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Background: Polymyositis/dermatomyositis (PM/DM) is an autoimmune disease that is sometimes complicated with rapidly progressive interstitial lung disease (RPILD). However, serum and lung biomarkers that can predict RPILD development remain unclear. Objectives: To determine potential serum and lung biomarkers that can predict RPILD development in patients with PM/DM‐ILD. Methods: In total, 49 patients with PM/DM‐ILD were enrolled. We measured the serum levels of 41 cytokines/chemokines, ferritin and anti‐MDA5 antibody, compared them between the RPILD (n = 23) and non‐RPILD (n = 26) groups, and ranked them by their importance through random forest analysis. To distinguish the two groups, we determined biomarker combinations by logistic regression analysis. We also measured the bronchoalveolar lavage fluid (BALF) levels of 41 cytokines/chemokines. Using immunohistochemistry, we examined IL‐15 expression in lung tissues. The IL‐15 production was also investigated using A549 and BEAS‐2B cells. Results: The RPILD group had significantly higher IL‐15, IL‐1RA, IL‐6, CXCL10, VCAM‐1, anti‐MDA5 antibody and ferritin serum levels than the non‐RPILD group, but it had a significantly low CCL22 level. Meanwhile, anti‐MDA5 antibody, IL‐15, CXCL8, CCL22, IL‐1RA and ferritin were the best combination to distinguish the two groups. IL‐15 and CCL22 were also predictive marker for RPILD development in anti‐MDA5 antibody‐positive patients. Additionally, the RPILD group had significantly high IL‐15 levels in BALF. The lung tissues expressed IL‐15, which increased after cytokine stimulation in the A549 cells. Conclusion: This study identified a combination of biomarkers predicting PM/DM‐RPILD progression, and IL‐15 is an important cytokine for predicting RPILD development and reflecting ILD severity. [ABSTRACT FROM AUTHOR]

Hepatitis B virus ( HBV) reactivation has been reported during antihepatitis C treatment in patients with hepatitis C virus ( HCV) and HBV co-infection. We aimed to evaluate the frequency and risk factors of HBV reactivation during anti- HCV therapy and compared those between interferon ( IFN)-free direct-acting antiviral ( DAA) therapies and IFN-based therapies. Three hundred and twenty-two patients with HCV infection receiving anti- HCV therapy were retrospectively screened. The baseline HBV infection statuses of all eligible patients and the HBV- DNA level of all patients with current or previous HBV infection were examined at the end of treatment. In patients with baseline anti- HBs positivity, changes in anti- HBs titre were evaluated. Of 287 patients who met the inclusion criteria, 157 had current (n=4) or previous (n=153) HBV infection; 85 were treated with IFN-free DAA therapies and 72 were treated with IFN-based therapies. Six patients experienced HBV reactivation (n=2) or HBV reappearance (n=4) after IFN-free DAA therapies, while no patient developed HBV reactivation after IFN-based therapies. The risk factors of HBV reactivation or reappearance were DAA therapies and a reduction in anti- HBs titre to <12 mIU mL−1 by the end of treatment. The decline changes of anti- HBs titre were significantly higher in patients treated with DAA therapies. Although HBV reactivation hepatitis was not observed, three of four patients with HBV reactivation or reappearance after achieving HCV eradication had viremia 8 weeks after completion of therapy. A significant proportion of patients develop HBV reactivation or reappearance without hepatitis after IFN-free DAA therapies. Low levels of anti- HBs and their decrease to <12 mIU mL−1 after treatment are significant risk factors for HBV reactivation or reappearance. [ABSTRACT FROM AUTHOR]

High rates of sustained virologic response ( SVR) has been achieved in Japanese patients with chronic hepatitis C virus ( HCV) genotype ( GT)1 and GT2 infection treated with ledipasvir/sofosbuvir ( LDV/ SOF) ±ribavirin ( RBV) and SOF+ RBV, respectively. We evaluated the effect of baseline HCV NS5A and NS5B resistance-associated variants ( RAVs) on treatment outcome and characterized variants at virologic failure. Baseline deep sequencing for NS5A and NS5B genes was performed for all GT1 patients. Deep sequencing of NS5A ( GT1 only) and NS5B ( GT1 and GT2) was performed for patients who failed treatment or discontinued early with detectable HCV RNA (i.e., >25 IU/ mL). In patients with HCV GT1 infection, 22.3% ( GT1a: 2/11; GT1b: 74/330) had ≥1 baseline NS5A RAV. The most frequent NS5A RAVs in GT1b were Y93H (17.9%, 59/330) and L31M (2.4%, 8/330). Despite the presence of NS5A RAVs at baseline, 100% and 97% of patients achieved SVR12, compared with 100% and 99% for those with no NS5A RAVs with LDV/ SOF and LDV/ SOF+ RBV, respectively. All patients with NS5B RAVs at baseline achieved SVR12. Of the 153 patients with GT2 infection ( GT2a 60.1%, GT2b 39.9%), 3.3% (5/153) experienced viral relapse. No S282T or other NS5B RAVs were detected at baseline or relapse; no change in susceptibility to SOF or RBV was observed at relapse. In conclusion, LDV/ SOF and SOF+ RBV demonstrate a high barrier to resistance in Japanese patients with HCV GT1 and GT2 infection. The presence of baseline NS5A RAVs did not impact treatment outcome in GT1 Japanese patients treated with LDV/ SOF for 12 weeks. [ABSTRACT FROM AUTHOR]

