Clinical Characteristics of Patients Infected with Hepatitis B Virus Genotypes A, B, and C

Journal of Gastroenterology. Jan, 2002  |  Pubmed ID: 11824798

The aim of the present study was to evaluate the clinical characteristics at first hospital consultation, according to the genotype of hepatitis B virus (HBV), in patients with chronic liver diseases and positivity for hepatitis B surface antigen (HBsAg) in metropolitan Tokyo.

Cholesterol is Increased in the Exofacial Leaflet of Synaptic Plasma Membranes of Human Apolipoprotein E4 Knock-in Mice

Neuroreport. Mar, 2002  |  Pubmed ID: 11930145

Inheritance of the apolipoprotein (apoE) epsilon4 allele is a risk factor for developing Alzheimer's disease (AD). The purpose of the present study was to determine effects of apoE-isoforms on the transbilayer distribution of cholesterol in synaptic plasma membranes (SPM) using mice expressing human apoE3 and apoE4. Total SPM cholesterol levels did not differ among the wild-type and apoE3 and apoE4 knock-in mice. However, a striking difference was observed in the transbilayer distribution of SPM cholesterol. ApoE4 knock-in mice showed an approximately 2-fold increase in exofacial leaflet cholesterol compared with apoE3 knock-in mice and wild-type mice. The results of this study suggest that pathogenic effects of apoE4 on AD development could be closely linked to alteration of cholesterol distribution in SPM.

A Network System of Medical and Welfare Information Service for the Patients, Their Families, Hospitals, Local Governments, and Commercial Companies in a Medical Service Area

Journal of Medical Systems. Jun, 2002  |  Pubmed ID: 12018611

A service information system using the Internet, which connected the various people who are related to medical treatment and nursing welfare, was constructed. An intractable neurological disease patient who lives in the Onga district, Fukuoka, Japan, and the people who are related to the service were chosen as test users in an experimental model. The communicated service information was divided into open-use data (electronic bulletin board, welfare service, medical care service, and link to private company service home page) and closed-use data (the individual patient's hysterics). The open data server was installed in an Internet service provider The open data could be accessed not only by the patient, but also by the family, information center, companies, hospitals, and nursing commodity store related to patient's nursing and medical treatment. Closed data server was installed in an information center (public health center). Only patient and information center staff can access the closed data. Patients should search and collect the service information of various medical and welfare services by themselves. Therefore, services prepared for the patient are difficult to know, and they cannot be sufficiently utilized. With the use of this information system, all usable service information became accessible, and patients could easily use it. The electronic bulletin board system (BBS) was used by patients for knowing each other or each others' family, and was used as a device for exchange of wisdom. Also, the questions for the specialist, such as doctor, dentist, teacher, physical therapist, care manager, welfare office staff member, and public health nurse, and the answers were shown on the BBS. By arranging data file, a reference of various patients in question and answer, which appeared in this BBS, was made as "advisory hints" and was added to the open data. The advisory hints became the new service information for the patients and their family. This BBS discovered the possibility of becoming an important information source for companies, hospital and, administration to know the requirements of patients and their families and the kind of services to be served. Although suppliers provide medical and welfare services for the patient, there is a tendency that the service information is sent by the suppliers at their own convenience. The information system in which various people participated was constructed in order to collect information for the patient, taking a patient-oriented approach. The result of the model test showed that this information system using Internet technology is a good system for both the service supplier and its receiver.

Apolipoprotein E (ApoE) Isoform-dependent Lipid Release from Astrocytes Prepared from Human ApoE3 and ApoE4 Knock-in Mice

The Journal of Biological Chemistry. Aug, 2002  |  Pubmed ID: 12042316

We have reported previously (Michikawa, M., Fan, Q.-W., Isobe, I., and Yanagisawa, K. (2000) J. Neurochem. 74, 1008-1016) that exogenously added recombinant human apolipoprotein E (apoE) promotes cholesterol release in an isoform-dependent manner. However, the molecular mechanism underlying this isoform-dependent promotion of cholesterol release remains undetermined. In this study, we demonstrate that the cholesterol release is mediated by endogenously synthesized and secreted apoE isoforms and clarify the mechanism underlying this apoE isoform-dependent cholesterol release using cultured astrocytes prepared from human apoE3 and apoE4 knock-in mice. Cholesterol and phospholipids were released into the culture media, resulting in the generation of two types of high density lipoprotein (HDL)-like particles; one was associated with apoE and the other with apoJ. The amount of cholesterol released into the culture media from the apoE3-expressing astrocytes was approximately 2.5-fold greater than that from apoE4-expressing astrocytes. In contrast, the amount of apoE3 released in association with the HDL-like particles was similar to that of apoE4, and the sizes of the HDL-like particles released from apoE3- and apoE4-expressing astrocytes were similar. The molar ratios of cholesterol to apoE in the HDL fraction of the culture media of apoE3- and apoE4-expressing astrocytes were 250 +/- 6.0 and 119 +/- 5.1, respectively. These data indicate that apoE3 has an ability to generate similarly sized lipid particles with less number of apoE molecules than apoE4, suggesting that apoE3-expressing astrocytes can supply more cholesterol to neurons than apoE4-expressing astrocytes. These findings provide a new insight into the issue concerning the putative alteration of apoE-related cholesterol metabolism in Alzheimer's disease.

Randomized, Controlled Trial of Natural Interferon-alpha Therapy for E-antigen-positive Chronic Hepatitis B Patients

Hepatology Research : the Official Journal of the Japan Society of Hepatology. Jun, 2002  |  Pubmed ID: 12048063

We evaluated the efficacy of long-term interferon (IFN) therapy in patients with e-antigen-positive chronic hepatitis B. The study design was a prospective, randomized controlled clinical trial. Fifty-three patients were randomly assigned into one of two groups, treated with 3 million units (MU) of IFN (low dose group; n=27) or 6 MU IFN (high dose group; n=26), administered twice weekly for 52 weeks. Responders were defined as patients whose hepatitis B virus (HBV)-DNA level, determined by branched DNA signal amplification and hepatitis B e-antigen (enzyme immunoassay) were negative and whose serum alanine transaminase (ALT) levels fell to within the normal range (ALT<50 IU/l) at 6 month after termination of IFN therapy. One patient in high dose group was dropped out because of transfer. Remainder 52 patients were examined by intention-to-treat (ITT) analysis. The response rates by ITT analysis were 40.7% (11/27) in low dose group and 20% (5/25) in high dose group. The difference between low and high dose group was not statistically significant. Univariate analysis of clinical factors that contribute to the response demonstrated that IFN therapy had a significant effect when, (1) the serum HBV-DNA level was <200 Meq/ml prior to the commencement of IFN therapy (P=0.0327). (2) Transient acute exacerbation of ALT was present during or after IFN therapy (P=0.0311). Multivariate analysis showed that the risk ratio for the development of response in patients with serum HBV-DNA level of less than 200 Meq/ml was 3.60 compared with patients with that of 200 Meq/ml or more than 200 Meq/ml (95% CI, 1.012-12.81). In conclusion, the results of this trial show that: (1) long-term twice weekly IFN therapy could be a worthwhile strategy for e-antigen-positive chronic hepatitis B patients with serum HBV-DNA level of less than 200 Meq/ml and (2) patients with transient acute exacerbation of ALT during or after IFN therapy could often respond well after exacerbation of ALT.

Viral Genotypes and Response to Interferon in Patients with Acute Prolonged Hepatitis B Virus Infection of Adulthood in Japan

Journal of Medical Virology. Dec, 2002  |  Pubmed ID: 12376960

Acute hepatitis B virus (HBV) infection was diagnosed in 57 adults admitted to Toranomon Hospital in Tokyo, Japan. Genotypes of HBV were determined by a serological method and compared to those in 1,077 patients with chronic hepatitis B. The distribution of genotypes were: genotype A (acute, 22.8% vs. chronic, 1.9%; P < 0.00001); B (14.0% vs. 9.4%); C (43.9% vs. 87.7%, P = 0.004); D (1.8% vs. 0.2%); F (1.8% vs. 0.2%); and unable to be typed (15.8% vs. 0.6%, P = 0.001). The infection persisted in seven (12%) of them. They included six (86%) of the seven patients who received prednisolone or glycyrrhizin during an acute phase of illness and one of the 41 (2%) who did not (P = 0.01). Interferon was given to the seven patients with acute prolonged HBV infection, and four of them responded by clearing hepatitis B e antigen (HBeAg) and surface antigen (HBsAg) from serum. Of the four responders, one was infected with HBV genotype B and three with genotype C. HBsAg persisted in the remaining three patients all of whom were infected with HBV genotype A, and HBeAg stayed positive in one of them. These results indicate that HBV genotype A prevails in Japanese patients with acute hepatitis B, and suggest a high efficacy of interferon in the adult patients with acute prolonged HBV infection, except in those infected with HBV genotype A.

The Influence of Hepatitis B Virus Genotype on the Development of Lamivudine Resistance During Long-term Treatment

Journal of Hepatology. Mar, 2003  |  Pubmed ID: 12586297

Genotype-dependent development of lamivudine resistance in hepatitis B virus (HBV) has not been reported.

Increased Vulnerability to Focal Ischemic Brain Injury in Human Apolipoprotein E4 Knock-in Mice

Journal of Neuropathology and Experimental Neurology. Mar, 2003  |  Pubmed ID: 12638732

Accumulating evidence suggests that among the 3 human apolipoprotein E (apoE) isoforms encoded by the human APOE gene, the e4 allele may act to exacerbate brain damage in humans and animals. This study aimed to compare the isoform-specific vulnerability conferred by human apoE to ischemic brain damage, using mice expressing human apoE isoforms (apoE2, apoE3, or apoE4) in place of mouse apoE, produced by the gene-targeting technique in embryonic stem cells (knock-in, KI). Homozygous human apoE2 (2/2), apoE3 (3/3), or apoE4 (4/4) KI mice were subjected to permanent focal cerebral ischemia by a modified intraluminal suture method. Twenty-four h thereafter, brain damage, (as estimated by infarct volume and neurologic deficit) was significantly worse in 4/4 KI mice versus 2/2 or 3/3 KI mice (p < 0.001 for each comparison), with no significant differences between 2/2 and 3/3 KI mice. Immunohistochemistry for human apoE expression revealed similar apoE distribution with no significant difference in the immunostaining intensity among the 3 lines of KI mice. Notably. increased expression of human apoE was detected in neurons and astrocytes in the peri-infarct area, and a punctate expression pattern was evident in the border between the infarct and peri-infarct areas in all KI mice subjected to ischemia. Taken together, our results show that apoE affects the outcome of acute brain damage in an isoform-specific fashion (apoE4 > apoE3 = apoE2) in genetically engineered mice.

Efficacy of Prolonged Interferon Therapy for Patients with Chronic Hepatitis C with HCV-genotype 1b and High Virus Load

Journal of Gastroenterology. 2003  |  Pubmed ID: 12640530

In patients with hepatitis C virus (HCV)-genotype 1b and a high virus load, of more than 1 Meq/ml by the DNA probe assay, the clearance of HCV-RNA was achieved in only 10% with a 6-month interferon (IFN) course. We therefore assessed the efficacy of prolonged IFN therapy in patients with HCV-genotype 1b and a high virus load.

Serum Levels of Gamma-globulin and Total Bilirubin Influence the Prevalence of Multiple Extrahepatic Complication in Patients with Hepatitis C Virus Infection

Hepatology Research : the Official Journal of the Japan Society of Hepatology. Jan, 2003  |  Pubmed ID: 12644034

Patients with chronic hepatitis C virus (HCV) infection develop various extrahepatic complications. In this study, we analyzed as following. (1) The prevalence and interrelation of multiple extrahepatic manifestations. (2) Exact factors that are related to multiple extrahepatic manifestations. Consecutive autopsies of 261 cases with HCV infection that had undergone autopsy in 1988-1998 were enrolled. One hundred and forty consecutive patients who had gastro enteric carcinoma and underwent autopsy after death in our institution during the same period were used as controls. These 140 patients did not have hepatitis virus and chronic hepatitis or liver cirrhosis histologically. The prevalence of glomerulonephritis (GN), sialadenitis, thyroiditis, and idiopathic pulmonary fibrosis (IPF) was determined histologically. 'Multiple extrahepatic complications' was defined as the presence of two or more of the above four extrahepatic complications. Multiple logistic regression analyses of the risk for the multiple extrahepatic manifestations were performed. GN was present in 58.6% (153 cases), sialadenitis in 16.1% (42 cases), thyroiditis in 7.7% (20 cases), and IPF in 5% (13 cases) in cases of HCV infection. In addition, 37 out of 261 (14.2%) and seven (2.7%) cases had two and three extrahepatic complications, respectively. Multivariate analysis showed that multiple extrahepatic complications correlated with high serum gamma-globulin levels (>/=2.5 g/dl) and high serum total bilirubin levels (>/=1.2 mg/dl) about 1 year before death. Moreover, about 70-80% of patients with sialadenitis, IPF, or thyroiditis had other extrahepatic manifestations. HCV-positive patients with high serum gamma-globulin or high total bilirubin are at high risk of multiple extrahepatic complications.

Phosphorylation State of Tau in the Hippocampus of Apolipoprotein E4 and E3 Knock-in Mice

Neuroreport. Apr, 2003  |  Pubmed ID: 12692466

The apolipoprotein E (apoE) epsilon 4 allele is associated with an increased risk of sporadic as well as late-onset familial Alzheimer's disease (AD). To accurately determine the isoform-specific effects of human apoE on AD-like phosphorylation of tau, hippocampi from human apoE knock-in (KI) mice were studied by quantitative immunoblotting. There was no significant difference in phosphorylation levels of tau at nine of the 13 epitopes, for six of eight tau kinases, or in protein levels of three tau phosphatases, between apoE3-KI and apoE4-KI mouse hippocampi. However, in apoE4-KI mice, phosphorylation of tau at Ser235 was increased to approximately 150%, that at Ser413 to approximately 140%, while that at Ser202/Thr205 and Thr205 were decreased to approximately 70%, and the protein level of tau protein kinase I/glycogen synthase kinase 3beta (TPKI/GSK3beta) was increased to approximately 120%, that of extracellular signal-regulated kinase 2 (ERK2) was increased to approximately 130%, compared with apoE3-KI mice.

