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Sex differences in the predictors for hepatocellular carcinoma (HCC) development after direct-acting antiviral (DAA) therapy was investigated. DAA therapy was given to 1438 (663 male, 775 female) patients. Sex differences in the HCC development rate and the factors contributing to HCC development after DAA therapy were investigated. Male patients had a significantly higher cumulative HCC incidence (log-rank test, P =  .007). On multivariate analysis, the fibrosis-4 index (HR = 1.11; 95%CI, 1.042-1.202, P =  .002) and posttreatment α-fetoprotein (AFP) (HR = 1.11; 95%CI, 1.046-1.197, P  =  .001) were found to be independent factors that contributed to HCC development following DAA therapy in female patients, whereas only posttreatment AFP (HR  =  1.090; 95%CI, 1.024-1.160, P  = .007) was an independent factor in male patients. The optimal posttreatment AFP cut-off values were set based on receiver operating characteristic curve analyses. The optimal posttreatment AFP cut-off value was much higher in females (6.0 ng/mL) than in male (3.5 ng/mL) patients. In conclusion both in male and female patients, posttreatment AFP was an independent predictor of HCC development after DAA therapy. However, the cut-off values differed between the sexes. In male patients, HCC could be seen in patients with relatively low posttreatment AFP levels; more careful observation might be needed in such patients., (© 2020 Wiley Periodicals LLC.)

Hyperammonemia is an important stimulator of myostatin expression, a negative regulator of muscle growth. After splenectomy or partial splenic artery embolization (PSE), hyperammonemia often improves. Thus, we investigated changes in skeletal muscle index (SMI) in patients following an operation on the spleen and in patients who did not undergo an operation on their spleen. The study was designed retrospectively, in which we analyzed data collected between January 2000 and December 2015. Patients were assigned to the splenectomy/PSE or nontreatment group. Changes in SMI (ΔSMI), ammonia (Δammonia), myostatin (Δmyostatin), irisin (Δirisin), and branched-chain amino acids/tyrosine molar ratio (ΔBTR) were analyzed between baseline and 5-year follow-up both before and after inverse probability of treatment weighting adjustment (IPTW). Patients (102) were enrolled (splenectomy/PSE, n = 45; nontreatment group, n = 57) before IPTW adjustment: ΔSMI (2.6 cm 2 /m 2 vs. -8.8 cm 2 /m 2 , respectively) ( P  < 0.001), Δmyostatin (-867 vs. -568, respectively) ( P  < 0.001), Δammonia (-34 and 16, respectively) ( P  < 0.001), and ΔBTR (0.89 and -0.665, respectively) ( P  < 0.001). There were no differences between splenectomy and PSE regarding these factors. Moreover, after IPTW adjustment, significant differences were observed between the splenectomy/PSE and nontreatment group for the median ΔBTR (0.89 and -0.64, respectively) ( P  < 0.001), Δammonia (-33 and 16, respectively) ( P  < 0.001), Δmyostatin (-894 and 504, respectively) ( P  < 0.001), and ΔSMI (1.8 cm 2 /m 2 and -8.2 cm 2 /m 2 , respectively) ( P  < 0.001). Conclusions: Both splenectomy and PSE were associated with the prevention of secondary sarcopenia in patients with LC. Moreover, it can be expected that muscle volume loss is reduced by splenectomy or PSE in patients with hyperammonemia., (© 2020 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Aim: For radiofrequency ablation to treat patients diagnosed with liver cancer, the ablation area cannot be envisaged beforehand, even by experts. This study aimed to assess the clinical feasibility of applying a combination of electric (E)-field and coronal (C)-plane simulations to ultrasound-ultrasound (US-US) fusion images., Methods: The study protocols were approved by the institutional ethics committee. Between October 2017 and July 2019, 151 patients with 151 hepatocellular carcinoma nodules (80 treated with navigation images and 71 without navigation images) were retrospectively compared in this cross-sectional study. The E-field, which is a simulated image that predicts the ablation area, was applied to the US-US fusion images. The C-plane is defined as a sagittal plane in relation to the original 2-D US images. The positions of each E-field area in the maximum cross-sectional area of the tumor were easily identified from C-plane results. The primary end-point of this study was achievement of an adequate safety margin (greater than 5 mm). The sphericity of the ablation volume was used as a secondary end-point., Results: The rate of achieving a sufficient safety margin was significantly higher in the group treated with navigation images (71/80) than in the group treated without navigation images (31/71, P < 0.001). The median sphericity was 0.55 with navigation images and 0.42 without navigation images (P < 0.001)., Conclusion: Using the combination of an E-field and a C-plane on US-US fusion images can be a feasible method for acquiring a sufficient safety margin., (© 2020 The Japan Society of Hepatology.)

In topological insulators (TIs), carriers originating from non-stoichiometric defects hamper bulk insulation. In (Bi,Sb) 2 (Te,Se) 3 TIs (BSTS TIs), however, Se atoms strongly prefer specific atomic sites in the crystal structure (Se ordering), and this ordering structure suppresses the formation of point defects and contributes to bulk insulation. It has accelerated the understanding of TIs' surface electron properties and device application. In this study, we select Pb(Bi,Sb) 2 (Te,Se) 4 (Pb-BSTS) TIs, which are reported to have larger bandgap compared to counterpart compound BSTS TIs. The Se ordering geometry was investigated by combining state-of-the-art scanning transmission electron microscopy and powder X-ray diffractometry. We demonstrated the existence of inner Se ordering in PbBi 2 (Te,Se) 4 and also in Pb-BSTS TIs. Quantitative analysis of Se ordering and a qualitative view of atomic non-stoichiometry such as point defects are also presented. Pb-BSTS TIs' Se ordering structure and their large gap nature has the great potential to achieve more bulk insulation than conventional BSTS TIs.

Background and Aims: Lipoprotein(a) [Lp(a)] is an important independent cardiovascular risk factor. However, Lp(a) levels are lower in patients with chronic liver disease than in healthy subjects. Furthermore, Lp(a) levels decrease as residual liver function declines. Although non-alcoholic fatty liver disease (NAFLD), especially advanced non-alcoholic steatohepatitis (NASH), increases the risk of cardiovascular diseases, the relationship between serum Lp(a) level and NASH is unknown. Thus, we examined the relationship between serum Lp(a) levels and biopsy-proved NAFLD and clarified the significance of Lp(a) measurements for cardiovascular disease screening in patients with NAFLD., Methods: A total of 176 patients with NAFLD were enrolled. Comprehensive blood chemistry tests and histological examinations of liver samples were conducted. The relationship between serum Lp(a) levels and NAFLD was analyzed., Results: Serum Lp(a) levels in advanced fibrosis (stage 3-4) were lower than those in non-advanced fibrosis (stage 0-2) (p < 0.05). After adjustment for age, sex, body mass index, alanine aminotransferase (ALT), creatinine (Cre), HbA 1c level, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and the use of lipid-lowering agents, the significant inverse association between advanced fibrosis and serum Lp(a) levels remained (p < 0.01). Although the Lp(a) level was inversely associated with an NAFLD Activity Score (NAS) of 5-8, there was no significant association between Lp(a) levels and NAS adjusted for age, sex, body mass index, ALT, Cre, HbA 1c level, HDL-C, LDL-C, TG, and the use of lipid-lowering agents., Conclusions: Advanced NASH is associated with low serum Lp(a) levels; therefore, Lp(a) levels may not be useful in evaluating cardiovascular risk., Competing Interests: Declaration of competing interest The authors declared they do not have anything to disclose regarding conflict of interest with respect to this manuscript., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective There is a paucity of information on whether the hepatitis B virus (HBV) vaccine, derived from HBV genotype C, can prevent mother-to-child transmission of HBV genotype D. The aim of this study was to clarify this issue. Methods The subjects consisted of 25 children (8.5±4.1 years old, 7 males, 18 females), born to 17 mothers who were chronically infected with HBV genotype D. Of these, 20 children were inoculated with the genotype C-derived vaccine, one was inoculated with the genotype A-derived vaccine, and one was inoculated with both the A- and C-derived vaccines. Information on the type of vaccine given to the remaining three children was not available. The serum levels of HB surface antigen (HBsAg), antibody to HBsAg (anti-HBs), and antibody to HB core (anti-HBc) of the children, as well as HBV markers of the mothers, were examined. Results All mothers were positive for HBsAg (6,563±11,005 IU/mL), negative for HBeAg, and positive for anti-HBe. HBV-DNA levels (log IU/mL) were <3.3 in 7 mothers, 3.3-4.3 in 9 mothers, and >4.3 in one mother. HBsAg and anti-HBc were negative in all children, regardless of the type of vaccine used. Anti-HBs were positive in 13 children and negative in 12. Conclusion All children born to mothers infected with genotype D, including 20 who were inoculated with the genotype C-derived vaccine, were negative for both HBsAg and anti-HBc. These results suggest that the genotype C-derived HB vaccine is effective in preventing mother-to-child transmission from mothers infected with HBV genotype D.