Repeated CECT after 3 months revealed deteriorations of the intrahepatic bile duct dilatation, wall thickness of the extrahepatic bile duct, and peritoneal thickening (Fig. The lymphoid tissue infiltrated along outside of the bile duct and Glisson's sheath, which caused extrahepatic and intrahepatic bile duct compression (Fig. Contrast-enhanced computed tomography (CECT) scan on admission showed stenosis of common bile duct (CBD) due to thickening of the wall (Fig. [Extracted from the article]

Significant associations of HLA-DP alleles with chronic hepatitis B ( CHB) infection are evident in Asian and Arabian populations, including Japanese, Han Chinese, Korean, and Saudi Arabian populations. Here, significant associations between CHB infection and five DPB1 alleles (two susceptibility alleles, DPB1*05:01 and *09:01, and three protective alleles, DPB1*02:01, *04:01, and *04:02) were confirmed in a population comprising of 2582 Japanese individuals. Furthermore, odds ratios for CHB were higher for those with both DPB1 susceptibility alleles than for those with only one susceptibility allele; therefore, effects of susceptibility alleles were additive for risk of CHB infection. Similarly, protective alleles showed an additive effect on protection from CHB infection. Moreover, heterozygotes of any protective allele showed stronger association with CHB than did homozygotes, suggesting that heterozygotes may bind a greater variety of hepatitis B-derived peptides, and thus present these peptides more efficiently to T-cell receptors than homozygotes. Notably, compound heterozygote of the protective allele (any one of DPB1*02:01, *04:01, and *04:02) and the susceptible allele DPB1*05:01 was significantly associated with protection against CHB infection, which indicates that one protective HLA-DPB1 molecule can provide dominant protection. Identification of the HLA-DPB1 genotypes associated with susceptibility to and protection from CHB infection is essential for future analysis of the mechanisms responsible for immune recognition of hepatitis B virus antigens by HLA-DPB1 molecules. [ABSTRACT FROM AUTHOR]

Introduction: The first series of analyses on Ryugu's fragments from the two collection sites have shown that the Hayabusa2 samples resemble CI chondrite-like materials [1]. These rock fragments underwent extensive aqueous alteration and are predominantly composed of hydrated minerals (serpentine, saponite) and other secondary minerals (carbonates, magnetites, sulfides) likely formed on Ryugu under the presence of liquid water. The isotopic composition of these phases can help understanding the source and distribution of water and volatile elements in the protoplanetary disk [e.g., 1-5]. However, direct estimates of the water D/H ratios cannot be obtained easily in chondritic rocks due to the difficulty in estimating the organic matter (OM) contribution to the whole H budget. Water D/H ratio in chondritic rocks is often approximated by the bulk D/H composition or estimated by mass balance calculations to remove the contribution of the organic components (e.g., [2]). In mass balance calculations, OM concentration and D/H composition are generally measured after solvent extraction [3] or chemical isolation from minerals [4], but about half of the total OM is not accessible with these techniques (e.g., [5]). In this study, we are using an analytical method by secondary ion mass spectrometry (SIMS) [6-7] to estimate the D/H ratio of water retained in the hydrated minerals of Ryugu's rock fragments and compared these results to water D/H ratios measured in different carbonaceous chondrites. Methods: H, D and C data were obtained with a SIMS IMS 1280-HR2 and the D/H ratios were corrected from instrumental mass fractionation using hydrous silicates and organic standards [6-7]. We previously determined the D/H ratios of hydrated minerals without hindrance from H in adjacent organic materials in carbonaceous chondrites from different groups and petrological types: we found that each group shows a distinct and unique water D/H signature [7]. We now have applied the same method on Ryugu's samples and estimated the Ryugu's water D/H ratio. Results and discussion: We obtained 95 analyses of the D/H and C/H ratios in the three fragments of Ryugu C0002, A0040 and A0094. All but 5 points follow a nice positive correlation between the D/H and the C/H ratios (RPearson = 0.72). Using this correlation, we estimated that the water D/H in Ryugu is of δDRyugu = +74 ± 117 ‰ (2σ). This value is similar within error to the water D/H measured for the CI carbonaceous chondrite Orgueil in the same session of measurement (δDOrgueil = +63 ± 138 ‰) and for CI and CV chondrites in our previous work (δDCI = +98 ± 103 ‰ and δDCV = -43 ± 64 ‰) [7], but it is disctinct from the water D/H measured for CM carbonaceous chondrites (δDCM = -358 ± 26 ‰) or in the ungrouped carbonaceous chondrites Bells and Essebi (δDBells/Essebi = +380 ± 64 ‰) [6-7]. Compared to Orgueil, Ryugu's data have higher C/H and D/H ratios consistent with bulk measurement showing that Ryugu's rocks contain less hydrogen than CIs [1]. It is possible that a part of the interlayer water in Orgueil might be of terrestrial origin [1, 8]. Five analyses show clear D-enrichments compared to the other points and could include some D-rich organic hotspots. The hydrogen isotopic compositions will be used to discuss the isotopic distribution of water in the protoplanetary disk at the time and place of the Ryugu asteroid formation. [ABSTRACT FROM AUTHOR]