Randomized Trial of Prolonged Interferon Retreatment for Chronic Hepatitis C Patients with HCV-genotype 1b and High Virus Load

Hepatology Research : the Official Journal of the Japan Society of Hepatology. Apr, 2003  |  Pubmed ID: 12699846

The aim of this study was to examine whether 78 week course of interferon (IFN) retreatment could improve the beneficial effect of IFN in chronic hepatitis C patients compared with 52 week course of IFN retreatment. Inclusion criteria were biopsy-proven chronic hepatitis, serum HCV-RNA level of more than 1 Meq/ml, HCV-genotype 1b, abnormal serum alanine aminotransferase (ALT), and transient negative conversion for HCV-RNA during the initial course of IFN therapy. Forty-one patients were randomly assigned to two groups, receiving total doses of: 1410 MU for 52 weeks (a 52 week-group: n=20), or 1995 MIU for 78 weeks (a 78 week-group: n=21). But three patients (one in the 52 week-group and two in the 78 week-group) were withdrawn from the study due to a transfer, refusal after randomization, and occurrence of malignant lymphoma before IFN retreatment, respectively. Therefore remainder 38 patients were studied about efficacy of IFN administration. A virological response (VR) to IFN therapy was defined as HCV-RNA negativity by the reverse transcription nested polymerase chain reaction both 3 and 6 months after the completion of IFN retreatment. A biochemical response (BR) was defined as normalization of ALT but positive HCV-RNA both 3 and 6 months after the cessation of IFN therapy. According to these criteria, VR was 36.8% (7/19) in the 52 week-group and 21.1% (4/19) in the 78 week-group. BR was 5.3%(1/19) in the 52 week-group and 21.1% (4/19) in the 78 week-group. There was no significant difference between the 52 week-group and the 78 week-group with respect to the effect of IFN. We conclude that 52 week course of IFN retreatment may be a sufficient strategy if patients, who have HCV-genotype 1b and high virus load, show negative HCV-RNA and normal ALT level during the first IFN therapy.

HBe Antigen Loss During Lamivudine Therapy is Not Caused by Mutations in Precore and Core Promoter Genes in Patients with Chronic Hepatitis B

Journal of Medical Virology. Jul, 2003  |  Pubmed ID: 12766997

HBe antigen (HBeAg) loss or seroconversion can occur during lamivudine therapy. The purpose of this study was to analyze nucleotide sequences in precore and core promoter regions, and examine the influence of mutations in these regions on the disappearance of HBeAg during lamivudine therapy. Serial serum samples were obtained from 51 patients (HBeAg loss in 26 patients) at commencement of therapy (baseline) and after 1 year of lamivudine therapy. Serum samples were amplified with PCR and nucleotide sequences of HBV were analyzed. At baseline, a precore stop codon mutation (A1896) was identified in 8 of 26 HBeAg loss patients and in 8 of 25 HBeAg non-loss patients. At 1 year, precore mutation was observed in 4 of 14 patients analyzed who showed HBeAg loss. At 1 year, however, a precore mutation was observed also in 3 of 9 analyzed patients who showed no HBeAg loss. Core promoter mutations were noted in 21 of 26 HBeAg loss patients and in 20 of 25 HBeAg non-loss patients. At 1 year, core promoter mutations were noted in 11 of 14 HBeAg loss patients and in 8 of 9 HBeAg non-loss patients. Our data suggested that during lamivudine therapy, core promoter and precore mutations do not influence HBeAg loss or seroconversion but may reduce the viral level upon HBeAg loss or seroconversion.

Precore Wild-type Hepatitis B Virus with G1896 in the Resolution of Persistent Hepatitis B Virus Infection

Intervirology. 2003  |  Pubmed ID: 12867753

Factors influencing the resolution of persistent hepatitis B virus (HBV) infection were sought for.

Efficacy of Lamivudine Therapy and Factors Associated with Emergence of Resistance in Chronic Hepatitis B Virus Infection in Japan

Intervirology. 2003  |  Pubmed ID: 12867757

Several reports have examined the efficacy of long-term lamivudine therapy and the risk factors involved in emergence of viral resistance in Japanese patients with hepatitis B virus (HBV) infection. However, the patient cohorts in such studies are relatively small.

Clinical Features of Hepatitis B Virus Genotype A in Japanese Patients

Journal of Gastroenterology. 2003  |  Pubmed ID: 12898358

Hepatitis B virus (HBV) genotype A is predominant in northern Europe and central Africa. In the present study, we examined the clinical features associated with HBV genotype A disease in the Tokyo metropolitan area.

Virological and Biochemical Relapse According to YMDD Motif Mutant Type During Long-term Lamivudine Monotherapy

Journal of Medical Virology. Dec, 2003  |  Pubmed ID: 14556262

Whether the type of lamivudine-resistant virus in hepatitis B virus (HBV) influences the clinical outcome, it is not completely understood. We evaluated the serial changes in YMDD motif mutant in 60 Japanese genotype C-HBV patients who received long-term lamivudine monotherapy. YIDD or YVDD alone tended to stop shifting to the mixed type (YVDD and YIDD) within 12 months after the detection of mutant virus. Hence, the characteristics, virological relapse (DNA breakthrough) and biochemical relapse (breakthrough hepatitis) of 49 patients, who could be classified into three types (continuous YVDD, continuous YIDD, and the mixed type), were investigated. YVDD and YIDD type tended to have the opposite background with regard to age, histology, and viral load. The mixed and YIDD types tended to have similar backgrounds, except for viral load. In the mixed type, both the HBeAg-positive rate and viral load as risk factors for emergence of the mutant tended to be high. Mutant virus, DNA breakthrough and breakthrough hepatitis emerged significantly earlier in the mixed type than the two other types. The incidence of severe breakthrough hepatitis accompanied by icteric flare-up tended to be higher in the mixed type than the other types. Our results suggest that the YMDD motif mutant type might emerge from different backgrounds and modulate the virological and biochemical relapse after the emergence. Large-scale studies of each mutant type should be conducted in the future to confirm these findings.

Usefulness of Serum KL-6 for Early Diagnosis of Idiopathic Pulmonary Fibrosis in Patients with Hepatitis C Virus

Hepatology Research : the Official Journal of the Japan Society of Hepatology. Oct, 2003  |  Pubmed ID: 14563421

The aim of this study was to evaluate when the serum level of KL-6, a sensitive marker for idiopathic pulmonary fibrosis (IPF), rise prior to clinical onset of IPF. Eight hepatitis C virus (HCV)-positive patients with IPF were enrolled in this trial. The serum samples of these eight patients were stored -80 degrees C every 1-3 month during a follow-up period and enzyme-linked immunosorbent assay (ELISA) for KL-6 was done at the same time. Diagnosis of IPF was based on computed tomography and/or histology. Diagnosis of clinical onset of IPF was based on presence of dyspnea, dry cough, and audible fine crackles. At 1 year before clinical onset of IPF, the sensitivities of serum marker for IPF were 75% (6/8) for KL-6, 25% (2/8) for each of lactic acid dehydrogenase (LDH) and C-reactive protein (CRP). At 2 years before clinical onset of IPF, the sensitivities of the same serum markers were 62.5% (5/8), 12.5% (1/8) and 0% (0/8), respectively. The sensitivity of KL-6 at 1 and 2 year before clinical onset of IPF was significantly higher compared with LDH and CRP. Our results indicate that many future patients with IPF may have high levels of serum KL-6 at 1 or 2 years before clinical onset of IPF, suggesting that changes in serum KL-6 level can provide useful information for the early diagnosis of IPF in patients with HCV.

A Pilot Study of Thymosin Alpha1 Therapy for Chronic Hepatitis B Patients

Internal Medicine (Tokyo, Japan). Oct, 2003  |  Pubmed ID: 14606705

The efficacy of thymosin alpha 1 (Talpha1) in patients with chronic hepatitis B still requires confirmation. We, therefore, evaluated the efficacy of therapy in patients with chronic hepatitis B.

Low Rate of YMDD Motif Mutations in Polymerase Gene of Hepatitis B Virus in Chronically Infected Patients Not Treated with Lamivudine

Journal of Gastroenterology. Jan, 2004  |  Pubmed ID: 14767732

Lamivudine is used for the treatment of chronic hepatitis B (CH-B), and exhibits excellent antiviral activity. However, longterm administration increases the likelihood of the emergence of resistant viruses, with an accompanying relapse of hepatitis. However, recent studies have reported lamivudine-resistant viruses in patients with CH-B before such treatment. The aim of this study was to investigate whether YMDD mutants occur in nature.

Severe Acute Exacerbation of Liver Disease May Reduce or Delay Emergence of YMDD Motif Mutants in Long-term Lamivudine Therapy for Hepatitis B E Antigen-positive Chronic Hepatitis B

Journal of Medical Virology. May, 2004  |  Pubmed ID: 15042641

The pretherapy factors that could influence the emergence of resistant hepatitis B virus (HBV) tyrosine-methionine-aspartate-aspartate (YMDD) motif mutants against lamivudine are not fully known in prolonged lamivudine therapy for hepatitis B e antigen (HBeAg)-positive chronic hepatitis B. We analyzed prospectively 116 consecutive lamivudine-naïve patients who received long-term lamivudine therapy (>1 year) by using multivariate regression analyses. The cumulative HBeAg loss rates were 29, 44, and 47% at 1, 2, and 3 years of treatment, respectively. Stepwise Cox's regression analyses indicated that pretherapy viral load was a significant factor associated with HBeAg loss (P = 0.0068). The cumulative emergence rates of YMDD mutants were 23% at 1 year, 45% at 2 year, and 47% at 3 year of treatment. Stepwise Cox's regression analyses indicated that patient age and presence or absence of severe acute exacerbation of liver disease were independent significant factors associated with emergence of YMDD mutants (P = 0.018 and 0.048, respectively). For the development of virological breakthrough, patient age, the presence or absence of severe acute exacerbation, and pretherapy viral load were independent significant factors (P = 0.028, 0.043, and 0.044, respectively). Severe acute exacerbation tended to reduce or delay development of biochemical breakthrough. The present study provides important information for the development of more effective and rational long-term lamivudine therapy for HBeAg-positive chronic hepatitis B patients infected exclusively with genotype

Sustained Negativity for HCV-RNA over 24 or More Months by Long-term Interferon Therapy Correlates with Eradication of HCV in Patients with Hepatitis C Virus Genotype 1b and High Viral Load

Intervirology. 2004  |  Pubmed ID: 15044832

We assessed whether sustained negativity for HCV-RNA over 24 or more months by long-term interferon (IFN) therapy correlates with eradication of HCV in patients with hepatitis C virus genotype 1b and high viral load or not.

Effect of Acute Self-limited Hepatitis C Virus (HCV) Superinfection on Hepatitis B Virus (HBV)-related Cirrhosis. Virological Features of HBV-HCV Dual Infection

Digestive Diseases and Sciences. Feb, 2004  |  Pubmed ID: 15104371

We investigated the virological impact of acute hepatitis C virus (HCV) superinfection on two patients with hepatitis B virus (HBV)-related cirrhosis. In both patients, chronic HBV-infection persisted while acute HCV infection resolved spontaneously. HBV DNA was transiently suppressed in both patients but increased with HCV resolution. In Case 1 (HBeAg-positive; wild type of basic core promoter [BCP] and precore [PreC]), fluctuations of HBV DNA and HBeAg state were accompanied by mutations of the BCP and PreC. In Case 2 (HBeAg-negative; mutant type of the BCP and PreC), changes in HBV DNA levels were associated with mutations of PreC. In both cases, mutant PreC changed to the wild type upon HCV resolution, and no nucleotide A insertion at position 193 of the HCV 5'-untranslated region, which influences HCV spontaneous clearance, was detected. The putative DNA-binding motif in the HCV core was SPRG (amino acids 99-102). HCV infection was associated with changes in the nucleotide sequences of the binding site for the nuclear receptor family in HBV enhancer 2 (Enh2) including the BCP rather than Enh1. Our results suggest that the impact of acute HCV infection on chronic HBV infection varies according to HBV virological state.

Efficacy of Interferon Retreatment After Relapse for Chronic Hepatitis C Patients with Biochemical Response After First Interferon Therapy

Journal of Gastroenterology. 2004  |  Pubmed ID: 15175944

With respect to interferon (IFN) treatment for chronic hepatitis C, normalization of alanine aminotransferase (ALT) as well as clearance of hepatitis C virus (HCV)-RNA after IFN therapy is important. It has been shown that the incidence of hepatocellular carcinoma (HCC) in patients with normal ALT is significantly lower than that in those with elevated ALT after IFN therapy. We assessed the efficacy of IFN retreatment for chronic hepatitis C patients who had a biochemical response (BR) after the first IFN therapy and reelevated ALT during follow up, by a case control study.

Augmented Delayed Infarct Expansion and Reactive Astrocytosis After Permanent Focal Ischemia in Apolipoprotein E4 Knock-in Mice

Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism. Jun, 2004  |  Pubmed ID: 15181372

Using homozygous human apolipoprotein E2 (apoE2) (2/2)-, apoE3 (3/3)-, or apoE4 (4/4)-knock-in (KI) mice, we aimed to examine whether an apoE isoform-specific exacerbation of delayed infarct expansion occurs after permanent middle cerebral artery occlusion (pMCAO). Compared with 2/2- or 3/3-KI mice, 4/4-KI mice exhibited significantly larger infarct volumes and worse neurologic deficits after pMCAO, with no significant differences between the latter two groups. Infarct volume in 4/4-KI mice was significantly increased from 1 to 5 days after pMCAO, whereas that in 2/2- or 3/3-KI mice was not significantly altered. DNA fragmentation in the peri-infarct area as detected by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphatenick end-labeling was increased to a similar degree in all of the KI mice by 5 days after pMCAO, with no significant differences among the mouse groups. At every time-point examined, human apoE was most markedly expressed in the peri-infarct area, with similar immunoreactivity among the three lines of KI mice. The glial fibrillary acidic protein immunoreactive burden in the peri-infarct area was progressively increased through 7 days in 4/4-KI mice, but not in 2/2- or 3/3-KI mice. Taken together, these data show that the apoE4 isoform acts to aggravate delayed infarct expansion and peri-infarct reactive astrocytosis during the subacute phase of pMCAO in genetically engineered apoE-KI mice.

