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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.

Background/aims: Alcoholic liver disease (ALD) is one of the leading causes of cirrhosis and yet efficient therapeutic strategies are lacking. Polyenephosphatidylcholine (PPC), a major component of essential phospholipids, prevented alcoholic liver fibrosis in baboons, but its precise mechanism remains uncertain. We aimed to explore the effects of PPC on ALD using ethanol-fed peroxisome proliferator-activated receptor alpha (Ppara)-null mice, showing several similarities to human ALD., Methods: Male wild-type and Ppara-null mice were pair-fed a Lieber-DeCarli control or 4% ethanol-containing diet with or without PPC (30 mg/kg/day) for 6 months., Results: PPC significantly ameliorated ethanol-induced hepatocyte damage and hepatitis in Ppara-null mice. These effects were likely a consequence of decreased oxidative stress through down-regulation of reactive oxygen species (ROS)-generating enzymes, including cytochrome P450 2E1, acyl-CoA oxidase, and NADPH oxidases, in addition to restoration of increases in Toll-like receptor 4 and CD14. PPC also decreased Bax and truncated Bid, thus inhibiting apoptosis. Furthermore, PPC suppressed increases in transforming growth factor-beta1 expression and hepatic stellate cell activation, which retarded hepatic fibrogenesis., Conclusions: PPC exhibited anti-inflammatory, anti-apoptotic, and anti-fibrotic effects on ALD as a result of inhibition of the overexpression of ROS-generating enzymes. Our results demonstrate detailed molecular mechanisms of the anti-oxidant action of PPC.

The activated mesangial cell is an important therapeutic target for the control of glomerulonephritis. The peroxisome proliferator-activated receptor alpha (PPARalpha) has attracted considerable attention for its anti-inflammatory effects; however, its roles in the mesangial cells remain unknown. To determine the anti-inflammatory function of PPARalpha in mesangial cells, wild-type and Ppara-null cultured mesangial cells were exposed to lipopolysaccharide (LPS). LPS treatment caused enhanced proinflammatory responses in the Ppara-null cells compared with wild-type cells, as revealed by the induction of interleukin-6, enhanced cell proliferation, and the activation of the nuclear factor (NF)-kappaB signaling pathway. In wild-type cells resistant to inflammation, constitutive expression of PPARalpha was undetectable. However, LPS treatment induced the significant appearance and substantial activation of PPARalpha, which would attenuate the proinflammatory responses through its antagonizing effects on the NF-kappaB signaling pathway. The induction of PPARalpha was coincident with the appearance of alpha-smooth muscle actin, which might be associated with the phenotypic changes of mesangial cells. Moreover, another examination using LPS-injected wild-type mice demonstrated the appearance of PPARalpha-positive cells in glomeruli, suggesting in vivo correlation with PPARalpha induction. These results suggest that PPARalpha plays crucial roles in the attenuation of inflammatory response in activated mesangial cells. PPARalpha might be a novel therapeutic target against glomerular diseases.

Acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) are characterized by a high mortality rate; therefore, ARDS/ALI in humans is a leading cause of morbidity and mortality in critically ill patients. As previously reported, cytokines play a critical role as signaling molecules that initiate, amplify, and perpetuate inflammatory responses on a local and systemic basis, and the polymyxin-B immobilized direct hemoperfusion system (PMX-DHP) is effective for the treatment of ARDS/ALI. Furthermore, another direct hemoperfusion system using the beta2-microglobulin-selective adsorbent column, Lixelle, the direct hemoperfusion treatment (Lixelle-DHP), has been applied in some cases to patients who are affected with systemic inflammatory response syndrome. The aim of this study is to evaluate the therapeutic efficacy of Lixelle-DHP in the treatment of ARDS/ALI. Four patients, aged 67-79 years old (mean 72 +/- 6.2 years), diagnosed with ARDS/ALI were treated with Lixelle-DHP. The P(a)O(2)/fraction of inspired oxygen (F(i)O(2)) ratio (PF ratio) was 90.0 +/- 22.9 before the treatment, and it increased to 129.9 +/- 5.6 at 72 h afterward the start of treatment. Inflammatory cytokines such as interleukin (IL)-1 beta, IL-6, soluble intercellular adhesion molecule 1 (sICAM-1) decreased significantly after the treatment. All patients were still alive after one month. However, while IL-2 had decreased significantly after the treatment, it had returned by the next treatment. It is possible that Lixelle-DHP might be able to improve the PF ratio and mortality rate as a result of decreased cytokines, and it has been suggested that Lixelle-DHP has a beneficial influence in the treatment of ARDS/ALI.