Objectives: Investigate immune responses of adenoidal lymphocytes against outer-membrane protein P6 purified from nontypeable Haemophilus influenzae (HI). Clarify the role of adenoids in regulating the colonization of HI in the nasopharynx.Study Design: Microbiological and immunological examinations of adenoids obtained from 21 children, 15 boys and five girls, from 1 to 13 years of age (median, 5 y), suffering from adenoidal hypertrophy complicated by otitis media with effusion (OME).Methods: The incidence of HI in adenoids was compared with the number of P6-specific immunoglobulin (Ig) A-secreting cells in adenoids, determined by enzyme-linked immunoassay.Results: Quantitative culture assay showed significant correlation between the numbers of HI in adenoids and those in nasopharyngeal secretions (NS). In children aged 5 years and younger, the numbers of P6-specific IgA-secreting cells in adenoids were significantly correlated with IgA antibody titers in NS (r = 0.68, P < .05). The numbers of P6-specific IgG- and IgA-secreting cells were lower in children aged 6 years and older than in children aged 5 years and younger. Furthermore, the number of P6-specific IgA-secreting cells was significantly increased in HI-negative subjects when compared with HI-positive subjects (P < .05).Conclusions: Adenoids play an important role as an effector site of the mucosal immune system in the upper respiratory tract. IgA immune responses in adenoids are responsible for the clearance of HI from the nasopharynx. [ABSTRACT FROM AUTHOR]

Inosine triphosphatase ( ITPA) genetic variants are strongly associated with ribavirin ( RBV)-induced anaemia during pegylated interferon ( PEG- IFN) plus RBV therapy. However, the treatment efficacy of ITPA genetic variants has not been fully explored. We enrolled 309 individuals infected with hepatitis C virus genotype 1, who were treated with PEG- IFN plus RBV for 48 weeks. The ITPA SNP: rs1127354 and IL28B SNP: rs8099917 were genotyped. We examined the risk factors for severe anaemia up to week 12 after the start of treatment and treatment efficacy. The incidence of severe anaemia, ≥3 g/dL reduction or <10 g/dL of haemoglobin ( Hb) up to week 12, was more frequent in patients with CC at rs1127354 [65% (145/224), 33% (73/224)] than in those with CA/ AA [25% (21/85), 6% (8/85)] ( P < 0.0001). ITPA genotype, pretreatment Hb level and age were independent predictive factors for severe anaemia: Hb < 10 g/dL. In IL28B favourable type, the sustained virologic response rate was higher in ≥60-year-old patients with CA/ AA than in those with CC [71% (22/31) vs 40% (26/65), P = 0.005], although there was no significant difference in treatment efficacy according to ITPA genetic variants in the <60-year-old patients. The proportion of patients administered ≥80% of the dosage of RBV was significantly higher in the patients with CA/ AA than in those with CC ( P = 0.025), resulting in a lower relapse rate. In conclusion, ITPA genetic variants were associated with severe RBV-induced anaemia and could influence the efficacy of PEG- IFN plus RBV treatment among elderly patients with IL28B favourable type. [ABSTRACT FROM AUTHOR]

Background Physical or psychological stress causes functional disorders in the upper gastrointestinal tract. This study aims to elucidate the ameliorating effect of exogenous acylated ghrelin or rikkunshito, a Kampo medicine which acts as a ghrelin enhancer, on gastric dysfunction during acute restraint stress in mice. Methods Fasted and postprandial motor function of the gastric antrum was wirelessly measured using a strain gauge force transducer and solid gastric emptying was detected in mice exposed to restraint stress. Plasma corticosterone and ghrelin levels were also measured. To clarify the role of ghrelin on gastrointestinal dysfunction in mice exposed to stress, exogenous acylated ghrelin or rikkunshito was administered, then the mice were subjected to restraint stress. Key Results Mice exposed to restraint stress for 60 min exhibited delayed gastric emptying and increased plasma corticosterone levels. Gastric motility was decreased in mice exposed to restraint stress in both fasting and postprandial states. Restraint stress did not cause any change in plasma acylated ghrelin levels, but it significantly increased the plasma des-acyl ghrelin levels. Administration of acylated ghrelin or rikkunshito improved the restraint stress-induced delayed gastric emptying and decreased antral motility. Ameliorating effects of rikkunshito on stress-induced gastric dysfunction were abolished by simultaneous administration of a ghrelin receptor antagonist. Conclusions & Inferences Plasma acylated/des-acyl ghrelin imbalance was observed in acute restraint stress. Supplementation of exogenous acylated ghrelin or enhancement of endogenous ghrelin signaling may be useful in the treatment of decreased gastric function caused by stress. [ABSTRACT FROM AUTHOR]