Root nodule (RN) symbiosis is a mutualistic interaction observed between nitrogen-fixing soil bacteria and nodulating plants, which are scattered in only four orders of angiosperms called nitrogen-fixing clade. Most of legumes engage in RN symbiosis with rhizobia. Molecular genetic analyses with legumes and non-leguminous nodulating plants revealed that RN symbiosis utilizes early signalling components that are required for symbiosis with arbuscular mycorrhizal (AM) fungi. However detailed evolutionary processes are still largely unknown. Comparative analyses with non-nodulating species phylogenetically related to legumes could be better strategies to study the evolution of RN symbiosis in legumes. Polygala paniculata is a non-leguminous species that belongs to a family different from legumes but that is classified into the same order, Fabales. It has appropriate characteristics for cultivation in laboratories: small body size, high fertility and short lifecycles. Therefore, we further assessed whether this species is suitable as a model species for comparative studies with legumes. We first validated that the plant we obtained in Palau was truly P. paniculata by molecular phylogenetic analysis using rbcL sequences. The estimated genome size of this species was less than those of two model legumes, Lotus japonicus and Medicago truncatula. We determined conditions for cultivation in vitro and for hairy root formation from P. paniculata seedlings. It would facilitate to investigate gene functions in this species. The ability of P. paniculata to interact with AM fungi was confirmed by inoculation with Rhizophagus irregularis, suggesting the presence of early signalling factors that might be involved in RN symbiosis. Unexpectedly, branching of root hairs was observed when inoculated with Mesorhizobium loti broad host range strain NZP2037, indicating that P. paniculata has the biological potential to respond to rhizobia. We propose that P. paniculata is used as a model plant for the evolutionary study of RN symbiosis.

Aim: Hypozincemia is associated with the progression of chronic liver diseases, but it is unknown whether hypozincemia promotes human hepatocarcinogenesis. Our aim is to evaluate the serum zinc levels in liver cirrhosis (LC) patients and clarify the relationship between the serum zinc levels and the development of hepatocellular carcinoma (HCC)., Methods: Cirrhotic patients without HCC (n = 299) were enrolled from 14 medical institutes in Japan as a multicenter prospective study (No. 2028). Of the 299 patients, 157 were included in the present study based on reliable and consistent serum zinc levels and no history of oral zinc supplementation. Clinical parameters associated with the development of HCC were determined. Furthermore, the cumulative incidence of HCC was analyzed using Kaplan-Meier methods and was calculated using the log-rank test. A Cox regression analysis was utilized for the multivariate analysis to evaluate the predictors of hepatocarcinogenesis., Results: Thirty of 157 patients (19.1%) developed HCC during an observation period of 3 years. Serum zinc levels were significantly decreased in hepatitis C virus-related LC (C-LC) patients with HCC (0.0180). The risk factors for incidence of HCC were hypozincemia (0.0014), high α-fetoprotein (0.0080), low branched chain amino acids-to-tyrosine ratio (0.0128), or female sex (0.0228). Hypozincemia (hazard ratio 1.61, 0.0324) was the only significant predictor of hepatocarcinogenesis by multivariate Cox regression analysis., Conclusions: Hypozincemia is associated with hepatocarcinogenesis in C-LC patients., (© 2019 The Japan Society of Hepatology.)

Hepatic stellate cells (HSCs) were reported to promote the progression of hepatocellular carcinoma (HCC), however its mechanism is uncertain. We previously reported that protein kinase R (PKR) in hepatocytes regulated HCC proliferation. In this study, we focused on the role of PKR in HSCs, and clarified the mechanism of its association with HCC progression. We confirmed the activation of PKR in a human HSC cell line (LX-2 cell). IL-1β is produced from HSCs stimulated by lipopolysaccharide (LPS) or palmitic acid which are likely activators of PKR in non-alcoholic steatohepatitis (NASH). Production was assessed by real-time PCR and ELISA. C16 and small interfering RNA (siRNA) were used to inhibit PKR in HSCs. The HCC cell line (HepG2 cell) was cultured with HSC conditioning medium to assess HCC progression, which was evaluated by proliferation and scratch assays. Expression of PKR was increased and activated in stimulated HSCs, and IL-1β production was also increased molecular. Key molecules of the mitogen-activated protein kinase pathway were also upregulated and activated by LPS. Otherwise, PKR inhibition by C16 and PKR siRNA decreased IL-1β production. HCC progression was promoted by HSC-stimulated conditioning medium although it was reduced by the conditioning medium from PKR-inhibited HSCs. Moreover, palmitic acid also upregulated IL-1β expression in HSCs, and conditioning medium from palmitic acid-stimulated HSCs promoted HCC proliferation. Stimulated HSCs by activators of PKR in NASH could play a role in promoting HCC progression through the production of IL-1β, via a mechanism that seems to be dependent on PKR activation., Competing Interests: The authors have declared that no competing interests exist.

Aim: The predictors for the development of hepatocellular carcinoma (HCC) after direct-acting antiviral (DAA) treatment were investigated., Methods: A total of 1174 patients with chronic hepatitis C virus infection were treated with DAA therapy (sofosbuvir and ledipasvir [n = 615], sofosbuvir and ribavirin [n = 380], and daclatasvir and asunaprevir [n = 179]) and achieved sustained virologic response (SVR). The HCC development rate and the factors that might contribute to the development of HCC after the end of DAA treatment were analyzed., Results: During the median observation period of 537 days, HCC developed in 33 cases. The incidence of HCC was 1.9%, 3.2%, and 4.1% at 1, 1.5, and 2 years after the end of DAA therapy, respectively. Multivariate analysis with pre- and post-treatment factors identified the Fibrosis-4 (FIB-4) index (hazard ratio [HR] = 1.09; 95% confidence interval [CI], 1.021-1.178; P = 0.011) and post-treatment α-fetoprotein (AFP) (HR = 1.11; 95% CI, 1.054-1.172; P < 0.001) as independent factors that contributed to the development of HCC after DAA therapy. Using these identified parameters, a new scoring system (0 to 2 points) was established. Patients in the high-score group (2 points) could be identified as having a significantly higher risk of HCC development, and the respective 1- and 2-year cumulative incidence rates of HCC were 6.1% and 14.4%., Conclusions: A high FIB-4 index and a high post-treatment AFP at the end of DAA treatment were the independent predictors for developing HCC after DAA treatment. For patients with these risk factors, extra attention to the possibility of HCC development is needed., (© 2018 The Japan Society of Hepatology.)

Objective Low urine pH is associated with several metabolic diseases, such as dyslipidemia, diabetes, and metabolic syndrome. However, the association between low urine pH and non-alcoholic fatty liver disease (NAFLD) remains unknown. Therefore, we conducted a community-based cross-sectional study to investigate this association. Methods Between April 2013 and March 2014, the records of 4,945 Japanese subjects who had undergone annual health checkups were reviewed to identify subjects who met the diagnostic criteria for NAFLD. Patients Based on urine pH, the participants were classified into four groups; a low urine pH was defined as ≤5.5. Of the 3,411 subjects who qualified for enrollment, 1,028 met the diagnostic criteria for NAFLD. Results The prevalence of NAFLD was significantly increased with decreasing urine pH in both men and women (p<0.01 and p=0.02, respectively). A multivariate analysis, including adjustments for age, metabolic markers, and the renal function, showed a significant association between low urine pH and NAFLD in men and women (odds ratio, 1.37; 95% confidence interval, 1.01-1.85, p=0.04 and odds ratio, 1.73; 95% confidence interval, 1.15-2.62, p<0.01, respectively). Conclusion Our study indicates that NAFLD is associated with a low urine pH in both sexes, findings that might help clinicians identify patients at high risk for NAFLD.

