Yoshiaki Katano

Objectives The aim of this study was to evaluate the efficacy and indication of combination therapy with ribavirin plus peginterferon-alpha-2b in chronic hepatitis C virus (HCV) patients aged 65 years and older. Methods Five hundred and ninety-one consecutive HCV patients were treated with combination therapy. These patients were divided into elder patients (>= 65 years) (n=115) and younger patients (< 65 years) (n=476). The clinical characteristics, sustained virological response (SVR) rates and discontinuation rates were compared between the two groups. Results Compared with younger patients, baseline haemoglobin levels and baseline platelet counts were significantly lower (P < 0.0001, P=0.013 respectively) and fibrosis was more advanced in elderly patients (P=0.0310). Moreover, the SVR rate was significantly lower (37.4 vs. 51.5%; P=0.0067) while the combination therapy discontinuation rate was significantly higher (32.2 vs. 17.0%; P=0.0003) in elderly patients. A multivariate analysis revealed that HCV load and genotype were significantly associated with an SVR in elderly patients. An SVR was achieved in over 50% of elderly male patients with genotype 1 and HCV RNA concentrations under 2 000 000 IU/ml. In contrast, the SVR rate was under 30% in elderly male patients with genotype 1 and with HCV RNA concentrations over 2 000 000 IU/ml and in all elderly female patients with genotype 1. Conclusions The SVR rate was lower in elderly patients than in younger patients. However, in elderly patients combination therapy was most beneficial for genotype 1 patients, male patients with HCV RNA concentrations < 2 000 000 IU/ml and patients with genotype 2.

Objectives The aim of this study was to evaluate the efficacy and indication of combination therapy with ribavirin plus peginterferon-alpha-2b in chronic hepatitis C virus (HCV) patients aged 65 years and older. Methods Five hundred and ninety-one consecutive HCV patients were treated with combination therapy. These patients were divided into elder patients (>= 65 years) (n=115) and younger patients (< 65 years) (n=476). The clinical characteristics, sustained virological response (SVR) rates and discontinuation rates were compared between the two groups. Results Compared with younger patients, baseline haemoglobin levels and baseline platelet counts were significantly lower (P < 0.0001, P=0.013 respectively) and fibrosis was more advanced in elderly patients (P=0.0310). Moreover, the SVR rate was significantly lower (37.4 vs. 51.5%; P=0.0067) while the combination therapy discontinuation rate was significantly higher (32.2 vs. 17.0%; P=0.0003) in elderly patients. A multivariate analysis revealed that HCV load and genotype were significantly associated with an SVR in elderly patients. An SVR was achieved in over 50% of elderly male patients with genotype 1 and HCV RNA concentrations under 2 000 000 IU/ml. In contrast, the SVR rate was under 30% in elderly male patients with genotype 1 and with HCV RNA concentrations over 2 000 000 IU/ml and in all elderly female patients with genotype 1. Conclusions The SVR rate was lower in elderly patients than in younger patients. However, in elderly patients combination therapy was most beneficial for genotype 1 patients, male patients with HCV RNA concentrations < 2 000 000 IU/ml and patients with genotype 2.

Primary copper toxicosis due to Wilson disease is clinically complex, often leading to delayed diagnosis. Because the metabolic disorder is frequently complicated by iron overload due to hypoceruloplasminemia, either a special stain or microanalysis has been recommended for liver biopsy specimens. Liver biopsy was performed in three patients in whom Wilson disease was highly suspected. Light microscopic study included rubeanic acid stain for copper and Berlin blue stain for iron. To improve the resolution of ultra-structures and preservation of toxic metals, short-term fixation with a 0.1% osmic acid solution was applied for X-ray probe microanalysis. Their diagnosis was confirmed by genetic study and copper chelation therapy. Two patients at the age of 17 and 23 years, respectively, demonstrated cirrhotic livers surrounded by fibrous septa, while a 7-year-old patient demonstrated fatty liver with mildly expanded portal tracts. Both copper grains stained with rubeanic acid and cuprothionein by microanalysis were found in the cirrhotic livers of aged patients. However, either morphological method failed to detect copper deposition in fatty liver tissues from the young patient. Iron deposits were also found in the cirrhotic livers of aged patients. The molecular basis of Wilson disease was confirmed by gene analysis. All patients responded to copper chelation therapy. A morphological method of special staining or microanalysis improved with a new fixative may be unreliable for detecting diffusely distributed copper in the early stage of Wilson liver disease.

Primary copper toxicosis due to Wilson disease is clinically complex, often leading to delayed diagnosis. Because the metabolic disorder is frequently complicated by iron overload due to hypoceruloplasminemia, either a special stain or microanalysis has been recommended for liver biopsy specimens. Liver biopsy was performed in three patients in whom Wilson disease was highly suspected. Light microscopic study included rubeanic acid stain for copper and Berlin blue stain for iron. To improve the resolution of ultra-structures and preservation of toxic metals, short-term fixation with a 0.1% osmic acid solution was applied for X-ray probe microanalysis. Their diagnosis was confirmed by genetic study and copper chelation therapy. Two patients at the age of 17 and 23 years, respectively, demonstrated cirrhotic livers surrounded by fibrous septa, while a 7-year-old patient demonstrated fatty liver with mildly expanded portal tracts. Both copper grains stained with rubeanic acid and cuprothionein by microanalysis were found in the cirrhotic livers of aged patients. However, either morphological method failed to detect copper deposition in fatty liver tissues from the young patient. Iron deposits were also found in the cirrhotic livers of aged patients. The molecular basis of Wilson disease was confirmed by gene analysis. All patients responded to copper chelation therapy. A morphological method of special staining or microanalysis improved with a new fixative may be unreliable for detecting diffusely distributed copper in the early stage of Wilson liver disease.

Objectives: Dendritic cell (DC) therapy frequently induces a measurable immune response. However clinical responses are seen in a minority of patients, presumably due to insufficient expansion of antigen-specific cytotoxic T lymphocytes (CTLs) capable of eradicating tumor cells. To increase therapeutic efficacy of DC-based vaccination, we have undertaken the first clinical trial involving a combination therapy of gemcitabine (GEM) with immunotherapy for patients with inoperable locally advanced pancreatic cancer. Methods: Patients (n = 5) received the treatment course, which consisted of intravenous GEM administration at 1000 mg/m(2) (day 1) and the endoscopic ultrasound-guided fine-needle injection of OK432-pulsed DCs into a tumor, followed by intravenous infusion of lymphokine-activated killer cells stimulated with anti-CD3 monoclonal antibody (CD3-LAKs) (day 4), at 2-week intervals. Results: No serious treatment-related adverse events were observed during the study period. Three of the 5 patients demonstrated effective responses to this clinical trial; 1 had partial remission and 2 had long stable disease more than 6 months. In the patient with partial remission, it has been shown that DC-based vaccination combined with GEM administration induces tumor antigen-specific CTLs. Conclusion: This combined therapy was considered to be synergistically effective and may have a role in the therapy of pancreatic cancer for inducing tumor antigen-specific CTLs.

