Search

Hepatitis B virus (HBV) is one of the most prevalent chronic viral infections that causes chronic hepatitis B (CHB). In Japan, genotypes B and C account for most of acute and chronic cases of hepatitis. However, previous studies showed that the prevalence of genotype A in CHB gradually increased every 5 years. Therefore, we have conducted a nationwide survey to comprehensively investigate the trends of HBV genotype distribution in CHB patients in Japan.4421 CHB patients were recruited between 2015 and 2016. Clinical characteristics and distribution of CHB patients among different age groups and genotypes in 2015-2016 was compared with those in 2000-2001, 2005-2006, and 2010-2011.The percentages of genotype A, B, C, and D were 4.0, 16.2, 79.1, and 0.7%, respectively. While the overall percentage of CHB patients with genotype A did not change in the past 5 years, CHB with genotype A increased in young adults. On the other hand, the peak distribution of CHB with genotypes B and C, two genotypes with the largest patient population, has shifted to an older age group.In Japan, the peak distribution for CHB with genotypes B and C advanced to an older age group while CHB with genotype A expanded in a younger age group. Given the universal HBV vaccination launch in Japan in 2016, these pre-vaccination survey data provide important baseline information for comparative studies of the impact of universal vaccination on HBV genotypes.

BackgroundThe novel coronavirus disease 2019 (COVID-19) undermines the benefits of cancer screening. To date, no study has identified specific infection control methods. We aimed to provide practical methods for COVID-19 risk reduction during breast cancer screening mammography (MMG) by examining an overview of potential contamination routes of aerosols and possible risks for patients and health care providers.MethodsComputational fluid dynamics (CFD) simulations were conducted for airflow and aerosol dispersion in a 3D virtual model of a mobile MMG laboratory room. This model was constructed based on the actual mobile screening MMG bus ‘Cosmos’ in the Chiba Foundation for Health Promotion & Disease Prevention. Examiner and patient geometries were obtained by scanning an actual human using a 3D Scanner. Contamination of the room was evaluated by counting the numbers of suspended and deposited aerosols.ResultsWe applied the CFD simulation model to the exhalation of small or large aerosols from a patient and examiner in the MMG laboratory. Only 14.5% and 54.5% of large and small aerosols, respectively, were discharged out of the room with two doors open. In contrast, the proportion of large and small aerosols discharged out of the room increased to 96.6% and 97.9%, respectively, with the addition of forced gentle wind by the blower fan. This simulation was verified by a mist aerosol experiment conducted in the mobile MMG laboratory.ConclusionAdding forced ventilation to a MMG laboratory with two doors open may enable risk reduction dramatically. This could be applied to other clinical situations.

Isolated systolic hypertension (ISH), defined as systolic blood pressure (SBP) ≥140 mmHg and diastolic BP (DBP)

// Kentaro Ishikawa 1 , Tetsuhiro Chiba 1 , Yoshihiko Ooka 1 , Eiichiro Suzuki 1 , Sadahisa Ogasawara 1 , Takahiro Maeda 1 , Masayuki Yokoyama 1 , Masanori Inoue 1 , Toru Wakamatsu 1 , Yuko Kusakabe 1 , Tomoko Saito 1 , Akinobu Tawada 1 , Makoto Arai 1 , Tatsuo Kanda 1 , Hitoshi Maruyama 1 , Fumio Imazeki 1 and Naoya Kato 1 1 Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan Correspondence to: Tetsuhiro Chiba, email: techiba@faculty.chiba-u.jp Keywords: hepatocellular carcinoma; transarterial chemoembolization; radiofrequency ablation; Barcelona Clinic Liver Cancer (BCLC) staging; propensity score matching Received: August 21, 2017 Accepted: March 11, 2018 Published: April 20, 2018 ABSTRACT Background and Aim: Transarterial chemoembolization (TACE) is the standard procedure for treating Barcelona clinic liver cancer (BCLC) stage B hepatocellular carcinoma (HCC). However, it is often carried out in the treatment of BCLC stage 0/A HCC for various reasons. This study aimed to elucidate the prognosis for BCLC stage 0/A HCC patients treated with TACE or with radiofrequency ablation (RFA). Materials and Methods: The prognosis of 242 BCLC stage 0/A HCC patients within Milan criteria who underwent initially TACE or RFA were retrospectively analyzed using propensity score matching analysis. Results: The analyses of baseline patient characteristics revealed that the maximum tumor size and the proportion of BCLC stage A patients were significantly higher in patients treated with TACE than in those treated with RFA ( P

