Sex Differences in Gut Microbiota.

Humans carry numerous symbiotic microorganisms in their body, most of which are present in the gut. Although recent technological advances have produced extensive research data on gut microbiota, there are various confounding factors (e.g., diet, race, medications) to consider. Sex is one of the important variables affecting the gut microbiota, but the association has not yet been sufficiently investigated. Although the results are inconsistent, several animal and human studies have shown sex differences in gut microbiota. Herein, we review these studies to discuss the sex-dependent differences as well as the possible mechanisms involved.

Oral administration of lactobacilli isolated from Jeotgal, a salted fermented seafood, inhibits the development of 2,4-dinitrofluorobenzene-induced atopic dermatitis in mice.

Certain strains of lactobacilli have been reported to exert favorable effects on atopic dermatitis (AD). Jeotgal, a traditional Korean food, is a salted fermented seafood known to harbor many lactic acid bacteria. In the present study, two novel lactobacillus strains were isolated from Jeotgal, and their anti-AD effects were investigated. Lactobacilli isolated from Jeotgal were identified, according to conjugated linoleic acid-producing activity, as Lactobacillus plantarum (JBCC105645 and JBCC105683). AD-like skin lesions were induced in BALB/c mice using dinitrofluorobenzene (DNFB). Ear swelling, histological analysis and serum immunoglobulin E (IgE) levels in mice were evaluated to investigate the anti-AD effects of lactobacilli. Cytokine production of ex vivo cluster of differentiation (CD)4+ T cells, and interleukin (IL)-12 production of in vitro macrophages were also evaluated to establish a putative mechanism of the action of lactobacilli. Administration of JBCC105645 or JBCC105683 suppressed ear swelling and serum IgE levels in DNFB-treated mice (P<0.05). Notably, JBCC105645 was more effective than JBCC105683 (P<0.05). Treatment with the lactobacilli also induced a significant decrease in IL-4 production with concomitant increase in interferon (IFN)-γ production in DNFB-exposed CD4+ T cells, and an increase in IL-12 production in macrophages (P<0.05). Taken together, the lactobacilli isolated from Jeotgal may suppress the development of AD-like skin inflammation in mice by modulating IL-4 and IFN-γ production in CD4+ T cells, presumably via enhancing IL-12 production by macrophages.

Hydrogen Treatment Protects against Cell Death and Senescence Induced by Oxidative Damage.

Hydrogen has potential for preventive and therapeutic applications as an antioxidant. However, micro- and macroparticles of hydrogen in water disappear easily over time. In order to eliminate reactive oxygen species (ROS) related with the aging process, we used functional water containing nanoparticle hydrogen. Nanoparticle hydrogen does not disappear easily and collapse under water after long periods of time. We used murine embryonic fibroblasts that were isolated from 12.5-day embryos of C57BL/6 mice. We investigated the ability of nanoparticle hydrogen in water to suppress hydroxyurea-induced ROS production, cytotoxicity, and the accumulation of ß-galactosidase (an indicator of aging), and promote cell proliferation. The accumulation of ß-galactosidase in the cytoplasm and the appearance of abnormal nuclei were inhibited by daily treatment of cells with hydrogen water. When the aging process was accelerated by hydroxyurea-induced oxidative stress, the effect of hydrogen water was even more remarkable. Thus, this study showed the antioxidant and anti-senescence effects of hydrogen water. Nanoparticle hydrogen water is potentially a potent anti-aging agent.

Factors Influencing the Diagnostic Accuracy of Acoustic Radiation Force Impulse Elastography in Patients with Chronic Hepatitis B.