Objectives: Dendritic cell (DC) therapy frequently induces a measurable immune response. However clinical responses are seen in a minority of patients, presumably due to insufficient expansion of antigen-specific cytotoxic T lymphocytes (CTLs) capable of eradicating tumor cells. To increase therapeutic efficacy of DC-based vaccination, we have undertaken the first clinical trial involving a combination therapy of gemcitabine (GEM) with immunotherapy for patients with inoperable locally advanced pancreatic cancer. Methods: Patients (n = 5) received the treatment course, which consisted of intravenous GEM administration at 1000 mg/m(2) (day 1) and the endoscopic ultrasound-guided fine-needle injection of OK432-pulsed DCs into a tumor, followed by intravenous infusion of lymphokine-activated killer cells stimulated with anti-CD3 monoclonal antibody (CD3-LAKs) (day 4), at 2-week intervals. Results: No serious treatment-related adverse events were observed during the study period. Three of the 5 patients demonstrated effective responses to this clinical trial; 1 had partial remission and 2 had long stable disease more than 6 months. In the patient with partial remission, it has been shown that DC-based vaccination combined with GEM administration induces tumor antigen-specific CTLs. Conclusion: This combined therapy was considered to be synergistically effective and may have a role in the therapy of pancreatic cancer for inducing tumor antigen-specific CTLs.

The interferon sensitivity-determining region (ISDR) is thought to be inhibited by the double-stranded RNA-dependent protein kinase (PKR). Several studies have reported a relationship between the ISDR and interferon (IFN) responsiveness. However, this relationship is controversial. The aim of this study was to investigate whether genomic heterogeneity of the ISDR among patients with hepatitis C virus (HCV) genotype 2a affects the response to pegylated-IFN-alpha 2a monotherapy. Eighty patients (47 men, 33 women; mean age: 54.2 +/- 12.9 years) infected with HCV genotype 2a were evaluated. HCV viral loads were determined by real-time PCR. The ISDR (amino acids 2193-2228) was examined by direct sequencing. Thirty-one patients received subcutaneous injections of pegylated-IFN-alpha 2a (180 mu g) once weekly for 24 weeks, and 35 patients received injections for 48 weeks. Fourteen patients withdrew from treatment. Of the remaining 66 patients, 51 (77.3%) showed a sustained virologic response. Factors related to sustained virologic response on multivariate analysis were rapid virologic response (negative HCV at 4 weeks; odds ratio: 0.033; 95% confidence interval (95% Cl) 0.003-0.363; P = 0.0052) and the number of mutations in the ISDR (odds ratio: 0.025; 95% Cl 0.001-0.476; P = 0.0141). There were no significant differences in other factors, including sex, age, aspartate aminotransferase, alanine aminotransferase, platelet count, duration of treatment, and HCV viral load. Rapid virologic response and the ISDR sequence variations are significantly associated with response to pegylated-IFN-alpha 2a monotherapy in Japanese patients with HCV genotype 2a. J. Med. Virol. 81:459-466,2009. (C) 2009 Wiley-Liss, Inc.

Objectives: Pancreatic cystic (PC) lesions are not necessarily rare, and it is important to diagnose whether PC lesions are neoplastic such as intraductal papillary mucinous neoplasm (IPMN) because of its malignant potential. Reports on PC lesions in hemodialysis (HD) patients are remarkably limited. The aim of this study was to clarify the prevalence and characteristics of PC lesions in HD patients. Methods: We reviewed 1012 consecutive HD patients and 11,100 patients (controls) without renal disease who underwent transabdominal ultrasonography between January 2003 and December 2005. Patients' sex ratio (female-to-male) was less, and the age was older in HD patients. Clinical findings of these patients were examined. Results: The prevalence both of PC lesions and IPMNs was significantly higher in HD patients than in controls (9.3% vs 1.3% and 2.8% vs 0.2%, P < 0.0001). The incidence of IPMNs in HD patients with PC lesions was higher than that in controls with PC lesions (29.8% vs 17.0%, P = 0.021). Multivariate logistic regression analysis revealed that the odds ratios of PC lesions and IPMNs were 6.38 (95% confidence interval, 4.82-8.45) and 9.39 (95% confidence interval, 5.36-16.49) in HD patients compared with controls. Conclusion: The prevalence of PC lesions in HD patients is higher, and HD patients with PC lesions have high prevalence of IPMNs.

Ursodeoxycholic acid (UDCA) is widely recognized as an effective compound in the treatment of chronic hepatitis and is known to modulate the redox state of the liver accompanied by an increase of GSH. In the present study, to access the antioxidative effect of UDCA and to clarify the molecular basis of the action on GSH level, we evaluated its effects in HepG2 cells exposed to excessive iron. UDCA inhibited both a decrease in the GSH level and an increase in the reactive oxygen species caused by excessive iron in the cells. UDCA increased the gene expression of the catalytic-and modifier-units of glutamine-cysteine ligase (GCL), which is a key enzyme in GSH synthesis. we further investigated the effect of UDCA on the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, and obtained results showing that UDCA-induced increase in the GSH level was prevented by LY294002, a PI3K inhibitor. In addition, Western blot analysis of Akt showed that, while the total Akt level remained unchanged, the phosphorylated Akt level was increased by UDCA, and this increase was also prevented by LY294002. Moreover, UDCA promoted the translocation of a transcription factor, nuclear factor-E2-related factor-2(Nrf2), into the nucleus, and this action was inhibited by LY294002. From these results, it was indicated that UDCA increased the GSH synthesis through an activation of the PI3K/Akt/Nrf2 pathway. This may be a primary mechanism of antioxidative action of UDCA concerned with its therapeutic effectiveness in chronic hepatitis. (C) 2008 Elsevier Inc. All rights reserved.

Background/Aims: Although the efficacy and safety of pegylated-interferon (PEG-IFN) alpha-2a and PEG-IFN alpha-2b have been comparatively studied, there are few study results available in which the two PEG-IFN products were strictly compared. To compare the effects of two PEG-IFN products on blood cell profile. Methodology: The time-course change in blood cell counts was compared between chronic hepatitis C patients with genotype 1b receiving PEG-IFN alpha-2a/ribavirin and PEG-IFN alpha-2b/ribavirin combination therapy. The comparison was made after matching patients from the two groups based on ribavirin apparent clearance (CL/F), a surrogate marker of the steady state blood ribavirin level, in order to eliminate the effect of ribavirin. Fifteen pairs of matched patients were selected. Results: The time-course change in hemoglobin did not differ significantly between the two groups. However, significantly greater reductions in both neutrophil and platelet counts were observed with PEG-IFN alpha-2a compared to PEG-IFN alpha-2b. A slightly longer period was required with PEG-IFN alpha-2a than with PEG-IFN alpha-2b for a reduction in neutrophil or platelet count large enough to necessitate dose reduction. Conclusions: Two types of PEG-IFN products affected the blood cell profile in different manners. Long-term monitoring of laboratory test values is necessary with PEG-TFN alpha-2a.

