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Background: Type A hepatitis is still a considerable problem in both underdeveloped and developed countries. Why some patients progress to fulminant type A hepatitis and others do not is unclear. Aims: To determine if nucleotide differences in the genome of hepatitis A virus (HAV) are responsible for the range of clinical severities, we analysed the 5' non-translated region (5'NTR) of the HAV genome, which has an internal ribosomal entry site and is important for cap independent translation of the viral message. Methods: Serum samples from 84 Japanese patients with sporadic type A hepatitis from five distant regions of Japan, comprising 12 patients with fulminant hepatitis (FH), 13 with severe acute hepatitis (AHs), and 59 with acute hepatitis (AH), were examined for HAV RNA. The fragment between nucleotides 75 and 638 of the 5'NTR was amplified by reverse transcription-polymerase chain reaction, and the nucleotide sequence was determined by direct sequencing. Results: Comparison of sequences of the 5'NTR revealed relatively fewer nucleotide substitutions in FH and AHs patients compared with the considerable sequence variations found in strains of AH. This tendency was most prominent between nucleotides 200 and 500. Strains from FH and AHs cases had fewer nucleotide substitutions (p<0.001) in this region. Conclusions: Nucleotide variations in the central portion of the 5'NTR of HAV may influence the severity of type A hepatitis. [ABSTRACT FROM AUTHOR]

A feature of hepatocellular carcinoma (HCC) is that antecedent liver cirrhosis and chronic hepatitis are common precursor conditions and during transition to malignancy some patients develop autoantibodies which were not present during the preceding chronic liver disease phase. Serum samples from such patients can be used to immunoscreen cDNA expression libraries to identify genes encoding the new autoantigens. We demonstrate here the de novo appearance of antibodies to p62, a cytoplasmic protein which has been shown to bind to a developmentally regulated fetal species of insulin-like growth factor II (IGF-II) mRNA. Another antibody appearing during the transition period was against CENP-F, a cell cycle-related nuclear protein with maximum expression in the G2 and M phases of the cell cycle and previously shown to have a high association with malignancy. In three additional patients in whom serial serum samples were examined, new appearance of anti‐p62 was detected in two patients and anti-CENP-F in one patient. This study demonstrates that transition to malignancy can be associated with autoantibody responses to certain cellular proteins which might have some role in tumorigenesis. [ABSTRACT FROM AUTHOR]

Examines the characteristics on T cells in patients with chronic hepatitis C (CHC). Role of T cells in the immunopathogenesis of hepatic inflammation; Analysis of the complementarity-determining region 3 size lengths of T cell receptor; Pathogenesis of hepatocyte destruction in CHC.

AbstractTo facilitate pancreatic stone retrieval, four patients with chronic pancreatitis and pancreatic stones underwent endoscopic pancreatic sphincter balloon dilation (EPSBD) rather than pancreatic sphincterotomy. Extracorporeal shock wave lithotripsy combined with endoscopic removal was carried out in three patients. Stone removal following EPSBD was completely successful in all four patients. Patients showed no severe complications during the dilation procedure. In one patient, to prevent pancreatitis, an endoscopic nasopancreatic drain was placed for 1 week after EPSBD. Compared with pancreatic sphincterotomy, EPSBD can be performed safely in patients with chronic pancreatitis to assist in the extraction of pancreatic duct stones. Use of the EPSBD procedure in cases of chronic pancreatitis provides a useful approach to improve endoscopic clearance of pancreatic duct stones. [ABSTRACT FROM AUTHOR]

Assessment of anti-proliferative effects of unmodified antisense oligodeoxynucleotides targeted against c-raf mRNA. Actions to unrelated antisense mechanism; Independence of the effects of phosphorothioate and phosphodiester; Modification of synthetic carriers.

A letter to the editor is presented in response to the article about autoimmune pancreatitis, which appeared in the previous issue.

A letter to the editor describing a study that investigated the association of Fc receptor-like 3 polymorphisms with autoimmune diseases in patients in Japan is presented.

Summary 1. RNA interference (RNAi) is a newly discovered cellular pathway for the silencing of sequence-specific genes at the mRNA level by the introduction of the cognate double-stranded (ds) RNA . Because antisense (AS) mechanisms have similar effects, we compared these two effects in human cancer cell lines, considering a possible application of RNAi for cancer therapy. 2. We tested RNAi effects by transfecting human hepatoma and pancreatic cancer cell lines with AS and sense (S) RNA expression plasmids corresponding to the exogenous luciferase gene or the endogenous c-raf gene in the form of complexes with a cationic lipopolyamine or a tumour-targeting peptide vector we developed. In addition, we compared the effects of small interfering RNA and AS oligoDNA complexed with the peptide vector. 3. From the viewpoint of AS actions, the effect of the AS RNA may be cancelled by the S RNA, although, interestingly, we found that the combination of the AS and S RNA expression plasmids was more effective than the AS RNA expression plasmids alone in reducing target gene expression, whereas the S RNA expression plasmids had no effects. The combination of the luciferase AS and S RNA had no effects on the expression of either the β-galactosidase gene or the c-raf gene. In the presence of 2-aminopurine (an inhibitor of dsRNA-activated protein kinase), the inhibitory effect of the combination of AS and S RNA on gene expression did not change in the case of the endogenous c-raf gene, but was reduced in the case of the exogenous luciferase gene. The effect of 22 nucleotide RNA duplexes corresponding to the luciferase gene was by one order stronger than that of the phosphorothioate AS DNA. 4. Thus, it is suggested that RNAi may be more potent than AS RNA in reducing target gene expression in human cancer cell lines, regardless of the length of dsRNA. With further studies on the RNAi phenomenon in cancer cells, RNAi could provide a novel approach for cancer gene therapy. [ABSTRACT FROM AUTHOR]