Liver diseases associated with hepatitis C virus (HCV) infection have become the major cause of mortality in patients with human immunodeficiency virus (HIV) infection since the introduction of highly active anti-retroviral therapy. HCV-related liver disease is more severe in HIV-infected patients than in non-HIV-infected patients, but the standard therapies used to treat chronic hepatitis C in HCV/HIV coinfected patients are the same as those for patients infected with HCV alone. HIV protease inhibitors might have potential to down-regulate HCV load of HCV/HIV coinfected patients. In this study, we evaluated the effects of nelfinavir on intracellular HCV replication using the HCV replicon system. We constructed an HCV replicon expressing a neomycin-selectable chimeric firefly luciferase reporter protein. Cytotoxicity and apoptosis induced by nelfinavir were assessed and synergism between nelfinavir and interferon (IFN) was calculated using CalcuSyn analysis. Nelfinavir dose-dependently repressed HCV replication at low concentrations (IC50, 9.88 μmol/L). Nelfinavir failed to induce cytotoxicity or apoptosis at concentrations that inhibited HCV replication. Clinical concentrations of nelfinavir (5 μmol/L) combined with IFN showed synergistic inhibition of HCV replication in our replicon model. Our results suggest that the direct effects of nelfinavir on the HCV subgenome and its synergism with IFN could improve clinical responses to IFN therapy in HCV/HIV coinfected patients. [ABSTRACT FROM AUTHOR]

It is widely accepted that daily exercise improves the dynamic standing balance of elderly persons. In the current study, 77 community-dwelling Japanese elderly persons (aged 71.1 ± 0.5 years) participated in a daily exercise program to assess its effect on their dynamic standing balance. The daily exercise consisted of walking, stretching, muscle strengthening, and balance exercises. The program ran for 31 months and the dynamic standing balance was assessed at the start of the program and again at 3, 7, 12, 19, 24, and 31 months. In most of the tests of dynamic standing balance, the measured values improved drastically in the first 7 months; thereafter, they either reached a plateau or continued to improve more slowly. These findings can contribute to the future planning of community-based exercise programs; in particular, the length of the program and the timing of changes to the exercise load. [ABSTRACT FROM AUTHOR]

Background Colorectal depressed tumours have a tendency to invade deeper mucosal layers and metastasize in the lymph nodes, despite their small size. Aim To investigate the clinical and endoscopic characteristics of depressed early colorectal cancers (intramucosal and submucosal adenocarcinoma) compared with non-depressed early cancers. Methods Five hundred and seventy consecutive early colorectal cancers obtained through endoscopic resection or surgical operation were studied. Early cancers were endoscopically classified as either the depressed or non-depressed type. The age and gender of the patients as well as the size and distribution of the cancers were compared between types. The tumour locations were classified into three groups: caecum to transverse colon (right colon), descending to sigmoid colon (left colon) and rectum. Results Patients were similar with respect to age and gender. The mean size of the depressed type was smaller than that of the non-depressed type (mean 8.4 mm vs. 13.3 mm; P < 0.0001). The rate of occurrence of depressed type in the right colon was higher than that of non-depressed type (49% vs. 23%) ( P = 0.0006). Among the early cancers, the incidence of the depressed type in the right colon was higher than that in the left colon and rectum (15% in the right colon, 7% in the left colon and 4% in the rectum; P < 0.01). Conclusions Compared with non-depressed early colorectal cancers, depressed cancers were smaller in size and more likely to be distributed in the right colon. [ABSTRACT FROM AUTHOR]

Background Effects of long-term administration of non-steroidal anti-inflammatory drugs (NSAIDs) on the colon have not been well characterized. Aim To investigate colonoscopic findings and prevalence of adverse events following long-term use of NSAIDs. Methods The study included 425 patients (mean 66.4 years) treated for over one year with NSAIDs, and 2125 age- and sex-matched patients without NSAIDs as controls. Eligible candidates were selected by medical record review for underlying diseases, pre-endoscopic symptoms, category of NSAIDs used, and duration of use. We used endoscopy to study lesion characteristics. Results The occurrence rate of colonic lesions or bleeding in the NSAIDs user (13/425, 3.1%) was higher than that in controls (28/2125, 1.3%) ( p = 0.017). Colitis was found in 10 of the 13 patients. The sigmoid colon, descending colon or both (70.0%) was commonly involved, and showed segmental ischemic colitis features in 8 of the 13 patients (61.5%). Among these, duration of use ranged from 1-30 years (mean 7.8). Nine of 13 patients (69.2%) took low-dose aspirin. Conclusion The prevalence of colonic lesions in long-term NSAIDs users is much lower than that of upper gastrointestinal side effects, but higher than that of colonic lesions in non-NSAIDs users. The most common features of NSAIDs-associated colitis were segmental ischeznia. [ABSTRACT FROM AUTHOR]

Type-I interferons (IFNs) and the interferon-stimulated genes (ISGs) play a major role in antivirus responses against hepatitis C virus (HCV) infection. In this study, we studied expression profiles of ISGs in cells supporting subgenomic HCV replication (Huh7/Rep), and screened their activities to suppress HCV replication. Real-time PCR analyses showed that the expression levels of 23 ISGs were significantly lower in Huh7/Rep than naive Huh7 cells due to transcriptional suppression of the interferon-stimulated response element (ISRE). Furthermore, the expression level of ISGs was also decreased in the cured Huh7 cells in which replicon had been eliminated (cHuh7), indicating adaptation of the cells to support HCV replication by downregulating ISGs. On the other hand, expression of HCV replicon was significantly suppressed by overexpression of several ISGs including PKR, MxA, IRF-9, GBP-1, IFI-6-16, IFI-27, 25OAS and IRF-1. Knock down of GBP-1, IFI-6-16 and IFI-27 by short hairpin RNA resulted in increase of HCV replication. Thus, we conclude that downregulation of ISG expression is required in the host cells supporting HCV replication and that several ISGs directly suppress HCV replication. The search for ISGs that regulate HCV replication may help to elucidate the cellular antiviral defence mechanisms against HCV infection. [ABSTRACT FROM AUTHOR]