Primary liver cancer, 95% of which is hepatocellular carcinoma (HCC), is ranked third in men and fifth in women as a cause of death from malignant neoplasms in Japan. The number of deaths and death rate of HCC began to increase sharply in 1975. These numbers peaked at 34,510 and 27.4/100,000, respectively, in 2004, but decreased to 33,662 annual deaths and a 26.7/100,000 death rate in 2006. Although hepatitis B virus (HBV) and hepatitis C virus (HCV) infection are both major causes of HCC, HCV-related HCC represents 70% of all cases. The incidence of HCC without hepatitis B surface antigen (HBsAg) or antibodies to HCV (anti-HCV) accounts for 8%-15% of HCC patients nationwide. Geographically, HCC is more frequent in western than eastern Japan, and death rates of HCC in each prefecture correlate with anti-HCV, but not HBsAg, prevalence. Interferon therapy for chronic hepatitis C reduces the risk of development of HCC, especially among patients with sustained virological response. Further research should focus on the mechanisms of carcinogenesis by HCV and HBV, development of more effective treatments, and establishment of early detection and preventative approaches. Better understanding of HCC unrelated to HCV and HBV, possibly caused by steatohepatitis and diabetes, should also be a major concern in future studies.

Background: Hepatoprotective therapies that include regular glycyrrhizin injections (GIs) are beneficial for chronic hepatitis C patients, but are sometimes insufficient for normalizing serum alanine aminotransferase (ALT) levels. Here, we evaluated whether the addition of minor bloodletting, named petit phlebotomy (PP), prior to each GI could further reduce serum ALT concentrations in such patients., Methods: Seventy-six hepatitis C virus (HCV)-infected patients receiving regular GI, with persistently abnormal serum ALT levels, were randomly divided into GI + PP and GI groups and monitored for 12 months. PP was performed before every GI to a total 60 ml of blood a week. The primary PP endpoint was a serum ferritin level of less than 20 ng/ml. PP was suspended upon reaching the endpoint, but was resumed as needed. The efficacy of the addition of PP was evaluated by measuring changes in serum ALT levels., Results: Two patients in each group dropped out because of the appearance of hepatocellular carcinoma. The remainder completed the 12-month treatment with no serious adverse events. Serum ALT and ferritin levels were significantly decreased in the GI + PP group (from 67 +/- 34 to 44 +/- 14 U/l and from 163 +/- 127 to 25 +/- 21 ng/ml, respectively, both P < 0.001), but these changes were not seen in the GI group. Although 20 patients in the GI + PP group had compensated cirrhosis, no significant reductions in serum albumin concentrations were observed., Conclusions: The addition of PP is effective and safe for improving serum aminotransferase levels in HCV-infected patients receiving regular GI, even in those with compensated cirrhosis.

The interferon sensitivity determining region (ISDR) of the hepatitis C virus (HCV) and T-helper type 1 and type 2 (Th1/Th2) ratio were analyzed along with other host and viral factors for their ability to predict the response of patients with chronic hepatitis C to pegylated interferon alpha-2b (Peg-IFN) and ribavirin (RBV) combination therapy. A total of 120 chronic hepatitis C patients with genotype 1 HCV and high baseline viral loads who were to undergo combination therapy scheduled for 48 weeks were enrolled. Sustained virologic response (SVR) was achieved in 54 (45%) of the 120 patients. The pretreatment factors significantly associated with SVR by logistic regression analysis were ISDR mutant [odds ratio (OR) = 86.0, P = 0.0008], Th1/Th2 ratio

Background/aims: Citrin deficiency caused by SLC25A13 gene mutations develops into adult-onset type II citrullinemia (CTLN2) and may be accompanied with hepatic steatosis and steatohepatitis. As its clinical features remain unclear, we aimed to explore the characteristics of fatty liver disease associated with citrin deficiency., Methods: The prevalence of hepatic steatosis in 19 CTLN2 patients was examined, and clinical features were compared with those of non-alcoholic fatty liver disease (NAFLD) patients without known SLC25A13 gene mutations., Results: Seventeen (89%) CTLN2 patients had steatosis, and 4 (21%) had been diagnosed as having NAFLD before appearance of neuropsychological symptoms. One patient had steatohepatitis. Citrin deficiency-associated fatty livers showed a considerably lower prevalence of accompanying obesity and metabolic syndrome, higher prevalence of history of pancreatitis, and higher serum levels of pancreatic secretory trypsin inhibitor (PSTI) than fatty livers without the mutations. Receiver operating characteristic curve analyses revealed that a body mass index < 20kg/m(2) and serum PSTI>29ng/mL were associated with citrin deficiency., Conclusions: Patients presenting with non-alcoholic fatty liver unrelated to obesity and metabolic syndrome might have citrin deficiency, and serum PSTI may be a useful indicator for distinguishing this from conventional NAFLD.