Accelerated Abeta Aggregation in the Presence of GM1-ganglioside-accumulated Synaptosomes of Aged ApoE4-knock-in Mouse Brain

FEBS Letters. Jul, 2004  |  Pubmed ID: 15225622

Aging and apolipoprotein E4 (apoE4) expression are strong risk factors for the development of Alzheimer's disease (AD); however, their pathological roles remain to be clarified. In the process of AD development, the conversion of the nontoxic amyloid beta-protein (Abeta) monomer to its toxic aggregates is a fundamental process. We previously hypothesized that Abeta aggregation is accelerated through the generation of GM1 ganglioside (GM1)-bound Abeta which acts as a seed for Abeta fibril formation. Here we report that GM1 level in detergent-resistant membrane microdomains (DRMs) of synaptosomes increased with age and that this increase was significantly pronounced in the apoE4- than the apoE3-knock-in mouse brain. Furthermore, we show that Abeta aggregation is markedly accelerated in the presence of the synaptosomes of the aged apoE4-knock-in mouse brain. These observations suggest that aging and apoE4 expression cooperatively accelerate Abeta aggregation in the brain through an increase in the level of GM1 in neuronal membranes.

Hepatocellular Carcinoma in Noncirrhotic Young Adult Patients with Chronic Hepatitis B Viral Infection

Journal of Gastroenterology. Jun, 2004  |  Pubmed ID: 15235872

The aims of this study were to define the clinical characteristics of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) in young adult patients without cirrhosis and to evaluate the efficacy of interferon (IFN) therapy on HCC recurrence.

Peripheral CD8+/CD25+ Lymphocytes May Be Implicated in Hepatocellular Injuries in Patients with Acute-onset Autoimmune Hepatitis

Journal of Gastroenterology. Jul, 2004  |  Pubmed ID: 15293135

The mechanism of liver injuries in autoimmune hepatitis (AIH) is not fully understood, especially because the onset is insidious and the clinical courses fluctuate with spontaneous exacerbation and improvement even without immunosuppressive therapies.

YMDD Mutants in Patients with Chronic Hepatitis B Before Treatment Are Not Selected by Lamivudine

Journal of Medical Virology. Oct, 2004  |  Pubmed ID: 15332287

Hepatitis B virus (HBV) mutants with mutations in the YMDD motif of viral DNA polymerase/reverse transcriptase are described in patients infected with HBV who have not received lamivudine therapy, but their pathogenetic potential is not clear. These mutants were detected by the polymerase chain reaction with peptide nucleic acid clamping in pretreatment sera from two patients who later received lamivudine. One patient developed acute exacerbation with hepatic encephalopathy and received lamivudine along with plasma exchange, which were effective on his illness. YIDD mutants were detected in all three pretreatment sera and both posttreatment sera from him. HBV DNA clones from pretreatment and posttreatment sera, however, did not have the same amino acid sequence. In the other patient who developed severe breakthrough hepatitis after receiving lamivudine, YIDD mutants were detected in two pretreatment and two posttreatment sera. When amino acid sequences of HBV DNA clones with the YIDD mutation were compared before and after he received lamivudine, however, they were not in accord. Hence, YIDD mutants in both patients with chronic hepatitis B before treatment were not selected by lamivudine after they had been placed on it. Numerous amino acid conversions were detected in HBV DNA clones with YIDD mutations, and some of them created stop codons in the overlapping S gene sequence. In Conclusion, HBV mutants with mutations in the YMDD motif in patients before treatment would not be selected by lamivudine or induce breakthrough hepatitis, and some of these would not be replication-competent due to stop codons in the S gene.

Single-stage Repair of Complete Atrioventricular Septal Defect and Coarctation of the Aorta in Neonate

The Japanese Journal of Thoracic and Cardiovascular Surgery : Official Publication of the Japanese Association for Thoracic Surgery = Nihon Kyōbu Geka Gakkai Zasshi. Aug, 2004  |  Pubmed ID: 15384714

Controversy over patients with complete atrioventricular septal defect (CAVSD) and coarctation of the aorta (CoA) continues: whether they should be treated with a primary total correction or a staged approach utilizing initial pulmonary artery banding during neonatal period. A 17-day-old neonate with Down's syndrome underwent definitive repair of CAVSD and CoA. With the postoperative course uneventful, he was discharged from the hospital on 19th postoperative day. Single-stage repair of CAVSD and CoA appears to offer a good prognosis provided that valve morphology is amenable to repair.

Efficacy of 6-month Interferon Therapy in Chronic Hepatitis B Virus Infection in Japan

Journal of Gastroenterology. Oct, 2004  |  Pubmed ID: 15549450

In Japan, there are few studies of long-term (more than 1 month) interferon (IFN) therapy for chronic hepatitis B (CHB). In this retrospective study, we investigated the efficacy and predictors of response to 6-month IFN therapy.

Interferon Therapy for 2 Years or Longer Reduces the Incidence of Hepatocarcinogenesis in Patients with Chronic Hepatitis C Viral Infection

Intervirology. 2004  |  Pubmed ID: 15564748

The purpose of this clinical study was to determine the effect of long-term interferon (IFN) administration on the incidence of hepatocellular carcinomas (HCC) in chronic hepatitis C patients, without eradication of hepatitis C virus (HCV) by IFN therapy.

Infection with Hepatitis B Virus Genotype A in Tokyo, Japan During 1976 Through 2001

Journal of Gastroenterology. Sep, 2004  |  Pubmed ID: 15565403

Because genotype A of hepatitis B virus (HBV) is not indigenous, there have been only few data on infection with it in Japan.

Efficacy of Lamivudine Treatment in Japanese Patients with Hepatitis B Virus-related Cirrhosis

Journal of Gastroenterology. Nov, 2004  |  Pubmed ID: 15580401

Several clinical trials have suggested that lamivudine therapy is effective in patients with hepatitis B virus (HBV)-related cirrhosis. However, there are few studies of lamivudine therapy in Japanese patients with HBV cirrhosis. The aim of this study was to evaluate the efficacy of lamivudine therapy in Japanese patients with cirrhosis, and to evaluate the clinical course after the emergence of YMDD mutants.

Adequate Timing of Ribavirin Reduction in Patients with Hemolysis During Combination Therapy of Interferon and Ribavirin for Chronic Hepatitis C

Journal of Gastroenterology. Nov, 2004  |  Pubmed ID: 15580403

Hemolytic anemia is one of the major adverse events of the combination therapy of interferon and ribavirin. Because of ribavirin-related hemolytic anemia, dose reduction is a common event in this therapy. In this clinical retrospective cohort study we have examined the suitable timing of ribavirin reduction in patients with hemolysis during combination therapy.

Clinical and Virological Characteristics of Untreated Patients with Chronic Hepatitis C Who Develop Serum Alanine Aminotransferase Flare-up

Journal of Medical Virology. Feb, 2005  |  Pubmed ID: 15602722

Among patients with chronic hepatitis C virus (HCV) infection, serum alanine aminotransferase (ALT) rarely increases above 500 IU/L. We examined the clinical and virological features of untreated patients with serum ALT > or = 500 IU/L. One thousand seven hundred and sixty adult patients with chronic HCV infection were followed-up. Among these patients, 22 developed ALT flare-up (M:F=13:9, median age, 50.5 years). We evaluated liver function tests, genotype, and viral titer in these patients and 44 randomly selected age- and sex-matched control without ALT flare-up. In four patients with ALT flare-up, we examined changes in viral loads and sequential changes in amino acid sequences of the core region, hypervariable region 1 (HVR1), and interferon sensitivity determining region (ISDR) before and after ALT flare-up. Multivariate analysis identified genotype 2 as the only significant determinant of ALT flare-up. ALT flare-up occurred in three of four patients without increase in viral load. Several alterations in amino acids were noted in HVR1 before and within 6 months of ALT flare-up. One or two alterations in the core region and many alterations in HVR1 were noted after ALT flare-up in some patients. Genotype 2 is an important factor for ALT flare-up. However, we could not directly relate ALT flare-up to these alterations in amino acids of the core region, HVR1, and ISDR.

Favorable Efficacy of Long-term Lamivudine Therapy in Patients with Chronic Hepatitis B: an 8-year Follow-up Study

Journal of Medical Virology. Apr, 2005  |  Pubmed ID: 15714490

The long-term efficacy of lamivudine therapy in patients with hepatitis B virus (HBV) infection is still not clear. In this study, 20 non-cirrhotic Japanese patients infected with HBV received lamivudine therapy for more than 1 year and were followed for a median period of 8.5 years (range, 6.7-8.7 years). The rates of HBe antigen (HbeAg) negative, HBV-DNA undetectable, and alanine aminotransferase (ALT) normal level at the start of lamivudine were 55%, 25%, and 20% and 85%, 80%, and were 80%, respectively, at the last visit, including patients who received additional treatment. The values at the last visit tended to and were significantly higher than those at the start. The values improved at the last visit regardless of the emergence of YMDD motif mutant and continuation of lamivudine. YMDD mutant and biochemical relapse with mutant virus (breakthrough hepatitis) appeared in 65% and 45% during follow-up, respectively, but severe breakthrough hepatitis occurred in only 5%. Furthermore, 80% of patients who received additional treatment for breakthrough hepatitis, regardless of continuation of lamivudine, were ALT normal level at the last visit, in contrast to 25% untreated. HBsAg clearance occurred in two patients of the discontinuous lamivudine group with non-vertical transmission, who were relatively young. One was infected with HBV genotype C with breakthrough hepatitis and the other had no YMDD mutant and was infected with genotype D, a rare type in Japan. None developed cirrhosis or hepatocellular carcinoma (HCC) during follow-up. Our results suggest that long-term lamivudine therapy improves long-term prognosis, especially when additional treatment for breakthrough hepatitis is used.

Hepatocyte Steatosis is an Important Predictor of Response to Interferon (IFN) Monotherapy in Japanese Patients Infected with HCV Genotype 2a: Virological Features of IFN-resistant Cases with Hepatocyte Steatosis

Journal of Medical Virology. Apr, 2005  |  Pubmed ID: 15714492

The role of hepatocyte steatosis in interferon (IFN) resistance is still unclear, especially in patients infected with hepatitis C virus (HCV) genotype 2a. The present study was conducted in 364 consecutive non-cirrhotic naive patients infected with genotype 2a, who were evaluated for the severity of steatosis and response to IFN monotherapy after a 24-week median duration of therapy. The patients were examined for factors associated with steatosis and treatment efficacy according to the grade of steatosis. Early viral kinetics was also evaluated in 64 patients for predictors of response to therapy. Nine IFN-resistant patients were assessed for the relationship between amino acid sequence of HCV core region/NS5A and severity of steatosis. Multivariate analysis identified two independent factors associated with steatosis; serum ferritin > or =200 microg/l and body mass index > or =25.0 kg/m(2). The sustained virological response rate in patients with high-grade steatosis was significantly lower than in the low-grade group. Study of early viral kinetics showed a significantly lower cumulative HCV-RNA negative rate for the high-grade than low-grade steatosis group. Sequence analysis of HCV core region/NS5A in IFN-resistant patients with or without steatosis failed to identify steatosis-specific amino acid substitutions associated with resistance. This study of HCV genotype 2a suggested that steatosis is associated with excess iron storage, and that it is an important predictor of efficacy of IFN monotherapy. Further large-scale studies are warranted to examine the role of amino acid substitutions on IFN resistance specific for steatosis.

Persistence of Acute Infection with Hepatitis B Virus Genotype A and Treatment in Japan

Journal of Medical Virology. May, 2005  |  Pubmed ID: 15779048

Among the 97 adult patients with acute hepatitis B who were admitted to the Toranomon Hospital in Metropolitan Tokyo during 28 years from 1976 to 2003, 31 (32%) were infected with hepatitis B virus (HBV) genotype A, nine (9%) with genotype B, 44 (45%) with genotype C, one (1%) each with genotypes E and F. HBV in the remaining 11 (11%) patients were untypeable. All the 31 patients with acute hepatitis B caused by HBV genotype A infection were male with a median age of 31 years, and 16 (52%) contracted infection through extramarital sexual contacts. The baseline HBV DNA level was higher in the seven (23%) patients in whom infection with HBV genotype A persisted than the remaining 24 (77%) with spontaneous resolution (median: >8.7 vs. 6.0 log genome equivalents/ml, P = 0.004). Persistent infection was more frequent in patients with maximum alanine aminotransferase <500 IU/L than > or =500 IU/L (83% [5/6] vs. 4% [1/25], P = 0.0001). Of the six patients with persistent HBV genotype A infection who received interferon and/or lamivuidine for treatment of chronic active hepatitis, three (50%) responded with the loss of hepatitis B e antigen (HBeAg); hepatitis B surface antigen (HBsAg) was cleared from serum in one patient who received interferon and lamivudine in sequence. HBV genotype A persisted along with HBeAg in the remaining three patients given antiviral therapy as well as another who was not treated. In conclusion, infection with HBV genotype A prevails in patients with acute hepatitis B in Japan where genotypes B and C are common, is often contracted sexually (16/31 [52%]) and tends to persist (7/31 [23%]). Infection was cleared in only one of the six (17%) patients who received antiviral therapy.

Bioprosthetic Dysfunction Caused by Preserved Native Valve in Tricuspid Position

Asian Cardiovascular & Thoracic Annals. Mar, 2005  |  Pubmed ID: 15793057

We report a 4-year-old girl who underwent replacement of a bioprosthetic valve in the tricuspid position due to rare bioprosthetic dysfunction. The bioprosthetic valve showed marked tricuspid insufficiency as well as stenosis caused by the adhesion of the preserved native valve leaflets to the undersurface of the implanted bioprosthesis.

