Mathematical theory of Bayesian statistics for unknown information source.

In statistical inference, uncertainty is unknown and all models are wrong. That is to say, a person who makes a statistical model and a prior distribution is simultaneously aware that both are fictional candidates. To study such cases, statistical measures have been constructed, such as cross validation, information criteria and marginal likelihood; however, their mathematical properties have not yet been completely clarified when statistical models are under- or over-parametrized. We introduce a place of mathematical theory of Bayesian statistics for unknown uncertainty, which clarifies general properties of cross validation, information criteria and marginal likelihood, even if an unknown data-generating process is unrealizable by a model or even if the posterior distribution cannot be approximated by any normal distribution. Hence it gives a helpful standpoint for a person who cannot believe in any specific model and prior. This paper consists of three parts. The first is a new result, whereas the second and third are well-known previous results with new experiments. We show there exists a more precise estimator of the generalization loss than leave-one-out cross validation, there exists a more accurate approximation of marginal likelihood than Bayesian information criterion, and the optimal hyperparameters for generalization loss and marginal likelihood are different. This article is part of the theme issue 'Bayesian inference: challenges, perspectives, and prospects'.

Gender-specific development of experimental autoimmune cholangitis induced by double-stranded RNA.

Here we investigated the gender difference in murine cholangitis resembling human primary biliary cholangitis (PBC) caused by synthetic double-stranded RNA, and underlying hepatic innate immune responses. Female C57Bl/6 mice given repeated injections of polyinosinic-polycytidylic acid (poly I:C) for 24 weeks developed overt cholangitis with positive serum anti-mitochondria-M2 antibody, whereas male mice showed minimal pathological changes without induction in autoantibody. Poly I:C induced hepatic inflammatory cytokines and type-I interferons predominantly in females. Hepatic expression levels of toll-like receptor (TLR) 3 and melanoma differentiation-associated protein (MDA) 5 were equivalent in both genders; however, both mRNA and protein levels of retinoic acid-inducible gene (RIG)-I were nearly doubled in female livers. Following 4-week injections of poly I:C, not only hepatic RIG-I, but also TLR3 and MDA5 showed female-predominance. Moreover, hepatic RIG-I levels were 25% lower in ovariectomized mice, whereas supplementation of 17 ß-estradiol enhanced hepatic RIG-I expression, as well as cytokine induction. These results clearly indicate that hepatic RIG-I expression is potentiated by estrogen, and triggers gender-dependent hepatic innate immune response against double-stranded RNA, which most likely play a pivotal role in the pathogenesis of autoimmune cholangiopathies including PBC.

A Soluble Fiber Diet Increases Bacteroides fragilis Group Abundance and Immunoglobulin A Production in the Gut.

Immunoglobulin A (IgA) is essential for defense of the intestinal mucosa against harmful pathogens. Previous studies have shown that Bacteroidetes, the major phylum of gut microbiota together with Firmicutes, impact IgA production. However, the relative abundances of species of Bacteroidetes responsible for IgA production were not well understood. In the present study, we identified some specific Bacteroidetes species that were associated with gut IgA induction by hsp60-based profiling of species distribution among Bacteroidetes The levels of IgA and the expression of the gene encoding activation-induced cytidine deaminase (AID) in the large intestine lamina propria, which is crucial for class switch recombination from IgM to IgA, were increased in soluble high-fiber diet (sHFD)-fed mice. We found that Bacteroides acidifaciens was the most abundant Bacteroidetes species in both sHFD- and normal diet-fed mice. In addition, the gut IgA levels were associated with the relative abundance of Bacteroides fragilis group species such as Bacteroides faecis, Bacteroides caccae, and Bacteroides acidifaciens Conversely, the ratio of B. acidifaciens to other Bacteroidetes species was reduced in insoluble high-fiber diet fed- and no-fiber diet-fed mice. To investigate whether B. acidifaciens increases IgA production, we generated B. acidifaciens monoassociated mice and found increased gut IgA production and AID expression. Collectively, soluble dietary fiber increases the ratio of gut Bacteroides fragilis group, such as B. acidifaciens, and IgA production. This might improve gut immune function, thereby protecting against bowel pathogens and reducing the incidence of inflammatory bowel diseases.IMPORTANCE Immunoglobulin A (IgA) is essential for defense of the intestinal mucosa against harmful pathogens. Gut microbiota impact IgA production, but the specific species responsible for IgA production remain largely elusive. Previous studies have shown that IgA and Bacteroidetes, the major phyla of gut microbiota, were increased in soluble high-fiber diet-fed mice. We show here that the levels of IgA in the gut and the expression of activation-induced cytidine deaminase (AID) in the large intestine lamina propria, which is crucial for class switch recombination from IgM to IgA, were correlated with the abundance of Bacteroides fragilis group species such as Bacteroides faecis, Bacteroides caccae, and Bacteroides acidifaciensB. acidifaciens monoassociated mice increased gut IgA production and AID expression. Soluble dietary fiber may improve gut immune function, thereby protecting against bowel pathogens and reducing inflammatory bowel diseases.

