Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1002/jgh3.12321

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Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/jgh3.12321

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

<title>Abstract</title><sec>
<title>Background</title>
Liver cancer is the second most common cause of cancer-related death. Every type of tumours including liver cancer contains cancer stem cells (CSCs). To date, the molecular mechanism regulating the development of liver CSCs remains unknown.


</sec><sec>
<title>Methods</title>
In this study, we tried to generate a new model of liver CSCs by converting mouse induced pluripotent stem cells (miPSCs) with hepatocellular carcinoma (HCC) cell line Huh7 cells conditioned medium (CM). miPSCs treated with CM were injected into the liver of BALB/c nude mice. The developed tumours were then excised and analysed.


</sec><sec>
<title>Results</title>
The primary cultured cells from the malignant tumour possessed self-renewal capacity, differentiation potential and tumorigenicity in vivo, which were found rich in liver cancer-associated markers as well as CSC markers.


</sec><sec>
<title>Conclusions</title>
We established a model of liver CSCs converting from miPS and showed different stages of stemness during conversion process. Our CSC model will be important to assess the molecular mechanisms necessary to develop liver CSCs and could help in defeating liver cancer.


</sec>

DOI： 10.1038/s41416-020-0792-z

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Other Link： http://www.nature.com/articles/s41416-020-0792-z

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AIMS: We assessed the problems and efficacy of glecaprevir + pibrentasvir (GLE/PIB) therapy for patients infected with hepatitis C virus (HCV) in the real world. METHOD: A total of 423 patients infected with HCV who started treatment at eight different centers in Japan were enrolled in the study. Glecaprevir (300 mg) and pibrentasvir (120 mg) were given once daily for 8 weeks to 246 non-cirrhotic direct-acting antiviral (DAA)-naive patients with HCV genotype (GT)-1 or -2, and for 12 weeks to patients who: were DAA-naive cirrhotic (n = 55), had experienced DAA failure (n = 78), were cirrhotic and had DAA failure (n = 37), and were other GT-1/2 (n = 7). Anti-HCV efficacy was defined as a sustained virologic response 12 weeks post-treatment (SVR12). The evaluation was undertaken in an intention-to-treat (ITT) population and in patients who were assessed at SVR12 (modified ITT population). RESULTS: In the ITT population, 220 (89%) patients on the 8-week regimen and 164 (93%) patients on the 12-week regimen achieved SVR12. The 30 dropout patients were predominantly men and with GT-2. All other DAA-naive GT-1 patients achieved SVR12. The 12-week regimen resulted in 100% SVR12 in 41 GT-2 patients. Nine patients did not achieve SVR12: two DAA naive with GT-2a, two GT-3b patients, two GT-1 patients with discontinuation, and three other GT-1 patients with a history of DAA failure. Four of seven patients who discontinued treatment due to severe adverse effects were more than 75 years old. CONCLUSIONS: Glecaprevir + pibrentasvir had a remarkable anti-HCV effect in GT-1 and GT-2 patients, but not in GT-3b patients. Although this therapy was reasonably safe, it is necessary to carefully consider elderly and dropout patients.

DOI： 10.1111/hepr.13410

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This study will assess the safety and efficacy of the administration of adenoviral vector expressing the human-reduced expression in immortalized cells (Ad-REIC) to a liver tumor in patients with hepatocellular carcinoma (HCC) or liver metastasis of pancreatic cancer. A Phase I clinical study of Ad-REIC administration to a liver tumor in a patient with HCC or liver metastasis of pancreatic cancer will be conducted. The study is a single-arm, prospective, nonrandomized, noncomparative, open-label, single-center trial performed in Okayama University Hospital, Okayama, Japan. Ad-REIC will be injected into the liver tumor under ultrasound guidance. Ad-REIC administration will be repeated a total of three-times every 2 weeks. The primary end point is the dose-limiting toxicity and incidence of adverse events. The secondary end points are the objective response rate and disease control rate. This study aims to expand the indication of Ad-REIC by assessing its safety and efficacy in patients with HCC or liver metastasis of pancreatic cancer.

DOI： 10.2217/fon-2019-0115

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Language：English  

Although cancers are often removed by surgery and treated by chemotherapy and/or radiation therapies, they often reoccur following treatment due to the presence of resistant residual cells such as cancer stem cells (CSCs). CSCs are characterized by their self-renewal, pluripotency, and tumorigenicity properties, and are promising therapeutic targets for the complete therapy of cancers; however, the number of CSCs in cancer tissue is typically too small to investigate fully. We have previously reported that CSCs could be established from induced pluripotent stem cells (iPSCs) using a conditioned medium during cancer cell culture. In the present study, mouse embryonic stem cells (mESCs) were observed to be converted to CSCs (mES-CSCs). This demonstrated that CSC induction does not exclusively occur following gene editing in somatic cells, and that conditioned medium from cancer cells may contain factors that can induce CSCs. Therefore, not only iPSCs but also mESCs, were demonstrated to be able to produce CSCs as one of the potentials of pluripotency of stem cells, suggesting that the conversion to CSCs is not specific to iPSCs. The resultant mES-CSCs would be also useful to generate tissue specific cancers and these naturally occurring cancers can contribute to drug screenings, but also undergo further investigation in order to reveal cancer mechanisms.

DOI： 10.3892/ol.2019.10614

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Metastasis develops when cancer cells spread from the primary site of a malignant tumor to the surrounding and distant tissues, and it is the most critical problem in cancer treatment. Our group developed cancer stem cells (CSCs) from induced pluripotent stem cells (iPSCs) in the presence of a conditioned medium (CM) of cancer-derived cells. The CSCs were characterized by the formation of malignant tumors in vivo, followed by metastasis. In this study, CSCs converted from mouse iPSCs in the presence of CM from hepatocellular carcinoma (HCC) cell line Huh7 cells. These converted cells (miPS-Huh7cm cells) were established as the metastatic cells. The generated CSCs were injected into the liver or spleen of nude mice. Almost one month after transplantation, the tumors were excised, and the primary cultured cells derived from the malignant tumors and metastatic nodules were evaluated by stemness and metastatic markers to compare their differences. The miPS-Huh7cm cells exhibited metastatic potential, and efficiently formed malignant tumors with lung and/or liver lesions in vivo, whereas the injected miPS formed teratoma. The primary cultured cells derived from the malignant tumors and metastatic nodules sustained the expression of stemness markers, such as Nanog, Klf4 and c-Myc, and acquired cancer stem markers, such as CD90, CD44 and ALDH1. Simultaneously, the expression of metastatic markers, such as Slug, Twist1 and vimentin, in primary cells derived from the malignant tumors, was higher than in metastatic nodules. The CSCs derived from iPSCs, forming malignant tumors and displaying high metastasis, will provide a good animal model to study the mechanisms of metastasis.

DOI： 10.3390/bioengineering6030073

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Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

The cancer stem cell (CSC) hypothesis suggests that tumors are sustained exclusively by a small population of the cells with stem cell properties. CSCs have been identified in most tumors and are responsible for the initiation, recurrence, and resistance of different cancers. In vitro CSC models will be of great help in revisiting the mechanism of cancer development, as well as the tumor microenvironment and the heterogeneity of cancer and metastasis. Our group recently described the generation of CSCs from induced pluripotent stem cells (iPSCs), which were reprogrammed from normal cells, and/or embryonic stem cells (ESCs). This procedure will improve the understanding of the essential niche involved in cancer initiation. The composition of this cancer-inducing niche, if identified, will let us know how normal cells convert to malignant in the body and how, in turn, cancer prevention could be achieved. Further, once developed, CSCs demonstrate the ability to differentiate into endothelial cells, cancer-associated fibroblasts, and other phenotypes establishing the CSC niche. These will be good materials for developing novel cancer treatments. In this protocol, we describe how to handle mouse iPSCs/ESCs and how to choose the critical time for starting the conversion into CSCs. This CSC generation protocol is essential for understanding the role of CSC in cancer initiation and progress.

DOI： 10.3390/mps2030071

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Language：English   Publisher：MOSBY-ELSEVIER  

DOI： 10.1016/j.surg.2018.12.012

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Daclatasvir (DCV) + asunaprevir (ASV) combination therapy has become available for patients with hepatitis C virus (HCV) serogroup 1 infection. We studied the efficacy of this therapy by focusing on the factors associated with sustained virological responses (SVR) including resistance-associated variants (RAVs) and mixed infection of different HCV genotypes. We enrolled 951 HCV serogroup 1-positive patients who received this combination therapy at our hospital or affiliated hospitals. The presence of RAVs in non-structural (NS) regions 3 and 5A was analyzed by direct sequencing. HCV genotypes were determined by PCR with genotype-specific primers targeting HCV core and NS5B regions. SVR was achieved in 91.1% of patients. Female sex, age > 70 years, and RAVs were significantly associated with non-SVR (p<0.01 for all). Propensity score-matching results among the patients without RAVs regarding sex, age, and fibrosis revealed that mixed HCV infection determined by HCV NS5B genotyping showed significantly lower SVR rates than 1B-mono infection (p=0.02). Female sex and RAVs were significant factors associated with treatment failure of this combination therapy for patients with HCV serogroup 1 infection. Mixed HCV infection other than 1B-mono infection would be useful for predicting treatment failure.

DOI： 10.18926/AMO/56178

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DOI： 10.1002/ccr3.1588

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Previously, we have succeeded in converting induced pluripotent stem cells (iPSCs) into cancer stem cells (CSCs) by treating the iPSCs with conditioned medium of Lewis lung carcinoma (LLC) cells. The converted CSCs, named miPS-LLCcm cells, exhibited the self-renewal, differentiation potential, and potential to form malignant tumors with metastasis. In this study, we further characterized miPS-LLCcm cells both in vivo and in vitro. The tumors formed by subcutaneous injection showed the structures with pathophysiological features consisting of undifferentiated and malignant phenotypes generally found in adenocarcinoma. Metastasis in the lung was also observed as nodule structures. Excising from the tumors, primary cultured cells from the tumor and the nodule showed self-renewal, differentiation potential as well as tumor forming ability, which are the essential characters of CSCs. We then characterized the epigenetic regulation occurring in the CSCs. By comparing the DNA methylation level of CG rich regions, the differentially methylated regions (DMRs) were evaluated in all stages of CSCs when compared with the parental iPSCs. In DMRs, hypomethylation was found superior to hypermethylation in the miPS-LLCcm cells and its derivatives. The hypo- and hypermethylated genes were used to nominate KEGG pathways related with CSC. As a result, several categories were defined in the KEGG pathways from which most related with cancers, significant and high expression of components was PI3K-AKT signaling pathway. Simultaneously, the AKT activation was also confirmed in the CSCs. The PI3K-Akt signaling pathway should be an important pathway for the CSCs established by the treatment with conditioned medium of LLC cells.

DOI： 10.1016/j.tranon.2018.03.001

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

Background and Aim: It remains unclear whether primary biliary cholangitis (PBC) represents a risk factor for secondary osteoporosis.
Methods: A case-control study was conducted to examine bone mineral density and bone turnover markers in middle-aged postmenopausal PBC patients without liver cirrhosis. We compared the incidence of low bone mineral density between propensity-score matched subgroups of PBC patients and healthy controls and investigated the mechanisms underlying unbalanced bone turnover in terms of the associations between bone turnover markers and PBC-specific histological findings.
Result: Our analysis included 128 consecutive PBC patients, all postmenopausal women aged in their 50s or 60s, without liver cirrhosis or fragility fracture at the time of PBC diagnosis. The prevalence of osteoporosis was significantly higher in the PBC group than in the control group (26% vs 10%, P = 0.015, the Fisher exact probability test). In most PBC patients (95%), the level of bone-specific alkaline phosphatase was above the normal range, indicating increased bone formation. On the other hand, the urine type I collagen-cross-linked N-telopeptide showed variable levels among our PBC patients, indicating unbalanced bone resorption. Advanced fibrosis was associated with low bone turnover. Lobular cholestasis, evaluated as aberrant keratin 7 expression in hepatocytes, showed significant negative correlations with bone formation and resorption, indicating low bone turnover.
Conclusion: Our results show that, compared with healthy controls, even non-cirrhotic PBC patients have significantly higher risk of osteoporosis. Moreover, lobular cholestasis was associated with low bone turnover, suggesting this feature of PBC may itself cause secondary osteoporosis in PBC patients.

DOI： 10.1111/jgh.13746

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Cancer Intelligence  

A 68-year-old Japanese woman underwent radiotherapy for gastric lymphoma. Although lymphangiectasia was sparsely observed in the second portion of the duodenum before radiotherapy, the number of pinpoint white spots obviously increased after the treatment. Although the duodenal lymphangiectasia gradually progressed, the patient had no features of protein-losing enteropathy. This case highlights the importance of endoscopic observation of the duodenum after irradiation to the abdomen as radiotherapy may secondarily cause intestinal lymphangiectasia.

DOI： 10.3332/ecancer.2017.752

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Cancer-associated fibroblasts (CAFs) are one of the most prominent cell types in the stromal compartment of the tumor microenvironment. CAFs support multiple aspects of cancer progression, including tumor initiation, invasion, and metastasis. The heterogeneous nature of the stromal microenvironment is attributed to the multiple sources from which the cells in this compartment originate. The present study provides the first evidence that cancer stem cells (CSCs) are one of the key sources of CAFs in the tumor niche. We generated CSC-like cells by treating mouse induced pluripotent stem cells with conditioned medium from breast cancer cell lines. The resulting cell population expressed both CSC and pluripotency markers, and the sphere-forming CSC-like cells formed subcutaneous tumors in nude mice. Intriguingly, these CSC-like cells always formed heterogeneous populations surrounded by myofibroblast-like cells. Based on this observation, we hypothesized that CSCs could be the source of the CAFs that support tumor maintenance and survival. To address this hypothesis, we induced the differentiation of spheres and purified the myofibroblast-like cells. The resulting cells exhibited a CAF-like phenotype, suggesting that they had differentiated into the subpopulations of cells that support CSC self-renewal. These findings provide novel insights into the dynamic interplay between various microenvironmental factors and CAFs in the CSC niche.

DOI： 10.1038/s41598-017-07144-5

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS INC  

Purpose: Despite the widespread use of percutaneous endoscopic gastrostomy (PEG) tubes, their placement may be associated with a variety of complications, including gastrocolic fistula. Materials and Methods: In total, seven high-risk individuals diagnosed using computed tomography (CT)-gastrocolonography (GC) underwent laparoscopic-assisted PEG (LAPEG) placement. Study endpoints included the success of LAPEG under local anesthetic and intravenous sedation, inability to thread the PEG tube, the eventual tube location, the number of tube adjustments needed, adverse events, the operating time, and PEG tube-related infection. Results: In total, 135 PEG procedures were performed during this study. Successful CT-GC was achieved in all 135 patients, and we successfully used a standard PEG technique to place the gastrostomy tube in 128 patients (95%). In seven patients (5%), the LAPEG technique was used because the transverse colon became interposed between the abdominal wall and the anterior wall of the stomach. LAPEG procedure-related minor complications were observed in two patients. Conclusions: LAPEG combined with CT-GC can be used for patients with difficult anatomical orientations and may minimize the risk of complications in PEG placement.

DOI： 10.1080/08941939.2016.1232451

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier Ltd  

Introduction Proton pump inhibitor (PPI) use is associated with the development of fundic gland polyps (FGPs)
discontinuing PPIs is associated with regression of FGPs. Here, we report a rare case of non-respondent FGPs after discontinuation of PPI that were successfully treated using an argon plasma coagulator (APC). Presentation of case We present the case of a 68-year-old woman with a history of polycytheamia vera. She also had gastroesophageal reflux disease (GERD) and had been taking 10 mg of omeprazole daily for the past three years. Esophagogastroduedenoscopy (GF) revealed over 100 pedunculated polyps in the gastric body and fundus. Histological examination of the specimens showed dilated oxyntic glands with flattened parietal and mucous cells. Based on these findings and the clinical history, a diagnosis of FGPs was made. Omeprazole use was then discontinued. Repeat GF performed 6 months and 1 year later showed a significant increase in the number and size of the polyps. APC treatment was performed every 6 months for 3 years. Further GF showed a significant decrease in the number and size of the FGPs 4 years after discontinuing PPI. Discussion We conclude that PPI use is a strong risk factor for the development of FGPs and discontinuing PPI is associated with regression of FGPs, but not in patients with polycythaemia vera. However, the mechanism involved in the interaction between FGP and polycytheamia vera remains unknown. Conclusion Non-respondent FGPs after discontinuation of PPI use may be successfully treated using APC.

DOI： 10.1016/j.ijscr.2017.02.039

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Background and Purpose: We aimed to determine the success rate and any complications using a percutaneous approach to the femoral vein (FV) for placement of a totally implantable access port (TIVAP), with a preoperative assessment of the femoral and iliac veins using computed tomography-venography (CT-V).
Methods: Aprospective study of 72 patients was conducted where placement of a TIVAP was attempted via the right FV, with the port placed in the anterior thigh, when subclavian vein or jugular vein access was contraindicated. Preoperative assessment of the femoral venous plexus was performed with CT-V in 72 patients.
Results: CT-V success was achieved in 72 of 72 patients (100%). The average distance between the inguinal ligament and the saphenofeomral (FV-GSV) junction was 42.8 +/- 12.9 mm. The FV approach had a 97% successful cannulation rate. Two patients had a thrombosis in either the femoral vein or the great saphenous vein. One procedural complication (1.4%) and one initial complication (1.4%) occurred. Late complications occurred in four patients (5.7%).
Conclusions: The percutaneous FV approach with CT-V guidance is an option for patients with multiple central venous cannulations, as well as those with bilateral breast cancer, or those undergoing hemodialysis. (C) 2016 Wiley Periodicals, Inc.

DOI： 10.1002/jso.24441

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BMJ PUBLISHING GROUP  

Background Oxidative stress may play pathogenic roles in the mechanisms underlying chronic hepatitis C (CHC). The impact of excessive oxidative stress and iron dysregulation on the development of hepatocellular carcinoma (HCC) after interferon therapy has not been established.
Methods We investigated the impact of oxidative stress and iron deposition on HCC development after therapy with pegylated interferon (PegIFN)+ribavirin in CHC patients. Systemic and intracellular iron homeostasis was evaluated in liver tissues, peripheral blood mononuclear cells and sera.
Results Of 203 patients enrolled, 13 developed HCC during the 5.6-year follow-up. High hepatic 8-hydroxy-2-deoxyguanosine (8-OHdG) levels were significantly associated with HCC development in multivariate analysis (p=0.0012) which was also significantly correlated with severity of hepatic iron deposition before therapy (p&lt;0.0001). Systemic and intracellular iron regulators of hepcidin and F-box and leucine-rich repeat protein 5 (FBXL5) expression levels were significantly suppressed in CHC patients (p=0.0032 and p=0.016, respectively) despite their significantly higher levels of serum iron and ferritin compared with controls. However, intracellular iron regulators of FBXL5 and iron regulatory proteins were regulated in balance with hepatic iron deposition. Significant correlations were observed among IL-6, bone morphogenetic protein 6, hepcidin and ferroportin, as regards systemic iron regulation.
Conclusions Measurement of hepatic oxidative stress before antiviral therapy is useful for the prediction of HCC development after interferon therapy. Low baseline levels of the intracellular iron regulators of FBXL5 in addition to a suppressed hepcidin level might be associated with severe hepatic iron deposition in CHC patients.

DOI： 10.1136/jclinpath-2015-203215

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DOI： 10.1002/ccr3.504

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：INT MEDICAL PRESS LTD  

Background: The efficacy of a direct-acting antiviral agent (DAA) is compromised by the development of drug resistance. The associations between resistance-associated virus (RAV) and therapeutic outcomes have not been well-understood.
Methods: A total of 30 patients with HCV genotype-1b were enrolled and treated for 24 weeks with asunaprevir (ASV) and daclatasvir (DCV). Viral sequences in non-structural (NS) regions 3 and 5A in serum and liver tissue before treatment were examined with direct sequencing, next-generation sequencing (NGS) and the PCR-invader method to evaluate the importance of drug-resistance in the prediction of the outcomes of ASV plus DCV therapy.
Results: Of 30 patients (22 treatment-naive patients, 2 interferon-intolerant patients and 6 non-responders), 25 patients (83.3%) achieved sustained virological response (SVR) 24 weeks after the treatment. Viral breakthrough occurred in three treatment-naive patients and one non-responder. One treatment-naive patient experienced viral relapse. Among 25 patients without RAV, 24 obtained SVR, whereas 5 patients had RAV with a 1.3 to 88% frequency, resulting in various therapeutic outcomes. As for HCV compartments, similar RAVs were detected in serum and liver tissue for a patient obtaining SVR despite HCV NS5A Y93H and another developed viral breakthrough although no RAV was detected. Direct sequencing could not detect RAVs in low frequency (1.3 to 12%) for three of four patients.
Conclusions: Low frequency of RAVs might not affect the outcomes of ASV plus DCV therapy. Deep sequencing and PCR-invader methods can detect clinically significant RAVs for ASV plus DCV therapy.