// Tatsuo Kanda 1, 2 , Shin Yasui 2 , Masato Nakamura 2 , Shingo Nakamoto 2 , Koji Takahashi 2 , Shuang Wu 2 , Reina Sasaki 2 , Yuki Haga 2 , Sadahisa Ogasawara 2 , Tomoko Saito 2 , Kazufumi Kobayashi 2 , Soichiro Kiyono 2 , Yoshihiko Ooka 2 , Eiichiro Suzuki 2 , Tetsuhiro Chiba 2 , Hitoshi Maruyama 2 , Fumio Imazeki 2 , Mitsuhiko Moriyama 1 and Naoya Kato 2 1 Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Tokyo 173-8610, Japan 2 Department of Gastroenterology, Chiba University, Graduate School of Medicine, Chiba 260-8670, Japan Correspondence to: Tatsuo Kanda, email: kandat-cib@umin.ac.jp Keywords: hepatitis C virus; direct-acting antivirals; autoimmune hepatitis; primary biliary cholangitis; sustained virological response Received: January 16, 2018 Accepted: January 30, 2018 Published: February 03, 2018 ABSTRACT Background: Interferon-free treatment can achieve higher sustained virological response (SVR) rates, even in patients in whom hepatitis C virus (HCV) could not be eradicated in the interferon treatment era. Immune restoration in the liver is occasionally associated with HCV infection. We examined the safety and effects of interferon-free regimens on HCV patients with autoimmune liver diseases. Results: All 7 HCV patients with autoimmune hepatitis (AIH) completed treatment and achieved SVR. Three patients took prednisolone (PSL) at baseline, and 3 did not take PSL during interferon-free treatment. In one HCV patient with AIH and cirrhosis, PSL were not administered at baseline, but she needed to take 40 mg/day PSL at week 8 for liver dysfunction. She also complained back pain and was diagnosed with vasospastic angina by coronary angiography at week 11. However, she completed interferon-free treatment. All 5 HCV patients with primary biliary cholangitis (PBC) completed treatment and achieved SVR. Three of these HCV patients with PBC were treated with UDCA during interferon-free treatment. Conclusions: Interferon-free regimens could result in higher SVR rates in HCV patients with autoimmune liver diseases. As interferon-free treatment for HCV may have an effect on hepatic immunity and activity of the autoimmune liver diseases, careful attention should be paid to unexpected adverse events in their treatments. Methods: Total 12 patients with HCV and autoimmune liver diseases [7 AIH and PBC], who were treated with interferon-free regimens, were retrospectively analyzed.

// Yuki Haga 1 , Tatsuo Kanda 1,2 , Shin Yasui 1 , Masato Nakamura 1 , Yoshihiko Ooka 1 , Koji Takahashi 1 , Shuang Wu 1 , Shingo Nakamoto 1,3 , Makoto Arai 1 , Tetsuhiro Chiba 1 , Hitoshi Maruyama 1 , Osamu Yokosuka 1 , Nobuo Takada 4 , Mitsuhiko Moriyama 2 , Fumio Imazeki 1,5 and Naoya Kato 1 1 Department of Gastroenterology, Chiba University, Graduate School of Medicine, Inohana, Chuo-ku, Chiba, Japan 2 Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo, Japan 3 Department of Molecular Virology, Chiba University, Graduate School of Medicine, Inohana, Chuo-ku, Chiba, Japan 4 Department of Internal Medicine, Toho University Sakura Medical Center, Shimoshizu, Sakura, Japan 5 Safety and Health Organization, Chiba University, Yayoicho, Inage-ku, Chiba, Japan Correspondence to: Tatsuo Kanda, email: // Keywords : hepatitis C virus; direct-acting antiviral failure; non-structural 5A (NS5A) inhibitors; resistance-associated variants; case reports Received : June 20, 2017 Accepted : December 23, 2017 Published : December 29, 2017 Abstract Background: Interferon-free treatment results in higher sustained virologic response (SVR) rates, with no serious adverse events in hepatitis C virus (HCV)-infected patients. However, in some patients with treatment-failure in HCV NS5A inhibitor-including interferon-free regimens, the treatment-emergent HCV NS5A resistance-associated variants (RAVs), which are resistant to interferon-free retreatment including HCV NS5A inhibitors, are observed. In HCV-infected Japanese patients with daclatasvir and asunaprevir treatment failure, retreatment with sofosbuvir and ledipasvir could lead to only ~70% SVR rates. Case summary: Three HCV genotype (GT)-1b-infected cirrhotic patients who discontinued the combination of daclatasvir and asunaprevir due to adverse drug reactions within 4 weeks; retreatment with sofosbuvir and ledipasvir combination could result in SVR in these patients without RAVs. One HCV GT-1b-infected cirrhotic patient who discontinued the combination of daclatasvir and asunaprevir due to viral breakthrough at week 10; retreatment with sofosbuvir and ledipasvir combination for this patient with the treatment-emergent HCV NS5A RAV-Y93H resulted in viral relapse at week 4 after the end of the treatment. Conclusion: Retreatment with sofosbuvir and ledipasvir is effective for HCV GT-1b patients who discontinue the combination of daclatasvir and asunaprevir within 4 weeks. The treatment response should be related to the existence of treatment-emergent HCV NS5A RAVs, but may not be related to the short duration of treatment.

Background: Genetic variation near the interferon lambda 3 (IFNL3) is known to be associated with response to pegylated interferon (pegIFN) and ribavirin combination therapy in patients with chronic hepatitis C virus (HCV) infection which is often accompanied by hepatic steatosis. Aims: We examined whether this genetic variation is associated with host lipids and treatment response. Methods: A total of 101 Japanese patients who had underwent liver biopsy before treatment with pegIFN and ribavirin for HCV genotype 1b infection were retrospectively analyzed for association between IFNL3 genotypes (rs8099917) and clinical factors including histopathological features of the liver. The presence of >5% steatosis in the liver specimen was defined as hepatic steatosis. Results: Forty patients (40%) had liver steatosis before therapy. Patients with IFNL3 minor genotype (non-TT) showed lower low-density lipoprotein cholesterol level (p=0.0045), higher γ-glutamyl transpeptidase level (p=0.0003) and higher prevalence of hepatic steatosis (p=0.0002). Advanced fibrosis [odds ratio (OR) 4.63, p=0.03] and IFNL3 major genotype (OR 0.13, p=0.001) were 2 independent factors for determining the presence of hepatic steatosis. Among the factors associated with sustained virological response, IFNL3 genotype was the most significant predictor, as per multivariate analysis. Conclusions: Our results confirmed that IFNL3 genotype is associated with hepatic steatosis as well as IFN response.