Background: Patients with liver cirrhosis often exhibit zinc deficiency. Although zinc is involved in many bioactivities, many aspects of clinical implications of zinc deficiency in liver cirrhosis remain unclear. We aimed to reveal the prevalence and implications of zinc deficiency in liver cirrhosis by assessing associations with parameters such as clinical symptoms and laboratory data., Methods: In 235 cirrhosis patients enrolled at multiple medical institutions in 2009, we assessed how blood zinc levels were associated with their clinical symptoms, patients characteristics, and liver function test results., Results: Blood zinc levels were most strongly correlated with blood albumin levels among the study parameters (r = 0.587, P < 0.0001). When blood albumin levels were ≤ 3.5 g/dL, blood zinc levels were < 70 μg/dL in 88% of patients. Additionally, significant correlations were observed with age (r = -0.253, P = 0.0014), aspartate aminotransferase levels (r = -0.254, P = 0.0020), total bilirubin levels (r = -0.222, P = 0.0053), prothrombin time (r = -0.255, P = 0.0029), branched-chain amino acid to tyrosine ratio (r = 0.357, P < 0.0001), Child-Pugh score (r = 0.469, P < 0.0001), ammonia levels (r = -0.246, P = 0.0028), and total cholesterol levels (r = 0.314, P < 0.0001). Blood zinc levels were significantly lower in patients with edema/ascites (P < 0.0001), those with hepatic encephalopathy (P = 0.0215), those receiving oral diuretics (P = 0.0045), and those receiving oral branched-chain amino acids (P < 0.0001) than in those without these conditions., Conclusions: Zinc deficiency is prevalent in cirrhosis patients, whereas nitrogen metabolic disorders, particularly hypoalbuminemia, can be an indicator of zinc deficiency. Thus, cirrhosis patients exhibiting a nitrogen metabolic disorder should be examined for the presence of zinc deficiency., Competing Interests: The authors declare that they have no conflict of interest.

Aim: We examined the prognosis of liver cirrhosis (LC) patients with and without portal hypertension (PHT) and muscle volume loss (MVL)., Methods: From 2006 to 2016, 346 LC outpatients (PHT/non-PHT = 173/173) were enrolled (median age, 69 years; men / women, 204/142; Child-Pugh A / B, 230/116; and presence of MVL 15.6% in each group) after propensity matching, following exclusion of those with hepatocellular carcinoma (HCC) beyond the Milan criteria and Child-Pugh C. Portal hypertension was defined as positive for significant esophagogastric varices; MVL was diagnosed based on a previously reported index using CT imaging. Overall survival rate (OSR) was evaluated from the viewpoints of PHT and MVL., Results: There were no significant differences in clinical background (age, gender, etiology, presence of HCC [within Milan criteria], or Child-Pugh class) between the groups. Although there was no significant difference regarding OSR between patients with and without MVL in the non-PHT group (P = 0.076, Holm's method), the OSR of patients with MVL in the PHT group was lower compared to those without MVL in both groups (P = 0.017 and P = 0.012, respectively, Holm's method). As a result, the OSR of patients with MVL (n = 54) was lower than the other patients (n = 292) (3- and 5-year OSR, 69.0% vs. 86.4% and 35.8% vs. 74.1%, respectively; P < 0.001). Multivariate Cox hazard analysis showed that positive for HCC (hazard ratio [HR], 2.028; 95% confidence interval [CI], 1.189-3.460; P = 0.009) and positive for MVL (HR, 2.768; 95% CI, 1.575-4.863; P < 0.001) were significant independent prognostic factors for death., Conclusion: Muscle volume loss and HCC, but not PHT, were found to be independent prognostic factors for death in LC patients., (© 2017 The Japan Society of Hepatology.)

Immunoglobulin G4-related sclerosing cholangitis (IgG4-SC) is often associated with type 1 autoimmune pancreatitis, and the frequency of isolated IgG4-SC seems to be quite low, making the diagnosis of isolated IgG4-SC challenging. A 63-year-old male was admitted to our hospital for frequent fever. Abdominal magnetic resonance cholangiopancreatography showed diffuse narrowing of the common bile duct and post-stenotic dilatation of the right posterior bile duct. Laboratory tests showed abnormalities in the levels of hepatobiliary enzymes and serum IgG4 levels. Endoscopic retrograde cholangiopancreatography showed diffuse narrowing of intrahepatic bile ducts and post-stenotic dilatation of the right posterior bile duct but no abnormalities in the pancreas. Intraductal ultrasonography showed symmetric circumferentially thickened walls of both narrowed and non-narrowed common bile ducts. Histologic examination of the common bile duct mucosa showed infiltration of IgG4-positive plasma cells. Laparoscopic observations showed discoloration with red lobular markings and multiple small depressed lesions. Liver histology showed mild cholangitis with infiltration of IgG4-positive plasma cells around the bile ducts. From these findings, the patient was diagnosed with isolated IgG4-SC. After treatment with a steroid, bile duct dilatations improved. Laparoscopy and intraductal ultrasonography were useful to diagnose isolated IgG4-SC.

Background/aim: Sarcopenia is recognized as a condition related to quality of life and prognosis in patients with chronic liver disease, although no useful strategy for improving muscle volume and strength has been established. Here, we evaluated the efficacy of supplementation with branched-chain amino acid (BCAA) administration and walking exercise., Patients and Methods: From December 2015 to July 2016, 33 Japanese outpatients with liver cirrhosis were enrolled (median: 67 years, HCV : HBV : alcohol : others=26 : 2 : 2 : 3, male : female=13 : 20, Child-Pugh A : B=30 : 3). None had a history of BCAA supplementation. After calculating the average number of daily steps using a pedometer for a 2-3-week period, BCAA supplementation (protein 13.5 g, 210 kcal/day) as a late evening snack and walking exercise (additional 2000 steps/day prescribed) were started. Body composition including muscle volume was analyzed using a bioelectrical impedance analysis method, and serological data and muscle strength (leg, handgrip) were evaluated at enrollment, and then 1, 2, and 3 months after starting the protocol., Results: The median average number of daily steps was 3791 (interquartile range: 2238-5484). The average period of BCAA supplementation was 2.7±0.7 months. During the period from enrollment to 3 months after starting the protocol, HbA1c and NH3 were not significantly changed, whereas the BCAA/tyrosine ratio improved (4.3±1.35 to 5.24±2.04, P=0.001). In addition, the ratios for average daily steps (1.595, P=0.02) as well as muscle volume, leg strength, and handgrip strength (1.013, 1.110, and 1.056, respectively; all P<0.01) were increased at 3 months., Conclusion: BCAA supplementation and walking exercise were found to be effective and easily implemented for improving muscle volume and strength in liver cirrhosis patients.

Aim: Assessing disease progression in patients with primary biliary cholangitis (PBC) is necessary in order to evaluate therapeutic effectiveness. Therefore, the aims of this study were to evaluate both the diagnostic accuracy of both real-time tissue elastography (RTE) and vibration-controlled transient elastography (VCTE), and the usefulness of hepatic and splenic elasticity as predictive markers for the progression of symptomatic PBC., Methods: The study participants were 44 patients with PBC. We assessed hepatic and splenic elasticity using RTE and VCTE and measured serum markers related to fibrosis and hepatic and splenic blood flow using Doppler ultrasonography. We then compared RTE and VCTE for diagnostic accuracy. Patients with asymptomatic PBC were followed every 1-3 months., Results: Both RTE and VCTE performed well and had superior diagnostic accuracy compared with biochemical markers. The areas under the receiver operating characteristic curve for RTE and VCTE were 0.92 and 0.92, 0.95 and 0.91, and 0.97 and 0.91 for F ≥ 2, F ≥ 3, and F = 4, respectively. During follow-up, nine patients (25.0%) developed liver-related symptoms. Multivariate analysis revealed that splenic elasticity assessed using RTE was a significant independent factor for the development of liver-related symptoms (odds ratio, 2.19; P = 0.024)., Conclusions: Real-time tissue elastography offered better diagnostic accuracy for severe fibrosis and cholangitis than VCTE. Splenic elasticity determined using RTE is a useful parameter for evaluating liver-related symptoms and an effective predictive marker of disease progression in patients with asymptomatic PBC., (© 2017 The Japan Society of Hepatology.)

