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Summary: Bovine viral diarrhoea virus (BVDV) infection in cattle can result in growth retardation, reduced milk production, reproductive disorders and death. Persistently infected animals are the primary source of infection. In Hokkaido, Japan, all cattle entering shared pastures in summer are vaccinated before movement for disease control. Additionally, these cattle may be tested for BVDV and culled if positive. However, the effectiveness of this control strategy aiming to reduce the number of BVDV‐infected animals has not been assessed. The aim of this study was to evaluate the effectiveness of various test‐and‐cull and/or vaccination strategies on BVDV control in dairy farms in two districts of Hokkaido, Nemuro and Hiyama. A stochastic model was developed to compare the different control strategies over a 10‐year period. The model was individual‐based and simulated disease dynamics both within and between herds. Parameters included in the model were obtained from the literature, the Hokkaido government and the Japanese Ministry of Agriculture, Forestry and Fisheries. Nine different scenarios were compared as follows: no control, test‐and‐cull strategies based on antigen testing of either calves or only cattle entering common pastures, vaccination of all adult cattle or only cattle entering shared pastures and combinations thereof. The results indicate that current strategies for BVDV control in Hokkaido slightly reduced the number of BVDV‐infected animals; however, alternative strategies such as testing all calves and culling any positives or vaccinating all susceptible adult animals dramatically reduced those. To our knowledge, this is the first report regarding the comparison of the effectiveness between the current strategies in Hokkaido and the alternative strategies for BVDV control measures. [ABSTRACT FROM AUTHOR]

A genetic polymorphism of the newly discovered interferon-λ 4 ( IFNL4) gene was associated with hepatitis C virus ( HCV) clearance in individuals of African ancestry. To assess whether a dinucleotide variant of IFNL4 (ss469415590) also affected treatment outcome of antiviral therapy in Japan, we genotyped 213 patients with chronic genotype 1 HCV infection and 176 healthy subjects. The ΔG allele was associated with treatment failure [odds ratio ( OR) 4.73, P = 0.019], as was the IFL3 rs8099917 single nucleotide polymorphism ( SNP) ( OR 5.06, P = 0.068). The correlation between ss469415590 and rs8099917 was high ( r2 = 0.92, D′ = 0.98). Multivariate analysis revealed that the rs8099917 SNP was independently associated with treatment failure ( OR 5.28, P = 0.009). Therefore, ss469415590 may be another predictive marker of antiviral therapy outcome in the Japanese population. [ABSTRACT FROM AUTHOR]

Current human leukocyte antigen (HLA) DNA typing methods such as the sequence-based typing ( SBT) and sequence-specific oligonucleotide ( SSO) methods generally yield ambiguous typing results because of oligonucleotide probe design limitations or phase ambiguity for HLA allele assignment. Here we describe the development and application of the super high-resolution single-molecule sequence-based typing ( SS-SBT) of HLA loci at the 8-digit level using next generation sequencing ( NGS). NGS which can determine an HLA allele sequence derived from a single DNA molecule is expected to solve the phase ambiguity problem. Eight classical HLA loci-specific polymerase chain reaction ( PCR) primers were designed to amplify the entire gene sequences from the enhancer-promoter region to the 3′ untranslated region. Phase ambiguities of HLA-A, -B, -C, - DRB1 and - DQB1 were completely resolved and unequivocally assigned without ambiguity to single HLA alleles. Therefore, the SS-SBT method described here is a superior and effective HLA DNA typing method to efficiently detect new HLA alleles and null alleles without ambiguity. [ABSTRACT FROM AUTHOR]

Summary Reasons for performing study: Broad ligament haemorrhage in peripartum mares is a life-threatening disease and there are few reports on the aetiology and pathogenesis of broad ligament haematoma. Objectives: To obtain information regarding the sites for the early diagnosis and pathogenesis of broad ligament haematoma of mares. Methods: Thirty-one mares that died of broad ligament haematoma peripartum were examined pathologically for bleeding sites. The arterial distribution of 5 young mares with several parities served as negative controls. Results: Age and/or multiparity were the predisposing factors for the disease. Arterial injuries were most commonly observed in the uterine artery (24 of 31 mares). Among these, the proximal uterine artery that lies within 15 cm of the bifurcation of the iliac artery was the most frequent site for rupture (18 mares). The lesions occurred preferentially at the bifurcations, lateral part of curvatures and abrupt flexures of the artery. The morphology of the injuries was classified into 3 types: ruptures with and without longitudinal fissures, and transections. Histologically, the arterial wall adjacent to the rupture showed atrophy of smooth muscle cells with fibrosis of the tunica media and disruption and/or calcification of the internal elastic lamina. Conclusions: Arterial injuries that led to broad ligament haematoma in peripartum mares occurred most frequently in the proximal uterine artery, and atrophy of smooth muscle cells with fibrosis of the arterial wall was as one of the predisposing factors in aged and multiparous mares. Potential relevance: Monitoring small aneurysms, mural tearing, medial fibrosis at the proximal uterine artery by transrectal echography could provide useful information for the early diagnosis and possible prevention of broad ligament haematoma of peripartum mares. [ABSTRACT FROM AUTHOR]