When mood states are impaired, daily life is severely disrupted. To maintain a specific mood state, both positive and negative moods must be controlled; however, methods to maintain a positive mood have not been fully established. Previous studies have suggested that heat-killed L. helveticus MCC1848 has the potential to improve positive moods. This study aimed to test the efficacy of heat-killed L. helveticus MCC1848 in maintaining and improving a positive mood with PANAS, a questionnaire specifically designed to assess positive and negative mood, as the primary endpoint. Healthy Japanese nursing students ( n = 46) were randomized to receive heat-killed L. helveticus MCC1848 (5 billion/day) or placebo powder for four weeks. Mood state was assessed before and two and four weeks after the intervention began; ingestion of heat-killed L. helveticus MCC1848 significantly improved PANAS 'Positive Affect' compared to the placebo. These results indicate that heat-killed L. helveticus MCC1848 is effective in enhancing positive mood.

We investigated the effects of heat-killed Lactobacillus helveticus MCC1848 on daily mood states in healthy young adults. Participants (n=58) were randomised to receive heat-killed L. helveticus MCC1848 powder or placebo powder for 4 weeks. During the study period, adverse events were recorded in the participant diary. Mood states were assessed before and 2 and 4 weeks after initiation of the intervention. The primary outcomes were the shortened version of the Profile of Mood States 2 (POMS 2) scores. Secondary outcomes included other mood state (State-Trait Anxiety Inventory (STAI); visual analogue scale (VAS)), quality of life (acute form of the SF-36v2), sleep (Athens Insomnia Scale (AIS)) and fatigue (Chalder Fatigue Scale (CFS)) scores. Four weeks of heat-killed L. helveticus MCC1848 intake, compared to placebo, significantly improved the shortened version of the POMS 2 'friendliness' and the VAS 'relaxed' scores, which are two indicators of positive mood states. On the other hand, heat-killed L. helveticus MCC1848 intake had no significant effects on negative mood state items (e.g. anger, nervousness, confusion) assessed by the shortened version of the POMS 2, STAI and VAS. AIS and CFS scores also showed no significant differences. No adverse effects were observed with 4 weeks of heat-killed L. helveticus MCC1848 intake. These results suggest that daily consumption of heat-killed L. helveticus MCC1848 is safe and has the potential to improve positive mood states. UMIN Clinical Trial Registry : UMIN000043697.

Competing Interests: Conflict of Interest None.

Context: The role of hepatic steatosis (HS) in the initial stages of developing type 2 diabetes remains unclear., Objective: We aimed to clarify the impact of HS indexed by Fatty Liver Index (FLI) and high-normal fasting plasma glucose (FPG) as risk factors for incident prediabetes in a nonobese cohort., Methods: Data from 1125 participants with ADA-defined normal glucose metabolism (median age 52 years; BMI 23.1 kg/m 2 ) were used for retrospective analysis. In the entire population, correlation between normal FPG and FLI was evaluated by multiple regression adjusted for age and sex. Follow-up data from 599 participants in whom 75-g OGTT was repeated 3.7 years later showed that 169 developed prediabetes. This was analyzed by the multivariate Cox proportional hazards model., Results: In the entire population, FLI was positively correlated with FPG ( P  < 0.01): mean FLI increased from 15.8 at FPG 4.2 mmol/L to 31.6 at FPG 5.5 mmol/L. Analysis of the 599 participants (2061 person-years) by Cox model, adjusted for sex, age, family history of diabetes, ISI MATSUDA , and Stumvoll-1, clarified an increased risk of prediabetes with high-normal FPG and FLI. Risk was increased 2.2 times with FLI ≥ 16.5 vs FLI < 16.5, P  < 0.001, and increased 2.1 times in participants with FPG ≥ 5.3 mmol/L, P  < 0.001. Cutoff values (unadjusted) were obtained by ROC at the point of the largest Youden's index using the entire range of the variables., Conclusion: Even among nonobese individuals, HS indexed by FLI and a high-normal FPG (≥ 5.3 mmol/L) are risk factors for prediabetes, independently from insulin., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

A 78-year-old woman was admitted for examination and treatment of melena. Although upper and lower gastrointestinal endoscopy and abdominal computed tomography showed no bleeding lesions, oral double-balloon endoscopy revealed a long, slender polyp covered with normal mucosa and accompanied with erosions in the proximal jejunum. Surgical resection was successful. Histopathologically, the polyp was 125 mm in length and composed of edematous mucosa with dilated blood vessels. The growth was diagnosed as a rare enteric muco-submucosal elongated polyp. Her melena improved postoperatively.

