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Introduction and Aims: This study aimed to investigate the effects of a developed school-based online health education programme with a periodontal examination results sheet for high school students on their subjective oral symptoms, knowledge and attitudes regarding oral health, and oral health behaviours., Methods: The participants were first- and second-year students aged 15 to 17 years (n = 847) at a high school in Japan. The students underwent a periodontal examination and were divided into periodontal condition (PC) and nonperiodontal condition (non-PC) groups. The students participated in the online oral health education programme, which included a periodontal examination results sheet after the examination. The data for identifying the effect of the programme were collected via questionnaire surveys at the periodontal examination (baseline), after 3 months, and after 1 year, and they were compared between baseline and 3 months later and between baseline and 1 year later by the chi-square test. Logistic regression analysis was used to determine the associations between the measured variables related to oral health at 3 months or 1 year and the presence/absence of periodontal conditions after adjustment for sex and variables at baseline., Results: A total of 628 students (74.1%) participated in this study. The percentages of individuals with knowledge of how many teeth they had, knowledge of periodontal disease, and experience with toothbrushing instruction increased significantly after 1 year in both groups (p < .05). The awareness of gingival swelling and bleeding and the use of fluoride toothpaste at 3 months were positively associated with the presence of periodontal conditions., Conclusions: This study showed that an online oral health education programme contributed to improving oral health knowledge and behaviours among high school students and that the awareness of periodontal conditions according to the periodontal examination results sheet might improve the awareness of gingival swelling and bleeding at 3 months., Competing Interests: Conflict of interest None disclosed., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: This study aims to investigate the utility of the Doppler effect on ultrasonography for the diagnosis of very early- and early-stage lumbar spondylolysis in adolescent patients., Methods: In total, 76 adolescent patients with acute and subacute low back pain were prospectively enrolled, with 46 having lumbar spondylolysis and the remaining 30 having low back pain without spondylolysis. MRI and/or computed tomograms scans revealed very early- and early-stage lumbar spondylolysis. Furthermore, positive Doppler findings in ultrasonography around the area from the facet joint to the laminae were investigated., Results: There were no significant differences in age (p > 0.99) and body mass index (p = 0.11) between cases with and without spondylolysis. Very early- and early-stage spondylolysis were observed in 27.6% and 72.4% of patients, respectively. Positive power Doppler was 91.3% and 33.3% in cases with and without spondylolysis, respectively, which was significantly higher in spondylolysis (p < 0.001). The sensitivity and specificity of this positive power Doppler were 91.4% and 66.7%, respectively. Furthermore, the rate of positive power Doppler was significantly higher in early-stage spondylolysis (p = 0.02), with 75.0% and 97.6% sensitivity in very early- and early-stage spondylolysis, respectively., Conclusions: A positive Doppler effect on ultrasonography is effective for screening very early- and early-stage spondylolysis in adolescent patients in an outpatient clinic., Competing Interests: Declaration of competing interest The Author declare that there is no conflict of interest., (Copyright © 2022 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Competing Interests: SE, JH, YN, HN, MY, SI, ST, and TA were involved in negotiations for health-related outcomes of the G7 Hiroshima Summit and Nagasaki Health Ministers' Meeting from the Ministry of Foreign Affairs of Japan. TO, MO, and NH were involved in negotiations for health-related outcomes of the G7 Hiroshima Summit and Nagasaki Health Ministers' Meeting from the Ministry of Health, Labour and Welfare of Japan. EH and KH led the negotiations for health-related outcomes of the G7 Hiroshima Summit and Nagasaki Health Ministers' Meeting as the Co-Chairs of the G7 Health Working Group, Japan. NI was involved in negotiations for health-related outcomes of the G7 Hiroshima Summit and Nagasaki Health Ministers' Meeting from the Cabinet Office of Japan. We declare no other competing interests. The views expressed in this Comment are those of the authors and do not necessarily represent those of their institutions.

Background & Aims: Patients with non-alcoholic fatty liver disease (NAFLD) and significant fibrosis (fibrosis stage ≥2) are candidates for pharmacological trials. The aim of this study was to perform a head-to-head comparison of the diagnostic test characteristics of three non-invasive stiffness-based models including MEFIB (magnetic resonance elastography [MRE] plus FIB-4), MAST (magnetic resonance imaging [MRI]-aspartate aminotransferase [AST]), and FAST (FibroScan-AST) for detecting significant fibrosis., Methods: This prospective study included 563 patients with biopsy-proven NAFLD undergoing contemporaneous MRE, MRI proton density fat fraction (MRI-PDFF) and FibroScan from two prospective cohorts derived from Southern California and Japan. Diagnostic performances of models were evaluated by area under the receiver-operating characteristic curve (AUC)., Results: The mean age of the cohort was 56.5 years (51% were women). Significant fibrosis was observed in 51.2%. To detect significant fibrosis, MEFIB outperformed both MAST and FAST (both p <0.001); AUCs for MEFIB, MAST, and FAST were 0.901 (95% CI 0.875-0.928), 0.770 (95% CI 0.730-0.810), and 0.725 (95% CI 0.683-0.767), respectively. Using rule-in criteria, the positive predictive value of MEFIB (95.3%) was significantly higher than that of FAST (83.5%, p = 0.001) and numerically but not statistically greater than that of MAST (90.0%, p = 0.056). Notably, MEFIB's rule-in criteria covered more of the study population than MAST (34.1% vs. 26.6%; p = 0.006). Using rule-out criteria, the negative predictive value of MEFIB (90.1%) was significantly higher than that of either MAST (69.6%) or FAST (71.8%) (both p <0.001). Furthermore, to diagnose "at risk" non-alcoholic steatohepatitis defined as NAFLD activity score ≥4 and fibrosis stage ≥2, MEFIB outperformed both MAST and FAST (both p <0.05); AUCs for MEFIB, MAST, and FAST were 0.768 (95% CI 0.728-0.808), 0.719 (95% CI 0.671-0.766), and 0.687 (95% CI 0.640-0.733), respectively., Conclusions: MEFIB was better than MAST and FAST for detection of significant fibrosis as well as "at risk" NASH. All three models provide utility for the risk stratification of NAFLD., Lay Summary: Non-alcoholic fatty liver disease (NAFLD) affects over 25% of the general population worldwide and is one of the main causes of chronic liver disease. Because so many individuals have NAFLD, it is not practical to perform liver biopsies to identify those with more severe disease who may require pharmacological interventions. Therefore, accurate non-invasive tests are crucial. Herein, we compared three such tests and found that a test called MEFIB was the best at detecting patients who might require treatment., Competing Interests: Conflict of interests Rohit Loomba serves as a consultant to Aardvark Therapeutics, Altimmune, Anylam/Regeneron, Amgen, Arrowhead Pharmaceuticals, AstraZeneca, Bristol-Myer Squibb, CohBar, Eli Lilly, Galmed, Gilead, Glympse bio, Hightide, Inipharma, Intercept, Inventiva, Ionis, Janssen Inc., Madrigal, Metacrine, Inc., NGM Biopharmaceuticals, Novartis, Novo Nordisk, Merck, Pfizer, Sagimet, Theratechnologies, 89 bio, Terns Pharmaceuticals and Viking Therapeutics. In addition, his institutions received research grants from Arrowhead Pharmaceuticals, Astrazeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, Galectin Therapeutics, Galmed Pharmaceuticals, Gilead, Intercept, Hanmi, Intercept, Inventiva, Ionis, Janssen, Madrigal Pharmaceuticals, Merck, NGM Biopharmaceuticals, Novo Nordisk, Merck, Pfizer, Sonic Incytes and Terns Pharmaceuticals. Co-founder of LipoNexus Inc. Claude B. Sirlin reports grants from GE, Siemens, Philips, Bayer, Gilead; personal consultation fees from Blade, Boehringer, and Epigenomics; consultation under the auspices of the University to AMRA, BMS, Exact Sciences, GE Digital, and IBM-Watson; lab service agreements from Enanta, Gilead, ICON, Intercept, Nusirt, Shire, Synageva, Takeda; royalties or honoraria from Wolters Kluwer and Medscape, respectively, for educational material outside the submitted work. The other authors disclose no conflicts. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Objectives: We report here a stingray spine (Dasyatidae) found embedded in the femur of a male skeleton from the archaeological site of Uedomari-5, Rebun Island, Hokkaido, Japan., Materials: A single well-preserved but incomplete human skeleton., Methods: Macroscopic observation and low power magnification, CT imaging, radiocarbon dating and stable isotope (carbon, nitrogen) analysis., Results: The stingray spine is tentatively identified as Bathytoshia brevicaudata. CT imaging shows no healing, indicating that death occurred shortly afterwards. The skeleton has been directly radiocarbon dated to the Okhotsk period (cal AD 429-827), with δ 13 C (-13.7‰) and δ 15 N (19.3‰) values indicating a diet focused on marine foods., Conclusions: The absence of healing in what would have been a non-lethal injury strongly suggests that the spine tipped an arrowhead, rather than being the result of an accidental encounter with a living stingray. It is possible that the injury reflects a period of increased conflict coinciding with, or following on from, the expansion of the Okhotsk culture from Sakhalin into northern Hokkaido., Significance: Uedomari-5 provides the first example, to our knowledge, of a stingray spine directly embedded in human bone at an archaeological site. More widely, the finding contributes to our knowledge of conflict in northern hunter-gatherer communities., Limitations: Given the early excavation date (1949-50), there is little contextual information available for the burials., Suggestions for Further Research: ZooMS (Zooarchaeology by Mass Spectrometry) may be able to identify the stingray species. Archival research may provide more information concerning the excavations at Uedomari-5., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Mitochondria change their morphology and inner membrane structure depending on their activity. Since mitochondrial activity also depends on their structure, it is important to elucidate the interrelationship between the activity and structure of mitochondria. However, the mechanism by which mitochondrial activity affects the structure of cristae, the folded structure of the inner membrane, is not well understood. In this study, the effect of the mitochondrial activity on the cristae structure was investigated by examining the structural rigidity of cristae. Taking advantage of the fact that unfolding of cristae induces mitochondrial swelling, we investigated the relationship between mitochondrial activity and the susceptibility to swelling. The swelling of individual isolated mitochondria exposed to a hypotonic solution was observed with an optical microscope. The presence of respiratory substrates (malate and glutamate) increased the percentage of mitochondria that underwent swelling, and the further addition of rotenone or KCN (inhibitors of proton pumps) reversed the increase. In the absence of respiratory substrates, acidification of the buffer surrounding the mitochondria also increased the percentage of swollen mitochondria. These observations suggest that acidification of the outer surface of inner membranes, especially intracristal space, by proton translocation from the matrix to the intracristal space, decreases the structural rigidity of the cristae. This interpretation was verified by the observation that ADP or CCCP, which induces proton re-entry to the matrix, suppressed the mitochondrial swelling in the presence of respiratory substrates. The addition of CCCP to the cells induced a morphological change in mitochondria from an initial elongated structure to a largely curved structure at pH 7.4, but there were no morphological changes when the pH of the cytosol dropped to 6.2. These results suggest that a low pH in the intracristal space may be helpful in maintaining the elongated structure of mitochondria. The present study shows that proton pumping by the electron transfer chain is the mechanism underlying mitochondrial morphology and the flexibility of cristae structure., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Aerosols in indoor air have various adverse effects on human health. Considering the use of forced ventilation and fan mixing (individually and in combination), the variation in charge number and their effects on aerosol transmission in confined spaces were explored in this study with the distinction of particle sources. In the case of sources originating from the external space, natural penetration acquires a greater number of negative charges. Forced ventilation of a confined space acts on the fate of particles in the neighboring confined space, while the internal fan has a negligible effect on both the number concentration and charge number of particles in the exterior. The combination of forced ventilation and fan mixing increases charge numbers, altering the lifetime of particles in the external regional environment by deposition or adsorption, particularly for neutralized particles. In the case of sources originating from the interior area, application of an internal fan weakens the ventilation effect from forced ventilation, resulting in internal particle loss by depositing on internal surfaces due to electrostatic charge, increasing the potential risk of resuspension. Additionally, source origin is associated with particle fate, and the charge generated under the action of external forces contributes to the transmission pathways and the fate of the particles in the air. This study investigates the transmission pathways and the fate of aerosols from the perspective of charge number, hopefully contributing to an in-depth understanding of the transmission mechanisms of toxic substances in confined spaces with aerosols as carriers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

To explore the impact of microplastic (MP) pollution on planktivorous fish, we examined the uptake and retention of MPs by Japanese anchovy (Engraulis japonicus) under laboratory conditions. MP uptake was size selective in adult anchovy-0.3-mm MPs were taken up in significantly larger amounts than 0.85-mm MPs-but not in juveniles. There were no significant differences in the uptake of MPs of three different colors, suggesting that anchovy do not select for MP coloration. More than 90% of the MPs were excreted within 20 h of ingestion, indicating that MP retention time is similar to the processing time of food items. Our findings suggest that Japanese anchovy tend to take up MPs that are equivalent in size to prey items, but that the impacts of MP ingestion are likely to be limited under the current state of oceanic MP contamination., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Conservative treatment including the use of a brace and cessation of sports activities is known to be effective in spondylolysis. However, there is some controversy regarding [1] the type of brace, and [2] the endpoint for bracing, and [3] the timing of resumption of sports activities. The aim of the current study was to investigate the appropriateness of early exercise and resumption of sports activities with a lumbar-sacral brace in very early- and early-stage lumbar spondylolysis., Methods: This prospective cohort study enrolled 45 patients with very early- and early-stage lumbar spondylolysis. A lumbar-sacral brace, structured to be a hard brace in the back and a mesh brace in the front, was used. Isometric exercises/stretching was started immediately after the initial visit. The number of patients for whom bone fusion was fully achieved on CT and the disappearance of signal intensity change on MRI were investigated., Results: In 12 cases of very early-stage spondylolysis, the average elapsed time until signal intensity disappearance as confirmed on MRI was 4.3 ± 1.6 months. Bony union on CT was confirmed in all cases. In 33 cases of early spondylolysis, signal intensity change disappeared on MRI within 5.2 ± 2.4 months. The rate of bony union was 94.3%, and the average period required to achieve bony union observable on CT was 3.7 ± 1.0 months., Conclusions: Sufficient bony union can be achieved by conservative treatment with early exercise and a lumbar-sacral brace in cases of very early and early spondylolysis., (Copyright © 2021 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

