Change of insulin sensitivity in hepatitis C patients with normal insulin sensitivity: a 5-year prospective follow-up study variation of insulin sensitivity in HCV patients.

BACKGROUND: Hepatitis C virus (HCV) infection is associated with a high prevalence of diabetes mellitus (DM). Insulin resistance (IR) is known to play a crucial role in the development of DM in chronic hepatitis C (CHC) patients. We prospectively investigated changes of insulin sensitivity in CHC patients during a 5-year period and analysed the factors significantly associated with IR. METHODS: Sixty-two CHC patients with normal insulin sensitivity (CHC group), and a healthy control group of 172 subjects matched by age, gender, body mass index and lifestyles were studied. We compared the initial baseline insulin sensitivity, metabolic parameters and incidence of IR at the end of the follow-up period between the two groups. The changes in insulin sensitivity, metabolic parameters and the development of IR were analysed as well as factors associated with the development of IR. RESULTS: IR developed in 22.5% of 62 CHC patients and 5.2% of 172 normal individuals (P < 0.001). HCV infection per se and the genotype 1 were independent risk factors for the development of IR. The duration of infection > or = 120 months, initial fasting glucose 90-100 mg/dL, fasting insulin > or = 10 microIU/mL and the homeostasis model assessment (HOMA-IR) 2.3-2.7 were significantly associated with the development of IR in the CHC group. CONCLUSION: HCV infection was an independent risk factor for the development of IR. All CHC patients, even those with normal insulin sensitivity, require careful monitoring for the development of IR.

Impact of non-alcoholic fatty liver disease on microalbuminuria in patients with prediabetes and diabetes.

BACKGROUND: It is unknown whether microalbuminuria is associated with non-alcoholic fatty liver disease (NAFLD) among patients with prediabetes and type 2 diabetes mellitus (DM). This study investigated the association of NAFLD with microalbuminuria among patients with prediabetes and diabetes. METHODS: We evaluated 1361 subjects who had an abnormal oral glucose tolerance test (OGTT) on routine screening. All participants were divided into two groups, prediabetes and newly diagnosed type 2 DM, and the association of NAFLD with metabolic parameters on microalbuminuria was analysed. RESULTS: The patients with NAFLD had higher prevalence rates of microalbuminuria (6.3% vs 19%; P = 0.001 in prediabetes, 4.5% vs 32.6%; P < 0.001 in diabetes) and also had a greater albumin-to-creatinine ratio (14.6 +/- 52.0 microg/mg Cr vs 27.7 +/- 63.9 microg/mg Cr; P = 0.051 in prediabetes, 11.4 +/- 21.4 microg/mg Cr vs 44.7 +/- 76.4 microg/mg Cr; P < 0.001 in diabetes) than those without NAFLD. The logistic regression analysis showed that NAFLD was associated with increased rates of microalbuminuria (odds ratio 3.66; 95%confidence interval (CI) 1.31-10.20, P = 0.013 in prediabetes, odds ratio 5.47;95% CI 1.01-29.61, P = 0.048 in diabetes), independently of age, sex, body mass index, waist circumference, liver enzymes, lipid profiles, HbA1c, insulin resistance as estimated by homeostasis model assessment, hypertension,smoking status and the metabolic syndrome. CONCLUSIONS: The results of our study revealed a strong relationship between microalbuminuria and NAFLD in the patients with prediabetes and newly diagnosed diabetes. Further studies are required to confirm whether NAFLD is a predictor of the development of microalbuminuria in patients with prediabetes and diabetes.

Evaluation of dual priming oligonucleotide-based multiplex PCR for detection of HBV YMDD mutants.

We evaluated the usefulness of dual priming oligonucleotide (DPO)-based multiplex PCR, Seeplex HBV Lami-DR assay (Seegene Institute of Life Sciences, Seoul, Korea), to detect lamivudine-resistant HBV mutants in a comparison with the use of TRUGENE HBV genotyping and restriction fragment mass polymorphism (RFMP). Sera from 44 chronic hepatitis B patients were analyzed for the presence of mutations at codons 180 and 204 by performing DPO-based multiplex PCR, RFMP, and TRUGENE. The overall concordance rate among the three assays was 40.9% (18/44). Concordance rates between multiplex PCR and RFMP or multiplex PCR and TRUGENE were 61.4% (27/44) and 50.0% (22/44), respectively. In ten patients, multiplex PCR identified additional mutants not found using the other two methods. DPO-based multiplex PCR is a highly sensitive method to identify minor mutant populations and could be a practical tool in the monitoring of lamivudine resistance.

Quality and effect of single dose versus split dose of polyethylene glycol bowel preparation for early-morning colonoscopy.