The interferon sensitivity-determining region (ISDR) is thought to be inhibited by the double-stranded RNA-dependent protein kinase (PKR). Several studies have reported a relationship between the ISDR and interferon (IFN) responsiveness. However, this relationship is controversial. The aim of this study was to investigate whether genomic heterogeneity of the ISDR among patients with hepatitis C virus (HCV) genotype 2a affects the response to pegylated-IFN-alpha 2a monotherapy. Eighty patients (47 men, 33 women; mean age: 54.2 +/- 12.9 years) infected with HCV genotype 2a were evaluated. HCV viral loads were determined by real-time PCR. The ISDR (amino acids 2193-2228) was examined by direct sequencing. Thirty-one patients received subcutaneous injections of pegylated-IFN-alpha 2a (180 mu g) once weekly for 24 weeks, and 35 patients received injections for 48 weeks. Fourteen patients withdrew from treatment. Of the remaining 66 patients, 51 (77.3%) showed a sustained virologic response. Factors related to sustained virologic response on multivariate analysis were rapid virologic response (negative HCV at 4 weeks; odds ratio: 0.033; 95% confidence interval (95% Cl) 0.003-0.363; P = 0.0052) and the number of mutations in the ISDR (odds ratio: 0.025; 95% Cl 0.001-0.476; P = 0.0141). There were no significant differences in other factors, including sex, age, aspartate aminotransferase, alanine aminotransferase, platelet count, duration of treatment, and HCV viral load. Rapid virologic response and the ISDR sequence variations are significantly associated with response to pegylated-IFN-alpha 2a monotherapy in Japanese patients with HCV genotype 2a. J. Med. Virol. 81:459-466,2009. (C) 2009 Wiley-Liss, Inc.

Objectives: Pancreatic cystic (PC) lesions are not necessarily rare, and it is important to diagnose whether PC lesions are neoplastic such as intraductal papillary mucinous neoplasm (IPMN) because of its malignant potential. Reports on PC lesions in hemodialysis (HD) patients are remarkably limited. The aim of this study was to clarify the prevalence and characteristics of PC lesions in HD patients. Methods: We reviewed 1012 consecutive HD patients and 11,100 patients (controls) without renal disease who underwent transabdominal ultrasonography between January 2003 and December 2005. Patients' sex ratio (female-to-male) was less, and the age was older in HD patients. Clinical findings of these patients were examined. Results: The prevalence both of PC lesions and IPMNs was significantly higher in HD patients than in controls (9.3% vs 1.3% and 2.8% vs 0.2%, P < 0.0001). The incidence of IPMNs in HD patients with PC lesions was higher than that in controls with PC lesions (29.8% vs 17.0%, P = 0.021). Multivariate logistic regression analysis revealed that the odds ratios of PC lesions and IPMNs were 6.38 (95% confidence interval, 4.82-8.45) and 9.39 (95% confidence interval, 5.36-16.49) in HD patients compared with controls. Conclusion: The prevalence of PC lesions in HD patients is higher, and HD patients with PC lesions have high prevalence of IPMNs.

Ursodeoxycholic acid (UDCA) is widely recognized as an effective compound in the treatment of chronic hepatitis and is known to modulate the redox state of the liver accompanied by an increase of GSH. In the present study, to access the antioxidative effect of UDCA and to clarify the molecular basis of the action on GSH level, we evaluated its effects in HepG2 cells exposed to excessive iron. UDCA inhibited both a decrease in the GSH level and an increase in the reactive oxygen species caused by excessive iron in the cells. UDCA increased the gene expression of the catalytic-and modifier-units of glutamine-cysteine ligase (GCL), which is a key enzyme in GSH synthesis. we further investigated the effect of UDCA on the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, and obtained results showing that UDCA-induced increase in the GSH level was prevented by LY294002, a PI3K inhibitor. In addition, Western blot analysis of Akt showed that, while the total Akt level remained unchanged, the phosphorylated Akt level was increased by UDCA, and this increase was also prevented by LY294002. Moreover, UDCA promoted the translocation of a transcription factor, nuclear factor-E2-related factor-2(Nrf2), into the nucleus, and this action was inhibited by LY294002. From these results, it was indicated that UDCA increased the GSH synthesis through an activation of the PI3K/Akt/Nrf2 pathway. This may be a primary mechanism of antioxidative action of UDCA concerned with its therapeutic effectiveness in chronic hepatitis. (C) 2008 Elsevier Inc. All rights reserved.

Background/Aims: Although the efficacy and safety of pegylated-interferon (PEG-IFN) alpha-2a and PEG-IFN alpha-2b have been comparatively studied, there are few study results available in which the two PEG-IFN products were strictly compared. To compare the effects of two PEG-IFN products on blood cell profile. Methodology: The time-course change in blood cell counts was compared between chronic hepatitis C patients with genotype 1b receiving PEG-IFN alpha-2a/ribavirin and PEG-IFN alpha-2b/ribavirin combination therapy. The comparison was made after matching patients from the two groups based on ribavirin apparent clearance (CL/F), a surrogate marker of the steady state blood ribavirin level, in order to eliminate the effect of ribavirin. Fifteen pairs of matched patients were selected. Results: The time-course change in hemoglobin did not differ significantly between the two groups. However, significantly greater reductions in both neutrophil and platelet counts were observed with PEG-IFN alpha-2a compared to PEG-IFN alpha-2b. A slightly longer period was required with PEG-IFN alpha-2a than with PEG-IFN alpha-2b for a reduction in neutrophil or platelet count large enough to necessitate dose reduction. Conclusions: Two types of PEG-IFN products affected the blood cell profile in different manners. Long-term monitoring of laboratory test values is necessary with PEG-TFN alpha-2a.

Objective: Hepatitis B virus (HBV) has been classified into 8 genotypes that have different geographic distributions. The clinical outcomes of acute hepatitis are dependent on genotype. The aim of this study was to investigate the distribution of HBV subgenotypes and basal core promoter (BCP)/precore (PC) regions in acute hepatitis patients in Central Vietnam to clarify the distributions and the clinical and virological differences. Methods: 27 patients with acute hepatitis B were studied. HBV subgenotypes and BCP/PC variants were determined by direct sequencing of the preS, BCP/PC regions, respectively. Results: HBV subgenotypes B4/Ba (n = 22) and C1/Cs (n = 5) were detected. Of the 27 patients, 3 developed fulminant hepatic failure, and all were infected with B4/Ba. Three patients had a BCP mutation, and 10 patients had a PC mutation in subgenotype B4/Ba. Three patients with C1/Cs had a BCP mutation. Two of 3 patients who progressed to fulminant hepatic failure had T1762, A1764, and A1896 simultaneously. None of the patients with acute, self-limited hepatitis carried these triple mutations. Conclusion: The prevalent HBV subgenotypes in patients with acute hepatitis B in Central Vietnam were B4/Ba and C1/Cs. BCP/PC variants have an association with the development of fulminant hepatic failure in subgenotype B4/Ba. Copyright (C) 2009 S. Karger AG, Basel

Objective: Hepatitis B virus (HBV) has been classified into 8 genotypes that have different geographic distributions. The clinical outcomes of acute hepatitis are dependent on genotype. The aim of this study was to investigate the distribution of HBV subgenotypes and basal core promoter (BCP)/precore (PC) regions in acute hepatitis patients in Central Vietnam to clarify the distributions and the clinical and virological differences. Methods: 27 patients with acute hepatitis B were studied. HBV subgenotypes and BCP/PC variants were determined by direct sequencing of the preS, BCP/PC regions, respectively. Results: HBV subgenotypes B4/Ba (n = 22) and C1/Cs (n = 5) were detected. Of the 27 patients, 3 developed fulminant hepatic failure, and all were infected with B4/Ba. Three patients had a BCP mutation, and 10 patients had a PC mutation in subgenotype B4/Ba. Three patients with C1/Cs had a BCP mutation. Two of 3 patients who progressed to fulminant hepatic failure had T1762, A1764, and A1896 simultaneously. None of the patients with acute, self-limited hepatitis carried these triple mutations. Conclusion: The prevalent HBV subgenotypes in patients with acute hepatitis B in Central Vietnam were B4/Ba and C1/Cs. BCP/PC variants have an association with the development of fulminant hepatic failure in subgenotype B4/Ba. Copyright (C) 2009 S. Karger AG, Basel

