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Biomedical subjects

Kojiro Michitaka

Publications and source records attributed to Kojiro Michitaka.

At least 37 records · Page 2Linked to original sources
PubMed2005

Administration of dendritic cells in cancer nodules in hepatocellular carcinoma.

Dendritic cells (DCs), the most potent antigen-presenting cells in vivo, are now used for cancer immunotherapy during which they are usually administered to the blood of patients with cancer. However, the route of administration of DCs affects the magnitude of immune responses. This study was conducted to assess the safety of the direct administration of DCs into cancer nodules. DCs were generated by culturing peripheral blood mononuclear cells with granulocyte-macrophage colony-stimulating factor and interleukin-4 for 7 days. After confirming the phenotype and function, one hundred thousand DCs were injected directly into the cancer nodules of 4 patients with hepatocellular carcinoma (HCC) under ultrasonography guidance 48 h after the administration of 100% ethanol. All patients were monitored for any alteration in generalized condition, signs of inflammation, and liver and kidney function for the next 14 days. In addition, the final assessment of the safety of the administration of DCs into cancer nodules was performed 6 months after therapy commencement. The injection of 100% ethanol disrupted the HCC nodules in all 4 patients. DCs were distributed uniformly in the cancer nodules as assessed by ultrasonography. The administration of DCs into cancer nodules was well tolerated by all patients and there were no immediate or delayed side effects. The tumor marker decreased in one patient after the direct administration of DCs. Direct administration of DCs into the cancer nodules of patients with HCC was safe.

Aged↗
PubMed2004

Comparison of genotypes C and D of the hepatitis B virus in Japan: a clinical and molecular biological study.

The genotype-related differences between genotype C and genotype D of the hepatitis B virus (HBV) remain unknown. The relationship was studied between the HBV genotypes and their clinical features, paying special attention to genotypes C and D. Serum samples from 413 HBV carriers were genotyped using an enzyme immunoassay (EIA) and by restriction fragment length polymorphism. The nucleotide sequences at the basic core promoter (BCP) and precore (PreC) regions were analysed by direct sequencing. The full genome sequences of three HBV genotype D cases were also examined. Almost all carriers with HBV genotype D were asymptomatic carriers (84.2%). Genotype D was not found in patients with liver cirrhosis and hepatocellular carcinoma. In contrast, carriers with genotype C had mainly chronic liver disease (63.2%; P<0.001). The ratio of hepatitis B e antigen (HBeAg)/anti-HBe was significantly higher in genotype C than in genotype D in the young age-matched group (P<0.01). The mutation at BCP (T1762, A1764) was significantly lower in genotype D than in genotype C among HBeAg-negative patients (P<0.05). The HBV full-genome sequences are very similar to certain HBV genotype D sequences from Europe. In conclusion, genotype C was associated with chronic liver disease, whereas genotype D was related to asymptomatic carriers with earlier HBeAg seroconversion. Thus, the outcome of chronic HBV infection may be different in persons infected with HBV genotypes C and D.

Adult↗
PubMed2004

Effect of mutation in the hepatitis C virus nonstructural 5B region on HCV replication.

BACKGROUND: We have reported that the presence of a mutation at the hepatitis C virus (HCV) nonstructural protein 5B (NS5B), defined as a change in amino acids at sites specific for a different reported genotype, was related to complete response (CR) to interferon (IFN) therapy in patients with chronic hepatitis C (CHC) with genotype 1b. The present study assessed the impact of the NS5B mutation on the replication of HCV in these patients. METHODS: Genotype-specific mutations of HCV NS5B were determined by direct sequencing. We measured HCV-RNA titers in serum by real-time detected polymerase chain reaction (PCR), and serum HCV core protein levels (as a marker of HCV-RNA replication) were measured using an enzyme immunoassay in patients with CHC genotype 1b. RNA-dependent RNA polymerase (RdRp) activity was measured by Behrens' method in liver cirrhosis patients infected with HCV (n = 13) and in those infected with hepatitis B virus (HBV; n = 2). RESULTS: The titers of HCV-RNA (n = 44) and the levels of HCV core protein (n = 41) were significantly lower in patients with the HCV genotype 1b mutant compared with wild-type HCV (P < 0.05). RdRp activity in liver tissue did not show any correlation with the HCV NS5B mutation. CONCLUSIONS: HCV NS5B genotype-specific mutations in HCV genotype 1b may influence HCV replication.

