Background and Objective: Hemodialysis (HD) patients are more inactive, leading to poor functional capacity and quality of life; this may be reversed with intradialytic exercise training. To systematically evaluate the efficacy and safety of intradialytic exercise for HD patients, we conducted a meta-analysis of the published randomized controlled trials. Data Sources and Methods: Medline, Embase, and Cochrane Central Register of Controlled Trials were systematically searched up to February, 2014. The reference lists of eligible studies and relevant reviews were also checked. Results: 24 studies of 997 patients were included. Compared with control, intradialytic exercise significantly improve Kt/V (SMD = 0.27, 95% CI 0.01-0.53), peak oxygen consumption (VO_2peak) (SMD = 0.53, 95% CI 0.30-0.76), and physical performance of physical function of life (SMD = 0.30, 95% CI 0.04-0.55). However, no significant improvements were found in the mental function of life. There was no significant difference with respect to musculoskeletal and cardiovascular complications between the intradialytic exercise groups and control groups. Further subgroup analysis found that, when the trial duration was more than 6 months, the intervention had significant effects on VO_2peak (SMD = 0.89, 95% CI 0.56-1.22). However, when the trial duration was less than 6 months, the change of VO_2peak was not significant (SMD = 0.19, 95% CI -0.13 to 0.51). Conclusion: Intradialytic exercise can improve Kt/V, VO_2peak, and the physical quality of life, and intradialytic exercise is safe for HD patients. Therefore, we put forward the suggestion that clinical guideline be updated to inform clinicians on the benefits of intradialytic exercise on HD patients. i 2014 S. Karger AG, Basel

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T cell immunoglobulin and mucin domain-containing protein 3 (Tim-3) is a newly identified negative immunomodulator that is up-regulated on dysfunctional T cells during viral infections. The expression and function of Tim-3 on human innate immune responses during HCV infection, however, remains poorly characterized. In this study, we report that Tim-3 is constitutively expressed on human resting CD14+ monocyte/macrophages (M/MØ) and functions as a cap to block IL-12, a key pro-inflammatory cytokine linking innate and adaptive immune responses. Tim-3 expression is significantly reduced and IL-12 expression increased upon stimulation with Toll-like receptor 4 (TLR4) ligand - lipopolysaccharide (LPS) and TLR7/8 ligand - R848. Notably, Tim-3 is over-expressed on un-stimulated as well as TLR-stimulated M/MØ, which is inversely associated with the diminished IL-12 expression in chronically HCV-infected individuals when compared to healthy subjects. Up-regulation of Tim-3 and inhibition of IL-12 are also observed in M/MØ incubated with HCV-expressing hepatocytes, as well as in primary M/MØ or monocytic THP-1 cells incubated with HCV core protein, an effect that mimics the function of complement C1q and is reversible by blocking the HCV core/gC1qR interaction. Importantly, blockade of Tim-3 signaling significantly rescues HCV-mediated inhibition of IL-12, which is primarily expressed by Tim-3 negative M/MØ. Tim-3 blockade reduces HCV core-mediated expression of the negative immunoregulators PD-1 and SOCS-1 and increases STAT-1 phosphorylation. Conversely, blocking PD-1 or silencing SOCS-1 gene expression also decreases Tim-3 expression and enhances IL-12 secretion and STAT-1 phosphorylation. These findings suggest that Tim-3 plays a crucial role in negative regulation of innate immune responses, through crosstalk with PD-1 and SOCS-1 and limiting STAT-1 phosphorylation, and may be a novel target for immunotherapy to HCV infection.

Tim-3 and PD-1 are powerful immunoinhibitory molecules involved in immune tolerance, autoimmune responses, and antitumor or antiviral immune evasion. A current model for Tim-3 regulation during immune responses suggests a divergent function, such that Tim-3 acts synergistically with TLR signaling pathways in innate immune cells to promote inflammation, yet the same molecule terminates Th1 immunity in adaptive immune cells. To better understand how Tim-3 might be functioning in innate immune responses, we examined the kinetics of Tim-3 expression in human CD14+ M/M(Ф) in relation to expression of IL-12, a key cytokine in the transition of innate to adaptive immunity. Here, we show that Tim-3 is constitutively expressed on unstimulated peripheral blood CD14+ monocytes but decreases rapidly upon TLR stimulation. Conversely, IL-12 expression is low in these cells but increases rapidly in CD14+ M/M(Ф) in correlation with the decrease in Tim-3. Blocking Tim-3 signaling or silencing Tim-3 expression led to a significant increase in TLR-mediated IL-12 production, as well as a decrease in activation-induced up-regulation of the immunoinhibitor, PD-1; TNF-α production was not altered significantly, but IL-10 production was increased. These results suggest that Tim-3 has a role as a regulator of pro- and anti-inflammatory innate immune responses.

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