Background/Aims: Efficient anti-fibrotic therapies are required for the treatment of liver cirrhosis. Hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) and cyclooxygenase-2 (COX-2) inhibitors have been reported to have anti-fibrotic effects. Here, we investigated whether combined treatment with a statin and a COX-2 inhibitor has synergistic anti-fibrotic effects. Methods: The effects of treatment strategies incorporating both simvastatin and a COX-2 inhibitor, NS-398, were investigated using an immortalized human hepatic stellate cell line (LX-2) and a hepatic fibrosis mouse model developed using thioacetamide (TAA) in drinking water. Cellular proliferation was investigated via 5-bromo-2-deoxyuridine uptake. Pro- and anti-apoptotic factors were investigated through Western blotting and real-time polymerase chain reaction analysis. Results: The evaluation of the anti-proliferative effects on LX-2 cells showed that the observed effects were more pronounced with combination therapy than with single-drug therapy. Moreover, hepatic fibrosis and collagen deposition decreased significantly in TAA-treated mice in response to the combined treatment strategy. The mechanisms underlying the anti-fibrotic effects of the combination therapy were investigated. The effects of the combination therapy were correlated with increased expression levels of extracellular signal-regulated kinase 1/2 signaling molecules, upregulation of the Bax/Bcl-2 signaling pathway, inhibition of the transforming growth factor-β signaling pathway, and inhibition of tissue inhibitor of matrix metalloproteinases 1 and 2. Conclusions The combination of simvastatin and NS-398 resulted in a synergistic anti-fibrotic effect through multiple pathways. These findings offer a theoretical insight into the possible clinical application of this strategy for the treatment of advanced liver diseases with hepatic fibrosis.

BACKGROUND/AIMS: Whether alcohol intake increases the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B virus (HBV) infection remains controversial. The aim of this study was to determine the effect of alcohol intake on the development of HCC. METHODS: Between January 2006 and August 2008, 146 patients with an initial diagnosis of HCC who were hospitalized in 3 major hospitals in the Incheon area were enrolled as cases. Another 146 cirrhotic patients, who matched the cases by age and sex, were enrolled as controls. All cases and controls were HBsAg positive, and had a history of lifetime alcohol intake. RESULTS: The cases and controls were aged 53+/-8 and 53+/-9 years (mean+/-SD), respectively, with each group comprising 118 males and 28 females. The basal laboratory data, distribution of Child-Pugh class, HBeAg positivity (31.5% vs. 37.7%), HBV DNA level (5.74+/-2.35 vs. 5.98+/-2.29 log(10) copies/mL), and proportion with a lifetime alcohol intake of more than 292 kg (30.8% vs. 34.9%) did not differ between cases and controls. The cumulative alcohol intake and the proportion of heavy drinkers did not differ between the two groups in male patients. CONCLUSIONS: Alcohol intake might not increase the risk of HCC in patients with HBV infection.
Adult ; Alcohol Drinking/*adverse effects ; Carcinoma, Hepatocellular/epidemiology/*etiology ; Case-Control Studies ; Cross-Sectional Studies ; DNA, Viral/blood ; Female ; Hepatitis B Surface Antigens/blood ; Hepatitis B, Chronic/*complications ; Humans ; Liver Cirrhosis/*complications/epidemiology ; Liver Neoplasms/epidemiology/*etiology ; Male ; Middle Aged ; Risk Factors

Barrett's esophagus is considered as a premalignant condition in which columnar epithelium replaces the normal esophageal squamous epithelium. The diagnosis of Barrett's esophagus is based on the endoscopic finding of columnar epithelium lining the distal esophagus and histologic confirmation of the presence of specialized intestinal metaplasia. According to the extent of the metaplastic lining from the esophagogastric junction, Barrett's esophagus has been divided into long-segment (> or =3 cm in length) and short-segment (<3 cm in length). Long-segment Barrett's esophagus can be easily identified at endoscopy, but it is difficult to separate short-segment Barrett's esophagus from intestinal metaplasia of cardia. It has been reported that Barrett's CK 7/20 pattern is an objective marker of Barrett's mucosa, and can differentiate Barrett's mucosa from gastric intestinal metaplasia. We report here two cases of adenocarcinoma of esophagus arising from short-segment Barrett's esophagus, diagnosed by endoscopic and histologic findngs, and treated by endoscopic mucosal resection.
Adenocarcinoma* ; Barrett Esophagus* ; Cardia ; Diagnosis ; Endoscopy ; Epithelium ; Esophagogastric Junction ; Esophagus ; Metaplasia ; Mucous Membrane