Background and Aim: The aim of this study is to confirm the efficacy of multipolar ablation with a new simulator system, three-dimensional (3-D) sim-Navigator, for patients with hepatocellular carcinoma by assessing relapse-free survival and shape of the ablation volume under clinical conditions., Methods: All participants provided written, informed consent, and study protocols were approved by the institutional ethics committee. Twenty-seven patients with 27 nodules were treated by no-touch ablation using the new simulator system. Another 21 patients with 21 nodules treated without the simulator system were enrolled as controls. Tumor progression and shape of ablation volume were assessed. Predictors of tumor progression were assessed by Cox proportional hazard model., Results: No significant differences in clinical characteristics were seen between groups. Mean sphericity was 0.48 ± 0.07 with 3-D sim-Navigator and 0.37 ± 0.07 without 3-D sim-Navigator (P < 0.001). Median surface-to-volume ratio and compactness were also significantly closer to those of a sphere with 3-D sim-Navigator (P = 0.017, P < 0.001). Relapse-free survival rates at 1 and 1.5 years were 94.1% and 82.4%, respectively, with 3-D sim-Navigator, compared with 83.2% and 55.5% without (P = 0.056). The only independent factor predicting relapse-free survival was use of 3-D sim-Navigator (hazard ratio, 0.12; 95%CI, 0.01-0.87; P = 0.035)., Conclusions: Ideal ablation area was acquired by this simulation and navigation system in clinics. This system improved local tumor progression by facilitating appropriate insertion of multiple electrodes., (© 2017 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

The tolerability and efficacy of sofosbuvir and ribavirin in patients infected with hepatitis C virus (HCV) genotype 2 were investigated under actual clinical conditions. A total of 208 patients with chronic HCV genotype 2 infection were treated with sofosbuvir 400 mg and ribavirin (weight-based dosing) for 12 weeks. Treatment discontinuation and sustained virological response 12 (SVR12) were evaluated. Moreover, factors associated with SVR12, hemoglobin decreasing to less than 10 g/dL during treatment, and alanine aminotransferase (ALT) non-normalization after treatment were evaluated. In all patients, SVR12 responses were 96.1% (200/208). About 6 of 8 patients (3.8%) who did not achieve SVR12 were re-treatment patients, and eight patients who did not achieve SVR all had liver cirrhosis. Multivariate analysis also identified body mass index (OR = 0.79; P < 0.001), platelet count (OR = 0.88; P = 0.003), and estimated glomerular filtration rate (eGFR) (OR = 0.96; P = 0.007) as independent contributing factors associated with hemoglobin decreasing to less than 10 g/dL during treatment, and only Mac-2 Binding Protein Glycosylation isomer (M2BpGi) (OR = 2.46; P = 0.017) as an independent contributing factor associated with ALT non-normalization after treatment. Cirrhotic patients may have a relatively high rate of treatment failure. In patients whose M2BpGi levels are elevated, their ALT tended to not normalize after treatment completion. These patients who did not achieve normalization of ALT after sofosbuvir plus RBV treatment need more careful observation for emergence of hepatocellular carcinoma even after achievement of SVR., (© 2017 Wiley Periodicals, Inc.)

Background: Palmitic acid is an important risk factor for the pathogenesis of non-alcoholic steatohepatitis (NASH), but changes in palmitic acid intestinal absorption in NASH are unclear. The aim of this study was to clarify changes in palmitic acid intestinal absorption and their association with the pathogenesis of NASH., Methods: A total of 106 participants were recruited to the study, of whom 33 were control subjects (control group), 32 were patients with NASH Brunt stage 1-2 [early NASH (e-NASH)], and 41 were patients with NASH Brunt stage 3-4 [advanced NASH (a-NASH)]. 13 C-labeled palmitate was administered directly into the duodenum of all participants by gastrointestinal endoscopy. Breath 13 CO 2 levels were measured to quantify palmitic acid absorption, and serum Apolipoprotein B-48 (ApoB-48) concentrations were measured after a test meal to quantify absorbed chylomicrons. Expressions of fatty acid (FA) transporters were also examined. The associations of breath 13 CO 2 levels with hepatic steatosis, fibrosis and insulin resistance was evaluated using laboratory data, elastography results and liver histology findings., Results: Overall, 13 CO 2 excretion was significantly higher in e-NASH patients than in the control subjects and a-NASH patients (P < 0.01). e-NASH patients had higher serum ApoB-48 levels, indicating increased palmitic acid transport via chylomicrons in these patients. Jejunal mRNA and protein expressions of microsomal triglyceride transfer protein and cluster of differentiation 36 were also increased in both NASH patient groups. The 13 CO 2 excretion of e-NASH patients was significantly correlated with the degree of hepatic steatosis, fibrosis and insulin resistance (P = 0.005, P < 0.001, P = 0.019, respectively)., Conclusions: Significantly upregulated palmitic acid absorption by activation of its transporters was evident in patients with NASH, and clinical progression of NASH was related to palmitic acid absorption. These dietary changes are associated with the onset and progression of NASH.

Farnesyl diphosphate synthase (FPS) is an essential enzyme in the biosynthesis of prenyl precursors for the production of primary and secondary metabolites, including sterols, dolichols, carotenoids and ubiquinones, and for the modification of proteins. Here we identified and characterized two FPSs (EuFPS1 and EuFPS2) from the plant Eucommia ulmoides. The EuFPSs had seven highly conserved prenyltransferase-specific domains that are critical for activity. Complementation and biochemical analyses using bacterially produced recombinant EuFPS isoforms showed that the EuFPSs had FPP synthesis activities both in vivo and in vitro. In addition to the typical reaction mechanisms of FPS, EuFPSs utilized farnesyl diphosphate (FPP) as an allylic substrate and participated in further elongation of the isoprenyl chain, resulting in the synthesis of geranylgeranyl diphosphate. However, despite the high amino acid similarities between the two EuFPS isozymes, their specific activities, substrate preferences, and final reaction products were different. The use of dimethylallyl diphosphate (DMAPP) as an allylic substrate highlighted the differences between the two enzymes: depending on the pH, the metal ion cofactor, and the cofactor concentration, EuFPS2 accumulated geranyl diphosphate as an intermediate product at a constant rate, whereas EuFPS1 synthesized little geranyl diphosphate. The reaction kinetics of the EuFPSs demonstrated that isopentenyl diphosphate and DMAPP were used both as substrates and as inhibitors of EuFPS activity. Taken together, the results indicate that the biosynthesis of FPP is highly regulated by various factors indispensable for EuFPS reactions in plants., (Copyright © 2017. Published by Elsevier B.V.)

A change in hepatic blood flow caused by the hepatic arterial buffer response (HABR) occurs as fatty liver disease progress. The aim of this longitudinal cohort study was to investigate whether fatty liver with the HABR induces metabolic disorders. In 2009 and 2010, 494 (89.5%) participants were enrolled. The median follow-up duration was 5.0 (interquartile range, 3.9-6.0) years. The hazard ratios of fatty liver with the HABR for incident metabolic disorders were assessed by Cox proportional hazard models. A non-fatty liver group (non-FL group, hepatorenal echo intensity ratio <1.12), a fatty liver without portal hypertension (FL group, hepatorenal echo intensity ratio ≥1.12 and ratio of the maximal blood velocity in the right hepatic artery to maximal blood velocity in the right portal vein <3.1) group, and a fatty liver with portal hypertension (FL-HABR group, hepatorenal echo intensity ratio ≥1.12 and ratio of the maximal blood velocity in the right hepatic artery to maximal blood velocity in the right portal vein ≥3.1) group were defined based on echo intensity and Doppler ultrasonography. Fatty liver with and without the HABR was significantly associated with the incidence of diabetes on multivariate analysis (non-FL versus FL group, hazard ratio, 3.36; 95% confidence interval, 1.05-12.85; FL versus FL with the HABR group, HR, 2.68; 95% confidence interval, 1.28-6.04). With respect to the incidence of hypertension and dyslipidemia, only FL with the HABR was a significant factor (hypertension, non-FL versus FL, P = 0.874, FL versus FL-HABR, P = 0.016, non-FL versus FL-HABR, P = 0.023; dyslipidemia, non-FL versus FL, P = 0.311, FL versus FL-HABR, P = 0.194, non-FL versus FL-HABR, P = 0.038). Conclusion : Fatty liver with the HABR is a high-risk condition for metabolic diseases. ( Hepatology Communications 2017;1:623-633).

