Search

Background and Aim Proton pump inhibitors (PPIs) are a potential cause of gastric carcinogenesis after Helicobacter pylori eradication. Thus, appropriate management including chemoprevention is required. The aim of this study was to evaluate the association between nonsteroidal anti‐inflammatory drugs (NSAIDs) and the incidence of post‐eradication gastric cancer in PPI users. Methods A multicenter retrospective cohort study was conducted. Patients who used a PPI (≥30 days) after H. pylori eradication between 2014 and 2019 were analyzed in nine hospital databases. Gastric cancer incidence was a primary outcome, and their association with NSAIDs use and clinical factors was evaluated. Hazard ratios were adjusted by age, sex, smoking, and Charlson Comorbidity Index. Results During the mean follow‐up period of 2.38 years, 1.13% (31/2431) of all patients developed gastric cancer. The cumulative incidence of gastric cancer in PPI users was 0.25% at 1 year, 0.51% at 3 years, and 1.09% at 5 years in the NSAID users and 0.89% at 1 year, 2.32% at 3 years, and 3.61% at 5 years in nonusers. NSAIDs were associated with a lower gastric cancer risk (adjusted hazard ratio = 0.28, P = 0.005). No gastric cancer was observed in the cyclooxygenase‐2 inhibitor users (n = 256). NSAID use with high dose and long duration was significantly associated with a lower incidence of gastric cancer. Conclusion NSAIDs were associated with a 60% decrease in the gastric cancer incidence in H. pylori‐eradicated PPI users, with dose and duration response effects. NSAIDs may be effective for chemoprevention against PPI‐related gastric cancer.

Spontaneous bile duct rupture is a rare condition in adults, with only 70 cases reported. Increased bile duct wall pressure may lead to rupture and biliary peritonitis. In this patient, the bile duct ruptured in the hepatic left triangular ligament. A 91-year-old man underwent endoscopic retrograde cholangiopancreatography for choledocholithiasis and endoscopic retrograde biliary drainage (ERBD) placement. One week later, removal of the ERBD and common bile duct stones and an endoscopic sphincterotomy (EST) were performed. Four days later, the patient had abdominal pain, increased inflammatory reaction, and jaundice. Abdominal computed tomography showed ascites, bile duct dilatation and fluid collection under the liver (10 cm in diameter). Emergency surgery was performed to drain the fluid. On laparotomy, encapsulated biliary ascites was seen. To search for the site of the leak, after cholecystectomy, a tube (C-tube) was inserted into the common bile duct via cystic duct stump. Because of uncontrollable bleeding, after packing with surgical gauze, the operation was temporarily stopped. The next day, reoperation was performed. Intraoperative cholangiography with contrast dye revealed the perforation site in the left triangular ligament and a partial resection was performed. Bile excretion from the C-tube was subsequently observed, but the patient’s jaundice did not improve. Although endoscopic retrograde cholangiopancreatography revealed that the EST site was normal, ERBD was placed again, and the jaundice gradually improved. Although EST was performed in this case, biliary peritonitis resulting from spontaneous bile duct rupture occurred. This case was very informative because biliary perforation may occur even after EST.

Background and Aims: It remains unclear whether obesity increases the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C who achieved a sustained virological response (SVR) with antiviral therapy. Methods: In this multicenter cohort study, we enrolled patients with chronic hepatitis C who achieved SVR with interferon (IFN)-based therapy (IFN group) or direct-acting antiviral (DAA) therapy (DAA group) between January 1, 1990, and December 31, 2018. The patients underwent regular surveillance for HCC. Cumulative incidence of and the risk factors for HCC development after SVR were assessed using the Kaplan-Meier method and Cox proportional hazard regression analysis, respectively. Results: Among 2,055 patients (840 in the IFN group and 1,215 in the DAA group), 75 developed HCC (41 in the IFN group and 34 in the DAA group) during the mean observation period of 4.1 years. The incidence rates of HCC at 1, 2, and 3 years were 1.2, 1.9, and 3.0%, respectively. Multivariate analysis revealed that in addition to older age, lower albumin level, lower platelet count, higher alpha-fetoprotein level, and absence of dyslipidemia, obesity (body mass index ≥25 kg/m2) and heavy alcohol consumption (≥60 g/day) were independent risk factors for HCC development, with adjusted hazard ratio (HR) of 2.53 (95% confidence interval [CI]: 1.51–4.25) and 2.56 (95% CI: 1.14–5.75), respectively. The adjusted HR was not significant between the 2 groups (DAA vs. IFN; HR 1.19, 95% CI: 0.61–2.33). Conclusions: Obesity and heavy alcohol consumption increased the risk of HCC development after SVR.

Simple Summary Helicobacter pylori is the most important cause of gastric cancer, and its eradication reduces the incidence of gastric cancer after endoscopic resection. However, incidence of metachronous gastric cancer is still high. More studies are needed to identify other chemopreventive drugs that may reduce the incidence of this disease. In this study, we focused on the alteration of the intragastric microbiome and examined the association between the use of antibiotics and probiotic drugs and risk of metachronous gastric cancer. Our findings suggest that the gut microbiome is associated with metachronous gastric cancer development. Abstract Metachronous gastric cancer often occurs after endoscopic resection. Appropriate management, including chemoprevention, is required after the procedure. This study was performed to evaluate the association between medication use and the incidence of metachronous gastric cancer after endoscopic resection. This multicenter retrospective cohort study was conducted with data from nine hospital databases on patients who underwent endoscopic resection for gastric cancer between 2014 and 2019. The primary outcome was the incidence of metachronous gastric cancer. We evaluated the associations of metachronous gastric cancer occurrence with medication use and clinical factors. Hazard ratios were adjusted by age and Charlson comorbidity index scores, with and without consideration of sex, smoking status, and receipt of Helicobacter pylori eradication therapy during the study period. During a mean follow-up period of 2.55 years, 10.39% (140/1347) of all patients developed metachronous gastric cancer. The use of antibiotics other than those used for H. pylori eradication was associated with a lower incidence of metachronous gastric cancer than was non-use (adjusted hazard ratio (aHR) 0.56, 95% confidence interval (CI) 0.38–0.85, p = 0.006). Probiotic drug use was also associated with a lower incidence of metachronous gastric cancer compared with non-use (aHR 0.29, 95% CI 0.091–0.91, p = 0.034). In conclusion, the use of antibiotics and probiotic drugs was associated with a decreased risk of metachronous gastric cancer. These findings suggest that the gut microbiome is associated with metachronous gastric cancer development.