In this study, a potential ecological risk index for site dynamic risk evolution was proposed with the development trend of the Hakanson approach. The possibility factor P i was attached to the contamination factor C f i , representing the burst probability factor of dynamic risk arising from the transformation of metal(loid) fractions, ascertained by the delayed geochemical hazard (DGH) methodology. The toxic effects of different elements were explored through a meta-analysis. The effects of soil pH and soil organic matter on the mobile fraction of elements were examined, and the toxic factors (Tr i ) of six elements (arsenic, cadmium, chromium, copper, lead, and zinc) were modified for the site application. A total of 16 case studies representing four soil types (agricultural soil, industrial zone, mining area, and soil of river basin) were tested, and the results indicated that the proposed index could provide an early warning of site risk dynamics., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Increasing evidence from pathological and biochemical investigations suggests that mitochondrial metabolic impairment and oxidative stress play a crucial role in the pathogenesis of mitochondrial diseases, such as mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome, and various neurodegenerative disorders. Recent advances in molecular imaging technology with positron emission tomography (PET) and functional magnetic resonance imaging (MRI) have accomplished a direct and non-invasive evaluation of the pathophysiological changes in living patients., Scope of Review: In this review, we focus on the latest achievements of molecular imaging for mitochondrial metabolism and oxidative stress in mitochondrial diseases and neurodegenerative disorders., Major Conclusions: Molecular imaging with PET and MRI exhibited mitochondrial metabolic changes, such as enhanced glucose utilization with lactic acid fermentation, suppressed fatty acid metabolism, decreased TCA-cycle metabolism, impaired respiratory chain activity, and increased oxidative stress, in patients with MELAS syndrome. In addition, PET imaging clearly demonstrated enhanced cerebral oxidative stress in patients with Parkinson's disease or amyotrophic lateral sclerosis. The magnitude of oxidative stress correlated well with clinical severity in patients, indicating that oxidative stress based on mitochondrial dysfunction is associated with the neurodegenerative changes in these diseases., General Significance: Molecular imaging is a promising tool to improve our knowledge regarding the pathogenesis of diseases associated with mitochondrial dysfunction and oxidative stress, and this would facilitate the development of potential antioxidants and mitochondrial therapies., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objectives: For older patients with pancreatic cancer (PC), the benefits of gemcitabine plus nab-paclitaxel (GnP) are still uncertain, and the toxicity may be excessive. We aimed to examine the efficacy and safety of modified GnP (m-GnP), which is a nab-paclitaxel reduced regimen, for older patients (≥75 years) with advanced PC., Materials and Methods: In total, 34 patients met the eligibility criteria for study inclusion between 2015 and 2020. We evaluated the overall survival (OS), progression-free survival (PFS), best response, and adverse events associated with m-GnP treatment., Results: The median OS and PFS were 15.4 months and 5.9 months, respectively. The best response was partial response in 29% (10/34), stable disease in 53% (18/34), and progressive disease in 15% of patients (5/34); one patient was not evaluated. Among the grade 3 or higher hematological adverse events, neutropenia was the most frequent, occurring in 38% of patients (13/34), whereas febrile neutropenia occurred in 3% (1/34). Grade 3 or higher non-hematological adverse events occurred in 12% of patients (4/34). Early discontinuation owing to intolerable adverse events occurred in one patient, and there were no chemotherapy-related deaths., Conclusions: The present study demonstrated that m-GnP exhibited good efficacy with acceptable toxicity. To avoid early discontinuation and maintain dose intensities, initial dose reduction may be a good option for older patients with PC when receiving GnP., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: We sought new markers to predict oral malodor., Study Design: Seventy-five adults complaining of oral malodor were classified into 3 groups clinically: no oral malodor, physiologic oral malodor, and periodontitis-derived oral malodor. In addition to conventional clinical parameters, 7 salivary components, occlusal force, and lip-closing force were compared among the groups., Results: Concerning the salivary components, cariogenic bacteria, occult blood, leukocytes, and ammonia differed significantly among the groups. Multiple logistic regression analyses indicated that tongue-coating scores and ammonia levels were significantly associated with genuine oral malodor, including physiologic oral malodor and periodontitis-derived oral malodor, and the tongue-coating score, plaque index, and occult blood level were significantly associated with periodontitis-derived oral malodor. Occlusal force and lip-closing force did not differ among the groups. However, there was a statistically significant interaction between occlusal force and lip-closing force in oral malodor in women (P = .019)., Conclusions: Novel salivary markers, ammonia levels, and occult blood levels may predict genuine oral malodor and periodontitis-derived oral malodor, respectively. An interaction effect between occlusal force and lip-closing force on oral malodor was identified in women., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Bone substitutes are widely accepted for various clinical applications. However, the usage is predominantly intraosseous implantation, whereas extraosseous on-lay grafting is rare and lacks scientific evidence. The purpose of this study is to elucidate whether osteoconduction occurs in on-lay grafted bone substitute., Methods: Custom-made interconnected porous calcium hydroxyapatite ceramic (IPCHA) was on-lay grafted with screw or anchor fixation (S- and A-groups, respectively) at the anterior aspect of the femur of skeletally mature Japanese white rabbits. At 3, 6 and 12 weeks postoperatively, 4 samples for each time point and each group were evaluated by microfocus computed tomography (micro-CT) and histology., Results: Volume-rendered three-dimensional micro-CT images showed a high-density calcified area infiltrating IPCHA from the femoral cortex as of 6 weeks. When quantified, the calcified volume per unit volume first showed no difference between the two groups at 3 weeks but increased over time, and became significantly greater in the S-group than in the A-group (p = 0.012 and 0.004 at 6 and 12 weeks, respectively). Histologically, IPCHA pores were first occupied by fibrous tissue at 3 weeks; then, the pores adjacent to the femoral cortex were gradually replaced by bony tissue as of 6 weeks for both fixations., Conclusions: IPCHA allowed new bone formation inside the material even though it was implanted in an on-lay fashion on the cortical bone. Our results suggested that on-lay grafted IPCHA exerted its osteoconductivity well, with more new bone forming in screw-fixated samples than in anchor-fixated samples., Competing Interests: Declaration of Competing Interest Tatsuo Mae received research fund from Zimmer Biomet G.K. and material provision from Aimedic MMT Co. Ltd. Minoru Yoneda is a consultant of Zimmer Biomet G.K. Yasuhiro Take, Shin-ichi Yamada, Yuta Tachibana, Shigeto Nakagawa, Ken Nakata, Hideki Yoshikawa: These authors, their immediate family, and any research foundation with which they are affiliated have not received any financial payments or other benefits from any commercial entity related to the subject of this article., (Copyright © 2020 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Due to the outbreak and spread of COVID-19, SARS-CoV-2 has been proven to survive in aerosols for hours. Virus-containing aerosols may intrude into an uncontaminated area from a confined source space under certain ventilated conditions. The penetration factor, which is the most direct parameter for evaluating the invasion process, can effectively reflect the penetration fraction of aerosols and the shielding efficiency of buildings. Based on the observed concentrations of aerosols combined with a widely used concentration model, four numerical calculations of the penetration factor are proposed in this study. A theoretical time-correction P est was applied to a size-dependent P avg by proposing a correction coefficient r, and the error analysis of the real-time P(t) and the derived P d were also performed. The results indicated that P avg supplied the most stable values for laboratory penetration simulations. However, the