Aim: This study aimed to compare multipolar radiofrequency ablation (RFA) with monopolar RFA as the major treatment for nodules of hepatocellular carcinoma in the caudate lobe., Methods: This retrospective study was approved by the institutional review board. Data were reviewed from 101 patients who met the Milan criteria and were treated by multipolar RFA (n = 22) or monopolar RFA (n = 79). After propensity score matching, complications and local tumor progression were compared between the two groups., Results: Before propensity score matching (n = 101), the 2-year relapse-free survival rates for multipolar and monopolar RFA (65.1% vs. 38.8%, respectively; P = 0.064) and the local tumor progression rate (12.5% vs. 14.9%, respectively; P = 0.313) were not significantly different. There were no significant differences between the two RFA techniques by treatment efficacy of transcatheter hepatic arterial embolization, location of tumor, and puncture route. After matching (n = 44), the 2-year relapse-free survival rate for the multipolar and monopolar groups (65.1% vs. 22.7%, respectively; P = 0.004) was significantly different, and the local tumor progression rate (12.5% vs. 22.9%, respectively; P = 0.004) was significantly different. No severe complications occurred in the patients treated by multipolar RFA., Conclusion: Multipolar RFA appears to be a safe and effective method for hepatocellular carcinoma nodules in the caudate lobe., (© 2016 The Japan Society of Hepatology.)

GaN-based light-emitting diodes (LEDs) have been widely accepted as highly efficient solid-state light sources capable of replacing conventional incandescent and fluorescent lamps. However, their applications are limited to small devices because their fabrication process is expensive as it involves epitaxial growth of GaN by metal-organic chemical vapor deposition (MOCVD) on single crystalline sapphire wafers. If a low-cost epitaxial growth process such as sputtering on a metal foil can be used, it will be possible to fabricate large-area and flexible GaN-based light-emitting displays. Here we report preparation of GaN films on nearly lattice-matched flexible Hf foils using pulsed sputtering deposition (PSD) and demonstrate feasibility of fabricating full-color GaN-based LEDs. It was found that introduction of low-temperature (LT) grown layers suppressed the interfacial reaction between GaN and Hf, allowing the growth of high-quality GaN films on Hf foils. We fabricated blue, green, and red LEDs on Hf foils and confirmed their normal operation. The present results indicate that GaN films on Hf foils have potential applications in fabrication of future large-area flexible GaN-based optoelectronics.

The acidic (leucine-rich) nuclear phosphoprotein 32 family member B (ANP32B), a highly conserved member of the acidic nuclear phosphoprotein 32 (ANP32) family, is critical for the development of normal tissue. However, its role in the development of hepatocellular carcinoma (HCC) is controversial. In this study, we elucidated the role of ANP32B in HCC cell lines and tissues. ANP32B expression in HCC cell lines was modulated using siRNA and ANP32B expression plasmids and lentiviruses. The levels of apoptosis-related proteins were analyzed by real-time RT-PCR and Western blotting. The expression of ANP32B in tissues from patients with HCC was investigated using real-time RT-PCR and immunohistochemistry. ANP32B knockdown by siRNA altered the expression of apoptosis-related proteins in HCC cell lines and reduced the expression of cleaved forms of caspase 3 and caspase 9, but not that of caspase 8, in HCC cells cultured with the pro-apoptotic agent staurosporine. Phosphorylated Bad was upregulated, whereas Bak was downregulated. Moreover, ABT-737, which binds to and inhibits anti-apoptotic proteins of the Bcl-2 family, rendered HCC cells resistant to apoptosis induced by ANP32B silencing. Conversely, ANP32B overexpression decreased Bad phosphorylation and upregulated Bak, but did not induce apoptosis because Bax expression was downregulated. In tissues from patients with HCC, a low tumor/non-tumor ratio of ANP32B mRNA expression was related to advanced UICC stage (p = 0.032). TUNEL-positive cells were observed in parallel with ANP32B expression in HCC tissues. ANP32B modulates Bad phosphorylation as well as Bak and Bax expression, resulting in regulation of apoptosis in HCC. These findings indicate the potential value of ANP32B as a therapeutic target for HCC.

The adult mammalian central nervous system (CNS) contains a population of slowly dividing oligodendrocyte precursor cells (OPCs), i.e., adult OPCs, which supply new oligodendrocytes throughout the life of animal. While adult OPCs develop from rapidly dividing perinatal OPCs, the mechanisms underlying their quiescence remain unknown. Here, we show that perinatal rodent OPCs cultured with thyroid hormone (TH) under hypoxia become quiescent and acquire adult OPCs-like characteristics. The cyclin-dependent kinase inhibitor p15/INK4b plays crucial roles in the TH-dependent cell cycle deceleration in OPCs under hypoxia. Klf9 is a direct target of TH-dependent signaling. Under hypoxic conditions, hypoxia-inducible factors mediates runt-related transcription factor 1 activity to induce G1 arrest in OPCs through enhancing TH-dependent p15/INK4b expression. As adult OPCs display phenotypes of adult somatic stem cells in the CNS, the current results shed light on environmental requirements for the quiescence of adult somatic stem cells during their development from actively proliferating stem/progenitor cells.

Eucommia ulmoides , a deciduous dioecious plant species, accumulates trans -1,4-polyisoprene (TPI) in its tissues such as pericarp and leaf. Probable TPI synthase ( trans -isoprenyl diphosphate synthase ( TIDS )) genes were identified by expressed sequence tags of this species; however, the metabolic pathway of TPI biosynthesis, including the role of TIDS s, is unknown. To understand the mechanism of TPI biosynthesis at the transcriptional level, comprehensive gene expression data from various organs were generated and TPI biosynthesis related genes were extracted by principal component analysis (PCA). The metabolic pathway was assessed by comparing the coexpression network of TPI genes with the isoprenoid gene coexpression network of model plants. By PCA, we dissected 27 genes assumed to be involved in polyisoprene biosynthesis, including TIDS genes, genes encoding enzymes of the mevalonate (MVA) pathway and the 2- C -methyl-D-erythritol 4-phosphate (MEP) pathway, and genes related to rubber synthesis. The coexpression network revealed that 22 of the 27 TPI biosynthesis genes are coordinately expressed. The network was clustered into two modules, and this was also observed in model plants. The first module was mainly comprised of MEP pathway genes and TIDS1 gene, and the second module, of MVA pathway genes and TIDS5 gene. These results indicate that TPI is likely biosynthesized by both the MEP and MVA pathways and that TIDS gene expression is differentially controlled by these pathways.

Hepatic aneurysms are rare, but can prove fatal once they rupture. Transcatheter arterial embolization (TAE) is performed as a prophylactic treatment. The position of the aneurysm determines the degree of difficulty of TAE. Maintaining blood flow to the liver can become difficult, particularly when the aneurysm is at an arterial junction. The patient was a 72-year-old man diagnosed with a hepatic aneurysm. The aneurysm was situated on the common hepatic artery at the junction of the gastroduodenal and proper hepatic arteries. TAE was performed with framing, followed by coil embolization. Blood flow to the liver was maintained via the gastroduodenal artery. Appropriate framing is important for safe and efficient TAE.