Background: The uric acid (UA) clearance test to evaluate the hyperuricemia phenotype requires a great deal of time. However, the utility of single spot urine is scarce. The study aimed to determine the diagnostic accuracy of single spot urine for predicting renal UA underexcretion (the decreased UA excretion) in men., Methods: A total of 73 male participants aged 20 - 74 years with a UA level of 6.0 - 7.9 mg/dL were enrolled in the study. Renal UA underexcretion was defined as < 7.3 mL/min using the 60-min method. Urinary UA to creatinine ratio (UACR), fractional clearance of urate (FCU), and the Simkin index were calculated. A receiver operating characteristic (ROC) analysis was performed to compare the diagnostic utility of these parameters for predicting UA underexcretion., Results: In the ROC analysis, the area under the curve values of the UACR, FCU, and the Simkin index for predicting UA underexcretion were 0.903 (95% confidence interval (CI): 0.830 - 0.976), 0.841 (95% CI: 0.749 - 0.933), and 0.779 (95% CI: 0.673 - 0.885), respectively. An optimal UACR cutoff of 0.460 (sensitivity 89.2%, specificity 80.6%, overall diagnostic accuracy 84.9%, positive predictive value 82.5%, and negative predictive value 87.9%) was identified., Conclusions: These results suggest that the UACR is a simple and efficient test with high sensitivity and specificity levels for predicting renal UA underexcretion in men., Competing Interests: None to declare., (Copyright 2020, Sakane et al.)

Background: Preventative measures have recently been taken to reduce the incidence of Alzheimer's disease worldwide. We previously showed that Met-Lys-Pro (MKP), a casein-derived angiotensin-converting enzyme inhibitory peptide with the potential to cross the blood-brain barrier, attenuated cognitive decline in a mouse model of Alzheimer's disease. However, the effect of MKP on cognitive function improvement in humans remains unknown. This exploratory study sought to investigate whether MKP intake could improve cognitive function in adults without dementia., Methods: A total of 268 community-dwelling adults without dementia participated in this 24-week randomized controlled trial. Participants were randomly allocated to the MKP (n = 134) or placebo (n = 134) group. The MKP group received four tablets daily, each containing 50 μg MKP, while the placebo group received four dextrin tablets containing no detectable MKP for 24 weeks. Scores on the Japanese version of the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog) were used as the primary outcome to compare cognitive function between the MKP and placebo groups. The study products were also evaluated for safety., Results: The intention-to-treat analysis showed that there was no significant difference between the groups in terms of the ADAS-cog total score. Orientation, as measured by the respective ADAS-cog subscale, was significantly improved compared to placebo at 24 weeks post-MKP administration ( P = 0.022). No serious adverse events due to MKP intake were observed., Conclusion: To the best of our knowledge, this is the first study to report the effects of MKP on human cognition. These preliminary results suggested the safety of daily MKP intake and its potential to improve orientation in adults without dementia. Further clinical studies are needed to confirm the present findings and the benefits of MKP on cognitive function., Competing Interests: NY, MT, KY, and FA are employed by Morinaga Milk Industry Co., Ltd., Tokyo, Japan. NS received a supervision fee from Morinaga Milk Industry Co., Ltd, Tokyo, Japan. The other authors have no conflicts of interest to report., (© 2020 Yuda et al.)

Glecaprevir/pibrentasvir (G/P) are direct-acting antivirals (DAAs) that achieve a high sustained virological response (SVR) rate for hepatitis C virus (HCV) infection. We investigated G/P effectiveness for HCV patients based on real-world experience and the clinical features of retreatment cases. HCV patients (n = 182) were compared for clinical features and outcomes between first treatment (n = 159) and retreatment (n = 23) G/P groups. Overall, 77 patients (42.3%) were male, the median age was 68 years, and 86/66/1/4 cases had genotype 1/2/1+2/3, respectively. An SVR was achieved in 97.8% (178/182) of cases by intention-to-treat analysis and 99.4% (178/179) of cases by per-protocol analysis. There were no remarkable differences between the first treatment and retreatment groups for male (42.8% vs. 39.1%, p = 0.70), median age (68 vs. 68 years, p = 0.36), prior hepatocellular carcinoma (5.8% vs. 8.7%, p = 0.59), or the fibrosis markers AST-to-platelet ratio index (APRI) (0.5 vs. 0.5, p = 0.80) and fibrosis-4 (FIB-4) index (2.2 vs. 2.6, p = 0.59). The retreatment group had a significantly more frequent history of interferon treatment (12.3% vs. 52.2%, p < 0.01) and the Y93H mutation (25.0% vs. 64.7%, p = 0.02). The number of retreatment patients who had experienced 3, 2, and 1 DAA treatment failures was 1, 3, and 19, respectively, all of whom ultimately achieved an SVR by G/P treatment. In conclusion, G/P was effective and safe for both HCV first treatment and retreatment cases despite the retreatment group having specific resistance mutations for other prior DAAs. As G/P treatment failure has been reported for P32 deletions, clinicians should consider resistance mutations during DAA selection., Competing Interests: SJ has received research grants from AbbVie and MSD. ET has received research grants from AbbVie, Takeda Pharmaceutical, Chugai Pharmaceutical, Astellas Pharma Inc, Sumitomo Dainippon Pharma, Eisai, and Nippon Kayaku. TU has received research grants from AbbVie, MSD, Daiichi Sankyo, and Otsuka Pharmaceutical. The other authors declare nothing to disclose regarding funding from industries or conflicts of interest with respect to this manuscript.

