The aim of this study was to characterize the in vivo action of lipoic acid (LA) in hepatic ischemia/reperfusion injury (IRI) and its effects on liver regeneration involving the investigation of mechanisms of action and effects on animal survival. Two groups of rats were compared: one group received 500 micromol alpha-LA injected via the inferior vena cava 15 min before the induction of 90 min of selective ischemia. The untreated group received vehicle. Influence of LA on IRI of the liver was determined in short- and long-term experiments. Cellular damage was decreased under preconditioning conditions with LA. Caspase 3, 8, and 9 activities were significantly lower in the LA group accompanied by a decrease in terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive hepatocytes. Electron micrographs in the untreated group showed massive mitochondrial damage. The survival rate as end point of liver function was markedly increased after pretreatment with LA. Increased levels of tumor necrosis factor alpha was shown by enzyme-linked immunosorbent assay as well as real-time reverse transcription-polymerase chain reaction in the LA group accompanied by increased mitotic index and Ki-67 staining in liver tissue. Attenuation of IRI of the rat liver in vivo by LA is accompanied by reduction of necrosis and apoptosis-related cell death, whereas liver regeneration is increased.
Background/Aim: α-Lipoic (LA) acid pretreatment has previously been described to reduce ischemia/reperfusion injury (IRI) after warm liver ischemia, whereas glycine pretreatment has been shown to be protective mostly in models of cold hepatic ischemia. The aim of this study was to determine whether glycine decreases IRI after warm hepatic ischemia. Furthermore we investigated whether doses of LA other than those used previously are also protective against IRI after warm hepatic ischemia. Methods: Selective liver ischemia was maintained over a period of 90 min. In long-term as well as short-term experiments we studied IRI in several groups comparing animal survival as the pivotal endpoint. Results: Animal survival was improved by glycine and 5,000 µmol LA, whereas all animals died within 3 days after pretreatment with 50 µmol LA. In the glycine group we observed a tendency towards decreased apoptosis-related cell death measured by the activity of caspase-3 in liver tissue and the percentage of TUNEL-positive hepatocytes in comparison to the untreated group. Serum α-glutathione S-transferase, lipid peroxidation, and caspase-3 activity as well as the percentage of TUNEL-positive hepatocytes and the percentage of liver necrosis were only significantly decreased by 5,000 µmol LA pretreatment. Liver tissue levels of tumor necrosis factor (TNF)α were reduced only in the glycine group whereas TNFα was increased in the untreated as well as the LA group. Levels of TNFα mRNA were upregulated in both the glycine- and LA-pretreated groups. Conclusion: Our data show that increased animal survival by glycine was accompanied by a reduced TNFα content in liver tissue. Protection by glycine is likely to result from a reduction in adverse TNFα effects. Administration of high-dose LA on the other hand led to a significant reduction in necrosis- and apoptosis-related cell death in IRI of the liver without a reduction in liver TNFα.
IP, consisting of 10 min of ischemia and 10 min of reperfusion, protects only partly against ischemia/reperfusion injury of the liver prior to 90 min of selective ischemia. IPsel did not influence ischemic tolerance of the liver. LA improved tolerance to ischemia, possibly by downregulation of pro-apoptotic Bax.
State-of-the-art surgical staging and adjuvant chemotherapy in early-stage ovarian carcinoma have an impact on patient's outcome, but compliance to guidelines and consensus recommendations is still poor. This article reports on our results before and after introduction of a quality assurance and management program in our clinic in 2001. Patients with ovarian carcinoma limited to the pelvis who underwent primary surgery in our hospital from 1997 to October 2007 were eligible for this study. Univariate and multivariate logistic regression analyses were performed to evaluate the impact of compliance with our management program and physician's experience in ovarian carcinoma surgery on achieving both standards of surgery and chemotherapy. In a total of 117 women, a significant impact on adherence to guideline-defined comprehensive surgical staging was found for poor Eastern Cooperative Oncology Group performance status (odds ratio [OR], 22.16; confidence interval [CI] 3.2-152.0; P = 0.002) and year of surgery before 2001 (OR, 47.60; CI, 9.20-245.22; P < 0.001). Tumor grading less than G3 (OR, 4.14; CI, 1.20-14.22; P = 0.02) was a statistically significant predictor for receiving standard adjuvant chemotherapy. Survival analyses showed a trend toward improved survival for patients having received guideline-adopted therapy, but event numbers were too low for adequate analyses. The introduction of a quality assurance program for treatment of ovarian carcinoma represents a major improvement of patient care. It led to a higher compliance with consensus recommendations and showed already a trend toward improved outcome. Further outcome research should focus on methods for implementation of guidelines in daily practice in institutions caring for patients with ovarian carcinoma.
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