IgG4 has been implicated in a diverse set of complex pathologies – e.g. autoimmune pancreatitis (AIP), idiopathic membranous nephropathy – and carries unique features including lack of activation of the classical complement pathway and a dynamic Fab-arm exchange. We recently showed that the rheumatoid factor (RF)-like activity of IgG4 is achieved through a hitherto unknown, Fc–Fc (and not Fab–Fc as is the case in classical RF; CRF) interaction; hence the name, novel RF (NRF). Here, we further explore the resemblance/difference between CRF and NRF. As heterophilic interactions of human IgM RF (CRF) are well known, we checked whether this is the case for IgG4. Human IgG4 showed variable reactivity to animal IgGs: reacting intensely with rabbit and mouse IgGs, but weakly with others. The binding to rabbit IgG was not through the Fab (as in CRF) but via the Fc piece, as was recently shown for human IgG (NRF). This binding correlates with the IgG4 concentration per se and could therefore be of diagnostic usage and incidentally explain some observed interferences in biological assays. In conclusion, here is defined a novel heterophilic antibody interaction and is established the universality of the unique Fc–Fc binding, both involving IgG4. [ABSTRACT FROM AUTHOR]

We sought to clarify the incidence and role of Helicobacter pylori ( H. pylori) seropositivity in patients with hepatitis C virus (HCV) infection and the effect of coinfection on interferon- α and ribavirin therapy. The presence of H. pylori was tested using a commercially available enzyme immunoassay in serum samples from 93 patients with chronic hepatitis C. Clinical features, HCV markers and response of HCV to interferon- α and ribavirin were compared between H. pylori-positive and H. pylori-negative patients. Anti- H. pylori antibody was detected in 45 (48%) of the 93 patients, whose median HCV-RNA level (495 vs 760 kIU/mL; P = 0.013) and platelet count (128 vs 158 × 103/ μL; P = 0.009) were significantly lower than in patients with HCV infection alone. Anti- H. pylori antibody levels were found to be significantly correlated with fibrosis score ( P = 0.0083, r = 0.33) but inversely related to platelet count ( P = 0.0037, r = −0.34). The sustained response rate for HCV clearance following interferon- α and ribavirin treatment did not differ between patients with and without anti- H. pylori seropositivity. The presence of H. pylori [odds ratio (OR) 8.61; 95% confidence interval (CI) 1.59–46.70] and fibrosis score (OR 30.13; 95% CI 5.44–166.78) were found by multivariate analysis to be associated with the decrease of platelet count during therapy. Coexistent H. pylori infection does not demonstrably influence the clinical course of chronic hepatitis C. A possible connection between H. pylori coinfection and thrombocytopenia was found during the treatment course, suggesting that preemptive eradication of H. pylori may facilitate completion of treatment and increased sustained virological response. [ABSTRACT FROM AUTHOR]

Although most cases of hepatocellular carcinoma (HCC) are associated with either the hepatitis B or C viruses (HBV, HCV), about 10–20% of HCCs occur in patients with chronic hepatitis that is aetiologically undefined. The aim of the present study was to determine the prevalence of the transfusion-transmitted SEN virus (SEN-V) in patients with HCC, including those patients who do not otherwise appear to be infected with HBV or HCV. Fragments of SEN-V subtypes D and H were amplified separately by PCR from the sera of 50 patients with HCC (31 from Canada and 19 from Japan) as well as from HCC and adjacent nontumourous liver tissues from eight of the Canadian patients. SEN-V DNA was found in the serum of 10 of 31 (32%) Canadian patients and eight of 19 (42%) Japanese patients [overall, 18 of 50 (36%) HCC patients]. SEN-V DNA was detected in the serum of 10 of 23 (43%) HCC patients with antibody to HCV (anti-HCV), six of 11 (55%) with hepatitis B surface antigen (HBsAg), and two of 16 (12%) without detectable anti-HCV or HBsAg. Twenty-three HCC patients in this study had ‘silent HBV,’ characterized by the detection of HBV DNA in the absence of HBsAg; eight of these (35%) also had SEN-V infections. SEN-V DNA was detected in HCC patients most typically in those with coexistent HBV or HCV infection. SEN-V was found in only one of seven HCC patients without HBV (without HBsAg or HBV DNA) or HCV and thus does not appear to be an important cause of ‘cryptogenic’ HCC. [ABSTRACT FROM AUTHOR]

We investigated the presence of antibodies to hepatitis E virus (anti-HEV) and hepatitis A virus (anti-HAV) by enzyme immunoassays in sera from 1015 individuals collected in 1974, 1984 and 1994. Age-specific profiles of anti-HEV remained unchanged with a peak at 40–49 years, while those of anti-HAV started to increase in individuals aged 20–29 years in 1974, 30–39 years in 1984 and 40–49 years in 1994. These results suggest that a silent HEV infection has been taking place in the last 20 years or so in Japan, while HAV infection has been terminated at least since 1974. [ABSTRACT FROM AUTHOR]