Nonalcoholic fatty liver disease (NAFLD) is classified as nonalcoholic steatohepatitis (NASH) or simple steatosis (SS) according to histological findings. It is well recognized that NASH may develop into cirrhosis and hepatocellular carcinoma (HCC), both with unfavorable prognoses. Although the outlook of SS is reported to be better than that of NASH, the long-term prognosis of SS remains unclear. Here, we report the case of a patient who was diagnosed as having SS by a first liver biopsy, and later developed into cirrhosis and HCC over a period of 27 years. In 1980, a 42-year-old Japanese man was admitted because of abnormal liver function tests. He had no history of alcohol intake and was negative for hepatitis virus markers and autoantibodies. A liver biopsy specimen showed macrovesicular steatosis without ballooned hepatocytes, Mallory hyaline, lobular inflammation, or perisinusoidal/perivenular fibrosis, confirming the diagnosis of SS. The patient's serum aminotransferase levels did not normalize despite repeated dietary instruction, and in 2001, liver histology demonstrated cirrhosis with mild steatosis and hepatocyte ballooning, leading to the diagnosis of NASH-related cirrhosis. HCC appeared in 2007. Overall, this patient progressed to cirrhosis and HCC in 20 and 27 years, respectively, following initial diagnosis. Platelet counts and degree of steatosis, as assessed by periodic ultrasonography, were seen to gradually reduce with progression of fibrosis. This case demonstrates that even a diagnosis of SS does not guarantee non-progression to cirrhosis and HCC, and careful follow-up is needed not only in patients with NASH, but also in those with SS.

Background/aims: Recent studies using transgenic mouse models have demonstrated that the presence of hepatitis C virus (HCV) singularly induces insulin resistance (IR). When evaluated in humans, the exclusion of other factors influencing IR, such as obesity, alcohol intake, hepatic inflammation and steatosis is needed, but only few studies have been performed to these ends. Therefore, we aimed at exploring the singular effects of HCV on glucose metabolism through analysis of HCV carriers with persistently normal serum aminotransferase., Methods: Non-obese, non-diabetic and non-alcoholic HCV carriers (n=30) were enrolled with 30 hepatitis B virus carriers matched by age, gender, body mass index and waist-to-hip ratio. All patients maintained normal serum aminotransferase (<30 U/L), hyaluronic acid (<50 ng/ml) and platelet count (>150 x 10(3)/microl) for more than 5 years without additional treatments, and had no signs of steatosis. We then compared fasting plasma glucose, serum insulin and adiponectin, and homoeostasis model assessment of IR (HOMA-IR) and HOMA-beta indices between the groups., Results: There were no significant differences in IR/secretion-associated markers or serum adiponectin. Multivariate analysis demonstrated that the presence of HCV was not an independent predictor of IR. HOMA-IR was strongly correlated with waist circumferences and serum gamma-glutamyltransferase in HCV carriers, but not with serum aminotransferase, high-sensitivity C-reactive protein, hyaluronic acid or HCV core antigen., Conclusions: These results suggest that the presence of HCV alone does not affect IR. Coexistence of hepatitis, steatosis and/or fibrosis may be important to the pathogenesis of IR induced by chronic HCV infection.

Hepatitis B virus (HBV) reactivation in patients with resolved HBV infection was found in 23 (4%) of 552 newly hepatitis B surface antigen-positive patients in Japan. Because one-fourth of cases develop into fulminant hepatic failure and mortality is 100%, management of HBV reactivation in patients with resolved HBV infection should be discussed.