BACKGROUND AND STUDY AIMS: The conventional procedure of ingestion of an entire dose of polyethylene glycol solution on the day before early-morning colonoscopy may result in poor bowel preparation. The aim of this study was to evaluate the efficacy and effect of a split-dose ingestion of polyethylene glycol for early-morning colonoscopy. METHODS: A total of 303 age- and sex-matched consecutive individuals presenting for medical check-ups were randomly assigned to receive either 4 L of polyethylene glycol solution with a soft diet on the day before colonoscopy (n = 152; group A), or 3 L of polyethylene glycol solution with a soft diet on the preceding day and then 1 L of the solution on the day of colonoscopy (n = 151; group B). The quality of bowel preparation was evaluated using the Ottawa scale, and the time to cecal intubation and the technical difficulty during the procedure were also recorded. RESULTS: There was no difference in compliance between group A (single-dose) and group B (split-dose). The quality of bowel preparation was better in group B compared with group A. When the participants were categorized according to compliance (good compliance, 116 in group A, 119 in group B; poor compliance, 36 in group A, 32 in group B), the quality of the bowel preparation had a higher score in the good compliance compared with the poor compliance group, and in group B this difference was usually significant. CONCLUSIONS: Split-dose bowel preparation with polyethylene glycol solution provided a better quality preparation than the conventional method for patients undergoing early-morning colonoscopy.

Gene amplification and protein overexpression of HER-2/neu in human extrahepatic cholangiocarcinoma as detected by chromogenic in situ hybridization and immunohistochemistry: its prognostic implication in node-positive patients.

BACKGROUND: In cholangiocarcinoma (CC), HER-2/neu protein overexpression has rarely been reported and the results are conflicting. The present study aimed to clarify the rates of HER-2/neu protein overexpression and gene amplification in human extrahepatic CC and to evaluate the correlation between HER-2/neu and several clinicopathologic features. PATIENTS AND METHODS: We investigated HER-2 gene amplification by chromogenic in situ hybridization (CISH) and HER-2/neu protein overexpression by immunohistochemistry in 55 extrahepatic CC patients who underwent curative surgery at our institution. RESULTS: Overexpression of HER-2/neu protein (staining intensity score > or = 2) was found in 16 out of 55 patients (29.1%). CISH revealed that HER-2 gene signals were increased in 10 out of 55 patients (18.1%). There was a positive and significant correlation between HER-2 gene amplification and HER-2/neu protein overexpression (Spearman's rho = 0.718, P < 0.01). In subgroup with lymph node metastases, HER-2 gene amplification by CISH was significant prognostic factor for survival (OR 43.6, 95% confidence interval 1.6-1219.6). CONCLUSIONS: HER-2/neu protein overexpression by HER-2 gene amplification may occur in human extrahepatic CC and constitute an independent prognostic factor in patients with lymph node metastases. In subgroup with lymph node metastases who exhibit HER-2/neu overexpression might constitute potential candidates for new adjuvant therapy, such as humanized monoclonal antibodies.

Clinical features associated with improvement of fatty liver disease.

BACKGROUND: We presumed that identification of the factors associated with improvement of fatty livers disease (FLD) would support the therapeutic options for FLD. The goal of this study was to clarify what clinical characteristics are associated with biochemical and sonographic improvements in the non-alcoholic population with fatty livers. METHODS: A total of 615 non-alcoholic men had elevated alanine aminotransferase (ALT) (> or = 40 IU/L) levels and sonographic evidence of a fatty liver, and their clinical characteristics were assessed at the beginning of the study and after 1 year of follow up. The improvement was defined as combination of normal ALT level and negative sonography for hepatic fat after 1 year. Programmed intervention or medications were not applied in this study population. RESULTS: The overall rate of improvement of FLD after a 1-year follow up was 37/615 (6.0%). The improvement was strongly associated with decrement of changes in bodyweight, body mass index, waist circumference, gamma-glutamyltransferase, fasting blood sugar, total cholesterol, triglycerides, low-density lipoprotein cholesterol, total cholesterol/high-density lipoprotein cholesterol ratio and homeostasis model assessment. Multivariate analysis showed that decrement of changes in bodyweight (odds ratio (OR) = 1.56; 95% confidence interval (95%CI): 1.27-1.92) per 1 kg, body mass index (OR = 2.42; 95%CI: 1.58-3.71) per 1 SD (0.8 kg/m2), waist circumference (OR = 2.13; 95%CI: 1.02-4.54) per 1 cm, and low-density lipoprotein cholesterol (OR = 1.64; 95%CI: 1.05-2.56) per 1 SD (22 mg/dL) were all independent predictors for improvement of FLD. CONCLUSIONS: These results suggest that the reduction of bodyweight is a major key point for the improvement of FLD.

Flavanone glycosides from Citrus junos and their anti-influenza virus activity.

By bioactivity-guided fractionation, a new flavanone triglycoside, naringenin 7-O-(2",6"-di-O-alpha-rhamnopyranosyl)-beta-glucopyranoside (1), as well as hesperetin 7-O-(2", 6"-di-O-alpha-rhamnopyranosyl)-beta-glucopyranoside (2), hesperidin (3) and narirutin (4) have been isolated from the fruits of Citrus junos Tanaka (Rutaceae). In addition, hesperetin 7-O-(2",6"-di-O-alpha-rhamnopyranosyl)-beta-glucopyranoside (2) is reported for the first time from this plant and inhibits the influenza A virus.