Summary When the water quality in Lake Tega was the worst among Japanese lakes in the 1970s, cyanobacteria (mainly the genus Microcystis) were observed to be the dominant species in the summer. Since 2000, for water quality improvement, a large amount of the Tone River water was discharged into Lake Tega, resulting in an improvement in the water quality together with transition of algal dominant species from cyanobacteria to diatoms (mainly the genus Cyclotella). Although several factors including nutrient concentration and daily renewal rate (d) could have been related to the succession of algal dominant species, these effects have not been understood very well. This study investigated the effects of the daily renewal rate and nitrate-nitrogen (hereafter nitrogen) concentration (N) on the competition between the cyanobacterium Microcystis aeruginosa and the diatom Cyclotella sp. through monoculture and monoxenic culture experiments. Based on the experimental results, a simulation model was constructed to predict the competitive growth pattern of each species. Monoxenic culture experiments showed that M . aeruginosa outcompeted Cyclotella sp. under conditions of N = 0.5 (1.0 mg-N L−1) and d = 5, 15, and 20%. The domination of M . aeruginosa could be attributed to smaller values for the half-saturation constant and the minimum nitrogen cell quota for this species with respect to Cyclotella sp. However, Cyclotella sp., possessing higher values of nitrogen cell quota and nitrogen uptake rate, dominated by an increasing nitrogen concentration (N = 1.0 mg L−1) and daily renewal rate (d = 30%). The competitive growth patterns of M . aeruginosa and Cyclotella sp. could roughly be predicted by the simulation model. These results suggested that the daily renewal rate as well as the nitrogen concentration, could affect the competition and be influential factors as to which species dominates between M . aeruginosa and Cyclotella sp.

This study isolated extracellular polysaccharides (EPS) as a powder material from cyanobacterial blooms and the powdered EPS was used to trigger colony formation of dispersed unicellular M. aeruginosa by controlling EPS concentration in culture medium. The effect of Ca2+ ions on the colony formation of M. aeruginosa was also investigated, then the interaction between EPS and Ca2+ ions on colony formation was discussed. The results showed that the addition of the powdered EPS into the medium did not cause morphological changes of M. aeruginosa, suggesting that EPS alone would not induce the colony formation of M. aeruginosa. On the other hand, a high concentration of calcium ions (1000 mg/l) caused colony formation. When EPS and Ca2+ ions in the culture medium were adjusted to 200 and 1000 mg/l, respectively, the colony density, the average cell number per colony and the particle size of M. aeruginosa showed ca. 1.7–2.0 times greater values than those in the Ca2+ added medium. Calcium ion contributed to the aggregation of M. aeruginosa via crosslinked reaction with negatively charged M. aeruginosa cells, and the addition of EPS possessing negatively charged functional groups such as carboxy groups could enhance the reaction, promoting the crosslinked reaction between EPS and Ca2+ ions.

Hepatitis B virus (HBV) is a major cause of acute and chronic hepatitis, cirrhosis and hepatocellular carcinoma, particularly in Asia-Pacific countries. The major complications in HBV carriers are hepatocellular carcinoma (HCC), liver failure and esophageal varices following the progression to cirrhosis, while some develop HCC without cirrhosis. The progression to liver fibrosis and these other complications could be prevented by treatment with nucleos(t)ide analogues (NUCs); however, NUCs must be continuously administered for a long time. Peginterferon could lead to HBV surface antigen loss. It is difficult to use peginterferon in HBV-infected patients with decompensated cirrhosis. Acute liver failure due to HBV infection and acute exacerbation of chronic hepatitis B could be treated by NUCs. Universal vaccination programs against HBV could prevent new HBV infections globally. Here, we review the currently available treatments for HBV infection.

Aim We analyzed the 5-year post-treatment response to peginterferon α-2a (PEG IFN-α-2a) in hepatitis B e-antigen (HBeAg) positive and negative chronic hepatitis B patients. Methods One hundred and thirty-seven chronic hepatitis B (CHB) patients receiving 90 μg or 180 μg of PEG IFN-α-2a for 24 or 48 weeks in phase II or III studies were enrolled in the study, including 100 HBeAg positive patients and 37 HBeAg negative patients; 121 patients (88.4%) had genotype C. Results Of the 137 patients, 94 received additional antiviral therapy because of viral reactivation and 43 did not receive any additional antiviral treatment during follow up. Five years upon PEG IFN-α-2a treatment, 32 patients (23.4%) who did not receive any additional antiviral agent after PEG IFN-α-2a therapy achieved a good response (normal serum alanine aminotransferase, low-level hepatitis B virus [HBV] DNA, and HBeAg negativity). Female sex and low HBV DNA levels by the end of treatment were independently associated with favorable 5-year post-treatment responses. Forty-eight-week administration of PEG IFN-α-2a showed a better response (26.4%) than 24-week administration (18.0%). Six patients (4.3%), four males and two females, cleared hepatitis B surface antigen (HBsAg) during the 5-year follow-up period. Conclusion The 48-week administration of PEG IFN-α-2a achieved better biochemical and virological responses than the 24-week administration, particularly in younger females. The 5-year post-treatment response rate was 23.4%; however, more than two-thirds of the patients received additional antiviral therapy because of viral reactivation after PEG IFN-α-2a treatment. HBsAg clearance was noted in six patients (4.3%). PEG IFN-α-2a is effective in young female patients.

