Research Interests: Biology, Cell Biology, Medicine, Gene expression, Cell Division, and 15 moreDNA, Cell line, Humans, Mice, Animals, Gene, Green Fluorescent Protein, Cell nucleus, Cell Proliferation, Amino Acid Sequence, Base Sequence, Gene Family, Biochemistry and cell biology, Dna Synthesis, and Medical biochemistry and metabolomics
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Research Interests: Virology, Medicine, In Vitro, Humans, Mutation, and 12 moreHepatitis C Virus, Interferon, Pegylated Interferon, Antibody, Combination drug therapy, chronic hepatitis C, Ribavirin, Antiviral Agents, Biochemistry and cell biology, Interferon Alpha, Hepacivirus, and Medical biochemistry and metabolomics
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Introduction: Limited data are currently available for patients with overt hepatic encephalopathy (OHE)) receiving physical exercise (PE). The aim of the current study is to prospectively examine the effect of PE on sarcopaenia in... more
Introduction: Limited data are currently available for patients with overt hepatic encephalopathy (OHE)) receiving physical exercise (PE). The aim of the current study is to prospectively examine the effect of PE on sarcopaenia in patients with OHE. Methods and analysis: At the time of patient recruitment, a precise assessment for nutritional status and daily physical activities will be performed in each subject. Study participants will be randomly assigned into two groups: (1) the PE group and (2) the control group. In the PE group, we will conduct guidance to study participants once a month at the outpatient nutrition guidance room. We will also instruct them to do exercise with >3 metabolic equivalents (mets; energy consumption in physical activities/resting metabolic rate) for 60 min per day and to do exercise >23 mets per week. Improvement of sarcopaenia as defined by muscle mass and muscle strength at 3 months after the randomisation will be the primary endpoint. Sarcopaenia will be defined based on the current Japanese guidelines. We prospectively compared the improvement of sarcopaenia in the two groups. Ethics and dissemination: This study has received approval from the Institutional Review Board at Hyogo college of medicine (approval no. 2768). Final data will be publicly disseminated irrespective of the study results. A report releasing study results will be submitted for publication in an appropriate journal after completion of data collection. Trial registration number: UMIN000029248; Pre-results. No patient is registered at the submission of our manuscript.
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The ultrasonography contrast agent Sonazoid provides parenchyma-specific contrast imaging (Kupffer imaging) based on its accumulation in Kupffer cells. This agent also facilitates imaging of the fine vascular architecture in tumors... more
The ultrasonography contrast agent Sonazoid provides parenchyma-specific contrast imaging (Kupffer imaging) based on its accumulation in Kupffer cells. This agent also facilitates imaging of the fine vascular architecture in tumors through maximum intensity projection (MIP). We examined the clinical utility of the malignancy grading system for hepatocellular carcinoma (HCC) using a combination of 2 different contrast-enhanced ultrasonography images. We studied 121 histologically confirmed cases of HCC (well-differentiated, 45; moderately differentiated, 70; poorly differentiated, 6). The results of Kupffer imaging were classified as (1) iso-echoic pattern or (2) hypo-echoic pattern. The MIP patterns produced were classified into one of the following categories: fine, tumor vessels were not clearly visualized and only fine vessels were visualized; vascular, tumor vessels were visualized clearly; irregular, tumor vessels were thick and irregular. Based on the combined assessment of Kupffer imaging and the MIP pattern, the samples were classified into 4 grades: Grade 1 (iso-fine/vascular), Grade 2 (hypo-fine), Grade 3 (hypo-vascular), and Grade 4 (hypo-irregular). The distribution of moderately and poorly differentiated HCCs was as follows: Grade 1, 4 % (1/24); Grade 2, 52 % (15/29); Grade 3, 85 % (44/52); and Grade 4, 100 % (16/16). The grading system also predicted portal vein invasion in 72 resected HCCs: Grade 1, 0 % (0/4); Grade 2, 13 % (1/8); Grade 3, 23 % (11/48); and Grade 4, 67 % (8/12). This new malignant grading system is useful for estimation of histological differentiation and portal vein invasion of HCC.
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Research Interests: Medicine and Hepatology
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Pegylated-interferon(PEG-IFN)/interferon monotherapy for patients with chronic hepatitis C has been used for two clinical aims; one is for the elimination of hepatitis C virus (HCV), and the other is for the inhibition of... more
Pegylated-interferon(PEG-IFN)/interferon monotherapy for patients with chronic hepatitis C has been used for two clinical aims; one is for the elimination of hepatitis C virus (HCV), and the other is for the inhibition of hepatocarcinogenesis. In patients with a rapid viral response to PEG-IFN, PEG-IFN monotherapy can efficiently eradicate HCV with decreased side effects. A low dose treatment of interferon is suggested to inhibit hepatocarcinogenesis in patients whose ALT or alpha-fetoprotein (AFP) was reduced in response to the treatment, although the benefits and adverse events of IFN therapy have to be carefully evaluated.