BACKGROUND/AIMS: To determine factors predictive of discordance in staging liver fibrosis using liver biopsy (LB) and acoustic radiation force impulse (ARFI) elastography in patients with chronic hepatitis B (CHB). METHODS: Consecutive patients with CHB who underwent LB and ARFI elastography on the same day from November 2010 to March 2013 were prospectively recruited from three tertiary hospitals. RESULTS: We analyzed 105 patients (median age of 47 years). The F0-1, F2, F3, and F4 fibrosis stages were identified in 27 (25.7%), 27 (25.7%), 21 (20.0%), and 30 (28.6%) patients, respectively. The areas under the receiver operating characteristics curves for ARFI elastography in assessing ≥ F2, ≥ F3, and F4 was 0.814, 0.848, and 0.752, respectively. The discordance of at least one stage between LB and ARFI was observed in 68 patients (64.8%) and of at least two stages in 16 patients (15.2%). In a multivariate analysis, advanced fibrosis stage (F3-4) was the only factor that was negatively correlated with one-stage discordance (p=0.042). Moreover, advanced fibrosis stage was negatively (p=0.016) correlated and body mass index (BMI) was positively (p=0.006) correlated with two-stage discordance. CONCLUSIONS: Advanced fibrosis stage (F3-4) was a predictor of nondiscordance between LB and ARFI elastography; BMI also influenced the accuracy of ARFI elastography.

Association of Intraplaque Hemorrhage and Acute Infarction in Patients With Basilar Artery Plaque.

BACKGROUND AND PURPOSE: High-resolution magnetic resonance imaging (HRMRI) is ideal for serial examination of diseased arterial walls because it is noninvasive and has superior capability of discriminating tissue characteristics. The aim of this study is to evaluate the prevalence and clinical relevance of intraplaque hemorrhage (IPH) in patients with basilar artery (BA) atherosclerosis using HRMRI. METHODS: We analyzed HRMRI and clinical data from 74 patients (45 symptomatic and 29 asymptomatic), all of whom had >50% BA stenosis. High-signal intensity within a BA plaque on magnetization-prepared rapid acquisition with gradient-echo was defined as an area with an intensity that was >150% of the signal from the adjacent muscle. The relationship between IPH within a BA plaque region and clinical presentation was analyzed. RESULTS: Thirty patients were positive for IPH on HRMRI (42.3%, 24 symptomatic and 6 asymptomatic). Symptomatic lesions in the MR-positive IPH group were significantly more prevalent than in the MR-negative group (80.0% versus 48.8%; P<0.01). Also, MR-predicted IPH was significantly more prevalent in the high-grade stenosis group (P<0.001) than in the low-grade group. The relative risk of an acute focal stroke event among patients who were magnetization-prepared rapid acquisition with gradient-echo-positive for IPH compared with patients who were magnetization-prepared rapid acquisition with gradient-echo-negative was 1.64. CONCLUSIONS: IPH within a BA plaque region on HRMRI is highly prevalent and is associated with acute stroke.

Transcriptome analysis indicates TFEB1 and YEATS4 as regulatory transcription factors for drug resistance of ovarian cancer.

Ovarian cancer is an intractable disease because patients with ovarian cancer frequently develop drug resistance after long-term chemotherapy. Despite the availability of cumulative information on drug-resistant patients, strategies to reverse drug resistance have still not been established. In this study, we analyzed drug resistance-associated transcription factors (TFs) in ovarian cancer. Gene expression profiles of 15 drug-resistant and 11 drug-sensitive patients with ovarian cancer were compared. Our results showed that TFs TFEB1 and YEATS4 regulated the expression of downstream target genes. These 2 TFs have already been implicated in tumorigenesis or metastasis. To our knowledge, this is the first study to evaluate the involvement of these TFs in drug resistance of ovarian cancer. Interestingly, 70% knockdown of each of these TFs with siRNAs resulted in approximately 20%~30% recovery of drug sensitivity. Further, combination treatment of ovarian cancer cells with TFEB1 and YEATS4 siRNAs resulted in 35% reversal of drug resistance. The effect of these TFs on chemoresistance seemed to be associated with intrinsic apoptosis-related pathways, such as p53 activation, and not with the suppression of drug transport. Thus, we suggest a novel approach to reverse chemoresistance of ovarian cancer by suppressing TFEB1 and YEATS4.

Pharmacogenomic analysis indicates potential of 1,5-isoquinolinediol as a universal anti-aging agent for different tissues.

