Factors Associated with the Refusal of Direct-Acting Antiviral Agents for the Treatment of Hepatitis C in Taiwan.

Background and Objectives: Direct-acting antiviral agents (DAA) are a safe and highly effective treatment for hepatitis C virus (HCV) infection. However, the uptake of DAA treatment remains a challenge. This study aims to examine the reasons for DAA refusal among HCV patients covered by the Taiwan National Health Insurance system. Materials and Methods: This retrospective observational study covered the period from January 2009 to December 2019 and was conducted at a single hepatitis treatment center in Taiwan. This study involved chart reviews and phone-based surveys to confirm treatment status and refusal causes. To confirm treatment status, subjects with HCV without treatment records were phone-contacted to confirm treatment status. Patients who did not receive treatment were invited back for treatment. If the patient refused, the reason for refusal was discussed. Results: A total of 3566 patients were confirmed with DAA treatment; 418 patients (179 patients who were lost to contact or refused the survey and 239 patients who completed the survey of DAA refusal) were included in the no-DAA-therapy group. Factors associated with receiving DAAs were hemoglobin levels, hepatitis B virus co-infection, and regular gastroenterology visits. Meanwhile, male sex, platelet levels, and primary care physician visits were associated with DAA refusal. The leading causes of treatment refusal were multiple comorbidities, low health literacy, restricted access to hospitals, nursing home residence, and old age. The rate of DAA refusal remains high (10%). Conclusions: The reasons for treatment refusal are multifactorial, and addressing them requires complex interventions.

Age-specific percentile-based prostate-specific antigen cutoff values predict the risk of prostate cancer: A single hospital observation.

Background: Testing for prostate-specific antigen (PSA) is often recommended for men with a potential risk of prostate cancer (PCa) before requiring advanced examination. However, the best PSA cutoff value remains controversial. Object: We compared the predictive performance of age-specific percentile-based PSA thresholds with a conventional cutoff of >4 ng/mL for the risk of PCa. Methods: We included men who received PSA measurements between 2003 and 2017 in a medical center in Taiwan. Logistic regression modeling was used to assess the association between age-specific percentile-based PSA thresholds and PCa risk in age subgroups. We further applied C-statistic and decision curve analysis to compare the predictive performance of age-specific percentile-based PSA with that of a conventional cutoff PSA. Results: We identified 626 patients with PCa and 40 836 patients without PCa. The slope of PSA in patients >60-year-old was almost 3 times that of those <60-year-old (0.713 vs 0.259). The risk effect sizes of the 75th percentile PSA cutoff (<60-year-old: 2.19; 60-70-year-old: 4.36; >70-year-old: 5.84 ng/mL) were comparable to those observed based on the conventional cutoff in all age groups. However, the discrimination performance of the 75th percentile PSA cutoff was better than that of the conventional cutoff among patients aged <60-year-old (C-statistic, 0.783 vs. 0.729, p < 0.05). The 75th percentile cutoffs also correctly identified an additional 2 patients with PCa for every 100 patients with PSA screening at the threshold probability of 20%. Conclusions: Our data support the use of the 75th percentile PSA cutoff to facilitate individualized risk assessment, particularly for patients aged <60-year-old.

Cardiothoracic ratio values and trajectories are associated with risk of requiring dialysis and mortality in chronic kidney disease.