Background and Aim: Entecavir is a potent inhibitor of both wild-type and lamivudine-resistant hepatitis B virus (HBV) with proven clinical efficacy. We conducted a randomized, double-blind, multicenter study in Japan (ETV-052) evaluating the efficacy and safety of two doses of entecavir in adult patients with lamivudine-refractory chronic hepatitis B infection. Methods: Eighty-four patients with chronic hepatitis B who were refractory to lamivudine therapy were switched from lamivudine to daily oral doses of 0.5 mg entecavir (41 patients) or 1 mg entecavir (43 patients) for 52 weeks. Results: The proportions of patients achieving the primary end-point (>= 2 log(10) reduction in HBV-DNA from baseline by polymerase chain reaction assay or undetectable HBV-DNA levels [< 400 copies/mL] at week 48) were 90% and 93% for entecavir 0.5 mg and 1 mg, respectively, with 33% of patients in each dosing group achieving < 400 copies/mL. The mean reduction in HBV-DNA from baseline was 3.58 and 3.75 log(10) copies/mL for entecavir 0.5 mg and 1 mg, respectively. High proportions of patients achieved alanine aminotransferase normalization at week 48 (0.5 mg 86%, 1 mg 78%). Histological improvement was observed in most patients (0.5 mg 52%, 1 mg 60%). Virological breakthrough (increase in HBV-DNA of >= 1 log(10) copies/mL from nadir) was observed in one patient but was not associated with selection of entecavir-associated resistance substitutions. Entecavir was well tolerated, with no patients discontinuing study drug due to adverse events. Conclusions: These findings indicate that entecavir is safe and effective for the treatment of Japanese adults with lamivudine-refractory chronic hepatitis B.

Serum ribavirin concentration is an important factor in antiviral therapy in combination with peginterferon (PEG-IFN) and ribavirin for patients with chronic hepatitis C in terms of both beneficial and adverse effects. We evaluated whether the serum ribavirin concentration can be predicted on the basis of renal function estimates. Serum creatinine and cystatin C concentrations were measured at the start of treatment in a total of 148 patients with chronic hepatitis C who underwent combination PEG-IFN and ribavirin therapy. Creatinine clearance (CrCl) and total clearance of ribavirin (CL/F) were calculated on the basis of the serum creatinine level. The glomerular filtration rate was calculated with two different formulae on the basis of the serum cystatin C level. These values were compared with serum ribavirin concentrations 4 weeks after the start of therapy. The cystatin C level increased with the progression of liver fibrosis, whereas the creatinine level was constant regardless of the degree of liver fibrosis. Significant correlation was not observed between the serum ribavirin concentration and serum creatinine level, cystatin C level, or calculated renal function estimates. However, significant correlation was found between the serum ribavirin concentration and CrCl and CL/F in patients who were given ribavirin > 800 mg/day. Overall, renal function estimates do not correlate with the serum ribavirin concentration in Japanese patients with chronic hepatitis C who undergo combination PEG-IFN and ribavirin therapy. Serum creatinine-based renal function estimates might be predictive for the serum ribavirin concentration only in patients with a daily ribavirin intake of 800 mg or more.

Background and Aim: Entecavir is a potent inhibitor of both wild-type and lamivudine-resistant hepatitis B virus (HBV) with proven clinical efficacy. We conducted a randomized, double-blind, multicenter study in Japan (ETV-052) evaluating the efficacy and safety of two doses of entecavir in adult patients with lamivudine-refractory chronic hepatitis B infection. Methods: Eighty-four patients with chronic hepatitis B who were refractory to lamivudine therapy were switched from lamivudine to daily oral doses of 0.5 mg entecavir (41 patients) or 1 mg entecavir (43 patients) for 52 weeks. Results: The proportions of patients achieving the primary end-point (>= 2 log(10) reduction in HBV-DNA from baseline by polymerase chain reaction assay or undetectable HBV-DNA levels [< 400 copies/mL] at week 48) were 90% and 93% for entecavir 0.5 mg and 1 mg, respectively, with 33% of patients in each dosing group achieving < 400 copies/mL. The mean reduction in HBV-DNA from baseline was 3.58 and 3.75 log(10) copies/mL for entecavir 0.5 mg and 1 mg, respectively. High proportions of patients achieved alanine aminotransferase normalization at week 48 (0.5 mg 86%, 1 mg 78%). Histological improvement was observed in most patients (0.5 mg 52%, 1 mg 60%). Virological breakthrough (increase in HBV-DNA of >= 1 log(10) copies/mL from nadir) was observed in one patient but was not associated with selection of entecavir-associated resistance substitutions. Entecavir was well tolerated, with no patients discontinuing study drug due to adverse events. Conclusions: These findings indicate that entecavir is safe and effective for the treatment of Japanese adults with lamivudine-refractory chronic hepatitis B.

Serum ribavirin concentration is an important factor in antiviral therapy in combination with peginterferon (PEG-IFN) and ribavirin for patients with chronic hepatitis C in terms of both beneficial and adverse effects. We evaluated whether the serum ribavirin concentration can be predicted on the basis of renal function estimates. Serum creatinine and cystatin C concentrations were measured at the start of treatment in a total of 148 patients with chronic hepatitis C who underwent combination PEG-IFN and ribavirin therapy. Creatinine clearance (CrCl) and total clearance of ribavirin (CL/F) were calculated on the basis of the serum creatinine level. The glomerular filtration rate was calculated with two different formulae on the basis of the serum cystatin C level. These values were compared with serum ribavirin concentrations 4 weeks after the start of therapy. The cystatin C level increased with the progression of liver fibrosis, whereas the creatinine level was constant regardless of the degree of liver fibrosis. Significant correlation was not observed between the serum ribavirin concentration and serum creatinine level, cystatin C level, or calculated renal function estimates. However, significant correlation was found between the serum ribavirin concentration and CrCl and CL/F in patients who were given ribavirin > 800 mg/day. Overall, renal function estimates do not correlate with the serum ribavirin concentration in Japanese patients with chronic hepatitis C who undergo combination PEG-IFN and ribavirin therapy. Serum creatinine-based renal function estimates might be predictive for the serum ribavirin concentration only in patients with a daily ribavirin intake of 800 mg or more.

