Sustained 3-Year Benefits in Quality of Life After Percutaneous Coronary Interventions in the Elderly: A Prospective Cohort Study.

BACKGROUND: Impact of percutaneous coronary interventions (PCI) on health-related quality of life (HRQOL) is important but under-reported in elderly patients. OBJECTIVES: To evaluate long-term health status in elderly patients who underwent PCI. METHODS: Consecutive patients who underwent PCI at a university-affiliated hospital from September 2009 to June 2012 were prospectively enrolled with HRQOL assessment at baseline (up to 2 weeks before PCI) and at 6-, 12-, and 36-month follow-up using the EuroQol five-dimensional questionnaire descriptive profile and visual analogue scale (VAS). Minimally important benefit (MIB) in HRQOL was defined as greater than half an SD improvement in the baseline VAS score. RESULTS: Of 1957 patients, 49.9%, 29.1%, and 21.0% were aged younger than 65 years, 65 to 74 years, and 75 years and older, respectively. Mean VAS scores at baseline (50.1 ± 20.5 vs. 51.6 ± 20.5 vs. 52.6 ± 21.8; P = 0.09) and at 36 months (72.9 ± 14.0 vs. 72.8 ± 16.1 vs. 72.0 ± 14.8; P = 0.77) were similar between the three age groups, respectively. MIB at 36 months was observed in 65.7%, 61.9%, and 61.2% of patients in each age group, respectively. Proportion of patients aged 75 years and older reporting problems in pain/discomfort and self-care reduced from 91.2% and 24.8% at baseline to 41.4% and 10.1% at 36 months, respectively (both P < 0.01). Independent predictors of MIB in HRQOL at 36 months in patients 75 years and older included poor baseline HRQOL, MIB at 6 months, and presentation with myocardial infarction (all P < 0.01). CONCLUSIONS: Elderly patients experienced sustained long-term improvement in quality of life comparable with younger patients after PCI. Our findings suggest that age per se should not deter against revascularization because of sustained benefit in HRQOL.

A role for STAT3 and cathepsin S in IL-10 down-regulation of IFN-gamma-induced MHC class II molecule on primary human blood macrophages.

IL-10, a potent anti-inflammatory cytokine, activates its primary mediator STAT3 to exert inhibitory effects on activated immune response. It has been reported that IFN-gamma signaling can be suppressed by IL-10, which deactivates macrophages and suppresses cell-mediated antigen presentation. Cathepsin S, a cysteine protease, plays a significant role in the antigen processing. We hypothesize that the IL-10-induced and STAT3-mediated signaling pathway interferes with IFN-gamma-induced immune responses in primary human blood macrophages. Here, we investigated whether IL-10 perturbs MHC-II levels via its effect on cathepsin S expression in antigen processing. We showed that the expression of cathepsin S and MHC-II, inducible by IFN-gamma, was down-regulated in the presence of IL-10. Additionally, we revealed that the inhibitory effect of IL-10 was demonstrated to be independent of the classical IFN-gamma-induced JAK2/STAT1 signaling cascade or the NF-kappaB pathway. Following STAT3 suppression with specific siRNA, the expression of IFN-gamma-induced surface MHC-II antigens and cathepsin S levels was restored, even in the presence of IL-10. Taken together, our results demonstrated that the immunosuppressive effects of IL-10-STAT3 on MHC-II antigen presentation may occur via the inhibition of cathepsin S expression.

A role for glycogen synthase kinase-3 in antagonizing mycobacterial immune evasion by negatively regulating IL-10 induction.

Mtb dysregulates monocyte/macrophage functions to produce a large amount of the immunosuppressive cytokine IL-10. An important function of IL-10 in promoting Mtb survival is the suppression of antigen presentation of monocytes/macrophages to T cells. This dampens the host immune responses and provides an opportunity for immune evasion. GSK3 has been shown to control the balance between pro- and anti-inflammatory cytokine productions. Here, we investigated whether GSK3 regulates IL-10 expression and mediates a protective role upon live mycobacterial challenge using BCG as a model. Our results showed that BCG increased Akt phosphorylation and inhibited GSK3 activity, resulting in increased IL-10 production. We confirmed further that suppression of GSK3 activities by a specific chemical inhibitor strongly enhanced BCG-induced IL-10 production. We also showed that IL-10 secreted by BCG-infected human PBMo was a major suppressor of subsequent IFN-gamma production by PBMC and HLA-DR expression on PBMo in response to BCG. Neutralization of PBMo-secreted IL-10 by anti-IL-10 antibodies restored the IFN-gamma production and HLA-DR surface expression. Taken together, GSK3 negatively regulates mycobacteria-induced IL-10 production in human PBMo. The kinase may play a role in restoring IFN-gamma secretions and subsequent antigen presentation in response to mycobacterial infection. In conclusion, our results suggest a significant role for GSK3 in guarding against mycobacterial evasion of immunity via IL-10 induction in the host.