DOI： 10.3851/IMP2976

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：E-CENTURY PUBLISHING CORP  

Pancreatic ductal adenocarcinoma (PDAC) is the most representative form of pancreatic cancers. PDAC solid tumours are constituted of heterogeneous populations of cells including cancer stem cells (CSCs), differentiated cancer cells, desmoplastic stroma and immune cells. The identification and consequent isolation of pancreatic CSCs facilitated the generation of genetically engineered murine models. Nonetheless, the current models may not be representative for the spontaneous tumour occurrence. In the present study, we show the generation of a novel pancreatic iPSC-converted cancer stem cell lines (CSCcm) as a cutting-edge model for the study of PDAC. The CSCcm lines were achieved only by the influence of pancreatic cancer cell lines conditioned medium and were not subjected to any genetic manipulation. The xenografts tumours from CSCcm lines displayed histopathological features of ADM, PanIN and PDAC lesions. Further molecular characterization from RNA-sequencing analysis highlighted primary culture cell lines (1st CSCcm) as potential candidates to represent the pancreatic CSCs and indicated the establishment of the pancreatic cancer molecular pattern in their subsequent progenies 2nd CSCcm and 3rd CSCcm. In addition, preliminary RNA-seq SNPs analysis showed that the distinct CSCcm lines did not harbour single point mutations for the oncogene Kras codon 12 or 13. Therefore, PDAC-CSCcm model may provide new insights about the actual occurrence of the pancreatic cancer leading to develop different approaches to target CSCs and abrogate the progression of this fatidic disease.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier Ltd  

Introduction Rhabdomyolysis associated with the use of pregabalin or azithromycin has been demonstrated to be a rare but potentially life-threatening adverse event. Here, we report an extremely rare case of rhabdomyolysis with purpura in a patient who had used pregabalin and azithromycin. Presentation of case We present the case of a 75-year-old woman with a history of fibromyalgia who was admitted with mild limb weakness and lower abdominal purpura. She was prescribed pregabalin (75 mg, twice daily) for almost 3 months to treat chronic back pain. Her medical history revealed that 3 days before admission, she began experiencing acute bronchitis and was treated with a single dose of azithromycin (500 mg). She had developed rapid onset severe myalgia, mild whole body edema, muscle weakness leading to gait instability, abdominal purpura and tender purpura on the lower extremities. Laboratory values included a white blood cell count of 25,400/mL and a creatinine phosphokinase (CPK) concentration of 1250 IU/L. Based on these findings and the patient's clinical history, a diagnosis of pregabalin- and azithromycin-induced rhabdomyolysis was made. Discussion The long-term use of pregabalin and the initiation azithromycin therapy followed by a rapid onset of rhabdomyolysis is indicative of a drug interaction between pregabalin and azithromycin. Conclusion We report an extremely rare case of rhabdomyolysis with purpura caused by a drug interaction between pregabalin and azithromycin. However, the mechanisms of the interactions between azithromycin on the pregabalin are still unknown.

DOI： 10.1016/j.ijscr.2016.07.007

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Elderly patients with chronic hepatitis C cannot tolerate standard combination therapy of peginterferon and ribavirin, which remains the backbone of therapy in many countries, including Japan. The efficacy and safety of low-dose peginterferon -2b in combination with low and escalating doses of ribavirin in older patients with high viral load genotype 1 were investigated in this randomized controlled trial. Thirty-two patients (age 60 years) were randomized into standard (group 1) or low (group 2) doses of peginterferon -2b in combination with low and escalating doses of ribavirin. Patients were evaluated for safety and efficacy of treatment. There was a higher virological response rate in group 1 than in group 2. However, the response in men was higher than in women in the early treatment phase and 24 weeks after treatment (P=0.008). There was no significant difference between the two groups in the virological response rate in men and women. Completion of therapy was higher in group 2 than in group 1 (31% vs. 13%, P=0.200). Dose modification of ribavirin was less frequent in group 2 than in group 1 (69% vs. 88%, P=0.200). These data suggest that combination therapy with low-dose peginterferon plus low and escalating doses of ribavirin may be safer in older patients than that with standard dose peginterferon, without impairing the treatment response. J. Med. Virol. 87:2082-2089, 2015. (c) 2015 Wiley Periodicals, Inc.

DOI： 10.1002/jmv.24276

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OKAYAMA UNIV MED SCHOOL  

The effectiveness of extending treatment duration as response guided therapy was previously reported for chronic hepatitis C (CHC) genotype 1, but is still controversial for genotype 2. The present study is a retrospective cohort study to investigate the effectiveness of extending treatment duration in therapy with pegylated interferon and ribavirin for patients with CHC genotype 2 by focusing on the timing at which patients obtained undetectable HCV RNA. A total of 306 patients who obtained undetectable HCV RNA by week 24 of treatment and completed 24 weeks of treatment were enrolled. Rapid virological response (RVR) to standard therapy was achieved by 122 patients (51%), and 89% of them obtained sustained virological response (SVR), while 69% of non-RVR patients achieved SVR. Non-RVR patients with undetectable HCV RNA at week 8, and insufficient adherence &lt; 80% pegylated interferon and ribavirin during the first 24 weeks, significantly improved their SVR rate by extended therapy. Among patients receiving extended therapy, drug adherences did not differ between SVR and non-SVR patients, indicating that extending treatment duration might compensate for insufficient antiviral effects due to insufficient drug adherences. This finding might be useful in creating a guideline for extending treatment duration for patients with CHC genotype 2.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Background. Post orthotopic liver transplantation (OLT) viral hepatitis is an immunological condition where immune cells induce hepatitis during conditions of immune-suppression. The immune-regulatory programmed death-1 (PD-1)/PD-ligand 1 system is acknowledged to play important roles in immune-mediated diseases. However, the PD-1/PD-L2 interaction is not well characterized, with PD-L2 also exhibiting an immunostimulatory function. We hypothesized that this atypical molecule could affect the recurrence of post-OLT hepatitis. To test this hypothesis, we conducted immunohistochemical staining analysis and in vitro analysis of PD-L2. Methods. The expression of PD-L2 was evaluated in liver biopsy specimens from patients with chronic hepatitis B (n = 15), post-OLT hepatitis B (n = 8), chronic hepatitis C (n = 48), and post-OLT hepatitis C (CH-C-OLT) (n = 14). The effect of calcineurin inhibitors (CNIs) and hepatitis C virus (HCV) on PD-L2 expression was investigated in hepatoma cell lines. Results. The PD-L2 was highly expressed on CH-C-OLT hepatocytes. Treatment of hepatoma cell lines with CNIs resulted in increased PD-L2 expression, especially in combination with HCV core or NS3 protein. Transfection of cell lines with PD-L2 containing plasmid resulted in high intercellular adhesion molecule-1 (ICAM-1) expression, which might enhance hepatitis activity. Conclusions. The PD-L2 is highly expressed on CH-C-OLT hepatocytes, whereas HCV proteins, in combination with CNIs, induce high expression of PD-L2 resulting in elevated expression of ICAM-1. These findings demonstrate the effect of CNIs on inducing PD-L2 and subsequent ICAM-1 expression, effects that may produce inflammatory cell infiltration in post-OLT hepatitis C.

DOI： 10.1097/TP.0000000000000572

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OKAYAMA UNIV MED SCHOOL  

A predictive marker of the rapid progression to hepatic failure is desired for patients with asymptomatic primary biliary cirrhosis (aPBC). We performed a systematic cohort analysis of 101 patients diagnosed as having aPBC and the rapid progression to liver failure in some, by focusing on cholestasis. Cholestasis was assessed by aberrant keratin7 (K-7) expressions in the patients' hepatocytes. Intralobular expressions of K-7 were found in 9 of the 101 patients. The grades of K-7 expression were significantly associated with the levels of alanine aminotransferase, alkaline phosphatase, and total bilirubin at the time of diagnosis, but not with bile duct loss or cholestasis. Stepwise logistic regression analysis revealed that high grades of K-7 expression correlated positively with high levels of total bilirubin. During the follow-up period, 8 patients developed jaundice, and the mean period until the development of jaundice was 5.2 years. The proportional hazards models for the risk of developing jaundice identified a high grade of aberrant K-7 expression in hepatocytes as the only significant risk factor. Aberrant K-7 expression in hepatocytes can be used as an additional marker to predict rapid progression to liver failure in patients with aPBC at the time of diagnosis.

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

It has been reported that elderly patients with chronic hepatitis C infection cannot tolerate standard combination therapy. In this randomized, controlled trial, the efficacy and safety of peginterferon alpha-2b plus a low and escalating dose of ribavirin in chronic hepatitis C patients with high viral load genotype 1 were investigated. Sixty-two patients were randomized into combination therapy with standard ribavirin dosing (group 1) or low and escalating ribavirin dosing (group 2). Patients were evaluated for safety and efficacy of treatment. There was no significant difference in the prevalence of virological response between the groups throughout the treatment as well as 24 weeks after treatment. However, the response in patients 60 years of age was higher in group 1 than in group 2 at early treatment phase (P=0.015). The prevalence of completion of therapy in patients 60 years of age tended to be higher in group 2 than in group 1 (50% vs. 0%, P=0.055). There was no significant difference in dose modification of peginterferon alpha-2b between the groups. However, dose modification of ribavirin was significantly more frequent in group 1 than in group 2 (60% vs. 24%, P=0.005). These data suggest that combination therapy with low and escalating dosing of ribavirin may be safer in elderly patients than that with standard dosing of ribavirin without impairing the treatment response. J. Med. Virol. 87:625-633, 2015. (c) 2015 Wiley Periodicals, Inc.

DOI： 10.1002/jmv.24097

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Background & Aims: Roles of alcohol consumption in non-alcoholic fatty liver disease are still controversial, although several cross-sectional studies have suggested the beneficial effect of light to moderate drinking on fatty liver. We analyzed the longitudinal relationship between drinking pattern and fatty liver.
Methods: We included 5297 Japanese individuals (3773 men and 1524 women) who underwent a baseline study in 2003 and follow-up at least once from 2004 to 2006. Generalized estimating equation was used to estimate any association between drinking pattern and fatty liver assessed by ultrasonography.
Results: At baseline, 1179 men (31.2%) and 235 women (15.4%) had fatty liver; 2802 men (74.2%) and 436 women (28.6%) reported alcohol consumption. At the latest follow-up, 348 of 2594 men (13.4%) and 101 of 1289 women (7.8%) had newly developed fatty liver; 285 of 1179 men (24.2%) and 70 of 235 women (29.8%) demonstrated a remission of fatty liver. In men, drinking 0.1-69.9 g/week (odds ratio, 0.79 [95% confidence interval, 0.68-0.90]), drinking 70.0-139.9 g/week (0.73 [0.63-0.84]), drinking 140.0-279.9 g/week (0.69 [0.60-0.79]), and drinking &gt;= 280.0 g/week (0.68 [0.58-0.79]) were inversely associated with fatty liver after adjusting for obesity, exercise, and smoking. In women, drinking 0.1-69.9 g/week (0.71 [0.52-0.96]) and drinking 70.0-139.9 g/week (0.67 [0.45-0.98]) were inversely associated with fatty liver after the adjustment.
Conclusions: Light to moderate alcohol consumption, or even somewhat excessive amounts especially in men, was likely to protect most individuals against fatty liver over time. (C) 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

DOI： 10.1016/j.jhep.2014.11.025

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Background and AimsSerum glycans have been reported to be promising diagnostic markers for many inflammatory diseases and cancers. The aims of this study were to investigate whole glycan expression in patients with non-alcoholic fatty liver diseases and to evaluate the potential use of glycan profiles as new clinical biomarkers to distinguish non-alcoholic steatohepatitis (NASH) from simple steatosis (SS).
MethodsWe collected sera from 42 histologically proven NASH and 15 SS patients prior to treatment. Serum glycan profiles were measured by comprehensive, quantitative, high-throughput glycome analysis, and diagnostic values of serum glycans for NASH prediction were examined.
ResultsAmong the 41 serum glycans examined, the expression levels of 8 glycans in NASH were significantly higher than those of SS. Out of these eight glycans, three glycans (m/z 1955, 2032, and 2584) showed high areas under the receiver operating characteristic curve (0.833, 0.863, and 0.866, respectively) for distinguishing NASH from SS. In multivariate analyses with clinical parameters and serum glycans, these three glycans were significant predictive factors for distinguishing NASH from SS. The odds ratio of m/z 1955, 2032, and 2584 were 48.5, 6.46, and 11.8, respectively. These glycans also correlated significantly with lobular inflammation, ballooning, and fibrosis, but not with steatosis.
ConclusionWe clearly demonstrated whole-serum glycan profiles in NASH patients, and the feasibility of serum glycans (m/z 1955, 2032, and 2584) as new noninvasive biomarkers for distinguishing NASH from SS.

DOI： 10.1111/jgh.12726

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Language：English   Publishing type：Research paper (scientific journal)  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier Ltd  

Introduction: Protein induced by vitamin K absence/antagonist-II (PIVKA-II) is an abnormal protein, and several reports have demonstrated the efficacy of PIVKA-II in the diagnosis of hepatocellular carcinoma (HCC). We report an extremely rare case of adenocarcinoma of the colon with a high serum PIVKA-II level. Presentation of Case: A 95-year-old woman presented with right lower quadrant pain and appetite loss. An abdominal computed tomography scan and ultrasonography showed an ascending colon tumor and multiple metastatic tumors in the liver. The serum level of PIVKA-II was extremely high, 11,900 ng/mL. Colonoscopic examination revealed a tumor accompanied by an ulcer in the ascending colon, which was highly suspicious for malignancy. Multiple biopsies showed well-differentiated adenocarcinoma of the colon, which was evaluated as colon cancer, stage IV. PIVKA-II-productive colon cancer was confirmed. Chemotherapy with TS-1 was administered. The patient died 3 months after initial admission. Discussion: The expression of PIVKA-II was detected in non-cancer areas, with non-specific expression observed in plasma cells in our case. There might be some possibility that hepatoid differentiation exists in other regions of the colon tumor or in the liver tumor, parenchymal cells or lung metastases, which were composed of PIVKA-II-positive and AFP-negative cells. Conclusion: To the best of our knowledge, high serum levels of PIVKA-II resulting from colon adenocarcinoma have not been reported previously. We report this rare case together with a review of the literature.

DOI： 10.1016/j.ijscr.2014.11.072

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier Ltd  

Introduction Rhabdomyolysis associated with the use of pravastatin has been demonstrated to be a rare but potentially life-threatening adverse effect of statins. Here, we report a rare case of rhabdomyolysis and purpura fulminans in a patient who had used pravastatin and developed chronic renal failure (CRF) necessitating the initiation of dialysis. Presentation of case We present the case of an 86-year-old man with chronic kidney disease (CKD) treated with dialysis who was admitted with back pain. He was prescribed and took pravastatin for almost 3 years to treat hyperlipidemia. He received hemodialysis therapy 7 times prior to presentation. Laboratory values included a serum creatine concentration of 6.6 mg/dl and a creatinine phosphokinase (CPK) concentration of 2350 IU/L. An abdominal computed tomography scan showed swollen muscles with reduced muscle density and air density in the multifidus muscle. Two days after admission, he had large, tender ecchymotic lesions and purpuric progressive skin necrosis over the back, abdomen, and upper and lower extremities. The patient died 6 days after the initial admission due to disseminated intravascular coagulation (DIC). Based on these findings and the clinical history, a diagnosis of pravastatin-induced rhabdomyolysis and purpura fulminans was made. Discussion The long-term use of statin therapy and the initiation of dialysis therapy due to ESRD, followed by a rapid onset of rhabdomyolysis within 6 days, is indicative of an elevated statin concentration. Conclusion We report an extremely rare case of pravastatin-induced rhabdomyolysis and purpura fulminans with DIC in a patient with CRF.

DOI： 10.1016/j.ijscr.2015.01.042

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Baishideng Publishing Group Co  

AIM: To investigate factors that accurately predict hepatocellular carcinoma (HCC) development after antiviral therapy in chronic hepatitis C (CHC) patients. METHODS: CHC patients who received pegylated interferon and ribavirin were enrolled in this cohort study that investigated the ability of alpha-fetoprotein (AFP) to predict HCC development after interferon (IFN) therapy. RESULTS: Of 1255 patients enrolled, 665 developed sustained virological response (SVR) during mean follow-up period of 5.4 years. HCC was occurred in 89 patients, and 20 SVR patients were included. Proportional hazard models showed that HCC occurred in SVR patients showing AFP ≥ 5ng/mL before therapy and in non-SVR patients showing AFP ≥ 5ng/mL before and 1year after therapy besides older age, and low platelet counts. SVR patients showing AFP ≥ 5ng/mL before therapy and no decrease in AFP to &lt
5ng/mL 1year after therapy had significantly higher HCC incidence than non-SVR patients showing AFP ≥ 5ng/ mL before therapy and decreased AFP (P = 0.043). AFP ≥ 5ng/mL before therapy was significantly associated with low platelet counts and high values of alanine aminotransferase (ALT) in stepwise logistic regression analysis. After age, gender, platelet count, and ALT was matched by propensity score, significantly lower HCC incidence was shown in SVR patients showing AFP &lt
5ng/mL before therapy than in those showing AFP ≥ 5ng/mL. CONCLUSION: The criteria of AFP &lt
5ng/mL before and 1year after IFN therapy is a benefical predictor for HCC development in CHC patients.

DOI： 10.4254/wjh.v7.i19.2220

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OKAYAMA UNIV MED SCHOOL  

Nursing support might help patients with chronic hepatitis C (CHC) remain in good mental and physical condition during interferon (IFN) therapy. However, the effects of nursing support have not been studied adequately in this context. This case-control study evaluated the effects of nursing support during IFN therapy. Twenty-four CHC patients who received pegylated IFN and ribavirin were enrolled. Nurses advised patients on the maintenance of their mental and physical condition at weekly visits, based on the results of written questionnaires. An additional 24 patients who received IFN therapy without nursing support and who were matched for age, sex, platelet count, viral serogroup and IFN regimen were selected with propensity score matching as controls. The patients with nursing support during IFN therapy achieved higher sustained virological responses (79%) than those without nursing support (58%). Adherence to the IFN and ribavirin regimens at 24 weeks of therapy were slightly higher in the patients with nursing support than those without it, but these differences were not statistically significant. Adherence to ribavirin after 24 weeks of therapy was significantly higher in those with nursing support than those without it (93% and 66%, p = 0.045). These results suggested that nursing support services could contribute to the virological responses of CHC patients by promoting drug-regimen adherence.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OKAYAMA UNIV MED SCHOOL  

It is not known how the immune system targets hepatitis C virus (HCV)-infected HLA-mismatched hepatocytes under immune-suppressed conditions after orthotopic liver transplantation (OLT). In addition, the relationship between the HCV-specific immune response and IL28B variants as predictors of HCV clearance has not been well-characterized. We determined the IL28B polymorphisms for 57 post-OLT HCV carriers, and we assessed the HCV-specific immune responses by measuring the peripheral blood mononuclear cell-derived HCV-specific interferon-gamma (IFN-gamma) response using an enzyme-linked immunospot assay. At 1-3 years after OLT, patients with no active hepatitis showed higher total spots on the immunospot assay. At &gt; 3 years after OLT, patients with resolved HCV showed higher levels of core, NS3, NS5A, and total spots compared to the chronic hepatitis patients. The IL28B major genotype in the donors correlated with higher spot counts for NS5A and NS5B proteins at 1-3 years after OLT. In the post-OLT setting, the HCV-specific immune response could be strongly induced in patients with no active hepatitis with an IL28B major donor or sustained virological response. Strong immune responses in the patients with no active hepatitis could only be maintained for 3 years and diminished later. It may be beneficial to administer IFN treatment starting 3 years after OLT, to induce the maximum immunological effect.

DOI： 10.18926/AMO/52898

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：INFORMA HEALTHCARE  

Objective: To determine the success rate and complications of using the external jugular vein (EJV) for central venous access with a preoperative estimate of the detailed anatomical orientation of the cervical venous plexus using computed tomography venography (CT-V). Design: Prospective, observational human study. Setting: Surgical intensive care unit. Patients: Fifty-two patients who were undergoing EJV cannulations with CT-V using a Multidetector Helical 16-section CT (MDCT). Intervention: The preoperative anatomical estimation of the cervical venous plexus was performed with CT-V using an MDCT. In particular, the angulation between the EJV and the right subclavian vein (SCV) was measured. The anatomical abnormalities and the angulation between the EJV and the anterior jugular vein (AJV), transverse cervical vein (TCV), and suprascapular vein (SSV) were estimated. Measurements and Main Results: The success of CT-V was achieved in 52 of 52 patients (100%). The mean angulation between the right EJV and the right SCV was 144 +/- 36 degrees in the obtuse-angle cases (88%) and 72 +/- 28 degrees in the sharp-angle cases (12%). A plexus of veins under the clavicle was most commonly responsible for insertion of the central venous catheter (CVC). The EJV approach resulted in a 93% rate of successful cannulations. No complications of pneumothorax or carotid artery puncture occurred during insertion procedures. Conclusions: The EJV route is associated with comparable technical success and lower major procedural complication. The EJV approach with CT-V guidance is an option as the initial method when central venous cannulation must be performed under suboptimal conditions.