The branched-chain alpha-keto acid dehydrogenase (BCKDH) complex is the most important regulatory enzyme in branched-chain amino acid (BCAA) catabolism. We examined the regulation of hepatic BCKDH complex activity in spontaneous type 2 diabetes Otsuka Long-Evans Tokushima Fatty (OLETF) rats and Zucker diabetic fatty rats. Hepatic BCKDH complex activity in these rats was significantly lower than in corresponding control rats. The amount of BCKDH complex in OLETF rats corresponded to the total activity of the complex. Activity and abundance of the bound form of BCKDH kinase, which is responsible for inactivation of the complex, showed an inverse correlation to BCKDH complex activity in OLETF rats. Dietary supplementation of 5% BCAAs for 10 weeks markedly increased BCKDH complex activity, and decreased the activity and bound form of BCKDH kinase in the rats. These results suggest that BCAA catabolism in type 2 diabetes is downregulated and enhanced by BCAA supplementation. (C) 2008 Elsevier Inc. All rights reserved.

The branched-chain alpha-keto acid dehydrogenase (BCKDH) complex is the most important regulatory enzyme in branched-chain amino acid (BCAA) catabolism. We examined the regulation of hepatic BCKDH complex activity in spontaneous type 2 diabetes Otsuka Long-Evans Tokushima Fatty (OLETF) rats and Zucker diabetic fatty rats. Hepatic BCKDH complex activity in these rats was significantly lower than in corresponding control rats. The amount of BCKDH complex in OLETF rats corresponded to the total activity of the complex. Activity and abundance of the bound form of BCKDH kinase, which is responsible for inactivation of the complex, showed an inverse correlation to BCKDH complex activity in OLETF rats. Dietary supplementation of 5% BCAAs for 10 weeks markedly increased BCKDH complex activity, and decreased the activity and bound form of BCKDH kinase in the rats. These results suggest that BCAA catabolism in type 2 diabetes is downregulated and enhanced by BCAA supplementation. (C) 2008 Elsevier Inc. All rights reserved.

Background. In endemic areas, including Japan, basal core promoter (BCP) and precore (PC) variants of hepatitis B virus (HBV) have been reported to be associated with the clinical outcome of acute hepatitis B patients. However, the associations of BCP/PC variants with clinical outcomes have not been observed in nonendemic areas. HBV subgenotypes, which show geographic variations in prevalence, may underlie this discrepancy in clinical outcomes. Little is known about the differences in the clinical and virological features of HBV subgenotypes and BCP/PC variants. The aim of this study was to investigate the distributions of subgenotypes and BCP/PC variants to identify clinical differences in acute hepatitis B patients. Methods. One hundred thirty-nine patients with acute hepatitis were enrolled. Nested polymerase chain reaction was used to amplify the pre-S region of HBV for genotyping and the BCP/PC regions for variant screening. Results. HBV subgenotypes A1 (n = 3), A2 (n = 28), B1 (n = 3), B2 (n = 9), C1 (n = 5), C2 (n = 84), C variant (n = 1), D2 (n = 3), and H (n = 3) were detected. BCP/PC variants were not associated with progression to chronic hepatitis. Patients infected with subgenotype C2 who progressed to fulminant hepatic failure frequently carried variants at nucleotides non-T1753 and non-T1754 and T1762, A1764, and A1896. Conclusions. BCP/PC variants would be associated with progression to fulminant hepatitis in subgenotype C2. Knowledge of HBV subgenotypes and BCP/PC variants is useful for developing strategies to treat acute hepatitis B patients.

Background. In endemic areas, including Japan, basal core promoter (BCP) and precore (PC) variants of hepatitis B virus (HBV) have been reported to be associated with the clinical outcome of acute hepatitis B patients. However, the associations of BCP/PC variants with clinical outcomes have not been observed in nonendemic areas. HBV subgenotypes, which show geographic variations in prevalence, may underlie this discrepancy in clinical outcomes. Little is known about the differences in the clinical and virological features of HBV subgenotypes and BCP/PC variants. The aim of this study was to investigate the distributions of subgenotypes and BCP/PC variants to identify clinical differences in acute hepatitis B patients. Methods. One hundred thirty-nine patients with acute hepatitis were enrolled. Nested polymerase chain reaction was used to amplify the pre-S region of HBV for genotyping and the BCP/PC regions for variant screening. Results. HBV subgenotypes A1 (n = 3), A2 (n = 28), B1 (n = 3), B2 (n = 9), C1 (n = 5), C2 (n = 84), C variant (n = 1), D2 (n = 3), and H (n = 3) were detected. BCP/PC variants were not associated with progression to chronic hepatitis. Patients infected with subgenotype C2 who progressed to fulminant hepatic failure frequently carried variants at nucleotides non-T1753 and non-T1754 and T1762, A1764, and A1896. Conclusions. BCP/PC variants would be associated with progression to fulminant hepatitis in subgenotype C2. Knowledge of HBV subgenotypes and BCP/PC variants is useful for developing strategies to treat acute hepatitis B patients.

Objective: We investigated the prevalence of antibody against hepatitis E virus (HEV) in Japanese patients with hemophilia. Methods: IgG antibody against HEV was measured in serum of 80 Japanese patients with hemophilia by enzyme-linked immunosorbent assay. The prevalence of HEV antibody was compared with the reported prevalence of HEV antibody in Japanese patients undergoing hemodialysis and in Japanese healthy blood donors. Characteristics of patients and coinfection with other transfusion-transmissible viruses were compared in patients with and without HEV antibody. Results: Anti-HEV IgG antibody was detected in 13 of 80 patients (16.3%). The prevalence was far higher than that reported in Japanese blood donors (3.7%) and was higher than that in Japanese patients undergoing hemodialysis (9.4%). The patients with HEV antibody were significantly older than those without. HEV antibody was not detected in patients ! 20 years of age and in patients who had received only virus-inactivated coagulation factors. No association was observed between positivity for anti-HEV antibody and severity of hemophilia or coinfection with other parenterally transmissible viruses. Conclusion: Our results suggest that the parenteral transmission of HEV may have occurred in Japanese patients with hemophilia via non-virus inactivated coagulation factors. Copyright (c) 2008 S. Karger AG, Basel.

Background Consideration of the prognosis of patients with liver cirrhosis is important when determining the appropriate timing of liver transplantation. Especially in Japan, where 99% of liver transplants are from living donors, timing is very important not only for the patient but also for the family, who need time to consider the various factors involved in living donations. Methods. To clarify the applicability of the Model for End-Stage Liver Disease (MELD) score in Japanese patients with cirrhosis, changes in the MELD score over 24 months were reviewed in 79 patients with cirrhosis who subsequently died of liver failure (n = 33) or who survived 24 months (n = 46). All patients had Child class B or C cirrhosis at the start of follow-up. We also compared their survival with that of 30 patients treated by living donor liver transplantation (LDLT) in our institute to determine the proper timing of transplantation in patients with cirrhosis. Results. Significant stratification of survival curves was observed for MELD scores of < 12, 12-15, 15-18, and > 18 (P = 0.0018). A significant survival benefit of LDLT was observed in patients with MELD score >= 15 (P = 0.0181.), and significantly more risk with transplantation was observed in those with MELD score < 15 compared with that of patients in whom the disease followed its natural course (P = 0.0168). Conclusions. MELD score is useful for predicting 1-year survival in Japanese patients with cirrhosis. MELD scores of 15 had discriminatory value for indicating a survival benefit to be gained by liver transplantation and thus can be used to help patients and their families by identifying patients who would benefit from LDLT.