Background and Aim Although gastric acid suppressants such as proton pump inhibitors (PPIs) and histamine‐2 receptor antagonists (H2RAs) are considered safe, the consequences of hypochlorhydria and hypergastrinemia caused by chronic use are unclear. This study aimed to investigate the association between the chronic use of gastric acid suppressants and high‐risk colorectal polyps, focusing on polyp size. Methods A population‐based, nested case–control study was conducted using data from the Japanese Diagnosis Procedure Combination database between 2014 and 2019. Cumulative PPI or H2RA use prior to polypectomy was evaluated during the study period. Endoscopic polypectomy was categorized as polypectomy 1 year prior to polypectomy. After adjusting for age, gender, and other confounders, a higher prevalence of high‐risk colorectal polyps was noted with PPI (OR: 2.67; 95% confidence interval: 2.37–3.01) and H2RA (OR: 1.86; 95% confidence interval: 1.52–2.26) use. Longer PPI or H2RA use was associated with increased risks of high‐risk colorectal polyps (P for trend, Chronic use of PPIs and H2RAs may be associated with high‐risk colorectal polyps. Requirements for long‐term gastric acid suppressant use should be reevaluated.

We investigated the association between early tumor shrinkage (ETS) and treatment outcome in patients with hepatocellular carcinoma treated with lenvatinib (LEN). A retrospective analysis was performed in 104 patients. ETS was defined as tumor shrinkage at the first evaluation in the sum of target lesions&rsquo, longest diameters from baseline according to the Response Evaluation Criteria in Solid Tumors (RECIST). The median overall survival (OS) was not reached, whereas the median progression-free survival (PFS) was 5.0 months. The receiver operating characteristic curve analysis in differentiating long-term responders (PFS &ge, 5.0 months) from short-term responders (PFS &lt, 5.0 months) revealed an ETS cut-off value of 10%. ETS &ge, 10% was significantly correlated with better PFS and OS compared with ETS &lt, 10%. Additionally, ETS &ge, 10% showed a better discrimination ability on prognosis compared with modified RECIST-based objective response at the first evaluation. Multivariate analysis confirmed ETS &ge, 10% as an independent predictor of better OS, as well as a Child&ndash, Pugh score of 5 and macrovascular invasion. In conclusion, ETS &ge, 10% was strongly associated with outcome in patients treated with LEN. This biomarker could allow earlier assessment of the treatment response and guide treatment decision-making for HCC.

Background and Aims The effectiveness of vonoprazan relative to that of proton pump inhibitors (PPIs) after gastric endoscopic submucosal dissection (ESD) is unclear. Although previous studies used post-ESD ulcer healing as the outcome measure, post-ESD bleeding rate is the most objective and appropriate outcome measure because it has less ascertainment bias. We aimed to compare the post-ESD bleeding rates between vonoprazan and PPIs. Methods This nationwide population-based retrospective cohort study was conducted between 2014 and 2018 and involved 9 hospitals. After 2 days of intravenous PPI administration, either vonoprazan or PPI was administrated from postoperative day 2 to 30. Results Overall, data of 1715 patients (627 patient pairs) were analyzed through propensity score matching. The vonoprazan group had significantly lower post-ESD bleeding rates than the PPI group (overall, 11.9% vs 17.2%, P = .008; bleeding between days 2 and 30, 7.8% vs 11.8%, P = .015). The readmission rate because of post-ESD bleeding was lower in the vonoprazan group (2.4% vs 4.1%, P = .081). Blood transfusion (2.1% vs 3.0%, P = .15) and additional surgery because of delayed perforation (.5% vs 1.0%, P = .32) were not significantly different between the 2 groups. No deaths within 30 days occurred in both groups. On Cox regression analysis, vonoprazan use, lesion location (antrum), aspirin use, direct oral anticoagulant use, and Charlson Comorbidity Index (≥2) were associated with an increased risk of post-ESD bleeding within 30 days. Conclusions Vonoprazan has a lower post-ESD bleeding rate than PPIs. Further prospective studies are required to confirm these results.

Hepatitis E virus subtype 3f (HEV-3f) strains are usually isolated in Europe and Thailand. Recently, HEV-3f strains were detected from six acute hepatitis E patients in Japan, none of whom had a history of travel to endemic areas. We inferred the origin and transmission route of the six HEV-3f strains. A time-scaled phylogenetic tree of the six strains with reference strains was constructed using a Bayesian statistical inference framework. The time-scaled tree indicated that the six strains independently derived from similar European strains between 2008 and 2014. The pattern suggested recent inflow of multiple HEV-3f strains from Europe to Japan. Japan imports a substantial amount of pork from European countries every year. The emergence of acute hepatitis cases caused by HEV-3f strains in Japan, in patients with no history of travel abroad, might be influenced by the increased opportunities to consume pork products imported from European countries.