Aim: Autoimmune hepatitis (AIH) is an organ-specific autoimmune disease characterized by chronic inflammation of the liver. Although the HLA DR4 allele is associated with type 1 AIH in Japanese, the exact genetic etiology of AIH remains undefined. The cytotoxic T-lymphocyte antigen 4 (CTLA4) is an inhibitory receptor expressed by T-cells that acts largely as a negative regulator of T-cell responses, and polymorphisms of CTLA4 have been reported to be associated with susceptibility to various autoimmune diseases. Therefore, we sought to clarify whether CTLA4 single-nucleotide polymorphisms are associated with disease susceptibility in Japanese patients with type 1 AIH., Methods: We genotyped 76 patients with AIH and 100 ethically matched controls for allelic determinants using TaqMan genotyping assays at four polymorphism sites: -1722 and -318 in the promoter; +49 in exon 1 and +6230 in the 3' untranslated region., Results: We observed no difference in the distribution of the alleles, genotypes, or haplotypes between patients and controls. Compared with -1722 C/C patients, -1722 T/T patients were younger (56 vs. 63 years; P = 0.01) and had significantly lower serum levels of aspartate aminotransferase (313 vs. 763 IU/L; P = 0.031) and bilirubin (1.1 vs. 8.6 mg/dL; P = 0.027). Analysis of allelic frequencies revealed no significant difference between patients with and without the HLA DR4 allele., Conclusion: These data suggest that the CTLA4 polymorphism is not associated with susceptibility to type 1 AIH in the Japanese population.

Since first being described in 1998, de novo autoimmune hepatitis (AIH) after liver transplantation has been reported in several cases suffering from non-autoimmune liver diseases and primary biliary cirrhosis (PBC). Glutathione S-transferase (GST) T1 genotype mismatches between donor and recipient have also been suggested to constitute a risk factor for de novo AIH. Here, we report a 33-yr-old woman who presented complaining of marked fatigue and jaundice four yr after living-donor liver transplantation for PBC. On examination, transaminase levels were highly elevated and ANA and antimitochondrial antibody M2 were positive. Histological findings showed zonal necrosis with lymphoplasmacytic infiltration closely resembling AIH. She had pretreatment AIH score of 16 and 19 points after relapse of de novo AIH. Two color fluorescence in situ hybridization with X and Y chromosome-specific probes clearly revealed that the hepatocytes were of donor origin and lymphocytes were of patient origin. The GSTT1 genotype of the patient and the donor were the same null type, suggesting that mechanisms other than GSTT1 mismatches may exist in de novo AIH development. In conclusion, recipient immune cells attacked the allogeneic transplanted liver of the patient via de novo AIH, although the exact participation of autoimmune mechanisms is unclear.

Recent studies have demonstrated that n-3 polyunsaturated fatty acids ameliorate nonalcoholic fatty liver disease. Although eicosapentaenoic acid (EPA), one of the major components of n-3 polyunsaturated fatty acids, is widely used as an antilipidemic agent, its single efficacy for nonalcoholic steatohepatitis (NASH) remains unclear. As such, we aimed to evaluate the efficacy and safety of EPA on 23 biopsy-proven NASH patients in a pilot trial. Highly purified EPA (2700 mg/d) was administered for 12 months and efficacy was assessed by biochemical parameters and liver histology. All patients completed the treatment with no adverse events, indicating acceptable tolerance to the treatment. After 12 months, serum alanine aminotransferase levels were significantly improved (from 79+/-36 to 50+/-20 U/L), and serum free fatty acids, plasma soluble tumor necrosis factor receptor 1 and 2 levels, and serum ferritin and thioredoxin levels, which may reflect hepatic oxidative stress, were significantly decreased. Body weight, blood glucose, insulin, and adiponectin concentrations remained unchanged. Seven of the 23 patients consented to undergo posttreatment liver biopsy, which showed improvement of hepatic steatosis and fibrosis, hepatocyte ballooning, and lobular inflammation in 6 patients. In conclusion, EPA treatment seems to be safe and efficacious for patients with NASH, largely due to its anti-inflammatory and antioxidative properties. To confirm these results, appropriately powered, controlled trials are needed.