Background. Direct-acting antiviral agents against HCV with or without peginterferon plus ribavirin result in higher eradication rates of HCV and shorter treatment duration. We examined which is better for predicting persistent virologic response, the assessment of serum HCV RNA at 12 or 24 weeks after the end of treatment for predicting sustained virologic response (SVR12 or SVR24, respectively) in patients treated by HCV NS3/4A protease inhibitors with peginterferon plus ribavirin. Methods. In all, 149 Japanese patients infected with HCV genotype 1b treated by peginterferon plus ribavirin with telaprevir or simeprevir were retrospectively analyzed: 59 and 90 patients were treated with telaprevir- and simeprevir-including regimens, respectively. HCV RNA was measured by TaqMan HCV Test, version 2.0, real-time PCR assay. SVR12 or SVR24, respectively, was defined as HCV RNA negativity at 12 or 24 weeks after ending treatment. Results. Total SVR rates were 78.0% and 66.7% in the telaprevir and simeprevir groups, respectively. In the telaprevir group, all 46 patients with SVR12 finally achieved SVR24. In the simeprevir group, 60 (93.8%) of the total 64 patients with SVR12 achieved SVR24, with the other 4 patients all being previous-treatment relapsers. Conclusions. SVR12 was suitable for predicting persistent virologic response in almost all cases. In simeprevir-including regimens, SVR12 could not always predict persistent virologic response. Clinicians should use SVR24 for predicting treatment outcome in the use of HCV NS3/4A protease inhibitors with peginterferon plus ribavirin for any group of real-world patients chronically infected with HCV.

Background and Aims The prevalence of sexually transmitted acute infections of the genotype A hepatitis B virus (HBV) has been increasing in Japan. Genotype A HBV is associated with an increased risk of HBV progression to chronic infection after acute hepatitis B (AHB) in adults. A nationwide survey was conducted to evaluate the geographic distribution, clinical, and virologic characteristics of genotype A AHB and chronic hepatitis B (CHB) in Japan. Methods Five hundred seventy AHB patients were recruited between 2005 and 2010, and 3682 CHB patients were recruited between 2010 and 2011. HBV genotypes were determined for 552 and 3619 AHB and CHB patients, respectively. Clinical characteristics were compared among different genotypes in AHB and CHB patients. Genomic characteristics of HBV genotype A were examined by molecular evolutionary analysis. Results Hepatitis B virus genotype A was the predominant genotype for AHB between 2005 and 2010. Phylogenetic analysis showed that all strains in the AHB patients with genotype A were classified into subtype Ae. Among CHB patients, the occurrence of genotype A was 4.1%, and genotype A was spreading in young adults. In genotype A CHB patients, early stage liver diseases were predominant, although liver diseases progressed to cirrhosis or hepatocellular carcinoma in some patients. Conclusions The distribution of HBV genotypes is quite different between AHB and CHB in Japanese patients. Genotype A infection is spreading in young adults of Japanese CHB patients. Sequences derived from Japanese AHB patients were identical to or closely resembled the sequences derived from other Japanese AHB patients.

In Lake Tega, Japan, the shift of dominant algal species was caused as a result of discharging water from the adjacent river into the lake. The transition from cyanobacteria (mainly the genus Microcystis) to diatoms (mainly the genus Cyclotella) resulted in a disappearance of algal blooms. Although some environmental conditions such as flow rate, nutrient concentration, and transparency were changed by the project, the decisive factor for the transition has not been clarified yet. For the effective control of algal blooms by water discharge, this study aimed to elucidate the effects of daily renewal rate and nitrogen concentration on the interspecific competition between Microcystis aeruginosa and Cyclotella sp. Monoculture experiments were conducted to obtain growth characteristics for each species and mixed culture experiments were performed to examine their competitive abilities under various daily renewal rates of the culture medium (15 and 30 %) and nitrate concentrations (71.4, 178, and 357 μM). In addition to prepared medium, Lake Tega water was also used for mixed culture experiments. The results showed that the increase in a daily renewal rate contributed to the dominance of Cyclotella sp., while a nitrate concentration had little influence on the competition. We conclude that algal blooms composed of the genus Microcystis would be controlled by maintaining a daily renewal rate up to 30 % or more, which corresponded to the dilution rate of 0.36 day−1, under a nitrate concentration of ≤357 μM. The study would include essential information for the management of lakes suffering from frequent occurrences of algal blooms.

We examined whether hepatitis C virus (HCV) genotype 1b core- and NS5A-region mutations are associated with response to peginterferon α-2b plus ribavirin combination therapy. A total of 103 patients with high HCV genotype 1b viral loads (≥100 KIU/mL) were treated with the combination therapy. Pretreatment mutations in the core region and interferon sensitivity determining region (ISDR) in the NS5A region were analyzed. In univariate analysis, arginine and leucine at positions 70 and 91 in the core region, defined as double wild (DW)-type, were associated with early virologic response (p = 0.002), sustained virologic response (SVR) (p = 0.004), and non-response (p = 0.005). Non-threonine at position 110 was associated with SVR (p = 0.004). Multivariate analysis showed the following pretreatment predictors of SVR: hemoglobin level ≥ 14 g/dL (odds ratio (OR) 6.2, p = 0.04), platelet count ≥ 14 × 104/mm3 (OR 5.2, p = 0.04), aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio &lt, 0.9 (OR 6.17, p = 0.009), DW-type (OR 6.8, p = 0.02), non-threonine at position 110 (OR 14.5, p = 0.03), and ≥2 mutations in the ISDR (OR 12.3, p = 0.02). Patients with non-DW-type, non-threonine at position 110, and &lt, 2 ISDR mutations showed significantly lower SVR rates than others (11/45 (24.4%) vs. 27/37 (73.0%), respectively, p &lt, 0.001). SVR can be predicted through core and NS5A region mutations and host factors like hemoglobin, platelet count, and AST/ALT ratio in HCV genotype 1b-infected patients treated with peginterferon and ribavirin combination therapy.