Abstract We recently cloned a c-Jun amino-terminal kinase (JNK) sequence from the C6/36 cell line, derived from the mosquito Aedes albopictus . We showed that SP600125, an inhibitor of JNK proteins, inhibits phagocytosis by C6/36 cells, suggesting that the JNK-like protein regulates phagocytosis. Here, we show that C6/36 cells constitutively express low levels of mRNA encoding the antibacterial peptides, cecropin and defensin, but that these mRNAs were up-regulated upon stimulation by lipopolysaccharide (LPS). Thus, the C6/36 cells have properties similar to those of mammalian macrophages. To characterize further the functional properties of C6/36 cells, we have assayed the role of the JNK-like protein in phagocytosis, endocytosis, and viral infection. C6/36 cells phagocytosed bacteria and artificial beads, and this was only slightly up-regulated following LPS stimulation, suggesting that newly stimulated JNK-like protein was not necessary for phagocytosis. SP600125 inhibited the acidification of intracellular compartments, including those involved in the endocytic pathway. Pretreatment of C6/36 cells with SP600125 or bafilomycin A1, but not cytochalasin D, inhibited the entry of West Nile virus (WNV), suggesting that WNV is internalized mainly by endocytosis, and that the JNK signalling pathway is important for endocytic entry. These findings indicate that the JNK-like protein regulates basic physiological functions, including phagocytosis and endocytosis and infection of WNV. [ABSTRACT FROM AUTHOR]

A six-month-old shiba dog with a one-month history of progressive motor dysfunction showed clinical signs of a cerebellar disorder, including ataxia, dysmetria and intention tremor of the head. Histopathological and ultrastructural studies revealed distended neurons packed with membranous cytoplasmic bodies throughout the central nervous system. The activities of lysosomal acid β-galactosidase in its leucocytes and liver were less than 2 per cent of the control levels, and the compound accumulated in the brain was identified as GM1 ganglioside. A sibling which died immediately after birth was shown to have a β-galactosidase deficiency in the brain and visceral organs. A family study revealed that the sire and dam of the probands were heterozygotes with approximately half of the normal level of β-galactosidase activity, suggesting an autosomal recessive pattern of inheritance. [ABSTRACT FROM PUBLISHER]

Focuses on the thermal imaging effect on morphology and electrical properties of biaxially oriented polypropylene films. Development of power capacitor dielectric systems; Physiochemical properties of polypropylene resins and films.

An 8-month-old dog with a history of gastrointestinal disturbances and neurological signs was presented with hyperammonemia. Necropsy revealed ascites, portosystemic collaterals, and an irregularly surfaced small liver. Histologically, there were diffuse neuronal necrosis and focal spongiform changes in the brain, and marked fibrosis in the liver. Hepatic encephalopathy was diagnosed. [ABSTRACT FROM AUTHOR]

The nutritional status of the very lowerucate rapeseed oil, Brassica napus var. 'Tower,' was compared with that of the high-erucate oil, Brassica napus var. 'Target', as well as with corn oil. The effect of randomization on the nutritional qualities of rapeseed oil was investigated as well. The feeding of diets containing the original and randomized 'Tower' oil or the original 'Target' oil, at the 20% level by weight, gave growth rates which were not significantly different from that for corn oil. However, the randomized 'Target' oil gave growth rates which were significantly less than all other groups. The growth results could not be explained simply on the basis of food consumption. The level of triglycerides in the hearts of rats fed the very low-erucate oils was not significantly different from the corn oil group. Triglyceride concentrations in the hearts of animals given the high-erucate oils were 7-12 times greater than all other groups. The level of total fatty acids in tissue phospholipids was the same regardless of dietary treatment. Fatty acid compositions of the tissue lipids were the same in animals fed either the original or randomized rapeseed oils. A much higher incidence of focal myocardial necrosis was found in animals receiving high-erucate rapeseed oil relative to animals given the corn oil. The incidence in rats fed diets containing very low-erucate rapeseed oil was intermediate between these latter two extremes. [ABSTRACT FROM AUTHOR]

We examined the progression of articular destruction and the production of tumour necrosis factor-α (TNF-α) in antigen-induced arthritis (AIA) in rabbits, i.e. flare-ups of inflammation induced by repeated intra-articular injections (single, twice and three times) of antigen. A marked progression of articular destruction and an infiltration of inflammatory cells in the synovium were observed with the increase in the number of antigen injections. An immunohistochemical analysis of the synovial lesions following three injections of antigen revealed that the lymphoid follicles consisted mainly of CD4+ T cells and IgG/IgM+ B cells. There were marked infiltrations of IgG+ plasma cells around the lymphoid follicles. In contrast, the production of TNF-α in the synovial fluid and the erythrocyte sedimentation rate (ESR), which is a marker of systemic inflammatory activity in rheumatoid arthritis, peaked at 6 h and 24 h, respectively, following the last injection of antigen. These values were also greater following the repeated injections of antigen compared with the single injection. The TNF-α was produced markedly in the joints at the onset of the flare-ups of arthritis following the repeated injections of antigen, and the elevation of the ESR and an acceleration of the inflammatory response in the synovium were observed with a concomitant progression of severe articular destruction, suggesting that the marked production of TNF-α at the time of flare-ups may be involved in the exacerbation of AIA in rabbits. [ABSTRACT FROM AUTHOR]