Background Factors associated with response to lenvatinib have not been clarified in patients with hepatocellular carcinoma (HCC). Patients and methods This study retrospectively analyzed 50 patients treated with lenvatinib as first-line therapy between March 2018 and March 2019. Patients were divided into two groups by the Modified Response Evaluation Criteria in Solid Tumours (mRECIST) (responders and non-responders, whose best overall responses were complete (CR)/partial response (PR) and stable (SD)/progressive disease (PD), respectively). Factors associated with response were assessed, including the relative dose intensity 8 weeks after lenvatinib induction (8W-RDI). Results The best overall responses were 0/22/14/14 of CR/PR/SD/PD. Multivariate analysis revealed that only 8W-RDI was significantly associated with response. The receiver operating characteristic curve for 8W-RDI in differentiating responders from non-responders revealed a cut-off value of 75%. Patients with 8W-RDI ≥75% experienced a higher response rate and longer progression-free survival than patients with 8W-RDI Conclusion Our results suggest that maintaining an RDI ≥75% during the initial 8 weeks of lenvatinib treatment has a favorable impact on response.

Aims Cardiovascular events are the leading cause of death among patients with non-alcoholic fatty liver disease (NAFLD), but their relationship remains unclear. This study examined the association between coronary atherosclerosis and liver fibrosis, represented by the coronary artery calcification (CAC) score and non-invasive fibrosis markers, respectively. Methods Among 698 patients with chest pain or electrocardiographic abnormalities who underwent coronary computed tomography (CT) between April 2006 and March 2010, those with known liver disorders or history of emergency coronary angioplasty were excluded, leaving 366 patients for this study. Diagnosis of NAFLD was based on abdominal CT and history of alcohol consumption. Subjects with CAC of 100 AU or more were categorized into the high-risk group for cardiovascular events. Patient records were examined for clinical parameters including CAC score and non-invasive fibrosis marker FIB-4 index. Results Ninety-four patients (25.7%) had NAFLD. In this group, univariate analysis identified old age, high diastolic blood pressure, high liver to spleen ratio and high FIB-4 index as risk factors for cardiovascular events and multivariate analysis identified age of 66 years or older and FIB-4 index of 2.09 or more as the significant risk factors. For the observation period until August 2014, the cumulative proportion of PCI performance was significantly higher in patients with FIB-4 of 2.09 or more than those with FIB-4 of less than 2.09. Conclusion The progression of arteriosclerosis and that of liver fibrosis may be associated in NAFLD patients. The FIB-4 index can be easily determined and thus can be a useful marker for predicting cardiovascular events in NAFLD patients.

The present paper deals with the damping characteristics of symmetrically laminated plates. First, the effect of laminate configuration on the damping characteristics is investigated for cantilevered laminated plates. To examine the effect of laminate configuration, the concept of specific damping capacity is introduced and the damping characteristics are represented on the lamination parameter plane, where the damped stiffness invariants are newly proposed in this paper. Next, the optimal laminate configurations for the cantilevered laminated plates with maximal damping subjected to the constraints on the natural frequencies are determined by using differential evolution in which lamination parameters are used as intermediate design variables. The relation between the laminate configurations and the damping characteristics is discussed based on the concept of lamination parameters.

Background and aim Hepatitis E virus (HEV) is mainly transmitted orally, either waterborne or zoonotic foodborne. Intestinal viruses such as rotavirus are known to induce type III interferon (IFN) in the gastrointestinal (GI) tract where type III IFN dominantly functions in comparison with type I IFN. Therefore, the aim of this study is to investigate the significance of type III IFN (IFN-λ3) in acute hepatitis E. Methods IFN-λ3 and HEV RNA levels in the sera of patients with acute HEV infection and in the supernatant of HEV-inoculated cells were measured, using an in-house high-sensitivity method and reverse transcription-polymerase chain reaction, respectively. Results High serum IFN-λ3 levels were found in the early phase of acute HEV infection, which normalized after resolution. Interestingly, serum IFN-λ3 levels correlated well with serum HEV RNA titers in the same sera, both of which showed the peak before the robust increase of transaminases. In vitro experiments demonstrated that HEV replicated well in the cells with little IFN-λ3 induction (Caco-2, A549) and recombinant IFN-λ3 inhibited HEV replication in a dose-dependent manner. In contrast, in HT-29 cells, a colon cancer cell line, HEV poorly replicated and induced IFN-λ3 in a titer-dependent manner. Conclusions These clinical and experimental observations suggest that HEV induced IFN-λ3 as a host innate immune response, which may play a protective role against HEV.

Key Clinical Message Hepatic hydrothorax is known as pleural effusion of hepatic origin, and is difficult to diagnose. We herein report the novel strategy combining radioisotope scintigraphy with chest drainage to definitively diagnose hepatic hydrothorax of an 85-year-old patient which would have been missed with conventional diagnostic methods.

Axial compressive simulations are performed on defective and non-defective multiwalledcarbon nanotubes (MWCNTs) using the molecular dynamics method, and the effectof defects upon the buckling behavior is discussed. In our previous study, changes in atomicstresses in MWCNTs with three layers were evaluated until buckling occurred. That studysuggested that the transition from homogeneous stress distributions to inhomogeneous onesplays an important role in the occurrence of buckling in MWCNTs, though the critical stressesor strains relating to buckling are dependent upon the structure and location of defects. In thepresent study, the atomic elastic stiffness of each atom, Bij , is evaluated to discuss the onsetof local buckling in MWCNTs with five layers. The det(Bij) of all atoms is found to change toa negative value long before buckling occurs, while the second smallest eigenvalues of Bij forsome atoms change to a negative value just prior to buckling. The existence of dense regions ofatoms that have two negative eigenvalues of Bij are found to vary as a function of the defectlocation, and to correspond with onset points of local buckling.