Invasive aspergillosis of skull base is a rare but potentially lethal disease which complicates fungal sinusitis and requires surgical debridement, and long term antifungal therapy. However, optimal duration of antifungal therapy and standard method to monitor of clinical response are not known. A 55-year-old diabetic female patient presented with headache and otalgia 4 months after surgery for non-invasive aspergilloma of sinus. Brain MRI findings revealed bone destructions at the skull base and mastoid process. Mastoidectomy and tympanoplasty were performed, and the resected specimen showed fungal hyphae invading the tissue. Amphotericin B was given for 9 weeks (a total dose of 3.3 g) with oral itraconazole, followed by itraconazole (400 mg daily) alone for another 12 weeks. Serial gallium scans, taken before treatment and at 8th and 16th weeks following therapy, showed gradual reduction in uptake of the lesions. We emphasize that non-invasive Aspergillus sinusitis may progress to invasive disease, and strong suspicion of invasiveness is mandatory, especially in immunocompromised patients including diabetes mellitus. Also, we suggest that gallium scan is useful for determining the presence and extent of the disease, and monitoring clinical response following therapy.
Amphotericin B ; Aspergillosis* ; Aspergillus ; Brain ; Debridement ; Diabetes Mellitus ; Earache ; Female ; Gallium ; Headache ; Humans ; Hyphae ; Immunocompromised Host ; Itraconazole ; Magnetic Resonance Imaging ; Mastoid ; Middle Aged ; Sinusitis ; Skull Base* ; Skull* ; Tympanoplasty

Invasive aspergillosis of skull base is a rare but potentially lethal disease which complicates fungal sinusitis and requires surgical debridement, and long term antifungal therapy. However, optimal duration of antifungal therapy and standard method to monitor of clinical response are not known. A 55-year-old diabetic female patient presented with headache and otalgia 4 months after surgery for non-invasive aspergilloma of sinus. Brain MRI findings revealed bone destructions at the skull base and mastoid process. Mastoidectomy and tympanoplasty were performed, and the resected specimen showed fungal hyphae invading the tissue. Amphotericin B was given for 9 weeks (a total dose of 3.3 g) with oral itraconazole, followed by itraconazole (400 mg daily) alone for another 12 weeks. Serial gallium scans, taken before treatment and at 8th and 16th weeks following therapy, showed gradual reduction in uptake of the lesions. We emphasize that non-invasive Aspergillus sinusitis may progress to invasive disease, and strong suspicion of invasiveness is mandatory, especially in immunocompromised patients including diabetes mellitus. Also, we suggest that gallium scan is useful for determining the presence and extent of the disease, and monitoring clinical response following therapy.
Amphotericin B ; Aspergillosis* ; Aspergillus ; Brain ; Debridement ; Diabetes Mellitus ; Earache ; Female ; Gallium ; Headache ; Humans ; Hyphae ; Immunocompromised Host ; Itraconazole ; Magnetic Resonance Imaging ; Mastoid ; Middle Aged ; Sinusitis ; Skull Base* ; Skull* ; Tympanoplasty