DNA Mutational Analysis↗
PubMed2004

Earlier recurrence of esophageal varices, following therapy, in patients with primary biliary cirrhosis (PBC) compared with non-PBC patients.

BACKGROUND: Variceal bleeding is a common, life-threatening complication of primary biliary cirrhosis (PBC). Recently, several reports have suggested that the existence of esophageal varices in patients with PBC is a significant factor in the assessment of disease prognosis. However, there have been no reports on the recurrence of esophageal varices following treatment in patients with PBC. In this study, we investigated the recurrence of esophageal varices in PBC patients and attempted to identify predictive factors for the recurrence of esophageal varices. METHODS: Between April 1993 and August 2003, 138 patients with esophageal varices who had been treated by endoscopic variceal ligation (EVL; 96 men and 42 women; age, 33-83 years; mean, 62.6 +/- 10.1 years), were enrolled in the present study. The diagnosis of esophageal varices was made by upper gastrointestinal endoscopy, and the varices were graded according to the criteria of the Japanese Research Society for Portal Hypertension. The relationship between the recurrence of esophageal varices and factors such as biochemical and hematological parameters, as well as the etiology of the liver disease, was analyzed using the Kaplan-Meier method and the multivariate Weibull regression model. RESULTS: PBC patients had an earlier recurrence of esophageal varices compared to non-PBC patients, and two factors, prothrombin time and etiology (PBC/non-PBC), were indicative of significantly earlier recurrence of esophageal varices. CONCLUSIONS: We should be extra careful in the follow-up of patients with PBC after therapy for esophageal varices.

Case-Control Studies↗
PubMed2004

Recent clinical features of Wilson's disease with hepatic presentation.

BACKGROUND: We carried out this study to evaluate recent clinical features of Wilson's disease (WD) with hepatic presentation, especially in terms of age, degree of liver injury, and association with hepatocellular carcinoma (HCC). METHODS: Sixteen patients with hepatic manifestations were diagnosed with WD in the period 1976-2003. We divided this period into two periods, "past" and "recent". The diagnosis was based on the presence of Kayser-Fleisher rings, low serum copper levels, low serum ceruloplasmin levels, increased urinary copper concentrations before or after D-penicillamine challenge, and increased hepatic copper concentrations. This retrospective study was done at Ehime University Hospital. RESULTS: Four patients, including a pair of siblings, had a family history of WD. Four patients had parental consanguinity. There were 6 patients aged over 40 years in the recent period, whereas no patients in the past period were over 40. Four patients had neurological manifestations. Ten patients had liver cirrhosis and 5 had chronic hepatitis. Two had fatty liver without obesity. All patients in the past period had liver cirrhosis. Three patients with liver cirrhosis were found to have HCC during the follow up. All patients were treated with either D-penicillamine or trientine chloride, or both. However, four patients had to discontinue these agents due to the side effects. CONCLUSIONS: Recently, the number of patients diagnosed with WD has been increasing, not only in terms of those with classical-type WD but also in terms of elderly patients or patients with non-cirrhotic liver injury such as fatty liver and chronic hepatitis. The various clinical features of WD should be recognized and particular attention should focus on HCC as a complication.

Adolescent↗
PubMed2004

CCR5 promoter polymorphism influences the interferon response of patients with chronic hepatitis C in Japan.

OBJECTIVE: Chemokines and chemokine receptors play important roles in the pathogenesis of chronic hepatitis C. Here, we explore the influence of genetic polymorphisms of chemokine and chemokine receptors such as regulated upon activation and T cell secreted (RANTES), CC chemokine receptor 5 (CCR5) and CCR2 on the outcome of interferon (IFN) monotherapy. METHODS: In a cohort of 105 patients with chronic hepatitis C as well as in 50 sustained responders and 55 nonresponders the presence of polymorphisms such as CCR5-Delta32, CCR5 59029G/A, CCR2 V64I and RANTES -403G/C was determined. RESULTS: Gender, age, liver histological staging, pretreatment ALT levels, total dose of IFN and frequencies of polymorphisms (CCR2 V64I and RANTES -403G/C) did not significantly differ between the two groups. A low viral load, hepatitis C virus (HCV) serotype 2 and CCR5 59029G/G were significantly associated with a higher probability of a sustained response (p < 0.01, p < 0.05, p < 0.05, respectively). Multiple logistic regression analysis showed that a low viral load, HCV serotype 2 and CCR5 59029G/G were independently associated with a sustained response [odds ratio 3.980 (1.647-9.621), p = 0.002; 3.584 (1.439-8.924), p = 0.006; 3.638 (1.163-11.379), p = 0.026, respectively]. CONCLUSION: These findings indicate that CCR5 59029 is a host genetic factor that is associated with responses to IFN therapy among Japanese patients with chronic hepatitis C.

