an image cytometric technique detected expression changes of other host cell proteins, cyclin-E and phosphorylated histone H3 at a single cell level.ConclusionsImage cytometry is a concise procedure to detect expression changes of Ad and host cell proteins at a single cell level, and is useful to analyze molecular events after the infection