The natural aging of multicellular organisms is marked by a progressive decline in the function of cells and tissues. The accumulation of senescent cells in tissues seems to eventually cause aging of the host. Nevertheless, gene expression that influences aging is unlikely to be conserved between tissues, and age-related loss of function seems to depend on a variety of mechanisms. This is a concern when developing anti-aging drugs in geriatric clinical pharmacology. We have sought a universal agent to redundantly cover gene expression despite the variation in differentially expressed genes between tissues. Using a minimally modified connectivity map, the poly (ADP-ribose) polymerase (PARP) inhibitor 1,5-isoquinolinediol was selected as a potent candidate, simultaneously applicable to various tissues. This choice was validated in vitro. Treatment of murine embryonic fibroblasts with 1,5-isoquinolinediol appeared to efficiently suppress the rate of replicative senescence at a concentration of 0.1 µM without resulting in cell death. The appearance of abnormal nuclei and accumulation of ß-galactosidase in the cytoplasm were inhibited by daily treatment with the agent. When the aging process was accelerated by hydroxyurea-induced oxidative stress, the effect was even more noticeable. Thus, 1,5-isoquinolinediol may potentially be developed as an agent to prolong life.

Leukopenia predicts remission in patients with inflammatory bowel disease and Behcet's disease on thiopurine maintenance.

BACKGROUNDS: The thiopurine drugs, azathioprine (AZA), and 6-mercaptopurine (6-MP) are well-established drugs for the treatment of inflammatory bowel disease (IBD). Although leukopenia is a well-recognized side effect of AZA/6-MP treatment, its association with therapeutic effects has yet to be determined. We therefore evaluated the influences of thiopurine-induced leukopenia on the long-term prognosis of IBD. METHODS: We included 196 IBD patients [45 with ulcerative colitis (UC), 68 with Crohn's disease (CD), and 83 with intestinal Behçet's disease (BD)] who were treated with AZA/6-MP and achieved remission between January 2006 and December 2012. We retrospectively analyzed patient characteristics, AZA/6-MP maintenance dose (mg/kg), the lowest white blood cell (WBC) count during AZA/6-MP treatment, duration of remission, and the occurrence of relapse. We compared the clinical variables between leukopenic (n = 120, WBC count <4,000/µL) and nonleukopenic (n = 76, WBC count ≥ 4,000/µL) patients. RESULTS: The two groups were well matched for baseline clinical characteristics. The cumulative relapse-free survival rate was higher in the leukopenic group than the nonleukopenic group by Kaplan-Meier survival analysis (log-rank test, P < 0.001). On multivariate analysis, age, duration of AZA/6-MP treatment, presence of macrocytosis, and the presence of leukopenia were negatively associated with relapse (odds ratios 0.975, 0.988, 0.563, and 0.390, respectively). On subgroup analysis, the cumulative relapse-free survival rate was significantly higher in the leukopenic group than in the nonleukopenic group for all types of IBDs, including UC, CD, and intestinal BD (log-rank test, P = 0.032, 0.047, and 0.002, respectively). CONCLUSION: Leukopenia during thiopurine maintenance therapy was associated with prolonged remission in patients with IBD and Behcet's disease.

Prognostic value of the combined use of transient elastography and fibrotest in patients with chronic hepatitis B.