The Chemical Chaperone 4-Phenylbutyric Acid Prevents Alcohol-Induced Liver Injury in Obese KK-Ay Mice.

BACKGROUND: Co-occurrence of metabolic syndrome and chronic alcohol consumption is increasing worldwide. The present study investigated the effect of the chemical chaperone 4-phenylbutyric acid (PBA)-which has been shown to alleviate dietary steatohepatitis caused by endoplasmic reticulum (ER) stress-on chronic-plus-binge ethanol (EtOH)-induced liver injury in a mouse model of obesity. METHODS: Male KK-Ay mice (8 weeks old) were fed a Lieber-DeCarli diet (5% EtOH) for 10 days. Some mice were given PBA intraperitoneally (120 mg/kg body weight, daily) during the experimental period. On day 11, mice were gavaged with a single dose of EtOH (4 g/kg body weight). Control mice were given a dextrin gavage after being pair-fed a control diet. All mice were then serially euthanized before or at 9 hours after gavage. RESULTS: Chronic-plus-binge EtOH intake induced massive hepatic steatosis along with hepatocyte apoptosis and inflammation, which was reversed by PBA treatment. Administration of PBA also suppressed chronic-plus-binge EtOH-induced up-regulation of ER stress-related genes including binding immunoglobulin protein (Bip), unspliced and spliced forms of X-box-binding protein-1 (uXBP1 and sXBP1, respectively), inositol trisphosphate receptor (IP3R), and C/EBP homologous protein (CHOP). Further, it blocked chronic-plus-binge EtOH-induced expression of the oxidative stress marker heme oxygenase-1 (HO-1) and 4-hydroxynonenal. Chronic EtOH alone (without binge) increased Bip and uXBP1, but it did not affect those of sXBP1, IP3R, CHOP, or HO-1. PBA reversed the prebinge expression of these genes to control levels, but it did not affect chronic EtOH-induced hepatic activity of cytochrome P450 2E1. CONCLUSIONS: Binge EtOH intake after chronic consumption induces massive ER stress-related oxidative stress and liver injury in a mouse model of obesity through dysregulation of the unfolded protein response. PBA ameliorated chronic-plus-binge EtOH-induced liver injury by reducing ER and oxidative stress after an EtOH binge.

Maternal High Fiber Diet during Pregnancy and Lactation Influences Regulatory T Cell Differentiation in Offspring in Mice.

Short-chain fatty acids (SCFAs), the end products of dietary fiber, influence the immune system. Moreover, during pregnancy the maternal microbiome has a great impact on the development of the offspring's immune system. However, the exact mechanisms by which maternal SCFAs during pregnancy and lactation influence the immune system of offspring are not fully understood. We investigated the molecular mechanisms underlying regulatory T cell (Treg) differentiation in offspring regulated by a maternal high fiber diet (HFD). Plasma levels of SCFAs in offspring from HFD-fed mice were higher than in those from no fiber diet-fed mice. Consequently, the offspring from HFD-fed mice had higher frequencies of thymic Treg (tTreg) and peripheral Tregs We found that the offspring of HFD-fed mice exhibited higher autoimmune regulator (Aire) expression, a transcription factor expressed in the thymic microenvironment, suggesting SCFAs promote tTreg differentiation through increased Aire expression. Notably, the receptor for butyrate, G protein-coupled receptor 41 (GPR41), is highly expressed in the thymic microenvironment and Aire expression is not increased by stimulation with butyrate in GPR41-deficient mice. Our studies highlight the significance of SCFAs produced by a maternal HFD for Treg differentiation in the thymus of offspring. Given that Aire expression is associated with the induction of tTregs, the maternal microbiome influences Treg differentiation in the thymus of offspring through GPR41-mediated Aire expression.