The mechanism of oxidative hair dyes (permanent hair color) in cuticle layers of human hair was studied. In general, it is considered that the oxidative hair dye deposits monomer into the cortex, and is polymerized with coloring in there. It was confirmed that not only cortex but also cuticle layers were dyed with the permanent hair color, through observation with the thin cross-section of the dyed hair. There were exogenous metals in the cuticle layers from tap water etc., and the transition metals increased the dyeing and decreased the bleaching. It was thought that the activity of oxidation reaction with hydrogen peroxide was increased in the cuticle layers, and permeability to the cortex was decreased. Furthermore, TEM findings suggested that the oxidation hair dyes mainly reacted in the β-layer/ δ-layer interface in the cuticle layers, unevenly distributing the metals in the β-layer of cuticular CMC. Keywords: hair, oxidative hair dye, hair color, bleach, cuticle, transition metal, ultrastructure, CMC, β-layer, oxidative reaction [ABSTRACT FROM AUTHOR]

Background: The diagnosis of metabolic dysfunction-associated steatotic liver disease (MASLD) requires at least one of five cardiometabolic criteria. It is unclear whether these criteria can be used as predictors and treatment targets for complications including liver-related events and major adverse cardiovascular events (MACE)., Aims: To investigate the relationship between cardiometabolic criteria and complications., Methods: We conducted a nationwide, population-based study of 979,352 patients with MASLD. We investigated relationships between a number of criteria at baseline and liver-related events or MACE risks. In a separate longitudinal analysis, we included patients with five criteria at baseline and investigated the relationship between improving the criteria and the incidence of complications after 1 year., Results: The cumulative incidence of MACE, but not liver-related events, increased with increasing baseline cardiometabolic criteria. In the longitudinal study, multivariable analysis using patients with five criteria (no improvement) as the reference, adjusted hazard ratios (95% confidence interval) of MACE in patients with 4, 3, 2, and 0-1 criteria (1 to 4-5 criteria improvement) were 0.55 (0.52-0.58, p < 0.001), 0.20 (0.17-0.22, p < 0.001), 0.13 (0.11-0.16, p < 0.001), and 0.06 (0.02-0.3, p < 0.001), respectively. The risk of MACE decreased as the cardiometabolic criteria improved. There was no significant association between improvement of the criteria and liver-related events., Conclusions: Cardiometabolic criteria can be used as predictors and treatment targets for cardiovascular event risk in MASLD. Developing predictors and therapeutic targets for liver-related events is a future challenge., (© 2024 John Wiley & Sons Ltd.)

Background: A multi-society consensus group proposed a new nomenclature for steatotic liver disease (SLD) including metabolic-dysfunction associated steatotic liver disease (MASLD), MASLD and increased alcohol intake (MetALD) and alcohol-associated liver disease (ALD). However, the risk of liver-related events, major adverse cardiovascular events (MACE) and all-cause mortality among various sub-groups is unknown., Aims: To evaluate the risk of liver-related events, MACE and death among patients with SLD., Methods: We conducted a nationwide, population-based study and enrolled 761,400 patients diagnosed with MASLD, MetALD or ALD. The primary endpoint was the occurrence of liver-related events, MACE and death in patients with MASLD, MetALD and ALD., Results: The cumulative incidence of liver-related events and death were highest in ALD, followed by MetALD and MASLD (p < 0.001 for both liver-related events and death), while the incidence of MACE was highest in MASLD, followed by MetALD and ALD (p < 0.001). Using MASLD as the reference and adjusting for age, sex, smoking, diabetes mellitus, dyslipidaemia and hypertension, the adjusted hazard ratios (95% confidence intervals) for liver-related events, MACE and death in MetALD were 1.42 (1.1-1.8), 0.68 (0.63-0.73) and 1.13 (0.98-1.3), respectively. In ALD, they were 3.42 (2.6-4.6), 0.58 (0.49-0.67) and 1.60 (1.3-2.0), respectively, for liver-related events, MACE and death., Conclusions: The new consensus nomenclature can be used to stratify the risk of complications and prognosis. The nomenclature is beneficial for risk stratification and identifying new mechanisms for disease-specific therapeutic implications., (© 2024 John Wiley & Sons Ltd.)