BACKGROUND & AIMS: Liver stiffness (LS) measurement using transient elastography and the FibroTest (FT) are alternatives to liver biopsy (LB) in assessing liver fibrosis. We investigated the prognostic role of the combined use of LS and FT in predicting liver-related events (LREs) in patients with chronic hepatitis B (CHB). METHODS: Consecutive patients with CHB who underwent LB, along with LS and FT on the same day were recruited. LRE was defined as hepatic decompensation, hepatocellular carcinoma (HCC) or liver-related death. RESULTS: A total of 151 patients (86 male) were analyzed. During follow-up (median 59.9 months), overall 18 (11.9%) patients experienced LREs. The areas under receiver-operating characteristic curves of LS, FT, LS + FT and LS × FT in predicting LRE were 0.701, 0.668, 0.702 and 0.741 respectively. After adjusting for age and histological fibrosis staging, significant variables in univariate analysis (both P < 0.05), LS + FT and LS × FT were independent predictors of LREs with hazard ratios (HRs) of 1.080 and 1.126 (all P < 0.05) respectively. When subjects were divided into three groups according to quartile stratification (low quartile, interquartile and high quartile) using LS + FT and LS × FT, cumulative LRE development rate significantly increased with a corresponding increase in value among three groups respectively (log-rank test, all P < 0.05). CONCLUSION: The combined use of LS and FT significantly predicted forthcoming LRE development, but with only a slight additional benefit compared to LS or FT alone.

Clinicopathologic characteristics of interval gastric cancer in Korea.

BACKGROUND/AIMS: Interval gastric cancer (IGC) is defined as cancer that is diagnosed between the time of screening and postscreening esophagogastroduodenoscopy (EGD). Un-fortunately, little is known about the characteristics of IGC in Korea, a country with a high incidence of gastric cancer. The aim of this study was to evaluate the clinicopathologic char-acteristics of IGCs in Korea. METHODS: From January 2006 to July 2011, a total of 81,762 subjects underwent screening EGD at Yonsei University Health Promotion Center, Seoul, Ko-rea. We defined missed cancer as cancer diagnosed within 1 year of screening EGD and latent cancer as cancer diag-nosed more than 1 year after EGD. RESULTS: A total of 16 IGC patients (17 lesions; three missed cancers and 14 latent can-cers) were identified, with a mean age of 60.68 years and a mean interval time of 19.64 months. IGCs tended to be undifferentiated (12/17, 70.6%), located in the lower body of the stomach (12/17, 70.6%) and exhibited flat/depressed endoscopic morphology (11/17, 64.7%). The patients with missed cancer were generally younger than the patients with latent cancer (51.3 years vs 62.8 years, p=0.037), and the patients with undifferentiated cancer were significantly younger than those with differentiated cancer (57.0 years vs 68.8 years, p=0.008). CONCLUSIONS: IGCs tended to be undif-ferentiated, located in the lower body of the stomach, and exhibited flat/depressed endoscopic morphology. (Gut Liver, 2015;9167-173).

Non-invasive prediction of development of hepatocellular carcinoma using transient elastography in patients with chronic liver disease.

Prognosis of patients with chronic liver disease is determined by the extent and progression of liver fibrosis, which may ultimately lead to hepatocellular carcinoma (HCC). Liver biopsy (LB) is regarded as the gold standard to estimate the extent of liver fibrosis. However, because LB has several limitations, the foremost being its invasiveness, several non-invasive methods for assessing liver fibrosis have been proposed. Of these, transient elastography (TE) provides an accurate representation of the extent of liver fibrosis. Furthermore, recent studies have focused on the usefulness of TE for assessing the risk of HCC development and HCC recurrence after curative treatment, and developed novel models to calculate the risk of HCC development based on TE findings. These issues are discussed in this expert review.

Factors predictive of high-risk adenomas at the third colonoscopy after initial adenoma removal.

Evaluating predictive factors for high-risk adenomas at the third colonoscopy based on two prior colonoscopies may help evaluate high-risk adenoma at the third colonoscopy. We analyzed clinical data of 131 patients at Severance Hospital from January 1997 to January 2011. All of them underwent two subsequent colonoscopies after removal of adenomas during an initial colonoscopy. Among 20 patients with high-risk adenoma at the first and second colonoscopies, 10 (50%) patients had high-risk adenoma at the third colonoscopy. Among the 67 patients who had high-risk adenoma only once at the first or second colonoscopy, 15 (22.4%) patients had high-risk adenoma at the third colonoscopy but among the 44 patients without high-risk adenoma at the first and second colonoscopies, only 1 (2.3%) patient had high-risk adenoma at the third colonoscopy (P < 0.001). A multivariate time dependent covariate Cox regression analysis confirmed that high-risk adenoma at the first and/or second colonoscopy (HR, 9.56; 95% CI, 2.37-38.54; P = 0.002) was independent predictor of high-risk adenoma at the third colonoscopy. Given these findings, data from two prior colonoscopies, not one prior examination, may help identify high-risk populations at the third colonoscopy who require careful colonoscopic surveillance.