DOI： 10.3109/08941939.2013.865818

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MOSBY-ELSEVIER  

DOI： 10.1016/j.surg.2012.12.006

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

Background and Purpose. The objective of this study was to determine the success rate and complications of using the percutaneous approach of the external jugular vein (EJV) for placement of a totally implantable venous-access port (TIVAP) with a preoperative estimate of the detailed anatomical orientation of the cervical venous plexus using computed tomography venography (CT-V).
Methods. A prospective cohort study of 45 patients in whom placement of a TIVAP was attempted via the right EJV was conducted. The preoperative anatomical estimation of the cervical venous plexus was performed with CT-V using a Multidetector Helical 16-section CT. The angulation between the right EJV and the right subclavian vein, anterior jugular vein, transverse cervical vein, and suprascapular vein was estimated.
Results. CT-V success was achieved in 45 of 45 patients (100 %). A plexus of veins under the clavicle was most commonly responsible for the insertion of the central venous catheter. The EJV approach resulted in a successful cannulation rate of 93 %. No initial complications of pneumothorax or carotid artery puncture occurred during insertion procedures. Late complications occurred in three patients. These included one port erosion (2 %), one catheter occlusion (2 %), and one wound hematoma (2 %). Catheter-related infections were observed in one patient (2 %).
Conclusions. The percutaneous EJV approach with CT-V guidance is an optional method for patients with multiple central venous cannulations, those in hemodialysis, or those with long catheter indwelling periods.

DOI： 10.1245/s10434-013-3405-8

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OKAYAMA UNIV MED SCHOOL  

The impact of hepatic steatosis on interferon therapy for patients with chronic hepatitis C (CHC) has been associated with single-nucleotide polymorphisms (SNP) of IL28B, patatin-like phospholipase domain-containing protein 3 (PNPLA3), and low-density lipoprotein (LDL) receptor. Whether this holds true for Japanese patients, however, remains unresolved. The present study prospectively enrolled 226 Japanese patients with CHC, and investigated the impact of hepatic steatosis and its related SNPs, including rs8099917 of IL28B, rs738409 of PNPLA3, and rs14158 of LDL receptor, on outcomes of peg-interferon and ribavirin therapy. In multivariate logistic regression analysis, significant factors affecting the severity of hepatic steatosis were high body mass index and the minor alleles of IL28B SNP (p = 0.020 and 0.039, respectively). The risk alleles of PNPLA3 SNP also showed weak association (p = 0.059). Severe steatosis and the minor alleles of IL28B SNP were significantly associated with null or partial virological response in patients with HCV genotype 1, as were female gender, and low LDL cholesterol (p = 0.049, and &lt;0.001, respectively). The SNP genotype of PNPLA3 and LDL receptor did not have a significant impact on therapeutic outcomes. With respect to the SNP sites examined, the SNP of PNPLA3 has a weak association with severe hepatic steatosis, but not with the outcome of interferon therapy.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Background and Aim: Chronic infection with hepatitis C virus (HCV) decreases health-related quality of life (HRQOL). The present study was planned to investigate the impact of HRQOL of patients with chronic hepatitis C (CHC) on the outcomes of therapy with pegylated interferon and ribavirin (RBV), in addition to IL28B polymorphisms.
Methods: The present study enrolled 228 CHC patients and assessed their HRQOLs prospectively with the 36-item short-form health survey.
Results: The patients with CHC have lower physical HRQOL status than the general population (P = 0.037, the Z-test). The patients with advanced liver diseases exhibited further decreases in HRQOL (P = 0.036, Spearman's rank correlation coefficient). The score of total HRQOL was significantly lower in the group with sustained virological response (SVR) to the therapy with pegylated interferon and RBV than the non-SVR group (P = 0.031, the Mann-Whitney U-test), with significantly lower scores of mental component and its comprising subscales in the SVR group. Stepwise multivariate logistic regression analysis showed that low HRQOL score &lt;= 400 points was significantly associated with SVR (odds ratio = 2.4, P = 0.013), independently from high platelet counts, low HCV RNA, favorable single-nucleotide polymorphism type of IL28B, and HCV serotype 2. The patients with low HRQOL score will have significantly less decrease in HRQOL score by 4 weeks of the treatment than those with high HRQOL score at baseline (P = 0.0045).
Conclusion: HRQOL is one of the significant predictor of the outcomes of therapy with pegylated interferon and RBV independently from IL28B polymorphism.

DOI： 10.1111/jgh.12337

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC MICROBIOLOGY  

We encountered a patient positive for anti-hepatitis C virus (HCV) whose serum HCV RNA was undetectable with the Roche AmpliPrep/Cobas TaqMan HCV assay (CAP/CTM) version 1 but showed a high viral load with the Abbott RealTime HCV assay (ART). Discrepancies in the detectability of serum HCV RNA were investigated among 891 consecutive patients who were positive for anti-HCV. Specific nucleotide variations causing the undetectability of HCV RNA were determined and confirmed by synthesizing RNA coding those variations. Serum samples with the discrepancies were also reassessed by CAP/CTM version 2. Among the 891 anti-HCV-positive patients, 4 patients had serum HCV RNA levels that were undetectable by CAP/CTM version 1 despite having levels of &gt; 5 log IU/ml that were detected by ART. All four patients had HCV genotype 2a and high titers of anti-HCV. Sequencing of the HCV 5' noncoding regions revealed 2 common variations, A at nucleotide (nt) 145 and T at nt 151. Synthesized RNAs of the HCV 5' noncoding region with standard (NCR145G151C) and variant nucleotides at nt 145 and nt 151 were quantified with CAP/CTM. RNAs of NCR145G151C and NCR145G151T were quantifiable with CAP/CTM version 1, while those of NCR145A151T and NCR145A151C went undetected. The substitution from G to A at nt 145 specifically conferred this undetectability, while this undetectability was reverted in synthesized HCV RNA with correction of this variation. Reassessment of these samples by CAP/CTM version 2 resulted in similar levels of HCV RNA being detected by ART. We conclude that HCV patients with undetectable HCV RNA by CAP/CTM version 1 should be reassessed for viral quantification.

DOI： 10.1128/JCM.02792-13

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer-Verlag Tokyo  

Fulminant hepatitis due to acute hepatitis C virus (HCV) infection is rarely observed. We present a case study of a 21-year-old male patient who developed HCV-associated fulminant hepatitis after receiving steroid pulse therapy for optic neuritis. Despite daily plasmapheresis, the disease progressed to irreversible liver failure with grade 3 hepatic encephalopathy by the 6th day after symptom onset. The patient received a liver transplant on the 8th day. Serum anti-HCV antibody was negative at that time, but became positive on the 12th day. Positive HCV RNA in the serum at admission was reported after transplantation. Positive changes in anti-HCV antibodies and acute hepatitis with massive necrosis in the histology of the explanted liver indicated fulminant hepatitis due to acute HCV infection. Because of severe hepatitis recurrence, he started 12 months of interferon therapy on the 48th day, and obtained sustained virological response. His anti-HCV antibodies became negative again by 1.5 years after cessation of therapy. HCV genomes recovered from the patient's serum on the 7th and 48th days revealed 2 different clones out of 20 clones with 30 % amino acid difference in hypervariable region 1 of HCV second envelope glycoprotein. One of the 2 clones expanded further after liver transplantation. We conclude that early diagnosis of HCV-associated fulminant hepatitis requires the detection of HCV RNA in the serum. Severe hepatitis recurrence after liver transplantation might occur in patients with fulminant hepatitis due to HCV because of its monoclonal expansion. © 2014 Springer.

DOI： 10.1007/s12328-014-0454-x

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Aim: Oxidative stress is associated with progression of chronic liver disease (CLD). This association is best established in chronic hepatitis C. However, the anti-oxidative state is not well characterized. The objective of the present study was to investigate the balance of oxidative and anti-oxidative stress in CLD patients. Methods: We recruited a study population of 208 patients, including healthy volunteers (HV
n=15), patients with hepatitis B virus (HBV)-related CLD without or with hepatocellular carcinoma (HBV-non-HCC, n=25, and HBV-HCC, n=50, respectively), and patients with hepatitis C virus (HCV)-related CLD without or with HCC (HCV-non-HCC, n=49, and HCV-HCC, n=69, respectively). Serum levels of reactive oxygen metabolites (ROM) and anti-oxidative markers (OXY-adsorbent test
OXY) were determined, and the balance of these values was used as the oxidative index. Correlations among ROM, OXY, oxidative index and clinical characteristics were investigated. Results: Patients with CLD exhibited elevated ROM and oxidative index compared to HV. Among patients with CLD, HCV positive status correlated with increased ROM. In CLD, HCV-HCC patients exhibited the highest ROM levels. Among HCV-related CLD patients, lower OXY correlated with HCC positive status, but was recovered by eradication of HCC. In HCV-HCC, lower OXY correlated with high PT-INR. Conclusion: HCV positive CLD patients displayed higher oxidative stress and HCV-HCC patients displayed lower anti-oxidative state. Anti-oxidative state depression was associated with liver reservoir-related data in HCV-HCC and could be reversed with HCC eradication. © 2012 The Japan Society of Hepatology.

DOI： 10.1111/hepr.12048

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Purpose: Several studies have reported an inverse association between moderate alcohol consumption and prevalence of fatty liver (FL) in men. We aimed to clarify this association in women. Methods: We collected health checkup data from 4,921 Japanese women without concurrent liver disease (mean age 46.4 years) and performed a cross-sectional study to evaluate the influence of alcohol drinking patterns (frequency and amount) on the prevalence of FL as assessed by ultrasonography. Results: Alcohol consumption was reported in 30.8 % of participants, and FL was observed in 13.8 % (15.5 % nondrinkers, 10.1 % drinkers). Alcohol consumption was inversely associated with FL prevalence [adjusted odds ratio (AOR) 0.79, 95 % confidence interval (CI) 0.63-0.98]. In analyses stratified by drinking frequency and/or amount of alcohol consumed, the risk of FL decreased for the following categories: 0.1-19.9 g/drinking day (AOR 0.61, 95 % CI 0.44-0.83) and 0.1-69.9 g/week (AOR 0.74, 95 % CI 0.55-0.98). The amount of alcohol consumed directly correlated with the prevalence of FL in daily drinkers (p &lt
0.05), whereas there was no correlation between the frequency of alcohol consumption and FL prevalence. Alanine aminotransferase levels were significantly lower for the following categories: 0.1-19.9 g/drinking day for 1-3 days a week (p = 0.016) and 0.1-69.9 g within 1-3 drinking days a week (p = 0.004). Conclusions: Minimal alcohol consumption appears to have protective effects against nonalcoholic FL disease in women, although an increase in the amount of alcohol consumed appears to nullify the protective effect. © 2013 Asian Pacific Association for the Study of the Liver.

DOI： 10.1007/s12072-013-9449-9

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Background The single nucleotide polymorphism (SNP) rs738409 in patatin-like phospholipase domain-containing protein 3 (PNPLA3) is associated with hepatic fat accumulation and disease progression in patients with nonalcoholic fatty liver disease and alcoholic liver disease (ALD). This study was conducted to determine whether PNPLA3 rs738409 SNPs affect development and prognosis of hepatocellular carcinoma (HCC) in patients with various liver diseases. Methods We enrolled 638 consecutive Japanese patients newly diagnosed with HCC between 2001 and 2010: 72 patients with hepatitis B virus (HBV), 462 with hepatitis C virus (HCV), and 104 with non-B non-C (NBNC). Results NBNC patients exhibited large tumors of advanced TNM stages at HCC diagnosis, and had significantly poorer prognosis than HBV or HCV patients (P&lt
0.001 and &lt
0.001, respectively
log-rank test). The G/G genotype of PNPLA3 rs738409 SNP had significantly higher distribution in NBNC patients (P&lt
0.001) and was significantly associated with higher body mass index (BMI) and an increased aspartate aminotransferase to platelet ratio index. No significant differences were observed in survival with differences in PNPLA3 SNP genotypes among the patients, although ALD patients with the G/G genotype of PNPLA3 SNP and low BMI had significantly poorer survival than those with high BMI (P = 0.028). Conclusions The G/G genotype of PNPLA3 rs738409 SNP was more frequently distributed, and associated with BMI and fibrosis among NBNC-HCC patients but not among HBV or HCV patients. These genotypes might affect HCC prognosis in ALD patients, but not in HBV, HCV, or NAFLD patients. © Springer 2012.

DOI： 10.1007/s00535-012-0647-3

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER INTERNATIONAL PUBLISHING AG  

The impact of single-nucleotide polymorphisms (SNP) of patatin-like phospholipase domain-containing protein 3 (PNPLA3) on development of hepatocellular carcinoma (HCC) is not clarified for Japanese patients with chronic hepatitis C. The present study investigated the associations of rs738409 PNPLA3 with HCC development after the antiviral therapy with peg-interferon and ribavirin for Japanese patients with hepatitis C virus serotype 1 and high viral load. Of the 271 patients enrolled in the study, 20 patients developed HCC, during a median follow-up period of 4.6 years. Multivariate analysis in the proportional hazards models revealed that sex, body mass index, platelet counts, and alpha feroprotein (AFP) had significant associations with HCC development (p = 0.011, 0.029, 0.0002, and 0.046, respectively). Multivariate regression analysis revealed that PNPLA3 148 M was significantly associated with serum AFP level (p = 0.032), other than body mass index, platelet count, and alanine aminotransferase (p = 0.0006, 0.0002, and 0.037, respectively), and that serum AFP level was significantly associated with PNPLA3 148 M (p = 0.017). Serum AFP level is an important factor in predicting HCC development after the antiviral therapy for Japanese patients with chronic hepatitis C, the mechanism of which might involve its significant associations with the SNP genotype of PNPLA3.

DOI： 10.1186/2193-1801-2-251

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

To clarify the factors associated with delayed reduction of HBV DNA during combination treatment with adefovir dipivoxil (ADV) and lamivudine (LAM) for patients with LAM-resistant hepatitis B virus (HBV), factors including patient characteristics, viral mutations, and drug metabolism were investigated during a 5-year observation period. Delayed reduction of HBV DNA was defined as delayed viral response of detectable HBV DNA after 3 years of combination therapy. Of 67 consecutive patients, 47 attained undetectable HBV DNA after 3 years of combination therapy, and the mean therapeutic duration was 5 years (range: 3.08.4 years). The patients with delayed viral response had high levels of HBV DNA and HBe antigen, while those with negative or low levels of HBe antigen were also negative for HBV DNA, even if they had high levels of HBV DNA. In the multivariate analysis with the proportional hazards model, a high baseline level of HBe antigen was negatively associated with viral decline to an undetectable level (P?=?0.013). A higher baseline of HBe antigen corresponded to a lower annual decline in HBV DNA (R?=?-0.38, P?=?0.004). No patients showed ADV-resistant mutations in the HBV reverse transcriptase region. Trough concentrations of LAM and ADV showed no clear associations with viral response. HBe antigen levels at the initiation of therapy, and reductions in these levels during therapy are predictive of the therapeutic response to combination therapy with ADV and LAM for patients with LAM-resistant HBV. J. Med. Virol. 84:15621570, 2012. (c) 2012 Wiley Periodicals, Inc.

DOI： 10.1002/jmv.23371

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Background and Aims: Recent routine testing for anti-mitochondrial antibodies has increased the number of patients with early primary biliary cirrhosis (PBC). The prevalence and clinical significance of esophageal varices in those patients remains obscure. Methods: A systematic cohort analysis of 256 PBC patients was performed to clarify the prevalence, characteristics, and prognosis of the patients with early PBC and esophageal varices. Results: Twenty-two patients had esophageal varices at the time of diagnosis: 5.5% (12/217) with early disease of histological stage 1 or 2, and 25.6% (10/39) with advanced disease of stage 3 or 4. Immediate treatments were required for two patients with early PBC: one for bleeding varices, and the other for large varices. The overall survival of the patients with early PBC and esophageal varices at diagnosis did not significantly differ from that of patients without esophageal varices (P = 0.66). High alkaline phosphatase (ALP) ratios (odds ratio = 2.3) and low platelet counts (odds ratio = 0.77) were significantly associated with the presence of esophageal varices in the patients with early PBC. Significant associations of these two factors with the development of esophageal varices during follow-up were also revealed (odds ratio = 1.4 and 0.88, respectively). The patients with early PBC and high ALP ratios = 1.9 had significantly high risks of developing esophageal varices during follow-up (P = 0.022). Conclusions: High ALP ratios and low platelet counts at diagnosis and decreased platelet counts during follow-up are useful predictors of esophageal varices in patients with early PBC.

DOI： 10.1111/j.1440-1746.2012.07114.x

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

Treatment of chronic hepatitis C virus (HCV) infection with interferon (IFN) prevents the development of hepatocellular carcinoma (HCC). The purpose of this study was to clarify the effect of previous IFN treatment before the development of HCC on recurrence and survival in HCV-related HCC patients.
Three hundred ninety-five patients who underwent curative treatment for HCV-related HCC were enrolled. Of these, 124 had received IFN treatment before the development of HCC (17 achieved sustained virological response [SVR group] and 107 did not [non-SVR group]), whereas 271 patients had never received IFN treatment (IFN-untreated group). The first and second recurrence and survival rates in these patient groups were statistically analyzed.
The first HCC recurrence rate was similar among patient groups. In contrast, the second HCC recurrence rate was significantly lower in the SVR group than in the non-SVR group (p = 0.003) and the IFN-untreated group (p = 0.006). In multivariate analysis, platelet count (p = 0.033) and number of tumors (p = 0.001) were associated with the first HCC recurrence, while SVR (p = 0.002) was the only factor associated with the second HCC recurrence. The survival rate was higher in the SVR group than in non-SVR and IFN-untreated groups, and SVR to previous IFN treatment was an independent factor associated with better survival (p &lt; 0.001).
SVR to previous IFN treatment before the development of HCV-related HCC was associated with lower risk of the second recurrence of HCC and better survival.

DOI： 10.1007/s10620-011-1934-1

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DOI： 10.1111/j.1443-1661.2011.01171.x

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Rhabdomyolysis associated with fenofibrate monotherapy is extremely rare. Here, we report a rare case of rhabdomyolysis of the psoas muscle in an 82-year-old man with chronic myelogenous leukemia (CML). He was prescribed fenofibrate because of a hypertriglyceridemia. The patient reported generalized muscle pain and right abdominal pain while receiving fenofibrate monotherapy. An abdominal computed tomography scan and an abdominal ultrasound showed a large and low attenuation and high echogenicity, respectively, in the right middle abdominal area. Laboratory values included a serum creatine concentration of 4.1 mg/dl and a creatinine phosphokinase concentration of 5,882 IU/l. During laparotomy, a large hematoma and necrotic mass was identified in the right psoas muscle. Histological examination revealed that the resected specimens were of the psoas muscle with irregular fiber sizes, degenerating fibers surrounding the inflammatory reaction, and fiber necrosis that is typical for polymyositis. Based on these findings and the clinical history, a diagnosis of fenofibrate-induced rhabdomyolysis was made. To the best of our knowledge, no patient has ever been diagnosed with fulminant psoas rhabdomyolysis due to a fenofibrate monotherapy. This report details the rare case of rhabdomyolysis in a patient with CML associated with fenofibrate monotherapy and offers a review of the literature. Copyright © 2011 S. Karger AG, Basel.

DOI： 10.1159/000331559

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL PUBLISHING, INC  

P&gt;Background
Moderate alcohol consumption may have certain beneficial effects against non-alcoholic fatty liver disease, which is associated with metabolic syndrome.
Aim
To determine the association between drinking pattern and fatty liver in Japanese men and women.
Methods
A cross-sectional study was performed with health checkup data including information concerning alcohol consumption and ultrasonographic assessment of fatty liver.
Results
We analysed 4957 men and 2155 women without reported liver diseases (median age, 49 years). In men, 40% of nondrinkers and 28% of drinkers had fatty liver. Alcohol consumption was inversely associated with fatty liver (adjusted odds ratio, 0.54; 95% confidence interval, 0.46-0.63). The prevalence of fatty liver in each category of drinking frequency was 38% (1-3 days/week), 29% (4-6 days/week), and 24% (daily drinking); there was a significant inverse correlation between drinking frequency and the prevalence of fatty liver (P &lt; 0.001). In women, 16% of nondrinkers and 10% of drinkers had fatty liver. Drinking less than 20 g on 1-3 days/week was associated with low prevalence of fatty liver (adjusted odds ratio, 0.47; 95% confidence interval, 0.23-0.96).
Conclusions
Alcohol consumption appears to protect against non-alcoholic fatty liver disease.

