No abstract

This study establishes normal values for anorectal pressure by 3D-HRM in asymptomatic volunteers. There are significant gender differences concerning squeeze patterns. Increasing age is associated with lower maximum resting pressure, mean resting pressure, and maximum squeeze pressure. Normal characteristic pressure morphology of anorectum can be obtained at rest, during squeeze, and bear down as in defecation by 3D-HRM.

Aldosterone is thought to modulate renal fibrosis, in part, through increasing plasminogen activator inhibitor type 1 (PAI-1), a major inhibitor of ECM degradation. The present study investigated aldosterone effects on PAI-1 and transforming growth factor (TGF)-beta(1) and asked whether PAI-1 effects were TGF-beta mediated and whether aldosterone and TGF-beta(1) acted synergistically to increase PAI-1 and decrease ECM degradation. Rat mesangial cells (MCs) and fibroblast cells [normal rat kidney (NRK)-49F] were used. (3)H-labeled ECM was produced by MCs. The effect of aldosterone and TGF-beta on ECM degradation by newly plated MCs or NRK-49F was measured by the release of (3)H into medium. Aldosterone markedly increased PAI-1 mRNA and protein in both cell types, increases completely blocked by spironolactone and partially blocked by TGF-beta neutralizing antibody. Adding both aldosterone and TGF-beta(1) produced PAI-1 mRNA and protein increases higher than the sum of increases seen with either compound alone. Aldosterone or TGF-beta(1) alone inhibited matrix degradation by 39 and 49% in MCs and 21 and 23% in NRK-49F, respectively. When both compounds were added, matrix degradation was further decreased by 93% in MCs and 61% in NRK-49F. The results indicate that aldosterone-induced PAI-1 increases are partially mediated by TGF-beta(1) and lead to decreased ECM degradation. While aldosterone alone induced TGF-beta(1) weakly, aldosterone and TGF-beta(1) added together produced dramatic synergistic effects on PAI-1 production and subsequent ECM accumulation. Thus the elevated aldosterone induced by renin-angiotensin-aldosterone system activation may amplify renin-angiotensin-aldosterone system profibrotic actions.

The aim of the present study was to investigate the overall clinical expression characteristics of the cluster of differentiation (CD)28 family receptors [CD28, inducible T-cell co-stimulator, programmed cell death protein 1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 and B- and T-lymphocyte attenuator] on T cells in patients with chronic hepatitis B (CHB), analyze the correlations among these receptors and the clinical parameters, and to investigate the effects of PD-1 blockade on the receptor expression profiles, T-cell function and other biological effects. The expression characteristics of the CD28 family of receptors, the effects of PD-1 blockade on the receptor expression profiles and the levels of interferon (IFN)-γ were investigated in the T cells of patients with CHB. In addition, the transcription factor, T-box 21 (T-bet) and GATA binding protein 3 (GATA-3) mRNA expression levels were investigated in the peripheral blood mononuclear cells (PBMCs) of patients with CHB. The expression levels of the CD28 family receptors in the T cells of patients with CHB demonstrated distinct characteristics, for example levels of PD-1 and CTLA-4 on CD4 T cells and ICOS, PD-1, and BTLA on CD8 T cells were increased in cells from patients with CHB compared with those from the healthy individuals. A significant positive correlation was demonstrated among the serum HBV DNA titers and the levels of PD-1 on CD8+ T cells with the highest expression of PD-1 corresponding to viral levels >106 IU/ml. A significant positive correlation was observed between the serum HBV DNA titers and the expression levels of BTLA on CD8+ T cells with the highest expression of BTLA corresponding to viral levels >106 IU/ml. PD-1 blockade altered the expression profiles of CD28 family receptors in the T cells of patients with CHB, partly enhanced T cell function and increased the ratio of T-bet/GATA-3 mRNA in PBMCs. Thus, CD28 family receptors are potential clinical indicators for the rapid monitoring of changes in T cell function during CHB treatment. Furthermore, PD-1 blockade has a therapeutic potential that may be enhanced by modulating the expression of co-stimulatory and -inhibitory receptors of the CD28 family.