Direct-acting antivirals with or without peginterferon α (PEG-IFN α) plus ribavirin are now available for the treatment of hepatitis C virus (HCV) infection. Direct-acting antivirals are potent inhibitors of HCV replication, but some of them occasionally possess serious adverse events. We experienced a 64-year-old female with chronic HCV genotype 1b infection who showed elevated alanine aminotransferase of 528 IU/l at week 9 after the commencement of treatment of simeprevir with PEG-IFN α-2a plus ribavirin. However, she achieved sustained virological response at week 24 after the end of treatment. In Japan, we also have to treat elderly patients infected with HCV and/or advanced hepatic fibrosis. Until an effective interferon-free regimen is established, direct-acting antivirals with PEG-IFN plus ribavirin may still play a role in the treatment for certain patients. To avoid serious results from adverse events, careful attention and follow-up will be needed in the treatment course of simeprevir with PEG-IFN plus ribavirin for chronic HCV infection.

OBJECTIVE The aim of this study was to explore the underlying pathophysiological mechanism for portal hypertension in primary biliary cirrhosis (PBC) using radiological findings. PATIENTS AND METHODS The study included 10 patients with PBC (Scheuer stage I, one patient; stage II, two patients; and cirrhosis, seven patients) and 29 patients with viral cirrhosis. Both groups underwent Doppler ultrasound and hepatic venous catheterization. The Doppler data, pressure data, and vascular enhancement findings were compared between the groups. RESULTS Hemodynamics in the portal trunk and hepatic vein upon Doppler sonography did not differ between patients with viral cirrhosis, cirrhotic PBC, and noncirrhotic PBC. The hepatic venous pressure gradient (mean±SD) was 225.5±77.1 mmH2O (range 125-445 mmH2O) in viral cirrhosis, 224.6±39.5 mmH2O (range 170-262 mmH2O) in cirrhotic PBC, and 41.3±7.4 mmH2O (range 33-47 mmH2O) in noncirrhotic PBC, being significantly higher in viral cirrhosis and cirrhotic PBC than noncirrhotic PBC (P=0.0005). The intrahepatic portal vein was detected in a retrograde manner on the hepatic venogram in 29/29 (100%) patients with viral cirrhosis (all with gastroesophageal varices), 7/7 (100%) patients with cirrhotic PBC (5/7 with gastroesophageal varices), and 3/3 (100%) patients with noncirrhotic PBC (none with gastroesophageal varices). The presence of veno-venous communication was found in 15/29 (51.7%) patients with viral cirrhosis, 6/7 (85.7%) patients with cirrhotic PBC, and 3/3 (100%) patients with noncirrhotic PBC. CONCLUSION The study suggested that sinusoidal blockage is the underlying pathophysiology even in the early-stage PBC, proved by the visible intrahepatic portal vein in three noncirrhotic PBC patients, and veno-venous communication in the liver is responsible for alleviated hepatic venous pressure gradient.

A commercially available activated carbon (AC) was oxidized using 1 M H2SO4 solution containing 2 M (NH4)2S2O8 oxidant with the solution to carbon ratio of 50 cm3 g−1 by changing oxidation period r...

In this study, introduction of acidic functional groups onto a carbon surface and their removal were carried out through two oxidation methods and outgassing to investigate the adsorption mechanism of aromatic compounds which have different polarity (benzene and nitrobenzene). Adsorption experiments for these aromatics in aqueous solution and n-hexane solution were conducted in order to obtain the adsorption isotherms for commercial activated carbon (BAC) as a starting material, its two types of oxidized BAC samples (OXs), and their outgassed samples at 900 °C (OGs). Adsorption and desorption kinetics of nitrobenzene for the BAC, OXs and OGs in aqueous solution were also examined. The results showed that the adsorption of benzene molecules was significantly hindered by abundant acidic functional groups in aqueous solution, whereas the adsorbed amount of nitrobenzene on OXs gradually increased as the solution concentration increased, indicating that nitrobenzene can adsorb favourably on a hydrophilic surface due to its high dipole moment, in contrast to benzene. In n-hexane solution, it was difficult for benzene to adsorb on any sample owing to the high affinity between benzene and n-hexane solvent. On the other hand, adsorbed amounts of nitrobenzene on OXs were larger than those of OGs in n-hexane solution, implying that nitrobenzene can adsorb two adsorption sites, graphene layers and surface acidic functional groups. The observed adsorption and desorption rate constants of nitrobenzene on the OXs were lower than those on the BAC due to disturbance of diffusion by the acidic functional groups.