BACKGROUND: The prognostic role of the cardiothoracic ratio (CTR) in chronic kidney disease (CKD) remains undetermined. METHODS: We conducted a retrospective cohort study of 3117 patients with CKD aged 18-89 years who participated in an Advanced CKD Care Program in Taiwan between 2003 and 2017 with a median follow up of 1.3(0.7-2.5) and 3.3(1.8-5.3) (IQR) years for outcome of end-stage renal disease (ESRD) and overall death, respectively. We developed a machine learning (ML)-based algorithm to calculate the baseline and serial CTRs, which were then used to classify patients into trajectory groups based on latent class mixed modelling. Association and discrimination were evaluated using multivariable Cox proportional hazards regression analyses and C-statistics, respectively. RESULTS: The median (interquartile range) age of 3117 patients is 69.5 (59.2-77.4) years. We create 3 CTR trajectory groups (low [30.1%], medium [48.1%], and high [21.8%]) for the 2474 patients with at least 2 CTR measurements. The adjusted hazard ratios for ESRD, cardiovascular mortality, and all-cause mortality in patients with baseline CTRs ≥0.57 (vs CTRs <0.47) are 1.35 (95% confidence interval, 1.06-1.72), 2.89 (1.78-4.71), and 1.50 (1.22-1.83), respectively. Similarly, greater effect sizes, particularly for cardiovascular mortality, are observed for high (vs low) CTR trajectories. Compared with a reference model, one with CTR as a continuous variable yields significantly higher C-statistics of 0.719 (vs 0.698, P = 0.04) for cardiovascular mortality and 0.697 (vs 0.693, P < 0.001) for all-cause mortality. CONCLUSIONS: Our findings support the real-world prognostic value of the CTR, as calculated by a ML annotation tool, in CKD. Our research presents a methodological foundation for using machine learning to improve cardioprotection among patients with CKD.

An enlarged heart occurs during various medical conditions and can result in early death. However, it is unclear whether this is also the case in patients with chronic kidney disease (CKD). Although the size of the heart can be measured on chest X-rays, this process is time consuming. We used artificial intelligence to quantify the heart size of 3117 CKD patients based on their chest X-rays within hours. We found that CKD patients with an enlarged heart were more likely to develop end-stage kidney disease or die. This could improve monitoring of CKD patients with an enlarged heart and improve their care.

Insomnia and Poor Sleep in CKD: A Systematic Review and Meta-analysis.

Rationale & Objective: Poor sleep quality and insomnia are pervasive among patients with advanced chronic kidney disease (CKD); however, these health issues have not been systematically evaluated. Study Design: Systematic review and meta-analysis. Setting & Study Populations: Adult patients with CKD not receiving kidney replacement therapy (KRT), as well as adults receiving KRT, including hemodialysis, peritoneal dialysis, and kidney transplantation. Selection Criteria for Studies: A systematic literature search using PubMed, Embase, and PsycNET, was conducted for articles published between January 1, 1990, and September 28, 2018. Data Extraction: Data on the prevalences of poor sleep quality and insomnia in patients with CKD, including those receiving and not receiving KRT, were extracted. Analytical Approach: Pooled prevalences were estimated using a random-effects meta-analysis and were stratified according to age, CKD stage, World Health Organization region, risk of bias, Pittsburgh Sleep Quality Index score, and the different criteria for insomnia that were used at diagnosis. Results: Of 3,708 articles, 93 were selected, and significant methodological heterogeneity was present. The pooled prevalences of poor sleep quality for CKD without KRT, hemodialysis, peritoneal dialysis, and kidney transplantation were 59% (95% CI, 44%-73%), 68% (95% CI, 64%-73%), 67% (95% CI, 44%-86%), and 46% (95% CI, 34%-59%), respectively. The corresponding prevalences of insomnia were 48% (95% CI, 30%-67%), 46% (95% CI, 39%-54%), 61% (95% CI, 41%-79%), and 26% (95% CI, 9%-49%), respectively. Insomnia was significantly more prevalent among patients aged 51-60 years and those aged >60 years than among those aged <50 years. The prevalence of insomnia in the European region was the lowest of all World Health Organization regions. Limitations: High interstudy heterogeneity. Conclusions: Approximately half of the patients with advanced CKD had poor sleep quality or insomnia, and the prevalence was even higher among those who received KRT. Kidney transplantation may reduce the burden of poor sleep quality and insomnia.

Application of machine learning methods for the prediction of true fasting status in patients performing blood tests.