Aims: Although therapeutic drug monitoring (TDM) of voriconazole is performed in outpatients to prevent treatment failure and toxicity, whether TDM should be performed in all or only selected patients remains controversial. This study evaluated the association between voriconazole trough concentrations and clinical events., Methods: We investigated the aggravation of clinical symptoms, incidence of hepatotoxicity and visual disturbances, change in co-medications and interaction between voriconazole and co-medications in outpatients receiving voriconazole between 2017 and 2021 in three facilities. Abnormal trough concentrations were defined as <1.0 mg/L (low group) and >4.0 mg/L (high group)., Results: A total of 141 outpatients (578 concentration measurements) met the inclusion criteria (treatment, 37 patients, 131 values; prophylaxis, 104 patients, 447 values). The percentages of patients with abnormal concentrations were 29.0% and 31.5% in the treatment and prophylaxis groups, respectively. Abnormal concentrations showed 50% of the concentrations at the first measurement in both therapies. Aggravation of clinical symptoms was most frequently observed in the low treatment group (18.2%). Adverse events were most common in the high group for both therapies (treatment, hepatotoxicity 6.3%, visual disturbance 18.8%; prophylaxis, hepatotoxicity 27.9%). No differences were found in changes to co-medications and drug interactions. In the prophylaxis group, prescription duration in the presence of clinical events tended to be longer than in their absence (47.4 ± 23.4 days vs 39.7 ± 21.9 days, P = .1132)., Conclusions: We developed an algorithm based on clinical events for appropriate implementation of TDM in outpatients. However, future interventions based on this algorithm should be validated., (© 2024 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: The characteristic endoscopic findings of non-Helicobacter pylori Helicobacter (NHPH) gastritis, including white marbled appearance and crack-like mucosa, have been reported. However, these findings can also manifest in H. pylori (HP)-infected gastritis. This study compared NHPH gastritis and mild atrophic HP gastritis to identify features that may enhance NHPH diagnosis., Materials and Methods: A total of 2087 patients underwent upper gastrointestinal endoscopy and were histologically evaluated by multiple gastric mucosal biopsies according to the updated Sydney System (USS) at Shinshu University Hospital between 2005 and 2023. Among them, nine patients were classified into the NHPH group and 134 patients with HP infection and mild atrophy were classified into the HP group for retrospective comparisons of endoscopic findings and clinicopathological characteristics., Results: All nine patients in the NHPH group (eight males [89%], median ± standard deviation [SD] age: 49 ± 13.0 years) were infected with H. suis. The 134 patients in the HP group contained 70 men (52%) and had a median ± SD age of 35 ± 19.9 years. Endoscopic findings were statistically comparable for white marbled appearance (three patients [33%] in the NHPH group and 37 patients [31%] in the HP group) and crack-like mucosa (three patients [33%] and 27 patients [20%], respectively). Diffuse redness was significantly less frequent in the NHPH group (one patient [14%] vs. 97 patients [72%], p < 0.001). White marbled appearance or crack-like mucosa without diffuse redness was significantly more common in the NHPH group (56% vs. 13%, p = 0.004), with a sensitivity and specificity of 56% and 87%, respectively. Mean USS neutrophil infiltration and Helicobacter density scores were significantly higher in the HP group (both p < 0.01), which might have influenced the endoscopic findings of diffuse redness., Conclusions: When endoscopic findings of white marbled appearance or cracked-like mucosa are present, evaluation for diffuse redness may contribute to a more accurate diagnosis of NHPH gastritis., (© 2024 John Wiley & Sons Ltd.)

Objective: Hepatic overexpression of the thrombospondin 2 gene (THBS2) and elevated levels of circulating thrombospondin 2 (TSP2) have been observed in patients with chronic liver disease. This study aimed to identify the specific cells expressing THBS2/TSP2 in non-alcoholic fatty liver disease (NAFLD) and investigate the underlying mechanism behind THBS2/TSP2 upregulation., Design: Comprehensive NAFLD liver gene datasets, including single-cell RNA sequencing (scRNA-seq), in-house NAFLD liver tissue, and LX-2 cells derived from human hepatic stellate cells (HSCs), were analysed using a combination of computational biology, genetic, immunological, and pharmacological approaches., Results: Analysis of the genetic dataset revealed the presence of 1433 variable genes in patients with advanced fibrosis NAFLD, with THBS2 ranked among the top 2 genes. Quantitative polymerase chain reaction (qPCR) examination of NAFLD livers showed a significant correlation between THBS2 expression and fibrosis stage (r = .349, p < .001). In support of this, scRNA-seq data and in situ hybridization demonstrated that the THBS2 gene was highly expressed in HSCs of NAFLD patients with advanced fibrosis. Pathway analysis of the gene dataset revealed THBS2 expression to be associated with the transforming growth factor beta (TGFβ) pathway and collagen gene activation. Moreover, the activation of LX-2 cells with TGFβ increased THBS2/TSP2 and collagen expression independently of the TGFβ-SMAD2/3 pathway. THBS2 gene knockdown significantly decreased collagen expression in LX-2 cells., Conclusions: THBS2/TSP2 is highly expressed in HSCs and plays a role in regulating fibrogenesis in NAFLD patients. THBS2/TSP2 may therefore represent a potential target for anti-fibrotic therapy in NAFLD., (© 2023 The Authors. Liver International published by John Wiley & Sons Ltd.)

Background and Aim: Helicobacter pylori eradication has been shown to reduce the risk of gastric cancer (GC), with the number of eradication therapy cases on the rise. However, GC can still occur after successful treatment, and the histological differences prior to eradication in patients with and without GC are unclear. This study investigated the pre-treatment histological risk factors for GC development following eradication therapy., Methods: We retrospectively enrolled consecutive adult patients diagnosed as having H. pylori infection between April 2004 and December 2018. Atrophy and intestinal metaplasia (IM) were histologically assessed according to the updated Sydney System. The operative link on gastritis assessment and the operative link on gastric intestinal metaplasia (OLGIM) were evaluated as well., Results: Of the 247 patients analyzed in this study, 11 (4.5%) experienced GC after eradication therapy. Histological IM scores in the GC group were significantly higher at all gastric biopsy sites (p < .05), and the proportion of OLGIM III/IV stage was significantly greater in GC patients (81.8% vs. 31.8%, p < .01). For GC prediction, the area under the receiver operating characteristic curve for IM score at the lesser curvature of the corpus was the highest among all biopsy sites and not inferior to OLGIM results., Conclusions: Patients with histological IM prior to H. pylori eradication, especially at the lesser curvature of the corpus, may be at elevated risk for GC development after eradication therapy and require close surveillance., (© 2022 John Wiley & Sons Ltd.)