The number of amino acid substitutions in the interferon sensitivity-determining region (ISDR) in the nonstructural 5A (NS5A) gene of hepatitis C virus (HCV) is closely associated with the interferon (IFN) response and viral load. Several HCV replicon-based studies have reported that ISDR sequences had an influence on viral replication in vitro. However, it is unclear as to how different ISDR sequences affect HCV replication. Various clinically observed ISDR sequences were introduced into HCV replicons and their contribution to viral replication was investigated using a colony formation assay and/or a transient replication assay. A mapping study of the ISDR was performed to identify the amino acid positions that critically affect replication. While no colonies were formed in the colony formation assay using HCV replicons with few mutations (0, 1 and 3) in the ISDR, numerous colonies (>200) appeared when using constructs with six mutations. Introduction of various distinct ISDR sequences with multiple mutations resulted in replication enhancement in transient assays. A mapping study identified several specific sites in the ISDR that critically affected replication, including codon 2209 which, in patients, was closely associated with a strong response to IFN. ISDR sequences associated with a clinical IFN response and viral load modulated the replication of HCV replicons, suggesting the importance of the ISDR sequence in HCV infection. [ABSTRACT FROM AUTHOR]

In hepatitis C virus (HCV) infection, serum viral load is important in the prediction of therapeutic efficacy. However, factors that affect the viral load remain poorly understood. To identify viral genomic elements responsible for the viral load, we investigated samples from a population of Irish women who were iatrogenically infected from a single HCV source by administration of HCV 1b-contaminated anti-D immune globulin between 1977 and 1978 (Kenny-Walsh, N Engl J Med 1999; 340: 1228). About 15 patients were divided into two groups, viral load increasing group (11 patients) and decreasing group (4 patients). Pairs of sera were collected from each patient at interval between 1.1 and 5.8 years. Full-length sequences of HCV genome were determined, and analyzed for changes in each patient. Sliding window analysis showed that the decreasing group had significantly higher mutation rates in a short segment of NS5B region that may affect the activity of RNA-dependent RNA polymerase. By comparing each coding regions, significantly higher mutation numbers were accumulated in NS5A region in the increasing group than the decreasing group (0.92 vs 0.16 nucleotides/site/year, P = 0.021). The mutation in certain positions of the HCV genome may be determinant factors of the viral load in a relatively homogeneous patient population. [ABSTRACT FROM AUTHOR]

In hepatitis C virus (HCV) genotype 2b infection, viral eradication (sustained viral response; sVR) is obtained in about 40% by interferon monotherapy, whereas a considerable proportion of non-sVR patients exhibit sustained biochemical response (sBR) showing normal biochemical values despite persistent viraemia. However, the mechanism of sBR has not yet been established. In this study, we analysed serial changes in full-length sequences of HCV genotype 2b before and after interferon (IFN) therapy in five patients with sBR and five with no response (NR; persistent viraemia and abnormal biochemical values after IFN therapy). The overall substitution rate of amino acids in the full-length HCV genome was higher in the sBR group than in the NR group [2.22 ± 0.48 (10−3 changes/site/year)vs1.04 ± 0.30:P = 0.002]. When the genetic changes were analysed for individual HCV proteins, the sBR group had significantly higher substitution rates of amino acid in NS4A [8.82 ± 2.80 (10−3 changes/site/year)vs0:P = 0.001]. These amino acid changes in sBR were mainly located in the binding motifs of HLA class I molecules including those frequently found in the Japanese population. These results demonstrated that the greater amino acid changes of HCV arising during interferon therapy are associated with the establishment of sBR. Although functional significance of these changes awaits further investigation, the finding that amino acid changes in NS4A in sBR patients are mainly located in the HLA class I binding motifs illustrated the potential roles of the escape mutations of HCV genome from CTLs in the decreasing activities of hepatitis in sBR. [ABSTRACT FROM AUTHOR]

Hepatitis C virus (HCV) subgenomic replicon has been reported to replicate efficiently and continuously in human hepatoma Huh-7 cells. To extend the previous results to other isolated HCV clones, we constructed another HCV replicon from HC-J4, one of chimpanzee-infectious HCV clones. An HCV replicon derived from HC-J4 (RpJ4) consists of HCV-5′ untranslated region, neomycin phosphotransferase gene, the encephalomyocarditis virus internal ribosomal entry site, HCV nonstructural region, NS3 to NS5B, and HCV-3′ untranslated region. The adaptive mutations known to be required for HCV-Con1 replicon were introduced in RpJ4 replicon, aa.(amino acids number according to HC-J4) 2197 serine to proline, deletion of serine at aa.2201, and aa.2204 serine to isoleucine (RpJ4-S2197P, RpJ4-S22001del, and RpJ4-S2204I). RpJ4/ISDR mutant and RpJ4-S2201del/ISDR mutant were also constructed by introducing six amino acid mutations into the interferon sensitivity determining region (ISDR). After transfection into Huh-7 cells and G418 selection, RpJ4 and RpJ4/ISDR mutants did not produce any colony. In contrast, G418-resistant cells were transduced efficiently by RpJ4-S2197P, RpJ4-S2204I, RpJ4-S2201del and RpJ4-S2201del/ISDR mutant, with the RpJ4-S2201del/ISDR mutant being most efficient. Hence the HCV replicon derived from HC-J4 can replicate efficiently following the introduction of adaptive mutations into the upstream region of ISDR. Moreover, additional introduction of mutations into ISDR further enhanced its replication. These findings demonstrate that the genetic structure of the NS5A domain is critical in HCV replications. [ABSTRACT FROM AUTHOR]