Formation of p62-positive inclusion body is associated with macrophage polarization in non-alcoholic fatty liver disease.

AIM: Hepatic inclusion composed of autophagy-specific substrate p62 is one of the histological features of non-alcoholic fatty liver disease (NAFLD) and can be a precursor to hepatic carcinogenesis. The expression of p62 was enhanced by not only autophagic dysfunction but also oxidative stress and inflammation. M1/M2 phenotypic balance of macrophages plays a pivotal role in the progression of NAFLD. We evaluated the correlation between macrophage polarization and the formation of p62 aggregation in NAFLD. METHODS: Liver biopsy specimens from NAFLD patients were analyzed by immunohistochemical staining for M1 macrophage marker CD11c, M2 macrophage marker CD163, and p62/SQSTM1 (p62). The histological severity of NAFLD is assessed by a NAFLD activity score (NAS). The number of autophagic vesicles in hepatocytes was visualized and counted by using transmission electron microscopy. RESULTS: The aggregation of p62 was undetectable in control, whereas hepatocytes with p62 aggregation were observed in approximately 88% of NAFLD specimens. The number of hepatocytes with p62 aggregation was positively correlated with the number of autophagic vesicles, serum alanine aminotransferase, NAS, fibrosis, and the number of CD11c-positive cells, but not CD163-positive cells. Assembly of CD11c-positive cells was observed around hepatocytes with p62 aggregation. The ratio of CD11c/CD163-positive macrophages was significantly associated with the formation of p62 aggregation. CONCLUSIONS: These findings indicate that chronic inflammation by M1-polarization of macrophages contributes to the disease progression from simple steatosis to non-alcoholic steatohepatitis in concert with autophagic dysfunction.

Usefulness of Demarcation of Differentiated-Type Early Gastric Cancers after Helicobacter pylori Eradication by Magnifying Endoscopy with Narrow-Band Imaging.

BACKGROUND/AIMS: Early gastric cancer after Helicobacter pylori (Hp) eradication is difficult to demarcate. We used the vessel plus surface classification system (VSCS) to determine whether magnifying endoscopy with narrow-band imaging (ME-NBI) could demarcate differentiated-type early gastric cancers after Hp eradication, and to identify causes of an unclear demarcation line (DL). METHODS: Among 100 lesions of differentiated-type early gastric cancer resected endoscopically, 34 lesions in the Hp-eradicated group and 66 in the Hp-infected group were retrospectively compared. Clinicopathological factors and ME-NBI findings, including the presence or absence of the DL, were examined. Histopathologically, histological gastritis, the surface structure at the tumor border, well-differentiated adenocarcinoma with low-grade atypia (tub1-low), and non-neoplastic epithelium (NE) coverage rate on the tumor surface and at the tumor border were evaluated. RESULTS: DL (-) cases were more frequent in the Hp-eradicated group (11.8%, 4/34) than in the Hp-infected group (1.5%, 1/66; p < 0.05). The Hp-eradicated group had a higher NE coverage rate than the Hp-infected group (p < 0.05). All DL (-) cases had tub1-low or NE at the tumor border. CONCLUSION: ME-NBI with VSCS can identify the DL in most patients (88.2%) with differentiated-type early gastric cancer after Hp eradication.

Improved Visibility of Barrett's Esophagus with Linked Color Imaging: Inter- and Intra-Rater Reliability and Quantitative Analysis.

BACKGROUND/AIMS: To evaluate the usefulness of linked color imaging (LCI) and blue LASER imaging (BLI) in Barrett's esophagus (BE) compared with white light imaging (WLI). METHODS: Five expert and trainee endoscopists compared WLI, LCI, and BLI images obtained from 63 patients with short-segment BE. Physicians assessed visibility as follows: 5 (improved), 4 (somewhat improved), 3 (equivalent), 2 (somewhat decreased), and one (decreased). Scores were evaluated to assess visibility. The inter- and intra-rater reliability (intra-class correlation coefficient) of image assessments were also evaluated. Images were objectively evaluated based on L* a* b* color values and color differences (ΔE*) in a CIELAB color space system. RESULTS: Improved visibility compared with WLI was achieved for LCI: 44.4%, BLI: 0% for all endoscopists; LCI: 55.6%, BLI: 1.6% for trainees; and LCI: 47.6%, BLI: 0% for experts. The visibility score of trainees compared with experts was significantly higher for LCI (p = 0.02). Intra- and inter-rater reliability ratings for LCI compared with WLI were "moderate" for trainees, and "moderate-substantial" for experts. The ΔE* revealed statistically significant differences between WLI and LCI. CONCLUSION: LCI improved the visibility of short-segment BE compared with WLI, especially for trainees, when evaluated both subjectively and objectively.