DOI： 10.1111/j.1365-2036.2010.04520.x

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：INFORMA HEALTHCARE  

Objective. Several treatment strategies for patients with chronic hepatitis C have been compared mainly in terms of their efficacy, and it has been found that pegylated interferon (IFN) plus ribavirin has become the standard therapy, but aged patients may not tolerate ribavirin and the cost-effectiveness of treatment should also be further considered. We conducted a study to evaluate the efficacy, safety, and cost-effectiveness of consensus IFN monotherapy with high-dose induction for patients with chronic hepatitis C in clinical practice. Material and Methods. We consecutively enrolled 104 patients with chronic hepatitis C. Patients were scheduled to receive 12 or 18 mu g of consensus IFN daily for 2 weeks, then three times a week for 22 weeks. Efficacy, safety, and cost-effectiveness were assessed. A Markov model was developed to investigate cost-effectiveness in patients with chronic hepatitis C treated by different IFN-based treatment strategies. Results. Of the 104 study patients, a sustained virological response (SVR) was achieved in 66 (63%). Logistic regression analysis revealed that genotype 2, lower hepatitis C virus RNA levels, and patient age were independently associated with SVR. The response rate was significantly higher in patients with genotype 2 (51/66, 77%) versus genotype 1 (15/38, 40%). Cost-effectiveness analysis in patients with genotype 2 revealed that high-dose induction with consensus IFN monotherapy was as highly cost-effective as pegylated IFN plus ribavirin. Conclusion. Consensus IFN monotherapy with high-dose induction shows high efficacy and cost-effectiveness in chronic hepatitis C patients with genotype 2 infection. Thus, it may be a reliable alternative in aged patients and for those excluded from standard combination therapy.

DOI： 10.3109/00365521.2010.516449

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Introduction. Gastric tumors in patients affected by neurofibromatosis type 1 are usually carcinoids or stromal tumors, and rarely adenocarcinomas. Case presentation. We report a case of an adenocarcinoma of the stomach in a 53-year-old Japanese man with neurofibromatosis type 1. An abdominal computed tomography scan and ultrasonography showed tumors in his liver. Gastric fibroscopy revealed a Borrmann type III tumor on his cardia that had spread to his esophagus and was highly suspicious for malignancy. Multiple biopsies showed an adenocarcinoma of the stomach, which was evaluated as gastric cancer, stage IV. Chemotherapy with TS-1 was performed. Our patient died four weeks after initial admission. Histological examination of a liver needle biopsy showed metastatic adenocarcinoma in his liver. Conclusion: To the best of our knowledge, high serum levels of -fetoprotein, carcinoembryonic antigen, and carbohydrate antigen 72-4, resulting from gastric adenocarcinoma, have not been reported previously in a patient with neurofibromatosis type 1. We report this rare case along with a review of the literature. © 2011 Kato et al
licensee BioMed Central Ltd.

DOI： 10.1186/1752-1947-5-521

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER TOKYO  

For patients with chronic hepatitis due to hepatitis B virus (HBV), factors predicting hepatocellular carcinoma (HCC) other than high levels of HBV-DNA and alanine aminotransferase (ALT) are needed to prevent HCC development, as many patients with chronic HBV infection fulfill these conditions. The purpose of this study was to clarify factors predictive of HCC development for those patients.
The study was a systematic cohort analysis of 303 consecutive patients with hepatitis B e-antigen, receiving laparoscopic examination for assessment of liver disease. Laparoscopic, histological, and clinical characteristics were investigated as related to HCC development.
HCC occurred in 27 patients during a mean follow-up of 8.0 +/- A 5.0 years, at the age of 37-72 years. Significant associations with HCC development were shown for liver cirrhosis, histological activity grade, reddish markings, and older age. Multivariate analysis revealed that HCC development was strongly associated with older age and male gender (P = 0.002 and P = 0.043, respectively). HCC occurred more frequently in patients of age a parts per thousand yen30 years even with early stage than in patients of age &lt; 30 years (P = 0.031). Severe reddish markings, a laparoscopic finding of widespread parenchymal destruction, were highly associated with HCC development in patients of age a parts per thousand yen30 years at diagnosis (odds ratio = 1.67, P = 0.034), while histological activity grade and ALT level were not (P = 0.075 and P = 0.69, respectively).
HCC development is associated with older age, male gender, and liver cirrhosis. Reddish markings, rather than histological activity or ALT level, can be useful to predict HCC for HBV patients of age a parts per thousand yen30 years.

DOI： 10.1007/s00535-010-0266-9

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Background: Studies on patients with hepatitis C virus (HCV) of genotype 1b have suggested that amino acids (aa) 70 and/or 91 of the HCV core protein affect the outcome of interferon (IFN)-alpha and ribavirin (RBV) therapy, although there are no clear supporting data in vitro. Aims: This study was designed to determine the differences among the antiviral activities of HCV core proteins with various substitutions at aa70 and/or aa91. Methods: The retroviral vectors expressing the HCV core proteins with substitutions of arginine/leucine, arginine/methionine, glutamine/leucine or glutamine/methionine at aa70/aa91 were transiently transfected or stably transducted into an immortalized hepatocyte line (PH5CH8), hepatoma cell lines and an HCV-RNA replicating cell line (sOR) to evaluate antiviral responses to IFN-alpha or IFN-alpha/RBV. Sequence analysis was performed using genome-length HCV-RNA replicating cells (OR6 and AH1) to evaluate HCV core mutations during IFN-alpha treatment. Results: The promoter activity levels of IFN-stimulated genes in the transiently transfected cells or the mRNA levels of 20-50-oligoadenylate synthetase in the stably transducted PH5CH8 cells were not associated with the HCV core aa70 and/or aa91 substitutions during IFN-alpha treatment. Antiviral responses to IFN-alpha or IFN-alpha/RBV treatment were enhanced in sOR cells stably transducted with the HCV core, although there were no differences in antiviral responses among the cells expressing different core types. Sequence analysis showed no aa mutations after IFN-alpha treatment. Conclusions: Antiviral activities were enhanced by HCV core transduction, but they were not associated with the HCV core aa70 and/or aa91 substitutions by in vitro analysis.

DOI： 10.1111/j.1478-3231.2010.02299.x

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Background/aim: There are many reports dealing with the risk factors for hepatocellular carcinoma (HCC) recurrence. However, in most of these reported studies, factors were analysed only at the initial treatment stage, and the predisposing factors for the recurrence during follow-up have not been well studied. The aim of this study is to evaluate the predisposing factors after treatments. Methods: Two hundred and seventy-one consecutive HCC patients curatively treated between January 1994 and March 2004 were followed up and analysed. The recurrence rate was estimated by the Kaplan-Meier method and the predisposing factors were evaluated by time-fixed Cox regression analysis and by time-dependent covariate analysis using multiple parameters. Results: The mean follow-up period was 4.86 years and recurrence was observed in 169 patients (62.4%). The recurrence rates were 27.9, 65.1 and 84.3% at 1, 3 and 5 years respectively. Among the variables determined before treatment, predisposing factors for recurrence were low serum albumin [&lt;= 3.5 g/dl, hazard ratio (HR) = 1.47, 95% confidence interval (CI) = 1.07-2.01] and multiple tumour number (HR = 2.04, 95% CI = 1.46-2.84) by time-fixed multivariate analysis. In the time-dependent analysis, six variables with 12 013 plots were examined. The multivariate analysis revealed that high des-g-carboxy prothrombin (DCP &gt;= 40mAU/ml, HR = 2.33, 95% CI = 1.61-3.39), high a-fetoprotein (AFP &gt;= 100 ng/ml, HR = 2.01, 95% CI = 1.3-3.35) and high alanine aminotransferase (ALT &gt;= 40 IU/L, HR = 1.52, 95% CI = 1.1-2.1) were significant predisposing factors for recurrence. Conclusion: Predisposing factors for the recurrence of HCC after treatment are different from those before treatments and special cautions are required when AFP, DCP or ALT is high during follow-up.

DOI： 10.1111/j.1478-3231.2010.02252.x

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Dendritic cells (DCs) in chronic hepatitis C patients display impaired function, although the details remain unclear. To investigate the hepatitis C virus (HCV) protein that has the most impact on DC function, we compared five recombinant proteins and seven HCV protein genes in modulating DC phenotype and function. Immature DCs (iDCs) were established from healthy donor peripheral blood monocytes with granulocyte-macrophage colony stimulating factor (GM-CSF) and IL-4. Lipopolysaccharide was used to establish mature DCs (mDCs). Cells were then pulsed with HCV recombinant proteins or transfected with HCV plasmids and subsequently assayed for cell surface marker expression by flow cytometry. For cytokine and proliferative T-cell response analysis, DCs were cultured with autologous CD4 T cells and tuberculin purified protein derivative (PPD). Mean fluorescent intensity of CD86 was reduced in HCV protein-pulsed iDCs. Proliferative T-cell responses and Th1 cytokine concentrations were reduced with HCV nonstructural proteins (NS), particularly with HCV NS4. HCV nonstructural proteins, particularly NS4, change the iDC phenotype and reduce antigen-specific T-cell stimulatory function with Th1 cytokine reductions.

DOI： 10.1111/j.1365-2893.2009.01213.x

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Interferon treatment for chronic hepatitis C reduces the incidence of hepatocellutar carcinoma (HCC) in sustained responders. However, estimation of the effect of interferon treatment on HCC development in nonresponders is yet to be fully implemented. We conducted a meta-analysis of 3 randomized controlled trials and 6 prospective cohort studies, including 3,246 patients (1,922 patients received interferon treatment) to estimate the effect of single-course interferon treatment on HCC development in patients with chronic hepatitis C. Single-course interferon treatment prevented HCC development (RR 0.45; 95% CI 0.31-0.65). This preventive effect was shown even in nonresponders (RR 0.48; 95% CI 0.25-0.90). By subgroup analyses, single-course interferon treatment reduced HCC incidence in cirrhotic patients (RR 0.49; 95% CI 0.29-0.84), patients with annual HCC incidence less than 3% in control group (RR 0.42; 95% CI 0.26-0.66) and patients with annual HCC incidence of 3% or more in control group (RR 0.46; 95% CI 0.26-0.83). Furthermore, HCC incidence was reduced in 3 studies with follow-up period less than 5 years (RR 0.38; 95% CI 0.21-0.66) and in 6 studies with follow-up period of 5 years or more (RR 0.46; 95% CI 0.28-0.76). In conclusion, single-course interferon treatment was shown to prevent HCC development in chronic hepatitis C, even in nonresponders. This preventive effect may be speculated to be due to anti-inflammatory effect on persistent necro-inflammation and blocking progression of fibrosis in liver. Even if sustained virological response is not achieved, interferon may be worth administering in order to reduce HCC incidence in patients with chronic hepatitis C.

DOI： 10.1002/ijc.25090

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Various clinical studies have indicated that interferon (IFN)-alpha treatment prevents the development of hepatocellular carcinoma (HCC) in people chronically infected with hepatitis C virus. However, it has been controversial whether IFN-alpha treatment prevents HCC recurrence. The aim of this study was to identify the preventive effect of IFN-alpha treatment after curative therapy of primary tumours within the Milan criteria (three or fewer nodules 3 cm or less in diameter or a single nodule of 5 cm or less) on HCC recurrence. We conducted a meta-analysis of five trials including 355 patients (167 patients received IFN-alpha treatment after curative therapy of primary tumours) and estimated relative risks (RRs) and 95% confidence intervals (CIs) for the effect of IFN-alpha on HCC recurrence according to the DerSimonian and Laird method. IFN-alpha treatment after curative therapy of primary tumours significantly prevented HCC recurrence (RR 0.33; 95%CI 0.19-0.58, P &lt; 0.0001) without a significant heterogeneity (Q = 4.52, P = 0.34). An evaluation using the Begg method suggested no evidence of publication bias. Sub-group analyses revealed that IFN-alpha treatment reduced HCC recurrence in two studies achieving sustained virologic response (SVR) rates &gt; 30% (RR 0.20; 95%CI 0.05-0.81, P = 0.02) and in three studies achieving SVR rates &lt; 30% (RR 0.44; 95%CI 0.23-0.84, P = 0.01). In conclusion, IFN-alpha treatment after curative treatment of primary tumour within Milan criteria may be effective for the prevention of HCC recurrence, and higher SVR rate may be associated with better preventive effect of IFN-alpha treatment on HCC recurrence.

DOI： 10.1111/j.1365-2893.2009.01181.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Background: Recently, simplified diagnostic criteria for autoimmune hepatitis have been proposed. Aim: We aimed to evaluate usefulness of the simplified criteria.
Methods: We applied the simplified criteria to 176 autoimmune hepatitis patients diagnosed according to the revised scoring system proposed in 1999 (original criteria). Furthermore, in order to compare predictabilities between these two diagnostic criteria, we included 168 patients with other liver disease than autoimmune hepatitis.
Results: Of 176 autoimmune hepatitis patients, 85% were diagnosed with autoimmune hepatitis according to the simplified criteria, and patients diagnosed according to the simplified criteria showed a higher frequency of antinuclear antibodies and/or smooth muscle antibodies of 1:80 or greater and slightly higher serum levels Of immunoglobulin G than those diagnosed according to the original criteria. However, 30% of male patients, 23% of patients with acute presentation, 50% of patients showing histological acute hepatitis and 46% of patients negative for antinuclear antibodies at presentation were not diagnosed with autoimmune hepatitis according to the simplified criteria. The simplified criteria showed lower sensitivity (85% vs. 100%) and higher specificity (99% vs. 93%) for autoimmune hepatitis than the original criteria.
Conclusions: The simplified criteria may be useless for the diagnosis of patients with atypical features, especially patients with histological acute hepatitis. (C) 2009 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.dld.2009.06.013

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P&gt;Background
The surveillance of hepatocellular carcinoma (HCC) has become prevalent, and the modalities for its treatment have improved.
Aim
To understand the changes that occur in the characteristics and prognostic factors of HCC with time.
Methods
Newly diagnosed HCC patients were divided into two groups; patients treated before 31 December 2000 (n = 504), and after 1 January 2001 (n = 746), and their clinical backgrounds and prognostic factors were analysed.
Results
The number of patients negative for both Hepatitis B surface antigen (HBsAg) and Hepatitis C virus antibody (HCVAb) increased with time (NBNC-HCC). The size of HCC decreased in patients who were positive for HBsAg (B-HCC) or HCVAb (C-HCC), whereas no difference was observed in NBNC-HCC. The patient survival of C-HCC improved; however, no difference was detected for NBNC-HCC. In multivariate analysis, low albumin, high aspartate aminotransferase (AST), ascites, large tumour size, multiple tumour number and high alpha-fetoprotein were risk factors for survival before 2000, whereas the presence of HBsAg was additionally selected as a good prognostic factor and AST was excluded after 2001.
Conclusions
The prognostic factors as well as clinical background of HCC changed with time, and the presence of HBsAg was found to be an additional good prognostic factor after 2001.

DOI： 10.1111/j.1365-2036.2009.04179.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：H G E UPDATE MEDICAL PUBLISHING S A  

Background/Aims: The aim of this study is to elucidate the effectiveness of radiofrequency ablation (RFA) for the treatment of metastatic liver cancers.
Methodology: From 74 patients with metastatic liver cancers treated by RFA, 40 patients including 23 colon cancer who had received curative resection of the primary tumor were analyzed.
Results: Recurrence of the tumor was observed in 29 (72.5%) patients. The most prevalent site of recurrence was the liver in both colon cancer (10/15, 66.7%) and non-colon cancer patients (12/14, 85.7%). Among the recurrence in the liver, the rate of intrahepatic distant recurrence (recurrence outside of the RFA-treated segment) was high in both colon cancer (55.6%) and non-colon cancer patients (69.0%). Local recurrence (recurrence at the RFA-treated segment) rate was low (32.6% and 32.9%, respectively) and none of single tumor less than 2cm in diameter showed local recurrence. The intrahepatic recurrence was single in 67.6% of the patients and 59.1% of the patients were re-treated by RFA.
Conclusions: RFA is a less-invasive method for the treatment of metastatic liver tumors and can be performed repetitively. Although the rate of intra-hepatic distant recurrence and extra-hepatic recurrence was high, good local control can be achieved by RFA.

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Background: In Caucasians with autoimmune hepatitis, patients with acute presentation have autoimmune thyroiditis and histological zone 3 necrosis more frequently.
Aim: We aimed at investigating clinical features of Japanese autoimmune hepatitis patients with acute presentation.
Methods: Of 176 patients retrospectively reviewed, 53 were diagnosed with acute presentation.
Results: Patients with acute presentation had higher serum levels of bilirubin and transaminase, lower frequencies of autoimmune thyroiditis and antinuclear antibodies of 1:160 or greater, and a higher frequency of zone 3 necrosis. Of the 53 patients with acute presentation, 10 showed histological acute hepatitis; however, advanced staging of fibrosis was found in 13 patients. In patients with acute presentation, those with histological acute hepatitis were younger than those with chronic hepatitis. The cumulative incidental rate of the normalization of serum alanine aminotransferase levels with prednisolone treatment was similar between patients with acute presentation and those with classical presentation.
Conclusions: In line with previous results, zone 3 necrosis is a histological characteristic of autoimmune hepatitis with acute presentation. Autoimmune hepatitis with acute presentation includes not only histological acute hepatitis but also acute exacerbation of pre-existing chronic disease. On the other hand, Japanese patients with acute presentation may also have different clinical features from Caucasian patients. (C) 2009 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.dld.2009.04.009

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

An 18-year-old Nepalese man was admitted due to general malaise and anorexia a month after coming to Japan. Laboratory tests showed elevation of transaminase and positivity for IgM anti-HEV antibody. Serum HEV RNA was detected by RT-PCR amplifications. An HEV genome phylogenetic tree, constructed using an 821-nucleotide sequence in the open reading frame 1, indicated that the genotype was 1. HEV genotype 1 is epidemic in South Asia, Africa and South America, and the incidence of acute hepatitis due to HEV genotype 1 is low in Japan. Thereafter, attention should be paid to HEV genotype 1 infection as an imported infectious disease.

DOI： 10.2169/internalmedicine.49.4221

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Recent routine testing for liver function and anti-mitochondrial antibodies has increased the number of newly diagnosed patients with primary biliary cirrhosis (PBC). This study investigated the prognosis of asymptomatic PBC patients, focusing on age difference, to clarify its effect on the prognosis of PBC patients.
The study was a systematic cohort analysis of 308 consecutive patients diagnosed with asymptomatic PBC. We compared prognosis between the elderly (55 years or older at the time of diagnosis) and the young patients (&lt; 55 years). The mortality rate of the patients was also compared with that of an age- and gender-matched general population.
The elderly patients showed a higher aspartate aminotransferase-to-platelet ratio, and lower alanine aminotransferase level than the young patients (P &lt; 0.01 and P = 0.03, respectively). The two groups showed similar values for alkaline phosphatase and immunoglobulin M. Death in the young patients was more likely to be due to liver failure (71%), while the elderly were likely to die from other causes before the occurrence of liver failure (88%; P &lt; 0.01), especially from malignancies (35%). The mortality rate of the elderly patients was not different from that of the age- and gender-matched general population (standardized mortality ratio, 1.1; 95% confidence interval, 0.6-1.7), although this rate was significantly higher than that of the young patients (P = 0.044).
PBC often presents as more advanced disease in elderly patients than in the young. However, the mortality rate of the elderly patients is not different from that of an age- and gender-matched general population.

DOI： 10.1007/s00535-009-0090-2

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

In a country such as Japan with the average age of patients with chronic hepatitis C treated with antivirals sometimes well above 60 years, the standard combination therapy is not well tolerated. In this randomized, prospective, controlled trial, we investigated the efficacy of 24-week peginterferon alpha monotherapy for easy-to-treat patients. A total of 132 patients chronically infected with hepatitis C virus (HCV) genotype 2 (n = 115) or low viral load HCV genotype 1 (&lt; 100 kIU/ml, n = 17) were treated with peginterferon alpha-2a (180 mu g/week). Patients with a rapid virological response (RVR, HCV RNA negative or &lt; 500 IU/ml at week 4) were randomized for a total treatment duration of 24 (group A) or 48 (group B) weeks. Patients who did not show RVR (group C) were treated for 48 weeks. Sustained virological response (SVR) was assessed by qualitative reverse-transcription polymerase chain reaction. One hundred eight of 132 (82%) patients with RVR were randomized. SVR rates were 60% (group A), 79% (group B), and 27% (group C), respectively. Similar SVR rates were achieved in patients infected with HCV genotype 2 with low pretreatment viral load (&lt; 1000 kIU/ml) in group A (81%) and group B (79%) (P = 0.801), whereas in those with higher viral load (a parts per thousand yen1000 kIU/ml), a lower SVR rate was identified in group A (26%) than in group B (67%) (P = 0.041). In conclusion, in patients infected with HCV genotype 2 and pretreatment viral load below 1000 kIU/ml who achieve RVR, 24-week treatment with peginterferon alpha-2a alone is clinically sufficient. Those who show no RVR or have higher baseline viral load, require alternative therapies.