Significance of Serum Ribavirin Concentration in Combination Therapy of Interferon and Ribavirin for Chronic Hepatitis C

Intervirology. 2005  |  Pubmed ID: 15812187

The purpose of this clinical retrospective cohort study was to determine the most suitable ribavirin concentration on combination therapy of interferon (IFN)-ribavirin.

Virological and Biochemical Relapse After Discontinuation of Lamivudine Monotherapy for Chronic Hepatitis B in Japan: Comparison with Breakthrough Hepatitis During Long-term Treatment

Intervirology. 2005  |  Pubmed ID: 15812192

Comparison of virological and biochemical relapse in patients with chronic hepatitis B, based on continuation or discontinuation of lamivudine monotherapy.

Virological Differences Between Patients Infected with Subtypes Ba and Bj of Hepatitis B Virus Genotype B

Journal of Gastroenterology and Hepatology. Apr, 2005  |  Pubmed ID: 15836705

Hepatitis B virus (HBV) genotype B is classified into subtype Ba with the recombination with genotype C in the precore region plus core gene and subtype Bj without recombination. Virological and clinical differences between infections with subtypes Ba and Bj, however, are yet to be determined.

Association of Amino Acid Substitution Pattern in Core Protein of Hepatitis C Virus Genotype 1b High Viral Load and Non-virological Response to Interferon-ribavirin Combination Therapy

Intervirology. 2005  |  Pubmed ID: 16024941

Patients with high titer (>/=100 kIU/ml) of hepatitis C virus (HCV) genotype 1b do not achieve highly sustained virological response rates to combination therapy with interferon plus ribavirin. Non-virological responders (NVRs, namely ultimate resistant cases) who do not achieve HCV-RNA negativity during treatment are also encountered. We investigated the pretreatment virological features of NVRs.

Usefulness of the Serum KL-6 Assay in Patients with Hepatitis C Virus

Intervirology. 2005  |  Pubmed ID: 16024944

The aim of this study is to evaluate the serum level of KL-6 in hepatitis C virus (HCV)-positive patients with chronic liver disease.

Long-term Follow-up of Interferon Monotherapy in 454 Consecutive Naive Patients Infected with Hepatitis C Virus: Multi-course Interferon Therapy May Reduce the Risk of Hepatocellular Carcinoma and Increase Survival

Scandinavian Journal of Gastroenterology. Jun, 2005  |  Pubmed ID: 16036529

The long-term effects of multi-course interferon (IFN) monotherapy in patients infected with hepatitis C virus (HCV) are still unclear.

Ross Procedure in an Infant Weighing 4.5 Kg: Eight Years Follow-up

The Japanese Journal of Thoracic and Cardiovascular Surgery : Official Publication of the Japanese Association for Thoracic Surgery = Nihon Kyōbu Geka Gakkai Zasshi. Dec, 2005  |  Pubmed ID: 16408468

A 6 month-old male infant (weight: 4.5 kg) with congenital aortic stenosis underwent aortic valve replacement with a pulmonary autograft (Ross procedure). The right ventricular outflow tract (RVOT) was reconstructed with a polytetrafluoroethylene (PTFE) -valved equine pericardial conduit. At the age of 5, re-RVOT reconstruction with an equine pericardial patch bearing a PTFE monocusp was required because of severe pulmonary stenosis resistant to 2 attempts of percutaneous transluminal pulmonary valvotomy. Currently, at the age of 8, the degree of aortic regurgitation is trivial and the pulmonary autograft is free of functional deterioration despite somatic growth.

Retentive Force of O-ring Attachment to Use Immediate Provisional Implant (IPI)-retained Overdenture

The European Journal of Prosthodontics and Restorative Dentistry. Dec, 2005  |  Pubmed ID: 16411569

This study evaluated the retentive force of the O-ring attachment to an Immediate Provisional Implant (IPI)-retained overdenture. Two sizes of O-rings (#1, #2) were placed on the IPI abutment head. As the controls, soft relining material, silicone lining material, and the PMMA resin were used to connect the IPI abutment head. The retentive forces (n=5, N) obtained at a crosshead speed of 40 mm/min were analyzed by ANOVA/Tukey's HSD test (alpha=0.05). O-ring #1 showed the significantly greatest force among all materials tested (p0.05). Appropriate retention was obtained using the smaller O-ring#1 for the IPI-retained overdenture.

Clinical and Virological Features of Non-breakthrough and Severe Exacerbation Due to Lamivudine-resistant Hepatitis B Virus Mutants

Journal of Medical Virology. Mar, 2006  |  Pubmed ID: 16419116

Patients who develop YMDD mutant during lamivudine therapy for hepatitis B virus (HBV) infection exhibit various clinical courses. Some patients show normal ALT levels, whereas others develop severe hepatitis exacerbations (SHEs) due to YMDD mutants. We studied 136 patients with YMDD mutant among 362 Japanese adult patients on lamivudine therapy. Clinical and virological features of patients without elevated HBV DNA after emergence of YMDD mutant (non-elevated group) were investigated. Moreover, virological analysis was also performed in patients with SHE due to YMDD mutants. Patients in the non-elevated group were characterized by HBeAg-negative pretreatment, HBeAg loss during therapy, a longer duration from commencement of therapy until emergence of YMDD mutant, and no mixed-type YMDD mutants. Patients with SHE had more substitutions in the reverse transcriptase (rt) region within the polymerase gene at the time of exacerbation than those without SHE, although no specific substitutions were noted. Sequence analysis of full-length HBV genome showed more substitutions in X, rt, and surface proteins in patients with SHE than in those without elevated HBV DNA level. In conclusion, negativity for HBeAg at commencement of therapy or before emergence of YMDD mutant was an important factor among non-elevated group. More substitutions in the rt region and the other proteins may be related to the emergence of severe hepatitis caused by lamivudine-resistant virus.

Measurement of Hepatitis B Virus Core-related Antigen is Valuable for Identifying Patients Who Are at Low Risk of Lamivudine Resistance

Liver International : Official Journal of the International Association for the Study of the Liver. Feb, 2006  |  Pubmed ID: 16420514

The clinical usefulness of hepatitis B virus core-related antigen (HBVcrAg) assay was compared with that of HBV DNA assay in predicting the occurrence of lamivudine resistance in patients with chronic hepatitis B.

Efficacy of Interferon Therapy in Elderly Patients with Chronic Hepatitis C

Intervirology. 2006  |  Pubmed ID: 16428887

We assessed the efficacy and safety of interferon (IFN) monotherapy in 84 elderly patients aged > or =65 years with chronic hepatitis C in a retrospective cohort study.

Long-term Outcome After Hepatitis B Surface Antigen Seroclearance in Patients with Chronic Hepatitis B

The American Journal of Medicine. Jan, 2006  |  Pubmed ID: 16431195

The aim of this study was to elucidate the long-term outcome after hepatitis B surface antigen (HBsAg) seroclearance in a large number of Japanese patients.

Functional Analysis of Hepatitis C Virus Envelope Proteins, Using a Cell-cell Fusion Assay

Journal of Virology. Feb, 2006  |  Pubmed ID: 16439538

Hepatitis C virus (HCV) envelope proteins mediate the entry of virus into cells by binding to cellular receptors, resulting in fusion of the viral membrane with the host cell membrane and permitting the viral genome to enter the cytoplasm. We report the development of a robust and reproducible cell-cell fusion assay using envelope proteins from commonly occurring genotypes of HCV. The assay scored HCV envelope protein-mediated fusion by the production of fluorescent green syncytia and allowed us to elucidate many aspects of HCV fusion, including the pH of fusion, cell types that permit viral entry, and the conformation of envelope proteins essential for fusion. We found that fusion could be specifically inhibited by anti-HCV antibodies and by at least one peptide. We also generated a number of insertional mutations in the envelope proteins and tested nine of these using the fusion assay. We demonstrate that this fusion assay is a powerful tool for understanding the mechanism of HCV-mediated fusion, elucidating mutant function, and testing antiviral agents.

Arterial Switch Operation Using Aortic Homograft for Transposition of the Great Arteries with Pulmonary Regurgitation

The Japanese Journal of Thoracic and Cardiovascular Surgery : Official Publication of the Japanese Association for Thoracic Surgery = Nihon Kyōbu Geka Gakkai Zasshi. Mar, 2006  |  Pubmed ID: 16613229

We report a case of a 15 month-old boy who underwent the arterial switch operation using cryopreserved aortic homograft for transposition of the great arteries with pulmonary regurgitation, with coexisting right ventricular outflow tract obstruction precluding atrial switch operation. Follow-up echocardiography at 6 months showed trivial neoaortic valve regurgitation, no significant systemic outflow obstruction, with good cardiac function. In small children, the choice of material for left ventricular outflow tract reconstruction is one of the most crucial issues. Cryopreserved homograft has been one of the primary options for the aortic valve replacement in small children because of the ease of suturing and excellent hemostasis.

Developmental Capacity of Antarctic Minke Whale ( Balaenoptera Bonaerensis ) Vitrified Oocytes Following in Vitro Maturation, and Parthenogenetic Activation or Intracytoplasmic Sperm Injection

Zygote (Cambridge, England). May, 2006  |  Pubmed ID: 16719944

The present study investigated the effects of the sexual maturity of oocyte donors on in vitro maturation (IVM) and the parthenogenetic developmental capacity of fresh minke whale oocytes. The effects of cytochalasin B (CB) pretreatment and two types of cryoprotectant solutions (ethylene glycol (EG) or ethylene glycol and dimethylsulfoxide (EG + DMSO)) on the in vitro maturation of vitrified immature whale oocytes were compared, and the developmental capacity of vitrified immature whale oocytes following IVM and intracytoplasmic sperm injection examined (ICSI). The maturation rate did not differ significantly with sexual maturity (adult, 60.9%; prepubertal, 53.1%), but the parthenogenetic activation rate of oocytes from adult donors (76.7%) was significantly higher (p < 0.05) than that of oocytes from prepubertal donors (46.4%). The maturation rates after vitrification and warming were not significantly different between the EG (22.2%) and EG + DMSO groups (30.2%), or between the CB-treated (30.4%) and non-CB-treated groups (27.3%). These results indicate that parthenogenetic activation of in vitro matured oocytes from adult minke whales was superior to that from prepubertal whales, but that the developmental capacity of the whale oocytes after parthenogenetic activation or ICSI was still low. The present study also showed that CB treatment before vitrification and two kinds of cryoprotectants did not improve the IVM rate following the vitrification of immature whale oocytes.

In Vitro Culture Conditions Using Chemically Defined Media for in Vitro Matured and Intracytoplasmically Inseminated Porcine Oocytes

The Journal of Reproduction and Development. Oct, 2006  |  Pubmed ID: 16905878

The present study investigated in vitro culture methods [droplet and Well of the Well (WOW)] using semi-defined and defined media [modified porcine zygote medium (mPZM)] and the additional effects of insulin on in vitro matured and intracytoplasmically inseminated porcine oocytes. In Experiment 1, in vitro matured and intracytoplasmically inseminated porcine oocytes were cultured for 6 days in the following four groups: 1) mPZM-3 (containing bovine serum albumin) + droplet (30 mul), 2) mPZM-3 + WOW, 3) mPZM-4 (containing polyvinyl alcohol) + droplet, and 4) mPZM-4+ WOW. The culture media (mPZM-3 and mPZM-4) and methods (droplet and WOW) did not significantly affect the cleavage rate, but the blastocyst rate of the oocytes cultured in mPZM-3 was significantly (P<0.01) higher than that of mPZM-4 (20.1 and 9.4%, respectively). The blastocyst rates as percentages of the cleaved oocytes (51.8 and 16.9%) and the hatched blastocyst rate as percentages of the number of blastocysts (12.3 and 2.2%) were also significantly (P<0.01) higher in mPZM-3 compared with those in mPZM-4. There was significant interaction (P<0.05) between the two main factors; the effects of the culture media and methods on the rate of hatched blasyocysts as percentages of the blastocysts produced and, the hatched blastocyst rate (20.3%) as percentages of the number of blastocysts produced in mPZM-3 were significantly (P<0.05) higher than in the other groups. In Experiment 2, the additional effects of insulin (100 ng/ml) in mPZM-3 and mPZM-4 media was investigated in the WOW culture system. Insulin addition did not improve cleavage, blastocyst formation, or the number of cells in blastocysts. However, as in Experiment 1, mPZM-3 resulted in a significantly higher blastocyst rate as percentages of the cleaved oocytes than mPZM-4 (33.9 and 18.4%). These results indicate that a chemically defined medium (mPZM-4) needs to be improved to provide more suitable culture conditions for in vitro development of in vitro matured and intracytoplasmically inseminated porcine oocytes. However, the WOW system may be a useful IVC method for blastocyst development of in vitro matured porcine oocytes following ICSI when a semi-defined medium (mPZM-3) is used.

Response to Long-term Lamivudine Treatment in Patients Infected with Hepatitis B Virus Genotypes A, B, and C

Journal of Medical Virology. Oct, 2006  |  Pubmed ID: 16927289

Response to lamivudine treatment longer than 1 year was compared in 15 patients persistently infected with hepatitis B virus (HBV) genotype A, 38 with genotype B, and 449 with genotype C. Patients with genotype A were younger (median age 37 [range 24-49] vs. 47 [24-67] or 44 [18-73], P = 0.015), possessed hepatitis B e antigen (HBeAg) more frequently (73% vs. 21% or 56%, P < 0.001) and HBV DNA in higher levels (8.6 [6.1-8.7] vs. 6.5 [<3.7-8.7] or 6.5 [<3.7-8.7] log genome equivalents (LGE)/ml, P = 0.024) than those with genotype B or C. During lamivudine, YMDD mutants (89% vs. 53% or 42%, P = 0.0001) and breakthrough hepatitis developed more often (47% vs. 21% or 29%, P = 0.023) in patients with genotype A than B or C. YMDD mutants elicited more frequently in patients with genotype A than B or C who were positive (82% [9/11] vs. 25% [2/8] or 48% [117/245], P = 0.037) or negative for HBeAg (75% [3/4] vs. 30% [9/30] or 33% [68/204], P = 0.003). HBeAg (hazard ratio 2.1 [95% confidence interval 1.53-2.92], P < 0.001) and genotype A (2.78 [1.08-7.12], P = 0.034) enhanced the emergence of YMDD mutants by the Cox proportional hazard model. The risk for breakthrough hepatitis was increased by the baseline alanine aminotransferase level <500 IU/L (2.56 [1.82-5.50], P = 0.018), HBeAg (2.11 [1.40-3.16], P < 0.001), cirrhosis (1.92 [1.24-2.97], P = 0.004) and HBV DNA > or =8.0 LGE/ml (1.57 [1.04-2.36], P = 0.03); it was influenced by genotypes only in patients with HBeAg. In conclusion, HBV genotypes help in predicting response to long-term lamivudine treatment and development of YMDD mutants in patients with chronic hepatitis B.