The fasting blood glucose (FBG) values extracted from electronic medical records (EMR) are assumed valid in existing research, which may cause diagnostic bias due to misclassification of fasting status. We proposed a machine learning (ML) algorithm to predict the fasting status of blood samples. This cross-sectional study was conducted using the EMR of a medical center from 2003 to 2018 and a total of 2,196,833 ontological FBGs from the outpatient service were enrolled. The theoretical true fasting status are identified by comparing the values of ontological FBG with average glucose levels derived from concomitant tested HbA1c based on multi-criteria. In addition to multiple logistic regression, we extracted 67 features to predict the fasting status by eXtreme Gradient Boosting (XGBoost). The discrimination and calibration of the prediction models were also assessed. Real-world performance was gauged by the prevalence of ineffective glucose measurement (IGM). Of the 784,340 ontologically labeled fasting samples, 77.1% were considered theoretical FBGs. The median (IQR) glucose and HbA1c level of ontological and theoretical fasting samples in patients without diabetes mellitus (DM) were 94.0 (87.0, 102.0) mg/dL and 5.6 (5.4, 5.9)%, and 92.0 (86.0, 99.0) mg/dL and 5.6 (5.4, 5.9)%, respectively. The XGBoost showed comparable calibration and AUROC of 0.887 than that of 0.868 in multiple logistic regression in the parsimonious approach and identified important predictors of glucose level, home-to-hospital distance, age, and concomitantly serum creatinine and lipid testing. The prevalence of IGM dropped from 27.8% based on ontological FBGs to 0.48% by using algorithm-verified FBGs. The proposed ML algorithm or multiple logistic regression model aids in verification of the fasting status.

Association of poorly controlled HbA1c with increased risk of progression to end-stage kidney disease and all-cause mortality in patients with diabetes and chronic kidney disease.

Glycosylated hemoglobin (HbA1c) targets for patients with chronic kidney disease (CKD) and type 2 diabetes remain controversial. To evaluate whether baseline HbA1c and HbA1c trajectories are associated with the risk of end-stage kidney disease (ESKD) and all-cause mortality, we recruited adult patients with CKD and type 2 diabetes from a "Pre-ESKD Program" at a medical center in Taiwan from 2003 to 2017. Group-based trajectory modeling was performed to identify distinct patient groups that contained patients with similar longitudinal HbA1c patterns. Cox proportional hazard models were used to estimate hazard ratios (HRs) of ESKD and mortality associated with baseline HbA1c levels and HbA1c trajectories. In the analysis related to baseline HbA1c (n = 4543), the adjusted HRs [95% confidence interval (CI)] of all-cause mortality were 1.06 (0.95-1.18) and 1.25 (95% CI, 1.07-1.46) in patients with an HbA1c level of 7%-9% (53-75 mmol/mol) and >9% (>75 mmol/mol), respectively, as compared with those with an HbA1c level < 7% (<53 mmol/mol). In the trajectory analysis (n = 2692), three distinct longitudinal HbA1c trajectories were identified: nearly optimal (55.9%), moderate to stable (34.2%), and poor control (9.9%). Compared with the "nearly optimal" HbA1c trajectory group, the "moderate-to-stable" group did not have significantly higher mortality, but the "poorly controlled" group had 35% higher risk of mortality (adjusted HR = 1.35, 95% CI = 1.06-1.71). Neither baseline levels of HbA1c nor trajectories were associated with ESKD risk. In conclusion, in patients with CKD and type 2 diabetes, poor glycemic control was associated with an elevated risk of mortality but not associated with a risk of progression to ESKD.

Electronic medical record-based deep data cleaning and phenotyping improve the diagnostic validity and mortality assessment of infective endocarditis: medical big data initiative of CMUH.

BACKGROUND: International Classification of Diseases (ICD) code-based claims databases are often used to study infective endocarditis (IE). However, the quality of ICD coding can influence the reliability of IE research. The impact of complementing the ICD-only approach with data extracted from electronic medical records (EMRs) has yet to be explored. METHODS: We selected the information of adult patients with discharge ICD codes for IE (ICD-9: 421, 112.81, 036.42, 098.84, 115.04, 115.14, 115.94, 424.9; ICD-10: I33, I38, I39) during 2005-2016 in China Medical University Hospital. Data extraction was conducted on the basis of the modified Duke criteria to establish a reference group comprising patients with definite or possible IE. Clinical characteristics and in-hospital mortality were compared between ICD-identified and Duke-confirmed cases. The positive predictive value (PPV) was used to quantify the IE identification performance of various phenotyping algorithms. RESULTS: A total of 593 patients with discharge ICD codes for IE were identified, only 56.7% met the modified Duke criteria. The crude in-hospital mortality for Duke-confirmed and Duke-rejected IE were 24.4% and 8.2%, respectively. The adjusted in-hospital mortality for ICD-identified IE was lower than that for Duke-confirmed IE by a difference of 5.1%. The best PPV was achieved (0.90, 95% CI 0.86-0.93) when major components of the Duke criteria (positive blood culture and vegetation) were integrated with ICD codes. CONCLUSION: Integrating EMR data can considerably improve the accuracy of ICD-only approaches in phenotyping IE, which can improve the validity of EMR-based studies and their applications, including real-time surveillance and clinical decision support.

