Hepatocyte-Specific Deficiency of DAX-1 Protects Mice from Acetaminophen-Induced Hepatotoxicity by Activating NRF2 Signaling.

Acetaminophen (APAP) is a widely used analgesic and antipyretic drug, but its overdose can cause acute liver failure. The dosage-sensitive sex reversal adrenal hypoplasia congenita critical region on the X chromosome, gene 1 (DAX-1, NR0B1), is an orphan nuclear receptor that acts as a transcriptional co-repressor of various genes. In this study, we identified the role of DAX-1 in APAP-induced liver injury using hepatocyte-specific Dax-1 knockout (Dax-1 LKO) mice. Mouse primary hepatocytes were used as a comparative in vitro study. APAP overdose led to decreased plasma alanine aminotransferase and aspartate aminotransferase levels in Dax-1 LKO mice compared to C57BL/6J (WT) controls, accompanied by reduced liver necrosis. The expression of the genes encoding the enzymes catalyzing glutathione (GSH) synthesis and metabolism and antioxidant enzymes was increased in the livers of APAP-treated Dax-1 LKO mice. The rapid recovery of GSH levels in the mitochondrial fraction of APAP-treated Dax-1 LKO mice led to reduced reactive oxygen species levels, resulting in the inhibition of the prolonged JNK activation. The hepatocyte-specific DAX-1 deficiency increased the protein expression of nuclear factor erythroid 2-related factor 2 (Nrf2) compared with WT controls after APAP administration. These results indicate that DAX-1 deficiency in hepatocytes protects against APAP-induced liver injury by Nrf2-regulated antioxidant defense.

Antioxidant and anti-inflammatory activities of phenolic compounds extracted from lemon myrtle (Backhousia citriodora) leaves at various extraction conditions.

Lemon myrtle leaves were extracted with ethanol at different temperatures (25, 50, and 80 °C) and times (2, 4, 6, and 10 h) to examine the effect of extraction conditions on total polyphenol contents (TPC), total flavonoid contents (TFC), their antioxidant, anti-inflammatory activities, and amount of phenolic compounds. Under optimal extraction conditions (80 °C and 6 h), the values were 23.37%, 102.72 mg gallic acid equivalents (GAE/g dry basis), 23.37 mg rutin equivalents (RE/g dry basis), 83.31%, 60.13%, and 1.10% for yield, TPC, TFC, DPPH, ABTS radical scavenging activity, and reducing power, respectively. In addition, total amount of the phenolic compounds of extract was determined as 43.9 µg/g. The anti-inflammatory effect was determined in lipopolysaccharide-stimulated RAW 264.7 cells and inhibited the production of inflammatory mediators such as nitric oxide (NO). These results indicate that extracts of lemon myrtle leaves have potential as a valuable natural product with antioxidant and anti-inflammatory.

Advanced fibrosis is not a negative pretreatment predictive factor for genotype 2 or 3 chronic hepatitis C patients.

BACKGROUND/AIMS: Chronic hepatitis C patients with advanced fibrosis have unsatisfactory sustained virological response (SVR) rates. Few data demonstrating the efficacy of combination therapy in chronic hepatitis C patients with advanced fibrosis in South Korea are available. The purpose of this study was to assess whether the stage of fibrosis impacts the efficacy of combination therapy for chronic hepatitis C. METHODS: We retrospectively reviewed data for a total of 109 patients with chronic hepatitis C, treated with peginterferon alfa and ribavirin. SVR according to the stage of liver fibrosis assessed by pretreatment liver biopsy and genotype results were analyzed. RESULTS: Data from 66 genotype 1 patients (60.6%) and 43 genotype 2 or 3 patients (39.4%) among the 109 patients were analyzed. SVR rates for the genotype 1 patients were significantly lower for the stage 3-4 group (32.1%) than the stage 0-2 group (78.9%; P<0.001). SVR rates (92.0% for stage 0-2, 77.8% for stage 3-4, P=0.184) of genotype 2 or 3 patients were not significantly different according to fibrosis stage. Likewise, the frequency of adverse events was not significantly different according to fibrosis stage. CONCLUSIONS: Compared to patients without advanced fibrosis, we can anticipate good SVR rates for genotype 2 or 3 patients with advanced fibrosis and they did not show an inferior tolerability for peginterferon and ribavirin combination therpy. Our results suggest that active treatment is needed for genotype 2 or 3 patients with advanced fibrosis.

Frozen Section Biopsy to Evaluation of Obscure Lateral Resection Margins during Gastric Endoscopic Submucosal Dissection for Early Gastric Cancer.

PURPOSE: To determine the diagnostic utility of a frozen section biopsy in patients undergoing endoscopic submucosal dissection (ESD) for early gastric neoplasms with obscure margins even with chromoendoscopy using acetic acid and indigo carmine (AI chromoendoscopy). MATERIALS AND METHODS: The lateral spread of early gastric neoplasms was unclear even following AI chromoendoscopy in 38 patients who underwent ESD between June 2007 and May 2011. Frozen section biopsies were obtained by agreement of the degree of lateral spread between two endoscopists. Thus, frozen section biopsies were obtained from 23 patients (FBx group) and not in the other 15 patients (AI group). RESULTS: No significant differences were observed for size, histology, invasive depth, and location of lesions between the AI and FBx groups. No false positive or false negative results were observed in the frozen section diagnoses. Adenocarcinoma was revealed in three patients and tubular adenoma in one, thereby changing the delineation of lesion extent and achieving free lateral margins. The rates of free lateral resection margins and curative resection were significantly higher in the FBx group than those in the AI group. CONCLUSIONS: Frozen section biopsy can help endoscopists perform more safe and accurate ESD in patients with early gastric neoplasm.