Classification of Hepatitis B Virus Genotypes by the PCR-Invader Method with Genotype-specific Probes

Journal of Virological Methods. Dec, 2006  |  Pubmed ID: 16934340

Hepatitis B virus is a worldwide public health problem. A simple and effective test to identify viral genotypes would greatly aid efforts to understand and control the spread of this disease. A serial invasive signal amplification reaction assay (PCR-Invader assay) was developed for distinguishing the known eight genotypes (A-H) and four subgenotypes (Aa, Ae, Ba, Bj) of hepatitis B virus (HBV). The preS/S and core regions were amplified by multiplex PCR and delivered to 12 wells containing genotype-specific Invader probes. By observing the fluorescence patterns in the wells, HBV sub/genotypes can be assigned. A total of 505 serum samples containing HBV/HBsAg in Japan was examined by PCR-Invader and compared the results with those from ELISA assays with monoclonal antibodies against epitopes on gene products of the preS2 region and with a genotype-specific probe assay (GSPA) based on the preS1 region. Genotypes determined by the PCR-Invader agreed with those of the ELISA method in 98.2% of cases and with the GSPA method in 97.1% of cases. Co-infection with two distinct genotypes was correctly identified by the PCR-Invader in four serum samples, as determined by GSPA. Thus, the PCR-Invader assay is a useful tool for detecting the 10 known HBV sub/genotypes.

Effect of Congestive Heart Failure on Mexiletine Pharmacokinetics in a Japanese Population

Biological & Pharmaceutical Bulletin. Nov, 2006  |  Pubmed ID: 17077526

The goal of this study was to evaluate the influence of congestive heart failure (CHF) on the clearance of mexiletine.

Cysteamine or Beta-mercaptoethanol Added to a Defined Maturation Medium Improves Blastocyst Formation of Porcine Oocytes After Intracytoplasmic Sperm Injection

Theriogenology. Apr, 2006  |  Pubmed ID: 16154628

The present study was carried out to investigate the effect of adding 100 microM cysteamine (Cys) or 100 microM beta-mercaptoethanol (beta-ME) to a defined maturation medium on in vitro maturation (IVM), and fertilization and developmental competence of in vitro matured porcine oocytes following intracytoplasmic sperm injection (ICSI). The two control media for IVM culture were modified TCM199 containing 10% (v/v) porcine follicular fluid (pFF) or 0.05% (w/v) polyvinyl alcohol (PVA), and Cys or beta-ME was supplemented to the PVA-control medium. There was no significant difference in the proportions of in vitro matured oocytes among the four treatment groups (94.5-98.4%). The percentages of pronuclear formation (51.0-64.2%) after ICSI were also not significantly different among the four groups. The cleavage rate (72.8%) in the oocytes treated with Cys showed no significant difference compared with those of the two control media containing pFF (72.2%) or PVA (61.5%), but was higher (P<0.05) than that in the oocytes treated with beta-ME (56.3%). However, the rates of blastocyst formation of Cys (36.7%), beta-ME (27.1%) and pFF (31.4%) were higher (P<0.05) than that using the control medium containing PVA (15.6%). The mean cell number of blastocysts ranged from 42 to 52 among the four groups, without significant differences. In conclusion, the addition of Cys or beta-ME to a defined maturation medium enhanced blastocyst formation after ICSI, to a level similar to that achieved by adding pFF.

Predictive Factors of Virological Non-response to Interferon-ribavirin Combination Therapy for Patients Infected with Hepatitis C Virus of Genotype 1b and High Viral Load

Journal of Medical Virology. Jan, 2006  |  Pubmed ID: 16299715

Patients with high viral load (> or =1.0 x 10(5) IU/ml) of hepatitis C virus (HCV) genotype 1b do not achieve high sustained virological response rates to interferon (IFN)/ribavirin combination therapy. Previous studies suggested that pretreatment amino acid (aa) substitution patterns in the HCV core region could affect virological non-response especially in patients who could not achieve HCV-RNA negativity during treatment. The present study evaluated 167 consecutive Japanese adults with high HCV genotype 1b viral load who received combination therapy for > or =24 weeks. A case-control study matched for age, sex, genotype, and viral load was conducted to investigate the predictive factors for virological non-response, especially absolute virological non-response (patients who could not achieve >2 log decline of HCV RNA from baseline during the initial 24 weeks of therapy). Virological non-response was identified in 26.3% of patients, and 45.5% of these were absolute virological non-responders. Multivariate analysis identified ribavirin dose <11.0 mg/kg, moderate-to-severe hepatocyte steatosis, and substitutions of aa 70 and/or 91 in the core region as significant independent factors associated with virological non-response. The majority of absolute virological non-responders had such substitutions in the core region (95.0%), as well as substitution of glutamine at aa 70 and/or methionine at aa 91 (90.0%). In the present work, such substitutions significantly affected the viral kinetics in virological non-responders. The results suggest that viral, host, and treatment-related factors determine the response to IFN/ribavirin combination therapy in patients with high HCV genotype 1b viral load, and that amino acid substitution patterns in the core region is potentially useful pretreatment predictor of virological non-response.

Virological Outcomes in Patients Infected Chronically with Hepatitis B Virus Genotype A in Comparison with Genotypes B and C

Journal of Medical Virology. Jan, 2006  |  Pubmed ID: 16299721

In a single hospital in Tokyo, the 87 patients infected persistently with hepatitis B virus (HBV) genotype A, the 413 with B, and the 3,389 with C were compared for virological outcome. Hepatitis B surface antigen (HBsAg) was cleared from the serum in 12% (3/26), 2% (2/112), and 3% (23/826) of patients with genotypes A, B, and C, respectively, at 5 years of follow-up (P = 0.0395). Hepatitis B e antigen (HBeAg) was cleared from serum more frequently in patients with genotype B than those with A or C (78% [32/41] vs. 58% [11/19] or 45% [251/562], P = 0.00001) at 5 years. Of the 45 individuals infected with genotype A and followed for 3 years or longer, HBeAg was more frequent (16% [3/19] vs. 73% [19/26], P = 0.0002) and levels of HBV DNA higher (median <2.6 [range: <2.6-5.6] vs. >7.6 [<2.6->7.6] log copies/ml, P = 0.001) in the 26 patients with biopsy-proven chronic hepatitis than the 19 asymptomatic carriers. Among the 26 hepatitis patients infected with HBV genotype A, decreases in HBV DNA were less frequent (20% [1/5] vs. 93% [13/14] or 86% [6/7], P = 0.0095) and increases in serum levels of hyaluronic acid > or =10 ng/ml commoner (80% [4/5] vs. 14% [2/14] or 14% [1/7], P = 0.017) in the patients who kept HBeAg than in those who seroconverted or who remained HBeAg-negative. In conclusion, patients persistently infected with HBV genotype A fare better than those with genotype B or C. However, high levels of HBV DNA continue in those in whom HBeAg persists along with fibrosis in the liver.

Predictive Factors of Early and Sustained Responses to Peginterferon Plus Ribavirin Combination Therapy in Japanese Patients Infected with Hepatitis C Virus Genotype 1b: Amino Acid Substitutions in the Core Region and Low-density Lipoprotein Cholesterol Levels

Journal of Hepatology. Mar, 2007  |  Pubmed ID: 17126448

We showed previously that amino acid (aa) substitutions in the HCV core region (HCV-CR) are predictors of non-virological response (NVR) to peginterferon (PEG-IFN) plus ribavirin (RBV) therapy. Here, we determined the predictive factors of sustained virological response (SVR) and early virologic response (EVR) to this treatment.

Long-term Outcome After Interferon Therapy in Elderly Patients with Chronic Hepatitis C

Intervirology. 2007  |  Pubmed ID: 17164553

The purpose of this study was to elucidate the long-term outcome after interferon (IFN) therapy in chronic hepatitis C elderly patients.

Versatile Roles of R-Ras GAP in Neurite Formation of PC12 Cells and Embryonic Vascular Development

The Journal of Biological Chemistry. Feb, 2007  |  Pubmed ID: 17179160

Ras GTPase-activating proteins (GAP) are negative regulators of Ras that convert active Ras-GTP to inactive Ras-GDP. R-Ras GAP is a membrane-associated molecule with stronger GAP activity for R-Ras, an activator of integrin, than H-Ras. We found that R-Ras GAP is down-regulated during neurite formation in rat pheochromocytoma PC12 cells by nerve growth factor (NGF), which is blocked by the transient expression of R-Ras gap or dominant negative R-ras cDNA. By establishing a PC12 subclone that stably expresses exogenous R-Ras GAP, it was found that NGF reduced endogenous R-Ras GAP but not exogenous R-Ras GAP, suggesting that down-regulation of R-Ras GAP occurs at the transcription level. To clarify the physiological role of R-Ras GAP, we generated mice that express mutant Ras GAP with knocked down activity. While heterozygotes are normal, homozygous mice die at E12.5-13.5 of massive subcutaneous and intraparenchymal bleeding, probably due to underdeveloped adherens junctions between capillary endothelial cells. These results show essential roles of R-Ras GAP in development and differentiation: its expression is needed for embryonic development of blood vessel barriers, whereas its down-regulation facilitates NGF-induced neurite formation of PC12 cells via maintaining activated R-Ras.

A Nucleotide Sequence Variation Detection System for the Core Region of Hepatitis C Virus-1b

Journal of Virological Methods. Apr, 2007  |  Pubmed ID: 17184852

Amino-acid substitution at positions 70 and 91 of the hepatitis C virus (HCV)-1b core region is a factor that contributes to a non-virological response in treatment using interferon/ribavirin combination. In this study, a system was developed for detection of nucleotide sequence variation in the core region that is simpler and less expensive than the current direct sequencing method. A PCR detection method using mutation-specific primers was developed, and amino acids at positions 70 and 91 were identified. The protein type was determined based on band intensity in electrophoresis, and classified into wild (70:R, 91:L), mutant (70:Q/H, 91:M) and competitive types. The detection rate, sensitivity and reproducibility were investigated in 108 patients with HCV-1b who were treated with interferon/ribavirin combination therapy, and correlation with the results of direct sequencing was examined. The detection rate was 94.4%, the sensitivity was 10 KIU/mL, the reproducibility was high, and in detectable cases the consistency with direct sequencing was 97.1%; inconsistency was noted in two competitive-type cases and in one case with an unusual amino-acid substitution. The results suggest that the system described in this paper provides an effective, simple and low-cost approach to detection of nucleotide sequence variation in the core region of HCV-1b.

Long-term Presence of HBV in the Sera of Chronic Hepatitis B Patients with HBsAg Seroclearance

Intervirology. 2007  |  Pubmed ID: 17259734

The aim of this study was to elucidate the presence of serum hepatitis B virus (HBV) DNA at a prolonged time after seroclearance of hepatitis B surface antigen (HBsAg).

Low Serum Level of Hepatitis B Core-related Antigen Indicates Unlikely Reactivation of Hepatitis After Cessation of Lamivudine Therapy

Hepatology Research : the Official Journal of the Japan Society of Hepatology. Aug, 2007  |  Pubmed ID: 17584261

Aim: The clinical significance of hepatitis B virus (HBV) core-related antigen (HBcrAg) in predicting the reactivation of hepatitis after halting lamivudine administration was analyzed. Methods: A total of 34 patients with chronic hepatitis B were enrolled. Lamivudine was administered for at least 6 months before cessation, and reactivation of hepatitis was defined as elevation of alanine aminotransferase levels to more than 80 IU/L within 12 months of cessation. Results: In total, 20 (59%) patients experienced hepatitis reactivation. Although concentrations of HBV DNA and HBcrAg in serum did not differ between the two groups of patients at the onset of lamivudine administration, HBcrAg serum levels were significantly higher (P = 0.009) in the reactivation patients (median 4.9, 25-75% range 4.7- 5.9 log unit/mL) than the non-reactivation patients (median 3.2, 25-75% range <3.0-4.5 log unit/mL) post-lamivudine treatment. The concentration of HBV DNA did not differ between the two groups (median <3.7, 25-75% range <3.7-<3.7 log copy/mL in the reactivation group vs. median <3.7, 25-75% range <3.7-<3.7 log copy/mL in the non- reactivation group). Receiver operating characteristic analysis of HBcrAg concentration showed an area under the curve of 0.764 in predicting patients without reactivation of hepatitis. Conclusion: HBcrAg can be a useful marker to identify patients who are not at risk of reactivation of severe hepatitis after discontinuation of lamivudine administration.

Prolonged-interferon Therapy Reduces Hepatocarcinogenesis in Aged-patients with Chronic Hepatitis C

Journal of Medical Virology. Aug, 2007  |  Pubmed ID: 17597485

The aim of this study was to elucidate the reduction of hepatocarcinogenesis by prolonged interferon (IFN) monotherapy in aged chronic hepatitis C patients. Inclusion criteria were biopsy-proven chronic hepatitis or liver cirrhosis, 60 years and over, elevated serum aminotransferase and positive hepatitis C virus (HCV)-RNA. One hundred and twenty patients satisfied the above criteria were treated with natural IFN-alpha (dose: 3 million unit (MU), two or three times weekly for 0.5-15.5 years, mean 2.47 years) (IFN group). Another 240 patients treated with herbal medicines excluding IFN were selected as control (no-IFN group). The patients not treated with IFN were matched 2:1 with IFN group patients for sex and age. The clinical and biological differences were compared after treatment with the IFN group and the untreated group. Serum alpha-fetoprotein (AFP) level decreased with statistical significance after initiation of treatment with IFN compared to no treatment. The 5- and 10-year cumulative rates of hepatocellular carcinoma (HCC) were 5.9 and 13.7%, and 17.1 and 32.8%, for the IFN and untreated group, respectively. HCC development occurred when histologic staging was advanced, and IFN was not given, the AFP level after treatment was >10 ng/ml. Cox regression analysis indicated that the relative risk of HCC in patients in the IFN group was 0.3 times of that in the untreated patients. The relative risk rate for HCC in severe fibrosis was 3.9 compared with mild or moderate fibrosis. In conclusion, long-term IFN therapy for aged patients with chronic HCV infection is effective in decreasing the serum AFP level and preventing hepatocarcinogenesis.