A 67-year-old male living in Tsu city, Mie prefecture, Japan was referred to our hospital for further examination of acute liver injury and was diagnosed as having clinical hepatitis E virus (HEV) infection in January 2010. The HEV strain (HE-JA11-1701) isolated from the patient belonged to genotype 3 and European-type subgenotype 3e. It was presumed that the patient had been infected from a wild boar (Sus scrofa leucomystax) because he consumed meat/viscera from a wild boar that he had captured himself as a hunter approximately 2 months before disease onset. A specimen of the boar meat/viscera that the patient had ingested was not available. However, the HE-JA11-1701 strain was 99.8% identical within the 412-nucleotide sequence of the open reading frame 2 region to a HEV strain (JBOAR012-Mie08) that had been recovered from a wild boar captured near the patient's hunting area in 2008. A phylogenetic analysis confirmed that the two HEV strains had a close genetic relationship and were segregated into subgenotype 3e, supported by a high bootstrap value of 99%. Of note, the HE-JA11-1701 and JBOAR012-Mie08 strains were remotely related to the 3e strains reported in Japan and European countries, with a nucleotide difference of 7.9-13.9%, reinforcing the uniqueness of the 3e strains obtained in the present study. These results strongly support our speculation that the patient developed acute hepatitis E via consumption of HEV-infected boar meat/viscera. Genetic analyses of HEV strains are useful for tracing infectious sources in sporadic cases of acute hepatitis E.

Acute hepatitis due to hepatitis E virus (HEV) is endemic in Bangladesh, but its epidemiological characteristics and virological features remain obscure. An outbreak of acute icteric hepatitis E occurred in Rajshahi, Bangladesh during 2010 when 200 patients with visible jaundice visited physicians within a period of 1 month (January-February). Clinical and epidemiological data were collected from these patients using questionnaires. Nucleic acids were isolated from 15 patients who were selected at random to ascertain their HEV genotypes. Near-complete nucleotide sequences of the HEV genome were detected in two patients and partial ORF2 regions in the other 13 patients. All patients tested positive for IgM antibodies to HEV but negative for other hepatitis viruses. Most patients were icteric and complained of vomiting, fever, itching, and abdominal pain. All 15 HEV sequences formed a single cluster within genotype 1a. Two of the 7,186-nt HEV sequences were 99.8% identical. This is the first study to report the clinical, epidemiological, and molecular characterization of an outbreak of acute hepatitis E in Bangladesh.

Summary Background In sub-Saharan Africa, it is unknown whether hepatitis E virus (HEV) infection is a common precipitating event of acute-on-chronic liver failure (ACLF). Aims To estimate the prevalence of HEV infection in general population and assess whether HEV is a common trigger of ACLF in cirrhotic patients in The Gambia, West Africa. Methods We first conducted an HEV sero-survey in healthy volunteers. We then tested cirrhotic patients with ACLF (cases) and compensated cirrhosis (controls) for anti-HEV IgG as a marker of exposure to HEV, and anti-HEV IgA and HEV RNA as a marker of recent infection. We also described the characteristics and survival of the ACLF cases and controls. Results In the healthy volunteers (n = 204), 13.7% (95% CI: 9.6–19.2) were positive for anti-HEV IgG, and none had positive HEV viraemia. After adjusting for age and sex, the following were associated with positive anti-HEV IgG: being a Christian, a farmer, drinking water from wells, handling pigs and eating pork. In 40 cases (median age: 45 years, 72.5% male) and 71 controls (39 years, 74.6% male), ≥70% were infected with hepatitis B virus. Although hepatitis B flare and sepsis were important precipitating events of ACLF, none had marker of acute HEV. ACLF cases had high (70.0%) 28-day mortality. Conclusions Hepatitis E virus infection is endemic in The Gambia, where both faecal-oral route (contaminated water) and zoonotic transmission (pigs/pork meat) may be important. However, acute HEV was not a common cause of acute-on-chronic liver failure in The Gambia.

We have attempted to reveal the deformation mechanism of amorphous metals by local lattice instability analysis, based on the positive definiteness of the atomic elastic stiffness coefficients, B i . In our previous study, changes in inhomogeneous structure are explained by the observation of the stability-switching or transition between detB i > 0 and detB i < 0. In this study, we have performed the indentation simulation on a binary amorphous metal, and discussed the inelastic deformation in the amorphous metal by Voronoi polyhedra analysis and the stability-switching of local lattice instability. The indentation simulation predicts that rearrangements of atoms occur not only on structures below the indentation point but also inside the amorphous metal structure. These structural changes produce a significant volume change in the Voronoi polyhedra, the stability-switching based on local lattice instability analysis, and a local volume reduction evaluated within scales of a few hundred atoms. [doi:10.2320/matertrans.M2012191]

Background Since previous studies have investigated the population dynamics of Japan-indigenous genotype 3 hepatitis E virus (HEV) using virus sequences, more nucleotide sequences have been determined, and new techniques have been developed for such analysis. Aims To prevent future hepatitis E epidemic in Japan, this study aimed to elucidate the cause of past HEV expansion. Methods The epidemic history of Japan-indigenous genotype 3 HEV was determined using the coalescent analysis framework. Bayesian skyline plot (BSP) and Bayesian estimate of phylogeny with relaxed molecular clock models were calculated using Markov chain Monte Carlo sampling. Results Japan-indigenous strains consist of New World strains (subtype 3a), Japanese strains (3b) and European strains (3e). The oldest lineage, 3b, appeared around 1929. Lineages 3a and 3e appeared around 1960. BSPs indicated similar radical population growth of the 3a and 3b lineages from 1960 to 1980. Conclusions Population dynamics of the three lineages shared some common characteristics, but had distinguishing features. The appearance of 3a and 3e lineages coincides with the increase of large-race pig importation from Europe and the USA after 1960. The epidemic phase of 3a and 3b strains from 1960 to 1980 could be related to increased opportunity for HEV infection arising from large-scale pig breeding since 1960. Our observations revealed new findings concerning the close relationship between the epidemic history of Japan-indigenous genotype 3 HEV and the improvement of the Japanese pig industry. Infection control in pig farms should be an effective method of preventing HEV infection in humans.