Objective: We investigated the prevalence of antibody against hepatitis E virus (HEV) in Japanese patients with hemophilia. Methods: IgG antibody against HEV was measured in serum of 80 Japanese patients with hemophilia by enzyme-linked immunosorbent assay. The prevalence of HEV antibody was compared with the reported prevalence of HEV antibody in Japanese patients undergoing hemodialysis and in Japanese healthy blood donors. Characteristics of patients and coinfection with other transfusion-transmissible viruses were compared in patients with and without HEV antibody. Results: Anti-HEV IgG antibody was detected in 13 of 80 patients (16.3%). The prevalence was far higher than that reported in Japanese blood donors (3.7%) and was higher than that in Japanese patients undergoing hemodialysis (9.4%). The patients with HEV antibody were significantly older than those without. HEV antibody was not detected in patients ! 20 years of age and in patients who had received only virus-inactivated coagulation factors. No association was observed between positivity for anti-HEV antibody and severity of hemophilia or coinfection with other parenterally transmissible viruses. Conclusion: Our results suggest that the parenteral transmission of HEV may have occurred in Japanese patients with hemophilia via non-virus inactivated coagulation factors. Copyright (c) 2008 S. Karger AG, Basel.

Background Consideration of the prognosis of patients with liver cirrhosis is important when determining the appropriate timing of liver transplantation. Especially in Japan, where 99% of liver transplants are from living donors, timing is very important not only for the patient but also for the family, who need time to consider the various factors involved in living donations. Methods. To clarify the applicability of the Model for End-Stage Liver Disease (MELD) score in Japanese patients with cirrhosis, changes in the MELD score over 24 months were reviewed in 79 patients with cirrhosis who subsequently died of liver failure (n = 33) or who survived 24 months (n = 46). All patients had Child class B or C cirrhosis at the start of follow-up. We also compared their survival with that of 30 patients treated by living donor liver transplantation (LDLT) in our institute to determine the proper timing of transplantation in patients with cirrhosis. Results. Significant stratification of survival curves was observed for MELD scores of < 12, 12-15, 15-18, and > 18 (P = 0.0018). A significant survival benefit of LDLT was observed in patients with MELD score >= 15 (P = 0.0181.), and significantly more risk with transplantation was observed in those with MELD score < 15 compared with that of patients in whom the disease followed its natural course (P = 0.0168). Conclusions. MELD score is useful for predicting 1-year survival in Japanese patients with cirrhosis. MELD scores of 15 had discriminatory value for indicating a survival benefit to be gained by liver transplantation and thus can be used to help patients and their families by identifying patients who would benefit from LDLT.

Aim: The aim of this study was to determine whether antiviral therapy with lamivudine is beneficial in patients after initial treatment for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Methods: Forty-nine consecutive patients with HBV-related HCC completely treated by hepatic resection or radiofrequency ablation were retrospectively enrolled in this study. Comparison was made between 16 patients who received lamivudine therapy at a dose of 100 mg/day after treatment for HCC (lamivudine group) and 33 patients who did not (control group) in terms of changes in remnant liver function, HCC recurrence and survival. Results: Cumulative recurrence rates of HCC did not significantly differ between the two groups (P = 0.622). However, median Child-Pugh score at the time of HCC recurrence was significantly different; 5 (range 5-6) in the lamivudine group versus 7 (range 5-12) in the control group (P = 0.005). All patients in the lamivudine group were able to receive curative treatment for recurrent HCC. In contrast, 10 of 15 patients in the control group were unable to receive curative optimal therapy for recurrent HCC due to deterioration of remnant liver function. The cumulative survival rates of patients in the lamivudine group tended to be higher than those of patients in the control group (P = 0.063). Conclusion: It is suggested that lamivudine therapy is beneficial for patients after initial treatment for HBV-related HCC because it contributes to improving remnant liver function, thus decreasing the risk of liver failure and increasing the chances of receiving available treatment modalities for recurrent HCC.

Aim: The aim of this study was to determine whether antiviral therapy with lamivudine is beneficial in patients after initial treatment for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Methods: Forty-nine consecutive patients with HBV-related HCC completely treated by hepatic resection or radiofrequency ablation were retrospectively enrolled in this study. Comparison was made between 16 patients who received lamivudine therapy at a dose of 100 mg/day after treatment for HCC (lamivudine group) and 33 patients who did not (control group) in terms of changes in remnant liver function, HCC recurrence and survival. Results: Cumulative recurrence rates of HCC did not significantly differ between the two groups (P = 0.622). However, median Child-Pugh score at the time of HCC recurrence was significantly different; 5 (range 5-6) in the lamivudine group versus 7 (range 5-12) in the control group (P = 0.005). All patients in the lamivudine group were able to receive curative treatment for recurrent HCC. In contrast, 10 of 15 patients in the control group were unable to receive curative optimal therapy for recurrent HCC due to deterioration of remnant liver function. The cumulative survival rates of patients in the lamivudine group tended to be higher than those of patients in the control group (P = 0.063). Conclusion: It is suggested that lamivudine therapy is beneficial for patients after initial treatment for HBV-related HCC because it contributes to improving remnant liver function, thus decreasing the risk of liver failure and increasing the chances of receiving available treatment modalities for recurrent HCC.

Aim: Studies of animal models have determined that liver regeneration after partial hepatectomy is mediated by a various cytokines. The aim of the present study was to evaluate the levels of these cytokines and subsets of circulating lymphocytes in healthy humans after partial hepatectomy. Methods: Four individuals underwent partial hepatectomy for living-related donor liver transplantation. We also evaluated for comparison, three patients with myoma uteri who underwent hysterectomy. Blood samples were obtained before surgery and on postoperative days (PD) 1, 3, and 7. Serum levels of hepatocyte growth factor, interleukin (IL)-6, -10, and plasma levels of transforming growth factor beta were measured. Results: Increased circulating levels of hepatocyte growth factor and transforming growth factor beta were observedafter hepatectomy. The levels of IL-6 and IL-10 peaked on PD 1. Circulating white blood cell counts increased remarkably, whereas lymphocyte count decreased particularly on PD 1 and 3. CD4/CD8 and T-helper cell (Th)1/Th2 ratios were still decreased on PD 7. The percentage of natural killer cells was increased on PD 1. Partial hepatectomy in healthy humans leads not only to decreased lymphocyte counts, but also to remarkable changes in lymphocyte subsets. Conclusions: These findings suggest that immune suppression after partial hepatectomy involves decreases in CD4(+) helper T cells, particularly Th1 cells.

Aim: Studies of animal models have determined that liver regeneration after partial hepatectomy is mediated by a various cytokines. The aim of the present study was to evaluate the levels of these cytokines and subsets of circulating lymphocytes in healthy humans after partial hepatectomy. Methods: Four individuals underwent partial hepatectomy for living-related donor liver transplantation. We also evaluated for comparison, three patients with myoma uteri who underwent hysterectomy. Blood samples were obtained before surgery and on postoperative days (PD) 1, 3, and 7. Serum levels of hepatocyte growth factor, interleukin (IL)-6, -10, and plasma levels of transforming growth factor beta were measured. Results: Increased circulating levels of hepatocyte growth factor and transforming growth factor beta were observedafter hepatectomy. The levels of IL-6 and IL-10 peaked on PD 1. Circulating white blood cell counts increased remarkably, whereas lymphocyte count decreased particularly on PD 1 and 3. CD4/CD8 and T-helper cell (Th)1/Th2 ratios were still decreased on PD 7. The percentage of natural killer cells was increased on PD 1. Partial hepatectomy in healthy humans leads not only to decreased lymphocyte counts, but also to remarkable changes in lymphocyte subsets. Conclusions: These findings suggest that immune suppression after partial hepatectomy involves decreases in CD4(+) helper T cells, particularly Th1 cells.