Branched‑chain amino acids (BCAAs) and trace element deficiencies are associated with poor prognosis in hepatitis C virus (HCV)‑infected patients. The aim of this study was to investigate the effects of BCAA and zinc‑enriched supplementation on prognostic factors in HCV‑infected patients. Fifty‑three HCV‑infected patients were enrolled in this multicenter randomized controlled trial. The patients were assigned to either the placebo (n=27) or supplement group (n=26; 6,400 mg/day BCAAs and 10 mg/day zinc) and were followed up for 60 days. Primary outcomes were prognostic factors for chronic liver disease, including the serum BCAA‑to‑tyrosine ratio (BTR), zinc levels and α‑fetoprotein (AFP) levels. There were no significant differences in any of the prognostic factors between the placebo and supplement groups at baseline. In the supplement group, the BTR and zinc levels were significantly increased compared with the placebo group (BTR: 5.14 ± 1.59 vs. 4.23 ± 1.14, P=0.0290; zinc: 76 ± 11 vs. 68 ± 11 µg/dl, P=0.0497). No significant differences were observed in AFP levels between the groups in the whole analysis. However, a stratification analysis showed a significant reduction in ΔAFP levels in the supplement group, with elevated AFP levels compared with the other groups (‑2.72 ± 3.45 ng/ml, P=0.0079). It was demonstrated that BCAA and zinc‑enriched supplementation increased the BTR and zinc levels in the HCV‑infected patients. Furthermore, the supplementation reduced the serum AFP levels in patients who had elevated serum AFP levels at baseline. Thus, BCAA and zinc‑enriched supplementation may prolong the survival of HCV‑infected patients by improving amino acid imbalance and zinc deficiency, and by partly downregulating AFP.

Determination of hepatitis C virus (HCV) genotypes plays an important role in the direct-acting agent era. Discrepancies between HCV genotyping and serotyping assays are occasionally observed. Eighteen samples with discrepant results between genotyping and serotyping methods were analyzed. HCV serotyping and genotyping were based on the HCV nonstructural 4 (NS4) region and 5′-untranslated region (5′-UTR), respectively. HCV core and NS4 regions were chosen to be sequenced and were compared with the genotyping and serotyping results. Deep sequencing was also performed for the corresponding HCV NS4 regions. Seventeen out of 18 discrepant samples could be sequenced by the Sanger method. Both HCV core and NS4 sequences were concordant with that of genotyping in the 5′-UTR in all 17 samples. In cloning analysis of the HCV NS4 region, there were several amino acid variations, but each sequence was much closer to the peptide with the same genotype. Deep sequencing revealed that minor clones with different subgenotypes existed in two of the 17 samples. Genotyping by genome amplification showed high consistency, while several false reactions were detected by serotyping. The deep sequencing method also provides accurate genotyping results and may be useful for analyzing discrepant cases. HCV genotyping should be correctly determined before antiviral treatment.

The use of phlebotomy is relatively common for ‘difficult-to-treat by antiviral therapies' hepatitis C virus (HCV)-infected patients and for certain patients having chronic liver diseases with an iron overload of the liver. In the present study, we retrospectively analyzed patients treated with phlebotomy and their adverse events. We observed the occurrence and recurrence of hepatocellular carcinoma, and the appearance of ascites in some patients infected with HCV as well as the reduction of serum ferritin and alanine aminotransferase levels. Severe adverse events necessitating a cessation of phlebotomy occurred independently of α-fetoprotein (≥10 ng/ml) in patients infected with HCV according to multivariate logistic regression analysis. These findings may serve as a basis for phlebotomy especially in older patients with chronic hepatitis C.

The short-term prognosis of patients with severe acute exacerbation of chronic hepatitis B (CHB) leading to acute liver failure is extremely poor. We have reported the efficacy of corticosteroid in combination with nucleoside analogue in the early stages, but virological efficacy has not been documented. Our aim was to elucidate the virological efficacy of this approach. Thirteen patients defined as severe acute exacerbation of CHB by our uniform criteria were prospectively examined for virological responses to treatment. Nucleoside analogue and sufficient dose of corticosteroids were introduced as soon as possible after the diagnosis of severe disease. Of the 13 patients, 7 (54%) survived, 5 (38%) died and 1 (8%) received liver transplantation. The decline of HBV DNA was significant between the first 2 weeks (P = 0.02) and 4 weeks (P < 0.01). Mean reduction in HBV DNA during the first 2 weeks was 1.7 ± 0.9 log copies per mL in overall patients, 2.1 ± 0.8 in survived patients and 1.2 ± 0.9 in dead/transplanted patients. The decline of HBV DNA was significant between the first 2 weeks (P = 0.03) and 4 weeks (P = 0.02) in survived patients, but not in dead/transplanted patients. Our study shows that corticosteroid treatment in combination with nucleotide analogue has sufficient virological effect against severe acute exacerbation of CHB, and a rapid decline of HBV DNA is conspicuous in survived patients.

Some patients with alcohol dependence may initially present with atypical laboratory and histological features resembling autoimmune hepatitis (AIH) or drug-induced liver injury (DILI). Even with liver biopsy, it may be difficult to diagnose certain patients with alcohol dependence. However, careful follow-up of our patient and consultations with the attending psychiatrist were successful in diagnosing alcohol dependence and its liver injury. The immune mechanisms of alcoholic liver diseases, AIH and DILI may be overlapping. Certain patients are suffering from AIH with flares on a background of alcohol abuse. Certain patients with alcohol abuse may have a past history of DILI. This might be consistent with the fact that alcohol dependence initially presents with atypical laboratory features of AIH or DILI. With careful observation, the clinician should remind himself that alcohol dependence is not always required for developing liver disease, since many patients with liver disease do not meet the criteria for alcohol dependence.