BACKGROUND AND OBJECTIVES: The aim of the study was to evaluate the difference of temporal lability in myocardial repolarization between acute non-Q (NQMI) and Q-wave myocardial infarction (QMI), and to discern whether the locations of myocardial infarction influence such temporal lability. SUBJECTS AND METHODS: Twelve patients with NQMI and 28 with QMI, including 16 anterior (AMI) and 12 inferior MI (IMI) patients were enrolled. Twenty four-hour ambulatory ECG recordings of each patient were analyzed, and the digitized data was partitioned into 30-min sections. The QT intervals were measured using a template matching strategy. We then calculated the low (LF:0.03 - 0.15 Hz) and high frequency (HF:0.15 - 0.4 Hz) power of the QT interval variability using an algorithm capable of removing the influence of the RR-interval on QT interval variability (Normalized Idioventricular QT variability Index:IV-QT). RESULTS: For patients with QMI, the low frequency IV QT (LF IV-QT) was higher than that of NQMI (1.941+/-0.101 and 1.556+/-0.114 respectively, p<0.05). No difference was seen in the high frequency IV QT (HF IV-QT) of the two groups. For QMI patients, both the LF IV-QT and HF IV-QT were higher in day time (6AM-6PM) than in night time (6PM-6AM). Comparing the differences of these indices by the location of QMI, both the LF IV-QT and HF IV-QT of AMI were higher than those of IMI patients (2.231+/-0.135 vs 1.355+/-0.131 and 2.341+/-0.161 vs 1.346+/-0.145 respectively, p<0.0005). Both indices of each group also demonstrated a circadian change. CONCLUSION: In cases of QMI, the temporal lability in myocardial repolarization is larger than that seen in NQMI. Moreover, it was worse in AMI than IMI. Finally, such temporal repolarization lability tends to have a circadian pattern in QMI.
Electrocardiography ; Electrocardiography, Ambulatory ; Humans ; Myocardial Infarction*

PURPOSE: The object of this study is to determine whether QT interval variability in patients with postoperative tetralogy of Fallot increases. METHODS: We enrolled 41 patients who had total correction of tetralogy of Fallot, and 31 healthy controls. They were 6-12 years old. Patients were divided into 2 groups : arrhythmia-positive patients(n=10) who had ventricular premature contractions more than 30/hour or who had couplets, and arrhythmia-negative patients(n=31). We selected the 10-minute arrhythmia-free portion of 24-hour ambulatory ECG recorded during sleep(1-3AM). We selected the 2nd beat of recordings for a template, then found the QT interval for each beat. The method was that T-wave shape best matches template T-wave under the time-stretch model. The mean heart rate and variance and mean QT interval and variance were computed and then a QT variability index(QTVI)-which represents the log ratio between QT interval variability and heart rate variability-was derived. RESULTS: Postoperative tetralogy of Fallot patients with/without ventricular arrhythmia showed significantly increased QTVI compared with the control(-0.481+/-0.310/-0.661+/-0.376 vs -1.200+/-0.380, P<0.0001). There was a trend that QTVI in patients with ventricular arrhythmia increased more than in patients without ventricular arrhythmia, but there were no statistical significances. CONCLUSION: QT interval variability increased in repaired tetralogy of Fallot patients with/without ventricular arrhythmia compared with the control. And this finding indicates that inhomogeneity of temporal ventricular repolarization exists in repaired tetralogy of Fallot patients.
Arrhythmias, Cardiac ; Electrocardiography ; Heart Rate ; Humans ; Tetralogy of Fallot*

PURPOSE: Re-188-Hydroxyethylidene diphosphonate (HEDP) is a new cost-effective agent for systemic radioisotope therapy of metastatic bone pain. We investigated the influence of carrier for labeling and biodistribution of Re-188-HEDP using HEDP kit with or without carrier (KReO4). MATERALS AND METHODS: The kits (HEDP 15 mg, gentisic acid 4 mg and SnCl2.2H2O 4.5 mg) with or without carrier (KReO4 0.1 mg) were labeled with Re-188 solution, made available from an in-house generator by boiling for 15 min. We compared the labeling efficiency and stability of carrier-added and carrier-free preparations of Re-188-HEDP. Biodistribution and imaging studies of each preparation were performed in ICR mice (1.85~3.7 MBq/0.1 ml) and SD rats (74.1~85.2 MBq/0.5 ml). RESULTS: The carrier-added preparation showed high labeling efficiency (95% at pH 5) and high stability in serum (88%, 3 hr). However, the carrier-free preparation showed low labeling efficiency (59% at pH 5) and low stability (43%, 3 hr). The carrier-added preparation showed high uptake in bone and low uptake in stomach and kidneys. However, the carrier-free preparation showed lower uptake in bone and higher uptake in both stomach and kidneys, which is supposed to be due to released perrhenate. The carrier-added preparation also showed better images with higher skeletal accumulation, lower uptake in other organs and lower soft tissue uptake than the carrier-free preparation. CONCLUSION: The results of these studies clearly demonstrate that addition of carrier perrhenate is required for high labeling efficiency, stability, bone uptake and good image quality of Re-188-HEDP.
Animals ; Etidronic Acid ; Hydrogen-Ion Concentration ; Kidney ; Mice ; Mice, Inbred ICR ; Rats ; Stomach