Overexpression of nuclear protein kinase CK2 Beta subunit and prognosis in human gastric carcinoma.

BACKGROUND: Gastric carcinoma is one of the most common malignancies in the world, yet little is known about the molecular process of its development and progression. The aims of this study are to correlate the expression of nuclear protein kinase CK2 beta subunit (CK2beta) with clinicopathologic parameters and patient survival. METHODS: Expression levels of nuclear CK2beta were analyzed in 104 gastric tissues from patients with gastric carcinoma by immunohistochemistry. A paired t test was used to analyze the differences in nuclear CK2beta expression between tumor and nontumor tissues in the same patient. A two-tailed chi (2) test was performed to determine the significance of the difference between nuclear CK2beta expression and clinicopathologic parameters. All time-to-event endpoints according to various clinicopathologic parameters were plotted by Kaplan-Meier method, and significance was then determined by univariate log-rank test. Cox proportional-hazards model was used for multivariate analysis to determine the independence of prognostic impact of nuclear CK2beta expression. RESULTS: Overexpression of nuclear CK2beta was significantly correlated with depth of invasion (P = 0.042). Patients with high expression levels of nuclear CK2beta had a significantly poorer overall survival rate compared with patients with low expression levels of nuclear CK2beta (P = 0.0006). On multivariate Cox regression analysis, overexpression of nuclear CK2beta and stage were proven to be independent prognostic markers for gastric carcinoma (P = 0.0036 and 0.0005, respectively). CONCLUSIONS: Overexpression of nuclear CK2beta can be a useful marker for predicting the outcome of patients with gastric carcinoma.

Premedication with pronase or N-acetylcysteine improves visibility during gastroendoscopy: an endoscopist-blinded, prospective, randomized study.

AIM: To assess the efficacy of premedicaton with pronase or N-acetylcysteine (NAC) at 20 min before upper gastrointestinal (UGI) endoscopy and to determine whether pronase or NAC pretreatment influences the reliability of the rapid urease test. METHODS: A total of 146 patients were prospectively and randomly assigned into the study groups according to different premedications before endoscopy. One endoscopist assessed mucosal visibility (MV) with scores ranged from 1 to 4 at four sites in the stomach. The sum of the MV scores from these four locations was defined as the total mucosal visibility (TMV) score. Identification of H pylori was performed using CLO test, histology, and serology. RESULTS: The Group with pronase premedication had a significantly lower TMV score than did the groups with gascon and gascon water (P < 0.001 and P < 0.01, respectively). The group with NAC had a significantly lower TMV score than the group with gascon (P < 0.01) and a trend of a lower MV score than the group with gascon water (P = 0.06). The TMV score did not significantly differ between the group with pronase and the group with NAC (P = 0.39 and P = 0.14, respectively). The sensitivity and specificity of the CLO test were 92.5% and 93.9%, respectively, in groups premedicated with pronase and NAC together. CONCLUSION: Premedication with pronase or NAC at 20 min before UGI endoscopy improves the mucosal visibility of the stomach. Neither pronase nor NAC produces any obvious interference with the CLO test for the identification of H pylori infection.

Aloe-emodin-induced apoptosis in human gastric carcinoma cells.

The purpose of this study was to investigate the anticancer effect of aloe-emodin, an anthraquinone compound present in the leaves of Aloe vera, on two distinct human gastric carcinoma cell lines, AGS and NCI-N87. We demonstrate that aloe-emodin induced cell death in a dose- and time-dependent manner. Noteworthy is that the AGS cells were generally more sensitive than the NCI-N87 cells. Aloe-emodin caused the release of apoptosis-inducing factor and cytochrome c from mitochondria, followed by the activation of caspase-3, leading to nuclear shrinkage and apoptosis. In addition, exposure to aloe-emodin suppressed the casein kinase II activity in a time-dependent manner and was accompanied by a reduced phosphorylation of Bid, a downstream substrate of casein kinase II and a pro-apoptotic molecule. These preclinical studies suggest that aloe-emodin represents a suitable and novel chemotherapeutic drug candidate for the treatment of human gastric carcinoma.