Two 71-year-old males (Case 1 and 2) with liver dysfunction were admitted to our hospital and diagnosed with acute hepatitis E due to detection of hepatitis E virus (HEV) RNA or IgM class anti-HEV in their sera. Since they ate the same rare wild boar meat at the same ritual, the boar meat was considered to be the infection source. Phylogenetic analysis showed that HEV strain identified in Case 1 segregated to a cluster of "Aichi/Shizuoka Strains". It seems that the "Aichi/Shizuoka Strain", an atypical genotype 4 strain compared to those found in other part of Japan, is prevailing within this small geographic area.

ペグインターフェロン（PEG-IFN）α2aまたはグリチルリチン製剤（強力ネオミノファーゲンC：SNMC）を投与開始し，24週以上継続可能であったC型慢性肝炎64例を対象とし，有効性・安全性をretrospectiveに比較検討した．平均観察期間（中央値，週）はPEG群154，SNMC群145，ALT値（中央値，IU/L）は投与前，24週，48週時点において，PEG群64，34，30，SNMC群80，47，52，AFP値（中央値，ng/mL）は投与前，24週，48週時点において，PEG群12，9.2，7.2，SNMC群12，12.5，18であった．投与中の血小板，Hb，好中球数はSNMC群と比較しPEG群で有意に低値を示したが，減量により全例継続可能であった．PEG群で3例（8％），SNMC群で3例（11％）にHCCが発現した．肝発癌抑制を目的としたPEG-IFNα2a少量及びSNMC療法は，共に肝機能改善効果を認めたが，PEG群で有意にALT値，AFP値が改善した．

Glass-like carbon (GC) is expected as a die material for press molding of glass micro optical devices. However, the mechanical and thermal properties are not enough to use as precision mold die. So, GC composites reinforced by vapor grown carbon fiber (GC/VGCF composites) were developed to improve the properties. The GC/VGCF composites achieved high thermal conductivity and bending strength, and the decreased linear expansion coefficient and good mold releasability. However, surface roughness of the GC/VGCF composites after focused ion beam (FIB) etching increased up to 50nm, when VGCF of 28vol% was added.

It is revealed that amorphous metals have many “unstable” atoms even at the equilibrium state, by local lattice instability analysis (LLIA) which discusses the positive definiteness of atomic elastic stiffness coefficients, Bαij. We have explored for relationships between the deformation and these unstable atoms in inhomogeneous or disordered structure. In the present study, we have discussed the changes in unstable atoms of det Bαij 0 atoms showdifferent stress. We have concluded that the stress relaxation is not caused by a straightforward image of “stabilization” or “destabilization”, but by “shuffle of atomic arrangement” which involves positive and negative switching simultaneously. In fact, we have observed many incidences of positive and negative stability-switching at the locally deformed area.

シカ及びイノシシの生食により感染したと思われるE型急性肝炎3例を経験したので報告する．症例1，2は71歳と48歳の男性で発症の約2カ月前に，偶然同一飲食店で別々にイノシシの肝を生食していた．症例3は69歳の男性で，発症の2カ月前から息子が狩猟で捕獲した複数頭のシカ生肉を頻回に自宅で調理し摂取していた．3症例とも入院時，肝逸脱酵素は著明に上昇していたが補液や安静で改善した．3症例の病初期血清におけるIgM-HEV抗体，IgG-HEV抗体，HEV-RNAが陽性でHEV genotypeは4型，塩基配列は相互に99.8％以上一致した．愛知県のヒト及びイノシシから分離されている「4型HEV愛知株」との間にも98.5％-99.8％の一致率を示し，北海道に蔓延するgenotype 4とは明らかに別系統であることが注目された．

A protective effect of Rho-kinase inhibitor on various organ injuries is gaining attention. Regarding liver injury, Rho-kinase inhibitor is reported to prevent carbon tetrachloride (CCl4)- or dimethylnitrosamine-induced liver fibrosis and hepatic ischemia-reperfusion injury in rats. Because Rho-kinase inhibitor not only improved liver fibrosis but also reduced serum alanine aminotransferase (ALT) level in CCl4-induced liver fibrosis, we wondered whether Rho-kinase inhibitor might exert a direct hepatocyte-protective effect. We examined this possibility in acute CCl4 intoxication in rats. Rho-kinase inhibitor, HA-1077, reduced serum alanine ALT level in rats with acute liver injury induced by CCl4 with the improvement of histological damage and the reduction of the number of apoptotic cells. In cultured rat hepatocytes in serum-free condition, HA-1077 reduced apoptosis evaluated by quantitative determination of cytoplasmic histone-associated DNA oligonucleosome fragments with the reduction of caspase-3 activity and the enhancement of Bcl-2 expression. HA-1077 stimulated phosphorylation of Akt, and wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PI3-kinase)/Akt pathway, abrogated the reduction of hepatocyte apoptosis by HA-1077 in vitro. Furthermore, wortmannin abrogated the reduction of serum ALT level by HA-1077 in rats with acute liver injury induced by CCl4, suggesting that the activation of PI3-kinase/Akt pathway may be involved in the hepatocyte-protective effect by Rho-kinase inhibitor in vivo. In conclusion, Rho-kinase inhibitor prevented hepatocyte damage in acute liver injury induced by CCl4 in rats and merits consideration as a hepatocyte-protective agent in liver injury, considering its direct antiapoptotic effect on hepatocytes in vitro.

To produce micro glass lens by mold-press, 3D micro lens die was fabricated on glass-like carbon (GC) by focused ion beam (FIB) etching. The dimensional accuracy and surface roughness, as well as transcriptional performance, were investigated. A precise and smooth die was completed by optimizing dwell time, current and step number of 2D bit map data, which agreed well with theoretical estimation. Micro glass lenses with different diameter and gradient angle were mold-pressed using the GC die. The diameter and sag were confirmed to be nearly equivalent to or just smaller than those of GC die.