time-correction is of little significance under current experimental conditions. P(t) and P d are suitable for rough evaluation under certain conditions due to the inevitability of particles detaching and re-entering after capture. The proposed optimal penetration factor and the error analysis of each method in this study can provide insight into the penetration mechanism, and also provide a rapid and accurate assessment method for preventing and controlling the spread of the epidemic., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The tail domain of the measles virus (MeV) N protein is typically phosphorylated at S479 and S510. However, the protein kinase responsible for this phosphorylation has not been identified. To identify the protein kinase responsible, we conducted an in vitro kinase assay in the presence of various protein kinase inhibitors. Phosphorylation of S479 and S510 was suppressed in the presence of SP600125. We demonstrated that purified PIM 3 kinase, which is sensitive to SP600125, successfully phosphorylated both phosphorylation sites. Inhibitors of PIM kinase, CX6258 and LY294002, also suppressed phosphorylation of the N protein. These findings indicate that PIM 3 kinase is associated with the tail domain of the N protein and that PIM 3 kinase regulates N protein phosphorylation., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Hashimoto encephalopathy (HE) is an autoimmune-mediated encephalopathy associated with anti-thyroid antibodies. We previously discovered serum autoantibodies against the NH 2 -terminal of α-enolase (NAE), which serve as a specific diagnostic biomarker for HE and may be involved in the autoimmune pathophysiology of HE, including vasculitis. Although the common findings of brain magnetic resonance imaging (MRI) in HE have been recognized as normal or non-specific white matter lesions, serial MRI changes have been less well studied. The aim of this study was to clarify detailed and longitudinal MRI changes in HE associated with anti-NAE antibodies., Methods: We investigated serial brain MR images in 12 Japanese patients with HE who had serum anti-NAE antibodies., Results: Brain MRI showed diffuse white matter abnormalities and/or multiple small subcortical lesions in 10 patients. These lesions were apparently non-specific; however, in 7 of these patients we observed expanding and diminishing white matter lesions, emerging subcortical high-intensity spots on diffusion-weighted images, or reversible limbic lesions, which worsened at relapse and improved after recovery following immunotherapies., Conclusion: MRI lesions that fluctuate according to the disease condition were frequently observed in HE patients with anti-NAE antibodies, which suggests that these fluctuation may be associated with the autoimmune pathophysiology of HE., (Copyright © 2019 Elsevier B.V. All rights reserved.)

It is well known that hepatocytes regenerate after liver injury, although it is difficult to reproduce this phenomenon in vitro. The goal of this research was to determine the factors that stimulate proliferation of primary mouse hepatocytes (PMHs) in vitro. We first tested knockdown (KD) of tumor protein 53 (p53) alone as well as partial hepatectomy (PH, performed 72 h prior to PMHs preparation) alone. However, neither intervention stimulated hepatocyte proliferation during the 72-h observation period in vitro. We then tested the combination of p53 KD with PH and found that these interventions together stimulated cell proliferation in vitro. Under these latter conditions we analyzed gene expression of these cells by mRNA sequencing (RNA-seq) and microRNA sequencing (miRNA-seq). TargetScan analysis, which determines the relationship between microRNAs and gene expression, found a relationship between downregulated mmu-mir-222 (miR-222) and upregulated genes such as mitogen-activated protein kinase kinase kinase 2 (Map3k2). To confirm this relationship, we performed miR-222 KD and overexpression (OE) and observed the expected changes in target gene expression. Furthermore, the finding that miR-222 KD or OE stimulates or suppresses, respectively, hepatocyte proliferation is well explained by the association between miR-222 and its target genes, which stimulate growth. Our results suggest that miR-222 is one of the key factors regulating PMH proliferation in vitro., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Mitochondrial functions are closely related to the membrane structure. Mitochondrial swelling, which is accompanied with dissipation of the crista structure and rupture of the outer membrane, have been observed as mitochondrial damage when mitochondria are under Ca 2+ -overload or oxidative stress. Although these phenomena have been well studied, the detailed behaviors of individual mitochondria upon swelling remain unknown. The aim of this study was to investigate the detailed behavior of mitochondrial volume upon addition of Ca 2+ . Here, we report for the first time, time-lapse measurements of single mitochondrion swelling and permeability transition induced by Ca 2+ by optical microscopy. We added 220 μM Ca 2+ to mitochondria, and found that 1) the swelling rate depended on the mitochondrion, 2) a small number of mitochondria showed step-like swelling, 3) cyclosporin A decreased the percentage of mitochondria that underwent swelling induced by Ca 2+ , but did not affect the amplitude of swelling, 4) permeability transition is necessary but not sufficient for Ca 2+ -induced swelling, 5) permeability transition is more sensitive to Ca 2+ than swelling, 6) Ca 2+ stimulated mitochondrial swelling after permeability transition. These results suggest that single mitochondrion measurement of swelling is a powerful tool for examining the regulation of mitochondrial structure., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The earliest evidence of human tuberculosis can be traced to at least the early dynastic periods, when full-scaled wet-rice agriculture began or entered its early developmental stages, in circum-China countries (Japan, Korea, and Thailand). Early studies indicated that the initial spread of tuberculosis coincided with the development of wet-rice agriculture. It has been proposed that the adaptation to agriculture changed human social/living environments, coincidentally favoring survival and spread of pathogenic Mycobacterial strains that cause tuberculosis. Here we present a possible case of spinal tuberculosis evident in the remains of a young female (M191) found among 184 skeletal individuals who were Neolithic wet-rice agriculturalists from the Yangtze River Delta of China, associated with Songze culture (3900-3200 B.C.). This early evidence of tuberculosis in East Asia serves as an example of early human morbidity following the adoption of the wet-rice agriculture., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: Elevated midnight cortisol levels induced by non-suppressed ACTH levels may lead to false-positive results for hypercortisolism in patients with adrenal incidentaloma. We investigated whether plasma ACTH-associated high midnight serum cortisol levels are correlated with other endocrinological findings with respect to hypothalamic-pituitaryadrenal function or hypercortisolism status., Methods: Two-hundred-forty-six patients with adrenocortical adenoma were evaluated via measurements of midnight ACTH and cortisol levels, a 1-mg dexamethasone suppression test (DST), and a cosyntropin-releasing hormone (CRH) stimulation test. Patients were divided into four groups according to their midnight plasma ACTH levels., Results: The groups with higher midnight ACTH levels had significantly higher basal ACTH levels. A positive relationship was observed between midnight serum cortisol and serum cortisol in the 1-mg DST for all groups; stronger associations were observed in the group with lower midnight ACTH. In the CRH test, peak, delta, and sigma ACTH had significant inverse relationships with midnight cortisol levels in the lowest and second lowest midnight ACTH groups. Patients with midnight cortisol levels >3.5 μg/dL were further divided into two groups according to whether their midnight plasma ACTH levels were below or above 10.0 pg/mL. There were significantly fewer patients with hypercortisolism in the higher ACTH group; midnight serum cortisol levels were associated with hypercortisolism only in the lower ACTH group., Conclusion: We demonstrated that midnight ACTH-associated cortisol values were not correlated with other endocrinological findings or hypercortisolism state. Measurement of midnight ACTH levels is important, and careful evaluation is needed for patients with higher midnight ACTH levels., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: The aim of this study was to evaluate the clinical utility of arterial spin labeling (ASL) magnetic resonance imaging (MRI) for the detection of cerebellar hypoperfusion in patients with spinocerebellar degeneration (SCD)., Methods: Regional cerebral blood flow (CBF) were obtained from ASL and 123 I-IMP single-photon emission computed tomography (SPECT) images by volume-of-interest analysis in patients with SCD (n = 16). Regional CBF were also measured by ASL in age-matched controls (n = 19) and by SPECT in separate controls (n = 17). The cerebellar CBF values were normalized to the CBF values for the whole gray matter (nCBF) in ASL and SPECT., Results: The mean cerebellar nCBF measured by ASL was lower in patients with SCD (0.70 ± 0.09) than in the controls (0.91 ± 0.05) (p < 0.001), which was consistent with the comparison using SPECT (0.82 ± 0.05 vs. 0.98 ± 0.05, p < 0.001). The cerebellar nCBF measured by ASL significantly correlated with that determined by SPECT in patients (r = 0.56, p < 0.001)., Conclusions: ASL imaging showed decreased cerebellar blood flow, which correlated with that measured by SPECT, in patients with SCD. These findings suggest the clinical utility of noninvasive MRI with ASL for detecting cerebellar hypoperfusion in addition to atrophy, which would aid the diagnosis of SCD., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: This paper reports the protocol of a randomised, double-blind, placebo-controlled study to test the efficacy, safety, and tolerability of lubiprostone (LUB) vs. placebo on suppressing gut permeability in non-alcoholic fatty liver disease (NAFLD) patients with constipation. NAFLD, including non-alcoholic steatohepatitis (NASH), is a common chronic liver disorder. Progression is associated with increased gut permeability and gut-derived endotoxins. Most NAFLD/NASH clinical trial drugs aim to improve liver function or systemic metabolism. LUB is a type 2 chloride channel activator used as a laxative for the treatment of patients with constipation. LUB suppresses gut permeability induced by non-steroidal anti-inflammatory drugs in healthy volunteers and lowers blood endotoxin levels. There have been no clinical studies of LUB for NAFLD/NASH patients., Methods: The study plans to enrol adult patients (20-85 years, planned enrolment, n = 150; planned sample size, n = 120) with NAFLD and constipation, alanine aminotransferase ≥40 IU/L, equivalent steatosis grade ≥1, and equivalent fibrosis stage <4 measured using non-invasive vibration-controlled transient elastography and magnetic resonance imaging. Participants will be randomly allocated into three groups: LUB 12 μg, LUB 24 μg, and a placebo group., Results: The primary endpoint will be changes in alanine aminotransferase from baseline at 12 weeks. The main secondary endpoint will be changes in intestinal permeability from baseline at 12 weeks using the lactulose mannitol ratio., Conclusions: This study will determine whether LUB improves gut permeability in NAFLD patients with constipation., Trial Registration: This trial is registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN000026635)., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The Fukushima Dai-ichi nuclear power plant accident released radiocesium in large amounts. The released radionuclides contaminated much of the surrounding environment, including sewers in urban areas of Fukushima prefecture. In this study we attempted to identify and quantify the sources of radiocesium contamination in separate sewerage systems and developed a compartment model based on the Radionuclide Migration in Urban Environments and Drainage Systems (MUD) model. Measurements of the time-dependent radiocesium concentration in sewer sludge combined with meteorological, demographic, and radiocesium dietary intake data indicated that rainfall-derived inflow and infiltration (RDII) and human excretion were the chief contributors of radiocesium contamination in a separate sewerage system. The quantities of contamination derived from RDII and human excretion were calculated and used in the modified MUD model to simulate radiocesium contamination in sewers in three urban areas in Fukushima prefecture: Fukushima, Koriyama, and Nihonmatsu Cities. The Nash efficiency coefficient (0.88-0.92) and determination coefficient (0.89-0.93) calculated in an evaluation of our compartment model indicated that the model produced satisfactory results. We also used the model to estimate the total volume of sludge with radiocesium concentrations in excess of the clearance level, based on the number of months elapsed after the accident. Estimations by our model suggested that wastewater treatment plants (WWTPs) in Fukushima, Koriyama, and Nihonmatsu generated about 1,750,000m 3 of radioactive sludge in total, a level in good agreement with the real data., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The hyaluronan (HA)-rich extracellular matrix plays dynamic roles during tissue remodeling. Versican and serum-derived HA-associated protein (SHAP), corresponding to the heavy chains of inter-α-trypsin inhibitor, are major HA-binding molecules in remodeling processes, such as wound healing. Versican G1-domain fragment (VG1F) is generated by proteolysis and is present in either remodeling tissues or the mature dermis. However, the macrocomplex formation of VG1F has not been clarified. Therefore, we examined the VG1F-containing macrocomplex in pressure ulcers characterized by chronic refractory wounds. VG1F colocalized with SHAP-HA in specific regions of the granulation tissue but not with fibrillin-1. A unique VG1F-SHAP-HA complex was isolated from granulation tissues using gel filtration chromatography and subsequent cesium chloride-gradient ultracentrifugation under dissociating conditions. Consistent with this molecular composition, recombinant versican G1, but not versican G3, interacted with the two heavy chains of inter-α-trypsin inhibitor. The addition of recombinant VG1 in fibroblast cultures enhanced VG1F-SHAP-HA complex deposition in the pericellular extracellular matrix. Comparison with other VG1F-containing macrocomplexes, including dermal VG1F aggregates, versican-bound microfibrils, and intact versican, highlighted the tissue-specific organization of HA-rich extracellular matrix formation containing versican and SHAP. The VG1F-SHAP-HA complex was specifically detected in the edematous granulation tissues of human pressure ulcers and in inflamed stages in a mouse model of moist would healing, suggesting that the complex provides an HA-rich matrix suitable for inflammatory reactions., (Copyright © 2018 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background: Statins are strong inhibitors of cholesterol biosynthesis and help to prevent cardiovascular disease. They also exert additional pleiotropic effects that include an anti-inflammatory action and are independent of cholesterol, but the molecular mechanisms underlying these additional effects have remained unclear. We have now examined the effects of atorvastatin on cardiac and adipose tissue inflammation in DahlS.Z-Lepr fa /Lepr fa (DS/obese) rats, which we previously established as a model of metabolic syndrome (MetS)., Methods and Results: DS/obese rats were treated with atorvastatin (6 or 20mgkg -1 day -1 ) from 9 to 13weeks of age. Atorvastatin ameliorated cardiac fibrosis, diastolic dysfunction, oxidative stress, and inflammation as well as adipose tissue inflammation in these animals at both doses. The high dose of atorvastatin reduced adipocyte hypertrophy to a greater extent than did the low dose. Atorvastatin inhibited the up-regulation of peroxisome proliferator-activated receptor γ gene expression in adipose tissue as well as decreased the serum adiponectin concentration in DS/obese rats. It also activated AMP-activated protein kinase (AMPK) as well as inactivated nuclear factor-κB (NF-κB) in the heart of these animals. The down-regulation of AMPK and NF-κB activities in adipose tissue of DS/obese rats was attenuated and further enhanced, respectively, by atorvastatin treatment., Conclusions: The present results suggest that the anti-inflammatory effects of atorvastatin on the heart and adipose tissue are attributable at least partly to increased AMPK activity and decreased NF-κB activity in this rat model of MetS., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Pneumococcal biliary tract infections (PBTIs) were reported as rare due to the bacterium's bile solubility. The purpose of this study was to determine the occurrence and clinical characteristics of PBTIs. A retrospective case series review was conducted from January 2006 to August 2014 at a tertiary referral university hospital in