Metachronous esophageal cancer and colon cancer treated by endoscopic mucosal resection.

Most cases of esophageal cancer and colorectal cancer in Taiwan are diagnosed in the advanced stage and treated by surgery or concurrent chemoirradiation. The detection rates of early esophageal cancer and early colorectal cancer are still low in Taiwan. Metachronous early esophageal cancer and early colorectal cancer have rarely been reported. Endoscopic mucosal resection (EMR) is a well-established method for treatment of early gastrointestinal cancer in Japan. We report a 77-year-old man with metachronous early esophageal cancer and early colorectal cancer detected by chromoendoscopy with 3% Lugol's iodine and 0.2% indigo carmine, respectively. These two lesions were successfully treated by EMR. Endoscopic mucosal resection of early cancer in the gastrointestinal tract may be considered in patients who are not suitable for open surgery.

Large early gastric cancers treated by endoscopic submucosal dissection with an insulation-tipped diathermic knife.

It is difficult to remove a large early gastric cancer (> or = 3 cm) in one-piece resection using conventional endoscopic mucosal resection. We tried to use an insulation-tipped (IT) diathermic knife to dissect these lesions. IT-endoscopic submucosal dissection (ESD) was performed in four aging patients with gastric malignancy. All lesions could be removed in one-piece resection by IT-ESD, although three of them exhibited remarkable fibrosis and ulceration. Three cases experienced curative treatment with IT-ESD after the pathologic evaluation, but it was not curative in one case because the pathology showed angiolymphatic invasion. This patient refused additional surgery in consideration of existing major systemic diseases. At 3 months to 1 year of follow-up, endoscopy showed no evidence of residual cancer. IT-ESD is effective in the treatment of large early gastric cancer and is an alternative treatment for early gastric cancer patients who are at risk for major operation.

Quantitative analysis of plasma HBV DNA for early evaluation of the response to transcatheter arterial embolization for HBV-related hepatocellular carcinoma.

AIM: Transcatheter arterial embolization (TAE) is an important palliative treatment for patients with hepatocellular carcinoma (HCC) who are poor candidates for surgery or percutaneous ablative therapy. It generally takes 4 wk after lipiodol-TAE to properly assess lipiodol retention on computed tomography (CT). HBV DNA is integrated into the genome of HCC cells, and circulating plasma DNA may serve as a marker for cell damage. We assessed changes in plasma HBV DNA after TAE in HBV-related HCC and correlated the levels with the pattern of lipiodol accumulation on CT. METHODS: Between April and June 2001, 14 patients with HBV-associated HCC who underwent TAE for inoperable or recurrent tumor were studied. Levels of plasma HBV DNA were measured by real-time quantitative PCR daily for five consecutive days after TAE. More than twofold elevation of circulating HBV DNA was considered as a definite elevation. Abdominal CT was performed 1-2 mo after TAE for the measurement of lipiodol retention. RESULTS: Circulating HBV DNA in 10 out of 13 patients was elevated after TAE, except for one patient whose plasma HBV DNA was undetectable before and after TAE. In group I patients (n = 6), the HBV DNA elevation persisted for more than 2 d, while in group II (n = 7), the HBV DNA elevation only appeared for 1 d or did not reach a definite elevation. There were no significant differences in age or tumor size between the two groups. Patients in group I had significantly better lipiodol retention (79.31+/-28.79%) on subsequent abdominal CT than group II (18.43+/-10.61%) (P = 0.02). CONCLUSION: Patients with durable HBV DNA elevation for more than 2 d correlated with good lipiodol retention measured 1 mo later, while others associated with poor lipiodol retention. Thus, circulating HBV DNA may be an early indicator of the success or failure of TAE.

Deformity of duodenal bulb, gastric metaplasia of duodenal regenerating mucosa and recurrence of duodenal ulcer: a correlated study.