Background/objectives: It has been unknown if attenuated insulin sensitivity (Si) in non-alcoholic fatty liver disease (NAFLD) is a cause or a result. We examined the impact of attenuated Si on NAFLD evolution., Subjects/methods: We observed 4856 NAFLD- and diabetes-free participants for a mean 2.9 years. Si was indexed by single point insulin sensitivity estimator (SPISE = [600 × HDL-c 0.185 ]/[TG 0.2  × BMI 1.338 ]), correlating with 1/HOMA-IR in an independent cohort (n = 1537, Spearman rho = 0.519, P < 0.01). Fatty liver (FL) was diagnosed by ultrasonography and diabetes by fasting plasma glucose (FPG) ≥ 7 mmol/L and/or glycohemoglobin A1c ≥ 6.5%. Multinominal comparison was performed with incident FL (FL w/oDM , n = 486), diabetes (DM w/oFL , n = 171), and FL plus diabetes (FL/diabetes, n = 58) as targets; none of the above (n = 4,138) was the control. SPISE was taken as a predictor with adjustment for covariates. Trajectory of SPISE during the 5 years before development of each condition was also assessed., Results: With SPISE tertile 3 (>10.06) as the reference, tertile 1 (<8.07) was related to incident FL w/oDM and FL/diabetes with OR (95% CI) 3.47 (2.60-4.63) and 1.78 (1.10-2.87), respectively, and tertile 2 (8.07-10.06) related to FL w/oDM with OR (95% CI) 1.38 (1.03-1.85). Low SPISE was not significantly related to incident diabetes. At -5 years, SPISE was 12% (P < 0.05) and 13% (P < 0.01) lower in those developed FL w/oDM and FL/diabetes, respectively, than the control. At year 0, SPISE in the two groups was 18% and 21% lower than the control, respectively (P < 0.01)., Conclusions: Attenuation of Si indexed by SPISE was a risk factor for NAFLD.

An injury of the somatosensory system causes neuropathic pain, which is usually refractory to conventional analgesics, thus warranting the development of novel drugs against this kind of pain. The mechanism of neuropathic pain in rats that had undergone left L5 spinal nerve transection was analyzed. Ten days after surgery, these rats acquired neuropathic pain. The patch-clamp technique was used on the isolated bilateral L5 dorsal root ganglion neurons. The current-clamped neurons on the ipsilateral side exhibited significantly higher excitability than those on the contralateral side. However, only neurons with diameters of 40-50 μ m on the ipsilateral side exhibited significantly larger voltage sags in response to hyperpolarizing current pulses than those on the contralateral side. Under the voltage clamp, only these neurons on the ipsilateral side showed a significantly larger density of an inward current at < -80 mV [hyperpolarization-activated nonselective cation ( I h ) current] with a rightward-shifted activation curve than that on the contralateral side. Ivabradine-an I h current inhibitor-inhibited I h currents in these neurons on both sides in a similar concentration-dependent manner, with an IC 50 value of ∼3 μ M. Moreover, the oral administration of ivabradine significantly alleviated the neuropathic pain on the ipsilateral side. An inhibitor of adenylyl cyclase or an antagonist of prostanoid EP4 receptors (CJ-023423) inhibited ipsilateral, but not contralateral I h , currents in these neurons. Furthermore, the intrathecal administration of CJ-023423 significantly attenuated neuropathic pain on the ipsilateral side. Thus, ivabradine and/or CJ-023423 may be a lead compound for the development of novel therapeutics against neuropathic pain., (Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.)

Direct-acting antiviral (DAA) treatment can achieve a high sustained virological response (SVR) rate in patients with hepatitis C virus (HCV) infection regardless of a history of hepatocellular carcinoma (HCC [+]). We examined 838 patients (370 men, median age: 69 years) who were treated with DAAs for comparisons of clinical findings between 79 HCC (+) (9.4%) and 759 HCC (-) (90.6%) patients and associations with treatment outcome. Male frequency was significantly higher in the HCC (+) group (60.8% vs 42.4%, P = 0.006). There were significant differences between the HCC (+) and HCC (-) groups for platelet count (115 vs 152 ×10 9 /L, P < 0.001), baseline alpha fetoprotein (AFP) (9.9 vs 4.5 ng/mL, P < 0.001) and the established fibrosis markers of FIB-4 index (4.7 vs 3.0, P < 0.001), AST-to-platelet ratio index (APRI) (1.1 vs 0.7, P = 0.009), M2BPGi (3.80 vs 1.78 COI, P < 0.001) and autotaxin (1.91 vs 1.50 mg/L, P < 0.001). The overall SVR rate was 94.7% and significantly lower in the HCC (+) group (87.3 vs 95.5%, P = 0.001). Multivariate analysis revealed that a history of HCC was independently associated with DAA treatment failure (odds ratio: 3.56, 95% confidence interval: 1.32-9.57, P = 0.01). In conclusion, patients with chronic HCV infection and prior HCC tended to exhibit more advanced disease progression at DAA commencement. HCC (+) status at the initiation of DAAs was significantly associated with adverse therapeutic outcomes. DAA treatment for HCV should therefore be started as early as possible, especially before complicating HCC., (© 2018 John Wiley & Sons Ltd.)