Gut Microbiota Composition Before and After Use of Proton Pump Inhibitors.

BACKGROUND: Recently, problems associated with proton pump inhibitor (PPI) use have begun to surface. PPIs influence the gut microbiota; therefore, PPI use may increase the risk of enteric infections and cause bacterial translocation. In this study, we investigated fecal microbiota composition, fecal organic acid concentrations and pH, and gut bacteria in the blood of the same patients before and after PPI use. METHODS: Twenty patients with reflux esophagitis based on endoscopic examination received 8 weeks of treatment with PPIs. To analyze fecal microbiota composition and gut bacteria in blood and organic acid concentrations, 16S and 23S rRNA-targeted quantitative RT-PCR and high-performance liquid chromatography were conducted. RESULTS: Lactobacillus species were significantly increased at both 4 and 8 weeks after PPI treatment compared with bacterial counts before treatment (P = 0.011 and P = 0.002, respectively). Among Lactobacillus spp., counts of the L. gasseri subgroup, L. fermentum, the L. reuteri subgroup, and the L. ruminis subgroup were significantly increased at 4 and 8 weeks after treatment compared with counts before treatment. Streptococcus species were also significantly increased at 4 and 8 weeks after PPI treatment compared with counts before treatment (P < 0.01 and P < 0.001, respectively). There was no significant difference in the total organic acid concentrations before and after PPI treatment. Detection rates of bacteria in blood before and after PPI treatment were 22 and 28%, respectively, with no significant differences. CONCLUSIONS: Our quantitative RT-PCR results showed that gut dysbiosis was caused by PPI use, corroborating previous results obtained by metagenomic analysis.

Efficacy and Acceptability of 1 Liter of Polyethylene Glycol with Ascorbic Acid vs. 2 Liters of Polyethylene Glycol Plus Mosapride and Sennoside for Colonoscopy Preparation.

BACKGROUND [color=black]Bowel preparation is an important factor for an optimal outcome of colonoscopy. Recently, polyethylene glycol (PEG) solution has been in common use for bowel cleansing for colonoscopy, but some patients are intolerant of PEG because of taste or volume. A low-volume PEG administered with ascorbic acid solution (PEG-Asc) was designed to improve tolerability, but the administration of this method is more complex than that with PEG alone. This study aimed to compare bowel cleansing efficacy, safety, and tolerability of 1 L PEG-Asc with a 2 L PEG preparation with use of sennosides and mosapride.[/color] MATERIAL AND METHODS [color=black]This was a prospective, single-center, non-inferiority trial that included 112 patients (PEG-Asc group, 68; PEG group, 44). The primary endpoint was the efficacy of colon cleansing assessed by endoscopists using a validated 4-point scale according to the Aronchick scale and was verified by a blinded investigator. Acceptability, tolerability, and adenoma detection rate (ADR) of these 2 regimens were secondary endpoints.[/color][color=black] [/color] RESULTS [color=black]We found no statistically significant differences between the groups in colon-cleansing efficacy or in the adenoma detection rate (ADR). Moreover, overall, patients significantly favored PEG-Asc over PEG, reflecting better acceptance of PEG-Asc. Additionally, more patients favored PEG-Asc over PEG for a hypothetical future colonoscopy. [/color] CONCLUSIONS [color=black]The alternate 1 L PEG-Asc regimen and standard 2 L PEG regimen were clinically equivalent with respect to cleansing efficacy, safety, and ADR, and more patients favored PEG-Asc than PEG. This alternate regimen may improve patient compliance and acceptance of surveillance colonoscopy.[/color].

Efficacy of cytapheresis for remission induction and dermatological manifestations of ulcerative colitis.