Interstitial pneumonitis in a patient with chronic hepatitis C and chronic renal failure on interferon therapy.

After 4-months of alpha interferon (IFN-α), a 64-year old woman with chronic hepatitis C developed a cough and dyspnea and showed diffuse infiltrative opacities on her chest X-ray. Her symptoms persisted after stopping the IFN-α therapy. Pulmonary function testing revealed a reduced forced vital capacity. High-resolution computed tomography of the lung showed peripheral and peribronchovascular ground glass attenuation and consolidation associated with reticulation. Bronchoalveolar lavage was performed for further evaluation and showed a lymphocyte level of 8.2%, an uncommon finding in IFN-α-induced interstitial pneumonitis. We performed a lung biopsy to diagnose her disease and it suggested interstitial pneumonitis. This was considered to be due to the immunomodulatory effects of INF-α. Although rare, any sign of significant pulmonary involvement should be evaluated.

Long-term result of endoscopic Histoacryl (N-butyl-2-cyanoacrylate) injection for treatment of gastric varices.

AIM: To evaluate the long-term efficacy and safety of endoscopic obliteration with Histoacryl(®) for treatment of gastric variceal bleeding and prophylaxis. METHODS: Between January 1994 and March 2010 at SoonChunHyang University Hospital, a total of 127 patients with gastric varices received Histoacryl(®) injections endoscopically. One hundred patients underwent endoscopic Histoacryl(®) injections because of variceal bleeding, the other 27 patients received such injections as a prophylactic procedure. RESULTS: According to Sarin classification, 56 patients were GOV1, 61 patients were GOV2 and 10 patients were IGV. Most of the varices were large (F2 or F3, 111 patients). The average volume of Histoacryl(®) per each session was 1.7 ± 1.3 cc and mean number of sessions was 1.3 ± 0.6. (1 session-98 patients, 2 sessions-25 patients, ≥ 3 sessions-4 patients). Twenty-seven patients with high risk of bleeding (large or fundal or RCS+ or Child C) received Histoacryl(®) injection as a primary prophylactic procedure. In these patients, hepatitis B virus was the major etiology of cirrhosis, 25 patients showed GOV1 or 2 (92.6%) and F2 or F3 accounted for 88.9% (n = 24). The rate of initial hemostasis was 98.4% and recurrent bleeding within one year occurred in 18.1% of patients. Successful hemostasis during episodes of rebleeding was achieved in 73.9% of cases. Median survival was 50 mo (95% CI 30.5-69.5). Major complications occurred in 4 patients (3.1%). The rebleeding rate in patients with hepatocellular carcinoma or GOV2 was higher than in those with other conditions. None of the 27 subjects who were treated prophylactically experienced treatment-related complications. Cumulative survival rates of the 127 patients at 6 mo, 1, 3, and 5 years were 92.1%, 84.2%, 64.2%, and 45.3%, respectively. The 6 mo cumulative survival rate of the 27 patients treated prophylactically was 75%. CONCLUSION: Histoacryl(®) injection therapy is an effective treatment for gastric varices and also an effective prophylactic treatment of gastric varices which carry high risk of bleeding.

Effect of glutathione on the cadmium chelation of EDTA in a patient with cadmium intoxication.

In order to evaluate the efficiency and renal protective effects of glutathione during Ca(++)-EDTA chelation therapy for chronic cadmium intoxication, we measured the renal excretion of cadmium, ß(2)-microglobulin, proteinuria, and hematuria during intravenous administration of glutathione with Ca(++)-EDTA in a 54-year-old patient with chronic cadmium intoxication. We administered 500 mg of Ca(++)-EDTA and 50 mg/kg of glutathione alone or in 1 L of normal saline over the next 24 hours and repeated this over 12 consecutive days. During the first 3 days, the basal levels (only saline administration) were determined; during the second 3 days, Ca(++)-EDTA only was administered, for the third sequence of 3 days, Ca(++)-EDTA with glutathione was provided, and for the last 3 days, glutathione alone was given. One month later, the same protocol was repeated. There were six blood and urine samples to analyze in each group. The blood cadmium level was higher when the EDTA was infused together with glutathione (7.44 ± 0.73 µg/L, p < 0.01) compared to the basal level of 4.6 ± 0.44 µg/L. Also, the renal cadmium excretion was significantly higher in the EDTA with glutathione group than in the basal group (23.4 ± 15.81 µg/g creatinine vs 89.23 ± 58.52 µg/g creatinine, p < 0.01). There was no difference in the protein/creatinine and ß(2)-microglobulin/creatinine ratio in the urine (p > 0.05) among the groups. Furthermore, microhematuria and proteinuria did not develop over the observation period of 6 months. These results suggest that glutathione administration with EDTA might be an effective treatment modality for patients with cadmium intoxication.