Background: Fatty liver disease is associated with glucose intolerance and hepatic insulin resistance. However, there are distinct etiologies for alcoholic versus non-alcoholic fatty liver disease (NAFLD), and it is unknown whether alcohol consumption influences the onset of glucose intolerance in fatty liver disease patients. Therefore, we investigated the relationship between fatty liver disease and the onset of impaired fasting glucose (IFG) with respect to alcohol consumption., Methods: The records of 6804 Japanese subjects were reviewed to identify those meeting the criteria for IFG. Male and female subjects were classified into five and four groups, respectively, based on average alcohol consumption (g/week). IFG onset was defined as fasting plasma glucose levels ≥110 mg/dl., Results: In the non-drinker, >0-70 g/week, >70-140 g/week, >140-210 g/week (men only), and >210 g/week (men only) or >140 g/week (women only) groups, 7.3, 6.7, 6.4, 9, and 6.4 % of men and 2, 1.7, 3.1, and 3.2 % of women, respectively, developed IFG. Fatty liver was positively associated with the onset of IFG in men of the >0-70 g/week group (adjusted hazard ratio [aHR], 2.808; 95 % confidence interval [CI] 1.605-5.049, p < 0.001) and women of the >70-140 g/week group (aHR, 4.193; 95 % CI, 1.036-14.584, p = 0.045) after adjusting for previously reported IFG risk factors. No associations were observed in the other groups., Conclusions: A small amount of alcohol consumption is a significant risk factor for the onset of IFG in NAFLD patients; onset risk differs according to the amount of alcohol consumption.

Heme oxygenase (HO) is a mono-oxygenase utilizing heme and molecular oxygen (O 2 ) as substrates to generate biliverdin-IXα and carbon monoxide (CO). HO-1 is inducible under stress conditions, while HO-2 is constitutive. A balance between heme and CO was shown to regulate cell death and survival in many experimental models. However, direct molecular targets to which CO binds to regulate cellular functions remained to be fully examined. We have revealed novel roles of CO-responsive proteins, cystathionine β-synthase (CBS) and progesterone receptor membrane component 1 (PGRMC1), in regulating cellular functions. CBS possesses a prosthetic heme that allows CO binding to inhibit the enzyme activity and to regulate H 2 S generation and/or protein arginine methylation. On the other hand, in response to heme accumulation in cells, PGRMC1 forms a stable dimer through stacking interactions of two protruding heme molecules. Heme-mediated PGRMC1 dimerization is necessary to interact with EGF receptor and cytochromes P450 that determine cell proliferation and xenobiotic metabolism. Furthermore, CO interferes with PGRMC1 dimerization by dissociating the heme stacking, and thus results in modulation of cell responses. This article reviews the intriguing functions of these two proteins in response to inducible and constitutive levels of CO with their pathophysiological implications., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Non-alcoholic steatohepatitis (NASH) is a common liver disorder caused by fatty liver. Because NASH is associated with fibrotic and morphological changes in liver tissue, a direct imaging technique is required for accurate staging of liver tissue. For this purpose, in this study we took advantage of two label-free optical imaging techniques, second harmonic generation (SHG) and auto-fluorescence (AF), using two-photon excitation microscopy (TPEM). Three-dimensional ex vivo imaging of tissues from NASH model mice, followed by image processing, revealed that SHG and AF are sufficient to quantitatively characterize the hepatic capsule at an early stage and parenchymal morphologies associated with liver disease progression, respectively.

Purpose: The tolerability and efficacy of simeprevir in combination with peginterferon and ribavirin in patients infected with hepatitis C virus (HCV) genotype 1 under actual clinical conditions were investigated., Methods: A total of 176 patients with chronic HCV genotype 1 infection were treated with simeprevir for 12 weeks plus Peg-IFN/RBV for 24 weeks. Overall, 107 (60.7 %) patients were aged 60 years or more, and 16 (9 %) patients were aged 70 years or more. Treatment discontinuation, sustained virological response 12 (SVR12), and viral relapse were evaluated and compared between younger patients and elderly patients., Results: The rates of undetectable HCV RNA at the end of treatment were 95.8, 100 and 93.1 % in treatment-naïve, prior relapse, and prior non-responders, respectively. However, the rates of SVR12 were 82.4, 88.2 and 69.2 %, respectively. Especially in prior non-responders, viral relapse was relatively frequent. Treatment discontinuation and SVR12 were not different between patients aged <70 and ≥70 years, but viral relapse after completing treatment was significantly more frequent in patients aged ≥70 years (p = 0.012)., Conclusions: In simeprevir with peginterferon and ribavirin therapy, viral relapse was relatively frequent. Especially in elderly patients, the relapse rate was high after completing treatment, instead of low frequency of discontinuation by the adverse events.

CO is a gaseous mediator generated by HO. Our previous studies revealed that CO generated from inducible HO-1 or from constitutive HO-2 modulates function of different heme proteins or enzymes through binding to their prosthetic ferrous heme to alter their structures, regulating biological function of cells and organs. Such CO-directed target macromolecules include sGC and CBS. In the liver, CO serves as a sinusoidal dilator through its action on sGC in hepatic stellate cells, while the same gas accounts for vasoconstrictor that inhibits H2S generated by CO-sensitive CBS in astrocytes. Since molecular O2 is a substrate for HO, the latter mechanism contributes to hypoxic vasodilation in neurovascular units. We have recently uncovered that stress-inducible CO in and around cancer cells suppresses CBS to result in decreased methylation of PFKFB3, the enzyme regulating PFK-1, leading to a shift of glucose biotransformation from glycolysis toward pentose phosphate pathway; such a metabolic remodeling causes chemoresistance through increasing NADPH and reduced glutathione under stress conditions for cancer cells. This article reviews the intriguing networks of CO-sensitive metabolic regulatory mechanisms in microcirculation and cancer., (© 2015 John Wiley & Sons Ltd.)

Purpose: The purpose of this study was to assess the accuracy and efficacy of a needle-tracking system in phantom and clinical studies using bipolar electrodes., Methods: To observe the tip of the electrode, a needle-tracking system with a volume navigation system was used. In the phantom study, the electrode was inserted at various angles and the error was verified. In the clinical study, 21 nodules close to extrahepatic organs or major vessels were enrolled between May and October 2014. After puncturing with the needle-tracking system, computed tomography (CT) was performed. The distances between the electrode tip and extrahepatic organs or major vessels were measured on both B-mode ultrasound (US) and CT. By comparing these distances, the accuracy of this system was evaluated., Results: In the phantom study, the deviation between the tip of the electrode and the virtual tip of the electrode was analyzed. The median values were within 2 mm at each puncture angle. In the clinical study, the difference between B-mode US and CT was less (mean value 1.17 ± 1.76 mm; range 0-3.5 mm)., Conclusion: The needle-tracking system is an accurate and useful system for bipolar radiofrequency ablation.

Background and Aim: Entecavir is one of the most-used nucleoside analogues for the treatment of patients with chronic hepatitis B virus (HBV) infection. The aim of this study was to clarify the effects of long-term entecavir treatment on the incidence of hepatocellular carcinoma (HCC)., Methods: The participants were 249 patients with chronic HBV infection who had been treated by entecavir for more than 2 years. Hepatic functional reserve and incidence of HCC were evaluated, and the factors that might contribute to the development of HCC were analyzed., Results: Prothrombin activity was significantly elevated at 60 months after starting entecavir (from 85.9 ± 17.4 to 97.0 ± 16.9%, p < 0.001). The albumin level was also significantly elevated at 60 months after starting entecavir (from 4.0 ± 0.5 to 4.3 ± 0.3 mg/dL, p < 0.001). The annual incidence of HCC decreased over time, and the incidence of HCC was only 1.8% at 5 years after starting entecavir. On multivariate analysis for HCC incidence, older age and low platelet count were significant, independent contributing factors., Conclusions: Long-term treatment with entecavir improved hepatic functional reserve and decreased the incidence of HCC over time after 3 years. To decrease the incidence of HCC, careful induction of long-term entecavir treatment in younger patients with chronic HBV infection and better hepatic functional reserve would be important.