The genetic factors affecting the natural history of nonalcoholic fatty liver disease (NAFLD), including the development of nonalcoholic steatohepatitis (NASH) and NASH-derived hepatocellular carcinoma (NASH-HCC), are still unknown. In the current study, we sought to identify genetic factors related to the development of NAFLD, NASH, and NASH-HCC, and to establish risk-estimation models for them. For these purposes, 936 histologically proven NAFLD patients were recruited, and genome-wide association (GWA) studies were conducted for 902, including 476 NASH and 58 NASH-HCC patients, against 7,672 general-population controls. Risk estimations for NAFLD and NASH were then performed using the SNPs identified as having significant associations in the GWA studies. We found that rs2896019 in PNPLA3 [p = 2.3x10-31, OR (95%CI) = 1.85 (1.67-2.05)], rs1260326 in GCKR [p = 9.6x10-10, OR (95%CI) = 1.38(1.25-1.53)], and rs4808199 in GATAD2A [p = 2.3x10-8, OR (95%CI) = 1.37 (1.23-1.53)] were significantly associated with NAFLD. Notably, the number of risk alleles in PNPLA3 and GATAD2A was much higher in Matteoni type 4 (NASH) patients than in type 1, type 2, and type 3 NAFLD patients. In addition, we newly identified rs17007417 in DYSF [p = 5.2x10-7, OR (95%CI) = 2.74 (1.84-4.06)] as a SNP associated with NASH-HCC. Rs641738 in TMC4, which showed association with NAFLD in patients of European descent, was not replicated in our study (p = 0.73), although the complicated LD pattern in the region suggests the necessity for further investigation. The genetic variants of PNPLA3, GCKR, and GATAD2A were then used to estimate the risk for NAFLD. The obtained Polygenic Risk Scores showed that the risk for NAFLD increased with the accumulation of risk alleles [AUC (95%CI) = 0.65 (0.63-0.67)]., Conclusions: We demonstrated that NASH is genetically and clinically different from the other NAFLD subgroups. We also established risk-estimation models for NAFLD and NASH using multiple genetic markers. These models can be used to improve the accuracy of NAFLD diagnosis and to guide treatment decisions for patients.

Aim: Past hepatitis B virus (HBV) infection is considered a risk factor for hepatocarcinogenesis, but the clinicopathological characteristics of non-B non-C hepatocellular carcinoma (NBNC-HCC) excluding past HBV infection have not been investigated. This study aimed to clarify the clinicopathological features of strictly defined NBNC-HCC., Methods: Among HCC patients who underwent surgical resection at our affiliated hospitals in Nagano prefecture, Japan, between 1996 and 2012, 77 were negative for serum anti-HBV core/surface antibodies in addition to HBV surface antigen and anti-hepatitis C virus antibody without signs of autoimmune liver disease, Wilson disease, or hemochromatosis. These patients were divided into the alcohol intake-positive group (ethanol intake >20 g/day, n = 31), non-alcoholic fatty liver group (steatosis >5% and ethanol intake <20 g/day, n = 30), and cryptogenic group (no ethanol intake or steatosis, n = 16). Preoperative clinical parameters, tumor and background liver pathology, and prognosis were analyzed., Results: Advanced fibrosis and steatosis were detected in 64% and 60% of all patients, respectively. Approximately 85% of the alcohol intake-positive patients had advanced fibrosis. Non-alcoholic fatty liver HCC subjects had the highest body mass index and prevalence of diabetes, but 30-40% had none to mild fibrosis. The cryptogenic group of HCC patients had the lowest incidence of accompanying hepatic inflammation/fibrosis but the largest tumor size. Recurrence/survival rates were comparable among the groups., Conclusions: Liver fibrosis and steatosis are risk factors of HCC regardless of past HBV infection and ethanol consumption. The present results also indicate the possibility of hepatocarcinogenesis independent of hepatic steatosis, inflammation and fibrosis, ethanol intake, and past HBV infection., (© 2016 The Japan Society of Hepatology.)

Background . A new agent, potassium-competitive acid blocker vonoprazan (VPZ) has potent acid-inhibitory effects and may offer advantages over conventional H. pylori eradication therapies. We aimed to compare the eradication rate between VPZ-based treatment and PPI-based one. Methods . This randomized controlled trial was designed to assign 141 patients with H. pylori- positive gastritis to VPZ group (VPZ 20 mg, amoxicillin 750 mg, and clarithromycin 200 or 400 mg twice daily for 7 days) or PPI group (rabeprazole 20 mg or lansoprazole 30 mg, amoxicillin 750 mg, and clarithromycin 200 or 400 mg twice daily for 7 days). Primary endpoints were eradication rates and adverse events. Results . Seventy of 72 patients in VPZ group and 63 of 69 patients in PPI group completed the treatment after 7 days. The eradication rate was significantly higher in VPZ group than PPI group by intention-to-treat analysis (95.8% versus 69.6%, P = 0.00003, 95% confidence interval [CI] 88.3-99.1% versus 57.3-80.1%) and per-protocol analysis (95.7% versus 71.4%, P = 0.0002, 95% CI 88.0-99.1% versus 58.7-82.1%). The incidence of adverse events was not different between the groups (26.3% in VPZ group versus 37.7% in PPI group, P = 0.15). Conclusion . VPZ-based regimen is more useful than that PPI-based regimen as a first-line H. pylori eradication therapy., Competing Interests: The authors have no conflict of interests to disclose.

Background: Moyamoya disease (MD) is an occlu- sive cerebrovascular disease with risks of cerebral ischemia or hemorrhage. Although cesarean section (CS) is the prevailing delivery mode for these parturi- ents to stabilize cerebral circulation, the preferable mode remains controversial. We have conducted vagi- nal delivery with neuraxial analgesia (NA) because safety with the procedure is equivalent to that with CS. The aim of this study is to investigate peripartum outcomes, particularly delivery mode and occurrence of cerebrovascular events, in women with MD., Methods: We retrospectively analyzed the data of parturients with MD for the previous 8 years., Results: Among 13 pregnancies during this period, eight were vaginal deliveries with NA, while CS was executed in five cases according to obstetric indica- tions. Instrumental deliveries were conducted in five among eight vaginal delivery cases. No cerebrovascular event occurred during delivery. A transient ischemic attack in one case of vaginal delivery and cerebral ischemia in CS were noted in the postpartum period., Conclusions: We successfully managed vaginal deliveries in the eight patients with MD using NA. NA provides pain relief and assures maternal hemody- namic and respiratory stability during delivery. Instru- mental delivery plays a key role in reducing the dura- tion of the second stage of labor.