Adult↗
PubMed2004

Hepatopulmonary syndrome in a patient with primary biliary cirrhosis.

A 54-year-old Japanese woman with primary biliary cirrhosis (PBC) was admitted to our hospital due to hepatic coma and refractory pleural effusion. The physical examination revealed clubbed fingers and collateral veins. The patient had an increased alveolar-arterial oxygen gas tension difference. The levels of anti-mitochondrial antibody (AMA) and AMA M2 was 80 times normal. A technetium 99m-labeled macro-aggregated human albumin scintigram showed uptake in the spleen and the kidneys. A diagnosis of hepatopulmonary syndrome (HPS) was made. HPS may be overlooked because of the lack of symptoms. We conclude that closer attention should be paid to the occurrence of HPS.

Female↗
PubMed2004

Gianotti-Crosti syndrome caused by acute hepatitis B virus genotype D infection.

A 12-year-old girl with Gianotti-Crosti syndrome caused by hepatitis B virus (HBV) infection was admitted due to eruption on her extremities. Laboratory findings revealed elevation of transaminase, positivity for HB surface antigen (HBsAg), and an IgM type anti-HB core. The eruption and level of transaminase improved, and HBsAg became negative within 2 months of onset. Analysis of the virus revealed it to be genotype D with a genomic length of 3,182 bases and the HBsAg serotype was ayw3, which is very rare in Japan. The possible relationship between Gianotti-Crosti syndrome and HBV genotype D infection is discussed.

Acrodermatitis↗
PubMed2004

Renal transplant recipient with chronic hepatitis C who obtained sustained viral response after interferon-beta therapy.

A 44-year-old Japanese woman with a history of living-related renal transplantation was treated with interferon-beta (IFN-beta) for chronic infection with sero-group 2 hepatitis C virus (HCV). Serum HCV-RNA titer was 160 kilo-international units/ml. Treatment with intravenous IFN-beta daily was given for 6 weeks. Serum HCV-RNA was undetectable at 3 weeks after initiating therapy. Renal graft rejection did not occur. Six months after completing therapy, she obtained sustained viral response. This case demonstrates that IFN-beta therapy safely induced clearance of HCV in a renal transplant recipient with stable renal function, low viral load and/or HCV sero-group 2.

Adult↗
PubMed2004

Production and efficacy of a dendritic cell-based therapeutic vaccine for murine chronic hepatitis B virus carrierer.

Recently a new field of immunological research and clinical application of vaccines for therapeutic purposes (vaccine therapy) has been developed for treating several chronic viral infections including chronic hepatitis B virus (HBV) infection. Administration of vaccine containing hepatitis B surface antigen (HBsAg) for 1 year has resulted in negative HBsAg and development of antibody to HBsAg (anti-HBs) in some, but not in all, HBV transgenic mouse (HBV-Tg). In order to develop more potent regimen of vaccine therapy for chronic HBV carrier, we prepared a dendritic cell (DC)-based therapeutic vaccine and evaluated their therapeutic potential in HBV-Tg. DCs were isolated from single cell suspensions of murine spleen cells by collagenase digestion, density centrifugation and depletion of lymphocytes. Spleen DCs were cultured with HBsAg (100 microg) for 24 h to produce HBsAg-pulsed DCs. HBV-Tg expressing HBsAg and HBV DNA in the sera were randomly assigned to receive either HBsAg-pulsed DCs (n = 20) or unpulsed DC (n = 20) or vaccine containing HBsAg (n = 39) or complete Freund's adjuvant (n = 20) or left untreated (n = 20). Only two intraperitoneal injections of HBsAg-pulsed DCs resulted in negative HBsAg and production of anti-HBs in the sera in all HBV-Tg (n = 20). However, administration of un-pulsed DCs (n = 20) or vaccine containing HBsAg (n = 39) or only complete Freund's adjuvant did not induce negative HBsAg or production of anti-HBs in any HBV-Tg within 6 months of therapy commencement. Taken together, this study showed that HBsAg-pulsed DCs represent a highly potent therapeutic vaccine for chronic HBV infection and inspire optimism of using this vaccine in clinical conditions. A clinical trial of HBsAg-pulsed DC in patients with chronic hepatitis B is warranted.