: A decrease in pepsinogen and gastrin levels 1–3 months after Helicobacter pylori eradication is well known. However, few data are available on the long-term progression of these decreases beyond 1 year after eradication, and there has been no investigation into whether pepsinogen and gastrin levels return to normal levels as defined by data from H. pylori-negative patients with dyspepsia. : We studied the effect of H. pylori eradication on pepsinogen and gastrin levels for more than 1 year, and compared levels to those in H. pylori-negative patients with dyspepsia. We also investigated the effect of H. pylori eradication on the course of atrophic corpus gastritis as reflected by histology, and on PGI levels and PG I/II ratio. : We enrolled 172 H. pylori-positive patients with dyspepsia who had undergone successful eradication therapy of more than 1 year's duration and 101 non-treated H. pylori-negative patients with dyspepsia. H. pylori status was assessed at entry and at each endoscopy after eradication by culture, histological results, the rapid urease test and the urea breath test. In both groups, patients were evaluated for fasting serum pepsinogen I and II and gastrin using a radioimmunoassay technique, and underwent detailed histological assessment according to the updated Sydney System. : In the H. pylori-negative patients, mean serum pepsinogen I and II, I/II ratio and gastrin levels were 52.6 ± 20.8 ng/mL, 9.2 ± 4.2 ng/mL, 6.0 ± 1.7 and 53.5 ± 29.2 pg/mL, respectively. In H. pylori-positive patients with long-term eradication, pepsinogen I and II, I/II ratio and gastrin levels were 81.3 ± 46.6 ng/mL, 25.9 ± 17.1 ng/mL, 3.4 ± 1.3 and 131.9 ± 130.8 pg/mL, respectively, before treatment. At 1–3 months after eradication, serum pepsinogen I and II levels in the H. pylori-positive patients decreased to levels similar to those in the negative patients, whereas pepsinogen I/II ratio and gastrin levels remained lower and higher, respectively, than in the negative patients. Serum pepsinogen I/II ratio and gastrin levels then became similar between the groups at 12–15 months after eradication. In histological findings, inflammation and neutrophil activity decreased by 1–3 months, and atrophy in the corpus and metaplasia in the antrum decreased by 12–15 months. : The results suggest that atrophic corpus gastritis and superficial gastritis are reversible, as indicated by both histological and serological findings in a long-term follow-up study. [ABSTRACT FROM AUTHOR]

We observed nishikinezumi, cinnamon-coloured (NC)/Fujita (F) mice aged between 5 and 28 weeks. These NC mice have skin eruptions that resemble human atopic dermatitis (AD) under conventional circumstances. We investigated the skin of eruptive and non-eruptive lesions in NC/F mice by using haematoxylin–eosin (H&E) staining, toluidine blue staining and immunohistopathological study with immunoglobulin (Ig)EℇRI, CD23, interleukin (IL)-4, IL-5, interferon (INF)-γ and Ia antigen. Histological examination of the eruptive lesions revealed the perivascular infiltration of many lymphocytes and mast cells into the upper dermis. Intracellular oedema of the epidermis, lymphocyte infiltration into the epidermis and liquefaction degeneration of the basal layer were also observed. The numbers of IL-4 and IL-5 positive cells in the eruptive lesions were larger than those of the non-eruptive lesions. IL-4 and IL-5 positive cells in the eruptive lesions increased weekly. Some IFN-γ positive cells were observed in the eruptive lesions after 21 weeks. IFN-γ positive cells were scarce in the skin of both the non-eruptive and eruptive lesions before 21 weeks. Serum IgE increased from 7 weeks to 21 weeks. We confirmed that these findings indicated that T helper (Th)2-dominant immunological activation transformed to a Th1-dominant situation. Many IgEℇRI positive cells were recognized in the dermis of the eruptive lesions by the time IgE had decreased. We assumed that the dermatitis before 21 weeks was an IgE-mediated allergy. We have previously reported that older NC/F mice had positive patch-test reactions to mites. Because serum IgE decreased after 21 weeks, dermatitis after 21 weeks might be associated more with cell-mediated delayed hypersensitivity than with IgE-mediated immediate allergy. [ABSTRACT FROM AUTHOR]

Reports on the application of a scintillator-based area detector to the neutron time-of-flight method by developing an electronics system for the detector. Spatial resolution which was consistent with a fiber width of 0.4 millimeter; Detection efficiency for thermal neutrons.