BACKGROUND: In ulcerative colitis (UC) patients, cytapheresis depletes elevated and activated leucocytes, which are known to release inflammatory cytokines including tumor necrosis factor (TNF)-α. Further, there are UC patients who develop erythema nodosum (EN) or pyoderma gangrenosum (PG) as extra-intestinal manifestations of UC. METHODS: Between 2008 and 2015, 181 consecutive patients with active UC received cytapheresis with either a granulocyte and monocyte apheresis (GMA) column or with a leucocyte removal filter (LCAP) as remission induction therapy. Each patient received weekly or intensive (2-3 sessions/week) cytapheresis up to 10 sessions. In 13 patients, UC was complicated by EN or PG. Lichtiger's clinical activity index (CAI) ≤4 meant remission, while ≥3 decrease in CAI meant response to therapy. Prednisolone sparing and the changes in the extra-intestinal manifestations were factored for assessing treatment efficacy. RESULTS: The overall remission and response rates were 52.5% and 71.8%, respectively, CAI fell from 9.4 ± 3.3 to 4.9 ± 3.5 (P < 0.001). The efficacy rates in subgroups on concomitant corticosteroid, anti-TNF or tacrolimus, and those without concomitant medications were not significantly different (P > 0.05). However, in 84 patients on prednisolone, the average daily prednisolone dose was reduced from 18.15 to 12.43 mg/day (P < 0.001) with 21.7% being corticosteroid free. All patients with EN or PG showed favorable response to cytapheresis, notably 2 EN patients achieving remission after just 2 cytapheresis sessions without concomitant medication. CONCLUSIONS: In this retrospective efficacy evaluation, cytapheresis was effective as remission induction therapy with steroid sparing effect and desirable safety profile. Further, patients with EN or PG responded favorably to cytapheresis.

Host response genes associated with nodular gastritis in Helicobacter pylori infection.

BACKGROUND: Chronic Helicobacter pylori infection in children induces lymphoid hyperplasia called nodular gastritis (NG) at the antral gastric mucosa. The aim of this study was to evaluate genes in gastric biopsy on microarray analysis, to identify molecules associated with NG on comparison with NG-negative pediatric corpus tissue and with H. pylori-infected adult tissue with atrophic gastritis (AG). METHODS: Eight pediatric and six adult H. pylori-infected patients, as well as six pediatric and six adult uninfected patients were evaluated. All infected adults had AG. NG was observed in the antrum of all eight pediatric patients and in the corpus of three patients. Adult and uninfected patients were free of NG; that is, only pediatric H. pylori-infected patients had NG. Total RNA was purified from gastric biopsy, and microarray analysis was performed to compare gene expression between groups. The three infected children with NG in both the antrum and corpus were excluded from analysis of corpus samples. RESULTS: The number of genes significantly up- or downregulated (fold change >3, P < 0.01) compared with uninfected controls varied widely: 72 in pediatric antrum, 45 in pediatric corpus, 103 in adult antrum and 71 in adult corpus. Nineteen genes had significantly altered expression in the antrum of NG tissue compared with NG-negative pediatric corpus tissue and adult AG tissue. The CD20 B-cell specific differentiation antigen had the most pronounced increase. Previously described regulators of NG development were not predominantly upregulated in the NG mucosa. CONCLUSIONS: CD20 overexpression may play an important role in lymphoid follicle enlargement and NG.

Spleen-derived lipocalin-2 in the portal vein regulates Kupffer cells activation and attenuates the development of liver fibrosis in mice.