AIM: To investigate the correlation among the presence and degree of gastric metaplasia of duodenal regenerating mucosa, the deformity of bulb and the recurrence of duodenal ulcer. METHODS: A total of 99 patients with duodenal ulcer were treated with H(2)-antagonist with or without antimicrobial therapy. All patients received follow-up endoscopic examinations 6 wk after treatment. When the ulcer(s) were noted to be healed, two biopsies were taken from the ulcer scar for histological study of gastric metaplasia, and 4 biopsies were taken from antrum for Helicobacter pylori (H pylori) study. Out of these cases, 44 received further follow-up endoscopic examinations after 3, 6 and 12 mo respectively for studying the recurrence rate of duodenal ulcers. The correlation among ulcer recurrence, degree of gastric metaplasia of regenerating mucosa, bulbar deformity, and colonization of H pylori in the stomach was then studied. RESULTS: The results showed that there was a strong correlation between the deformity of duodenal bulb and the degree of gastric metaplasia of regenerating duodenal mucosa. The recurrence rate of duodenal ulcer had a significant difference between patients with and without H pylori colonization in the stomach (P<0.001). The greater the degree of gastric metaplasia of duodenal regenerating mucosa, the higher the recurrence rate of duodenal ulcer (P = 0.021). The more deformed the duodenal bulb, the higher the incidence of recurrence of duodenal ulcer (P = 0.03). CONCLUSION: There is a correlation among deformity of duodenal bulb, gastric metaplasia of duodenal regenerating mucosa and recurrence of duodenal ulcer. A more severely deformed duodenal bulb is closely related to a greater extent of gastric metaplasia. Both factors contribute to the recurrence of duodenal ulcer.

Anti-Helicobacter pylori therapy significantly reduces Helicobacter pylori -induced gastric mucosal damage in Mongolian gerbils.

AIM: To investigate the effectiveness of 4 d' anti-Helicobacter pylori therapy on the H pylori-infected Mongolian gerbils based on physiological and pathological changes. METHODS: We used 6-wk-old male gerbils orally inoculated with H pylori (ATCC43504, 2X10(8) CFU/mL). Seven weeks after H pylori inoculation, the animals of study group received 4 d' anti-H pylori triple therapy (H pylori-eradicated group). Seven days later, all animals of the H pylori-eradicated and control groups (H pylori-infected and H pylori-uninfected groups) were sacrificed. We examined gastric mucosal lesions macroscopically, studied gastritis microscopically and determined the stomach weight ratio, myeloperoxidase (MPO) activity and prostaglandin (PG) E(2) level. RESULTS: The results showed that both macroscopic and histological gastric damages were significantly less in H pylori-eradicated group than H pylori-infected group. Stomach weight ratio, MPO activity and PGE(2) levels were significantly higher in H pylori-infected group than those in the other two groups. CONCLUSION: Four days' anti-H pylori therapy was effective in the improvement of H pylori-induced gastric lesions in Mongolian gerbils.

Protective effects of Ginkgo biloba extract on the ethanol-induced gastric ulcer in rats.

AIM: To evaluate the preventive effect of Ginkgo biloba extract (GbE) on ethanol-induced gastric mucosal injuries in rats. METHODS: Female Wistar albino rats were used for the studies. We randomly divided the rats for each study into five subgroups: normal control, experimental control, and three experimental groups. The gastric ulcers were induced by instilling 1 mL 50% ethanol into the stomach. We gave GbE 8.75, 17.5, 26.25 mg/kg intravenously to the experimental groups respectively 30 min prior to the ulcerative challenge. We removed the stomachs 45 min later. The gastric ulcers, gastric mucus and the content of non-protein sulfhydryl groups (NP-SH), malondialdehyde (MDA), c-Jun kinase (JNK) activity in gastric mucosa were evaluated. The amount of gastric juice and its acidity were also measured. RESULTS: The findings of our study are as follows: (1) GbE pretreatment was found to provide a dose-dependent protection against the ethanol-induced gastric ulcers in rats; (2) the GbE pretreatment afforded a dose-dependent inhibition of ethanol-induced depletion of stomach wall mucus, NP-SH contents and increase in the lipid peroxidation (increase MDA) in gastric tissue; (3) gastric ulcer induced by ethanol produced an increase in JNK activity in gastric mucosa which also significantly inhibited by pretreatment with GbE; and (4) GbE alone had no inhibitory effect on gastric secretion in pylorus-ligated rats. CONCLUSION: The finding of this study showed that GbE significantly inhibited the ethanol-induced gastric lesions in rats. We suggest that the preventive effect of GbE may be mediated through: (1) inhibition of lipid peroxidation; (2) preservation of gastric mucus and NP-SH; and (3) blockade of cell apoptosis.