Background & Aims: Hepatic ischemic preconditioning decreases sinusoidal endothelial cell injury and Kupffer cell activation after cold ischemia/reperfusion, leading to improved survival of liver transplant recipients in rats. Ischemic preconditioning also protects livers against warm ischemia/reperfusion injury, in which hepatocyte injury is remarkable. We aimed to determine whether ischemic preconditioning directly protects hepatocytes and to elucidate its mechanisms. Methods: Rats were injected with gadolinium chloride to deplete Kupffer cells or with N -acetyl-l-cysteine, superoxide dismutase, or catalase to scavenge reactive oxygen species. Livers were then preconditioned by 10 minutes of ischemia and 10 minutes of reperfusion. Subsequently, livers were subjected to 40 minutes of warm ischemia and 60 minutes of reperfusion in vivo or in a liver perfusion system. In other rats, livers were preconditioned by H 2 O 2 perfusion instead of ischemia. In the other experiments, livers were perfused with nitro blue tetrazolium to detect reactive oxygen species formation. Results: Ischemic preconditioning decreased injury in hepatocytes, but not in sinusoidal endothelial cells. Kupffer cell depletion itself did not change hepatocyte injury after ischemia/reperfusion, indicating no contribution of Kupffer cells to ischemia/reperfusion injury. However, Kupffer cell depletion reversed hepatoprotection by ischemic preconditioning. Reactive oxygen species formation occurred in Kupffer cells after ischemic preconditioning. Scavenging of reactive oxygen species reversed the effect of ischemic preconditioning, and H 2 O 2 preconditioning mimicked ischemic preconditioning. Conclusions: Ischemic preconditioning directly protected hepatocytes after warm ischemia/reperfusion, which is not via suppression of changes in sinusoidal cells as in cold ischemia/reperfusion injury. This hepatocyte protection was mediated by reactive oxygen species produced by Kupffer cells.

Hepatocyte growth factor (HGF) has pleiotropic effects. Up-regulation of HGF activity in vivo may be beneficial. Branched-chain amino acids (BCAAs) are known to modulate various cellular functions. When starved rats received intraperitoneal injections of valine, leucine or isoleucine, only leucine treatment increased both hepatic and circulating levels of HGF in a dose-dependent manner, up to 1.5 and 2.3 times higher, respectively, than in controls. When young growing rats with free access to food were injected with leucine once a day for a week, HGF levels and liver weights were significantly higher than those of control rats. Furthermore, 1 week of leucine treatment of adult rats resulted in elevated serum albumin levels with an increase in HGF levels. Taken together with our previous report showing that leucine stimulates HGF production by hepatic stellate cells in culture, leucine, among BCAAs, may induce an increase in HGF production by the liver in vivo.

Background & Aims: Sphingosine 1-phosphate (S1P), a ligand for G protein-coupled endothelial differentiation gene-1 (Edg-1), Edg-3, Edg-5, Edg-6, and Edg-8, elicits a variety of responses by cells. Prominent among these is cell proliferation. S1P is abundantly stored in platelets and released upon their activation, suggesting that S1P plays a pathophysiologic role in vivo. Because the major part of injected S1P was distributed into the liver in mice, we wondered whether the liver would be one of its targets. The effects of S1P on hepatocytes, the major constituent cells in the liver, were examined. Methods & Results: Northern blot analysis revealed the expression of Edg-1 and Edg-5 messenger RNA (mRNA) in cultured rat hepatocytes, in which S1P decreased DNA synthesis induced by hepatocyte growth factor (HGF) or epidermal growth factor (EGF) without affecting total protein synthesis. This inhibitory effect was attenuated by inactivation of small GTPase Rho with C3 exotoxin but not by inactivation of G i with pertussis toxin. Moreover, in the presence of JTE-013, a newly developed and specific binding antagonist for Edg-5, the inhibitory effect was also cancelled. Finally, the administration of S1P after 70% partial hepatectomy in rats reduced the peak of DNA synthesis in hepatocytes with increased Rho activity. Furthermore, Edg-5 but not Edg-1 mRNA expression was enhanced in hepatocytes 24–72 hours after partial hepatectomy, which coincides with decreasing hepatocyte proliferation. Conclusions: S1P has an antiproliferative property in rat hepatocytes by activating Rho via Edg-5. Our results raise the possibility that S1P is a negative regulator in liver regeneration.

Hepatitis E virus (HEV) is a growing public health problem in many countries. In this study, we investigated HEV seroprevalence among the general population in the Siem Reap province, Cambodia, and performed HEV genetic analysis with the aim to develop an HEV prevention strategy. This seroepidemiological cross-sectional study conducted from 2010 to 2014 included 868 participants from four different locations in Siem Reap province, Cambodia. They answered questionnaires and provided blood samples for the analysis of hepatitis virus infections. Among the participants (360 men and 508 women; age range, 7-90 years), the prevalence of anti-HEV IgG was 18.4% (95% confidence interval: 15.9-21.0); HEV RNA was detected in two participants (0.23%) and was classified as genotype 3 and 4. Full-length genome of the genotype 4 isolate, CVS-Sie10, was sequenced; it contained 7,222 nucleotides and three ORFs and demonstrated high sequence identity with the swine China isolates swGX40 (95.57%), SS19 (94.37%), and swDQ (91.94%). Multivariate logistic regression analysis revealed that men, elderly people, and house workers were risk groups significantly associated with the positivity for anti-HEV IgG. This is the first report on the detection of HEV genotype 4 in humans in Cambodia and on the complete genome sequence of HEV genotype 4 from this country. Our study demonstrates that new HEV infection cases occur frequently among the general population in Cambodia, and effective preventive measures are required.