The liver has an immune tolerance against gut-derived products from the portal vein (PV). A disruption of the gut-liver axis leads to liver injury and fibrosis. The spleen is connected to the PV and regulates immune functions. However, possible splenic effects on liver fibrosis development are unclear. Lipocalin-2 (Lcn2) is an antimicrobial protein that regulates macrophage activation. To clarify the role of the spleen in liver fibrosis development, we induced liver fibrosis in mice after splenectomy, and investigated liver fibrosis development. Liver fibrosis resulted in significantly increased splenic Lcn2 levels, but all other measured cytokine levels were unchanged. Splenectomized mice showed enhanced liver fibrosis and inflammation accompanied by significantly decreased Lcn2 levels in PV. Lipopolysaccharide-stimulated primary Kupffer cells, resident liver macrophages, which were treated with recombinant Lcn2 (rLcn2) produced less tumor necrosis factor-α and Ccl2 and the activation of hepatic stellate cells, the effector cells for collagen production in the liver, was suppressed by co-culture with rLcn2-treated Kupffer cells. In addition, the involvement of gut-derived products in splenectomized mice was evaluated by gut sterilization. Interestingly, gut sterilization blocked the effect of splenectomy on liver fibrosis development. In conclusion, spleen deficiency accelerated liver fibrosis development and decreased PV Lcn2 levels. The mechanism of splenic protection against liver fibrosis development may involve the splenic Lcn2, triggered by gut-derived products that enter the liver through the PV, regulates Kupffer cells activated by the gut-liver axis. Thus, the splenic Lcn2 may have an important role in regulating the immune tolerance of the liver in liver fibrosis development.

Distinct endoscopic characteristics of sessile serrated adenoma/polyp with and without dysplasia/carcinoma.

BACKGROUND AND AIMS: Sessile serrated adenoma/polyp (SSA/P) is a colorectal polyp that has malignant potential. However, the dysplastic components within an SSA/P can be difficult to detect. This study aimed to clarify the endoscopic characteristics of SSA/P with advanced histology. METHODS: We examined 462 endoscopically or surgically resected lesions that were pathologically diagnosed as SSA/P, including 414 without and 41 with cytologic dysplasia, and 7 with invasive carcinoma. We retrospectively studied the clinicopathologic and endoscopic characteristics and performed pit pattern analysis. RESULTS: A stepwise increase in the size of the SSA/P series was identified along with their dysplastic progression, although 19 of 48 (39.6%) SSA/Ps with dysplasia/carcinoma were ≤10 mm in size. Most lesions were covered with a mucus cap. Macroscopically, (semi)pedunculated morphology, double elevation, central depression, and reddishness were found more frequently in SSA/P with cytologic dysplasia and invasive carcinoma ([semi]pedunculated morphology, 17.1%/28.6%; double elevation, 63.4%/57.1%; central depression, 9.8%/28.6%; reddishness, 39.0%/85.7%) than in those without dysplasia (4.6%, 4.6%, 3.9%, and 3.4%, respectively). Furthermore, the presence of at least 1 of these 4 markers had high sensitivity (91.7%) for identifying the dysplasia/carcinoma within a SSA/P, with a specificity of 85.3%. In the pit pattern analysis, all SSA/Ps without dysplasia exhibited type II pit pattern only, whereas 94.4% of SSA/Ps with dysplasia/carcinoma showed type II in addition to type IIIL, IV, VI, or VN pit patterns. CONCLUSIONS: In an SSA/P series, endoscopic characteristics, including (semi)pedunculated morphology, double elevation, central depression, and reddishness, in addition to the use of magnifying endoscopy, may be useful to accurately diagnose advanced histology within an SSA/P.

L-carnitine prevents metabolic steatohepatitis in obese diabetic KK-Ay mice.

AIM: Pharmacological treatment for metabolic syndrome-related non-alcoholic steatohepatitis has not been established. We investigated the effect of L-carnitine, an essential substance for ß-oxidation, on metabolic steatohepatitis in mice. METHODS: Male KK-Ay mice were fed a high-fat diet (HFD) for 8 weeks, with supplementation of L-carnitine (1.25 mg/mL) in drinking water for the latter 4 weeks. RESULTS: Serum total carnitine levels were decreased following HFD feeding, whereas the levels were reversed almost completely by L-carnitine supplementation. In mice given L-carnitine, exacerbation of hepatic steatosis and hepatocyte apoptosis was markedly prevented even though HFD feeding was continued. Body weight gain, as well as hyperlipidemia, hyperglycemia, and hyperinsulinemia, following HFD feeding were also significantly prevented in mice given L-carnitine. High-fat diet feeding elevated hepatic expression levels of carnitine palmitoyltransferase 1A mRNA; however, production of ß-hydroxybutyrate in the liver was not affected by HFD alone. In contrast, L-carnitine treatment significantly increased hepatic ß-hydroxybutyrate contents in HFD-fed mice. L-carnitine also blunted HFD induction in sterol regulatory element binding protein-1c mRNA in the liver. Furthermore, L-carnitine inhibited HFD-induced serine phosphorylation of insulin receptor substrate-1 in the liver. L-carnitine decreased hepatic free fatty acid content in 1 week, with morphological improvement of swollen mitochondria in hepatocytes, and increases in hepatic adenosine 5'-triphosphate content. CONCLUSIONS: L-carnitine ameliorates steatohepatitis in KK-Ay mice fed an HFD, most likely through facilitating mitochondrial ß-oxidation, normalizing insulin signals, and inhibiting de novo lipogenesis in the liver. It is therefore postulated that supplementation of L-carnitine is a promising approach for prevention and treatment of metabolic syndrome-related non-alcoholic steatohepatitis.