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Background/aims: A well-differentiated hepatocellular carcinoma-derived cell line, HuH-7 proliferates autonomously in serum-free medium. Human hepatoma-derived growth factor, which was purified from the conditioned medium of HuH-7 cells,... more
Background/aims: A well-differentiated hepatocellular carcinoma-derived cell line, HuH-7 proliferates autonomously in serum-free medium. Human hepatoma-derived growth factor, which was purified from the conditioned medium of HuH-7 cells, stimulates the growth of HuH-7 cells by an autocrine fashion, and fibroblasts and endothelial cells by a paracrine fashion. We investigated the role of protein kinase C in the proliferation of HuH-7 cells and the growth activity of hepatoma-derived growth factor. Methodology: The effects of a selective protein kinase C inhibitor, H-7 on the proliferation of HuH-7 and 3T3 fibroblasts stimulated by hepatoma-derived growth factor were examined by DNA synthesis and cell growth assay. Results: H-7 suppressed the growth of HuH-7 cells. The ID50 of H-7 on the growth of HuH-7 cells was about 25 microM, and the growth of HuH-7 cells was almost completely inhibited by not less than 50 microM of H-7. H-7 inhibited the growth activity of hepatoma-derived growth factor for Swiss 3T3 fibroblasts. The ID50 of H-7 on the activity of hepatoma-derived growth factor for 3T3 fibroblasts was about 25 microM, too. HA1004, used as a negative control of H-7, failed to inhibit the growth of HuH-7 cells and the activity of hepatoma-derived growth factor. The growth of HuH-7 cells was stimulated significantly by about 40% by a protein kinase C activator, SC-9. H-7 did not suppress hepatoma-derived growth factor production in HuH-7 cells. Conclusions: These findings suggest that protein kinase C plays an important role in the growth of HuH-7 hepatoma cells and may be participated as a pathway in signal transduction of hepatoma-derived growth factor.
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The aim of the study described here was to clarify the diagnostic value of the fluttering sign, a new sign that characterizes hepatic hemangiomas in gray-scale ultrasonography (US). It refers to a phenomenon in which the speckled... more
The aim of the study described here was to clarify the diagnostic value of the fluttering sign, a new sign that characterizes hepatic hemangiomas in gray-scale ultrasonography (US). It refers to a phenomenon in which the speckled echogenicity inside the hemangioma changes continuously and seems to be moving. A total of 172 hemangiomas diagnosed with contrast-enhanced US were evaluated. The fluttering sign was found in 123 of 172 hemangiomas (71.5%). Its prevalence was significantly higher than that of the marginal strong echo (89/172, 51.7%, p < 0.001), posterior acoustic enhancement (103/172, 59.9%, p = 0.031) and chameleon sign (100/172, 58.1%, p = 0.013). In addition, the fluttering sign was observed significantly more frequently in mixed or hypo-echoic tumors than in hyper-echoic tumors (p < 0.001), relatively large tumors (p < 0.001) and tumors that were less than 5 cm from the body surface (p = 0.015). The fluttering sign in gray-scale US has great potential to be a new complementary sign for the diagnosis of hemangioma.
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AimShear wave elastography (SWE) in patients with chronic liver diseases is a noninvasive useful method for the diagnosis of liver fibrosis severity, which can be an alternative to liver biopsy. However, the liver stiffness measurement... more
AimShear wave elastography (SWE) in patients with chronic liver diseases is a noninvasive useful method for the diagnosis of liver fibrosis severity, which can be an alternative to liver biopsy. However, the liver stiffness measurement using SWE can be affected by various factors including hepatic inflammation, extrahepatic cholestasis, heart failure, and underlying liver diseases. The aim of this study is to clarify the correlation between liver stiffness using SWE and hepatic necroinflammation serologically and pathologically.MethodsA total of 843 patients with chronic liver disease who received liver biopsy were analyzed. Liver stiffness measurement using transient elastography (TE) and virtual touch quantification (VTQ) were carried out on the same day as the liver biopsy. The correlation between SWE and hepatic inflammation was analyzed serologically and pathologically.ResultsThe liver stiffness values increased significantly with the progression of liver fibrosis and inflammation (overall p &lt; 0.001). In patients with F0–1, F2, and F3, TE and VTQ values of A2 or A3 were significantly higher than those of A0 or A1 (p value, all &lt;0.05), but not in patients with F4. The median alanine aminotransferase (ALT) values increased significantly with the progression of liver inflammation (p &lt; 0.001). Moreover, TE and VTQ in patients with ALT ≥70 IU/L were significantly higher than those in patients with ALT &lt;70 IU/L (p &lt; 0.01), but not in patients with F4.ConclusionShear wave elastography can be affected by hepatic necroinflammation in F0–F3 fibrosis, but not in F4.