Multipuncture radiofrequency ablation is expected to produce a large ablated area and reduce intrahepatic recurrence of hepatocellular carcinoma; however, it requires considerable skill. This study evaluated the utility of a new simulator system for multipuncture radiofrequency ablation. To understand positioning of multipuncture electrodes on three-dimensional images, we developed a new technology by expanding real-time virtual ultrasonography. We performed 21 experimental punctures in phantoms. Electrode insertion directions and positions were confirmed on computed tomography, and accuracy and utility of the simulator system were evaluated by measuring angles and intersections for each electrode. Moreover, to appropriately assess placement of the three electrodes, puncture procedures with or without the simulator were performed by experts and non-experts. Technical success was defined as maximum angle and distance ratio, as calculated by maximum and minimum distances between electrodes. In punctures using 2 electrodes, correlations between angles on each imaging modality were strong (ultrasound vs. simulator: r = 0.991, p<0.001, simulator vs. computed tomography: r = 0.991, p<0.001, ultrasound vs. computed tomography: r = 0.999, p<0.001). Correlations between distances in each imaging modality were also strong (ultrasound vs. simulator: r = 0.993, p<0.001; simulator vs. computed tomography: r = 0.994, p<0.001; ultrasound vs. computed tomography: r = 0.994, p<0.001). In cases with 3 electrodes, distances between each electrode correlated strongly (yellow-labeled vs. red-labeled: r = 0.980, p<0.001; red-labeled vs. blue-labeled: r = 0.953, p<0.001; yellow-labeled vs. blue-labeled: r = 0.953, p<0.001). Both angle and distance ratio (expert with simulator vs. without simulator; p = 0.03, p = 0.02) were significantly smaller in procedures performed by experts using the simulator system. The new simulator system appears to accurately guide electrode positioning. This simulator system could allow multipuncture radiofrequency ablation to be performed more effectively and comfortably.

3,5,3'-triiodo-L-thyronine regulates the glucose metabolism, lipid metabolism, and hepatic steatosis. Several groups have shown the relationships between hypothyroidism and nonalcoholic fatty liver and hypothyroidism and nonalcoholic steatohepatitis (NASH). However, the effect of hyperthyroidism on NASH has not yet been investigated. We herein report effects of thyroid hormone on the pathological condition of NASH in a patient with NASH complicated by Graves' disease. In our case, the liver enzyme level improved with the increasing thyroid hormone level; however, the liver enzyme level was aggravated with the improving thyroid hormone level. Therefore, hyperthyroidism may improve the pathological condition of NASH.

Bile duct injury is a potential complication of radiofrequency ablation (RFA). Bipolar RFA devices have recently become available. Because visibility of the bipolar RFA electrodes is not good on ultrasonography, more careful usage of the electrodes to avoid bile ducts is needed. We present a case with hepatocellular carcinoma (HCC) located near the B5 intrahepatic bile duct. To view the bile duct, we used contrast medium for ultrasonography, administered through a biliary drainage catheter for endoscopic nasobiliary drainage (ENBD). Infusing the contrast medium allowed clear visualization of the HCC adjacent to the major bile duct during RFA. We also used a navigation system for bipolar RFA to confirm positions of the electrodes and HCC. We confirmed complete ablation of the HCC while avoiding bile duct injury and late bile duct stenosis. Administration of contrast medium for ultrasonography through an ENBD tube appears useful to avoid bile duct injury during RFA.

Background: Epidemiologic studies show an association between short sleep duration and the presence of nonalcoholic fatty liver disease (NAFLD). This study examined the association between short sleep duration and the onset of NAFLD., Methods: This community-based, retrospective, longitudinal cohort study included 6,370 Japanese subjects who had undergone annual health check-ups more than twice at a single center between April 2003 and March 2010. After excluding 3,941 subjects, the records of 2,429 Japanese subjects were reviewed., Results: Two groups comprised the study cohort: those with short (≤ 6 h) sleep durations (n = 1,543) and those with moderate (7-8 h) sleep durations (n = 886). During the observation period, 296 subjects developed NAFLD. Multivariate analysis identified an association between short sleep duration and the reduced onset of NAFLD in men (odds ratio: 0.551, 95% confidence interval 0.365-0.832, p = 0.005). There was no association between short sleep duration and NAFLD onset in women. The prevalence of NAFLD onset in men increased significantly as sleep duration increased, as follows: 12.5, 18.4, and 27.4% among subjects who had sleep durations of ≤ 4, 5-6, and 7-8 h, respectively (p = 0.02)., Conclusions: This study demonstrates an association between sleep duration and NAFLD onset. Short sleep duration reduced the risk of NAFLD onset in men. Correct recognition is important to prevent disease progression and further complications.

Purpose: This study aimed at prospectively evaluating bile duct anatomy on ultrasonography and evaluating the safety and utility of radiofrequency ablation (RFA) assisted by virtual ultrasonography from gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI)., Methods: The institutional review board approved this study, and patients provided written informed consent prior to entry into the study. Bile duct anatomy was assessed in 201 patients who underwent Gd-EOB-DTPA-enhanced MRI for the evaluation of hepatic tumor. Eighty-one of these patients subsequently underwent RFA assisted by ultrasound imaging. In 23 patients, the tumor was located within 5 mm of the central bile duct, as demonstrated by MRI., Results: Virtual ultrasonography constructed by Gd-EOB-enhanced MRI was able to visualize the common bile duct, left hepatic duct, and right hepatic duct in 96.5, 94.0, and 89.6 % of cases, respectively. The target hepatic tumor nodule and biliary duct could be detected with virtual ultrasonography in all patients, and no severe complications occurred., Conclusion: The running pattern of the bile ducts could be recognized on conventional ultrasound by referencing virtual ultrasonography constructed by Gd-EOB-DTPA-enhanced MRI. RFA assisted by this imaging strategy did not result in bile duct injury.

Background: Nonalcoholic fatty liver disease (NAFLD) is a risk factor for diabetes and cardiovascular disease that could progress to nonalcoholic steatohepatitis, cirrhosis, and liver failure. We aimed to assess the relationship between NAFLD and lifestyle habits., Methods: Using a community-based, cross-sectional design, the records of 11,094 Japanese subjects who had undergone at least 1 annual health checkup were reviewed., Results: Of the 6,370 subjects who qualified for enrolment, 1,346 met the diagnostic criteria for NAFLD. The prevalence rate (PR) of NAFLD increased significantly to 36.6, 41.5, and 41.1 % with no snacking, snacking less than once/day, and snacking ≥2 times/day, respectively, in men (P = 0.0495) and to 10.8, 11.7, and 15.3 %, respectively, in women (P = 0.002). In men, the NAFLD PR decreased significantly to 48.8, 36.9, and 29.9 % with no exercise, exercise consciousness, and periodical exercise, respectively (P < 0.001). In women, the NAFLD PR decreased significantly to 19.3, 13.5, 11, and 8 % with sleep durations of ≤4, 5-6, 7-8, and ≥9 h, respectively (P = 0.003). Periodical exercise was identified as an independent factor associated with NAFLD in men (odds ratio 0.707, 95 % confidence interval 0.546-0.914; P = 0.008)., Conclusions: Performing regular exercise was associated with a reduced risk for NAFLD in men. Men with a high risk for NAFLD can be identified using questionnaires on exercise in an outpatient setting. Disease progression and further complications may be prevented by educating high-risk NAFLD patients about the importance of exercise.

