Clinical Significance of Peripheral Blood T Lymphocyte Subsets in Helicobacter pylori-Infected Patients

Background. Helicobacter pylori chronically colonizes gastric/duodenal mucosa and induces gastroduodenal disease and vigorous humoral and cellular immune responses. Methods. In order to clarify the immunological changes induced by this infection, we determined the percentage and, as indicated, ratios of the following cells in peripheral blood of 45 H. pylori-infected patients and 21 control subjects: CD4+ T cell, CD8+ T cells, T helper 1 cells (Th1), T helper 2 cells (Th2), CD4+CD25+ T cells, Foxp3+ regulatory T cells (Tregs), CD4/CD8 ratio, and Th1/Th2 ratio. Results. The percentage of CD8+ T cells was significantly lower in H. pylori-infected patients (mean ± SD; 18.0 ± 7.1%) compared to control subjects (mean ± SD; 23.2 ± 7.8%) (P < 0.05). The CD4/CD8 ratio was significantly higher in H. pylori-infected patients (mean ± SD; 3.1 ± 2.4) compared to control subjects (mean ± SD; 2.1 ± 1.0) (P < 0.05). The Th1/Th2 ratio was significantly lower in H. pylori-infected patients (mean ± SD; 10.0 ± 8.5) compared to control subjects (mean ± SD; 14.5 ± 9.0) (P < 0.05). The percentage of CD4+CD25+ T cells in H. pylori-infected patients (mean ± SD; 13.2 ± 6.2%) was significantly higher than that in control subjects (mean ± SD; 9.8 ± 3.4%) (P < 0.05). However, there was no significant difference in Tregs. Conclusion. Tregs did not decrease, but the activation of humoral immunity and Th2 polarization were observed in the peripheral blood of H. pylori-infected patients. In some cases, these changes may induce systemic autoimmune diseases

Optimization of Ridge Parameters in Multivariate Generalized Ridge Regression by Plug-in Methods

Abstract Generalized ridge (GR) regression for a univariate linear model was proposed simultaneously with ridge regression b

Clinical application of the Personal Dialysis Capacity (PDC) test: Serial analysis of peritoneal function in CAPD patients

Clinical application of the Personal Dialysis Capacity (PDC) test: Serial analysis of peritoneal function in CAPD patients.BackgroundPeritoneal damage has been reported since the beginning of CAPD therapy.MethodsTo clarify the change of peritoneal function in CAPD patients, we used the Personal Dialysis Capacity (PDC) test in 22 patients with 49 serial studies and 14 patients with single studies. The data were expressed at the condition of 2.5% (2.27g/dl of glucose), four times at 2,000 ml/day.ResultsIn the mass analysis, the urea generation rate, creatinine generation rate, PNA/PCR, and water removal via the peritoneum (PD) were kept at the same level for almost eight years, and then gradually decreased. Urine volume and residual renal creatinine clearance (CCr) became zero at six years. On the other hand, PD CCr increased gradually with the time course of CAPD, and therefore the total CCr remained at the level of 6.0ml/min even after six years. Weekly urea KT/V decreased gradually from almost 2.800 to 2.000. The protein loss remained approximately 7.0g/day for the initial five years, then became 6.0g/day, except in five patients who showed levels above 10.0g/day on the first test of PDC. Weekly urea KT/V was correlated with residual renal CCr (P < 0.005), and significantly correlated with total CCr (weekly urea KT/V = -0.2798 + 0.3720 × total CCr; r = 0.915, P < 0.001). In the serial analysis, when the first and the last tests were compared, the urea generation rate increased significantly (mean ± sd, 2.800 ± 3.204 vs. 3.882 ± 3.382; P < 0.0001); however, water removal via PD (1364 ± 887 vs. 813 ± 609; P = 0.021), total ultrafiltration (1762 ± 841 vs. 1124 ± 843; P = 0.042), and weekly urea KT/V (2.285 ± 0.486 vs. 2.112 ± 0.512; P = 0.026) decreased significantly. The delta water removal via PD/duration became negative (-10.03 ± 6.59 ml/week) in all 7 patients after more than four years, however, it was positive (+14.40 ± 7.84 ml/week) in 6 of 10 patients after less than one year.ConclusionThese results suggest that water removal via PD increases within one year, then decreases after four years. The PDC test is useful to evaluate the change of peritoneal function in mass and serial analyses

Gp91phox (NOX2) in classically activated microglia exacerbates traumatic brain injury

<p>Abstract</p> <p>Background</p> <p>We hypothesized that gp91^phox(NOX2), a subunit of NADPH oxidase, generates superoxide anion (O₂^-) and has a major causative role in traumatic brain injury (TBI). To evaluate the functional role of gp91^phoxand reactive oxygen species (ROS) on TBI, we carried out controlled cortical impact in gp91^phoxknockout mice (gp91^phox-/-). We also used a microglial cell line to determine the activated cell phenotype that contributes to gp91^phoxgeneration.</p> <p>Methods</p> <p>Unilateral TBI was induced in gp91^phox-/-and wild-type (Wt) mice (C57/B6J) (25-30 g). The expression and roles of gp91^phoxafter TBI were investigated using immunoblotting and staining techniques. Levels of O₂^-and peroxynitrite were determined <it>in situ </it>in the mouse brain. The activated phenotype in microglia that expressed gp91^phoxwas determined in a microglial cell line, BV-2, in the presence of IFNγ or IL-4.</p> <p>Results</p> <p>Gp91^phoxexpression increased mainly in amoeboid-shaped microglial cells of the ipsilateral hemisphere of Wt mice after TBI. The contusion area, number of TUNEL-positive cells, and amount of O₂^-and peroxynitrite metabolites produced were less in gp91^phox-/-mice than in Wt. In the presence of IFNγ, BV-2 cells had increased inducible nitric oxide synthase and nitric oxide levels, consistent with a classical activated phenotype, and drastically increased expression of gp91^phox.</p> <p>Conclusions</p> <p>Classical activated microglia promote ROS formation through gp91^phoxand have an important role in brain damage following TBI. Modulating gp91^phoxand gp91^phox-derived ROS may provide a new therapeutic strategy in combating post-traumatic brain injury.</p