Eradication of Helicobacter pylori significantly reduced gastric damage in nonsteroidal anti-inflammatory drug-treated Mongolian gerbils.

AIM: To examine the effect of eradication of Helicobacter pylori prior to usage of NSAIDs, by investigating gastric inflammatory activity, myeloperoxidase (MPO) activity, prostaglandin (PG) E2 synthesis in H pylori-infected, and H pylori-eradicated gerbils followed by administration of indomethacin and rofecoxib. METHODS: Six-week-old male gerbils were orally inoculated with H pylori. Seven weeks later, anti-H pylori triple therapy and vehicle were given to gerbils respectively and followed by oral indomethacin (2 mg/kg.d) or rofecoxib (10 mg/kg.d) for 2 wk. We examined the area of lesions, gastric inflammatory activity, PGE2 synthesis and MPO activity in the stomach. RESULTS: In indomethacin and rofecoxib-treated gerbils, the following results were obtained in H pylori-infected group vs H pylori-eradicated group respectively: hyperplasia area of the stomach (mm2): 82.4+/-9.2 vs 13.9+/-3.5 (P<0.05), 30.5+/-5.1 vs 1.3+/-0.6 (P<0.05); erosion and ulcer area (mm2): 14.4+/-4.9 vs 0.86+/-0.5 (P<0.05), 1.3+/-0.6 vs 0.4+/-0.3 (P<0.05); score of gastritis: 7.0+/-0.0 vs 3.6+/-0.5 (P<0.05), 7.0+/-0.0 vs 2.7+/-0.5 (P<0.05); MPO activity (micromol H2O2/min/g tissue): 104.7+/-9.2 vs 9.0+/-2.3 (P<0.05), 133.5+/-15.0 vs 2.9+/-0.7 (P<0.05); PGE2 synthesis (pg/mg wet weight/min): 299.2+/-81.5 vs 102.8+/-26.2 (P<0.05), 321.4+/-30.3 vs 11.9+/-4.8 (P<0.05). CONCLUSION: Eradication of H pylori reduced gastric damage of NSAID-treated Mongolian gerbils. Rofecoxib caused less severe gastric damage than indomethacin in H pylori-eradicated gerbils.

Effect of lipopolysaccharide on diarrhea and gastrointestinal transit in mice: roles of nitric oxide and prostaglandin E2.

AIM: To investigate the effect of lipopolysaccharide (LPS) on the diarrheogenic activity, gastrointestinal transit (GIT), and intestinal fluid content and the possible role of nitric oxide (NO) and prostaglandin E2 (PGE2) in gastrointestinal functions of endotoxin-treated mice. METHODS: Diarrheogic activity, GIT, and intestinal fluid content as well as nitric oxide and PGE2 products were measured after intraperitoneal administration of LPS in mice. RESULTS: LPS dose-dependently accumulated abundant fluid into the small intestine, induced diarrhea, but decreased the GIT. Both nitric oxide and PGE2 were found to increase in LPS-treated mice. Western blot analysis indicated that LPS significantly induced the protein expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 in mice intestines. Pretreatment with N(G)-nitro-L-arginine-methyl ester (L-NAME, a non-selective NOS inhibitor) or indomethacin (an inhibitor of prostaglandin synthesis) significantly attenuated the effects of LPS on the diarrheogenic activity and intestine content, but reversed the GIT. CONCLUSION: The present study suggests that the pathogenesis of LPS treatment may mediate the stimulatory effect of LPS on nitric oxide and PGE2 production and NO/prostaglandin pathway may play an important role on gastrointestinal function.

Effects of epidermal growth factor and its signal transduction inhibitors on apoptosis in human colorectal cancer cells.