Background: Nodular gastritis is most often one of the manifestations of Helicobacter pylori (H. pylori) infection, which is a risk factor for gastric cancer. This study aimed to determine if the histological characteristics of nodular gastritis differed across classes of age., Methods: We conducted a retrospective analysis of consecutive patients who had undergone esophagogastroduodenoscopy with multiple mucosal biopsies of the stomach between 2003 and 2019 for evaluation of updated Sydney System scores. We analyzed and compared the histological characteristics of pediatric (≤15 years old), young (16-29 years old), and older (≥30 years old) patients., Results: Of the 1321 patients enrolled, 1027 patients (78%) had H. pylori infection, with 214 patients (21%) of them displaying nodular gastritis. Among nodular gastritis patients, mononuclear cell infiltration Sydney System scores in the gastric body were significantly higher in the older group than in the pediatric (p < .001) and young (p < .001) groups. Similar results were seen for neutrophil infiltration scores in the gastric body. To clarify the characteristics of older nodular gastritis, we investigated 1056 older patients (66 with nodular gastritis, 754 with atrophic gastritis, and 236 H. pylori-negative). The scores for mononuclear and neutrophil cell infiltration in the gastric body were significantly higher in nodular gastritis patients than in atrophic gastritis patients (both p < .001) and patients negative for H. pylori (both p < .001)., Conclusions: The inflammatory changes in the gastric body in older nodular gastritis patients were more severe as compared with those in pediatric and young nodular gastritis patients in addition to older atrophic gastritis patients., (© 2021 John Wiley & Sons Ltd.)

Aim: Thrombospondins are a family of multidomain and secretory glycoproteins. Among them, thrombospondin 2 (TSP2) encoded by TSP2 gene has been reported to be involved in various functions such as collagen/fibrin formation, maintenance of normal blood vessel density and cell adhesion properties. Microarray analyses ranked TSP2 as one of the most highly up-regulated genes in the fibrotic liver in patients with non-alcoholic fatty liver disease (NAFLD). Since TSP2 possesses unique properties as a secretory protein, we hypothesized that hepatic TSP2 gene expression levels would be reflected in serum TSP2 levels. In this study, we examined the relationship between serum TSP2 concentrations and clinicopathological findings in NAFLD patients., Methods: One hundred and thirty NAFLD patients who had undergone liver biopsy between 2009 and 2015 were retrospectively enrolled. Serum samples were collected at the time of biopsy, and TSP2 was measured by enzyme immunoassays., Results: Serum TSP2 levels moderately correlated with ballooning (r = 0.56, P < .001) and fibrosis stage (r = 0.53, P < .001). The AUC values of TSP2 for predicting mild fibrosis (≧F1), moderate fibrosis (≧F2) and severe fibrosis (≧F3) were 0.73, 0.76 and 0.82 respectively. Additionally, NAFLD activity score (NAS) correlated best with TSP2 (r = 0.52, P < .001) compared to conventional NAFLD-related biomarkers, such as cytokeratin 18 M30, hyaluronic acid, type IV collagen 7S, APRI and FIB-4 index., Conclusion: Serum TSP2 levels reflected hepatocyte ballooning, fibrosis and NAS in NAFLD patients. For clinical application of serum TSP2 as a predictor of NAFLD histological activity, additional validation and mechanistic investigations are required., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background/purpose: Although ursodeoxycholic acid (UDCA) is a first-line treatment for primary biliary cholangitis (PBC), 20%-30% of patients with PBC exhibit an incomplete response to UDCA. Recently, the UDCA Response Score was proposed for predicting response to UDCA using pretreatment parameters in patients with PBC. We aimed to validate the UDCA Response Score in Japanese patients with PBC., Methods: Registry data of Japanese patients (n = 873) were collected. Patients with data on all clinical parameters required for calculating the UDCA Response Score were selected. The endpoint was UDCA response, defined as alkaline phosphatase <1.67 times the upper limit of the normal value after 12 months of UDCA treatment., Results: All parameters were available in 804 patients (male/female = 120/684, age 58.9 [interquartile range 51.1-66.9] years). Bezafibrate was commenced within 12 months of UDCA in 78 patients (9.7%) because of the lack of an early response. We found that the endpoint was not reached in these 78 patients, and the area under the receiver operating characteristic curve (AUROC) of the score was 0.74 (95% confidence interval [CI] 0.70-0.79). The AUROC was 0.77 (95% CI 0.70-0.83) in patients undergoing UDCA monotherapy (n = 726). Finally, the AUROC of the modified UDCA Response Score using only data from the treatment start date was 0.80 (95% CI 0.70-0.90) in patients receiving a combination therapy of UDCA and bezafibrate (n = 160)., Conclusion: The validity of the UDCA Response Score was acceptable in Japanese patients; this score will be informative in patients treated with a combination therapy of UDCA and bezafibrate., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background & Aims: Primary biliary cholangitis (PBC) is an autoimmune liver disease characterized by portal inflammation and immune-mediated destruction of intrahepatic bile ducts that often leads to liver decompensation and liver failure. Although the biochemical response to ursodeoxycholic acid (UDCA) can predict disease outcome in PBC, few biomarkers have been identified as prognostic tools applicable prior to UDCA treatment. We therefore sought to identify such indicators of long-term outcome in PBC in the Japanese population., Methods: The prebiopsy serum samples and subsequent clinical data of 136 patients with PBC treated with UDCA were analysed over a median follow-up period of 8.8 years. Serum levels of biomarkers related to microbial translocation (sCD14, EndoCAb and I-FABP) were measured along with those of 33 cytokines and chemokines and additional auto-antibodies. Associations between the tested parameters and the clinical outcomes of liver decompensation and liver-related death/liver transplantation were evaluated using the Cox proportional hazards model with stepwise methods and Kaplan-Meier analysis., Results: Elevated levels of serum IL-8, and sCD14 before UDCA therapy were significantly associated with both liver decompensation and liver-related death/liver transplantation. In multivariate analyses, IL-8≥46.5 pg/mL or sCD14≥2.0 μg/mL at enrolment demonstrated the same results. Kaplan-Meier analysis also revealed IL-8 and sCD14 to be significantly associated with a poor outcome. sCD14 was significantly correlated with IL-8. EndoCAb and I-FABP were not related to disease outcome., Conclusions: Serum IL-8 and sCD14 levels before UDCA therapy represent noninvasive surrogate markers of prognosis in patients with PBC., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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