A 39-year-old female with facioscapulohumeral muscular dystrophy (FSHD) was scheduled for thoracoscopic resection of an anterior mediastinal tumor. She had slowly progressive weakness and atrophy in the fascial and shoulder girdle muscles. General anesthesia was induced and maintained with propofol, remifentanil, and fentanyl combined with thoracic paravertebral block. Rocuronium-induced neuromuscular blockade was evaluated with acceleromyography at the corrugator supercilii, masseter, and adductor pollicis muscles. There was no reaction at the atrophic corrugator supercilii muscle in response to train-of-four (TOF) stimulation even before rocuronium administration. In contrast twitch responses at the masseter and adductor pollicis muscles to TOF stimulation could be evoked and the duration of action of rocuronium was found to be similar to that of the normal population. The perioperative course was uneventful. Neuromuscular monitoring sites should be carefully selected in FSHD patients because of possible inability to monitor neuromuscular function at the atrophic muscles.

Background: The number of hepatocellular carcinoma (HCC) patients with non-viral etiologies is increasing in Japan. We conducted a nation-wide survey to examine the characteristics of those patients., Methods: After we assessed the trend of patients who were first diagnosed with HCC at 53 tertiary care centers in Japan from 1991 to 2010, we collected detailed data of 5326 patients with non-viral etiology. The etiologies were categorized as autoimmune hepatitis, primary biliary cirrhosis, alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), unclassified, and other. Baseline characteristics at initial diagnosis, the modality of the initial treatment, and survival status were collected via a website. Survival of the patients was assessed by the Kaplan-Meier method and Cox proportional hazard regression., Results: The proportion of patients with non-viral etiologies increased from 10.0% in 1991 to 24.1% in 2010. Of the patients, 92% were categorized as ALD, NAFLD, or unclassified. Body mass index (BMI) was ≥ 25 kg/m(2) in 39%. Diabetes was most prevalent in NAFLD (63%), followed by unclassified etiology (46%) and ALD (45%). Approximately 80% of patients underwent radical therapy, including resection, ablation, or transarterial chemoembolization. Survival rates at 3, 5, 10, 15, and 20 years were 58.2, 42.6, 21.5, 15.2, and 15.2%, respectively. Multivariate analysis revealed that patients with BMI > 22 and ≤ 25 kg/m(2) showed the best prognosis versus other BMI categories, after adjusting by age, gender, tumor-related factors, and Child-Pugh score., Conclusions: Most cases of non-B, non-C HCC are related to lifestyle factors, including obesity and diabetes. Slightly overweight patients showed the best prognosis.

Natural killer cells play a key role in the immune control of viral infections. Killer immunoglobulin-like receptors (KIRs) regulate natural killer cell activation and inhibition through the recognition of their cognate HLA class I ligands. We assessed the predictive factors of a sustained virological response (SVR) in 200 Japanese patients with chronic genotype 1b hepatitis C who were treated with telaprevir (TVR), pegylated-interferon-α2b (PEG-IFN), and ribavirin (RBV) triple therapy (92 patients) or PEG-IFN/RBV therapy alone (108 patients). Sixteen KIR genotypes, HLA-A, -B and -C ligands, and an interleukin (IL) 28B polymorphism (rs8099917) were analyzed. We observed that triple therapy, white blood cell count, hemoglobin value, hepatitis C viral load, a rapid virological response (RVR), IL28B TT genotype, and KIR3DL1-HLA-Bw4 genotype were associated with an SVR. In multivariate regression analysis, we identified an RVR (P < 0.000001; odds ratio [OR] = 20.95), the IL28B TT genotype (P = 0.00014; OR = 5.53), and KIR3DL1-HLA-Bw4 (P = 0.004, OR = 3.42) as significant independent predictive factors of an SVR. In conclusion, IL28B and KIR3DL1/HLA-Bw4 are independent predictors of an SVR in Japanese patients infected with genotype 1b HCV receiving TVR/PEG-IFN/RBV or PEG-IFN/RBV therapy., (Copyright © 2014 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

This report summarizes the use of gemcitabine for the treatment of malignant lymphoma. Gemcitabine is a deoxycytidine antagonist that has characteristics different from those of the deoxycytidine antagonist cytarabine(Ara-C). International guidelines based on the results of recent clinical studies recommend the use of gemcitabine as monotherapy and in combination therapy, particularly for relapsed and refractory malignant lymphomas. Clinical studies on gemcitabine monotherapy up to 2012 reported response rates of 51-75% for peripheral T -cell lymphoma and cutaneous T-cell lymphoma. Regarding combination therapy, the GDP regimen consisting of gemcitabine, dexamethasone, and cisplatin was associated with response rates of 62-70% for relapsed or refractory Hodgkin lymphoma and 45-53% for relapsed or refractory non-Hodgkin lymphoma, thereby displaying comparable efficacy to existing salvage chemotherapy regimens. The GDP regimen has a favorable safety profile and is also associated with favorable autologous transplantation rates, which suggests its potential as induction chemotherapy before autologous transplantation. Concerning adverse reactions requiring clinical caution, lung disorder was reported in 8 of 27 patients(30%)who received a regimen of gemcitabine in combination with bleomycin.