Hepatitis B virus (HBV) has been classified into eight genotypes and can be further divided into several subgenotypes that have different geographic distributions. Because of increased human migration, the prevalence of rare subgenotypes is increasing in Japanese patients with acute hepatitis B. Lamivudine-resistant strains of HBV have begun to emerge in association with chronic hepatitis B. The aim of this study was to investigate the distribution of HBV subgenotypes and lamivudine-resistant strains in patients in Japan with acute hepatitis B. One hundred twenty-three patients with acute hepatitis B and 123 with chronic hepatitis B were studied. HBV subgenotypes and lamivudine-resistance mutations were determined by direct sequencing of the preS and polymerase region, respectively. HBV subgenotypes Aa (n = 3), Ae (n = 23), Ba (n = 7), Bi (n = 3), Cs (n = 7), Ce (n = 76), D (n = 2), and H (n = 2) were detected in patients with acute hepatitis. In patients with chronic hepatitis, HBV subgenotypes Ae (n = 4), Ba (n = 1), Bj (n = 18), and Ce (n = 100) were found. Non-common Japanese subgenotypes, that is, non-Bj and non-Ce, were detected more frequently in patients with acute hepatitis (35.8%) than in patients with chronic hepatitis (4.1%) (Odds ratio, 0.076; 95% Cl, 0.029-0.200; P < 0.0001). Lamivudine-resistance mutations were detected in chronic hepatitis patients with breakthrough hepatitis but not in other patients. In conclusion, the prevalence of uncommon Japanese HBV subgenotypes is expected to increase, although larnivudine-resistant strains have not yet been found in patients with acute hepatitis B.

Background/Aims: The 5'-untranslated region (5'UTR) of hepatitis C virus (HCV) is a useful region for determinations of genotype and viral load. 5'UTR can be used for simultaneous analysis of HCV genotype and viral load, therefore several assays have been described. A method which used direct sequencing of the 5'UTR can also be used to identify mutations in this region. The objective of the present study was to evaluate possible associations of 5'UTR mutations with responsiveness to interferon (IFN) therapy in chronic hepatitis C patients. Methodology: Seventy patients with chronic hepatitis C were included in this study. The relations between responsiveness to IFN therapy and HCV genotype, viral load, and 5'UTR mutations before IFN treatment were evaluated. Results: We detected HCV genotype la (n=5),1b (n=32), 2a (n=15), 2b (n=12), and 3a (n=6). Forty-eight patients were non-sustained responders (NR). Seven of 37 (18.9%) patients with the la or lb genotype were sustained responders (SR), and 14 of 27 (51.9%) patients with genotype 2a or 2b were SR. Responses of patients with genotype 1 were poorer than those of patients with genotype 2. HCV viral loads of all SR patients infected with genotype la or lb were less than 100 KIU/mL, but more than 50% of SR patients infected with genotype 2a or 2b bad viral loads over 100 KIU/mL. Thus, viral load in patients with genotype 1 is strongly associated with IFN sensitivity. 5'UTR were well conserved, and there were no differences in the distribution of genotypes between SR and NR. Conclusions: The 5'UTR is a suitable region for determining HCV genotype and viral load, which are predictors of responsiveness to IFN therapy, but specific mutations of the 5'UTR do not appear to be associated with responsiveness to IFN.

Hepatitis B virus (HBV) has been classified into eight genotypes and can be further divided into several subgenotypes that have different geographic distributions. Because of increased human migration, the prevalence of rare subgenotypes is increasing in Japanese patients with acute hepatitis B. Lamivudine-resistant strains of HBV have begun to emerge in association with chronic hepatitis B. The aim of this study was to investigate the distribution of HBV subgenotypes and lamivudine-resistant strains in patients in Japan with acute hepatitis B. One hundred twenty-three patients with acute hepatitis B and 123 with chronic hepatitis B were studied. HBV subgenotypes and lamivudine-resistance mutations were determined by direct sequencing of the preS and polymerase region, respectively. HBV subgenotypes Aa (n = 3), Ae (n = 23), Ba (n = 7), Bi (n = 3), Cs (n = 7), Ce (n = 76), D (n = 2), and H (n = 2) were detected in patients with acute hepatitis. In patients with chronic hepatitis, HBV subgenotypes Ae (n = 4), Ba (n = 1), Bj (n = 18), and Ce (n = 100) were found. Non-common Japanese subgenotypes, that is, non-Bj and non-Ce, were detected more frequently in patients with acute hepatitis (35.8%) than in patients with chronic hepatitis (4.1%) (Odds ratio, 0.076; 95% Cl, 0.029-0.200; P < 0.0001). Lamivudine-resistance mutations were detected in chronic hepatitis patients with breakthrough hepatitis but not in other patients. In conclusion, the prevalence of uncommon Japanese HBV subgenotypes is expected to increase, although larnivudine-resistant strains have not yet been found in patients with acute hepatitis B.

Background/Aims: The 5'-untranslated region (5'UTR) of hepatitis C virus (HCV) is a useful region for determinations of genotype and viral load. 5'UTR can be used for simultaneous analysis of HCV genotype and viral load, therefore several assays have been described. A method which used direct sequencing of the 5'UTR can also be used to identify mutations in this region. The objective of the present study was to evaluate possible associations of 5'UTR mutations with responsiveness to interferon (IFN) therapy in chronic hepatitis C patients. Methodology: Seventy patients with chronic hepatitis C were included in this study. The relations between responsiveness to IFN therapy and HCV genotype, viral load, and 5'UTR mutations before IFN treatment were evaluated. Results: We detected HCV genotype la (n=5),1b (n=32), 2a (n=15), 2b (n=12), and 3a (n=6). Forty-eight patients were non-sustained responders (NR). Seven of 37 (18.9%) patients with the la or lb genotype were sustained responders (SR), and 14 of 27 (51.9%) patients with genotype 2a or 2b were SR. Responses of patients with genotype 1 were poorer than those of patients with genotype 2. HCV viral loads of all SR patients infected with genotype la or lb were less than 100 KIU/mL, but more than 50% of SR patients infected with genotype 2a or 2b bad viral loads over 100 KIU/mL. Thus, viral load in patients with genotype 1 is strongly associated with IFN sensitivity. 5'UTR were well conserved, and there were no differences in the distribution of genotypes between SR and NR. Conclusions: The 5'UTR is a suitable region for determining HCV genotype and viral load, which are predictors of responsiveness to IFN therapy, but specific mutations of the 5'UTR do not appear to be associated with responsiveness to IFN.