To investigate the mechanism behind JC virus (JCV) cell specificity we performed electrophoretic mobility shift assays (EMSA) using probes derived from the JCV transcriptional control region (JCV-TCR). Using nuclear extracts from the JCV-susceptible neuroblastoma cell line IMR-32, EMSA revealed a 670 kDa JCV-TCR-binding protein complex designated as #3-bp. This complex could not be detected in nuclear extracts from non-susceptible cell lines. Using column chromatographic purifi-cation and microsequencing, we identified cleavage stimulation factor (CstF) as a component of #3-bp. However, as CstF is present in many cell types, we speculated that the IMR-32-specific component(s) of #3-bp bind CstF. We performed a yeast two-hybrid assay using CstF-77 as the bait against a HeLa cDNA-subtracted IMR-32 cDNA library. This analysis detected binding between CstF-77 and the RNA helicase DDX1. Subsequently, biotinylated DNA affinity precipitation and chromatin immunoprecipitation assays also confirmed that DDX1 binds specifically to JCV-TCR. Our findings indicate that an association between DDX1 and the JCV-TCR may play a significant role in JCV infection in IMR-32 cells.

Recently, we demonstrated that the DEAD box protein 1 (DDX1), an RNA helicase, and the cleavage stimulation factor (CstF) form a complex that binds to the JC virus transcriptional control region (JCV-TCR). Here, we examined the function of DDX1, which is expressed at much higher levels in the JCV-susceptible cell line IMR-32 than in non-susceptible cell lines. DDX1 had no effect on the replication efficiency of JCV, but overexpression of DDX1 significantly increased transactivation of the JCV promoter. Furthermore, DDX1 enhanced the expression of JCV proteins in JCV infected cells, and knockdown of DDX1 using small interfering (si) RNA suppressed the expression of JCV proteins. Our results clearly demonstrate that DDX1 regulates proliferation of JCV in vitro through transcriptional activation.

Background/aims: As detecting mild steatosis is difficult by abdominal ultrasonography (US), nonalcoholic steatohepatitis (NASH) with mild steatosis may sometimes be confused with cryptogenic chronic hepatitis. We aimed to test this possibility and to isolate factors that may indicate NASH., Methods: First, 53 Japanese patients diagnosed as having cryptogenic chronic hepatitis by laboratory examination and US were enrolled. These patients were histologically divided into NASH and non-NASH groups, and their clinical features were compared. Second, the diagnostic accuracy of predictors of NASH was examined prospectively., Results: Fifteen patients (28%) were histologically diagnosed as having NASH with mild steatosis. Multivariable analysis revealed that body mass index (BMI) and serum ferritin level were independent predictors of NASH. The best cutoff values to detect NASH were assessed by using receiver-operating characteristic curves: BMI>25.2 kg/m(2) and serum ferritin level >142 ng/ml. When both markers were concomitantly negative, the negative predictive value to detect NASH was 100%., Conclusions: In cases of mild steatosis, US is not a perfect tool for the accurate diagnosis of NASH. BMI and serum ferritin level are useful discriminators of NASH from cryptogenic chronic hepatitis, and might be helpful markers for diagnosing NASH more accurately in Japanese patients.