Background and Aim Gastric ulcer healing is a complex process involving cell proliferation and tissue remodeling. Sonic hedgehog (Shh) activates the Shh signaling pathway, which plays a key role in processes such as tissue repair. Shh and interleukin 1β (IL1β) have been reported to influence the proliferation of gastric mucosa. We evaluated the relationships between the speed of gastric ulcer healing and the levels of expression of Shh and IL1β. Methods The study included 45 patients (mean age 71.9 ± 9.0 years; M/F, 30/15) who underwent endoscopic submucosal dissection (ESD) for gastric cancer, followed by standard dose of oral proton-pump inhibitor for 4 weeks. Subsequently, the size of ESD-induced artificial ulcers were measured to determine the speed of gastric ulcer healing, and regenerating mucosa around the ulcers and appropriately matched controls were collected from patients by endoscopic biopsy. Polymerase chain reaction (PCR) array analysis of genes in the Shh signaling pathway was performed, and quantitative reverse transcription (RT)-PCR was used to measure IL1β mRNA. Results The levels of Shh and IL1β mRNA were 3.0 ± 2.7-fold and 2.5 ± 2.5-fold higher, respectively, in regenerating mucosa of artificial ulcers than in appropriately matched controls, with the two being positively correlated (r = 0.9, P

Treatment with systemic corticosteroids is often used for acute liver failure (ALF), but this has increased the number of profoundly immunocompromised patients and cases of opportunistic infection.Between January 2007 and December 2012, all patients (n = 51) referred to the Chiba University Hospital for treatment of ALF were studied. Patients with prothrombin activity of 40 % or less of the standardized values were defined as having ALF. Patient age, sex, cause of ALF, alanine aminotransferase and total bilirubin levels, prothrombin activity and total amount of corticosteroid were analyzed to determine the factors associated with the occurrence of opportunistic infection.Opportunistic infections occurred in 21.6 % (n = 11) of ALF patients. Thirty-five patients underwent systemic corticosteroid therapy, and 31.4 % of those patients showed opportunistic infections. Cytomegalovirus (n = 9, 81.8 %) and Pneumocystis jiroveci (n = 6, 54.5 %) were the microorganisms frequently suspected as the causes of opportunistic infection. In 7 (63.6 %) of the 11 cases of opportunistic infection, 2 or more species of microorganism were detected. Seven patients (63.6 %) with opportunistic infection were cured by treatment. Cox regression analysis for the patients who underwent systemic corticosteroid therapy steroid treatment revealed that age over 52 years (compared to younger patients: odds ratio = 9.62, 95 % confidence interval = 1.22-76.9) was only the predictive factor for the occurrence of opportunistic infection.Opportunistic infections are not rare in ALF patients, and the appropriate diagnosis and treatment of these infections are critical during ALF treatment.

The proportion of patients who progress to chronicity following acute hepatitis B (AHB) varies widely worldwide. Moreover, the association between viral persistence after AHB and hepatitis B virus (HBV) genotypes in adults remains unclear. A nationwide multicenter study was conducted throughout Japan to evaluate the influence of clinical and virological factors on chronic outcomes in patients with AHB. For comparing factors between AHB patients with viral persistence and those with self-limited infection, 212 AHB patients without human immunodeficiency virus (HIV) coinfection were observed in 38 liver centers until serum hepatitis B surface antigen (HBsAg) disappeared or a minimum of 6 months in cases where HBsAg persisted. The time to disappearance of HBsAg was significantly longer for genotype A patients than that of patients infected with non-A genotypes. When chronicity was defined as the persistence of HBsAg positivity for more than 6 or 12 months, the rate of progression to chronicity was higher in patients with genotype A, although many cases caused by genotype A were prolonged cases of AHB, rather than chronic infection. Multivariate logistic regression analysis revealed only genotype A was independently associated with viral persistence following AHB. A higher peak level of HBV DNA and a lower peak of alanine aminotransferase (ALT) levels were characteristics of AHB caused by genotype A. Treatment with nucleotide analogs (NAs) did not prevent progression to chronic infection following AHB overall. Subanalysis suggested early NA initiation may enhance the viral clearance. Conclusion: Genotype A was an independent risk factor for progression to chronic infection following AHB. Our data will be useful in elucidating the association between viral persistence after AHB, host genetic factors, and treatment with NAs in future studies. (Hepatology 2014;58:89–97)

Aim We tried to characterize the pathological features of patients who developed hepatocellular carcinoma (HCC) with the negative results of both serous hepatitis B surface antigen and hepatitis C virus antibody (non-B, non-C). Methods In a multicenter study in Kyushu, Japan, we studied the histopathological characteristics of non-cancerous liver tissues in 129 patients (103 men and 26 women) with non-B, non-C HCC. The histological liver damage was evaluated for fibrosis (stage) and inflammation (grade) according to the Ludwig classification of chronic hepatitis. In addition, we examined the hepatitis B virus (HBV) genome in serum samples and liver tissues of 20 patients with non-B, non-C HCC. Results Positivity of serum hepatitis B core (HBc) antibody, alcohol abuse, diabetes and non-alcoholic steatohepatitis were present in 61 (47%), 76 (59%), 57 (44%) and eight (6%) patients, respectively. The degree of fibrosis was mild (stage 1.6 ± 1.2). The stage of patients with neither serum HBc antibody nor alcohol abuse was significantly lower than the stage of patients with HBc antibody and no alcohol abuse (P