Structural basis for improved efficacy of therapeutic antibodies on defucosylation of their Fc glycans

Removal of the fucose residue from the N-glycans of the Fc portion of immunoglobulin G (IgG) results in a dramatic enhancement of antibody-dependent cellular cytotoxicity (ADCC) through improved affinity for Fcγ receptor IIIa (FcγRIIIa). Here, we present the 2.2-Å structure of the complex formed between nonfucosylated IgG1-Fc and a soluble form of FcγRIIIa (sFcγRIIIa) with two N-glycosylation sites. The crystal structure shows that one of the two N-glycans of sFcγRIIIa mediates the interaction with nonfucosylated Fc, thereby stabilizing the complex. However, fucosylation of the Fc N-glycans inhibits this interaction, because of steric hindrance, and furthermore, negatively affects the dynamics of the receptor binding site. Our results offer a structural basis for improvement in ADCC of therapeutic antibodies by defucosylation

The Fab portion of immunoglobulin G contributes to its binding to Fcγ receptor III

Most cells active in the immune system express receptors for antibodies which mediate a variety of defensive mechanisms. These receptors interact with the Fc portion of the antibody and are therefore collectively called Fc receptors. Here, using high-speed atomic force microscopy, we observe interactions of human, humanized, and mouse/human-chimeric immunoglobulin G1 (IgG1) antibodies and their cognate Fc receptor, FcγRIIIa. Our results demonstrate that not only Fc but also Fab positively contributes to the interaction with the receptor. Furthermore, hydrogen/deuterium exchange mass spectrometric analysis reveals that the Fab portion of IgG1 is directly involved in its interaction with FcγRIIIa, in addition to the canonical Fc-mediated interaction. By targeting the previously unidentified receptor-interaction sites in IgG-Fab, our findings could inspire therapeutic antibody engineering

The Satb1 Protein Directs Hematopoietic Stem Cell Differentiation toward Lymphoid Lineages

SummaryHow hematopoietic stem cells (HSCs) produce particular lineages is insufficiently understood. We searched for key factors that direct HSC to lymphopoiesis. Comparing gene expression profiles for HSCs and early lymphoid progenitors revealed that Satb1, a global chromatin regulator, was markedly induced with lymphoid lineage specification. HSCs from Satb1-deficient mice were defective in lymphopoietic activity in culture and failed to reconstitute T lymphopoiesis in wild-type recipients. Furthermore, Satb1 transduction of HSCs and embryonic stem cells robustly promoted their differentiation toward lymphocytes. Whereas genes that encode Ikaros, E2A, and Notch1 were unaffected, many genes involved in lineage decisions were regulated by Satb1. Satb1 expression was reduced in aged HSCs with compromised lymphopoietic potential, but forced Satb1 expression partly restored that potential. Thus, Satb1 governs the initiating process central to the replenishing of lymphoid lineages. Such activity in lymphoid cell generation may be of clinical importance and useful to overcome immunosenescence

Seafood, Serum Liver Enzymes, PFOS and PFOA in Blood

Objective: Perfluorooctanesulfonate (PFOS) and perfluorooctanoate (PFOA) have been shown to accumulate in the human body. The purpose of the present study was to examine the factors associated with the blood levels of PFOS and PFOA. Methods: A cross-sectional study was performed on 307 men and 301 women (aged 16−76 years) living in 15 prefectures in Japan. Blood levels of PFOS and PFOA were measured by liquid chromatography-mass spectrometry. Hepatic enzymes (γ-GTP, GOT, and GPT) and ω-3 polyunsaturated fatty acids (DHA and EPA) levels in serum were also measured. Associations between the levels of PFOS and PFOA in blood and the intake frequency of 41 kinds of dishes, foods and beverages and the serum levels of liver enzymes and ω-3 polyunsaturated fatty acids were examined using rank correlations. Results: Frequency of intake of boiled fish in broth, sliced raw fish and coastal fish showed significant positive correlations with PFOS concentrations in blood after adjustments for potential confounders. Serum levels of GOT, GPT, DHA and EPA showed significant positive correlations with PFOS and PFOA in blood. There was also a significant regional difference in the blood levels of PFOS and PFOA, with medians being highest in the Tokai/Hokuriku/Kinki region. Conclusions: These findings suggest that the concentrations of PFOS in blood were mainly associated with fish consumption and that the levels of PFOS and PFOA were associated with the serum levels of liver enzymes in Japanese populations. Further investigations are required to clarify the reason for the regional differences in blood levels of PFOS and PFOA in Japan