Inhibition of human nasopharyngeal carcinoma growth and metastasis in mice by adenovirus-associated virus-mediated expression of human endostatin.

Nasopharyngeal carcinoma (NPC) is a highly malignant and frequently metastasized tumor. Endostatin has been shown to inhibit NPC growth, but its efficacy against NPC metastasis has not been shown in vivo. Here, we established a NPC metastasis model in mice by transplanting EBV-positive NPC cells, C666-1, in the livers of nude mice and observed lung metastasis. Furthermore, we showed that tail vein injection of recombinant adeno-associated virus encoding human endostatin (rAAV-hEndo) significantly prolonged the median survival rate of NPC metastasis-bearing mice (from 22 to 37 days, P < 0.01). The rAAV-hEndo treatment resulted in a statistically significant reduction in tumor growth and microvessel formation. It also increased the apoptotic index in the primary liver tumor but not in the normal liver tissue. Importantly, no formation of liver or lung metastasis was detected. The potent inhibition of NPC metastasis suggests the feasibility of combining rAAV-hEndo gene therapy with other therapies for the prevention and treatment of NPC metastasis.

Estrogen modulation of endothelium-derived relaxing factors by human endothelial cells.

We report the modulatory effects of estrogen on release of endothelium-derived relaxing factors (EDRFs) in a human endothelial cell line, EA.hy926. Using bioassay, we showed that EA.hy926 released EDRF including nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF) measured by relaxation of pre-contracted endothelium-denuded rabbit aortic rings. This EDRF production was significantly higher in cells treated for 24 h with 17-beta-estradiol (10(-6)mol/L) than control cells. Addition of L-NAME to the perfusate of cells caused the relaxation induced by the endothelial cell perfusate to become transient and abolished the enhancement of relaxation due to estrogen treatment. Addition of K(Ca) channel blockers to the perfusate abolished the L-NAME-resistant relaxation of the bioassay ring. Using real-time PCR, we demonstrated that eNOS expression in estrogen-treated cells was significantly higher than controls. These results show that estrogen exerts a potentially important vasculo-protective effect by stimulating NO but not EDHF production.

Sequential opening of IP(3)-sensitive Ca(2+) channels and SOC during alpha-adrenergic activation of rabbit vena cava.

Alpha(1)-aderenoceptor-mediated constriction of rabbit inferior vena cava (IVC) is signaled by asynchronous wavelike Ca(2+) oscillations in the in situ smooth muscle. We have shown previously that a putative nonselective cationic channel (NSCC) is required for these oscillations. In this report, we show that the application of 2-aminoethoxyphenyl borate (2-APB) to antagonize inositol 1,4,5-trisphosphate (InsP(3))-sensitive Ca(2+) release channels (IP(3)R channels) can prevent the initiation and abolish ongoing alpha(1)-aderenoceptor-mediated tonic constriction of the venous smooth muscle by inhibiting the generation of these intracellular Ca(2+) concentration ([Ca(2+)](i)) oscillations. The observed effects of 2-APB can only be attributed to its selective inhibition on the IP(3)R channels, not to its slight inhibition of the L-type voltage-gated Ca(2+) channel and the sarco(endo)plasmic reticulum Ca(2+) ATPase. Furthermore, 2-APB had no effect on the ryanodine-sensitive Ca(2+) release channel and the store-operated channel (SOC) in the IVC. These results indicate that the putative NSCC involved in refilling the sarcoplasmic reticulum (SR) and maintaining the tonic contraction is most likely an SOC-type channel because it appears to be activated by IP(3)R-channel-mediated SR Ca(2+) release or store depletion. This is in accordance with its sensitivity to Ni(2+) and La(3+) (SOC blockers). More interestingly, RT-PCR analysis indicates that transient receptor potential (Trp1) mRNA is strongly expressed in the rabbit IVC. The Trp1 gene is known to encode a component of the store-operated NSCC. These new data suggest that the activation of both the IP(3)R channels and the SOC are required for PE-mediated [Ca(2+)](i) oscillations and constriction of the rabbit IVC.