DOI： 10.1007/s12072-009-9134-1

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Aim:
The peak age of the presentation of autoimmune hepatitis (AIH) is between 40 years and 50 years. Elderly patients have been reported to have higher frequencies of concurrent thyroid or rheumatic diseases and histological cirrhosis and a lower occurrence of treatment failure. In this study, we assessed the clinical features of Japanese type 1 AIH in adolescence and early adulthood.
Methods:
Fifteen patients aged &lt; 30 years (group 1) were compared with 79 patients aged between 40 years and 50 years (group 2).
Results:
At presentation, patients aged &lt; 30 years accounted for 9% of the study population. Although frequencies of extrahepatic concurrent autoimmune diseases were similar between groups 1 and 2, a tendency toward a lower frequency of concurrent autoimmune thyroiditis was shown in group 1 (0 vs. 18%, P = 0.08). Group 1 had a lower frequency of human leukocyte antigen DR4 (27 vs. 78%, P = 0.002), and histological acute hepatitis was shown more frequently in group 1 (27 vs. 4%, P = 0.002). However, there were no differences in frequencies of the normalization of serum transaminase levels after the introduction of corticosteroid treatment or relapse after the normalization of serum transaminase levels between the two groups.
Conclusions:
Japanese type 1 AIH patients in adolescence and early adulthood respond well to corticosteroid treatment. However, they may frequently show atypical features, and the diagnosis of type 1 AIH in adolescence and early adulthood may be difficult and should be made carefully.

DOI： 10.1111/j.1872-034X.2009.00510.x

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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).
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.
ETVr emerged in two Japanese nucleoside-naive CHB patients after prolonged therapy and incomplete suppression and in one patient after &lt; 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.

DOI： 10.1007/s12072-008-9108-8

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL PUBLISHING, INC  

Adherence to combination therapy with interferon (IFN) or pegylated IFN plus ribavirin for chronic hepatitis C patients is important for a better virological response. However, the impact of the patient&apos;s treatment experience and treatment centre on adherence to combination therapy has not been fully analysed. In this prospective study, we analysed the factors that might have an effect on adherence to therapy in patients who had initial or retreatment IFN therapy.
We consecutively enrolled 363 patients with chronic hepatitis C; 221 were IFN naive and 142 were undergoing retreatment. The mean ages of the naive and retreatment groups were 54.8 and 55.7 years respectively. IFN alpha-2b was administered daily for 2 weeks, followed by three times per week for 22 weeks, while ribavirin was administered daily. We evaluated the tolerability and response to combination therapy and analysed its relevant factors.
Of the 363 patients, 189 (52%) achieved 80% adherence. The multivariate logistic regression analysis revealed that retreatment, centre with more patients treated, patient age (&lt; 55 years), male, genotype 2 and dosage of IFN per weight (&lt; 0.13 million units/kg) were associated with achievement of 80% adherence to combination therapy. Accordingly, the achievement of 80% adherence was more frequent in the retreatment (62%) than that in the naive group (46%) (P &lt; 0.01) and in centres with more patients treated (57%) than in those with less patients treated (46%) (P=0.03).
The present data suggest that the patient&apos;s motivation and the physician&apos;s treatment experience may be important for a better adherence to combination therapy for patients with chronic hepatitis C.

DOI： 10.1111/j.1478-3231.2008.01964.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL PUBLISHING, INC  

Antinuclear antibodies (ANA) are the main serologic markers of type 1 autoimmune hepatitis (AIH); however 20-30% of patients are negative for ANA. We assessed the clinical features of ANA-negative patients.
A retrospective analysis was performed of 176 patients with type 1 AIH (153 females, median age 55 years). A diagnosis of AIH was made based on the revised scoring system proposed by the International Autoimmune Hepatitis Group. ANA titers were measured using a standard indirect immunofluorescence technique.
Thirty-eight patients (22%) had low titers of ANA (1:40 or 1:80), and 114 (65%) had high titers (&gt;= 1:160). Of 24 ANA-negative patients, 15 were positive for smooth muscle antibodies (SMA). Three of nine both ANA- and SMA-negative patients developed ANA during follow-up. The other six were diagnosed based on histological characteristics. Thirteen ANA-negative patients relapsed after the normalization of serum alanine aminotransferase (ALT) levels. ANA-negative patients more frequently showed acute presentation and, at presentation, had lower serum immunoglobulin G levels, higher serum levels of bilirubin and transaminase, and higher frequencies of histological acute hepatitis and zone 3 necrosis than those with high titers. However, the frequency of advanced stage of fibrosis was similar. The response to corticosteroids was not different among the three groups.
ANA-negative type 1 AIH shows acute-onset more frequently but may include not only acute autoimmune hepatitis, but also acute exacerbation of inactive chronic disease. Regarding the diagnosis of ANA-negative AIH, the determination of ANA during follow-up and the response to immunosuppressive treatment may be helpful.

DOI： 10.1111/j.1872-034X.2008.00454.x

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Background and Aims: A prospective, non-randomized cohort study on long-term lamivudine treatment, comparing efficacy, drug resistance, and prognosis for various stages of chronic hepatitis B virus ( HBV)- related liver disease was performed to elucidate the significance and indication of lamivudine for individual patients at each stage of disease.
Methods: A total of 158 cases consisting of 87 chronic hepatitis, 28 compensated cirrhosis, and 43 decompensated cirrhosis, with serum HBV-DNA &gt; 5 log(10) copies/mL and with elevated alanine aminotransferase (ALT) over twice the upper normal limit or complications of hepatic insufficiency, were administered 100 mg of lamivudine daily and monitored for HBV markers, biochemistry, and prognosis.
Results: Lamivudine reduced HBV-DNA and ALT equally in all groups. Serum albumin, prothrombin time (%), and platelet count increased in all groups. The increased margin of albumin was the highest in the decompensated cirrhosis and higher in the compensated cirrhosis than the chronic hepatitis groups. Cumulative incidence of virologic breakthrough was 16%, 42%, 49%, and 53% at 12, 24, 36, and 48 months, respectively, and the strongest predictive factor for lamivudine resistance was persistent HBV-DNA at 3 months. Ascites, encephalopathy, and jaundice improved in the majority of patients with decompensated cirrhosis. On the other hand, hepatic failure developed or deteriorated in 10 patients after virologic breakthrough, and nine of them had decompensated cirrhosis.
Conclusions: Lamivudine was effective in reducing HBV-DNA and improving hepatic reserve at all stages and was most beneficial and significant for decompensated cirrhosis. Meanwhile, close monitoring of viral load and immediate rescue treatment for lamivudine resistance is necessary to prevent hepatic failure in decompensated cirrhosis.

DOI： 10.1111/j.1440-1746.2007.05240.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER TOKYO  

Acute liver failure from abuse of volatile substances is not usual. We encountered a case involving a 27-year-old man with acute liver and kidney failure followed by severe brain edema, probably caused by abuse of glue containing trichloroethylene. The clinical course was observed from the first day, when serum transaminases were normal, until death on day 12. The trichloroethylene metabolite trichloroacetate was detected in his urine.

DOI： 10.1007/s00535-007-2146-5

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Aim: Human leukocyte antigen (HLA) DR status affects the clinical features of autoimmune hepatitis. In Caucasians, patients with DR3 have poorer outcomes. In Japan, the relationship between HLA DR status and clinical features has yet to be fully examined.
Methods: We investigated 79 patients with type 1 autoimmune hepatitis who underwent liver biopsy and were screened for HLA DR status by the polymerase chain reaction sequence specific oligonucleotide hybridization method.
Results: Fifty-five patients had DR4 and 23 had DR2. Thirteen patients had both DR2 and DR4. None had DR3. Of patients aged &lt; 30 years, 70% did not have DR4. A tendency toward higher serum levels of immunoglobulin G was seen in patients with DR4 compared to those without, while patients with neither DR2 nor DR4 had lower serum levels of immunoglobulin G than those with only DR2 and those with only DR4. Patients with DR2 had a lower frequency of concurrentautoimmune disease. Concurrence of thyroid disease was seen only in patients with DR4. The cumulative incidental rate of the normalization of serum alanine aminotransferase levels within six months after the introduction of corticosteroid treatment was not associated with HLA DR status.
Conclusion: HLA DR status is considered to affect the clinical features of Japanese patients with type 1 autoimmune hepatitis. Japanese patients with DR2 may have different clinical features from others. In addition, diagnoses of type 1 autoimmune hepatitis should be made carefully in Japanese patients with neither DR2 nor DR4 and in those aged &lt; 30 years.

DOI： 10.1111/j.1872-034X.2007.00204.x

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Aim: In Caucasians in northern Europe and North America, type 1 autoimmune hepatitis is characterized by susceptibility to human leukocyte antigens DR3 and DR4, and patients with zone III necrosis more frequently have an acute onset of the disease and a lower frequency of cirrhosis than those without. In Japanese patients, however, type 1 autoimmune hepatitis is primarily associated with DR4, and there are almost no DR3-positive patients. Thus, the clinical features of Japanese patients with type 1 autoimmune hepatitis and zone III necrosis may be different from those reported previously for Caucasians.
Methods: We investigated 160 consecutive patients with type 1 autoimmune hepatitis (20 males and 140 females; median age, 55 years; range, 16-79 years).
Results: Forty-seven patients (29%) had zone III necrosis, and these patients had lower serum levels of albumin and higher serum levels of total bilirubin, aspartate aminotransferaseand alanine aminotransferase. Histologically, zone III necrosis was found more frequently in patients with acute hepatitis than in those with chronic hepatitis. However, there was no difference in the frequency of cirrhosis between patients with and without zone III necrosis. In addition, normalization of serum alanine aminotransferase levels within six months after the introduction of corticosteroid treatment was slightly more frequent in patients with zone III necrosis (95% vs. 88%).
Conclusions: In Japanese patients, zone III necrosis may reflect not only acute autoimmune hepatitis, but also acute exacerbation of pre-existing chronic disease. Furthermore, patients with zone III necrosis may respond better to corticosteroid treatment than those without.

DOI： 10.1111/j.1872-034X.2007.00125.x

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Background. Hepatitis B virus infection is the most frequent cause of fulminant hepatic failure. Recently, systemic inflammatory response syndrome has been reported to be important in patients with fulminant hepatic failure. However, prognostic factors for fulminant hepatitis B have not been fully examined. In this study, we analyzed prognostic factors for fulminant hepatitis B in order to accurately identify patients with fatal outcomes. Methods. Of 110 consecutive patients with fulminant hepatic failure, 36 (33%) were diagnosed with fulminant hepatitis B. Five of the 36 patients received liver transplants, and we analyzed prognostic factors associated with fatal outcomes in the other 31 patients, who consisted of 15 men and 16 women with a median age of 45 (range, 20-74) years. Results. Eleven patients (35%) survived without liver transplantation, and the remaining 20 (65%) died. Nonsurvivors were older and had a higher prevalence ratio of systemic inflammatory response syndrome than survivors. Treatments were similar between survivors and nonsurvivors. Using a multivariate Cox proportional hazard model, age (&gt; 45 years), systemic inflammatory response syndrome, and ratio of total to direct bilirubin (&gt; 2.0) were associated with fatal outcomes. In particular, 1-week and overall survival rates of patients with systemic inflammatory response syndrome at the time of diagnosis were 39% and 8%, respectively, while those of patients without systemic inflammatory response syndrome were 94% and 56%, respectively. Conclusions. Systemic inflammatory response syndrome strongly affects the shortterm prognosis of patients with fulminant hepatitis B, and patients with systemic inflammatory response syndrome might need urgent liver transplantation.

DOI： 10.1007/s00535-007-2029-9

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Background and aim: Many patients continue to die due to the rapid development of cerebral edema and/or multiple organ failure prior to receiving a liver transplantation.
Methods: We investigated the prognostic factors associated with 1-week fatal outcomes after the diagnosis of fulminant hepatic failure, which were associated with fatal outcomes prior to receiving liver transplantation, in 104 patients with non-acetaminophen-related fulminant hepatic failure.
Results: With a multivariate logistic regression analysis, age (&gt; 40 years), systemic inflammatory response syndrome (SIRS) and plasma prothrombin activities (&lt;= 10%) were significantly associated with fatal outcomes at 1 week after diagnosis in 104 patients. At the time of diagnosis, 50 patients (48%) were in a state of SIRS. Significant differences were observed between patients with and without SIRS regarding the period from the initial symptoms to the diagnosis of fulminant hepatic failure, hepatic coma grade, serum alanine aminotransferase level, serum creatinine level and plasma prothrombin activity. With a multivariate logistic regression analysis, age (&gt; 40 years), cause of fulminant hepatic failure (viral hepatitis), plasma prothrombin activity (&lt;= 10%) and no administration of protease inhibitor were significantly associated with the 1-week fatal outcomes of 50 patients with SIRS.
Conclusions: Patients with SIRS exhibited hepatic failure of increased severity and SIRS may reduce the probability of receiving a liver transplantation. In order to estimate the efficacy of protease inhibitor for patients with SIRS, a prospective randomized trial is required.

DOI： 10.1111/j.1440-1746.2007.04874.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OKAYAMA UNIV MED SCHOOL  

We report herein a case with acute hepatitis due to hepatitis B virus genotype Ale, concurrent with amebic colitis. A 39-year-old homosexual Japanese man was admitted to our hospital with jaundice. Laboratory tests showed an elevation of transaminase and positivity for hepatitis B surface antigen and IgM-type antibody to hepatitis B core antigen. The hepatitis B virus genotype was determined to be Ae. Furthermore, a mud-like stool with blood and mucous had sometimes been noted during the past 3 years, and amebic colitis was shown by colonofiberscopy during hospitalization. The patient was diagnosed with acute hepatitis B, concurrent with amebic colitis, and was successfully treated with lamivudine and metronidazole. In Japanese patients with acute hepatitis B virus genotype A infection, homosexual activity tends to be high. Furthermore, in Japanese homosexual men, amebiasis has been increasing. Thus, in Japanese patients with acute hepatitis B, a determination of genotype should be performed in order to investigate the route of transmission of hepatitis B virus, and a search for amebiasis should be performed in patients with acute hepatitis due to hepatitis B virus genotype A. Furthermore, education of homosexual men regarding hepatitis B virus, hepatitis B virus vaccination, and amebiasis is urgently required.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Hepatitis B immunoglobulin (HBIg) and lamivudine combination has been accepted as the best way to control hepatitis B recurrence after liver transplantation. However, the optimal dose of HBIg and the target titer of hepatitis B surface antibody (HBsAb) remain unclear. We report our satisfactory experience with high-dose HBIg in the early period followed by low-dose HBIg with lamivudine. Subjects comprised five patients with fulminant hepatitis (FH) and 18 patients with liver cirrhosis (LC) who underwent liver transplantation. HBIg at a dosage of 200 IU/kg per day was administered for one week postoperatively. Thereafter, HBIg was administered only for HBsAb titer &lt; 100 IU/L. After six months, HBIg was withdrawn in FH and administered in LC only for HBsAb titer &lt; 10 IU/L. Lamivudine was administered to two FH and all LC cases. Although two patients with LC showed transient hepatitis B surface antigen (HBsAg) recurrence, all patients remained HBsAg-negative at the final follow-up date. This method allows reliable and cost-effective control of hepatitis B recurrence.

DOI： 10.1097/01.tp.0000246310.75638.86

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

Objective In Caucasian type 1 autoimmune hepatitis patients with a main susceptibility of human leukocyte antigen DR3 and DR4, elderly patients have a higher frequency of concurrent autoimmune disease and cirrhosis at presentation. However, in Japanese patients, the disease is dominantly associated with DR4, and their clinical features may be different from those of previous reports. In this study, we assessed the clinical features of Japanese elderly patients with type 1 autoimmune hepatitis.
Methods We investigated 160 consecutive patients with type 1 autoimmune hepatitis, consisting of 34 elderly patients (65 years) and 126 younger patients (&lt; 65 years).
Results There were no differences in form of clinical onset, frequencies of concurrent autoimmune disease, positive proportions of anti-nuclear antibody and/or anti-smooth muscle antibody, and human leukocyte antigen DR status between the two groups. However, the elderly patients had lower serum levels of albumin (p= 0.0049), and higher frequencies of cirrhosis (F4) and pre-cirrhosis (F3) (p= 0.014) compared with the younger patients. In contrast, in elderly patients, the cumulative incidental rate of the normalization of serum alanine aminotransferase levels within 6 months after the introduction of initial treatment was higher in those treated with prednisolone &gt;= 20 mg/day than those treated only with ursodeoxycholic acid (p= 0.001).
Conclusion We speculate that more years may pass between the occurrence of the disease and the presentation in Japanese elderly patients than in younger patients, and we considered that, even in elderly patients, those with advanced fibrosis should be treated with prednisolone in order to prevent progress of the disease into liver failure.

DOI： 10.2169/internalmedicine.46.0420

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：KARGER  

Objective: The aim of this study was to determine the association between pretreatment intrahepatic mRNA levels of interferon receptor and interferon-stimulated genes and response to interferon therapy for genotype 1b chronic hepatitis C. Methods: Forty-four patients with genotype 1b chronic hepatitis C who underwent liver biopsy and then received interferon therapy participated in this study. Pretreatment intrahepatic mRNA levels of interferon receptor genes (IFNAR1, IFNAR2b, and IFNAR2c) and interferon-stimulated genes (OAS1 and PKR) were quantified by competitive polymerase chain reaction. Results: In the genes examined, only IFNAR1 mRNA level was significantly higher in patients with sustained virological and biochemical response to interferon therapy versus those with nonsustained response (p &lt; 0.01). Moreover, mRNA expression ratios of IFNAR1 to IFNAR2 were also significantly higher in patients with sustained virological and biochemical response to IFN therapy (p &lt; 0.01 and p &lt; 0.05, respectively). On the other hand, mRNA levels of IFNAR2b, IFNAR2c, and PKR were significantly higher in patients with histologically active or advanced liver rather than patients with mild or less advanced liver. Conclusions: High intrahepatic mRNA levels of IFNAR1 and mRNA ratio of IFNAR1 to IFNAR2 before treatment may be associated with a favorable response to interferon therapy.

DOI： 10.1159/000096310

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We encountered a case of peritoneal dissemination of hepatocellular carcinoma, successfully treated with a combination therapy of interferon-alpha-2b and oral tegafur/uracil. A 67-year-old Japanese man who underwent a hepatectomy developed peritoneal dissemination. A combination therapy of subcutaneous interferon-alpha-2b and intravenous 5-fluorouracil was started. Four weeks later, he felt severe general fatigue and nausea, and intravenous 5-fluorouracil was replaced with oral tegafur/uracil. At 3 months after the initiation of chemotherapy, enhanced computed tomography showed markedly reduced peritoneal dissemination. A combination therapy of interferon-alpha-2b and oral tegafur/uracil is facile and may be effective for extrahepatic metastasis of hepatocellular carcinoma.

DOI： 10.2169/internalmedicine.46.6362

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PROFESSOR D A SPANDIDOS  

Interferon (IFN) combined with 5-Fluorouracil (5-FU) treatment has recently been reported to show beneficial effects in patients with advanced hepatocellular carcinoma. IFNa is usually provided for this combination therapy. In this study, we investigated the molecular mechanisms of apoptosis induction in hepatoma cell lines with IFNa and 5-FU combination therapy from the view point of 5-FU's additive effect on interferon-related signaling pathways. Five hepatoma cell lines (Hep3B, Huh7, HLE, PLC/PRF/5, and HepG2) were tested for apoptosis inducibility by IFN alpha in the absence or presence of 5-FU. Hep3B was the most apoptosis sensitive to IFN plus 5-FU treatment. The JAK/STAT pathway transcriptional factor ISRE was activated more synergistically when 5-FU was added to IFN alpha treatments. Caspase-3, -9, and especially caspase-8 activity was higher with IFN a plus 5-FU than IFN or 5-FU alone. Inhibition of caspase-8, -9, c-Jun N-terminal kinase (INK), phosphatidylinositide 3-kinase (PI3K), and p38 mitogen-activated protein kinase (p38 MAPK) revealed that caspase-8 inhibition was the most effective at decreasing the apoptotic effects of IFN and/or 5-FU. In JAK1 and ISGF3y-silenced Hep3B cells, the apoptosis induction and caspase-8 activation levels by IFN, even in combination with 5-FU, were abrogated. In conclusion, caspase-8 is the most important factor that controls IFN and 5-FU-induced apoptosis in hepatoma cell lines.