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AimThe pathogenic process underlying the development of hepatocellular carcinoma (HCC) is not yet clear in patients with chronic hepatitis C virus who receive direct‐acting antiviral therapy and achieve sustained virological response.... more
AimThe pathogenic process underlying the development of hepatocellular carcinoma (HCC) is not yet clear in patients with chronic hepatitis C virus who receive direct‐acting antiviral therapy and achieve sustained virological response. This study investigated two risk factors for HCC in these patients; specifically, hepatic fibrosis and steatosis.MethodsA total of 355 patients in whom hepatitis C virus was eradicated by direct‐acting antiviral were evaluated. Fibrosis and steatosis were assessed using transient elastography (TE) and the controlled attenuation parameter (CAP). Inverse probability weighting was applied to patient age, sex, albumin–bilirubin, α‐fetoprotein, history of HCC, TE, or CAP.ResultsThe 12‐, 24‐, and 36‐month cumulative incidence rates of HCC were 0.9%, 2.4%, and 4.1%, respectively. Univariate analysis with the Cox proportional hazards model showed that whereas a high TE value (≥10 kPa) was significantly associated with HCC development (HR 7.861, 95% CI 2.126–29.070; p = 0.002), CAP was not. Additionally, univariate analysis with the Cox proportional hazards model adjusted by inverse probability weighting showed that a high TE value was significantly associated with HCC development (HR 3.980, 95% CI, 1.036–15.290; p = 0.044), whereas CAP was not. The cumulative inverse probability weighting‐adjusted incidence of HCC rates at 12, 24, and 36 months were 0.0%, 0.5%, and 1.7%, respectively, in patients with a low TE value, and 2.5%, 5.1%, and 7.6%, respectively, in those with a high TE value.ConclusionA high TE value was a risk factor for HCC in hepatitis C virus patients who received direct‐acting antiviral therapy and achieved sustained virological response.
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Background/aims: We studied the effect of initial daily administration of interferon for the treatment of chronic hepatitis C, especially in patients with intermediate viral load. Methodology: Consecutive patients who met the inclusion... more
Background/aims: We studied the effect of initial daily administration of interferon for the treatment of chronic hepatitis C, especially in patients with intermediate viral load. Methodology: Consecutive patients who met the inclusion criteria were randomly enrolled into two groups in this study. All patients analyzed could be treated with interferon-alpha for 6 months. Patients in group A were administered 6 million units of interferon-alpha subcutaneously daily initially for 2 weeks and then thrice weekly. Patients in group B were treated with the same dose of interferon-alpha thrice weekly from the first administration. We decided the criteria of complete remission as the absence of serum HCV-RNA at both points of the end of interferon treatment and 6 months later. Results: Due to the relationship between the efficacy and serum viral load, we decided the criteria of the intermediate load as the quantitative value of serum HCV-RNA to be not lower than 10(5.0) and not higher than 10(6.5) copies/ml. Seventy-six and 78 patients, whose genotype and quantitative value of serum HCV-RNA could be measured before treatment, were analyzed in group A and B, respectively. The rate of complete remission in group A (40.8%) was higher than that in group B (25.6%), significantly (p = 0.046). In the intermediate viral load group, the rate of complete remission in group A (52.3%) was significantly higher than that in group B (29.3%) (p = 0.045). In the patients with genotype 1 b virus, the rate of complete remission had a tendency to be higher in group A (33.3%) than in group B (17.4%) (not significant). In the patients with genotype 2, the rate of complete remission was higher in group A (77.8%) than in group B (41.2%) (significant, p = 0.041). Conclusions: These results suggest that the initial daily interferon administration is necessary to gain a higher rate of serum HCV-RNA eradication in patients with intermediate viral load in chronic hepatitis C.
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Chondrocyte maturation and vascular invasion of cartilage are essential in the process of endochondral ossification. Cbfa1‐deficient (Cbfa1−/−) mice displayed a complete absence of osteoblast and osteoclast maturation as well as severely... more
Chondrocyte maturation and vascular invasion of cartilage are essential in the process of endochondral ossification. Cbfa1‐deficient (Cbfa1−/−) mice displayed a complete absence of osteoblast and osteoclast maturation as well as severely inhibited chondrocyte maturation in most parts of the skeleton. Although chondrocyte maturation and mineralization were observed in restricted areas of Cbfa1−/− mouse skeleton, vascular invasion of calcified cartilage was never noted. To investigate the possibility of chondrocyte maturation and vascular invasion in Cbfa1−/− cartilage and the role of the hematopoietic system in the process of vascular invasion, we transplanted embryonic day 18.5 (E18.5) Cbfa1−/− femurs, which are composed of immature chondrocytes, into spleens of normal mice. One week later, the transplanted femurs contained terminally differentiated chondrocytes expressing osteopontin, bone sialoprotein (BSP), and matrix metalloproteinase (MMP) 13. In the diaphyses of the transplants, the cartilage matrix was mineralized and the cartilage was invaded by vascular vessels and osteoclasts. However, chondrocyte maturation and vascular invasion were severely retarded in comparison with transplants of E14.5 wild‐type femurs, in which the cartilage was rapidly replaced by bone, and neither mature osteoblasts nor bone formation were observed. In primary culture of Cbfa1−/− chondrocytes, transforming growth factor (TGF) β1, platelet‐derived growth factor (PDGF), interleukin (IL)‐1β, and thyroid hormone (T3) induced osteopontin and MMP‐13 expression. These findings indicated that factors in the hematopoietic system are able to support vascular invasion of cartilage independent of Cbfa1 but are less effective without it, suggesting that Cbfa1 functions in cooperation with factors from bone marrow in the process of growth plate vascularization.