Outcomes in patients with rheumatoid arthritis and myocardial infarction

Background

Patients with rheumatoid arthritis have an increased risk for accelerated atherosclerosis. It is unknown, however, whether rheumatoid arthritis also increases in-hospital mortality after a myocardial infarction or influences the therapy patients receive.

Methods

A cross-sectional analysis of 1,112,676 patients with myocardial infarction in the 2003-2005 Nationwide Inpatient Sample was performed.

Results

Patients with rheumatoid arthritis were 39% more likely to receive medical therapy (odds ratio [OR], 1.39; 95% confidence interval [CI], 1.30-1.49) than interventional therapy. By using logistic regression, we adjusted for confounding variables to determine the effect of rheumatoid arthritis on the selection of therapy and found that rheumatoid arthritis itself was associated with a 38% increased likelihood of undergoing thrombolysis (OR, 1.38; 95% CI, 1.10-1.71) and a 27% increased likelihood of undergoing percutaneous coronary intervention (OR, 1.27; 95% CI, 1.17-1.39). For the primary outcome measure, we determined that patients with rheumatoid arthritis overall had a 24% better in-hospital mortality compared with other patients with a myocardial infarction (OR, 0.76; 95% CI, 0.68-0.86), which was 34% better after adjusting for confounding variables (OR, 0.66; 95% CI, 0.59-0.74). This better in-hospital mortality was seen in patients with rheumatoid arthritis undergoing medical therapy (adjusted OR, 0.67; 95% CI, 0.59-0.75) and percutaneous coronary intervention (adjusted OR, 0.47; 95% CI, 0.32-0.70), but not in patients undergoing thrombolysis or coronary artery bypass grafting.

Conclusions

Among patients with myocardial infarction, rheumatoid arthritis was associated with an increased use of thrombolysis and percutaneous coronary intervention. Moreover, patients with rheumatoid arthritis had an in-hospital survival advantage, particularly those undergoing medical therapy and percutaneous coronary intervention.     

Regression of prostate cancer xenografts by RLIP76 depletion

RLIP76 plays a central role in radiation and chemotherapy resistance through its activity as a multi-specific ATP-dependent transporter which is over-expressed in a number of types of cancers. RLIP76 appears to be necessary for cancer cell survival because both in vitro cell culture and in vivo animal tumor studies show that depletion or inhibition of RLIP76 causes selective toxicity in malignant cells. RLIP76 induces apoptosis in cancer cells through the accumulation of endogenously formed GS-E. The results of our in vivo studies demonstrate that administration of RLIP76 antibodies, siRNA or anti-sense to mice bearing xenografts of PC-3 prostate cancer cells leads to near complete regression of established subcutaneous xenografts with no apparent toxic effects. Since anti-RLIP76 IgG (which inhibit RLIP76-mediated transport), siRNA and antisense (which deplete RLIP76) showed similar tumor regressing activities, our results indicate that the inhibition of RLIP76 transport activity at the cell surface is sufficient for observed anti-tumor activity. These studies indicate that RLIP76 serves a key effector function for the survival of prostate cancer cells and that it is a valid target for cancer therapy.     

Pyruvate inhibits galactosemic changes in cultured cat lens epithelial cells

An attempt was made to maintain cat lens epithelial cells (CLEC) in culture and study the morphology, growth and survival of these cells in vitro. The influence of incorporation of galactose (30 mM) into the culture medium on the morphology and biochemistry of CLEC in the primary culture was then investigated. To establish the effect of galactose on CLEC, various biochemical parameters associated with galactosemic cataract such as aldose reductase (AR), Na+K+ATPase, glutathione, polyol and soluble/insoluble proteins were estimated after 24 h of incubation. The effect of pyruvate (5 mM), a 'physiological antioxidant', on the changes induced by galactose in CLEC was studied. CLEC in culture showed regular hexagonal cells with prominent nuclei. The CLEC culture attained confluency in 11 days during primary culture and semiconfluency in 14 days in two subsequent passages. Vacuolization and significantly raised AR activity, polyol levels and insoluble protein contents were observed; they had no effect on Na+K+ATPase and soluble protein after 24 h of incubation in the culture medium with galactose. Supplementation of pyruvate (5 mM) resulted in a lesser number of vacuoles together with a positive modulation of these parameters.     