p53, known as a tumor suppressor gene, is a transcription factor that regulates various cellular functions. Recently, several growth factor gene promoters, including that of transforming growth factor α (TGF-α), were shown to be direct targets of p53-mediated transcription. Hepatic p53 mRNA is up-regulated during liver regeneration in rats. The aim of this study is to examine the role of p53 in hepatocyte proliferation. p53 protein levels were examined in rat hepatocytes cultured in the medium containing hepatocyte growth factor (HGF). p53 levels began to increase after 6 hours of incubation, reached a maximum at 18 hours, and decreased thereafter. DNA synthesis increased at 12 hours and peaked at 30 hours. When hepatocytes were incubated with p53 antisense oligonucleotide in addition to HGF, increases of p53 and TGF-α levels were suppressed, and DNA synthesis was reduced. The increases of TGF-α levels and DNA synthesis were also suppressed by a chemical inhibitor of p53, pifithrin-α. In rats after two-thirds partial hepatectomy, hepatic p53 increased and reached maximal levels around 16 hours when hepatic HGF levels have been shown to reach a maximum followed by an increase in hepatic TGF-α levels or hepatocyte proliferation. In contrast, sham-operated rats showed minor elevations of hepatic p53 levels. In conclusion, p53 production is stimulated by HGF and may contribute to the proliferation of rat hepatocytes. Considering previous findings indicating the importance of endogenous TGF-α for the proliferation of hepatocytes stimulated by HGF, TGF-α might play a role in HGF-p53 mediated hepatocyte proliferation. (H EPATOLOGY 2002;36:336-344.)

Brief periods of ischemia followed by reperfusion render tissues resistant against subsequent prolonged ischemia, a phenomenon called ischemic preconditioning. The effect of ischemic preconditioning on liver transplantation was investigated in relation to sinusoidal endothelial cell injury and Kupffer-cell activation, which are prominent features of storage and reperfusion injury leading to liver graft failure. Rat livers were preconditioned by 5 or 10 minutes of ischemia and 5 minutes of reperfusion and stored in University of Wisconsin (UW) solution for 30 hours. Livers were then reperfused for 15 minutes with physiological buffer containing trypan blue. Under these conditions, injury occurs predominantly to sinusoidal endothelial cells, reflected by trypan blue staining of nonparenchymal cells in histological sections. Ischemic preconditioning decreased nonparenchymal cell killing by more than 50%. When half the liver was preconditioned, sinusoidal endothelial cells were also protected in the contralateral half. Other stored livers were reperfused with nitroblue tetrazolium, which is converted to insoluble formazan by superoxide radicals. Ischemic preconditioning decreased the intensity of formazan deposition over Kupffer cells. Finally, stored livers were transplanted into nontreated rats. Ischemic preconditioning improved recipient long-term survival after 30 hours of cold ischemic storage in UW solution from 30% to 80% and decreased serum tumor necrosis factor-α levels in posthepatic blood 4 hours postoperatively from 98 to 54 pg/mL. In conclusion, ischemic preconditioning protects sinusoidal endothelial cells and suppresses Kupffer-cell activation after storage and reperfusion. As a result, graft survival improves after liver transplantation. Moreover, ischemia to half the liver confers protection to the other half. Such heterologous preconditioning provides a new means to protect liver tissue against ischemia-reperfusion injury without imposing ischemia on the target tissue. ( Liver Transpl 2001;7:292-299. )

We encountered a series of sporadic cases of hepatitis E (n=8) from late September to middle of October 2009 in Sapporo and its suburbs. Surprisingly, HEV sequences from these patients segregated to a very compact cluster, suggesting a single-source epidemic. Moreover, they are closely related to the "Sapporo strain" or the "Kitami/Abashiri strain" which is known to have caused severe hepatitis in Kitami and Abashiri area, far from Sapporo, several years before. Advanced livestock marketing and food-distribution system might have caused the spread of this HEV strain.

A brief period of liver ischemia decreases sinusoidal endothelial cell killing after cold liver storage and improves graft survival after liver transplantation, a phenomenon called ischemic preconditioning. In this study, we investigated the mechanism of sinusoidal endothelial cell protection after ischemic preconditioning. Livers were preconditioned by 5 minutes of ischemia and 5 minutes of reperfusion. Subsequently, livers were stored for 30 hours in cold University of Wisconsin (UW) solution and reperfused briefly with physiological buffer containing Trypan blue. Ischemic preconditioning decreased sinusoidal endothelial cell killing after storage/reperfusion, as assessed by Trypan blue staining of nonparenchymal cells. Adenosine A(2) receptor blockade prevented the protective effect of ischemic preconditioning. By contrast, adenosine A(1) receptor blockade did not prevent protective ischemic preconditioning. Other rat livers were treated with adenosine A(1) and A(2) receptor agonists or dibutyryl-cyclic adenosine monophosphate (DB-cAMP) before storage. The adenosine A(2) receptor agonist, CGS-21680, and DB-cAMP decreased sinusoidal endothelial cell killing to the same extent as ischemic preconditioning, but the adenosine A(1) receptor agonist, 2-chloro-N(6)-cyclopentyladenosine (CCPA), had no effect. The adenosine A(2) agonist and prostaglandin E(2), another agent that preconditions sinusoidal endothelial cells against storage/reperfusion injury, but not the adenosine A(1) agonist, increased cAMP levels in cultured sinusoidal endothelial cells. In conclusion, an adenosine A(2) receptor pathway coupled to increased cAMP mediates sinusoidal endothelial cell protection by ischemic preconditioning.