Introduction: This study prospectively evaluated the efficacy and safety of pemetrexed and carboplatin followed by maintenance pemetrexed in chemo-naïve patients with advanced nonsquamous non-small cell lung cancer (NSCLC)., Methods: A total of 109 patients received pemetrexed (500 mg/m(2)) and carboplatin (area under the curve = 6 mg/mL·min) every 21 days. For patients without disease progression after 4 cycles, pemetrexed was continued until disease progression or unacceptable toxicity. Pre-planned subgroup analysis results based on the presence of epidermal growth factor receptor (EGFR) mutations are also presented., Results: The median number of treatment cycles was 5 (range: 1-30) in the entire study period. Most of the grade ≥ 3 toxicities observed were hematologic in nature, with no increase in the relative incidence associated with continuation maintenance therapy with pemetrexed. Among the 106 total patients assessable for efficacy, the objective response rate was 35.8 %, median progression free survival (PFS) 5.7 months, and median overall survival (OS) 20.2 months. Sixty patients received maintenance pemetrexed (median: 4 cycles, range: 1-26 cycles); median PFS from the beginning of induction treatment was 7.5 months. From the subgroup analysis for EGFR mutation status, the median OS of EGFR wild-type patients (n=61) was 20.2 months., Conclusions: Pemetrexed/carboplatin followed by pemetrexed was well tolerated and active for front-line treatment of advanced nonsquamous NSCLC. Encouraging survival outcomes were observed even in EGFR-wild type patients.

An emergency caesarean section was performed in a 38-year-old parturient with pregnancy-induced hypertension at week 31 of gestation because of nonreassuring fetal status. A chest X-ray revealed mild spinal scoliosis. We attempted a combined spinal-epidural anesthesia in the parturient because the Cobb angle was only 28 degrees. However, we failed to achieve epidural puncture at the T12-L1 and L1-2 interspaces using a paramedian approach. In addition, we failed to achieve the puncture of the subarachnoid spaces at L3-4 and L4-5 using medial and paramedian approaches. Finally, we succeeded in puncturing the subarachnoid space at L5-S1 using the median approach, and injected 11 mg of hyperbaric bupivacaine. Analgesia was achieved from the T6 to S regions, and the caesarean section was completed uneventfully. A postoperative X-ray and computed tomography scan revealed that the rotation of the lumbar spine was so severe that the spaces between the laminae of the lumbar regions were shifted to the left and narrowed. Therefore, the puncture of the epidural and subarachnoid spaces was difficult, suggesting that the degree of lumbar spine rotation is more important than the thoracic spine curvature for successful epidural and spinal anesthesia in parturients with scoliosis.

This prospective, non-randomized, multicenter cohort study analyzed the safety and efficacy of a steroid-free immunosuppressive (IS) protocol for hepatitis C virus (HCV)-positive living donor liver transplant (LDLT) recipients in Japan. Of 68 patients enrolled from 13 transplant centers, 56 fulfilled the inclusion/exclusion criteria; 27 were assigned the steroid-free IS protocol (Fr group) and 29 the traditional steroid-containing IS protocol (St group). Serum HCV RNA levels increased over time and were higher in the St group until postoperative day 90 (POD 14, p=0.013). Preemptive anti-HCV therapy was started in a higher percentage of recipients (59.3%) in the Fr group than in the St group (31.0%, p=0.031), mainly due to early HCV recurrence. The incidence of HCV recurrence at one yr was lower in the Fr group (22.2%) than in the St group (41.4%; p=0.066). The incidence of acute cellular rejection was similar between groups. New onset diabetes after transplant, cytomegalovirus infection, and renal dysfunction were significantly less frequent in the Fr group than in the St group (p=0.022, p<0.0001, p=0.012, respectively). The steroid-free IS protocol safely reduced postoperative morbidity and effectively suppressed both the HCV viral load in the early post-transplant period and HCV recurrence in HCV-positive LDLT recipients., (© 2012 John Wiley & Sons A/S.)

Unlabelled: The long-term outcome of patients with autoimmune hepatitis (AIH) in Japan has not been well-defined. The aim of this study was to clarify the outcome of this disease over a long follow-up period compared with that of the general Japanese population as well as that among patients. A total of 203 AIH patients were enrolled for a mean follow-up period of 131 months. All patients were treated with corticosteroids with or without azathioprine. The overall survival of AIH patients was similar to that of the general population in Japan. The prognosis of AIH subgroups divided according to disease severity, sex, incidence of relapse, liver histology, presence of cirrhosis, probable or definite AIH score, antibody to hepatitis B core antigen antibody positivity, or human leukocyte antigen DR4-positivity did not differ greatly among patients. However, the prognosis of patients experiencing two or more relapses was significantly poorer than that of patients with remission or a single relapse both in univariate (P < 0.001) and multivariate (P = 0.020) analyses. The development of liver malignancy was also a possibility among AIH patients with multiple relapses. Severe adverse effects of corticosteroids were rare, even in patients who underwent long-term treatment., Conclusion: Repeated relapses of AIH are significantly associated with a poorer long-term prognosis in Japan. AIH patients can expect a similar prognosis to that of the general population, provided they are adequately managed with continuous low doses of immunosuppressive therapy, especially after the first relapse., (Copyright © 2012 American Association for the Study of Liver Diseases.)