Animals↗
PubMed2003

Change of acute hepatitis B transmission routes in Japan.

BACKGROUND: Many years have passed since various prophylactic policies for preventing hepatitis B virus (HBV) transmission were begun. We studied the chronological alterations in HBV infectious routes in patients with acute hepatitis B in the past 27 years. METHODS: Seventy-two patients with acute HBV infection who were admitted to our hospital during the period 1976 to 2002 were enrolled in this study. This study was divided into two periods (first period, 1976-1990; and second period, 1991-2002), and the HBV infectious routes were studied. RESULTS: Infectious routes have been changing. Posttransfusion hepatitis was seen only in the first period. In the second period, sexual transmission was the major infectious route (68%), followed by infection at a medical facility or occupational exposure such as needlestick injury (8%). CONCLUSIONS: Transmission from sexual contact has become the main infectious route of HBV in Japan.

Acute Disease↗
PubMed2003

Esophagogastric varices as a prognostic factor for the determination of clinical stage in patients with primary biliary cirrhosis.

BACKGROUND: Primary biliary cirrhosis (PBC) is usually classified as either asymptomatic PBC (a-PBC) or symptomatic PBC (s-PBC). Although the proportion of a-PBC versus s-PBC patients has been consistently increasing, it is not clear whether the present criteria for the staging of PBC are optimal or not. We investigated the clinical stage of PBC patients from the standpoint of esophagogastric varices (EGV). METHODS: One hundred and nine PBC patients were enrolled in this retrospective study. We investigated the clinical features of PBC based on laboratory data, histological stage, symptoms, and existence of EGV. In addition, the clinical course and prognosis in patients who were periodically followed up were also studied. RESULTS: (1) EGV was detected in a-PBC patients, and there was no difference in the grade of EGV between a-PBC and s-PBC patients. (2) a-PBC patients with EGV had more liver damage than those without EGV, and a-PBC patients with EGV had a poorer prognosis than those without EGV. (3) Three of 11 patients who progressed from a-PBC to s-PBC within 3 years had EGV. (4) One of 3 a-PBC patients with EGV had progressed to s-PBC at 3-year follow-up. CONCLUSIONS: These results indicate that EGV is one of the most important factors for evaluating PBC. Therefore, we would like to propose that a-PBC patients with EGV should either be included in the presently defined s-PBC class, or that new prognostic classes of PBC be created that include EGV as a prognostic factor.

Adult↗
PubMed2003

Complete genome sequence of hepatitis B virus (HBV) from a patient with fulminant hepatitis without precore and core promoter mutations: comparison with HBV from a patient with acute hepatitis infected from the same infectious source.

BACKGROUND/AIMS: There is a paucity of information regarding hepatitis B virus (HBV) from patients with fulminant hepatitis (FH) without precore (pre-C, nt 1896) and core promoter (CP, nt 1762, 1764) mutations. METHODS: Pre-C and CP mutations were studied in eight patients with FH and 26 patients with acute hepatitis (AH) due to HBV. One patient with FH (FH1) was infected with HBV without these mutations. Interestingly, the sera of the infectious source (IS1) and of a patient with AH (AH1) infected from IS1 were available. Complete HBV genomes from these three patients were analyzed. RESULTS: These mutations were found in seven of eight FH and five of 26 AH (P<0.01). HBV from FH1, IS1 and AH1 belonged to genotype D. Nucleotide difference between FH1 and AH1 was six of 3182 bases (nt 493, 998, 1173, 2928, 3067, and 3078). Two and five substitutions of deduced amino acid sequences were found in the pre-S1 and polymerase regions, respectively. The same nucleotide substitutions at nt 493, 1173, 2928 and 3067 were found in several patients with FH in our laboratory or GenBank. CONCLUSIONS: These six nucleotide substitutions of HBV DNA could be candidates of mutations relating to FH.