Use of finger-piece method for indocyanine green clearance test.

AIM: The indocyanine green (ICG) finger-piece method (FPM), which allows measurement of the ICG concentration by mounting a light sensor onto a finger, is used to assess liver function. We compared the ICG FPM with the conventional ICG blood sampling method (BSM) in patients with liver disorders. METHODS: Ninety consecutive patients simultaneously underwent the ICG BSM and ICG FPM. After ICG administration, blood samples were collected at 5, 10, and 15 min for the ICG BSM. The ICG concentration was measured through the finger piece by an ICG clearance meter. RESULTS: Seventy-one patients (78.9%) had Child-Pugh class A liver disease, and 19 (21.1%) had class B or C. The FPM-measured ICG plasma disappearance rate was positively correlated with the BSM-measured values (r = 0.886, P < 0.001). Bland-Altman analysis showed good agreement between the two methods (mean difference, 0.012 ± 0.018). The FPM-measured ICG plasma disappearance rate was positively correlated with the BSM-measured values both in patients with Child-Pugh class A liver disease (r = 0.821, P < 0.001) and class B or C liver disease (r = 0.859, P < 0.001). CONCLUSION: The ICG FPM may be an alternative to the ICG BSM for liver function assessment.

Aldo-keto reductase family 1 member B10 is associated with hepatitis B virus-related hepatocellular carcinoma risk.

AIM: Recent reports have indicated that aldo-keto reductase family 1 member B10 (AKR1B10), a cancer-related oxidoreductase, was upregulated in some chronic liver diseases. However, few studies have reported AKR1B10 expression in chronic hepatitis B virus (HBV)-infected patients. The aim of the present study was to analyze AKR1B10 expression and its relevance on hepatocellular carcinoma (HCC) development in patients with chronic HBV infection. METHODS: Expression of AKR1B10 in the liver of 119 chronic HBV-infected patients was assessed and quantified immunohistochemically. A multivariate Cox model was used to estimate the hazard ratios of AKR1B10 expression for HCC development. The cumulative incidences of HCC were evaluated using Kaplan-Meier analysis. RESULTS: Expression of AKR1B10 in the study cohort ranged from 0% to 84%. During the median follow-up time (6.2 years), 13 patients developed HCC. Multivariate analysis revealed that high AKR1B10 expression (≥15%) was an independent risk factor for HCC (hazard ratio, 10.8; 95% confidence interval, 3.0-38.6; P < 0.001). The 5-year cumulative incidences of HCC were 20.6% and 2.6% in patients with high and low AKR1B10 expression, respectively (P < 0.001). Patients with high AKR1B10 expression had significantly higher alanine aminotransferase levels during follow-up than those with low expression, even though antiviral treatment decreased HBV-DNA levels in both groups. CONCLUSION: Chronic HBV-infected patients with high hepatic AKR1B10 expression had an increased risk of HCC development. This suggests that AKR1B10 upregulation might play a role in the early stages of HBV-related hepatocarcinogenesis.

Distinct Involvement of the Sonic Hedgehog Signaling Pathway in Gastric Adenocarcinoma of Fundic Gland Type and Conventional Gastric Adenocarcinoma.