Japan. Patients with a blood or bile culture positive for Streptococcus pneumoniae diagnosed with definite cholangitis or cholecystitis according to Tokyo Guideline 2013 were enrolled in this study. Data on clinical information, treatments, and outcomes were collected. During 104 months, 48 cases of positive blood cultures and 13 cases of positive bile cultures were recorded, and after excluding 43 and 5 of these, respectively, a total of 10 patients were diagnosed with PBTI. Most patients (9/10) had biliary tract problems and biliary devices in place. PBTIs were not rare; conversely, they were a relatively common cause of pneumococcal bacteremia in this center treating a high volume of biliary tract illnesses., (Copyright © 2016 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Volatile Organic Compounds (VOCs) in indoor air were investigated at 39 private residences in Selangor State, Malaysia to characterize the indoor air quality and to identify pollution sources. Twenty-two VOCs including isomers (14 aldehydes, 5 aromatic hydrocarbons, acetone, trichloroethylene and tetrachloroethylene) were collected by 2 passive samplers for 24h and quantitated using high performance liquid chromatography and gas chromatography mass spectrometry. Source profiling based on benzene/toluene ratio as well as statistical analysis (cluster analysis, bivariate correlation analysis and principal component analysis) was performed to identify pollution sources of the detected VOCs. The VOCs concentrations were compared with regulatory limits of air quality guidelines in WHO/EU, the US, Canada and Japan to clarify the potential health risks to the residents. The 39 residences were classified into 2 groups and 2 ungrouped residences based on the dendrogram in the cluster analysis. Group 1 (n=30) had mainly toluene (6.87±2.19μg/m 3 ), formaldehyde (16.0±10.1μg/m 3 ), acetaldehyde (5.35±4.57μg/m 3 ) and acetone (11.1±5.95μg/m 3 ) at background levels. Group 2 (n=7) had significantly high values of formaldehyde (99.3±10.7μg/m 3 ) and acetone (35.8±12.6μg/m 3 ), and a tendency to have higher values of acetaldehyde (23.7±13.5μg/m 3 ), butyraldehyde (3.35±0.41μg/m 3 ) and isovaleraldehyde (2.30±0.39μg/m 3 ). The 2 ungrouped residences showed particularly high concentrations of BTX (benzene, toluene and xylene: 235μg/m 3 in total) or acetone (133μg/m 3 ). The geometric mean value of formaldehyde (19.2μg/m 3 ) exceeded an 8-hour regulatory limit in Canada (9μg/m 3 ), while those in other compounds did not exceed any regulatory limits, although a few residences exceeded at least one regulatory limit of benzene or acetaldehyde. Thus, the VOCs in the private residences were effectively characterized from the limited number of monitoring, and the potential health risks of the VOCs exposure, particularly formaldehyde, should be considered in the study area., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The wide application of surfactants and engineered nanomaterials (ENMs) in industrial and consumer products lead to the high possibility of their co-presence in natural water environment, making it important to study the effect of surfactants on the environmental behavior and fate of ENMs. In this work, we selected an anionic sodium dodecyl sulfate (SDS) and a nonionic nonylphenol ethoxylate (NPEO, Tergitol NP-9) to study their effects on the aggregation and sedimentation of a 20nm ZnO ENM in different water matrices. The adsorption of SDS and NP-9 by ZnO ENM were fitted with Langmuir model, and the maximum adsorption capacities were 43.73±4.62mg/g and 13.79±1.09 respectively. As the surfactant concentration increased from 0 to 0.030% (m:v), SDS reduced the zeta potential of ZnO ENM from 17.56±2.13 to -27.96±2.59mV, whereas NP-9 did not affect the zeta potential. After a 24-h batch reactor experiment, SDS and NP-9 reduced 93.02% and 80.26% of the aggregate size of ZnO ENM (50mgL -1 ) in maximum at surfactant concentrations≥0.015%. The ZnO ENM was not stable in natural aqueous matrices, mainly because of the relatively high ionic strength. However, surfactants were found to reduce the aggregation and sedimentation of ZnO ENM in six natural water matrices in different degrees. With the presence of 0.030% SDS in tap water, maximum reduction rates of aggregate size and sedimentation were recorded as 69.54% and 26.69%, respectively. The results of this study indicate that the presence of surfactants may alter the behaviors and fate of ENMs in natural water environment., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The high likelihood of the coexistence of surfactants and engineered nano-materials (ENMs) in aqueous environments redoubles the need to study the effects of surfactants on the behavior and transport of nano-materials. In this study, we chose anionic sodium dodecyl sulfate (SDS) and nonionic nonylphenol ethoxylate (NPEO, Tergitol NP-9) to study the effect of surfactants on the behaviors of a typical TiO 2 ENM in water environment. An adsorption isotherm and zeta potential study showed that both surfactants could be adsorbed onto the surface of nano-TiO 2 but that only SDS can significantly decrease the zeta potential of TiO 2 . For a better simulation of the dynamic natural water environment, we conducted a 24-h batch experiment to study the aggregation behaviors of nano-TiO 2 in the presence of SDS or NP-9 surfactants and recorded the sedimentation of the aggregates in solutions containing the surfactants over a 24h-period. SDS and NP-9 both reduced the growth of the TiO 2 aggregates and retarded the aggregate sedimentation at surfactant concentrations ≥0.015% (w:v). The aggregation of TiO 2 was far more remarkable in six environmental water matrices from different natural origins than in Milli-Q water, mainly because of the relatively high ionic strength of the former. The introduction of surfactants, however, still retarded the aggregation and sedimentation of TiO 2 in the six environmental water matrices. SDS exerted a stronger reductive effect than NP-9. This study reveals that the presence of surfactants may increase the bioavailability and environmental risk of nanomaterial contaminants by retarding the aggregation and promoting the transport of nanomaterials in natural aqueous environments., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Beta-agonists and sulfonamides are widely used for treating both humans and livestock for bronchial and cardiac problems, infectious disease and even as growth promoters. There are concerns about their potential environmental impacts, such as producing drug resistance in bacteria. This study focused on their spatial distribution in surface water and the identification of pollution sources in the Langat River basin, which is one of the most urbanized watersheds in Malaysia. Fourteen beta-agonists and 12 sulfonamides were quantitatively analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). A geographic information system (GIS) was used to visualize catchment areas of the sampling points, and source profiling was conducted to identify the pollution sources based on a correlation between a daily pollutant load of the detected contaminant and an estimated density of human or livestock population in the catchment areas. As a result, 6 compounds (salbutamol, sulfadiazine, sulfapyridine, sulfamethazine, sulfadimethoxine and sulfamethoxazole) were widely detected in mid catchment areas towards estuary. The source profiling indicated that the pollution sources of salbutamol and sulfamethoxazole were from sewage, while sulfadiazine was from effluents of cattle, goat and sheep farms. Thus, this combination method of quantitative and spatial analysis clarified the spatial distribution of these drugs and assisted for identifying the pollution sources., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background & Aims: The pathogenesis of non-alcoholic fatty liver disease (NAFLD) is affected by epigenetic factors as well as by genetic variation., Methods: We performed targeted-bisulfite sequencing to determine the levels of DNA methylation of 4 CpG islands (CpG99, CpG71, CpG26, and CpG101) in the regulatory regions of PNPLA3, SAMM50, PARVB variant 1, and PARVB variant 2, respectively. We compared the levels of methylation of DNA in the livers of the first and second sets of patients with mild (fibrosis stages 0 and 1) or advanced (fibrosis stages 2 to 4) NAFLD and in those of patients with mild (F0 to F2) or advanced (F3 and F4) chronic hepatitis C infection. The hepatic mRNA levels of PNPLA3, SAMM50, and PARVB were measured using qPCR., Results: CpG26, which resides in the regulatory region of PARVB variant 1, was markedly hypomethylated in the livers of patients with advanced