To evaluate the efficacy of intracerebral (IC) immunization, mice were immunized with formalin-inactivated pseudorabies virus (PRV) by either subcutaneous (SC) or IC injection, and then 10(6) plaque-forming units of PRV were introduced into the hindleg of the immunized or non-immunized mice by intramuscular injection. The antibody titer in serum was elevated and boosted by additional immunization via both the SC and IC routes, but was higher after IC immunization. Intracerebrally immunized mice were completely protected from mortality and neurological signs, whereas all the non-immunized and 80% of the subcutaneously immunized mice died after developing neurological signs. In mouse models, IC immunization is more effective at inducing a protective immune response against the transneural spread of PRV than SC immunization.

Severe hemorrhage at multiple organs is frequently observed in chickens infected with highly pathogenic avian influenza (HPAI) A viruses. In this study we examined whether HPAI virus infection leads to coagulation disorder in chickens. Pathological examinations showed that the fibrin thrombi were formed in arterioles at the lung, associated with the viral antigens in endothelial cells of chickens infected intravenously with HPAI virus. Hematological analyses of peripheral blood collected from the chickens revealed that coagulopathy was initiated at early stage of infection when viral antigens were detected only in the endothelial cells and monocytes/macrophages. Furthermore, gene expression of the tissue factor, the main initiator of blood coagulation, was upregulated in the spleen, lung, and brain of HPAI virus-infected chickens. These results suggest that dysfunction of endothelial cells and monocytes/macrophages upon HPAI virus infection may induce hemostasis abnormalities represented by the excessive blood coagulation and consumptive coagulopathy in chickens.

We describe a patient with acute nonlymphocytic leukaemia (ANLL) derived from myelodysplastic syndrome in whom the Philadelphia chromosome (Ph1) first emerged at the late stage of ANLL transformation. Cytogenetically, the Ph1 chromosome was not detected until the late stage of ANLL transformation, 14 months after the transformation following a 3-month history of refractory anaemia with excess of blasts. The cells with and without the Ph1 chromosome had a common abnormal chromosome, t(3;3) (q21;q26). The reverse transcription-polymerase chain reaction analysis showed no bcr/abl message at diagnosis. However, the mRNA encoding P210bcr/abl was detected in the early stage of ANLL transformation. Furthermore, the mRNAs encoding both P210bcr/abl and P190bcr/abl were detected in the late stage of ANLL transformation when the Ph1 chromosome was detected by cytogenetic analysis. These evidences support a multistep pathogenesis of leukaemias, and the products of bcr/abl fusion gene may influence the course of disease.

Acute promyelocytic leukaemia (APL) associated with a t(15;17) translocation generates a PML/RAR alpha chimaeric gene which is transcribed as a fusion PML/RAR alpha mRNA. To clarify the pathophysiologic role of PML/RAR alpha in APL patients, we examined the expression of PML/RAR alpha in haemopoietic colonies in five patients with APL by reverse transcriptase polymerase chain reaction (RT-PCR) analysis. By the two-step RT-PCR method, we demonstrated that PML/RAR alpha positive clones were present in progenitor cells including both CFU-GM and BFU-E in two cases. This result suggests that the translocation of PML/RAR alpha occurred in a pluripotent stem cell in some APL patients. In four patients we detected two amplified cDNA fragments of 780 and 640 bp which presumably arose by alternative splicing of the PML gene. Interestingly, of CFU-GM and BFU-E colonies examined in four patients, there were three different types of colonies: those expressing only the 780 bp fragment, those expressing only the 640 bp fragment, and those expressing both fragments. This suggests that alternative splicing was clonally determined in each colony. We describe a useful RT-PCR technique for the study of gene expression in a limited number of haemopoietic precursor cells.

A 41-year-old woman with desmoplastic trichoepithelioma associated with pigmented nevus presented. Pigmented nevus had been present on her face at birth. She had received cryotherapy and dermabrasion at a small part of the pigmented nevus. As a result of the therapy, the discoloration disappeared. The lesion lately increased and became hard. Histologically, the lesion was composed of two distinctive but intimately mixed cellular components; nevus cells and basaloid cells. In the pigmented lesion, basaloid cells were not present. To our knowledge, this is the first reported case of desmoplastic trichoepithelioma associated with nevocellular nevus in Japan.

To clarify the role of transferrin receptors in cases of altered iron metabolism in clinical pathological conditions, we studied: number of binding sites; affinity; and recycling kinetics of transferrin receptors on human erythroblasts. Since transferrin receptors are mainly present on erythroblasts, the number of surface transferrin receptors was determined by assay of binding of 125I-transferrin and the percentage of erythroblasts in bone marrow mononuclear cells. The number of binding sites on erythroblasts from patients with an iron deficiency anemia was significantly greater than in normal subjects (p less than 0.01). Among those with an aplastic anemia, hemolytic anemia, myelodysplastic syndrome, and polycythemia vera compared to normal subjects, there were no considerable differences in the numbers of binding sites. The dissociation constants (Kd) were measured using Scatchard analysis. The apparent Kd was unchanged (about 10 nmol/L) in patients and normal subjects. The kinetics of endocytosis and exocytosis of 125I-transferrin, examined by acid treatment, revealed no variations in recycling kinetics among the patients and normal subjects. These data suggest that iron uptake is regulated by modulation of the number of surface transferrin receptors, thereby reflecting the iron demand of the erythroblast.