Objectives: Autoimmune pancreatitis (AIP) is characterized by high serum IgG4 concentrations, lymphoplasmacytic inflammation, and a favorable response to corticosteroid treatment. Although the HLA DRB1*0405-DQB1*0401 haplotype and Fc receptor-like 3 polymorphisms have been associated with AIP, the role of other genetic factors is largely unknown. As cytotoxic T-lymphocyte antigen 4 (CTLA4) polymorphisms have recently been linked with several autoimmune diseases, we sought to determine if CTLA4 polymorphisms and serum sCTLA4 levels were associated with AIP as well., Methods: Five CTLA4 polymorphisms, located at -1722, -658, and -318 in the promoter, +49 in exon 1, and +6230 in the 3' untranslated region, were genotyped in 59 patients with AIP and 102 healthy subjects. Serum sCTLA4 levels were also determined in cohorts of 52 patients and 32 controls., Results: Compared with healthy subjects, we found a significant increase in the +6230 G/G genotype (64%vs 42%, odds ratio [OR] 2.48, P= 0.011) in AIP patients. Haplotype 2, which had the +6230A, was associated with AIP resistance (OR 0.49, P= 0.011). The +49A/A and +6230A/A genotypes were associated with an enhanced risk of relapse (OR 5.45, P= 0.038 and OR 12.66, P= 0.022). Additionally, median serum sCTLA4 levels were significantly higher in patients with AIP (8.9 ng/mL) compared with healthy subjects (2.9 ng/mL, P < 0.001). The +6230 G/A polymorphism did not influence sCTLA4 levels in AIP patients., Conclusions: Our findings suggest that AIP is associated with a genetic polymorphism in CTLA4 and is positively correlated with serum sCTLA4 levels.

Transgenic mice expressing HCV core protein develop hepatic steatosis and hepatocellular carcinoma (HCC), but the mechanism underlying this process remains unclear. Because PPARalpha is a central regulator of triglyceride homeostasis and mediates hepatocarcinogenesis in rodents, we determined whether PPARalpha contributes to HCV core protein-induced diseases. We generated PPARalpha-homozygous, -heterozygous, and -null mice with liver-specific transgenic expression of the core protein gene (Ppara(+/+):HCVcpTg, Ppara(+/-):HCVcpTg, and Ppara(-/-):HCVcpTg mice. Severe steatosis was unexpectedly observed only in Ppara(+/+):HCVcpTg mice, which resulted from enhanced fatty acid uptake and decreased mitochondrial beta-oxidation due to breakdown of mitochondrial outer membranes. Interestingly, HCC developed in approximately 35% of 24-month-old Ppara(+/+):HCVcpTg mice, but tumors were not observed in the other genotypes. These phenomena were found to be closely associated with sustained PPARalpha activation. In Ppara(+/-):HCVcpTg mice, PPARalpha activation and the related changes did not occur despite the presence of a functional Ppara allele. However, long-term treatment of these mice with clofibrate, a PPARalpha activator, induced HCC with mitochondrial abnormalities and hepatic steatosis. Thus, our results indicate that persistent activation of PPARalpha is essential for the pathogenesis of hepatic steatosis and HCC induced by HCV infection.

Background: Fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) has been widely used for the diagnosis of pancreatic cancer. Because autoimmune pancreatitis is easily misdiagnosed as pancreatic cancer and can be tested for by FDG-PET analysis based on the presence of suspected pancreatic cancer, we attempted to clarify the differences in FDG-PET findings between the two conditions., Methods: We compared FDG-PET findings between 15 patients with autoimmune pancreatitis and 26 patients with pancreatic cancer. The findings were evaluated visually or semiquantitatively using the maximum standardized uptake value and the accumulation pattern of FDG., Results: FDG uptake was found in all 15 patients with autoimmune pancreatitis, whereas it was found in 19 of 26 patients (73.1%) with pancreatic cancer. An accumulation pattern characterized by nodular shapes was significantly more frequent in pancreatic cancer, whereas a longitudinal shape indicated autoimmune pancreatitis. Heterogeneous accumulation was found in almost all cases of autoimmune pancreatitis, whereas homogeneous accumulation was found in pancreatic cancer. Significantly more cases of pancreatic cancer showed solitary localization, whereas multiple localization in the pancreas favored the presence of autoimmune pancreatitis. FDG uptake by the hilar lymph node was significantly more frequent in autoimmune pancreatitis than in pancreatic cancer, and uptake by the lachrymal gland, salivary gland, biliary duct, retroperitoneal space, and prostate were seen only in autoimmune pancreatitis., Conclusions: FDG-PET is a useful tool for differentiating autoimmune pancreatitis from suspected pancreatic cancer, if the accumulation pattern and extrapancreatic involvement are considered. IgG4 measurement and other current image tests can further confirm the diagnosis.