NAFLD. Conversely, CpG99 in the regulatory region of PNPLA3 was substantially hypermethylated in these patients. These differences in DNA methylation were replicated in a second set of patients with NAFLD or chronic hepatitis C. PNPLA3 mRNA levels in the liver of the same section of a biopsy specimen used for genomic DNA preparation were lower in patients with advanced NAFLD compared with those with mild NAFLD and correlated inversely with CpG99 methylation in liver DNA. Moreover, the levels of CpG99 methylation and PNPLA3 mRNA were affected by the rs738409 genotype., Conclusions: Hypomethylation of CpG26 and hypermethylation of CpG99 may contribute to the severity of fibrosis in patients with NAFLD or chronic hepatitis C infection., (Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Aim: The aim of the study was to evaluate the effect of mouth cleaning with hinokitiol-containing gel on oral malodor., Methods: An open-label, randomized, controlled trial was conducted to assess oral malodor and clinical parameters related to oral malodor before and after mouth cleaning with hinokitiol-containing gel (n = 9) or with gel not including hinokitiol (n = 9). Mouth cleaning included the teeth, gingiva, and tongue and was carried out 3 times per day for 4 weeks., Results: Organoleptic test (OLT) scores (P = .021), levels of hydrogen sulfide (P = .008) and methyl mercaptan (P = .020), frequency of bleeding on probing, average probing pocket depth, and plaque index significantly improved in the group using hinokitiol. In contrast, only the OLT score (P = .031) significantly improved in the control group after the treatment regimen., Conclusion: Mouth cleaning with hinokitiol-containing gel may be effective for reduction of oral malodor., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Hepatitis C virus (HCV) induces endoplasmic reticulum (ER) stress which, in turn, activates the unfolding protein response (UPR). UPR activates three distinct signalling pathways. Additionally, UPR induces autophagy (UPR-autophagy pathways). On the other hand, it has become clear that some positive-single-strand RNA viruses utilize autophagy. Some groups have used the siRNA silencing approach to show that autophagy is required for HCV RNA replication. However, the mechanism of induction of the UPR-autophagy pathways remain unclear in the cells with HCV., Method and Results: we used a genome-length HCV RNA (strain O of genotype 1b) replication system (OR6) in hepatoma cells (HuH-7-derived OR6 cells). As control, we used OR6c cells from which the HCV genome had been removed by treatment with interferon-α. The UPR-autophagy pathways were activated to a greater degree in the OR6 cells as compared to the OR6c cells. Rapamycin, mTOR-independent autophagy inducer, activated HCV replication in the OR6 cells. On the other hand, HCV replication in the cells was inhibited by 3-methyladenine (3-MA), which is an inhibitor of autophagy. Salubrinal (Eukaryotic Initiation Factor 2(eIF2)-alpha phosphatase inhibitor), 3-ethoxy-5, 6-dibromosalicylaldehyde (X-box binding protein-1 (XBP-1) splicing inhibitor) and sp600125 (c-Jun N-terminal kinases (JNK) inhibitor) inhibited HCV replication and autophagy. Additionally, HCV replication and autophagy were inhibited more strongly by combination of these inhibitors., Conclusion: Our results suggest that UPR-autophagy pathways exert an influence on HCV replication. Therefore, control these pathways may serve as a novel therapeutic strategy against replication of HCV., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: The differences in the small intestinal toxicity of low-dose aspirin based on the type of aspirin used remains unclear. The purpose of this study was to evaluate the differences in the small bowel mucosal injury between buffered and enteric-coated aspirin users by capsule endoscopy., Methods: We retrospectively reviewed the findings in chronic low-dose aspirin users (>3 months) who underwent capsule endoscopy for the investigation of obscure gastrointestinal bleeding. The patients were classified into two groups based on the type of low-dose aspirin that they had been prescribed (enteric-coated aspirin group or buffered aspirin group), and evaluated the numbers of small bowel lesions and the Lewis score., Results: Capsule-endoscopic findings of a total of 70 patients taking low-dose aspirin were reviewed. Significant differences in the number of erosions and ulcers were observed between the buffered and enteric-coated aspirin groups (P=0.017 and P=0.037, respectively). The median Lewis score for the small bowel mucosal inflammatory change was significantly higher in the enteric-coated aspirin group than in the buffered aspirin group (P=0.035)., Conclusions: The results of this study suggested that enteric-coated aspirin might be more injurious to the small bowel mucosa than buffered aspirin., (Copyright © 2012 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Objectives: Radiolabeled Cu-diacetyl-bis (N(4)-methylthiosemicarbazone) (*Cu-ATSM), including (60/62/64)Cu-ATSM, is a potential imaging agent of hypoxic tumors for positron emission tomography (PET). We have reported that *Cu-ATSM is trapped in tumor cells under intracellular overreduced states, e.g., hypoxia. Here we evaluated *Cu-ATSM as an indicator of intracellular overreduced states in mitochondrial disorders using cell lines with mitochondrial dysfunction., Methods: Mitochondrial DNA-less ρ(0)206 cells; the parental 143B human osteosarcoma cells; the cybrids carrying mutated mitochondria from a patient of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) (2SD); and that carrying wild-type one (2SA) were used. Cells were treated under normoxia or hypoxia, and (64)Cu-ATSM uptake was examined to compare it with levels of biological reductant NADH and NADPH., Results: ρ(0)206 cells showed higher (64)Cu-ATSM uptake than control 143B cells under normoxia, whereas (64)Cu-ATSM uptake was not significantly increased under hypoxia in ρ(0)206 cells. Additionally, (64)Cu-ATSM uptake showed correlate change to the NADH and NADPH levels, but not oxygenic conditions. 2SD cells showed increased (64)Cu-ATSM uptake under normoxia as compared with the control 2SA, and (64)Cu-ATSM uptake followed NADH and NADPH levels, but not oxygenic conditions., Conclusions: (64)Cu-ATSM accumulated in cells with overreduced states due to mitochondrial dysfunction, even under normoxia. We recently reported that (62)Cu-ATSM-PET can visualize stroke-like episodes maintaining oxygen supply in MELAS patients. Taken together, our data indicate that *Cu-ATSM uptake reflects overreduced intracellular states, despite oxygenic conditions; thus, *Cu-ATSM would be a promising marker of intracellular overreduced states for disorders with mitochondrial dysfunction, such as MELAS, Parkinson's disease and Alzheimer's disease., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Aims: Cirrhotic patients commonly have a liver zinc deficiency, which may aggravate liver fibrosis due to the lack of antioxidative effects of zinc. This study examined the ability of polaprezinc, N-(3-aminopropionyl)-l-histidinato zinc, to prevent fibrosis in a rat model of thioacetamide (TAA)-induced hepatic fibrosis., Main Methods: Liver cirrhosis was induced by orally administering TAA for 20 weeks. The rats were cotreated with one of the following for the last 10 weeks of TAA treatment: (1) polaprezinc (50 or 200mg/kg/day); (2) l-carnosine (155 mg/kg/day), which contained equal amounts of l-carnosine as 200mg/kg/day polaprezinc; (3) zinc sulfate (112 mg/kg/day) or (4) zinc-l-aspartic complex (317.8 mg/kg/day). Both zinc supplementations contained equal amounts of zinc as high-dose polaprezinc., Key Findings: Hepatic zinc levels fell significantly in rats treated with TAA for 20 weeks. Cotreating with high-dose polaprezinc and zinc-l-aspartic complex for 10 weeks prevented hepatic zinc loss. Hepatic hydroxyproline and tissue inhibitor of metalloproteinases-1 (TIMP-1) were significantly higher in rats treated with TAA for 20 weeks than 10 weeks, whereas polaprezinc prevented changes in these fibrosis markers and reduced hepatic transforming growth factor-β1 protein concentration, macroscopic and histologic changes. TAA caused oxidative stress-related changes in the liver that were prevented by high-dose polaprezinc and partially by zinc-l-aspartic complex. Treatment with l-carnosine, low-dose polaprezinc or zinc sulfate for 10 weeks did not affect liver fibrosis progression or oxidative stress-related changes., Significance: Polaprezinc may prevent ongoing fibrosis by preventing zinc depletion, oxidative stress and fibrosis markers in cirrhotic livers., (Copyright © 2011. Published by Elsevier Inc.)