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Background
Although the prognosis of type 1 autoimmune hepatitis is generally good with immunosuppressive treatment, the disease progresses in some patients despite the treatment. The prognosis may be determined by the clinical course.
Aim
To evaluate the long-term prognosis and assess the predictive factors for a serious event, including the development of hepatocellular carcinoma or death.
Methods
Sixty-nine patients with type 1 autoimmune hepatitis were prospectively followed up regularly, with a median follow-up period of 96 months (49-201 months).
Results
During the follow-up period, three patients (4%) developed hepatocellular carcinoma, and two of these three patients died. Another patient died of liver failure. The 10-year survival rate was 98%, and the 10-year hepatocellular carcinoma-free rate was 93%. The four patients experiencing a serious event received higher maintenance doses of corticosteroid during their follow-up periods than those did not. However, serum alanine aminotransferase levels during the follow-up period were higher in these four patients than in the others.
Conclusions
Persistent elevation of serum alanine amniotransferase levels during the follow-up period, rather than factors existing prior to medical treatment is considered to be an important prognostic factor, and it is indicated that poor outcomes may result from the resistance to immunosuppressive treatment.

DOI： 10.1111/j.1365-2036.2006.03113.x

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DOI： 10.1111/j.1440-1746.2006.04339.x

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Recently, unusual patients with autoimmune hepatitis, such as male patients, have increased.
To assess clinical feature of Japanese males with type 1 autoimmune hepatitis compared with females.
We investigated consecutive 160 patients with type 1 autoimmune hepatitis, who consisted of 20 males and 140 females, with a median age of 55 (16-79) years.
Compared with females, males had a lower frequency of definite diagnosis according to the revised scoring system proposed by the International Autoimmune Hepatitis Group (40% vs. 85%) and lower serum levels of immunoglobulin G [1932 (1085-3850) mg/dL vs. 2624 (1354-6562) mg/dL]. However, they were similar in age, form of clinical onset, symptomatic concurrent autoimmune disease, human leucocyte antigen DR status and frequency of cirrhosis at the time of diagnosis. The normalization of serum alanine aminotransferase levels within 6 months after the introduction of corticosteroid treatment was lower in males compared with females (73% vs. 93%).
In male patients, a diagnosis of autoimmune hepatitis should be made carefully. In Japanese patients with a dominant frequency of human leucocyte antigen DR4, gender may affect the response to corticosteroid treatment.

DOI： 10.1111/j.1365-2036.2006.03013.x

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Background: The benefit of surveillance of hepatocellular carcinoma (HCC) for patients with hepatitis C virus (HCV) infection, in terms of long-term survival, has not yet been established.
Methods: A total of 384 consecutive anti-HCV-positive HCC patients admitted to our hospital between January 1991 and October 2003 were enrolled. Patients were categorized into two groups, a surveillance group (182 patients) and a non-surveillance group (202 patients), according to tumor detection in a surveillance program based on periodical examination via ultrasound sonography and alpha fetoprotein determination at 6-month intervals, and their survival rates were compared.
Results: Although there were no significant differences in age and Child-Pugh classes between the two groups, the surveillance group exhibited a smaller tumor size (19 vs. 35 mm) and a higher incidence of single HCC (67% vs. 46%), compared with the non-surveillance group (each, P &lt; 0.001). The cumulative survival rate in the surveillance group was higher than that in the non-surveillance group (5 years survival, 46% vs. 32%, P &lt; 0.001). When the survival after correction of the lead-time bias in the surveillance group was analyzed according to the Child-Pugh classification, the surveillance program was found to have had a favorable outcome in Child-Pugh class A patients, but not in Child-Pugh class B/C patients.
Conclusions: HCC surveillance for patients with HCV infection can lead to discovery of tumors at an early stage, especially in Child-Pugh class A, resulting in a favorable outcome.

DOI： 10.1111/j.1478-3231.2006.01270.x

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Background
Although a few adult cases of fulminant-type autoimmune hepatitis have been reported, their clinical features and prognosis have remained uncertain.
Aim
To assess the clinical features and prognosis of patients with fulminant-type autoimmune hepatitis.
Methods
Eleven patients (10%) diagnosed with fulminant-type autoimmune hepatitis in accordance with the 1999 criteria of the International Autoimmune Hepatitis Group were analysed.
Results
All 11 patients were female, with a median age of 53 years. Five patients survived without liver transplantation, one received a liver transplantation, and five died without liver transplantation. Nine patients (82%) survived for 2 weeks or more following diagnosis, without liver transplantation. Except for the patient receiving a liver transplantation, serum total bilirubin levels measured during the clinical course were significantly higher in non-survivors than in survivors, although the accompanying serum alanine aminotransferase levels measured for the two groups were similar. Most significantly, serum total bilirubin levels in non-survivors worsened during days 8-15, while levels in survivors improved during the same period.
Conclusions
The short-term prognosis for patients with fulminant-type autoimmune hepatitis may be good. However, patients whose serum total bilirubin levels worsen during days 8-15 should be considered for liver transplantation.

DOI： 10.1111/j.1365-2036.2006.02894.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OKAYAMA UNIV MED SCHOOL  

This study was conducted to develop a simple surrogate index comprised of routinely available laboratory tests to reflect the histological fibrosis stage. Clinical characteristics and laboratory data from 368 and 249 consecutive patients with chronic hepatitis C, a training cohort and a validation cohort, respectively, were retrospectively evaluated. Platelet (Plt) count and albumin (Alb) level contributed to the discrimination of the respective fibrosis stages. We derived the fibrosis index (FI), FI = 8.0 - 0.01 x Plt (10(3)/mu l) - Alb (g/dl), from a multiple regression model. FI significantly correlated with the histological fibrosis stage in both the initial and validation cohort at rho = 0.691 and rho = 0.661, respectively (Spearman's rank correlation coefficient, p &lt; 0.0001). The sensitivity and positive predictive value of FI at a cutoff value &lt; 2.10 for predicting fibrosis stage F0-1 were 66.8% and 78.8% in the initial cohort and 68.5% and 63.6% in the validation cohort, respectively. Corresponding values of FI at a cutoff value &gt;= 3.30 for the prediction of F4 were 67.7% and 75.0% in the initial cohort and 70.8% and 81.0% in the validation cohort. The fibrosis index comprised of platelet count and albumin level reflected the histological fibrosis stage in patients with chronic hepatitis C.

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL PUBLISHING  

Background: Platelet count has been shown to correlate with the hepatic fibrosis stage in chronic hepatitis C (CHC). The aim of the present study was to assess hepatic fibrosis progression or regression of CHC patients by long-term monitoring of the platelet count.
Methods: A total of 429 interferon (IFN)-treated CHC patients were studied. Follow-up data on the platelet count were collected every 6 months after IFN therapy. The IFN response was defined as follows: complete responders (CR, n = 121) demonstrating persistent clearance of serum hepatitis C virus (HCV) RNA; biochemical responders (BR, n = 94) demonstrating alanine aminotransferase (ALT) normalization for &gt;= 6 months without eradication of HCV-RNA; and non-responder (NR, n = 214) demonstrating all other patterns.
Results: In comparison with the baseline level, mean platelet count increased in the CR group from 0.5 years after IFN therapy (for each point, P &lt; 0.01), but significantly decreased in the NR group from I year after IFN therapy (for each point, P &lt; 0.01). In the BR group, an increase in mean platelet count was observed from 0.5 to 3.5 years following IFN therapy (for each point, P &lt; 0.01), followed by a gradual decrease.
Conclusion: An increase from baseline values in platelet count was observed, regardless of the presence of HCV-RNA, in both the CR and BR groups, suggesting the importance of ALT normalization in preventing hepatic fibrosis progression in IFN-treated CHC patients. (C) 2006 Blackwell Publishing Asia Pty Ltd.

DOI： 10.1111/j.1440-1746.2006.04201.x

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：JOHN WILEY & SONS INC  

In contrast to the United States, Japanese patients with chronic hepatitis C currently treated with interferon are generally 10 to 15 years older. Older patients, however, tend to experience more frequent adverse events. This study was conducted to clarify the effect of patient age on the efficacy and safety of combination therapy. We consecutively enrolled 208 patients with naive chronic hepatitis C. Patients were classified into three groups according to age: younger than 50 years of age (n = 52); 50 to 59 years old (n = 83); and 60 years of age or older (n = 73). Interferon alpha-2b therapy was administered daily for 2 weeks, followed by 3 times per week for 22 weeks, while ribavirin was administered daily. Of the 208 study patients, discontinuation of therapy or dose reduction was required in 116 (56%) and was more frequent in older patient groups: 38%, 48%, and 77% for the &lt;50, 50-59, and &gt;= 60-year-old patient groups, respectively (P &lt; .001). Multivariate analysis showed patient age to be independently associated with adherence to therapy. A sustained virological response was achieved in 77 (37%) patients, with genotype, viral load, and adherence to therapy associated with this achievement. A tendency toward a lower sustained virological response rate was seen in the older patients. In conclusion, patient age is an important factor contributing to the safety of combination therapy. Thus, treatment schedule should be modified, or other therapeutic modalities should be considered for older patients with chronic hepatitis C.

DOI： 10.1002/hep.20984

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Background/Aims: Autoimmune hepatitis shows a good response to immunosuppressive treatment, and the prognosis may be determined by the clinical course. The present study was conducted in order to analyze the factors contributing to the outcomes of patients with type I autoimmune hepatitis.
Methods: Eighty-four consecutive patients with type 1 autoimmune hepatitis were followed up regularly for a median follow-up period of 70.5 months (16.2-163 months). We analyzed the prognostic factors using time-fixed and time-dependent Cox proportional hazard models. The end point was progression of the disease to decompensated liver cirrhosis.
Results: Seventy-seven patients (92%) were treated with prednisolone during the follow-up period, and 11 patients (13%) developed decompensated liver cirrhosis. Using a time-dependent multivariate model, the starting dose of corticosteroid (dose of prednisolone &lt; 20 mg/day), relapse within 3 months after the normalization of serum alanine aminotransferase levels with initial treatment, and elevated serum alanine aminotransferase levels during the follow-up period (&gt; 40 IU/L), all showed a significant association with progression of the disease.
Conclusions: The prognosis of type 1 autoimmune hepatitis on adequate immunosuppressive treatment improves when the serum alanine aminotransferase level persists at &lt;= 40 IU/L. Factors existing prior to medical treatment may not affect the prognosis. (c) 2005 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

DOI： 10.1016/j.jhep.2005.06.006

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Background. Many patients with fulminant hepatic failure die before receiving liver transplantation because of the difficulty of pinpointing the suitable timing for liver transplantation. The revised King's College criteria are useful for patients with acetaminophen-related fulminant hepatic failure; however, in those with non-acetaminophen-related fulminant hepatic failure, a new prognostic system that can accurately identify the suitable timing for liver transplantation is required.
Methods. Using the first sample consisted of eighty patients with fulminant hepatic failure, we examined 2-week poor prognostic parameters at the time of diagnosis of fulminant hepatic failure (day 1) and on days 4, 8, and 15, respectively, and a 2-week prognostic scoring model was constructed. To confirm the accuracy of this model, validation was performed in the second sample consisting of 26 patients.
Results. Cause of fulminant hepatic failure (hepatitis B virus or indeterminate), hepatic coma grade (III or IV), systemic inflammatory response syndrome (yes) and ratio of total to direct bilirubin (&gt; 2.0) were associated with 2-week outcomes during days 1-15. Each of these four parameters was valued at + 1. The 2-week survival rate inpatients scoring &lt; 3 was &gt;= 80% in contrast to less than 30% in patients scoring &gt;= 3. When this scoring model was applied to the second sample, the sensitivity, specificity, and positive and negative predictive values were 87.5%, 90.0%, 93.3%, and 81.8%, respectively.
Conclusions. This scoring model may be useful for predicting 2-week outcomes and determining the suitable timing for liver transplantation in patients with non-acetaminophen-related fulminant hepatic failure.

DOI： 10.1097/01.tp.000173651.39645.35

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OKAYAMA UNIV MED SCHOOL  

Lamivudine is widely used to treat patients with hepatitis B. However, the outcomes in patients with hepatocellular carcinoma (HCC) treated with lamivudine have not been established. This study was conducted to evaluate the outcomes of lamivudine treatment for patients with HCC using an untreated, matched control group. Thirty patients with controlled HCC orally received lamivudine. As controls, 40 patients with HCC who were not treated with lamivudine and matched for clinical features were selected. The lamivudine-treated and untreated groups were compared with respect to changes in liver function, HCC recurrence, survival, and cause of death. In the lamivudine-treated group, there was significant improvement in the Child-Pugh score at 24 months after starting treatment, while no improvement was observed in the untreated group. There was no significant difference in the cumulative incidence of HCC recurrence and survival between the groups. However, there was a significant difference in the cumulative incidence of death due to liver failure (P = 0.043). A significant improvement in liver function was achieved by lamivudine treatment, even in patients with HCC. These results suggest that lamivudine treatment for patients with HCC may prevent death due to liver failure. Further prospective randomized studies using a larger number of patients are required.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

A 57-year-old woman was admitted due to a hemorrhage from esophageal varices. Laboratory tests showed liver dysfunction, elevated immunoglobulin G levels and positivity for anti-nuclear antibodies. Serum hepatitis B virus and hepatitis C virus markers were negative. The liver biopsy specimen was compatible with autoimmune hepatitis, and low-dose prednisolone was started. During the follow-up, her serum alanine aminotransferase levels continued to fluctuate between 40 and 60 IU/l. Nine years later, hepatocellular carcinoma 20 mm in diameter was detected. This case suggests that hepatocellular carcinoma develops even if serum alanine aminotransferase levels are maintained at less than twice the upper normal limit.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL PUBLISHING ASIA  

Background: The prevalence of prior hepatitis B virus (HBV) infection in hepatocellular carcinoma (HCC) patients and its role in hepatocarcinogenesis are not clear. The aim of the present study is to clarify the importance of prior HBV infection in development of HCC.
Methods: Of 1288 consecutive HCC patients between January 1999 and October 2002, 1008 patients were enrolled. To determine the influence of prior HBV infection in hepatitis B surface antigen (HBsAg)-negative HCC, the prevalence of antibody to hepatitis B core antigen (anti-HBc) was examined according to age, and the clinical features were compared between the anti-HBc positive and the negative groups.
Results: The proportion of HBsAg-negative HCC patients, HCC patients with antibody to hepatitis C virus (anti-HCV; C-HCC) and HCC patients negative for both HBsAg and anti-HCV (nBnC-HCC), increased with age. The anti-HBc-positive rates in C-HCC patients also increased with age. Those rates in nBnC-HCC patients were &gt; 50% in all age groups. Furthermore, it was found that the anti-HBc-positive rates of these patients were higher than those of corresponding control patients. Tumor size and a positive rate for vessel involvement both in C-HCC and nBnC-HCC patients were larger and higher, respectively, in anti-HBc-positive patients compared with anti-HBc-negative patients, although the difference in nBnC-HCC did not reach statistical significance because of the small numbers. These tumor characteristics were similar to those of B-HCC patients.
Conclusion: A possible contribution of prior HBV infection to the development of HCC is indicated. (C) 2005 Blackwell Publishing Asia Pty Ltd.

DOI： 10.1111/j.1400-1746.2005.03823.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

Background: Insulin-like growth factor binding protein (IGFBP)-3 functions as a carrier of insulin-like growth factors (IGFs) in circulation and a mediator of the growth suppression signal in cells. There are two reported p53 regulatory regions in the IGFBP3 gene; one upstream of the promoter and one intronic. We previously reported a hot spot of promoter hypermethylation of IGFBP-3 in human hepatocellular carcinomas and derivative cell lines. As the hot spot locates at the putative upstream p53 consensus sequences, these p53 consensus sequences are really functional is a question to be answered.
Methods: In this study, we examined the p53 consensus sequences upstream of the IGFBP-3 promoter for the p53 induced expression of IGFBP-3. Deletion, mutagenesis, and methylation constructs of IGFBP-3 promoter were assessed in the human hepatoblastoma cell line HepG2 for promoter activity.
Results: Deletions and mutations of these sequences completely abolished the expression of IGFBP-3 in the presence of p53 overexpression. In vitro methylation of these p53 consensus sequences also suppressed IGFBP-3 expression. In contrast, the expression of IGFBP-3 was not affected in the absence of p53 overexpression. Further, we observed by electrophoresis mobility shift assay that p53 binding to the promoter region was diminished when methylated.
Conclusion: From these observations, we conclude that four out of eleven p53 consensus sequences upstream of the IGFBP-3 promoter are essential for the p53 induced expression of IGFBP-3, and hypermethylation of these sequences selectively suppresses p53 induced IGFBP-3 expression in HepG2 cells.

DOI： 10.1186/1471-2407-5-9

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL MUNKSGAARD  

Background: Although a variety of papers demonstrated inhibited hepatocarcinogenesis with interferon (IFN) therapy for chronic hepatitis C, a small number of hepatocellular carcinomas (HCCs) were still observed even in sustained virologic responders. Aims: To clarify factors affecting the development of HCC, we analyzed the frequency of HCC in sustained virologic responders over a long-term observation period. Methods: Seven hundred and ninety-two out of the 2623 IFN-treated hepatitis C patients who had undergone liver biopsy showed sustained virologic response. Screening for development of HCC was performed periodically during an average follow-up of 5.1 years. Fibrosis of the pretreatment liver biopsy sample was graded. Risk factors for HCC were analyzed by using Cox proportional hazards regression. Results: Of 792 patients, 23 developed HCC. Univariate analysis showed that stage of hepatic fibrosis, age, and alcohol consumption were significantly associated with a risk of HCC (P&lt;0.001). There was a significant difference in the cumulative incidence between patients stratified according to these variables (P&lt;0.001). Conclusions: Pretreatment hepatic fibrosis score, age, and alcohol consumption may affect development of HCC even in sustained virologic responders. Thus, patients with these factors should be carefully followed even after eradication of the virus.

DOI： 10.1111/j.1478-3231.2004.0956.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：KLUWER ACADEMIC/PLENUM PUBL  

The hepatitis B virus (HBV) gene has been detected in hepatocellular carcinoma (HCC) tissue negative for the hepatitis B surface antigen and positive for the hepatitis C virus (HCV) antibody, but the precise role of the HBV gene in hepatocarcinogenesis has yet to be clarified. We studied the HBV gene in liver tissue several years before the emergence of HCC. Eleven patients diagnosed with HCV-positive chronic liver disease and who developed HCC were assigned to group A. HBV DNA was detected in 8 of the 11 patients (73%). Twenty-five patients, who did not develop HCC, were selected as group B. Six of the group B patients were classified as DNA-positive (24%). The HBV DNA in liver tissue was found to be significantly related to HCC development (P &lt; 0.01). Thus, the presence of the HBV gene in patients with chronic HCV associated-liver injury appears to promote hepatocarcinogenesis, although prospective studies are needed to confirm this result.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OKAYAMA UNIV MED SCHOOL  

To improve the efficacy of interferon (IFN) treatment for chronic hepatitis C, we have proposed the twice-daily administration of IFN-beta as a promising induction therapy. In this study, we demonstrated differences between the clearance of circulating HCV-RNA and the induction of anti-viral actions during the first 2 weeks of treatment. Nine patients with a high viral load and genotype 1b were randomly assigned to 3 groups: group A received 3MU of IFN-beta twice a day at intervals of 5 and 19 h; group B received 3MU of IFN-beta twice a day at intervals of 10 and 14 h; group C received 6MU of IFN-alpha once a day with ribavirin. The expression of OAS2, PKR, and MxA, in peripheral blood mononuclear cells (PBMCs) were quantified by real-time polymerase chain reaction method. The viral clearance showed a bi-phasic pattern, and those in the second phase of groups A and B were significantly steeper than that of group C. The peak level of OAS2 during the first phase was correlated with the first phase decay. The MxA expression tended to be higher in group A and B than in group C. The expression of these 3 proteins tended to decrease at day 6 in group C, but increase in groups A and B. These might make differences in the viral decay during the second phase.

DOI： 10.18926/AMO/32825

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Language：Japanese   Publishing type：Research paper (scientific journal)  

A 28-year-old man with hepatitis Be antigen positive chronic hepatitis B was retreated for high hepatitis B virus (HBV)-DNA levels due to an unsatisfactory course with IFN-β in 1997, and IFN-α (HLBI) 6 MIU, following IFN-β with recombinant IFN-α in 1998. In July 1999, the patient switched to consecutive IFN-α (BALL-1) 5 MIU daily for two weeks, and then, three times a week. In January 2000, month 5 of retreatment, seroconversion developed with HBV-DNA positivity (by TMA method). We tried lamivudine (LAM) 100 mg daily from December 2000 with the above IFN. One month after combination, his HBVDNA levels had become undetectable (by TMA), and IFN was discontinued. In May 2001, month 6 of LAM intervention, his ALT normalized with undetectable HBV-DNA levels (by real-time PCR). His ALT levels were normal with HBV-DNA negativity (by TMA) for a six-month period. He could eventually go off LAM treatment in October 2001. As of April 2002, month 6 of LAM termination, his ALT values remained within the normal range and he was HBV-DNA negative (by TMA and real-time PCR). This good clinical course suggests that long-term IFN therapy combined with LAM follow-up may be one of the best therapies for incurable IFN-resistant hepatitis B.