Persistent infection of hepatitis C virus (HCV) can lead to a high risk for hepatocellular carcinoma (HCC). HCV core protein plays important roles in HCV-related hepatocarcinogenesis, because mice carrying the core protein exhibit multicentric HCCs without hepatic inflammation and fibrosis. However, the precise mechanism of hepatocarcinogenesis in these transgenic mice remains unclear. To evaluate whether the core protein modulates hepatocyte proliferation and apoptosis in vivo, we examined these parameters in 9- and 22-month-old transgenic mice. Although the numbers of apoptotic hepatocytes and hepatic caspase 3 activities were similar between transgenic and nontransgenic mice, the numbers of proliferating hepatocytes and the levels of numerous proteins such as cyclin D1, cyclin-dependent kinase 4 and c-Myc, were markedly increased in an age-dependent manner in the transgenic mice. This increase was correlated with the activation of peroxisome proliferator-activated receptor alpha (PPARalpha). In these transgenic mice, spontaneous and persistent PPARalpha activation occurred heterogeneously, which was different from that observed in mice treated with clofibrate, a potent peroxisome proliferator. We further demonstrated that stabilization of PPARalpha through a possible interaction with HCV core protein and an increase in nonesterified fatty acids, which may serve as endogenous PPARalpha ligands, in hepatocyte nuclei contributed to the core protein-specific PPARalpha activation. In conclusion, these results offer the first suggestion that HCV core protein induces spontaneous, persistent, age-dependent and heterogeneous activation of PPARalpha in transgenic mice, which may contribute to the age-dependent and multicentric hepatocarcinogenesis mediated by the core protein., (Copyright 2007 Wiley-Liss, Inc.)

Background and Objective: In Japan the prevalence of the hepatitis C virus (HCV) antibody is highest in the elderly population. Therefore, it is important for elderly patients to undergo interferon (IFN) therapy. In patients with HCV genotype 1b and a high viral load, the sustained virological response (SVR) rate is lower in older compared with younger patients receiving combination antiviral therapy. In addition, inadequate adherence to combination therapy is often seen in elderly patients, and is associated with reduced response rates. The aim of this retrospective analysis was to evaluate the effects of host-related factors (i.e. sex, age, baseline HCV RNA level, bodyweight and fibrosis stage) and peginterferon (PEG IFN)-alpha-2a plus ribavirin dose reductions on SVR rates., Methods: A total of 192 treatment-naive patients with a HCV genotype 1b infection and a high viral load were included in the analysis. Patients had been enrolled into a phase III trial of 48 weeks of treatment with PEG IFN-alpha-2a plus ribavirin or PEG IFN-alpha-2a plus placebo. All patients were evaluated for effect of drug exposure on SVR. In addition, the impact of host-related factors or dose reductions on SVR was assessed., Results: Approximately 30% of patients were considered elderly (> or =60 years of age). The overall SVR rate was significantly higher in patients treated with combination therapy versus monotherapy (59.4% vs 24.0%, p < 0.001). Attainment of an SVR following combination therapy was not influenced by any factor evaluated in the analysis, although elderly males were associated with decreased SVR rates. Younger age (odds ratio [OR] 1.081; 95% CI 1.125, 1.034; p = 0.0009), lower baseline HCV RNA levels (OR 1.003; 95% CI 1.006, 1.001; p = 0.006) and a severe fibrosis stage (F3/4) [OR 6.194; 95% CI 1.037, 37.000; p = 0.0455] significantly increased the likelihood of achieving an SVR with monotherapy. In the combination therapy group, patients maintaining a full dosage schedule of PEG IFN-alpha-2a and ribavirin and those requiring dose reductions of either study drug had similar SVR rates (64.5% vs 61.9%). However, the SVR rate was reduced to 33.3% among patients who discontinued combination therapy. Three out of the 31 patients who received the full dosage schedule were elderly patients. In addition, of the 15 patients who discontinued combination therapy, three were <50 years of age and six were > or =60 years of age. The SVR rate was reduced in patients with cumulative PEG IFN-alpha-2a and ribavirin doses of <60%; the majority of these patients were elderly., Conclusion: The attainment of an SVR following PEG IFN-alpha-2a plus ribavirin combination therapy was not influenced by any of the host-related factors evaluated in this analysis, although elderly males were associated with a decreased SVR rate. Younger age, male sex and lower baseline HCV RNA levels significantly increased the likelihood of achieving an SVR with monotherapy. In addition, dose reductions appeared to have a negative impact on SVR in elderly patients. Therefore, it is important to minimize PEG IFN-alpha-2a and ribavirin dose reductions by effectively managing treatment-related adverse events in elderly patients.