Ideal Timing of Surgical Repair of Isolated Complete Atrioventricular Septal Defect

Interactive Cardiovascular and Thoracic Surgery. Feb, 2007  |  Pubmed ID: 17669760

The ideal timing and optimal management of surgical repair for isolated complete atrioventricular septal defect (CAVSD) still remains controversial. To determine outcomes after the surgical repair of CAVSD, we reviewed 100 consecutive patients who underwent complete repair at our institute between January 1992 and August 2003. Among these 100 patients, 52 were female and 73 had Down's syndrome. Twelve had received preceding pulmonary artery banding. A two-patch repair was employed in all cases. The patients' median age and weight were 4.5 (1.2-48) months and 4.7 (2.5-12.5) kg, respectively. The mean stays in the intensive care unit and in the hospital were 5.3+/-3.8 and 25.4+/-18.1 days, respectively. The median duration of mechanical ventilation was 11.6 h. There were two in-hospital deaths, in patients 5.2 and 5.9 months of age. Both had underlying Down's syndrome, and significant pulmonary vascular obstructive disease (PVOD) was detected on postmortem specimen. The operative outcome of CAVSD was generally satisfactory. PVOD can progress rapidly from four to five months, especially with Down's syndrome. Therefore, in order to avoid progression to irreversible PVOD, surgical intervention within four months of birth may be appropriate in such patients.

Serum KL-6 Level is Elevated in Chronic Hepatitis C Patients with Combination Therapy of Pegylated Interferon and Ribavirin

Internal Medicine (Tokyo, Japan). 2007  |  Pubmed ID: 17675762

The aim of this study was to evaluate whether or not combination therapy of pegylated interferon (IFN) and ribavirin for chronic hepatitis (CH) C patients enhances the serum level of KL-6, a sensitive marker for interstitial pneumonia.

Prediction of Response to Pegylated Interferon and Ribavirin in Hepatitis C by Polymorphisms in the Viral Core Protein and Very Early Dynamics of Viremia

Intervirology. 2007  |  Pubmed ID: 17728547

To evaluate power of amino acid polymorphisms in core protein of hepatitis C virus (HCV) for predicting sustained virological response (SVR) to pegylated interferon (Peg-IFN)/ribavirin, when they were combined with virological response.

Comparison of Interferon and Lamivudine Treatment in Japanese Patients with HBeAg Positive Chronic Hepatitis B

Journal of Medical Virology. Sep, 2007  |  Pubmed ID: 17607775

The aim of this study was to elucidate the long-term outcome after interferon (IFN) or lamivudine (LMV) treatment in Japanese patients with hepatitis B e antigen (HBeAg) positive chronic hepatitis B. Inclusion criteria were biopsy proven chronic hepatitis or liver cirrhosis, no history of IFN or LMV treatment. Three hundred twenty-seven patients satisfied above criteria were treated with IFN or LMV. The primary end point of our study was serum clearance of HBeAg and decrease of serum HBV-DNA to < or =5 LEG/ml after the initiation of treatment. This study was a retrospective cohort study. Attainment of serum clearance of HBeAg and decrease of serum HBV-DNA to < or =5 LEG/ml was regarded as response. Two hundred eighty-six patients had got response after the initiation of treatment. The cumulative rate of response was 28.0% in the first year, 56.2% at the 5th year and 82.5% at the 10th year. Response occurred when HBV-DNA load was high level of more than 7 LEG/ml, and serum ALT level was more than 100 IU/L, HBV genotype was B. IFN and LMV were the similar effect on response (P = 0.410). On IFN therapy, cumulative rate of response in patients of <35 years was higher than that in patients > or =35 years (P = 0.002). Our results suggest that (1) IFN and LMV are the similar effect on response, (2) IFN therapy is more effective for younger patients.

Amino Acid Substitutions in the Hepatitis C Virus Core Region Are the Important Predictor of Hepatocarcinogenesis

Hepatology (Baltimore, Md.). Nov, 2007  |  Pubmed ID: 17657816

We showed previously that amino acid (aa) substitutions in hepatitis C virus core region (HCV-CR) are negative predictors of virologic response to pegylated interferon (IFN) plus ribavirin therapy. HCV-CR induces hepatocellular carcinoma in transgenic mice, but the clinical impact is still unclear. To evaluate the impact of aa substitutions in HCV-CR on hepatocarcinogenesis, we performed a follow-up study on 313 noncirrhotic consecutive naïve patients infected with HCV genotype 1b who received IFN monotherapy. The median follow-up was 14.7 years. A sustained virologic response (SVR) after the first IFN was achieved by 65 patients (20.8%) (group A). Of 248 patients (79.2%) of non-SVR after first IFN, 112 (35.8%) did not receive additional IFN (group B), and the remaining 136 (43.5%) received multicourse IFN monotherapy (group C). As a whole, cumulative hepatocarcinogenesis rates in double wild-type (arginine at aa 70/leucine at aa 91) of HCV-CR were significantly lower than those in nondouble wild-type. Multivariate analyses identified 3 parameters (fibrosis stage 3, nondouble wild-type of HCV-CR, and group B) that tended to or significantly influenced hepatocarcinogenesis independently. With regard to hepatocarcinogenesis rates in group C according to HCV-CR and the mean alanine aminotransferase (ALT) during IFN-free period, significantly higher rates were noted in patients of nondouble wild-type with ALT levels of more than 1.5 times the upper limit of normal (25.7%) compared with the others (2.4%). Conclusion: Amino acid substitutions in the HCV-CR are the important predictor of hepatocarcinogenesis. In multicourse IFN therapy to nondouble wild-type, we emphasize the importance of reducing the risk of hepatocarcinogenesis by mean ALT during an IFN-free period below 1.5 times the upper limit of normal.

Loss of Hepatitis B Surface Antigen from the Serum of Patients with Chronic Hepatitis Treated with Lamivudine

Journal of Medical Virology. Oct, 2007  |  Pubmed ID: 17705186

Although loss of hepatitis B e antigen (HBeAg) from the serum is sought by treatment with lamivudine, clearance of hepatitis B surface antigen (HBsAg) is the eventual goal of any antiviral therapy. In a single hepatology center in the Metropolitan Tokyo, 486 patients with chronic hepatitis B were followed up for longer than 3 years after they started treatment with lamivudine. HBsAg disappeared from the serum in 17 (3.5%). Age >or=50 years and low HBsAg levels (hemagglutination titer or=50 years at the start of lamivudine was the only factor predicting the loss of HBsAg (hazard ratio: 2.96 [95% confidence interval: 1.14-7.68], P = 0.028). By the method of Kaplan-Meier performed on the 486 patients, the loss of HBsAg was estimated to occur in 3% and 13% of patients, respectively, who had received lamivudine therapy for 5 and 10 years. These results indicate that loss of HBsAg occurs in a minority (3.5%) of patients with chronic hepatitis B who receive lamivudine therapy and more frequently in those with lower HBsAg titers and older ages at the start of treatment.

Interferon-induced Prolonged Biochemical Response Reduces Hepatocarcinogenesis in Hepatitis C Virus Infection

Journal of Medical Virology. Oct, 2007  |  Pubmed ID: 17705189

The aim of this study was to elucidate indicator of interferon (IFN) therapy for reducing hepatocellular carcinoma (HCC) in chronic hepatitis C patients without eradicating hepatitis C virus (HCV) RNA during IFN therapy. Inclusion criteria were biopsy-proven chronic hepatitis or liver cirrhosis, IFN period for more than 1.5 years and persistently positive HCV-RNA during IFN therapy. Two hundred thirty-six patients satisfied above criteria were treated with IFN for 1.5-5 years (median 1.8 years, mean 2 years). Mean age was 55.1 years and male was 145 (61%). Eighty-one (34%) patients had severe fibrosis of the liver. These patients were prospectively monitored about HCC after the termination of IFN therapy. We regarded biochemical response (BR) as normalization of serum aminotransferase and alpha-fetoprotein for more than 1 year during IFN therapy. Cumulative rate of development of HCC after the termination of IFN therapy was 9.1% at 5th year and 26.5% at 10th year. Cox proportional analysis showed that HCC development after the termination of IFN therapy occurred when histological staging was advanced (P < 0.0001) and BR was not achieved (P = 0.009), age was >60 years (P = 0.026). The relative risk of HCC development in patients with BR was 0.36 compared with patients without BR. The attainment of BR during IFN therapy is effective in reducing hepatocarcinogenesis for patients with chronic HCV infection.

Predictors of Viral Kinetics to Peginterferon Plus Ribavirin Combination Therapy in Japanese Patients Infected with Hepatitis C Virus Genotype 1b

Journal of Medical Virology. Nov, 2007  |  Pubmed ID: 17854035

For chronic hepatitis C virus (HCV) infection, evaluation of response to peginterferon (PEG-IFN) plus ribavirin (RBV) therapy based on viral kinetics is useful as an early predictor of treatment efficacy, but the underlying mechanisms of the different viral kinetics to treatment are still unclear. The response to 48-week PEG-IFN-RBV combination therapy was evaluated in 160 Japanese adult patients infected with HCV genotype 1b and determined the rapid virological response (at 4 weeks), early virological response (at 12 weeks), end-of treatment response, and sustained virological response (6 months after end of treatment). The proportion of patients who showed rapid, early and sustained virological, and end-of treatment responses were 50%, 73%, 47%, and 71%, respectively. Furthermore, 66% of patients who achieved early virological response also showed sustained virological response. Multivariate analysis identified substitutions of amino acid (aa) 70 and 91 in the HCV core region (double-wild-type) as a predictor of early HCV-RNA negativity, rapid, early, and sustained virological responses and end-of treatment response, and lipid metabolic factors (high levels of LDL cholesterol and total cholesterol) as predictors of early and rapid virological responses and end-of treatment response. Male sex and low levels of alpha-fetoprotein were other predictors of sustained virological response. Furthermore, female sex and severity of liver fibrosis were determinants of lack of sustained virological response in spite of early virological response. This study identified predictors of efficacy of PEG-IFN-RBV therapy based on viral kinetics in Japanese patients infected with HCV genotype 1b.

Side Effects of Combination Therapy of Peginterferon and Ribavirin for Chronic Hepatitis-C

Internal Medicine (Tokyo, Japan). 2007  |  Pubmed ID: 18025763

The aim of this study was to elucidate the side effects after combination therapy of peginterferon and ribavirin for Japanese patients with chronic hepatitis C.

Prolonged Hepatitis After Acute Infection with Genotype H Hepatitis B Virus

Internal Medicine (Tokyo, Japan). 2007  |  Pubmed ID: 18025766

We present a case report of a Japanese patient who showed prolonged infection after acute hepatitis B with genotype H. The patient was a 60-year-old man who underwent an annual health care check every year for several years and was never pointed out to have any liver damage, and markers for hepatitis B and C were negative. He was found to be positive for hepatitis B surface antigen (HBsAg) at his health care check in December 2005. After one month, he had an elevated aminotransferase level with hepatitis B e antigen and a high level of serum HBV DNA. He was diagnosed as having acute hepatitis B. On HBV genotype, he had genotype H by the direct sequence method, and he was given a 100 mg of lamivudine daily. However, his acute hepatitis tended to go toward prolonged infection. After two months, he was treated with interferon daily for 28 days. He had negative HBsAg in August 2006. Genotype H, the newest type of hepatitis B, could be the type which shows a poor response to lamivudine. The present paper is the first report, describing the clinical course of acute hepatitis B with genotype H from onset to remission.

[Psychiatric Background of Social Withdrawal in Adolescence]

Seishin Shinkeigaku Zasshi = Psychiatria Et Neurologia Japonica. 2007  |  Pubmed ID: 18064873

In recent years, Japan's mental health welfare service personnel are encountering a growing number of adolescents in whom social withdrawal persists for extended periods. The provision of treatment and support for these individuals has become a challenge that needs to be addressed on a nationwide scale. This study was conducted to identify the guidelines for treating and assisting adolescents who manifest social withdrawal behaviors, and to clarify the psychiatrist's role. Of the consultation requests sent to the Yamanashi Prefectural Mental Health Welfare Center, cases of adolescents manifesting social withdrawal behaviors were classified into the following three groups and studied: (1) the Consultation Group (the subject himself/herself came to the center and made use of the consultation and assistance services), (2) the Non-Consultation Group (only the subject's family came to the center for consultation, and the staff were unable to meet him/her), and (3) the Consultation-after-Family Support Group (those subjects in the Consultation Group whom the staff could finally meet after one year or more of consultations with the family). As a result, we learned that adolescent cases of social withdrawal could be diagnosed and classified, in principle, according to the current diagnostic criteria (DSM-IV), and that, from here on, we aim to psychiatrically elucidate the pathology by focusing on international diagnostic criteria. We also showed that, compared with the Consultation Group, the Non-Consultation Group had a greater number of subjects with no employment history. The subjects within this group, moreover, tended to exhibit even more serious problems, and there was a possibility that the family structure and circumstances influenced whether or not the subjects visited the center for consultation. We also determined some of the issues related to assistance and support provided to individuals who fail to come to the center for consultation. Furthermore, we showed the possibility that psychiatry and psychiatrists play a wide variety of roles in dealing with the issue of social withdrawal in adolescence. These include: (a) cases in which a psychiatrist is called upon to provide diagnosis and treatment, (b) cases in which non-medical consultation service institutes play a central role in providing assistance in daily living and matters relating to employment, and a psychiatrist is called upon to provide adequate diagnosis and guidance, and (c) cases in which a psychiatrist collaborates and cooperates with private sector support groups.