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：BRITISH MED JOURNAL PUBL GROUP  

Background and aim: Complement receptor type 1 (CR1) is a transmembrane protein, and human erythrocyte CR1 (E-CR1) is involved in the transport of circulating immune complexes (IC) from the circulation to the reticuloendothelial system, including the liver and spleen. In chronic viral hepatitis, increased levels of IC containing viral particles and an association with various extrahepatic manifestations have been reported. However, regulatory mechanisms for IC levels are not fully understood.
Patients/subjects and methods: We analysed IC, E-CR1, and quantitative polymorphism of the CR1 gene in 149 patients with chronic viral liver diseases and in 64 normal blood donors using an enzyme linked immunosorbent assay, radioimmunoassay, and polymerase chain reaction-restriction fragment length polymorphism, respectively. We also analysed the effect of CR1 gene polymorphism on IC binding to E-CR1 using molecular methods.
Results: E-CR1 levels in patients with chronic hepatitis and chronic viral liver diseases as a whole correlated inversely with increased levels of IC. Moreover, significantly high levels of IC were observed in patients with chronic hepatitis C (CH-C) who were homozygous for the E-CR1 low density allele. We also found low levels of E-CR1 in liver cirrhosis and CH-C but not in CH-B. Low levels of E-CR1 in CH-C were observed, even after considering the polymorphism of the CR1 gene. Finally, we demonstrated CR1 gene polymorphism dependent binding of hepatitis virus containing IC.
Conclusions: Our results emphasise the important role of E-CR1 in clearance of IC from the circulation and the acquired, rather than inherited, decrease in E-CR1 in chronic viral liver diseases, especially of type C.

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC CLINICAL CHEMISTRY  

Background: 2',5.-Oligoadenylate synthetases (2-5AS) are type I interferon (IFN)-induced proteins with antiviral capacity. Three major forms of 2-5AS with distinct enzymatic activities have been described in IFN-treated human cells. We. measured, distinct forms of 2-5AS MRNA to analze the relationship with its enzymatic activity and response to IFN therapy in chronic hepatitis C.
Methods: We established a method to quantify p40/p46 and p69/p71 forms of 2-5AS mRNA by use of reverse transcription followed by competitive PCR. The 2-5AS mRNA concentrations, were measured in peripheral blood mononuclear cells from 40 patients with chronic hepatitis C and 28 control individuals.
Results: Reconstitution experiments and comparison with Northern blot analyses revealed that our method accurately. and linearly quantified 2-5AS mRNA. 2-5AS mRNA concentrations and 2-5AS enzymatic activity were correlated (P &lt;0.03). Our data demonstrated a correlation in 2-5AS mRNA between p40/p46 and p69/p71 (P &lt;0.02), indicating a. similar regulation of the expression of these genes. Our data also demonstrated that pretreatment concentrations of 2-5AS mRNA correlated with responses to IFN therapy in chronic hepatitis C.
Conclusions: Our method for measuring 2-5AS mRNA concentrations could provide art important marker for selecting patients for IFN therapy and may be useful for the development of more effective therapeutic strategies for chronic hepatitis C. (C) 2002 American Association for Clinical Chemistry.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OKAYAMA UNIV MED SCHOOL  

The preS2 region of the hepatitis B virus (HBV) has been reported to have human polymerized albumin receptor (PAR) activity, which correlates with viral replication. Here, we studied the genomic sequence of the preS region from rare patients lacking PAR activity, despite active viral replication. PAR and DNA polymerase activity was identified in 178 HBe antigen-positive HBV carriers, and a significant correlation between 2 markers was shown, except in 2 hepatitis patients lacking PAR activity. Nucleotide sequences of the preS region of HBV from both patients were examined by direct sequencing of PCR products. In one patient, a 45-base deletion was found to overlap half of the putative polymerized human albumin binding site in the preS2 region. In the other patient, a point mutation at the first nucleotide of the start codon of the preS2 region of HBV was found. There was no such genomic change in the 3 control HBV sequences. These results indicate that the preS2 region is necessary for binding of polymerized human albumin, and this is the first report of naturally existing mutant virus with no or low PAR activity.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCI IRELAND LTD  

In the present study, we have analyzed the amount of precore wild-type hepatitis B virus (HBV) (wild-type) and precore mutant HBV (nt 1896: G --&gt; A) (precore mutant) of HBV carriers; 31 asymptomatic healthy carriers (ASC) and 28 patients with chronic hepatitis (CH). Wild-type and precore mutant were quantified using sensitive and specific quantification methods: competitive wild-type-sequence-specific assay and competitive mutation-site-specific assay with different sets of specific primers and internal controls. Median serum levels of wild-type and precore mutant were 9.60 and 8.60 log copies/ml (median percentages of precore mutant in total HBV-DNA: 11.7%) in HBeAg(+) ASC, 8.48 and 8.00 (33.3%) in HBeAg(+) CH, and 6.30 and 6.85 (84.7%) in anti-HBe(+) CH, respectively, showing higher levels of the relative amount of precore mutant to wild-type along with HBeAg/anti-HBe status. Only precore Mutant, but not wild-type was detected in anti-HBe(+) ASC. Although median percentages of precore mutant at the anti-HBe(+) ASC and CH stages were much higher than those at the HBeAg(+) ASC and CH stages, a Substantial amount of precore mutant was found even at the HBeAg(+) stages. Existence of a substantial amount of precore mutant even in HBeAg(+) ASC suggests that the occurrence of precore mutant is not always closely associated with seroconversion from HBeAg to anti-HBe. (C) 2002 Elsevier Science B.V. All rights reserved.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：GEORG THIEME VERLAG KG  

Background and Study Aims: Antimitochondrial antibody (AMA)-negative primary biliary cirrhosis (PBC) has been difficult to diagnose. Laparoscopic features of AMA-negative PBC were evaluated in comparison with those of AMA-positive PBC and autoimmune hepatitis.
Patients and Methods: 71 patients who fulfilled the diagnostic criteria for PBC were enrolled in the study; 48 were AMA-positive and 23 were AMA-negative. As a disease control, 46 autoimmune hepatitis patients were included. Both the frequency and specificity of each laparoscopic finding were evaluated. A laparoscopic scoring system was introduced, which used, common and uncommon laparoscopic findings, and was evaluated for the diagnosis of AMA-negative PBC.
Results: The characteristic laparoscopic findings for AMA-positive PBC were yellowish-white marking (92%), dark-brown discoloration (73%), gentle undulation (67%), reddish patch (38%), and yellowish-white nodules (32%). On the other hand, laparoscopic findings such as trench-like depression, reddish markings, and wide and small depressions were uncommon in PBC compared with autoimmune hepatitis. The frequencies of characteristic and uncommon laparoscopic findings did not differ statistically between AMA-positive and AMA-negative PBC, but were different between AMA-positive or AMA-negative PBC and autoimmune hepatitis. Scores based on common and uncommon laparoscopic findings were 5.5 +/- 1.5 (mean +/-SD) in AMA-positive PBC, 5.6 +/- 2.0 in AMA-negative PBC, and -0.30 +/- 0.5 in autoimmune hepatitis.
Conclusion: The laparoscopic findings in AMA-negative PBC did not differ from those of AMA-positive PBC. A laparoscopic scoring system may be helpful in the diagnosis of AMA-negative PBC.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC CANCER RESEARCH  

Background: The matrix-degrading proteinases are believed to play an important role in the invasion and metastasis of hepatocellular carcinoma (HCC), but no one has ever seen the in situ matrix-degrading activity in HCCs.
Purpose: To demonstrate the cellular localization of actual gelatinolytic activity and to investigate the invasive potential of human HCC.
Experimental design: HCC cases (30) were subjected to in situ gelatin zymography and SDS-gelatin gel zymogram.
Results: In situ gelatin zymography revealed a heterogeneous gelatinolytic activity in HCC cells, as well as stromal cells of noncancerous livers. The gelatinolytic intensity was stronger in 15 HCC nodules than in the corresponding noncancerous livers and was significantly associated with the cancer invasion to the capsule of the HCCs and to the portal veins. An intense gelatinolytic activity was detected in HCC cells in the front of tumor invasion. SDS-gelatin gel zymogram revealed gelatinases A and B that were mostly in latent forms.
Conclusions: The present study demonstrates high gelatinolytic activity at the invasive front of HCCs at a cellular level and that HCC has an invasive potential with the gelatin (matrix)-degrading metalloproteinases. Furthermore, it suggests the importance of the activation mechanism of gelatinolytic enzymes in the invasion and metastasis of HCCs.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OKAYAMA UNIV MED SCHOOL  

It has been documented that the serum complement activities measured by hemolytic assay (CH50) are decreased after storage of sera at a low temperature in some patients with chronic hepatitis C. However, the mechanism of this phenomenon has not been identified yet. Here, we tried to elucidate factors involved in the cold activation of complement (CAC). To clarify what pathway is activated in CAC, we measured complement cleavage products after cold storage of sera. C4d increased significantly after 12 h-storage at cold temperatures in 5 CAC (+) sera compared with 5 CAC (-) (P &lt; 0.01) and 3 control sera (P &lt; 0.05), while Bb did not increase in any of the groups. In order to determine whether IgG or IgG complex is necessary for CAC, 8 CAC (+) sera were incubated with Protein G Sepharose gel beads, and all of them retained hemolytic activities to some extent after cold storage. Column chromatography through Superose 6HR of CAC-positive serum identified the fractions containing molecules that induced CAC in normal serum, which were depleted by treatment with protein G Sepharose. In conclusion, CAC in hepatitis C seems to occur via a classical or lectin pathway, and the IgG complex produced in hepatitis C virus infection may be an important factor in inducing CAC, a common extrahepatic manifestation of hepatitis C.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC  

To improve the efficacy of interferon (IFN) therapy for chronic hepatitis C, we proposed a therapy with twice-a-day injection of IFN beta as the induction. To assess its biological enhancement, we compared antiviral activities in vitro using intermittent treatment schedules simulating the clinical condition. FL cells were treated with IFN beta twice in 12 h interval (Single treatment, 1000 and 0 IU/ml; Double treatment, 500 IU/ml each) and challenged with Sindbis virus. Antiviral activities were determined with 50% cytopathic effect. Activities and mRNA expressions of 2'5'oligoadenylate synthetase (2'5'AS) were also examined. Single treatment showed its peak activity at 9 h, while Double treatment was at 3 h after the second treatment. Double treatment had a significantly higher peak activity. The up-regulated activities of 2'5'AS lasted much longer with Double treatment. The present findings demonstrated Double treatment could induce efficient biological enhancement, which is thought based on the priming effect. (C) 2000 Academic Press.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER MEDICAL ASSOC  

Eleven cases of hepatitis B virus (HBV) infection (5 cases of acute hepatitis B and 6 of subclinical infection) were detected among 65 members of our university's American football team during a period of 19 months. All tested positive for antibody to the hepatitis B surface antigen (HB, Ag) or core antigen (HBcAg). The incidence of HBV infection among team members (20.4%) was significantly higher (P&lt;.001) than among students who tested positive for andibody to HBsAg throughout the university (1.8%). We also detected a single carrier of hepatitis B e antigen (HB,Ag) on the team. Analysis of HB,Ag subtypes in 3 of 5 players with acute hepatitis B indicated that their subtype (adr) was identical to that of the HBeAg carrier. All players with acute hepatitis B belonged to the same training group, which also included the HBeAg carrier. Our analysis suggests that horizontal transmission of HBV can occur even in a sports team, probably due to contact with open wounds during training.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MARY ANN LIEBERT INC PUBL  

To improve the long-term efficacy of interferon (IFN) for treatment of chronic hepatitis C virus (HCV) infection, we proposed induction therapy with twice-a-day IFN-beta injection, This study was intended to clarify the antiviral mechanism. Thirty patients were randomly assigned to two groups: group A (twice-a-day therapy) received 3 MU IFN-beta intravenously (i.v.) twice a day for 2 weeks; group B (once-a-day therapy) received 6 MU of IFN-beta daily, HCV RNA, IFN-beta, alanine aminotransferase (ALT), 2'5'-oligoadenylate synthetase (2'5'-AS) activity, and beta(2)-microglobulin in serum were compared between the two groups during the first 2 weeks of IFN therapy. The clearance rate of serum HCV RNA in group A (86.7%) was significantly higher than that in group B (13.3 %) at day 3 (p = 0.0006), No accumulation of IFN-beta was shown in serum throughout the therapy, The ratio (day 3/day 1) of 2'5'-AS activity was significantly higher in group A. Multivariate analysis indicated twice-a-day IFN-beta injection therapy led to significantly early clearance of circulating HCV. Twice-a-day IFN-beta injection therapy could induce biologically enhanced antiviral activities and be an efficient induction therapy for eradication of HCV.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：EATON PUBLISHING CO  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：EDITRICE KURTIS S R L  

Serial measurements of body mass index (BMI), serum concentrations of testosterone (T), estradiol (E) and leptin (L) were performed before and after gonadotropin (Gn) therapy in an 18-year-old male subject (BMI 25.4 kg/m(2)) with idiopathic hypothalamic hypogonadism (IHH). We also measured the BMI and serum concentrations of L in 99 age-matched healthy subjects. Serum L correlated significantly with BMI in control subjects (r=0.84, p&lt;0.0001). Baseline serum concentrations of L in our case were markedly high and both T and E were very low, but On therapy resulted in a gradual decrease in L and improvement in T and E, finally reaching the control levels of BMI-matched subjects. Our results demonstrate that T is a powerful negative modulator of serum L independent of BMI in conditions associated with low T levels, such as IHH. (C) 2000, Editrice Kurtis.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：P J D PUBLICATIONS LTD  

To identify the serum factors that affect circulating leptin levels, we measured the serum concentrations of leptin, testosterone (T), estradiol (E), serum alanine aminotransferase, total cholesterol and uric acid (UA) in healthy male adolescents (age, 18.3 +/- 0.1 years, n=96). We also measured body mass index (BMI), percent body fat and thickness of skin fold to assess the effect of body constitution on serum leptin level. Since serum concentration of leptin significantly correlated with BMI (r=0.820, p&lt;0.001), we analyzed the relation-ship between leptin/BMI ratio (L/BMI) and serum parameters. Analysis of data of subjects with normal serum T level showed a significant inverse correlation between L/BMI and serum T levels (n=96, r=-0.294, p&lt;0.005), but no such correlation was present among non-obese subjects (n=70) with BMI of +/- 20% of normal (22 kg/m(2)). There was no correlation between L/BMI and serum E level. Serum UA level significantly correlated with L/BMI in both the test group (n=96, r=0.520, p&lt;0.001) and non-obese subjects (r=0.369, p&lt;0.005). Stepwise multiple regression analysis showed that UA independently and significantly influenced serum leptin levels in both the test and control groups. Our results demonstrate that T weakly influences serum leptin concentration, and that UA concentrations strongly influences serum leptin in healthy male adolescents independent of their obesity level.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

OBJECTIVE: The aim of this study was to elucidate the relationship between serum leptin levels and fatty liver in male adolescents.
METHODS: We investigated the relationship between the concentration of circulating leptin and fatty liver by measuring the serum concentration of leptin in 384 male students who received the matriculation health examination in Okayama University in 1996 (n = 197; age, 18-20 yr) or 1997 (n = 87; age, 18-20 yr).
RESULTS: Serum leptin levels correlated positively with body mass index (BMI), percent body fat (%FAT), thickness of skin fold (TSF), and serum concentration of ALT in 197 subjects. Examination of serum leptin in 67 subjects with BMI greater than or equal to 24.2 but &lt;28.6 kg/m(2) showed a progressively higher levels in subjects with high serum ALT. Serum leptin levels in subjects with abnormally high serum ALT (greater than or equal to 37 IU/L) were significantly higher (p &lt; 0.05) than in subjects with normal serum ALT independent of BMT, %FAT, and TSF. Serum leptin levels were also significantly higher in subjects with fatty Liver (detected by abdominal ultrasonography), independent of BMI and %FAT, compared with subjects without fatty liver. Stepwise multiple regression analysis showed that serum leptin level was an independent risk factor for fatty liver. In addition, serum leptin levels correlated with serum ALT (r = 0.518; p &lt; 0.0005) and cholinesterase (r = 0.511; p &lt; 0.0005) levels in 48 subjects with fatty liver.
CONCLUSIONS: Our results demonstrated that serum leptin concentrations are high in male adolescents with simple obesity and are associated with high serum ALT or fatty liver. independent of BMI and %FAT, suggesting that the concentration of circulating leptin correlates with fatty liver caused by accumulation of visceral fat. (C) 1999 by Am. Cell. of Gastroenterology.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER VERLAG  

The anti-HLA-DQ3 monoclonal antibodies (mAb) KS13, SO1, SO2, SO3, SO4, and SO5 recognize spatially close but distinct antigenic determinants, since they crossinhibit each other in their binding to HLA-DQ3 antigens, but do not share idiotopes recognized in their antigen combining site by syngeneic and anti-id antisera and mAb. Furthermore, mAb SO1, SO3, SO4, and SO5 react also with HLA-DQ allospecificities other than HLA-DQ3. Sequence analysis of the heavy (V-H) and light (V-L) chain variable region of the six mAb revealed preferential usage of V-H 36-60 and V-K 12/13 gene families. However, the individual V-H and V-L germline gene usage by the six mAb is diverse and the utilization of D, J(H), and J(L) gene segments is heterogeneous. The diverse usage of V-H and V-L. gene segments and heterogeneous amino acid sequences of V-H and V-L CDR, together with the heterogeneous idiotypic profile, may reflect the complexity of the determinants recognized by the six mAb on HLA-DQ3 antigens. The results we have presented provide for the first time information about the structural basis of the diversity of antibodies recognizing human histocompatibility antigens.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：VCH PUBLISHERS INC  

Interest in the characterization of idiotype cascades in the HLA antigenic system has been stimulated by their potential role in the immune response to mismatched HLA allospecificities and in the survival of kidney allografts. Since no information is available about the structural organization of idiotypic cascades in the HLA system, we have sequenced the variable regions of the heavy (V-H) and light (V-L) chains of mouse anti-HLA-DQ3 monoclonal antibody (mAb) KS13 elicited by cell membrane-bound antigens, of syngeneic anti-HLA-DQ3 mAb S2B154 elicited by anti-idiotypic (anti-id) mAb K03-34 and of five syngeneic anti-id mAb elicited by mAb KS13. mAb KS13 and S2B154,which have been previously shown to be very similar in their specificity and idiotypic profile, share several structural characteristics. Their V-H and V-L regions are encoded by the same V-H, V-K and J(H) genes, display relatively similar V(D)J rearrangements and differ only through a few amino acid substitutions. Among the five anti-id mAb elicited by mAb KS13, mAb R1-38 and R18-9 utilize multiple genetic elements that are different from those used by anti-id mAb K03-34, K03-256 and K03-335. These results indicate that diverse V region combinations can confer an anti-id specificity in the antigenic system analyzed. mAb K03-34, K03-256 and K03-335 originate from the same B cell clone, since they use the same V, D and J genes and possess identical V(D)J rearrangements. The latter three anti-id mAb differ only by point mutations, which have dramatic effects on the HLA-DQ3 antigen mimicry properties of the three anti-id mAb. mAb K03-34 is the only one to induce anti-HLA-DQ3 antibodies both in syngeneic and xenogeneic hosts. The antigen mimicry properties of anti-id mAb K03-34 depend upon its three-dimensional conformation, since no significant amino acid sequence homology has been found between its V-H and V-L regions and alpha(1) and beta(1) domains of HLA-DQ3 antigens.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC GASTROENTEROL  

Antibody to hepatitis B core antigen (anti-HBc) was measured by radioimmunoassay in 127 asymptomatic hepatitis B surface antigen (HBsAg) carriers (ASC; mean age 19) who had normal serum alanine aminotrasferase (ALT) levels and 16 patients with chronic hepatitis B (CH; 19). All 16 CH patients, who were positive for hepatitis B e antigen (HBeAg) and 5 ASC cases who were negative for both HBeAg and its antibody (anti-HBe), had high anti-HBc titers. Anti-HBc titers in 27 (56.3%) of the 48 HBeAg-positive ASC and 18 (24.3%) of the 74 anti-HBe-positive ASC were relatively low. Two of the ASC were HBeAg-positive/anti-HBc-negative. In a follow-up study of the 19 HBeAg-positive ASC with low or negative anti-HBc titers, 5 had abnormal serum ALT levels and increased anti-HBc titers. In contrast, in the other 14 of these subjects, serum ALT levels remained normal and the low anti-HBc titers remained unchanged and/or decreased. The serological profile of HBsAg-positive/low or negative anti-HBc titer and increased anti-HBc titer with abnormal serum ALT levels are not necessarily exceptional in HBeAg-positive adolescent ASC. It is suggested that anti-HBc is associated with the liver damage that occurs before adolescence in chronic hepatitis B virus infection.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer-Verlag  

Polypeptides encoded by the pre-Sl and pre-S2 genes of hepatitis B virus (HBV) (pre-Sl antigen and pre-S2 antigen) were detected by enzyme-linked immunosorbent assay (ELISA) in 137 serum samples of patients with HBV infection. The HBV-DNA level closely correlated with the titer of pre-S antigens. However, HBV-DNA levels more closely correlated with the titer of the pre-Sl antigen [HBV-asymptomatic carrier (ASC): n=40, r=0.800, P&lt
0.01
chronic hepatitis B (CH): n=60, r=0.730, P&lt
0.01] than with the titer of the pre-S2 antigen [ASC: r=0.675, P&lt
0.01
CH: r=0.575,P&lt
0.01]. Thirty patients with CH, in whom hepatitis e antigen (HBeAg) was cleared after acute exacerbation (AE) [alanine aminotransferase (ALT) level&gt
200 IU/L] and the ALT level normalized, were followed for 12 months and classified into two groups: Group 1, those in whom HBeAg reappeared with an elevated ALT level within 12 months, and Group 2, those in whom HBeAg was persistently cleared from the serum and a normal ALT level continued. Of the 30 patients, 24 (80%) were classifed into Group 1 and 6 (20%) were classified into Group 2. Changes in serum levels of HBV markers a month before and after AE were observed. The HBV-DNA level and DNA-P activity became negative after AE in both groups. The titer of pre-Sl antigen also decreased after AE, and no significant differences were observed between Group 1 and Group 2. In contrast, the titer of pre-82 antigen and pAR activity decreased more significantly in Group 2 than in Group 1. These results suggest that the detection of the pre-S2 antigen and pAR activity in sera seems to be more useful as a prognostic test for patients with HBV infection than the detection of pre-Sl antigen, HBV-DNA, DNA-P or HBeAg. © 1990 The Japanese Society of Gastroenterology.

