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Biomedical subjects

Yoshizumi Shintani

Publications and source records attributed to Yoshizumi Shintani.

13 recordsLinked to original sources
PubMed2006

[The efficacy of safety winged steel needles on needlestick injuries].

Safety winged steel needles were introduced at the University of Tokyo Hospital in January 2001. We studied their effect in needlestick injuries. A total of 952 'needlestick and sharp-object injuries were reported. From January 1999 to December 2004, Cases of injury with winged steel needles decreased dramatically soon after safety devices were introduced, from 19.8% in Apr.-Dec.2000 to 6.7% in 2001 and 5.5% in 2002 (p < .01). They began to increase, however, in July 2002, decreased again after medical staff members mere given lectures and notices by e-mail. Due to the introduction of safety devices, cases classified as a "while recapping a used needle" and "when puncturing rubber stoppers" decreased. Among 17 injuries with safety winged steel needles, the most common cases were "safety mechanism not activated". We estimated that 76.5% of cases with safety winged steel needles could be prevented if they were used properly. In conclusion, the introduction of safety winged steel needles effectively reduced cases of injury with such needles. It is thus important to regularly remind hospital staff of safety device techniques and information reduce the such injuries.

Equipment Design↗
PubMed2005

Hepatitis C virus core protein exerts an inhibitory effect on suppressor of cytokine signaling (SOCS)-1 gene expression.

BACKGROUND/AIMS: Suppressor of cytokine signaling (SOCS)-1, a negative feedback regulator of cytokine signaling pathway, also has a tumor suppressor activity, the silencing of its gene by hypermethylation is suggested to contribute to hepatocarcinogenesis. We studied the effect of the core protein of hepatitis C virus (HCV) on the expression of SOCS-1 gene. METHODS: HCV core gene transgenic mice, which develop hepatocellular carcinoma late in life, HepG2 cells expressing the core protein, and human liver tissues were analyzed. RESULTS: The expression of SOCS-1 gene was significantly suppressed in the liver of core gene transgenic mice and HepG2 cells expressing the core protein, while that of SOCS-3 gene was conserved. SOCS-1 expression levels also decreased in HCV-positive human liver tissues. The core protein differentially down-regulated the expression of signal transducer and activator of transcription (STAT) target genes, but rather enhanced STAT1 and STAT3 activation after interleukin-6 stimulation in mouse liver tissues and cells. CONCLUSIONS: HCV core protein down-regulates the expression of SOCS-1 gene. This is a mechanism leading to SOCS-1 silencing, an alternative to the hypermethylation of the gene; this effect of the core protein may modulate the intracellular signaling pathway, contributing to the pathogenesis in HCV infection including hepatocarcinogenesis.

Animals↗
PubMed2004

Methylation status of suppressor of cytokine signaling-1 gene in hepatocellular carcinoma.

BACKGROUND: Silencing of the suppressor of cytokine signaling ( SOCS-1) by aberrant methylation at the CpG island in the coding region gene has been reported in hepatocellular carcinoma (HCC). However, principally, it is methylation in the 5'-noncoding region but not that in the coding region which determines the regulation of gene expression. METHODS: Methylation-specific PCR was performed for the analysis of methylation status both in the 5'-noncoding region and the CpG island of SOCS-1 from 22 HCC tissue samples with adjacent non-HCC tissue samples and from two cell lines. RESULTS: Using primers in the CpG island, 9 of 22 HCC samples exhibited aberrant methylation of SOCS-1, while only 1 of 22 adjacent non-HCC samples did so. The unmethylation pattern was detected in 1 of 22 HCC and in 5 of 22 non-HCC samples. Thus, aberrant methylation of SOCS-1 was significantly associated with HCC ( P = 0.0076 by Fisher's exact test). Using primers in the 5'-noncoding region, aberrant methylation was observed in 12 of 22 HCC and in 2 non-HCC samples. The unmethylated pattern was observed in 5 of 22 HCC and in 10 of 22 non-HCC samples ( P = 0.0042). There was no significant correlation between the methylation status of SOCS-1 and clinicopathological findings, such as the presence or absence of cirrhosis or the histological grade of HCC. CONCLUSIONS: Aberrant methylation of the SOCS-1 had a significant correlation with HCC. The rate of aberrant methylation was similar in the 5'-noncoding region and in the CpG island. Aberrant methylation of SOCS-1 may be associated with hepatocarcinogenesis, although further studies are necessary.