Shikonin, an ingredient of Lithospermum erythrorhizon induced apoptosis in HL60 human premyelocytic leukemia cell line.

Apoptosis is a new therapeutic target of cancer research. Shikonin isolated from Lithospermum erythrorhizon, a traditional oriental medicinal herb, was observed to induce apoptosis in HL60 human premyelocytic leukemia cell line. Shikonin induced DNA fragmentation into the multiples of 180 bp and increased the percentage of hypodiploid cells in flow cytometry after propidium iodide staining. The increase of apoptotic cells was preceded by the activation of caspase-3, which was reported to play a central role in apoptotic process. The DNA fragmentation induced by shikonin was completely inhibited by the pretreatment of z-VAD-fmk, a specific inhibitor of caspase, clearly showing that the mode of cell death is apoptotic.

The trefoil gene family are coordinately expressed immediate-early genes: EGF receptor- and MAP kinase-dependent interregulation.

The trefoil gene family of mucus cell-secreted proteins is a critical mediator of gastrointestinal mucosal restitution. Transcription of trefoil genes is induced during mucosal repair, but the regulatory mechanisms involved are unknown. Mice deficient in the intestine-specific peptide intestinal trefoil factor (ITF), in which colonic restitution is lethally impaired, showed reduced expression of the gastric trefoil genes SP and pS2, suggesting that trefoil peptides may individually regulate transcription of the entire family. In gastric cell lines, the trefoils were shown to act in a manner suggestive of immediate-early genes capable of auto- and cross-induction through cis-acting regulatory regions. Trefoil-mediated transcriptional regulation required activation of the Ras/MEK/MAP kinase signal transduction pathway. EGF receptor (EGF-R) activation was also necessary for trefoil auto- and cross-induction, and both spasmolytic polypeptide (SP) and ITF stimulation of gastric cell lines led to phosphorylation of EGF-R. Nevertheless, ITF and ITF-thioredoxin cell surface binding at 4 degrees C colocalized not with EGF-R, but with CD71, which is found in clathrin-coated pits, suggesting that integration of trefoil peptide responses may occur after internalization. As EGF-R expression is itself strongly induced after mucosal damage, the trefoil/EGF-R relationship may be pivotal in the generation and maintenance of the mucosal repair phenotype.

Tanshinone IIA isolated from Salvia miltiorrhiza BUNGE induced apoptosis in HL60 human premyelocytic leukemia cell line.

Apoptosis is a new therapeutic target of cancer research. Tanshinone IIA isolated from Salvia miltiorrhiza BUNGE, a traditional oriental medical herb, was observed to induce apoptosis in HL60 human premyelocytic leukemia cell line. Tanshinone IIA induced DNA fragmentation into the multiples of 180 bp and increased the percentage of hypodiploid cells in flow cytometry after propidium iodide (PI) staining. Tanshinone IIA-induced apoptosis is accompanied by the specific proteolytic cleavage of poly(ADP-ribose) polymerase (PARP) and the activation of caspase-3, a major component in apoptotic cell death mechanism.

Mice lacking secretory phospholipase A2 show altered apoptosis and differentiation with Helicobacter felis infection.

BACKGROUND & AIMS: Infection with Helicobacter pylori uniformly leads to a chronic superficial gastritis that may progress to atrophic gastritis, a premalignant process. A mouse model of Helicobacter felis infection was used to study possible genetic determinants of the response to infection. METHODS: Three inbred mouse strains with known secretory phospholipase A2 (sPLA2) genotypes [BALB/c (+/+), C3H/HeJ (+/+), and C57BL/6 (-/-)] were orally infected with H. felis and examined longitudinally using routine histology, immunocytochemistry, electron microscopy, proliferating cell nuclear antigen, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling, and Northern and Western blot studies. RESULTS: Only the C57BL/6 strain showed increased gastric fundic proliferation and apoptosis in response to infection. In addition, the C57BL/6 mouse showed a marked loss of parietal and chief cells, along with a marked expansion of an aberrant gastric mucous cell lineage that stained positive for spasmolytic polypeptide. In contrast, no significant change in these cell types was observed in BALB/c and C3H/HeJ strains. Increased expression of sPLA2 was observed in BALB/c and C3H/HeJ after H. felis infection, whereas sPLA2 expression was absent in C57BL/6 mice. CONCLUSIONS: H. felis infection leads to increased apoptosis and altered cellular differentiation in the C57BL/6 mouse, a strain that lacks gastric sPLA2 expression. Because sPLA2 has been identified recently as the MOM1 (modifier of MIN) locus that influences polyp formation in the colon, these studies suggest that sPLA2 may also influence the gastric epithelial response to Helicobacter infection.