Background: Immunoglobulin (Ig) G4-associated autoimmune hepatitis (AIH) is a recently identified and possibly new disease entity. However, the epidemiology and clinical features of IgG4-associated AIH remain uncertain. The aim of this study was to determine the prevalence and the clinical, serological, and histological characteristics of IgG4-associated AIH., Methods: We examined the clinical features, serum IgG4 concentration, liver biopsy histology, and IgG4-bearing plasma cell infiltration of 60 patients with type 1 AIH and 22 patients with autoimmune pancreatitis., Results: High serum IgG4 concentration (≥ 135 mg/dL) and IgG4-bearing plasma cell infiltration in the liver (≥ 10/high-power fields [HPFs]) were found in 2 of the 60 (3.3%) patients with type 1 AIH. These patients had high serum levels of IgE, giant cell change, and rosette formation in the liver. Although corticosteroid therapy reduced the serum IgG4 concentration and normalized liver enzymes and histology, one patient developed IgG4-related sclerosing cholangitis after 5 years of follow-up., Conclusions: Because IgG4-associated AIH was found in over 3% of Japanese patients with type 1 AIH in our cohort, further studies are needed on this possible new disease entity and its impact on the diagnostic guidelines of AIH.

Background & Aims: To evaluate the long-term efficacy of entecavir in nucleoside-naïve chronic hepatitis B patients., Methods: One hundred and sixty-seven patients treated with entecavir 0.01mg, 0.1mg or 0.5mg for 24-52weeks in Phase II studies entered rollover study ETV-060 and received entecavir 0.5mg daily. Responses were evaluated among patients with available samples., Results: After 96weeks in ETV-060 (120-148weeks total entecavir treatment time), 88% (127/144) of patients had HBV-DNA <400 copies/ml; 90.1% (128/142) had alanine aminotransferase (ALT) 1x the upper limit of normal (ULN) among those with abnormal baseline ALT; and 26% (32/121) achieved HBe seroconversion among those HBeAg(+) at baseline. A subset of 66 patients received entecavir 0.5mg (approved dose) from Phase II baseline: at week 96 in ETV-060, 83% (48/58) had HBV-DNA <400 copies/ml, 88% (52/59) had ALT 1x ULN, and 20% (10/49) achieved HBe seroconversion. Twenty-one out of 66 patients had paired baseline and on-treatment biopsies: 100% (21/21) and 57% (12/21) demonstrated histologic improvement, and improvement in fibrosis, respectively, over 3years. The 3-year cumulative probability of resistance was 3.3% for all patients and 1.7% for the 0.5mg subset., Conclusions: Long-term entecavir for nucleoside-naïve patients resulted in high rates of virological, biochemical, and histological response, with minimal resistance., (Copyright 2010. Published by Elsevier B.V.)

Background: The Japanese Liver Transplantation Society presented its first report on donor morbidity in 2003. The Society has been continuing to survey outcomes in living liver donors in Japan., Methods: By using a uniform comprehensive medical record review process, data were collected on 3565 living liver donors who had donated grafts by the end of December 2006 at 38 Japanese centers., Results: Preoperative problems were reported in 2 donors, intraoperative problems in 27, and postoperative complications in 270. In total, 299 donors (8.4%) suffered complications related to liver donation. Postoperative complications included biliary complications in 3.0%, reoperation in 1.3%, severe after-effects in two (0.06%), and death (apparently related to donor surgery) in one donor (0.03%). The incidence of postoperative complications in left and right lobe donors was 8.7% and 9.4%, respectively., Conclusions: The accumulated experience indicates a reduction in the incidence of donor complications, especially for right lobe resection. One donor death and two cases of severe after effects related to liver donation have been reported during 18 years of living donor liver transplantation experience in Japan.

Background: Entecavir (ETV) is a potent nucleoside analogue against hepatitis B virus (HBV), and emergence of drug resistance is rare in nucleoside-naive patients because development of ETV resistance (ETVr) requires at least three amino acid substitutions in HBV reverse transcriptase. We observed two cases of genotypic ETVr with viral rebound and biochemical breakthrough during ETV treatment of nucleoside-naive patients with chronic hepatitis B (CHB)., Results: Case 1: A 44-year-old HBeAg-positive man received ETV 0.1 mg/day for 52 weeks and 0.5 mg/day for 96 weeks consecutively. HBV DNA was 10.0 log(10) copies/ml at baseline, declined to a nadir of 3.1 at week 100, and rebounded to 4.5 at week 124 and 6.7 at week 148. Alanine aminotransferase (ALT) level increased to 112 IU/l at week 148. Switching to a lamivudine (LVD)/adefovir-dipivoxil combination was effective in decreasing HBV DNA. Case 2: A 47-year-old HBeAg-positive man received ETV 0.5 mg/day for 188 weeks. HBV DNA was 8.2 log(10) copies/ml at baseline, declined to a nadir of 2.9 at week 124, and then rebounded to 4.7 at week 148 and 6.4 at week 160. ALT level increased to 72 IU/l at week 172. The ETVr-related substitution (S202G), along with LVD-resistance-related substitutions (L180M and M204V), was detected by sequence analysis at week 124 in both case 1 and case 2., Conclusions: ETVr emerged in two Japanese nucleoside-naive CHB patients after prolonged therapy and incomplete suppression and in one patient after <0.5 mg of dosing. ETV patients with detectable HBV DNA or breakthrough after extended therapy should be evaluated for compliance to therapy and potential emergence of resistance.