Selection of a Virus Strain Resistant to Entecavir in a Nucleoside-naive Patient with Hepatitis B of Genotype H

Journal of Clinical Virology : the Official Publication of the Pan American Society for Clinical Virology. Jun, 2007  |  Pubmed ID: 17442615

Effects of Human Apolipoprotein E Isoforms on the Amyloid Beta-protein Concentration and Lipid Composition in Brain Low-density Membrane Domains

Journal of Neurochemistry. May, 2007  |  Pubmed ID: 17472586

Apolipoprotein E4 (apoE4) encoded by epsilon 4 allele is a strong genetic risk factor for Alzheimer's disease (AD). ApoE4 carriers have accelerated amyloid beta-protein (A beta) deposition in their brains, which may account for their unusual susceptibility to AD. We hypothesized that the accelerated A beta deposition in the brain of apoE4 carriers is mediated through cholesterol-enriched low-density membrane (LDM) domains. Thus, the concentrations of A beta and various lipids in LDM domains were quantified in the brains of homozygous apoE3 and apoE4 knock-in (KI) mice, and in the brains of those mice bred with beta-amyloid precursor protein (APP) transgenic mice (Tg2576). The A beta 40 and A beta 42 concentrations and the A beta 42 proportions in LDM domains did not differ between apoE3 and apoE4 KI mice up to 18 months of age. The A beta 40 concentration in the LDM domains was slightly, but significantly higher in apoE3/APP mice than in apoE4/APP mice. The lipid composition of LDM domains was modulated in an apoE isoform-specific manner, but its significance for A beta deposition remains unknown. These data show that the apoE isoform-specific effects on the A beta concentration in LDM domains do not occur in KI mouse models.

Novel Action of Apolipoprotein E (ApoE): ApoE Isoform Specifically Inhibits Lipid-particle-mediated Cholesterol Release from Neurons

Molecular Neurodegeneration. 2007  |  Pubmed ID: 17504523

Since the majority of apolipoprotein E (apoE) existing in the cerebrospinal fluid is associated with high-density lipoprotein (HDL), one should focus on the role of the apoE-HDL complex rather than on that of free apoE in cholesterol metabolism in the central nervous system. However, the apoE-isoform-specific effect of apoE-HDL on cholesterol transport remains unclarified.

Changes in Viral Loads of Lamivudine-resistant Mutants During Entecavir Therapy

Hepatology Research : the Official Journal of the Japan Society of Hepatology. 2008  |  Pubmed ID: 17573951

Aim: Entecavir therapy is effective against lamivudine-resistant virus in patients with hepatitis B virus infection. We investigated viral load changes of YMDD mutant virus (rtM204I [YIDD sequence], rtM204V [YVDD]) in serial serum samples during entecavir treatment for lamivudine-resistant virus and determined changes in viral precore and core promoter mutants. Methods: Nineteen patients were treated in randomized, double-blind phase II clinical trials of entecavir at 0.5 or 1.0 mg for breakthrough hepatitis due to lamivudine-resistant virus. Viral changes in YMDD mutants (rtM204I, rtM204V), amino acid changes in the polymerase reverse transcriptase region and precore/core promoter mutations at 52 weeks were determined in 18 patients. Results: Changes in viral loads of rtM204I and rtM204V were similar. No differences in load changes were seen betweenthe 0.5 and 1.0 mg groups. However, load changes for rtM204I alone were greater than those for the rtM204I + rtM204V mixed-type (P = 0.042, at both 40 and 52 weeks). Load changes in rtM204I and rtM204V with G1896A tended to be greater than those without. Moreover, G1896A was replaced by wild-type virus in two patients at 52 weeks. Conclusion: RtM204I only or the existence of precore mutation was more sensitive to entecavir therapy against lamivudine-resistant virus.

Generation of a Functional and Durable Vascular Niche by the Adenoviral E4ORF1 Gene

Proceedings of the National Academy of Sciences of the United States of America. Dec, 2008  |  Pubmed ID: 19036927

Vascular cells contribute to organogenesis and tumorigenesis by producing unknown factors. Primary endothelial cells (PECs) provide an instructive platform for identifying factors that support stem cell and tumor homeostasis. However, long-term maintenance of PECs requires stimulation with cytokines and serum, resulting in loss of their angiogenic properties. To circumvent this hurdle, we have discovered that the adenoviral E4ORF1 gene product maintains long-term survival and facilitates organ-specific purification of PECs, while preserving their vascular repertoire for months, in serum/cytokine-free cultures. Lentiviral introduction of E4ORF1 into human PECs (E4ORF1(+) ECs) increased the long-term survival of these cells in serum/cytokine-free conditions, while preserving their in vivo angiogenic potential for tubulogenesis and sprouting. Although E4ORF1, in the absence of mitogenic signals, does not induce proliferation of ECs, stimulation with VEGF-A and/or FGF-2 induced expansion of E4ORF1(+) ECs in a contact-inhibited manner. Indeed, VEGF-A-induced phospho MAPK activation of E4ORF1(+) ECs is comparable with that of naive PECs, suggesting that the VEGF receptors remain functional upon E4ORF1 introduction. E4ORF1(+) ECs inoculated in implanted Matrigel plugs formed functional, patent, humanized microvessels that connected to the murine circulation. E4ORF1(+) ECs also incorporated into neo-vessels of human tumor xenotransplants and supported serum/cytokine-free expansion of leukemic and embryonal carcinoma cells. E4ORF1 augments survival of PECs in part by maintaining FGF-2/FGF-R1 signaling and through tonic Ser-473 phosphorylation of Akt, thereby activating the mTOR and NF-kappaB pathways. Therefore, E4ORF1(+) ECs establish an Akt-dependent durable vascular niche not only for expanding stem and tumor cells but also for interrogating the roles of vascular cells in regulating organ-specific vascularization and tumor neo-angiogenesis.

A Rho-kinase Inhibitor Improves Cardiac Function After 24-hour Heart Preservation

The Journal of Thoracic and Cardiovascular Surgery. Dec, 2008  |  Pubmed ID: 19114210

The Rho-kinase signaling pathway is associated with coronary vasculopathy and myocardial dysfunction after cardiac transplantation. This study evaluated whether using a Rho-kinase inhibitor during allograft storage could limit early endothelial dysfunction and improve myocardial performance after reperfusion.

Effect of Implant Support on Distal-extension Removable Partial Dentures: in Vivo Assessment

The International Journal of Oral & Maxillofacial Implants. Nov-Dec, 2008  |  Pubmed ID: 19216279

The use of a limited number of implants for support of a removable partial denture (RPD) changes a Kennedy Class I or II situation to that of a Class III. This in vivo pilot study evaluated implant-supported distal-extension removable partial dentures (RPD) in 5 partially edentulous patients.

Efficacy in Patients with Dose Reduction in Combination Therapy of Peginterferon and Ribavirin for Chronic Hepatitis C

Intervirology. 2008  |  Pubmed ID: 18309242

The aim of this study was to elucidate efficacy after dose reduction in combination therapy of peginterferon and ribavirin for chronic hepatitis C.

The Efficacy of Short-term Interferon-beta Therapy for Chronic Hepatitis C Patients with Low Virus Load

Internal Medicine (Tokyo, Japan). 2008  |  Pubmed ID: 18310963

The aim of this study was to elucidate the efficacy of short-term interferon (IFN) therapy for chronic hepatitis C patients with low virus load.

Low Risk of Adefovir Resistance in Lamivudine-resistant Chronic Hepatitis B Patients Treated with Adefovir Plus Lamivudine Combination Therapy: Two-year Follow-up

Journal of Hepatology. Jun, 2008  |  Pubmed ID: 18433925

We studied the long-term efficacy (median follow-up of 28 months) of adefovir (ADV) in combination with lamivudine (LAM) in 132 LAM-resistant Japanese patients with chronic genotype C-dominant hepatitis B virus (HBV) infection.

The Effect of Bucolome, a CYP2C9 Inhibitor, on the Pharmacokinetics of Losartan

Drug Metabolism and Pharmacokinetics. 2008  |  Pubmed ID: 18445991

Losartan, a selective angiotensin receptor antagonist, is mainly metabolized by CYP2C9 to an active carboxylic acid, E3174, which is pharmacologically more potent inhibitor than the parent compound. We evaluated the effect of bucolome, a CYP2C9 inhibitor, on the pharmacokinetics of losartan and E3174, which were measured by high performance liquid chromatography in human volunteers and rats. A randomized crossover design study with two phases was done in the volunteer study. In the first phase, the volunteers received losartan 25 mg alone orally (LOS group), and, in the second phase, losartan 25 mg was given after repeated oral administration of 300 mg bucolome for 7 days (LOS+BUC group). In the LOS group, the maximum concentration (C(max)) and area under the concentration curve (AUC) of losartan were significantly higher than in the LOS+BUC group. On the other hand, in the LOS+BUC group, the C(max) and AUC of E3174 were significantly lower than in the LOS group. In the rat study, male Wistar ST rats were used. In the first phase, the rats orally received losartan 10 mg/kg alone or after bucolome was given repeatedly at a dose of 20, 50, or 200 mg/kg for 7 days. In the second phase for steady state, the rats were given losartan 10 mg/kg for 14 days (group A) or losartan 10 mg/kg and bucolome 50 mg/kg for 14 days (Group B). Bucolome at doses 50 and 200 mg/kg significantly increased the AUC losartan and significantly decreased the AUC of 3174. At the steady state, there were no significant differences in AUC of losartan between Group A and B, but the C(max) and AUC of E3174 were significantly lower in Group B than Group A.

Substitution of Amino Acid 70 in the Hepatitis C Virus Core Region of Genotype 1b is an Important Predictor of Elevated Alpha-fetoprotein in Patients Without Hepatocellular Carcinoma

Journal of Medical Virology. Aug, 2008  |  Pubmed ID: 18551609

Previous studies identified amino acid (aa) substitutions of the hepatitis C virus core region of genotype 1b (HCV-1b core region) and elevated serum alpha-fetoprotein (AFP) levels as predictors of poor virologic response to pegylated interferon (PEG-IFN) plus ribavirin (RBV), and also as risk factors for hepatocarcinogenesis. The present study evaluated the impact of aa substitutions of HCV-1b core region on AFP, as a surrogate marker of hepatocarcinogenesis, on AFP levels in 569 Japanese patients with HCV-1b but without HCC, and investigated the predictive factors of elevated AFP (> or =11 microg/L). High AFP levels were detected in 27.4% of the patients. The rate of hepatocarcinogenesis in a group of 109 patients who received IFN monotherapy and followed-up for 15 years, was significantly higher in patients with abnormal than normal AFP. Multivariate analysis of 569 patients identified fibrosis stage (F3,4), aspartate aminotransferase (> or =76 IU/L), substitution of aa 70 (glutamine or histidine), and platelet count (<15.0 x 10(4)/microl) as significant determinants of elevated AFP. In 49 patients with abnormal AFP levels and substitutions at aa 70 who were treated with PEG-IFN + RBV, the rate of normalization of AFP was significantly lower in non-virological responders (28.6%) than in transient (71.4%) and sustained (100%) virological responders. The results indicated that substitution of aa 70 of HCV-1b core region is an important predictor of elevated AFP in non-HCC patients, and that eradication of the mutant virus normalizes AFP. The results highlight the importance of eradication of mutant type virus of aa 70 for reducing the risk of hepatocarcinogenesis.

Efficacy of Low-dose Intermittent Interferon-alpha Monotherapy in Patients Infected with Hepatitis C Virus Genotype 1b Who Were Predicted or Failed to Respond to Pegylated Interferon Plus Ribavirin Combination Therapy

Journal of Medical Virology. Aug, 2008  |  Pubmed ID: 18551610

The efficacy of interferon (IFN) monotherapy for non-responders to pegylated interferon (PEG-IFN) plus ribavirin (RBV) combination therapy is still unclear. To evaluate the impact of IFN monotherapy on biochemical response, 200 consecutive patients infected with HCV genotype 1b, who received low-dose intermittent IFN-alpha monotherapy, were investigated. A median IFN dose per day of 3 million units was administered during a median period of 74 weeks. As a whole, the ALT normalization rates were 50.5, 65.9, 58.4, and 61.7% at 4, 12, 24, and 48 weeks, respectively. In 40 patients, who had abnormal AFP levels at the start of treatment, 52.5% achieved normalization of AFP within 48 weeks. Multivariate analysis identified indocyanine green retention rate at 15 min as the parameter that influenced significantly and independently ALT normalization. ALT normalization rates of patients who were predicted to be poor responders to PEG-IFN plus RBV combination therapy (but not substitutions of amino acid 70 and/or 91 in the HCV core region, female sex, and lower levels of low-density lipoprotein cholesterol) were similar to others. Furthermore, the ALT normalization rates in non-responders to combination therapy were 29.2, 60.9, 60.0, and 40.0% at 4, 12, 24, and 48 weeks, respectively. The results suggest that low-dose intermittent IFN monotherapy is an efficacious therapeutic regimen for patients unsuitable for PEG-IFN plus RBV, including non-responders, because it can lead to ALT normalization and thus a reduced risk of hepatocarcinogenesis.

The Efficacy of Short-term Interferon-beta Therapy for Type C Cirrhotic Patients with Genotype 2a and Low Virus Load

Internal Medicine (Tokyo, Japan). 2008  |  Pubmed ID: 18552464

The aim of this study was to elucidate the efficacy of short-term interferon (IFN) therapy for type C cirrhotic patients with genotype 2a and low virus load.

Suitable Treatment Period in Patients with Virological Response During Combination Therapy of Peginterferon and Ribavirin for Chronic Hepatitis C

Internal Medicine (Tokyo, Japan). 2008  |  Pubmed ID: 18628577

The aim of this study was to determine the suitable treatment period in patients who achieve virological response during combination therapy of peginterferon and ribavirin for chronic hepatitis C virus infection.