Although overt hepatitis B virus (HBV) infec- tion promotes the onset of hepatocellular carcinoma (HCC) in hepatitis C virus (HCV)-infected patients, the effect of occult HBV infection remains unclear. The aim of this study was to investigate the effect of occult HBV infection on the early-onset of HCC in HCV-infected patients. A total of 173 HCC patients with HCV infection were enrolled and classified into 2 groups according to the median age of HCC onset: the early-onset group (n=91; 61.1±5.6 years) and the late-onset group (n=82; 73.8±3.7 years). Independent factors associated with the early-onset of HCC were assessed by multivariate analysis. In the overall analysis, independent risk factors for the early-onset of HCC were the white blood cell count and alanine aminotransferase level, but not the presence of HBV DNA. In a stratification analysis according to albumin levels of ≥3.5 g/dl, the presence of HBV DNA was a significant independent risk factor for the early-onset of HCC (OR 145.18, 95% CI 1.38-15296.61, P=0.036), whereas the presence of antibodies against hepatitis B core antigen was not found to be a risk factor. The presence of HBV DNA was not a risk factor for the early-onset of HCC in the overall analysis. However, its presence was an independent factor for the early-onset of HCC in HCV-infected patients with an albumin level of ≥3.5 g/dl. Thus, occult HBV infection may accelerate hepatocarcino genesis in HCV-infected patients with relatively low carcinogenic potential.

AIM Acute liver failure (ALF) is a worldwide problem despite its rare incidence because of its extremely high mortality. There are no beneficial therapies except for emergency liver transplantation for ALF. However, in Japan where the problem of a shortage of donor livers still remains, therapies other than transplantation must be further investigated for patients with ALF. Our aim was to elucidate the efficacy of high-dose corticosteroid (CS) in decreasing liver enzyme levels in the early stage of ALF. METHODS Thirty-one consecutive Japanese patients with viral ALF in the early stage were prospectively examined for their clinical and biochemical features and treatment responses during 2 weeks after the start of treatment. Nineteen were treated with high-dose methylprednisolone, and 12 having clinical and biochemical backgrounds with no significant difference were treated without CS. RESULTS The aspartate aminotransferase : alanine aminotransferase ratio became lower in patients treated with CS than in controls (P

Purpose Clinical application of biomarker candidates discovered by proteomic analysis is challenging. The purpose of this study was to standardize preanalytical conditions for measurement of serum levels of fibrinogen alpha C-chain 5.9 kDa fragment (FIC 5.9) and to test the diagnostic value of this peptide for detection of early hepatic fibrosis in patients with hepatitis C virus (HCV)-related chronic hepatitis. Experimental design Serum FIC 5.9 levels were measured by a sandwich ELISA. Effects on the serum FIC 5.9 level of temperature, the time between venipuncture and serum separation, and the types of collection tubes used were examined. The diagnostic value of serum FIC 5.9 as an early indicator of hepatic fibrosis due to HCV was then assessed. Results FIC 5.9 was produced in a time- and temperature-dependent manner after venipuncture. Abnormal FIC 5.9 values were found in 89.5% of FI stage patients. Receiver operating characteristic analyses confirmed the superiority of FIC 5.9 over other conventional markers for early detection of fibrosis. Conclusions and clinical relevance The serum FIC 5.9 level may be an early indicator of hepatic fibrosis in HCV-related chronic liver diseases. This study provides an example of a pipeline from biomarker discovery by proteome analysis to assay optimization and preliminary clinical validation.

Summary Backgrounds and aims Gastric submucosal tumors (SMTs) are often detected during routine gastroendoscopy but little is known about their natural history. The aim of this study was to evaluate the natural course of gastrointestinal mesenchymal tumors (GIMTs) in the stomach. Patients and methods From October 2001 to November 2011, a total of 228 gastric SMTs were evaluated by endoscopic ultrasonography (EUS). Based on the findings of EUS and enhanced CT, we diagnosed these tumors as lipomas, cysts, aberrant pancreases, extramural compressions, and GIMTs. The gastric GIMTs which were examined by EUS twice or more were included in this study and the factors associated with an increase in the size of gastric GIMTs were analyzed. Results Fifty GIMTs were followed by EUS twice or more. The mean age was 66.4 ± 8.3 years old and the mean period of follow-up was 23.8 ± 21.7 months. Fourteen (28%) of 50 GIMTs increased in size and the time taken for gastric GIMTs to double in size was 19.1 ± 18.2 months. In multivariate logistic regression analysis, age (odds ratio [OR] = 1.12, 95% confidence interval [CI] = 1.03–1.21), non-upper area of the stomach (OR = 5.08, 95%; CI = 1.37–18.8) and the detection of an anechoic lesion on EUS (OR = 5.90, 95%; CI = 1.10–31.8) were the factors predicting an increase in size of gastric GIMTs. Conclusions We evaluated gastric SMTs by EUS and clarified the factors predicting the growth of gastric GIMT. EUS is indispensable for the diagnosis and management of gastric SMTs.

Some patients infected with hepatitis C virus (HCV) genotype 2 could be cured with treatment shorter than 24 weeks using peginterferon plus ribavirin, but there are still treatment-refractory patients. Direct-acting antivirals (DAAs) are not currently available for HCV genotype 2 patients, different from genotype 1 patients, in clinical practice. We investigated 29 HCV genotype 2-infected Japanese patients who had been previously treated and failed to clear HCV. We retreated them with peginterferon alfa-2a plus ribavirin and measured HCV RNA level to assess the efficacy and safety of this treatment in patients who had failed previous therapy. We found that retreatment of HCV genotype 2-infected Japanese patients with peginterferon alfa-2a plus ribavirin for 24-48 weeks led to 60 to 66.6% sustained virological response (SVR) in patients previously treated with (peg-)interferon monotherapy and to 69.9% SVR in relapsers previously treated with peginterferon plus ribavirin. Attention should be paid to certain patients with unique features. Selection of patients according to their previous treatment could lead to optimal therapy in HCV genotype 2 treatment-experienced patients.