Plasma elimination of cholyl‐lysyl‐fluorescein (CLF): a pilot study in patients with liver cirrhosis

Abstract: Background: Cholyl‐lysyl‐fluorescein (CLF) is a fluorescein‐labelled bile acid whose biological behaviour closely resembles that of naturally occurring cholyl glycine. Aim: The aim of this study was to analyze the CLF plasma elimination in patients with liver cirrhosis. Methods: A dose of CLF at 0.02 mg/kg b.w. was administered i.v. in 26 patients with liver cirrhosis and 9 healthy volunteers. Blood samples were collected before injection and then at 10 min intervals over 60 min. Plasma fluorescence was measured by a luminescence spectrometer and residual fluorescence over the time of the study was compared in each group. Routine liver function tests (rLFTs) were performed before each injection. Results: Plasma elimination of CLF was significantly impaired in patients with cirrhosis compared to healthy subjects with p values <0.0001 at each analyzed time point. CLF test showed 100% sensitivity for liver cirrhosis when residual fluorescence was measured 30, 40, 50 and 60 min after injection. Routine LFTs showed 85% sensitivity for bilirubin, 84% for total bile acids, 69% for aspartate aminotransferase 62% for albumin and 50% for alkaline phosphatase. CLF elimination measured 60 min after injection correlated with Child‐Pugh score (r=0.3945; p<0.05) and albumin (r_s=0.6451; p<0.001). No adverse reaction or side effects of CLF were observed. Conclusions: CLF test clearly distinguished between the two analyzed groups and was more sensitive than routine liver function tests. The test appears safe, simple to perform and analyze and after validation in larger cohorts of patients may have the potential to become a useful dynamic test of liver function.     

Green tea polyphenol-induced epidermal keratinocyte differentiation is associated with coordinated expression of p57/KIP2 and caspase 14

Epigallocatechin-3-gallate (EGCG), the most abundant polyphenol in green tea, exerts chemopreventive effects by selectively inducing apoptosis in tumor cells. In contrast, EGCG accelerates terminal differentiation in normal human epidermal keratinocytes (NHEK) mediated partially by up-regulation of p57/KIP2, a cyclin-dependent kinase inhibitor that confers growth arrest and differentiation. However, it is unclear if EGCG modulates caspase 14, a unique regulator of epithelial cell terminal differentiation associated with cornification. Here, we examined the effect of EGCG on caspase 14 expression in NHEK and correlated the protein and mRNA expression of p57/KIP2 with those of caspase 14 in either normal keratinocytes or p57/KIP2-expressing tumor cells (OSC2, an oral squamous cell carcinoma cell line). Additionally, paraffin-embedded normal and untreated psoriatic (aberrant keratinization) skin sections from humans were assessed for caspase 14 by immunohistochemistry. In NHEK, EGCG induced the expression of caspase 14 mRNA and protein levels within a 24-h period. The expression of p57/KIP2 in OSC2 cells was adequate to induce caspase 14 in the absence of EGCG; this induction of caspase 14 was down-regulated by transforming growth factor-beta1. In human psoriatic skin samples, caspase 14 staining in the upper epidermis was reduced, especially in nuclear areas. These results suggest that, in addition to p57/KIP2, EGCG-induced terminal differentiation of epidermal keratinocytes involves up-regulation of caspase 14. Further understanding of how EGCG modulates cellular differentiation may be useful in developing green tea preparations for selected clinical applications.     

Glutathione-conjugate transport by RLIP76 is required for clathrin-dependent endocytosis and chemical carcinogenesis

Targeted depletion of the RALBP1-encoded 76-kDa splice variant, RLIP76, causes marked and sustained regression of human xenografts of lung, colon, prostate, and kidney cancers without toxicity in nude mouse models. We proposed that the remarkable efficacy and broad spectrum of RLIP76-targeted therapy is because its glutathione-conjugate (GS-E) transport activity is required for clathrin-dependent endocytosis (CDE), which regulates all ligand-receptor signaling, and that RLIP76 is required not only for survival of cancer cells but also for their very existence. We studied RLIP76 mutant proteins and the functional consequences of their expression into RLIP76(-/-) MEFs, identified key residues for GS-E binding in RLIP76, established the requirement of RLIP76-mediated GS-E transport for CDE, and showed a direct correlation between GS-E transport activities with CDE. Depletion of RLIP76 nearly completely blocked signaling downstream of EGF in a CDE-dependent manner and Wnt5a signaling in a CDE-independent manner. The seminal prediction of this hypothesis-RLIP76(-/-) mice will be deficient in chemical neoplasia-was confirmed. Benzo[a]pyrene, dimethylbenzanthracene, and phorbol esters are ineffective in causing neoplasia in RLIP76(-/-). PMA-induced skin carcinogenesis in RLIP76(+/+) mouse was suppressed completely by depletion of either PKCα or RLIP76 by siRNA or antisense and could be restored by topical application of RLIP76 protein in RLIP76(-/-) mouse skin. Likewise, chemical pulmonary carcinogenesis was absent in female and nearly absent in male RLIP76(-/-) mice. In RLIP76(-/-) mice, p53, p38, and JNK activation did not occur in response to either carcinogen. Our findings show a fundamental role of RLIP76 in chemical carcinogenesis.