Antiviral efficacies of currently available rescue therapies for multidrug-resistant chronic hepatitis B.

BACKGROUND/AIMS: The incidence of multidrug-resistant (MDR) chronic hepatitis B (CHB) during sequential lamivudine (LAM) and adefovir dipivoxil (ADV) treatment is increasing. We investigated the antiviral efficacies of various rescue regimens in patients who failed sequential LAM-ADV treatment. METHODS: Forty-eight patients (83.3% of whom were HBeAg-positive) who failed sequential LAM-ADV treatment were treated with one of the following regimens: entecavir (ETV) (1 mg) monotherapy (n=16), LAM+ADV combination therapy (n=20), or ETV (1 mg)+ADV combination therapy (n=12). All patients had confirmed genotypic resistance to both LAM and ADV and were evaluated every 12 weeks. RESULTS: The baseline characteristics and treatment duration did not differ significantly among the study groups. During the treatment period (median duration: 100 weeks), the decline of serum HBV DNA from baseline tended to be greatest in the ETV+ADV group at all-time points (week 48: -2.55 log(10) IU/mL, week 96: -4.27 log(10) IU/mL), but the difference was not statistically significant. The ETV+ADV group also tended to have higher virologic response rates at 96 weeks compared to the ETV monotherapy or LAM+ADV groups (40.0% vs. 20.0% or 20.0%, P=0.656), and less virologic breakthrough was observed compared to the ETV monotherapy or LAM+ADV groups (8.3% vs. 37.5% or 30.0%; P=0.219), but again, the differences were not statistically significant. HBeAg loss occurred in one patient in the ETV+ADV group, in two in the ETV monotherapy group, and in none of the LAM+ADV group. The safety profiles were similar in each arm. CONCLUSIONS: There was a nonsignificant tendency toward better antiviral efficacy with ETV+ADV combination therapy compared to LAM+ADV combination therapy and ETV monotherapy for MDR CHB in Korea, where tenofovir is not yet available.

Crohn's duodeno-colonic fistula preoperatively closed using a detachable endoloop and hemoclips: a case report.

Duodeno-colonic fistula is an enterocolonic fistula that occurs as a complication of Crohn's disease. Symptoms of duodeno-colonic fistula are similar to those of Crohn's disease, such as weight loss and diarrhea. The treatment of choice is surgery, although medical treatment may also be considered. However, surgery is recommended when all available medical therapies have been ineffective. In this case, we report a secondary duodeno-colonic fistula due to Crohn's disease that was temporarily managed by an endoscopic procedure with a detached endoloop and hemoclips as a bridging therapy to final surgical repair.

Discordance between liver biopsy and FibroTest in assessing liver fibrosis in chronic hepatitis B.

BACKGROUND AND AIMS: The FibroTest (FT) demonstrated excellent diagnostic performance in the prediction of liver fibrosis in patients with chronic hepatitis B (CHB). Here, we aimed to identify predictors of discordance between FT and liver biopsy (LB) in Asian patients with CHB. METHODS: Consecutive patients with CHB who underwent both LB and FT on the same day between 2007 and 2010 were recruited from three medical institutes. Laboratory evaluations including specific parameters for calculating FT score, such as α2-macroglobulin, apolipoprotein A1, haptoglobin, γ-glutamyl transpeptidase, and total bilirubin levels, were obtained. The Batts and Ludwig scoring system was used for histological analysis. RESULTS: A total of 330 patients (200 male and 130 female) were analyzed. Discordances of at least two fibrosis stages between FT and LB were observed in 30 (9.1%) patients; using FT, fibrosis was underestimated in 25 patients and overestimated in 5 patients with reference to LB. Patients with discordance had a higher proportion of F3-4 (P<0.001) and F4 (P = 0.012) compared with those with nondiscordance. The discordance rate was significantly higher in those with F3-4 than those with F1-2 (15.4% vs. 3.0%, P<0.001). Multivariate analysis demonstrated F3-4 at LB as the only independent factor for discordance (P<0.001; odds ratio 5.95). After adjusting fibrosis stages, neither necroinflammatory activity on histology nor serum ALT level influenced FT values independently. CONCLUSION: Advanced fibrosis stage (F3-4) is the sole factor of discordance between FT and LB in Asian patients with CHB.