OBJECTIVES: We studied the circadian rhythm of nonlinear heart rate dynamics in healthy subjects. BACKGROUND: The frequency of sudden cardiac death increases in the morning. The relationship between decreased complexity of heart rate dynamics and sudden cardiac death has been documented. An understanding of the circadian variation in the complexity of cardiac dynamics may be important and to predict and prevent this sudden cardiac death. METHODS: Dynamic 24-hour electrocardiographic recordings were obtained from 30 healthy ambulant subjects aged 41 to 50 years and the digitized data was partitioned into sections of 30 minutes' duration. For each section, four indexes obtained from separate algorithms of nonlinear dynamics of RR interval - correlation dimension, Lyapunov exponent, approximate entropy, and fractal dimension - were calculated. Normalized low- (0.04-0.1 hertz) and high-frequency (>0.15 hertz) components were also calculated. RESULTS: All the four indexes of nonlinear dynamics showed a remarkably similar circadian rhythm: a prominent morning dip preceded by a steep decline during the late night, a recovery during the evening and a peak around midnight. In the morning, the low frequency component rose rapidly with concomitant withdrawal of the high frequency component. CONCLUSION: The complexity of cardiac dynamics decreases significantly in the morning, and this may contribute to the ominously increased rate of cardiac death in the morning hours.
Circadian Rhythm* ; Death ; Death, Sudden, Cardiac ; Electrocardiography ; Entropy ; Fractals ; Heart Rate ; Nonlinear Dynamics

PURPOSE: This study aimed to characterize the autonomic and chaotic control of heart rate and circadian rhythm in asymptomatic patients with postoperative tetralogy of Fallot (pTOF). METHODS: Twenty-four-hour electrocardiogram recordings were obtained in 30 asymptomatic pTOF patients and in 30 age-and sex-matched controls, aged between 6 and 11 years. The data was digitized and partitioned into sections of 30- minute'durations. For each section, time-domain and frequency-domain measures (low- and high- frequency component) of heart rate variability and three measures based on chaotic dynamics- approximate entropy, correlation dimension and Lyapunov exponent-were calculated. RESULTS: In pTOF patients, 24-hour mean values of the time domain measures, high-frequency component, and all chaotic measures were significantly lower, while 24-hour mean value and all 6-hour mean values of the low-frequency component were significantly higher; all 6- hour mean values of high-frequency component, except from 6am to midday, were significantly lower. In pTOF patients, all 6-hour mean values of all three chaotic measures were significantly lower. In pTOF patients, the day- night circadian variation seen in controls was diminished (time- domain measures) or absent (low- and high- frequency component). CONCLUSION: Even in asymptomatic patients with pTOF, who are thought to be at minimal risk of fatal arrhythmia, a sustained increase in sympathetic activity and decrease in vagal activity, abnormal circadian rhythm of the autonomic activity, and decreased cardiac chaos were found. When other arrhythminogenic risk factors are superimposed, these abnormalities may contribute to the development of fatal arrhythmia and sudden death.
Arrhythmias, Cardiac ; Child* ; Circadian Rhythm* ; Death, Sudden ; Electrocardiography ; Entropy ; Heart Rate ; Humans ; Risk Factors ; Tetralogy of Fallot*