Carcinoma, Hepatocellular↗
PubMed2004

Hepatitis C virus infection and diabetes: direct involvement of the virus in the development of insulin resistance.

BACKGROUND & AIMS: Epidemiological studies have suggested a linkage between type 2 diabetes and chronic hepatitis C virus (HCV) infection. However, the presence of additional factors such as obesity, aging, or cirrhosis prevents the establishment of a definite relationship between these 2 conditions. METHODS: A mouse model transgenic for the HCV core gene was used. RESULTS: In the glucose tolerance test, plasma glucose levels were higher at all time points including in the fasting state in the core gene transgenic mice than in control mice, although the difference was not statistically significant. In contrast, the transgenic mice exhibited a marked insulin resistance as revealed by the insulin tolerance test, as well as significantly higher basal serum insulin levels. Feeding with a high-fat diet led to the development of overt diabetes in the transgenic mice but not in control mice. A high level of tumor necrosis factor-alpha, which has been also observed in human chronic hepatitis C patients, was considered to be one of the bases of insulin resistance in the transgenic mice, which acts by disturbing tyrosine phosphorylation of insulin receptor substrate-1. Moreover, administration of an anti-tumor necrosis factor-alpha antibody restored insulin sensitivity. CONCLUSIONS: The ability of insulin to lower the plasma glucose level in the HCV transgenic mice was impaired, as observed in chronic hepatitis C patients. These results provide a direct experimental evidence for the contribution of HCV in the development of insulin resistance in human HCV infection, which finally leads to the development of type 2 diabetes.

Animals↗
PubMed2004

Prevalence of measles, rubella, mumps, and varicella antibodies among healthcare workers in Japan.

OBJECTIVES: To evaluate the immune status of healthcare workers (HCWs) against measles, rubella, mumps, and varicella in Japan, and to promote an adequate vaccination program among HCWs. SETTING: University of Tokyo Hospital. PARTICIPANTS: Eight hundred seventy-seven HCWs. DESIGN: Serologic screening for measles, rubella, mumps, and varicella was performed on HCWs. Antibodies against measles, rubella, and mumps were detected using hemagglutination inhibition (HI) assay ($4.20 per test). If serum was negative by HI assay, enzyme-linked immunosorbent assay (EIA) was performed ($12.60 per test). Anti-varicella antibodies were detected by EIA only. RESULTS: Among tested HCWs, 98.5%, 90.4%, 85.8%, and 97.2% had immunity to measles, rubella, mumps, and varicella, respectively. All those born before 1970 were seropositive for measles. However, individuals susceptible to rubella, mumps, and varicella were present in all age groups. The sensitivities and negative predictive values of HI assay compared with EIA were 86.6% and 11.3% for measles, 99.1% and 92.2% for rubella, and 47.8% and 24.1% for mumps, respectively. For measles and mumps, prevaccination screening by HI assay in combination with EIA led to significant savings compared with EIA only. In contrast, it was estimated that prevaccination screening using only HI assay would be more economical for rubella. CONCLUSIONS: Aggressive screening and vaccination of susceptible HCWs was essential regardless of age. Prevaccination serologic screening using a combination of HI assay and EIA was more economical for measles and mumps.

Adult↗
PubMed2003

Serum lipid profile of patients with genotype 1b hepatitis C viral infection in Japan.

Hepatitis C virus (HCV) infection is associated with the development of steatosis in the liver. Recently, infection with genotype 3a HCV has been reported to have a closer association with hepatic steatosis than that with genotype 1 or 2 HCV. Moreover, infection with genotype 3a HCV but not with genotype 1 has been shown to be associated with serum hypocholesterolemia or hypobetalipoproteinemia in European countries. We conducted a case control study to characterize the serum lipid profile in patients infected with genotype 1b HCV, which is the most prevalent HCV genotype in Japan. These patients had significantly lower serum cholesterol levels than those infected with HBV or genotype 2a HCV who had similar liver disease progression and body mass index. Further analysis of serum apolipoproteins revealed that not only apolipoprotein B but also apolipoprotein CII and apolipoprotein CIII levels were significantly reduced, while apolipoprotein AI, AII and E levels were similar in patients infected with genotype 1b HCV and those with HBV or genotype 2a HCV. These results indicate that, in Japan, infection with genotype 1b HCV is a cause of lipid metabolism disturbances, which may be associated with the pathogenesis of hepatitis C liver disease.