DOI： 10.1007/BF02779333

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.2957/kanzo.31.585

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Language：English   Publishing type：Research paper (scientific journal)  

An enzyme-linked immunosorbent assay (ELISA) was developed to detect subtypic determinants (d, y, w and r) of hepatitis B surface antigen (HBsAg) with monoclonal antibodies in a total of 182 sera of 91 HBsAg positive asymptomatic carriers (ASC, mean age
18 years old) and 91 HBsAg positive patients with chronic liver disease (CH, mean age : 33 years old) in Japan. In 91 ASC, the number of adr was 68 (74.7%), that of adw was 18 (19.8%), that of ayw was 2 (2.2%), and that of adwr was 3 (3.3%). In 91 CH, the number of adr was 88 (96.7%), that of adw was 1 (1.1%), that of adyr was 1 (1.1%), and that of adwr was 1 (1.1%). Thirty-six (52.9%) in 68 ASC of adr were positive anti-HBe. In contrast, 14 (77.8%) in 18 ASC of adw were positive anti-HBe. In five (5.7%) in 88 CH of adr, the subtype of adr changed to adwr in acute exacerbation. The quantitive level of subtypic determinant w reached its peak before the peak of serum transaminase, parallel to the quantitive level of HBsAg and binding activity of polymerized human serum albumin receptor on hepatitis B virus particles and DNA-polymerase activity. However, the number of adwr in 91 ASC was 3 (3.3%) with normal level of the serum transaminase. These results suggest that HBsAg positive carriers of adw seem to become positive anti-HBe earlier than HBsAg positive carriers of adr, and that the compound subtype of adwr doesn't always seem to be associated with liver damage. © 1990, The Japan Society for Clinical Immunology. All rights reserved.

DOI： 10.2177/jsci.13.65

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OKAYAMA UNIV MED SCHOOL  

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Language：English   Publishing type：Research paper (scientific journal)  

An enzyme-linked immunosorbent assay(ELISA)was developed to detect polypeptide coded by the pre-S(2)region of hepatitis B virus (HBV) DNA with monoclonal antibody in 120 sera containing hepatitis B virus surface antigen particles. Binding sites for polymerized human serum albumin (pHSA) have been found to be encoded by the pre-S(2) region of hepatitis B virus genome. There can be seen a close correlation between the titers of pre-S (2) polypeptide and those of HBV-pHSA receptor (HBV-pAR) (HBV-asymptomatic carrier : r= 0.826, P&lt
0.01, chronic hepatitis : r=0.787, P&lt
0.01). The titers of pre-S (2) polypeptide of sera from 75 hepatitis B e antigen (HBeAg) positive carriers (mean±SD) was 92±9 in asymptomatic carrier(ASC), 78±21 in chronic persistent hepatitis (CPH), 66±31 in chronic aggressive hepatitis activity moderate (CAH2A), 44±28 in chronic aggressive hepatitis activity severe (CAH2B), 30±6 in liver cirrhosis (LC), and 21±30 in 15 anti-HBe positive ASC, Under interferon treatment in patient with CAH2B, the titer of pre-S (2) polypeptide as well as HBV-pAR activity was significantly reduced before HBeAg was reduced and the serum transaminase was normalized. These results suggest that the ELISA described for detection of pre-S(2) polypeptide might be useful as a prognostic test for HBV-carriers. © 1988, The Japan Society for Clinical Immunology. All rights reserved.

DOI： 10.2177/jsci.11.593

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Language：English   Publishing type：Research paper (scientific journal)  

We examined the activity of the hepatitis B virus (HBV) associated polymerized human serum albumin receptor (HBV-pAR) and the antibody to HBV-pAR (anti-pAR) in the sera from 14 patients of chronic hepatitis B treated with interferon (IFN) by enzyme-linked immunosorbent assay (ELISA). Seroconversion (SC) of HBeAg was observed in 4 cases at the end of the IFN therapy (treatment), and in 4 cases 6 months after treatment. These cases as above had low HBV-pAR activities before treatment or rapidly decreasing HBV-pAR activities during the treatment. In cases whose HBV-pAR activities decreased minimally during the treatment in spite of the temporal disappearance of HBeAg after the treatment, it reappeared with the exacerbation of S-GPT. On the other hand, S-GPT remained in normal range in the cases with low HBV-pAR levels and positive anti-pAR antibody at the time of SC. These results indicate that HBV-pAR activity and anti-pAR antibody might be more useful markers for determing the outcome of hepatitis B patients treated with IFN. © 1988, The Japan Society for Clinical Immunology. All rights reserved.

DOI： 10.2177/jsci.11.665

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Total pages：100p   Language：Japanese

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Total pages：100p   Language：Japanese

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Total pages：75p   Language：Japanese

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Language：Japanese   Publisher：(公社)全国大学保健管理協会  

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Language：Japanese   Publisher：(公社)全国大学保健管理協会  

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Language：Japanese   Publisher：(公社)全国大学保健管理協会  

学生健診における尿糖陽性者への2次健診について、その意義と尿糖陽性者への事後処置の妥当性を、本施設(大学保健管理センター)で糖負荷試験を施行していた2004年以前と、随時血糖、75g糖負荷試験、尿検査を行い、HbA1c 6.0%以上や血糖著明高値の者は近隣の病院へ紹介を行っている2005年以降の結果の比較から検討した。その結果、尿糖陽性者に対する2次健診として、75g糖負荷試験群とHbA1c群を比較すると、75g糖負荷試験群でより高い頻度で耐糖能異常が指摘でき、HbA1cを指標とした場合、耐糖能異常を見逃す可能性が高いことが分かった。

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Language：Japanese   Publisher：(公社)全国大学保健管理協会  

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Language：Japanese   Publisher：(公社)全国大学保健管理協会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(公社)全国大学保健管理協会  

新入生が学生生活に良好に適応していくためには、大学や教職員がどのような配慮をすればよいかを探る目的で、新入生への無記名アンケートを実施した。調査対象は2017年度岡山大学の全新入生で、そのうち2051名(回収率90.4%)の回答を得た。入学後に不安を感じる事柄は、勉強面76.0%、人間関係43.8%、生活一般23.0%であった。勉強面で不安なことは、学力面53.1%、履修登録37.6%、部活動との兼ね合い23.5%であった。履修登録では、授業選択が困難63.8%、履修登録制度が判りにくい31.7%、web入力が困難12.7%であった。自力で履修登録ができた者は45.2%であった。パソコンが苦手・少し苦手な学生は78.1%であった。人前で話すことが苦手な学生の割合は37.7%であり、人前で話すことが苦手でない学生に比べて、勉強面への不安を持つものが有意に多かった。今回の調査結果から、新入生には、勉強面での不安を感じている学生が圧倒的に多いことが判明した。勉強面において、履修登録の教職員側からのさらなる支援、パソコン習熟授業の必修科目化、人前で話すことが苦手な学生を援助機関に繋げる啓発活動と合わせて授業内での教職員の配慮は、新入生のメンタルヘルス不調の発生を抑制すると推測された。このように新入生へのメンタルヘルスの講義と並行して、就学環境・システムに対する働きかけが、メンタルヘルス一次予防にとって重要であると考える。(著者抄録)

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(公社)全国大学保健管理協会  

本学では医療系学生全員に対し、臨床実習開始前に定期検査としてインターフェロンγ遊離試験を実施している。試験方法は、2007〜2010年度はクォンティフェロンTB-2Gを使用し、2011年度、2012年度、2016年度はクォンティフェロンTBゴールド(QFT-3G)、2013〜2015年度はTスポットTB(T-SPOT)を使用した。今回、QFT-3Gを使用した年度とT-SPOTを使用した年度とで陽性率や事後措置を比較検討した。結果、QFT-3GはT-SPOTに比べて陽性および判定保留の頻度が有意に高かった。ただしQFT-3Gは陽性率・判定保留率とも年度による差が大きいことから、結果の解釈に注意を要すると考えられた。

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J-GLOBAL

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J-GLOBAL

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Language：Japanese   Publisher：(公社)全国大学保健管理協会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(公社)全国大学保健管理協会  

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Language：Japanese   Publisher：(一社)香川県医師会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(株)アークメディア  

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Language：Japanese   Publisher：(公社)全国大学保健管理協会  

本学では受動喫煙防止対策として、平成26年4月1日より敷地内全面禁煙とした。措置後の職員における受動喫煙の状況を評価する目的で、本学津島地区定期健康診断を受診した職員を対象としてアンケート調査と尿中コチニン測定を行った。全面禁煙施行1年4ヵ月後の平成27年8月(措置後:アンケート1,122名、コチニン測定589名)の結果を、全面禁煙実施3年8ヵ月前の平成22年8月の定期健診時(措置前:アンケート1,112名、コチニン測定506名)の調査結果と比較した。尿中コチニンは、喫煙者では措置前後のいずれも全例陽性であった。一方、非喫煙者では、23.3%から2.8%と尿中コチニン陽性率が著しく減少していた(P&lt;0.001)。アンケート調査に基づく受動喫煙の自覚と尿中コチニンの関係の検討では、非喫煙者では自覚の無い受動喫煙も14.6%から1.8%と減少していた。措置前後の大学構内での受動喫煙を自覚した者の割合は、非喫煙者において38.0%から15.0%へと半減していた。周囲の喫煙状況では、55.1%から27.4%と減少しており、特に職場の同僚の喫煙が20.6%から5.8%と目立って減少していた。敷地内全面禁煙の導入により自覚的および他覚的にも受動喫煙が著しく減少し、受動喫煙防止対策として有効と考えられた。今後、喫煙を継続している職員への禁煙教育および大学周囲での喫煙に対する対策が必要である。(著者抄録)

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：W B SAUNDERS CO-ELSEVIER INC  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：W B SAUNDERS CO-ELSEVIER INC  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：WILEY-BLACKWELL  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：W B SAUNDERS CO-ELSEVIER INC  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：W B SAUNDERS CO-ELSEVIER INC  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：W B SAUNDERS CO-ELSEVIER INC  

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Language：Japanese   Publisher：(公社)全国大学保健管理協会  

医療系学生932名を対象とし、第3期・4期予防接種が導入される前の2003年、2007年に入学した群と、導入後の2010年、2014年に入学した群に分け、麻疹、風疹、水痘、ムンプスの抗体陽性率を群間比較した。結果、麻疹の抗体陽性率は2003年57%、2007年46%、2010年94%、2014年94%であり、導入後の群が有意に高値であった。風疹の抗体陽性率は2003年81%、2007年54%、2010年67%、2014年56%であり、2003年が最も高値であった。水痘は2003年97%、2007年98%、2010年89%、2014年94%、ムンプスは2003年78%、2007年61%、2010年69%、2014年69%であり、一定の傾向はみられなかった。

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Language：Japanese   Publisher：(公社)全国大学保健管理協会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：全国大学メンタルヘルス研究会  

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Language：Japanese   Publisher：(公社)日本生化学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Other Link： http://search.jamas.or.jp/link/ui/2015264385

Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：W B SAUNDERS CO-ELSEVIER INC  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER SCIENCE BV  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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平成26年度に本学の入学時健診を受けた学生のうち採血の同意が得られ実施した2206名(男子1272名、女子934名)を対象としてeGFRを含む腎機能測定を行い、若年者においてCKDやその予備軍がどの程度存在するのか、また、早期からの予防対策にはどのような視点が重要かを明らかにするための検討を行った。腎機能測定の結果、eGFRが90ml/min/1.73m2未満の者は男子110名(8.6%)、女子46名(4.9%)であった。血清クレアチニンが1.0mg/dl以上は男子39名(3.1%)で、女子にはいなかった。簡易クレアチニンクリアランスが100ml/min未満は男子59名(4.6%)、女子83名(8.9%)であった。腎関連以外の検査値とeGFRとの関係について検討するため、eGFR値を層別化して比較したところ、男女ともeGFRの低下に伴い[BMI][尿酸(UA)]が漸増する傾向を示し、男子では[LDL-コレステロール(LDL-C)]も漸増する傾向を示した。このことから、将来のCDK患者を減らすためには[BMI][UA][LDL-C]高値の若者に対して早期から指導・介入を行うことが重要な可能性が示唆された。

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平成23年7月、岡山大学病院にメンタル系産業医が新たに配置されることになり、当保健管理センターの精神科医が担当となった。同病院では、平成24年度にメンタルヘルス不調が原因で3ヵ月以上休職した看護師が29名おり、このうち新人看護師が16名(55%)を占めていた。そこで当センターでは、新人看護師に対して早期からメンタルヘルス支援を行うことで、メンタルヘルス不調による休職者を減らせるのではないかと考え、平成25年から新人看護師採用時にメンタルヘルス研修を実施した。研修内容は、「社会人としての心構え」「陥りやすい考え方」「ストレス」などについてレクチャーし、その後、ストレスマネジメントシートを配布し、各自記入させた。最後に参加者全員にマイクを回してストレス対処法などを発表させ、情報共有した。研修の効果を検証するため、終了後に新人看護師・師長などにアンケートや聞き取り調査を行った結果、有効であったことが確認された。

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Language：Japanese   Publisher：(一社)日本内科学会  

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Language：Japanese   Publisher：(一社)香川県医師会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本移植学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本アレルギー学会  

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2014&ichushi_jid=J00009&link_issn=&doc_id=20140417070603&doc_link_id=%2Fcw4aller%2F2014%2F006303%2F279%2F0601-0601%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcw4aller%2F2014%2F006303%2F279%2F0601-0601%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER SCIENCE BV  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(公社)全国大学保健管理協会  

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Language：Japanese   Publisher：(公社)全国大学保健管理協会  

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Language：Japanese   Publisher：(公社)全国大学保健管理協会  

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Language：Japanese   Publisher：(公社)全国大学保健管理協会  

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Language：Japanese   Publisher：(公財)大原記念倉敷中央医療機構倉敷中央病院  

症例は28歳女性.38℃台の発熱,嘔気,全身倦怠感にて発症.近医で感冒と診断され解熱薬を内服.第3病日より褐色尿を認め,黄疸も出現したため第6病日に当院に緊急入院.入院時,HBs抗原・IgM-HBc抗体陽性.トランスアミナーゼの著明な上昇とプロトロンビン(PT)活性の低下(14%)を認めるも,意識は清明で肝萎縮も認めなかった.lamivudine内服,ステロイドパルス療法で入院翌日にはトランスアミナーゼ値は急速に低下し,肝萎縮も認めなかったが,PT活性は14%と改善せず,急激な意識レベルの低下を認めたために移植施設に転院.転院後は,3回の血漿交換で肝不全から急速に離脱した.第16病日にはHBs抗原は陰性化し,第33病日に行った肝生検では広汎肝壊死は認めず,急性肝炎回復期の像であった.臨床経過から本例の肝不全および意識障害には一過性の強いエネルギー代謝抑制による肝臓および脳の機能抑制が関与したと推測された.(著者抄録)

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(公社)全国大学保健管理協会  

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Language：Japanese   Publisher：(公社)全国大学保健管理協会  

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Language：Japanese   Publisher：(公社)全国大学保健管理協会  

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Language：Japanese   Publisher：(公社)全国大学保健管理協会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：WILEY-BLACKWELL  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：WILEY-BLACKWELL  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：WILEY-BLACKWELL  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(NPO)日本高齢消化器病学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

大学職員における受動喫煙の認識と実態把握を目的として、職員506名(うち喫煙者25名を含む)を対象に、尿中と血液中のニコチン代謝産物であるコチニンの濃度測定および喫煙・受動喫煙に関するアンケート調査を行った。尿中と血液中のコチニン濃度は有意に正の相関を示した(p&lt;0.001)。「アンケートによる受動喫煙の自覚」と「尿中コチニン濃度から判定した受動喫煙の有無」の一致率は65.2%と、両者の間には乖離がみられた。受動喫煙の客観的評価に尿中コチニン濃度の測定は有用であり、受動喫煙防止対策にも有効と考えられた。(著者抄録)

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Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2013&ichushi_jid=J05953&link_issn=&doc_id=20130524300003&doc_link_id=%2Fci6respo%2F2013%2F000203%2F003%2F0175-0181%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fci6respo%2F2013%2F000203%2F003%2F0175-0181%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(公社)全国大学保健管理協会  

平成23年7月、岡山大学病院(以降、当院と略す)にメンタルヘルス系産業医が新たに配置されることになり、保健管理センターの常勤精神科医が担当になった。メンタルヘルス系産業医として活動するにあたり、独自に復職支援のガイドラインを作成し、これに基づいた支援を行った。本稿では、復職支援のガイドラインを紹介するとともに、産業医活動開始後1年間に関わったメンタルヘルス不調が原因で休業した看護職の復職支援の結果を報告する。ガイドラインの特徴は、支援チームで復職支援を行うこと、休業に入る時期や復職の時期の目安を示したこと、産業医が休業と復職の時期を見立てることなどである。復職にあたっては、休業者の持つスキルと部署が求めるスキルとの相性を考慮した復職部署の決定、および休業者のストレスマネジメント力の向上が重要であることが示唆された。(著者抄録)

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：W B SAUNDERS CO-ELSEVIER INC  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(公社)全国大学保健管理協会  

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Language：Japanese   Publisher：(公社)全国大学保健管理協会  

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Language：Japanese   Publisher：(公社)全国大学保健管理協会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：English   Publisher：WILEY-BLACKWELL  

Peritoneovenous shunt (PVS) is accepted as a treatment for refractory ascites due to liver cirrhosis. Infection is a well-known complication of shunting. However, the effects of PVS in terms of complications for renal disease are unclear. We encountered a case involving a 52-year-old man with alcoholic liver cirrhosis and complications of nephrotic syndrome that were worsened by PVS. He received PVS for refractory ascites due to alcoholic liver cirrhosis before coming to our hospital for evaluation for liver transplantation. Nephrotic syndrome was then identified due to cirrhosis-related membranoproliferative glomerulonephritis (MPGN). Prednisolone was administrated at 60 mg/day for MPGN. On day 5, he showed grade IV hepatic encephalopathy (West Haven criteria). Tapering prednisolone and intestinal cleansing with lactulose treatment improved hepatic encephalopathy, but hyperammonemia persisted and the PVS was removed. After shunt removal, urinary protein levels decreased from 46 g/day to 0.30.5 g/day and ammonia levels decreased. PVS may increase the excretion of urinary protein and increase ammonia levels in patients with complications of glomerulonephritis.

DOI： 10.1111/j.1872-034X.2012.01012.x

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：WILEY-BLACKWELL  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(公社)全国大学保健管理協会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(公社)全国大学保健管理協会  

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