AIM: The study investigated if EGF signaling inhibitors, EGF antibody and tyrphostin 51 (a tyrosine kinase inhibitor), mediated the action of EGF on apoptosis and the expression of EGF receptors and p21 (a cyclin-dependent kinase inhibitor) of human colorectal cancer cells. METHODS: Human colorectal adenocarcinoma cells (SW480) were incubated with 0.6 mL/L dimethyl sulfoxide (DMSO, the control group), 225 ng/mL (37.5 nmol/L) EGF in 0.6 mL/L DMSO, 225 ng/mL EGF+2.5 microg/mL (17 nmol/L) EGF antibody in 0.6 mL/L DMSO, or 225 ng/mL EGF+215 ng/mL (0.8 micromol/L) tyrphostin 51 in 0.6 mL/L DMSO. RESULTS: After 48 h incubation, the levels of EGF in medium significantly increased (P<0.05) in the EGF-treated groups. The numbers of apoptotic cells were significantly fewer (P<0.05) in the EGF + EGF antibody and EGF + tyrphostin 51 groups than those in the control and EGF groups after 12 h treatments. The expression of phosphorylated EGF receptors in the EGF, EGF + EGF antibody, and EGF + tyrphostin 51 groups was 176.8%, 62.4%, and 138.1% of the control group, respectively. The expression of p21 protein in the EGF, EGF + EGF antibody, and EGF + tyrphostin 51 groups was 115.7%, 4.8%, and 61.5% of the control group, respectively. CONCLUSION: The data suggest that EGF antibody and tyrphostin 51 can inhibit the action of EGF on apoptosis in human colorectal cancer cells through down-regulation of EGF receptor and p21 expression.

Effects of Ginkgo biloba extract on cytoprotective factors in rats with duodenal ulcer.

AIM: To investigate the effects of Ginkgo biloba extract on cytoprotective factors in rats with duodenal ulcer. METHODS: Sprague-Dawley rats were randomly divided into four groups: sham operation without ginkgo, sham operation with ginkgo, duodenal ulcer without ginkgo, and duodenal ulcer with ginkgo. Rats with duodenal ulcer were induced by 500 mL/L acetic acid. Rats with ginkgo were intravenously injected with Ginkgo biloba extract from the tail at a dose of 0.5 mg/(kg/d) for 7 and 14 days. RESULTS: Pathological result showed that duodenal ulcer rats with ginkgo improved mucosal healing and inflammation compared with those without ginkgo after 7 d treatment. After 14 d treatment, duodenal ulcer rats with ginkgo significantly increased weight gain (34.0+/-4.5 g versus 24.5+/-9.5 g, P<0.05) compared with those without ginkgo. Duodenal ulcer rats significantly increased cell proliferation (27.4+/-4.0 and 27.8+/-2.3 BrdU-labeled cells in duodenal ulcer rats with and without ginkgo versus 22.4+/-3.5 and 20.8+/-0.5 BrdU-labeled cells in sham operation rats with and without ginkgo, P<0.05) compared with sham operation rats. Mucosal prostaglandin E(2) concentration significantly increased by 129% (P<0.05) in duodenal ulcer rats with ginkgo compared with that in those without ginkgo. Duodenal ulcer rats without ginkgo significantly decreased superoxide dismutase activity in the duodenal mucosa and erythrocytes (19.4+/-6.7 U/mg protein versus 38.1+/-18.9 U/mg protein in the duodenal mucosa, and 4.87+/-1.49 U/mg protein versus 7.78+/-2.16 U/mg protein in erythrocytes, P<0.05) compared with sham operation rats without ginkgo. However, duodenal ulcer rats with ginkgo significantly increased erythrocyte superoxide dismutase activity (8.22+/-1.92 U/mg protein versus 4.87+/-1.49 U/mg protein, P<0.05) compared with those without ginkgo. Duodenal ulcer rats without ginkgo significantly increased plasma lipid peroxides (4.18+/-1.12 micromol/mL versus 1.60+/-1.10 micromol/mL and 1.80+/-0.73 micromol/mL, P<0.05) compared with sham operation rats without ginkgo and duodenal ulcer rats with ginkgo during the experimental period. CONCLUSION: Ginkgo biloba extract can improve weight gain and mucosal healing in duodenal ulcer rats by the actions of cytoprotection and antioxidation.