The interferon sensitivity-determining region (ISDR) is useful as a predictive marker of the response to interferon (IFN) therapy for chronic hepatitis patients with a Japan-specific subtype (J-type) of hepatitis C virus (HCV) genotype 1b. This marker is not useful for predicting responsiveness of a worldwide subtype (W-type) of HCV 1b, which could explain the restricted usefulness of this system only to Japan. In the present study, we examined the predictive value of the ISDR for ribavirin combination therapy. A total of 79 patients with HCV 1b comprising 35 patients with J-type and 44 patients with W-type were treated with IFN in combination with ribavirin for more than 48 weeks. Mutations in the ISDR were detected more frequently often seen in J-type HCV 1b than in W-type; however, the sustained virological response (SVR) rate for the combination therapy was similar between the two subtypes. Multivariate analysis revealed that factors associated with SVR were IFN dose and the number of amino acid substitutions in ISDR but not with subtypes J and W. The correlation between the number of substitutions in ISDR and responses to IFN-ribavirin combination therapy was restricted to patients with J-type HCV 1b. The ISDR is a useful predictive marker for response to IFN-ribavirin combination therapy in J-type HCV.

The interferon sensitivity-determining region (ISDR) is useful as a predictive marker of the response to interferon (IFN) therapy for chronic hepatitis patients with a Japan-specific subtype (J-type) of hepatitis C virus (HCV) genotype 1b. This marker is not useful for predicting responsiveness of a worldwide subtype (W-type) of HCV 1b, which could explain the restricted usefulness of this system only to Japan. In the present study, we examined the predictive value of the ISDR for ribavirin combination therapy. A total of 79 patients with HCV 1b comprising 35 patients with J-type and 44 patients with W-type were treated with IFN in combination with ribavirin for more than 48 weeks. Mutations in the ISDR were detected more frequently often seen in J-type HCV 1b than in W-type; however, the sustained virological response (SVR) rate for the combination therapy was similar between the two subtypes. Multivariate analysis revealed that factors associated with SVR were IFN dose and the number of amino acid substitutions in ISDR but not with subtypes J and W. The correlation between the number of substitutions in ISDR and responses to IFN-ribavirin combination therapy was restricted to patients with J-type HCV 1b. The ISDR is a useful predictive marker for response to IFN-ribavirin combination therapy in J-type HCV.

Background: Recently genotype A which is rare in the patients in chronic hepatitis B (CHB) was frequently noted in patients with acute hepatitis B (AHB). To investigate their clinical and virological features, we studied the AHB patients in the past 5 years. Patients and Methods: 98 patients with AHB and 80 patients with CHB admitted to our hospital between 1998 and 2003 were studied. Results: Genotype A was not found in CHB but was frequently noted in AHB (p < 0.001). Comparison of the clinical features of acute hepatitis between the two major genotypes, A and C, homosexual and heterosexual with multiple partners were frequently seen among genotype A patients (p < 0.001). On the other hand, infection from steady partner showed a tendency to be more frequent in genotype C (p = 0.065). In genotype A, the levels of HBV-DNA on admission was higher (p = 0.007) and AHB has significantly more frequently progress to chronic infection than in genotype C (p = 0.028). Phylogenetic analysis of genotype A revealed that almost all strains from homosexual men belonged not to the African type A1 but to the Western type A2. Conclusions: Genotype A has increased recently among AHB in Japan. This fact may correlate to promiscuous intercourse in high risk group. Prophylactic efforts should be considered to prevent the prevailing of genotype A.

Background: Recently genotype A which is rare in the patients in chronic hepatitis B (CHB) was frequently noted in patients with acute hepatitis B (AHB). To investigate their clinical and virological features, we studied the AHB patients in the past 5 years. Patients and Methods: 98 patients with AHB and 80 patients with CHB admitted to our hospital between 1998 and 2003 were studied. Results: Genotype A was not found in CHB but was frequently noted in AHB (p < 0.001). Comparison of the clinical features of acute hepatitis between the two major genotypes, A and C, homosexual and heterosexual with multiple partners were frequently seen among genotype A patients (p < 0.001). On the other hand, infection from steady partner showed a tendency to be more frequent in genotype C (p = 0.065). In genotype A, the levels of HBV-DNA on admission was higher (p = 0.007) and AHB has significantly more frequently progress to chronic infection than in genotype C (p = 0.028). Phylogenetic analysis of genotype A revealed that almost all strains from homosexual men belonged not to the African type A1 but to the Western type A2. Conclusions: Genotype A has increased recently among AHB in Japan. This fact may correlate to promiscuous intercourse in high risk group. Prophylactic efforts should be considered to prevent the prevailing of genotype A.

Leucine stimulates protein synthesis by modulating the mammalian target of rapamycin (mTOR) signaling pathway. We hypothesized that promotion of the branched-chain amino acid (BCAA) catabolism might influence the leucine-induced protein synthesis. Clofibric acid (an active metabolite of clofibrate) is known to promote the BCAA catabolism by activation of branched-chain alpha-keto acid dehydrogenase complex (BCKDC), the rate-limiting enzyme of the BCAA catabolism. In the present study, we examined the phosphorylation state of mTOR, eukaryotic initiation factor 4E-binding protein-1 (4E-BP1), and ribosomal protein S6 kinase 1 (S6K1) in liver of rats with or without activation of the BCKDC by clofibrate treatment. Clofibrate-treated rats were prepared by oral administration of clofibrate 5 It before sacrifice. In order to stimulate phosphorylation of components in the mTOR signaling pathway, rats were orally administered with leucine I h before sacrifice. Clofibrate treatment almost fully activated hepatic BCKDC and significantly decreased the plasma leucine concentration in rats without leucine administration, resulting in decreased mTOR and 4E-BP1 phosphorylation. Similarly, in rats administered with leucine, clofibrate treatment attenuated the predicted increase in plasma leucine concentration as well as the phosphorylation of mTOR, 4E-BP1, and S6K1. These results suggest that BCAA catabolism enhanced by clofibrate treatment has significant influences on the leucine-induced activation of translation initiation processes. (c) 2006 Elsevier Inc. All rights reserved.

Leucine stimulates protein synthesis by modulating the mammalian target of rapamycin (mTOR) signaling pathway. We hypothesized that promotion of the branched-chain amino acid (BCAA) catabolism might influence the leucine-induced protein synthesis. Clofibric acid (an active metabolite of clofibrate) is known to promote the BCAA catabolism by activation of branched-chain alpha-keto acid dehydrogenase complex (BCKDC), the rate-limiting enzyme of the BCAA catabolism. In the present study, we examined the phosphorylation state of mTOR, eukaryotic initiation factor 4E-binding protein-1 (4E-BP1), and ribosomal protein S6 kinase 1 (S6K1) in liver of rats with or without activation of the BCKDC by clofibrate treatment. Clofibrate-treated rats were prepared by oral administration of clofibrate 5 It before sacrifice. In order to stimulate phosphorylation of components in the mTOR signaling pathway, rats were orally administered with leucine I h before sacrifice. Clofibrate treatment almost fully activated hepatic BCKDC and significantly decreased the plasma leucine concentration in rats without leucine administration, resulting in decreased mTOR and 4E-BP1 phosphorylation. Similarly, in rats administered with leucine, clofibrate treatment attenuated the predicted increase in plasma leucine concentration as well as the phosphorylation of mTOR, 4E-BP1, and S6K1. These results suggest that BCAA catabolism enhanced by clofibrate treatment has significant influences on the leucine-induced activation of translation initiation processes. (c) 2006 Elsevier Inc. All rights reserved.