Journal Article↗
PubMed2003

Hepatitis C virus core protein activates ERK and p38 MAPK in cooperation with ethanol in transgenic mice.

In human chronic hepatitis C, alcohol intake is a synergistic factor for the acceleration of hepatocarcinogenesis. Recently, we showed a significant increase of reactive oxygen species (ROS) in hepatitis C virus (HCV) core-transgenic mice fed ethanol-containing diets. Because previous studies indicated that ROS is closely associated with mitogen-activated protein kinases (MAPK), we examined activities of c-Jun N-terminal kinase, p38 MAPK, and extracellular signal-regulated kinase (ERK) in the liver of core-transgenic and nontransgenic mice with short-term ethanol feeding. Activity of ERK and p38 MAPK was increased in core-transgenic mice compared with nontransgenic mice, whereas neither ERK nor p38 MAPK was activated in core-transgenic mice with normal diets. In addition, activity of cyclic-AMP and serum responsive element, downstream pathways of p38 MAPK and ERK, was also increased. Comparison of gene expression profiles by cDNA microarray and real-time PCR revealed that galectin-1, which is associated with cell transformation, was significantly increased in ethanol-fed core-transgenic mice. On the other hand, glutathione S-transferase (GST), which plays a key role in protecting cells from oxidative stress, was decreased. In conclusion, these results suggest that HCV core protein cooperates with ethanol for the activation of some MAPK pathways, and leads to the modulation of several genes, contributing to the pathogenesis of liver disease of HCV-infected patients with high ethanol consumption.

Activating Transcription Factor 2↗
PubMed2003

Acute hepatitis E with elevated creatine phosphokinase.

Acute hepatitis E is caused by infection with hepatitis E virus, which is endemic in developing countries. Recently, the number of cases with acute hepatitis E is increasing in Japan due to increased travel to the endemic areas. This paper reports a case of a Japanese man with acute hepatitis E who had a history of traveling to south China. Serum creatine phosphokinase was elevated on admission without symptoms of muscle damage (isoenzyme MM 100%), and normalized in parallel with resolution of hepatitis, raising the possibility of an association between elevation of creatine phosphokinase and acute hepatitis E. However, we need to investigate further the incidence of elevation of serum creatine phosphokinase in many cases with acute viral hepatitis including hepatitis A, B, and C to determine whether muscle disorder is characteristic of acute hepatitis E.

Creatine Kinase↗
PubMed2002

Alteration of intrahepatic cytokine expression and AP-1 activation in transgenic mice expressing hepatitis C virus core protein.

Hepatitis C virus (HCV) infection often leads to the development of hepatocellular carcinoma (HCC), but its molecular mechanism has not been clearly elucidated. Previously, transgenic mice constitutively expressing HCV core protein have been shown to develop HCC, suggesting a pivotal role of the core protein in hepatocarcinogenesis. Here, we analyzed the expression of cytokines associated with a variety of cellular processes, including cell proliferation, in the mouse model for HCV-associated HCC to define the molecular events prior to oncogenesis. The expression of tumor necrosis factor-alpha and interleukin-1beta was increased at both protein and mRNA levels. In addition, the activities of c-Jun N-terminal kinase and activator protein-1 (AP-1), downstream effectors, were enhanced, while IkappaB kinase or nuclear factor-kappaB activities were not enhanced. Thus, the altered in vivo expression of cytokines with AP-1 activation in consequence to the core protein expression may contribute to hepatocarcinogenesis in persistent HCV infection.

Animals↗
PubMed2002

Interaction of hepatitis C virus core protein with retinoid X receptor alpha modulates its transcriptional activity.