Activated Kupffer cells provoke massive liver necrosis after endotoxin stimulation through microcirculatory disturbance caused by sinusoidal fibrin deposition in rats undergoing 70% hepatectomy. In these rats, serum activities of purine nucleoside phosphorylase (PNP) and alanine transaminase (ALT) were increased at 1 and 5 hours, respectively, following endotoxin administration. When 70% resected liver was perfused with Dulbecco's modified Eagle medium (DMEM) containing heat-inactivated fetal calf serum, the increase in both enzyme activities was not affected by addition of endotoxin during perfusion, suggesting that activated Kupffer cells injured neither sinusoidal endothelial cells nor hepatocytes. The activity of tissue factor, an initiator of blood coagulation cascade, was much higher in Kupffer cells isolated from partially hepatectomized rats than in those from normal rats. In contrast, mRNA expressions of tissue factor pathway inhibitor (TFPI) as well as thrombomodulin were almost undetectable in normal and partially resected livers. When recombinant human TFPI was injected intravenously in 70% hepatectomized rats, TFPI was markedly stained on the surfaces of sinusoidal endothelial cells and microvilli of hepatocytes on immunohistochemistry. In these rats, endotoxin-induced liver injury was significantly attenuated compared with rats given no TFPI. Similar attenuation was also found in rats receiving recombinant human thrombomodulin. These results suggest that fibrin deposition developing in 70% hepatectomized rats after endotoxin administration may be caused by deranged blood coagulation in the hepatic sinusoids through increasing tissue factor activity in Kupffer cells and minimal TFPI and thrombomodulin in endothelial cells. The destruction of sinusoidal endothelial cells as well as hepatocytes may occur as a result of microcirculatory disturbance caused by such sinusoidal fibrin deposition.

The objective of the present study was to investigate the role of oxygen radicals in the acute gastric mucosal injury induced by taurocholate combined with serotonin (TCA-5HT) in rats. Just after taurocholate had been given intragastrically at a dose of 30mM/rat, serotonin was injected subcutaneously at a dose of 20mg/kg. Superficial hemorrhagic erosions were observed on the glandular stomach 2h after administration of TCA-5HT. The level of lipid peroxides and that of α-tocopherol in the gastric mucosa significantly increased and decreased, respectively, with time after TCA-5HT treatment. Myeloperoxidase (MPO) activity, an index of neutrophil infiltration, in the gastric mucosa also increased significantly. Pretreatment with the combination of recombinant human Cu, Zn-superoxide dismutase (hSOD) and catalase significantly inhibited the gastric mucosal injury, accumulation of lipid peroxides, and the decrease in α-tocopherol content in the gastric mucosa. Polaprezinc, a new synthetic antioxidant, significantly inhibited gastric mucosal injury and the accumulation of lipid peroxides in the gastric mucosa. All these results suggest that oxygen radicals and lipid peroxidation are involved in the pathogenesis of the acute gastric mucosal injury induced by TCA-5HT.

A partial ORF2 protein of hepatitis E virus (HEV) was expressed in E. coli, purified, and used as solid-phase ligand as well as tracer-ligand labeled with peroxidase, in an antigen-antibody-antigen Sandwich ELISA system, to detect antibodies to HEV. This new system showed higher sensitivity of detecting anti-HEV than conventional ELISA system which needs specific antibodies against IgG, IgM, or IgA of concerned animal species as tracer-ligands. Since our new ELISA system is universally applicable to any animal species without needing specific antibodies, it will be useful in further elucidating the animal reservoirs of HEV.

Activated Kupffer cells and hepatic macrophages can produce massive liver necrosis through microcirculatory disturbance due to sinusoidal fibrin deposition. This mechanism is involved in the development of liver injury after endotoxin administration in rats pretreated with heat-killed Propionibacterium acnes (P.acnes) or undergoing 70% liver resection. The significance of CD14, a receptor for lipopolysaccharide and its binding protein, was evaluated in both models in relation to the activation mechanisms of Kupffer cells and hepatic macrophages. Northern blot analysis revealed that CD14 mRNA expression was increased in the liver of rats following P.acnes administration. In these rats, hepatic macrophages immediately after isolation showed marked increased of CD14 mRNA expression compared to Kupffer cells from normal rats. In contrast, CD14 mRNA expression was minimal in partially resected liver. Interleukin (IL)-18 and IL-2 mRNA expression in the liver and interferon (IFN)-gamma mRNA expression in the spleen were significantly increased in P.acnes-treated rats compared to normal rats, while these increases were absent in partially hepatectomized rats. Thus, CD14 expressed on hepatic macrophages after activation through a cytokine network of IL-18, IFN-gamma, and IL-2 may contribute to endotoxin-induced liver injury in P.acnes-treated rats. In contrast, in partially hepatectomized rats, this network may not operate during Kupffer cell activation, and the liver injury might develop through endotoxin receptors other than CD14 on the cells.

Nitric oxide (NO) modulation of ischemia-reperfusion injury was investigated by measuring lipid peroxide and neutrophil accumulation in rat stomachs treated with N G -nitro- l -arginine ( l -NNA), a specific NO synthase inhibitor. Ischemia-reperfusion injury was induced in the rat stomach. Treatment with l -NNA for 3 days at a dose of 3 mg/kg/day significantly enhanced this injury. This enhancement was reversed by the simultaneous administration of l -arginine at a dose of 30 mg/kg/day. Both thiobarbituric acid (TBA)-reactive substances, an index of lipid peroxidation, and myeloperoxidase (MPO) activity, an index of tissue-associated neutrophil accumulation, were increased in the gastric mucosa after ischemia-reperfusion. l -NNA treatment enhanced these increases in TBA-reactive substances and MPO activity. The increase in the area of gastric erosions correlated closely with accumulation of TBA-reactive substances as well as the increase in MPO activity. Enhancement of ischemia-reperfusion injury by l -NNA treatment was inhibited by injection with anti-neutrophil antibody, anti-platelet activating factor (PAF) antagonist, and anti-leukotriene B 4 (LTB 4 ) receptor antagonist. In addition, the increase in TBA-reactive substances and MPO activity was decreased by these antibodies or antagonists. Enhancement of reperfusion-induced gastric mucosal injury associated with inhibition of NO synthesis may involve neutrophil infiltration and lipid peroxide accumulation in the gastric mucosa, mediated by PAF and LTB 4 .