Introduction: To clarify the role of oxidative stress and mitochondrial dysfunction in the pathogenesis of Parkinson's disease (PD) in living patients, positron emission tomography (PET) with [(62)Cu]diacetyl-bis(N(4)-methylthiosemicarbazone) ([(62)Cu]ATSM) was applied to functional imaging of oxidative stress mainly due to mitochondrial dysfunction in the striata of patients with PD., Methods: Fifteen PD patients who presented with lateral dominant symptoms at onset and six healthy controls underwent [(62)Cu]ATSM PET. Dynamic PET data acquisition was performed, and standardized uptake values (SUVs) were obtained from the delayed phase of dynamic data by means of region of interest analysis. The striatum-to-cerebellum SUV ratio (S/C ratio) was calculated from the SUV in all subjects of the striatum and the cerebellar cortex., Results: The mean S/C ratio of the bilateral striata of the patients (1.15±0.10) was significantly increased compared with that of the controls (1.08±0.02) (P<.05). In the patients, the S/C ratio of the bilateral striata showed a positive correlation with the Unified Parkinson's Disease Rating Scale (UPDRS) rating (r=0.52, P<.05), and the S/C ratio of the striatum contralateral to the initially affected body side showed a strong positive correlation with the UPDRS rating (r=0.62, P<.05)., Conclusions: [(62)Cu]ATSM PET imaging demonstrated that striatal oxidative stress was enhanced in PD patients compared with the controls and increased with the progression of disease severity, particularly in the contralateral striatum. These findings indicated that oxidative stress associates with striatal neurodegeneration in PD., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Nodular fasciitis, a benign soft tissue tumor, occurs most frequently in the forearm and is generally divided into subcutaneous, intramuscular, and fascial types. Intraneural nodular fasciitis has been reported in only 5 patients previously. We present the case of a 79-year-old woman with nodular fasciitis within the median nerve at the proximal forearm. Carpal tunnel syndrome was suspected at the initial visit, but high median nerve palsy and a mass at the proximal forearm were found a few months later. Subtotal resection of the tumor within the median nerve was performed and histological diagnosis indicated nodular fasciitis. There was no evidence of recurrence at follow-up 1 year and 3 months after surgery. Motor weakness had resolved but sensation was compromised., (Copyright © 2011 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)

Objective:   To assess the psychosomatically subjective symptoms of subjects with neurotic tendencies complaining of halitosis., Design:   Breath malodour was measured in 368 patients using organoleptic test and gas chromatography. Neurotic tendency and subjective symptoms were assessed using the Cornell Medical Index (CMI)., Results:   Of the 79 subjects who met the criteria for neurotic tendencies according to CMI scores, 58 (73.4%) had oral malodour, whereas 21 (26.6%) did not. Coated tongue, periodontal pocket, and daily drinking were significantly more common in subjects with oral malodour. On the CMI questionnaire, subjects with no oral malodour more frequently responded 'yes' to questions about fatigue and psychological problems in their families. Additionally, many answered that they had perceived their own bad breath., Conclusions:   Difficulties experienced by subjects with neurotic tendencies and oral malodour may manifest primarily in oral conditions, whereas those experienced by individuals with neurotic tendencies and no oral malodour may manifest primarily in psychosomatic symptoms., (© 2011 FDI World Dental Federation.)

Due to recent domestic measles outbreaks in Japan, the Japanese government has mandated measles vaccination at ages 14 and 17 since April 2008. Since then, the number of people receiving measles vaccination has increased in Japan. Measles vaccination may cause serious neurological complications including encephalopathy, although the incidence is very low. We report here an adult case of posterior reversible encephalopathy syndrome (PRES) and myeloradiculoneuropathy following measles vaccination. Brain MRI demonstrated typical findings of PRES, high intensity signals in the occipital lobes on FLAIR imaging, isointensity signals on diffusion weighted imaging, with an increase in the apparent diffusion coefficient (ADC). Vasoconstriction mainly in the posterior cerebral arteries was detected by MRA. Physicians should keep in mind the possible occurrence of PRES and myeloradiculoneuropathy following measles vaccination., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Background: The mechanisms by which a derangement of glucose metabolism causes high blood pressure are not fully understood., Objectives: This study aimed to clarify the relation between salt sensitivity of blood pressure and insulin resistance, which are important subcharacteristics of hypertension and impaired glucose metabolism, respectively. Effects on the renin-angiotensin and sympathetic nervous systems were also studied., Design: The state of glucose metabolism was assessed by a hyperinsulinemic euglycemic glucose clamp technique and a 75-g oral-glucose-tolerance test in 24 essential hypertensive patients who were lean and without diabetes or chronic kidney disease. The subjects were classified as salt-sensitive or salt-resistant on the basis of the difference (Delta mean blood pressure > or =5%) between 24-h ambulatory blood pressure monitoring results on the seventh day of low-salt (34 mmol/d) and high-salt (252 mmol/d) diets. Urine and blood samples were collected for analyses., Results: There was a robust inverse relation between the glucose infusion rate (GIR) and the salt sensitivity index. The GIR correlated directly with the change in urinary sodium excretion and was inversely related to the change in hematocrit when the salt diet was changed from low to high, which is indicative of salt and fluid retention in salt-sensitive subjects. The GIR also showed an inverse correlation compared with the changes in urinary norepinephrine excretion, plasma renin activity, and plasma aldosterone concentration., Conclusions: Salt sensitivity of blood pressure is strongly associated with insulin resistance in lean, essential hypertensive patients. Hyperinsulinemia, sympathetic overactivation, and reduced suppression of the renin-angiotensin system may play a role in this relation.