Abstract Aims To investigate the effect of smoking on soluble adhesion molecules in middle-aged diabetic patients. Methods One hundred out-patients with Type 2 diabetes and 100 age- and sex-matched non-diabetic subjects without clinical macrovascular disease were selected. Soluble serum levels of adhesion molecules were analysed using enzyme immunoassay. Carotid atherosclerosis was assessed using an ultrasound system. Results When compared with non-diabetic subjects, soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular adhesion molecule-1 (sICAM-1), and sE-selectin were found at significantly high levels in diabetic patients and significantly higher levels of sICAM-1, sE-selectin, and sP-selectin were observed in current smokers than never-smokers among diabetic or non-diabetic subjects, respectively. The combined, but not enhanced, effects of diabetes mellitus and smoking were observed in sICAM-1 and sE-selectin levels. Additionally, levels of sICAM-1 (P < 0.05) and sE-selectin (P < 0.01), but not sP-selectin, were high in ex-smokers when compared with never-smokers among diabetic patients. Diabetic smokers were also found to have marked carotid atherosclerosis, which was related to increased levels of sICAM-1. Conclusions Our present study shows that levels of adhesion molecules were higher in diabetic smokers than diabetic non-smokers or non-diabetic smokers, and that cessation after chronic smoking did not restore the levels of sICAM-1 and sE-selectin, though sP-selectin levels were restored. These data suggest a possible mechanism for accelerated atherosclerosis induced by smoking in patients with diabetes. [ABSTRACT FROM AUTHOR]

However, there was no report that endoscopic myotomy for rectal tumor with severe fibrosis after surgical hemorrhoids treatment. This case suggested that endoscopic myotomy is useful for treating large tumors with severe fibrosis after surgical hemorrhoids treatment, while avoiding stoma formation. [Extracted from the article]

A 79-year-old man with chronic kidney disease was referred to our hospital for the workup of anemia that progressed in 1 month (hemoglobin level, from 10.1 to 4.9 g/dL).Unenhanced computed tomography (CT) revealed dilation of the main pancreatic duct (MPD) and atrophic pancreatic parenchyma lesion was identified. (c) Contrast-enhanced computed tomography showing a relatively hypervascular mass (arrow) including a noncontrast lesion in the pancreatic tail 1 day after endoscopic retrograde pancreatography. gl Microscopically, the MPD was filled with tumour cells with high-grade dysplasia, showing complex intraductal papillo-tubular growth with hemorrhage around the tumour (b,c). [Extracted from the article]

A 17-year-old boy with X-linked inhibitor of apoptosis (XIAP) deficiency was referred to our hospital for hematopoietic stem cell transplantation (HSCT). Before HSCT, colonoscopy revealed a stricture of the ileocecal valve with an active ulcer (Fig. a), in addition to active multiple ulcers in his large intestine (Fig. b,c). Before hematopoietic stem cell transplantation (HSCT), the ileocecal valve (arrow) was mildly stenosed with an active ulcer (a), and there were multiple active ulcers in the transverse colon (b) and sigmoid colon (c). [Extracted from the article]

The article presents a case study of a 80-year-old Japanese woman who was referred for examination of a pancreas head mass lesion. The patient was diagnosed with multiple myeloma 2 years before referral, and computed tomography and endoscopic ultrasonography showed a mass in the pancreas head involving the distal bile duct. Biopsy specimen from the distal BD showed infiltration of few plasma cells without IgG4 staining. final diagnosis was pancreatic ductal adenocarcinoma complicated by MM.

The article presents a case report of an old woman which shows a potential role of less invasive transurethral endoscopic therapy for problem in the graft pancreas located in the pelvis after pancreatico-duodeno-cystostomy.

The article focuses on the case of a 30-year-old woman with a rare well-differentiated neuroendocrine tumor in the bile duct with spontaneous regression diagnosed by endoscopic ultrasound and fine needle aspiration (EUS-FNA). Topics discussed include the persistent epigastric discomfort and hiccups experienced by the woman and the result of her contrast-enhanced computed tomography (ECT) which showed a round-shaped mass in the perihilar bile duct.

The article presents a case study of a 56-year-old man who was referred due to the further examination of a calcified abdominal mass on plain radiography and the splenic artery aneurysm diagnosis was made through radiographic imaging with no symptoms.

Background and Aims: The prognostic impact of previous-HBV-infection (pHBV) in non-HBV-related hepatocellular carcinoma (non-HBV-related-HCC) and the prevalence, characteristics and significance of recently developed high-sensitivity HBs antigen positivity (hHBsAg+) in these patients remain unclear. We aimed to close these gaps., Methods: We retrospectively screened patients with newly diagnosed non-HBV-related-HCC (standard HBsAg-test negative) at Hokkaido University. Patients with complete clinical information and preserved serum for hHBsAg+ were included. We evaluated the prevalence, characteristics and prognostic impact of pHBV and hHBsAg+ in non-HBV-related-HCC., Results: A total of 401 non-HBV-related-HCC patients were included (288 with pHBV/113 without pHBV). In non-HBV-related-HCC, pHBV did not affect overall survival (OS). Among non-HBV-related-HCC patients with pHBV, 11.8% (34/288) were hHBsAg+ and had more advanced stages of HCC, higher AFP levels, higher vascular invasion rates, and significantly shorter OS than others (OS: 19.3 vs. 61.4 months, p = 0.012). Comparison of OS among non-HBV-related-HCC patients without pHBV (group 1), those with pHBV and without hHBsAg+ (group 2), and those with pHBV and hHBsAg+ (group 3) revealed significantly shorter OS in group 3 (19.3, 56.6 and 66.4 months in groups 1, 2 and 3, respectively; p = 0.036). Multivariate Cox regression indicated that compared with group 1, only group 3 was significantly and independently associated with shorter OS (HR: 2.044, p = 0.011). Subgroup analysis revealed that this association was particularly evident in non-HBV-related-HCC patients with non-B-non-C aetiology and advanced HCC., Conclusions: In non-HBV-related-HCC patients, hHBsAg+, not pHBV, is significantly and independently associated with poor prognosis., (© 2024 John Wiley & Sons Ltd.)