Acute Disease↗
PubMed2003

The effects of hepatitis B virus core promoter mutations on hepatitis B core antigen distribution in hepatocytes as detected by laser-assisted microdissection.

BACKGROUND/AIMS: The severity of liver damage in patients with chronic hepatitis B is dependent on several factors such as subcellular localization of hepatitis B core antigen (HBcAg) and mutation of hepatitis B virus (HBV) DNA. Here we studied the interrelationship between these two factors both in situ and in vitro. METHODS: Hepatocytes from liver biopsies showing expression of HBcAg only in the cytoplasm (n=6), only in the nucleus (n=4) and in both cytoplasms or nucleus of different hepatocytes (n=5) were picked up by laser-assisted microdissection and were checked for nucleotide sequences of core promoter region of HBV DNA. HepG2 and Huh7 cell lines transfected with wild and mutant HBV DNA were checked for localization of HBcAg. RESULTS: The frequencies of core promoter mutations at nucleotide (nt) 1762 and nt 1764 was significantly higher in hepatocytes with cytoplasmic expression of HBcAg compared to that of nuclear expression of HBcAg (P<0.05). Cytoplasmic expression of HBcAg was observed more frequently in HepG2 and Huh7 cells transfected with HBV mutant type (nt 1762 and 1764) than HBV wild type (P<0.05). CONCLUSIONS: Cytoplasmic localization of HBcAg was associated with HBV DNA mutations at nt 1762 and 1764.

Adolescent↗
PubMed2003

Diagnosis of drug-induced liver injury in Japanese patients by criteria of Consensus Meetings in Europe.

Eighty-five Japanese patients with drug-induced liver injury were assessed by criteria of Consensus Meetings in Europe on causality assessment of drug-induced liver injury. Histopathological investigation was performed for all patients to confirm the diagnosis. We divided these patients into two groups by the date of disease onset. Cases before 1989 were defined as past cases, and those after 1990 as recent cases, because the clinical-pathological characteristics of drug-induced liver injury have changed due to the ability to diagnose hepatitis C virus infection since 1990. Fifty-seven patients with drug-induced liver injury were enrolled as past cases, and 28 as recent cases. For past cases, the results of assessment by the criteria of Consensus Meetings in Europe were as follows: 'very likely': 14 patients (25%), 'likely': 23 patients (40%), 'possible': 15 patients (26%), 'dubious': five patients (9%), and 'unlikely': none (0%). For recent cases, the results were as follows: 'very likely': six patients (22%), 'likely': 14 patients (42%), 'possible': six patients (22%), 'dubious': two patients (7%), and 'unlikely': none (0%). There were no differences between the past and recent cases in distribution of assessment. More than 90% of patients were assessed as 'possible' or more, and the remaining seven patients were assessed as 'dubious'. No patients were assessed as 'unlikely'. Five of seven patients assessed as 'dubious' had long-term cholestasis, and two had alcohol consumption. These results indicated that the criteria of Consensus Meetings in Europe were useful for diagnosing drug-induced liver injury in Japanese patients.

Journal Article↗
PubMed2003

Specially designed needle-guide for intercostal puncture of hepatocellular carcinoma seen on computed tomography and not visualized on ultrasonography.

Ultrasound (US)-guided ethanol injection therapy is becoming popular as a therapeutic tool for treating hepatocellular carcinoma (HCC); however, there are some HCCs seen on computed tomography (CT) and not visualized on US. The aim of this study was to learn whether ethanol could be injected into such tumors correctly using a specially designed needle-guide for intercostal puncture on US. We developed a new needle-guide attachment for US. In vitro experiments were done with gelatin gel and porcine liver to evaluate the accuracy of the puncture depth. We calculated the difference between the distance from the surface to the needle tip and the set depth as errors. Fifteen patients with HCC in which CT revealed a tumor but US did not were subjected to US-guided ethanol injection using this needle-guide, and the entry of ethanol into tumors was confirmed by subsequent enhanced CT. The errors were within 1.0 mm in the in vitro experiments using gelatin gel and porcine liver. In all HCC patients, ethanol was injected accurately. This new needle-guide may be useful for needle insertion to HCCs seen on CT and not visualized on US.

Journal Article↗