BACKGROUND/AIMS: Gastric adenocarcinoma of fundic gland type (GAFG), which is a rare variant of gastric cancer, is reportedly associated with both Wnt/ß-catenin signaling activation and guanine nucleotide binding protein, alpha stimulating complex (GNAS) mutations. This study aimed to elucidate potential roles of the Sonic hedgehog (Shh) signaling pathway in GAFG. METHODS: We performed immunostaining for ß-catenin and Shh signal-associated proteins, including Patched (Ptch), Smoothened (Smo), and Glioma-associated oncogene-1 (Gli1), and the direct sequencing of GNAS/BRAF/KRAS in 27 GAFGs, and compared them with 30 conventional gastric adenocarcinomas (CGAs). RESULTS: GAFGs exhibited significantly lower immunoreactivity scores for Ptch, Smo, and Gli1 than CGAs. Moreover, while the Ptch score was significantly lower in the GAFG tumor areas than in the non-neoplastic areas adjacent to GAFG, the score was significantly higher in the CGA tumor areas than in the non-neoplastic areas. Similar trends were observed in the scores for Smo and Gli1. ß-Catenin expression and GNAS mutations were found in 22 (81%) and 8 (30%) of the 27 GAFGs respectively. Gli1 expression was significantly associated with mutations in GNAS. CONCLUSION: GAFG and CGA exhibited distinct Ptch, Smo, and Gli1 expression patterns. Downregulation of the Shh signaling pathway, as well as activation of the Wnt/ß-catenin signaling pathway, may therefore be associated with tumorigenesis in GAFG.

A Randomized, Double-Blind, Pilot Study of the Effect of Famotidine on Acotiamide Treatment for Functional Dyspepsia.

BACKGROUND/AIMS: Acotiamide, a prokinetic drug, is used to treat functional dyspepsia (FD), especially postprandial distress syndrome (PDS). However, a treatment for FD patients with PDS and/or epigastric pain syndrome (EPS) has not been established. We investigated the efficacy of famotidine in combination with acotiamide for FD. METHODS: Fifty blindly randomized FD patients received placebo with acotiamide, or famotidine with acotiamide, for 4 weeks. Treatment efficacy was assessed by overall treatment effects (OTE), total, PDS and EPS symptom scores, and impairment of quality of life (QOL). RESULTS: After OTE assessment, patients who felt affected by treatment comprised 40.9 and 57.9% of famotidine and placebo groups, respectively, after 4 weeks' treatment, with no significant difference between groups. A significant decrease was seen in total, PDS, and EPS symptom scores, and in QOL impairment, after 4 weeks' treatment compared with pretreatment scores for famotidine and placebo groups, but was not observed between groups. The proportion of patients showing a ≥50% decrease in EPS symptom scores was greater in the famotidine than that in the placebo group for every observation point, with the greatest difference observed after 2 weeks' treatment. CONCLUSION: The effectiveness of famotidine and acotiamide combination therapy in FD was similar to the effectiveness of acotiamide therapy alone.

Epigenetic regulation of Wnt/ß-catenin signal-associated genes in gastric neoplasia of the fundic gland (chief cell-predominant) type.

Gastric neoplasia of the fundic gland (chief cell-predominant) type (GNCCP) is a rare variant of gastric tumor. This tumor is associated with activation of the Wnt/ß-catenin signaling pathway; however, the mechanisms underlying this activation remain unknown. To elucidate potential roles of Wnt/ß-catenin signal-associated gene methylation in GNCCP, we performed ß-catenin immunostaining and methylation-specific polymerase chain reaction (PCR) for their associated genes, including SFRPs, APC, AXIN2, and MCC, in 26 GNCCPs [i.e., 11 intramucosal (GNCCP-Ms) and 15 submucosal tumors (GNCCP-SMs)], and compared with 27 fundic gland polyps (FGPs), 12 FGPs with dysplasia (FGP-Ds), 27 conventional gastric adenocarcinomas (CGAs). Nuclear ß-catenin labeling indices were higher in GNCCPs and CGAs than in FGPs and FGP-Ds. SFRPs, APC, and AXIN2 were more frequently methylated in GNCCPs and CGAs (SFRP1, 88%/96%; SFRP2, 85%/93%; SFRP4, 73%/81%; APC, 81%/81%; AXIN2, 81%/85%; respectively) than in FGPs and FGP-Ds (37%/50%; 41%/42%; 41%/58%; 37%/33%; 41%/50%; respectively). A significant correlation was seen between nuclear ß-catenin expression and methylation of SFRP1 in GNCCPs. Furthermore, nuclear ß-catenin expression was significantly frequent in high-methylated GNCCPs than in low-methylated tumors. In conclusion, our results suggest that activation of this pathway, mediated by gene methylation, may be associated with progression of some GNCCP cases, similar to CGAs.