Combination treatment of localized concurrent chemoradiation therapy and transarterial chemoembolization in locally advanced hepatocellular carcinoma with intrahepatic metastasis.

PURPOSE: Although sorafenib has been approved for treating advanced hepatocellular carcinoma (HCC), its high cost, frequent adverse events, and unsatisfactory efficacy remain unresolved. We evaluated the efficacy and safety of the combination treatment of localized concurrent chemoradiation therapy (CCRT) for locally advanced HCC with portal vein thrombosis (PVT) and transarterial chemoembolization (TACE) for intrahepatic metastasis. METHODS: Between January 2006 and June 2011, 30 patients with HCC with portal vein invasion and intrahepatic metastasis were enrolled. After TACE for intrahepatic metastasis, localized CCRT (45 Gy over 5 weeks with conventional fractionation and hepatic artery infusional chemotherapy using 5-fluorouracil as a radiosensitizer, administered during the first and fifth weeks of radiotherapy) was used to treat main HCC with PVT. The modified response evaluation criteria in solid tumors (mRECIST) were used to evaluate tumor response. RESULTS: The median age of the patients (26 men, 4 women) was 51 years. Objective response rates were 30.0% (9/30) and 32.1% (9/28) in the intention-to-treat and per protocol analyses, respectively. The median progression-free survival (PFS) and overall survival (OS) were 4.5 and 9.8 months, respectively. Baseline α-fetoprotein (AFP) correlated significantly with PFS (P = 0.008), whereas baseline AFP, completion of the protocol, and overall radiological response influenced OS significantly (all P < 0.05). All adverse events were predictable and manageable with conservative care. CONCLUSIONS: Combination treatment of localized CCRT and TACE was effective and tolerable in patients with locally advanced HCC with PVT and intrahepatic metastasis. This protocol may be an alternative option when sorafenib cannot be prescribed.

Applicability of BCLC stage for prognostic stratification in comparison with other staging systems: single centre experience from long-term clinical outcomes of 1717 treatment-naïve patients with hepatocellular carcinoma.

BACKGROUND: The most informative staging system regarding survival outcomes for treatment-naïve hepatocellular carcinoma (HCC) remains debated. We evaluated prognostic values of Barcelona Clinic Liver Cancer (BCLC) stage compared with other staging systems, and identified discrepancies between treatment options chosen in Korean clinical practice and BCLC guidelines. METHODS: Between 2003 and 2008, 1717 prospectively enrolled patients with treatment-naïve HCC were analysed. Prognostic ability of each staging system was assessed using time-dependent receiver-operating characteristic (ROC) curves. RESULTS: The most common aetiology was hepatitis B virus (1238, 72.1%); 167 (9.8%) patients were classified as BCLC stage 0, 526 (30.6%) as A, 333 (19.4%) as B, 608 (35.4%) as C and 83 (4.8%) as D. Median overall survival was 22.5 months, and 1-, 2-, 3-, 4-, and 5-year survival rates were 62.6, 48.3, 39.9, 34.7, and 29.3% respectively. Of six staging systems, BCLC had the highest area under ROC (AUROC; 0.821) for overall survival, followed by JIS (0.809), Tokyo score (0.771), CLIP (0.746), CUPI (0.701) and GRETCH (0.685) system. In both subgroups stratified according to treatment strategy (curative vs. palliative), BCLC also showed the best AUROCs (curative, 0.708/palliative, 0.807) for overall survival. Regarding discrepancies between treatment options chosen in our cohort and BCLC guidelines, more than half with very early/early-stage HCC underwent transarterial chemoembolization, rather than resection or local ablative therapy; most of those with advanced-stage HCC received intra-arterial chemotherapy-based treatments rather than sorafenib. CONCLUSION: BCLC was the best long-term prognostic model for treatment-naïve HCC in a large-scale Korean cohort. However, treatment modalities did not exactly match BCLC paradigm.