Hepatic steatosis and hepatocellular carcinoma (HCC) are common and serious features of hepatitis C virus (HCV) infection, and the core protein has been shown to play distinct roles in the pathogenesis. Here we report the direct interaction of HCV core protein with retinoid X receptor alpha (RXRalpha), a transcriptional regulator that controls many aspects of cell proliferation, differentiation, and lipid metabolism. The core protein binds to the DNA-binding domain of RXRalpha, leading to increase the DNA binding of RXRalpha to its responsive element. In addition, RXRalpha is activated in cells expressing the core protein as well as in the livers of the core-transgenic mice that would develop hepatic steatosis and HCC later in their lives. Using promoter genes of cellular retinol binding protein II (CRBPII) and acyl-CoA oxidase as reporters, we also show that the expression of the core protein enhances the transcriptional activity regulated by the RXRalpha homodimer as well as by the heterodimer with peroxisome proliferator activated receptor alpha. Furthermore, expression of the CRBPII gene is also up-regulated in the livers of HCV core-transgenic mice. In conclusion, these results suggest that modulation of RXRalpha-controlled gene expression via interaction with the core protein contributes to the pathogenesis of HCV infection.

Animals↗
PubMed2002

Molecular mechanism of viral hepatocarcinogenesis.

Overwhelming lines of epidemiological evidence have indicated that chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV) is a major risk for the development of hepatocellular carcinoma (HCC). In the pathogenesis of HCC associated with HBV or HCV, it remains controversial whether these hepatitis viruses play a direct role or merely an indirect role. By virtue of transgenic mice established by us, it has become evident that the product of the HBV X gene (HBx protein) and the core protein of HCV have an oncogenic potential, although the pathways through which these two viral proteins operate may differ. The findings in our studies indicate that HBV and HCV are directly involved in hepatocarcinogenesis, albeit other factors such as continued cell death and regeneration associated with chronic hepatitis may play a role as well. Combined, our results suggest that there might be a mechanism in the development of HCC in persistent infection with hepatitis viruses that is distinct from that in other cancers. Similarly to the pathogenesis of other malignancies represented by colorectal cancer, the accumulation of a set of genetic aberrations may also be necessary for a multistage development of HCC. However, HBx protein and HCV core protein, to which an oncogenic potential is attributed, may allow some of the multiple stages skipped in hepatocarcinogenesis. Unlike for the other cancers, therefore, infection with HBV or HCV may be capable of inducing HCC in the absence of a complete set of genetic aberrations. Such a scenario would explain an unusually high incidence and multicentric nature of HCC developing in chronic hepatitis B or C.

Animals↗
PubMed1999

Induction of apoptosis after switch-on of the hepatitis B virus X gene mediated by the Cre/loxP recombination system.

The HBx protein of hepatitis B virus is a multifunctional protein that is implicated in the pathogenesis of hepatocellular carcinoma by regulating gene transcription, causing cell proliferation and, as shown recently, inducing cell death. However, analysis of the effects of HBx in stable cultured cell clones has been hampered because only cell lines that adapted to the effects of HBx were selected during the establishment of cell clones. Here, we describe a system in which transcription of the X gene of hepatitis B virus is switched on by the use of the site-specific Cre recombinase. Two human liver cell lines, HLF and HepG2, were used, the former with a mutant p53 allele and the latter with wild-type p53. The stable cell clones isolated, which carried the X gene in a transcriptionally silent state, were infected with recombinant adenovirus carrying Cre recombinase. Ninety-six hours after adenovirus infection, cell clones that expressed HBx had undergone TUNEL-positive cell death with characteristics of apoptosis. Apoptosis was induced despite concomitant inactivation of the p53 protein as a result of its cytoplasmic translocation by HBx. In contrast, neither the X gene-carrying cells infected with wild-type adenovirus nor various control cells infected with Cre-expressing adenovirus exhibited apoptosis. These results indicate that the expression of HBx protein leads to liver cell apoptosis independently of the p53 pathway. The significance of HBx-induced apoptosis in natural infection is unclear, but it may contribute to the development of hepatitis and serve to spread progeny virus to neighbouring cells while evading the host immune responses.

Adenoviridae↗