Introduction: Overweight is a negative prognostic factor in the general population in the long term. However, the role of body mass index (BMI) in the short-mid term in advanced tumours is unclear. The present analysis investigates the role of BMI weight classes in a large sample of patients affected by HCC and receiving atezolizumab plus bevacizumab or lenvatinib as first-line treatment., Methods and Material: The cohort included consecutive patients affected by BCLC-c and BCLC-B HCC patients from a multicenter international study group who received atezolizumab plus bevacizumab or lenvatinib as first-line therapy. Population was stratified according to the BMI in under-, over- and normal-weight according to the conventional thresholds. The primary objective of the study was to evaluate the prognostic and predictive impact of BMI in patients affected by advanced or intermediate HCC. Survival curves were estimated using the product-limit method of Kaplan-Meier. The role of stratification factors was analysed with log-rank tests., Results: 1292 consecutive patients with HCC were analysed. 466 (36%) patients were treated with lenvatinib and 826 (64%) patients were treated with atezolizumab plus bevacizumab. In the atezolizumab plus bevacizumab arm, 510 (62%) patients were normal-weight, 52 (6%) underweight and 264 (32%) overweight. At the univariate analysis for OS, underweight patients had significantly shorter OS compared to normal-weight patients, whereas no differences were found between normal-weight versus overweight. Multivariate analysis confirmed that underweight patients had significantly shorter OS compared to normal-weight patients (HR: 1.7; 95% CI: 1.0-2.8; p = .0323). In the lenvatinib arm, 26 patients (5.6%) were categorized as underweight, 256 (54.9%) as normal-weight, and 184 (39.5%) as overweight. At the univariate analysis for OS, no significant differences were found between normal-weight versus underweight and between normal-weight versus overweight, which was confirmed at multivariate analysis., Conclusion: Our analysis highlighted a prognostic role of BMI in a cohort of patients with advanced HCC who received atezolizumab plus bevacizumab, while no prognostic role for low BMI was apparent in patients who received lenvatinib., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Japan became the world's first country to cover Helicobacter pylori eradication for chronic gastritis under its National Health Insurance (NHI) system in February 2013. Thereafter, H. pylori eradication dramatically increased and gastric cancer deaths began to decrease in Japan. However, the details of gastric cancer deaths and its prevention in the very elderly have not been fully elucidated., Methods: We analyzed the temporal trend of gastric cancer deaths referencing data from Ministry of Health, Labour and Welfare reports and "Cancer Statistics in Japan-2021" and assessed the numbers of H. pylori test and gastric cancer screening using a national database and a report of cancer screening in Shimane Prefecture, respectively., Results: Although gastric cancer deaths in total population have clearly decreased since 2013, those in people aged 80 years and older are still increasing. People aged 80 years and older represent 9% of the total population and accounted for half of all gastric cancer deaths in 2020. The numbers of H. pylori eradication and gastric cancer screening in people aged 80 years and older were 25% and 25% of those in other generations, respectively., Conclusion: In spite of a dramatic increase in H. pylori eradication and a clear decrease in gastric cancer deaths in Japan, gastric cancer deaths in people aged 80 years and older are increasing. This might be due to fewer H. pylori eradication in the elderly than in other generations, indicating the difficulty of gastric cancer prevention in the very elderly., (© 2023 The Authors. Helicobacter published by John Wiley & Sons Ltd.)

Background: A persistently high methylation level in gastric mucosa after Helicobacter pylori (H. pylori) eradication is presumed to be a risk for metachronous gastric cancer (MGC); however, long-term changes in aberrant DNA methylation and histological gastritis have been unclear. Our aim was to examine changes in DNA methylation and histological gastritis according to the occurrence of MGC., Methods: Subjects were classified into three groups: 25 patients in whom MGCs occurred after the initial endoscopic resection (ER) for early gastric cancer and H. pylori eradication (MGC group), 17 patients in whom MGC did not occur for more than 5 years after the initial ER and H. pylori eradication (non-MGC group) and 29 patients without a history of gastric cancer who succeeded in eradication more than 5 years ago (HP group). Aberrance of DNA methylation in three genes (miR-124a-3, EMX1, NKX6-1) and histological score of atrophy and intestinal metaplasia (IM) were evaluated using biopsy samples before and more than a mean of 5 years after H. pylori eradication. Also, the mean Z-score was calculated using Z-score values of the three genes., Results: The methylation level of miR-124a-3 in the HP group and non-MGC group and that of EMX1 in the HP group significantly decreased in the long term after eradication. In the MGC group, H. pylori eradication did not improve aberrant methylation, and the mean Z-score significantly increased. There were significant positive correlations between methylation levels in miR-124a-3 and EMX1 and histological findings after eradication., Conclusions: A persistently high methylation level after H. pylori eradication reflected precancerous mucosal conditions and led to long-term MGC., (© 2022 John Wiley & Sons Ltd.)