"Normal" liver stiffness values differ between men and women: a prospective study for healthy living liver and kidney donors in a native Korean population.

BACKGROUND AND AIM: Liver stiffness (LS) measurement can distinguish individuals with potential liver disease (LD) from the general population. However, if LS is sex-sensitive, prevalence of LD may be incorrectly estimated when the same reference LS value is applied irrespective of sex. Here, we evaluated whether normal ranges of LS differ between healthy men and women. METHODS: LS was measured in a cohort of healthy living liver and kidney donors, none of whom suffered from diabetes mellitus, hypertension, hepatitis B or C virus infection, heart or liver dysfunction, or metabolic syndrome. Patients with abnormal laboratory findings related to potential LD (platelet count < 150 × 10(3) /µL; aspartate aminotransferase > 40 IU/L; alanine aminotransferase [ALT] > 40 IU/L; albumin < 3.3 g/dL; total bilirubin > 1.2 mg/dL; gamma-glutamyl transpeptidase > 54 IU/L; alkaline phosphatase > 115 IU/L) were excluded. RESULTS: Among 242 patients analyzed, the mean age was 34.1 for men (n = 121) and 40.5 years for women (n = 121) (P < 0.001). Men had a higher mean LS value than women (5.2 ± 1.2 vs 4.8 ± 1.1 kPa/P < 0.001). Multivariate-linear regression analysis identified sex as the only independent factor for LS values (ß = 0.361/P = 0.021). Using the 5th-95th percentiles, we determined normal LS ranges of 3.7-7.0 kPa in men and 3.3-6.8 kPa in women. In subgroups with ALT < 30 IU/L (subgroup-1, n = 216) and ALT < 20 IU/L (subgroup-2, n = 163), men had significantly higher LS values than women (5.2 ± 1.3 vs 4.7 ± 1.1 kPa/P = 0.003 and 5.1 ± 1.2 vs 4.7 ± 1.1 kPa/P = 0.030, respectively), demonstrating an independent sex effect (ß = 0.483/P = 0.003 and ß = 0.389/P = 0.030, respectively). CONCLUSIONS: An independent sex effect on LS values was confirmed. Thus, sex-specific references should be used for effective screening based on LS measurements.

Amelioration of hyperglycemia by intestinal overexpression of glucagon-like peptide-1 in mice.

To investigate whether the local production of glucagon-like peptide-1 (GLP-1) in the intestine can differentiate intestinal stem/progenitor cells into insulin-producing cells, we intra-intestinally injected a recombinant adenovirus expressing GLP-1 (rAd-GLP-1) into diabetic mice. There were no significant differences in body weight or food intake between rAd-GLP-1- and rAd-betaGAL-treated control mice. rAd-GLP-1-treated mice showed intestinal insulin mRNA expression, insulin- and glucagon-positive cells in the intestine, and significantly increased serum insulin, but not glucagon. rAd-GLP-1 injection significantly reduced blood glucose levels and improved glucose tolerance compared with controls. Expression of transcription factors related to beta cell differentiation, neurogenin 3 (ngn3) and neurogenin differentiation factor (NeuroD), was detected in the intestine at 2 weeks after rAd-GLP-1 injection. We suggest that expression of GLP-1 in the intestine by intra-intestinal delivery of rAd-GLP-1 may induce differentiation of intestinal stem/progenitor cells into insulin-producing cells, mediated by ngn3 and NeuroD expression, contributing to lowered blood glucose levels in diabetic mice.