Purpose: To prospectively evaluate whether the characteristics of hepatic blood flow change during the early stages of fibrosis in patients with nonalcoholic fatty liver disease (NAFLD)., Materials and Methods: All participants provided written informed consent, and the study protocols were approved by the institutional ethics committee. A total of 121 patients with NAFLD that was diagnosed at histologic examination were enrolled. Hepatic blood flow was measured by means of Doppler ultrasonography (US), and the ratio of arterial to portal blood flow (arterioportal ratio) was calculated. Elasticity of the spleen was measured by means of real-time tissue elastography. The elastic ratio was measured as the value in the small splenic vessel divided by the value of the splenic parenchyma. The arterioportal ratio and splenic elasticity were compared in patients with all stages of fibrosis (F0-F4) and with all levels of platelet counts. Correlations among the resistive index of the hepatic artery and that of the splenic artery, the fibrosis 4 index, hepatic elasticity, arterioportal ratio, splenic elasticity, and platelet counts were analyzed. Univariate and multivariate logistic regression analyses were performed. Correlations in patients with platelet counts greater than 200 000/μL also were analyzed., Results: The mean ± standard deviation arterioportal ratio was significantly higher at fibrosis stage 2 (2.4 ± 0.6) than at fibrosis stage 0 (1.8 ± 0.4) in patients with NAFLD (P < .01). Increased splenic stiffness at earlier stages of fibrosis also was observed in patients with NAFLD (fibrosis stage 2, 4.4 ± 2.3; fibrosis stage 0, 3.2 ± 1.9; P < .05). In patients with NAFLD with platelet counts higher than 200 000/μL, pericellular fibrosis was the only significant predictor of hepatic hemodynamic change at multivariate analysis (odds ratio, 7.17; 95% confidence interval: 1.33, 57.13; P = .021)., Conclusion: Change in hepatic blood flow occurred during the earliest stage of hepatic fibrosis in patients with NAFLD because of outflow block in the sinusoidal area., (© RSNA, 2014.)

A 62-year-old woman with hepatocellular carcinoma (HCC) and asthma presented with acute abdominal pain and a decreased hemoglobin level. Peritoneal fluid was detected around the lesion, and rupture was suspected based on the findings of computed tomography. Extravasation of the HCC tumor was not detected on angiography with iodine contrast agent; however, such extravasation was clearly observed on angiography with carbon dioxide (CO2). CO2 angiography is sometimes utilized in patients with arterial bleeding. This modality be more effective and safe than angiography with iodine contrast agent for assessing potential ruptured HCC lesions.

A 36-year-old Japanese woman took over-the-counter (OTC) medication for headaches for 20 days. Subsequently, five days after discontinuing the medication, a skin rash developed over the patient's upper and lower limbs and face, in addition to a fever, brown urine and serious liver dysfunction. Drug lymphocyte stimulation tests implicated ibuprofen, a main component of the OTC drugs, which has the potential to induce this pathology, and a diagnosis of drug-induced liver injury with multiform exudative erythema was made. The patient's symptoms and liver function tests returned to normal following treatment with systemic steroids.

Aim: The purpose of this study was to clarify the frequency of hypophosphatemia and other clinical features in patients with hepatitis B undergoing long-term therapy with adefovir dipivoxil (ADF)., Methods: Seventeen hepatitis B patients treated with a combination of lamivudine and ADF were analyzed. They were divided into two groups: patients who developed hypophosphatemia (P < 2.5 mg/dL) (group A) and those who did not (group B). The frequency of hypophosphatemia and other clinical features were retrospectively analyzed., Results: There were six patients (35.3%) in group A. The treatment period was 57.3 ± 15.6 and 61.8 ± 25.7 months in groups A and B, respectively. No differences were found between the groups prior to treatment. Among the six patients in group A, osteomalacia was observed in two, while a pathological fracture of the scapula was found in one. Decreases in phosphate (96 weeks after starting ADF), estimated glomerular filtration rate (eGFR) (48 weeks) and uric acid (24 weeks) levels, and increases in creatinine and alkaline phosphatase were noted in group A., Conclusion: Hypophosphatemia occurred in 35% of the patients under the long-term treatment with ADF. Although it was not possible to predict the decrease in phosphate before ADF therapy, decreases in uric acid and eGFR may be the early events relating to low phosphatemia., (© 2013 The Japan Society of Hepatology.)

Cell transplantation therapy with oligodendrocyte precursor cells (OPCs) is a promising and effective treatment for diseases involving demyelination in the central nervous system (CNS). In previous studies, we succeeded in producing O4(+) oligodendrocytes (OLs) from mouse- and human-induced pluripotent stem cells (iPSCs) in vitro; however, the efficiency of differentiation into OLs was lower for iPSCs than that for embryonic stem cells (ESCs). To clarify the cause of this difference, we compared the expression of proteins that contribute to OL differentiation in mouse iPSC-derived cells and in mouse ESC-derived cells. The results showed that the expression levels of cyclin dependent kinase inhibitor P27/Kip1, mitogen-activated protein kinase (MAPK) JNK3, and transcription factor Mash1 were lower in iPSC-derived cells. In contrast, the expression levels of MAPK P38α, P38γ, and thyroid hormone receptor β1 were higher in iPSC-derived cells. We attempted to compensate for the expression changes in P27/Kip1 protein and Mash1 protein in iPSC-derived cells through retrovirus vector-mediated gene expression. Although the overexpression of Mash1 had no effect, the overexpression of P27/Kip1 increased the differentiation efficiency of iPSC-derived cells into O4(+) OLs.

Background & Aims: Although a low plasma level of branched-chain amino acids (BCAAs) is a marker of cirrhosis, it is not clear whether BCAA supplements affect disease progression. We performed a multicenter study to evaluate the effects of BCAA supplementation on hepatocarcinogenesis and survival in patients with cirrhosis., Methods: We enrolled 299 patients from 14 medical institutions in Japan in a prospective, multicenter study in 2009; 267 patients were followed through 2011. Patients were given BCAA supplements (5.5-12.0 g/day) for more than 2 years (n = 85) or no BCAAs (controls, n = 182). The primary end points were onset of hepatocellular carcinoma (HCC) and death. Factors associated with these events were analyzed by competing risk analysis., Results: During the study period, 41 of 182 controls and 11 of 85 patients given BCAAs developed HCC. On the basis of the Cox and the Fine and Gray models of regression analyses, level of α-fetoprotein, ratio of BCAA:tyrosine, and BCAA supplementation were associated with development of HCC (relative risk for BCAAs, 0.45; 95% confidence interval, 0.24-0.88; P = .019). Sixteen controls and 2 patients given BCAAs died. Factors significantly associated with death were Child-Pugh score, blood level of urea nitrogen, platelet count, male sex, and BCAA supplementation (relative risk of death for BCAAs, 0.009; 95% confidence interval, 0.0002-0.365; P = .015) in both regression models., Conclusions: On the basis of a prospective study, amino acid imbalance is a significant risk factor for the onset of HCC in patients with cirrhosis. BCAA supplementation reduces the risk for HCC and prolongs survival of patients with cirrhosis., (Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. HCC is generally considered to spread via the bloodstream and local recurrence often occurs in the blood drainage area determined by computed tomography during hepatic arteriography (CTHA), despite complete ablation of the primary nodule. This study was conducted in order to prospectively assess the rate of local recurrence in the blood drainage area depicted by delayed-phase CTHA. The participants comprised 364 consecutive patients (260 men and 104 women; mean age, 67.4±8.6 years), enrolled between April, 2002 and December, 2011. The participants were divided into two groups, according to whether the ablation area covered the entire blood drainage area as defined by delayed-phase CTHA (group A) or not (group B). Local tumor progression was compared between the two groups. The median time to recurrence was significantly shorter for group B (434 days) compared to that for group A (1,474 days; P=0.0037). The cumulative local recurrence rates for group A were 0, 0 and 1.5% at 1, 3 and 5 years postoperatively, respectively, whereas the recurrence rates for group B were 3.8, 17.0 and 22.8% at 1, 3 and 5 years, respectively (P<0.0001). In conclusion, the safety margin for radiofrequency ablation should be defined as the blood drainage area and ablation should aim at acquiring adequate safety margins.

Background. Information regarding the progression of acute hepatitis B virus (HBV) infection to chronic infection in adults is scarce. Methods. Twenty-five adult patients with acute HBV infection (14 men and 11 women, 18-84 years old), whose clinical features progressed to those of chronic infection (group A) or did not (group B), were studied retrospectively. Results. There were 3 and 22 patients in groups A and B, respectively. Two of the 3 patients of group A lacked the typical symptoms of acute hepatitis. No differences were found between groups with respect to age, sex, or HBV genotypes. However, total bilirubin and alanine aminotransaminase levels were significantly lower in group A. Conclusions. Three of the 25 adult patients with acute HBV infection progressed to chronic infection. Hepatitis was mild in these patients. Patients with mild acute hepatitis B or unapparent HBV infection may have a higher risk of progressing to chronic infection.