Binocular Open-view Shack-Hartmann Wavefront Sensor with Consecutive Measurements of Near Triad and Spherical Aberration

Applied Optics. Sep, 2008  |  Pubmed ID: 18758533

We have developed a binocular open-view Shack-Hartmann wavefront sensor for measuring time variation of binocular accommodation, vergence, pupil sizes (i.e., the binocular near triad), and monochromatic aberrations. The device measures these values16 times per second for up to 1 min. Our purpose is to introduce the new instrument. We have confirmed the accuracy of the device. Refractions for a 4 mm pupil were accurate across the range of measurements of model eyes and normal human eyes. We measured binocular dynamics of accommodation, vergence, and spherical aberrations.

Change of Hepatitis B Virus Genotypes in Acute and Chronic Infections in Japan

Journal of Medical Virology. Nov, 2008  |  Pubmed ID: 18814241

During 35 years from 1971 to 2005, 153 patients with acute and 4,277 with chronic HBV infection visited the Toranomon Hospital in Tokyo, Japan. They were grouped into seven 5-year periods, and HBV genotypes/subgenotypes were determined. Patients with acute HBV infection were younger (P = 0.046), predominantly male (P = 0.004), possessed higher alanine aminotransferase levels (P < 0.001), positive more frequently for HBeAg (P < 0.001), and had lower HBV DNA loads (P = 0.014) than those with chronic infection. Sexual transmission was more frequent in patients with acute than chronic HBV infection (67% vs. 3%, P < 0.001). The number of patients with acute infection increased throughout 1971-2005. Patients with chronic infection increased since 1971, peaked in 1986-1990 and then decreased. The number of patients increased since 1990-2000 again, however, reflecting recent boost of acute HBV infection. The distribution of HBV genotypes was considerably different between patients with acute and chronic infections (A, B, and C: 28.6%, 10.3%, and 59.5% vs. 3.0%, 12.3%, and 84.5%, respectively, P < 0.001). Since 1991, genotype A foreign to Japan started to increase sharply in patients with acute infection, and gradually in those with chronic infection. There was a trend for the foreign subgenotype B2/Ba to increase recently (P < 0.05). Despite immunoprophylaxis of high-risk babies born to carrier mothers with hepatitis B e antigen, implemented nationally since 1986, acute and chronic infections with HBV have been increasing in Japan. Based on genotypes/subgenotypes changing with time, the resurgence of hepatitis B could be attributed to infections, with foreign HBV genotypes/subgenotypes, spreading swiftly by sexual contact.

The Efficacy of 24-week Interferon Monotherapy for Type C Liver Cirrhosis in Japanese Patients with Genotype 1b and Low Virus Load

Intervirology. 2008  |  Pubmed ID: 18841028

The aim of this study was to elucidate the efficacy of interferon (IFN) therapy in liver cirrhosis Japanese patients with genotype 1b and low virus load.

Natural Human Interferon Beta Plus Ribavirin Combination Therapy in Japanese Patients Infected with Hepatitis C Virus and a High Viral Load

Internal Medicine (Tokyo, Japan). 2008  |  Pubmed ID: 18981624

The aim of this pilot study was to determine the safety and efficacy of natural human interferon beta (nIFNbeta) plus ribavirin (RBV) in patients with chronic hepatitis C who did not respond to pegylated interferon alpha (PEG-IFN), with special emphasis on the incidence of mental disorders or refusal for fear of adverse effects.

Virological Response and Hepatocarcinogenesis in Lamivudine-resistant Hepatitis B Virus Genotype C Patients Treated with Lamivudine Plus Adefovir Dipivoxil

Intervirology. 2008  |  Pubmed ID: 19229115

The long-term efficacy of adefovir dipivoxil in combination with lamivudine to chronic hepatitis B virus (HBV) infection is still unclear.

Combination Therapy of Peginterferon and Ribavirin for Chronic Hepatitis C Patients with Genotype 1b and Low-virus Load

Internal Medicine (Tokyo, Japan). 2009  |  Pubmed ID: 19252344

The aim of this study was to evaluate the efficacy of combination therapy of peginterferon and ribavirin in patients infected with hepatitis C virus (HCV) genotype 1b and low virus load.

The Efficacy of Interferon-beta Monotherapy for Elderly Patients with Type C Hepatitis of Genotype 2

Internal Medicine (Tokyo, Japan). 2009  |  Pubmed ID: 19687576

The aim of this study was to elucidate the efficacy of interferon (IFN)-beta monotherapy for elderly patients of > or = 70 years with type C hepatitis (HCV) of genotype 2.

Association of Amino Acid Substitution Pattern in Core Protein of Hepatitis C Virus Genotype 2a High Viral Load and Virological Response to Interferon-ribavirin Combination Therapy

Intervirology. 2009  |  Pubmed ID: 19729953

Substitution of amino acids (aa) 70 and 91 in the core region of HCV genotype 1b is a useful pretreatment predictor of poor response to interferon + ribavirin combination therapy, but the impacts of aa substitutions in the core region of HCV genotype 2a are still not clear.

Development of a Disposable Maglev Centrifugal Blood Pump Intended for One-month Support in Bridge-to-bridge Applications: in Vitro and Initial in Vivo Evaluation

Artificial Organs. Sep, 2009  |  Pubmed ID: 19775262

MedTech Dispo, a disposable maglev centrifugal blood pump with two degrees of freedom magnetic suspension and radial magnetic coupling rotation, has been developed for 1-month extracorporeal circulatory support. As the first stage of a two-stage in vivo evaluation, 2-week evaluation of a prototype MedTech Dispo was conducted. In in vitro study, the pump could produce 5 L/min against 800 mm Hg and the normalized index of hemolysis was 0.0054 +/- 0.0008 g/100 L. In in vivo study, the pump, with its blood-contacting surface coated with biocompatible 2-methacryloyloxyethyl phosphorylcholine polymer, was implanted in seven calves in left heart bypass. Pump performance was stable with a mean flow of 4.49 +/- 0.38 L/min at a mean speed of 2072.1 +/- 64.5 rpm. The maglev control revealed its stability in rotor position during normal activity by the calves. During 2 weeks of operation in two calves which survived the intended study period, no thrombus formation was seen inside the pump and levels of plasma free hemoglobin were maintained below 4 mg/dL. Although further experiments are required, the pump demonstrated the potential for sufficient and reliable performance and biocompatibility in meeting the requirements for cardiopulmonary bypass and 1-week circulatory support.

Glucose Depletion Enhances Sensitivity to Shear Stress-induced Mechanical Damage in Red Blood Cells by Rotary Blood Pumps

Artificial Organs. Sep, 2009  |  Pubmed ID: 19775265

The metabolic process in red blood cells (RBCs) is anaerobic. The life-dependent adenosine triphosphate (ATP) for survival of cells is produced through glycolytic process. The aim of the study was to evaluate the effects of the glucose level on the mean corpuscular volume, mean corpuscular hemoglobin concentration, and hemolysis rate during hemolysis study by rotary blood pumps. The shear stress generated by rotary blood pumps may enhance glucose utilization by RBCs with depletion of glucose affecting ATP production and, consequently, cell size, shape, and morphology. The shear stress increases metabolism of RBCs consuming more energy ATP which is produced anaerobically from glycolytic process. Hence, in the closed circuit testing of rotary blood pumps, depletion of glucose might occur after prolonged pumping, which in turn affects metabolic process of RBCs by changing their size, shape, and morphology. It is thus suggested to monitor and control the glucose level of the fluid that suspends RBCs depending on the study duration.

Implant Overdenture Using Konus Telescope on One-piece Implant: a Case Report

The European Journal of Prosthodontics and Restorative Dentistry. Dec, 2009  |  Pubmed ID: 20158062

An implant-retained Konus (tapered double crown) telescopic complete overdenture was fabricated for a mandibular edentulous patient. The Konus telescopic overdenture coping crowns and framework assembly were cast with commercially pure (CP) titanium, joined using laser welding and placed on four one-piece implants. Sufficient retention and stability were obtained using this method.

Outcomes Following Surgical Repair of Aortic Arch Obstructions with Associated Cardiac Anomalies

European Journal of Cardio-thoracic Surgery : Official Journal of the European Association for Cardio-thoracic Surgery. Apr, 2009  |  Pubmed ID: 19150241

To assess outcomes of surgical repair of aortic arch obstructions with associated cardiac anomalies, we reviewed our institutional experience.

Correlation Between Serum Hepatitis B Virus Core-related Antigen and Intrahepatic Covalently Closed Circular DNA in Chronic Hepatitis B Patients

Journal of Medical Virology. Jan, 2009  |  Pubmed ID: 19031469

Nucleos(t)ide analogues are utilized for the treatment of chronic HBV infection, and HBe seroconversion and HBV DNA levels are commonly used as markers of viral status and as primary treatment endpoints. Recently, a new assay was prepared for the detection of serum HBV core-related antigen (HBcrAg), consisting of HBcAg, HBeAg, and p22cr, which is a precore protein from amino acid -28 to at least amino acid 150, by coding the precore/core region. In this study, we examined the correlation between serum HBcrAg concentration and viral status by the analysis of serum HBeAg, HBsAg, peripheral HBV DNA, and intrahepatic covalently closed circular DNA (cccDNA) in 57 chronic hepatitis B patients. Intrahepatic cccDNA was detected in all 57 patients, 42 patients were HBcrAg-positive, and serum HBcrAg concentration level was closely correlated with cccDNA. Additionally, positive HBcrAg concentration level results were observed in 6 out of 13 HBsAg seroclearance patients and 20 out of 31 HBV DNA-negative patients. Moreover, the correlation between HBcrAg and cccDNA in these 31 HBV DNA-negative patients was statistically significant (r = 0.482, P = 0.006). These data suggest that serum HBcrAg concentration is well correlated with intrahepatic cccDNA level, and that the measurement of serum HBcrAg may be clinically useful for monitoring intrahepatic HBV viral status, especially in patients under treatment with nucleos(t)ide analogues.

Efficacy of Entecavir Treatment for Lamivudine-resistant Hepatitis B over 3 Years: Histological Improvement or Entecavir Resistance?

Journal of Gastroenterology and Hepatology. Mar, 2009  |  Pubmed ID: 19226381

Long-term lamivudine therapy is required for patients with chronic hepatitis B, because hepatitis reappears frequently after it has withdrawn. However, hepatitis B virus (HBV) mutants resistant to lamivudine emerge frequently accompanied by breakthrough hepatitis.

A Matched Case-controlled Study of 48 and 72 Weeks of Peginterferon Plus Ribavirin Combination Therapy in Patients Infected with HCV Genotype 1b in Japan: Amino Acid Substitutions in HCV Core Region As Predictor of Sustained Virological Response

Journal of Medical Virology. Mar, 2009  |  Pubmed ID: 19152407

Substitution of amino acid (aa) 70 and 91 in the core region of HCV genotype 1b is a useful pretreatment predictor of efficacy of 48-week peginterferon (PEG-IFN) plus ribavirin (RBV) therapy. Here, we determined the efficacy of 72-week PEG-IFN/RBV and the predictive factors to such therapy in a case-control study matched for sex, age, and periods from the start of treatment to initial point of HCV RNA-negative. We compared the treatment efficacy of 72-week regimen in 65 patients with that of 48-week in 130 patients, who were infected with HCV genotype 1b and treated with PEG-IFN/RBV. They consisted mainly of late virological responders (LVR) (HCV RNA-positive at 12 weeks and negative at 24 weeks after start of treatment). Sustained virological response (SVR) was achieved by 61.5% and 32.3% of patients of the 72- and 48-week groups, respectively, while non-virological response was noted in 9.2% and 29.2% of the respective groups. Multivariate analysis identified substitution of aa 70 and 91 (Arg70 and/or Leu91) and duration of treatment (72-week) as independent parameters that significantly influenced SVR. For Arg70 and/or Leu91 of core region, SVR rate was significantly higher in 72- (68.0%) than 48-week group (37.8%). For wild-type of ISDR, SVR rate was significantly higher in 72- (61.2%) than in 48-week group (29.3%). We conclude that 72-week PEG-IFN/RBV improves SVR rate for LVR, especially those with Arg70 and/or Leu91 of core region or wild-type of ISDR. Substitution of aa 70 and 91 is also a useful pretreatment predictor of response to 72-week PEG-IFN/RBV.

Engraftment and Reconstitution of Hematopoiesis is Dependent on VEGFR2-mediated Regeneration of Sinusoidal Endothelial Cells

Cell Stem Cell. Mar, 2009  |  Pubmed ID: 19265665

Myelosuppression damages the bone marrow (BM) vascular niche, but it is unclear how regeneration of bone marrow vessels contributes to engraftment of transplanted hematopoietic stem and progenitor cells (HSPCs) and restoration of hematopoiesis. We found that chemotherapy and sublethal irradiation induced minor regression of BM sinusoidal endothelial cells (SECs), while lethal irradiation induced severe regression of SECs and required BM transplantation (BMT) for regeneration. Within the BM, VEGFR2 expression specifically demarcated a continuous network of arterioles and SECs, with arterioles uniquely expressing Sca1 and SECs uniquely expressing VEGFR3. Conditional deletion of VEGFR2 in adult mice blocked regeneration of SECs in sublethally irradiated animals and prevented hematopoietic reconstitution. Similarly, inhibition of VEGFR2 signaling in lethally irradiated wild-type mice rescued with BMT severely impaired SEC reconstruction and prevented engraftment and reconstitution of HSPCs. Therefore, regeneration of SECs via VEGFR2 signaling is essential for engraftment of HSPCs and restoration of hematopoiesis.

Amino Acid Substitutions in the Hepatitis C Virus Core Region of Genotype 1b Are the Important Predictor of Severe Insulin Resistance in Patients Without Cirrhosis and Diabetes Mellitus

Journal of Medical Virology. Jun, 2009  |  Pubmed ID: 19382270

Previous studies provided a direct experimental evidence for the contribution of HCV core protein in the development of insulin resistance (IR), but the clinical impact of HCV core region on IR is still not clear. The present study evaluated the impact of Amino acid (aa) substitutions of HCV-1b core region on IR in 123 Japanese patients infected with HCV-1b without cirrhosis and diabetes mellitus, and investigated the treatment efficacy of 48-week pegylated interferon (PEG-IFN) plus ribavirin (RBV) according to HOMA-IR values. Patients with IR (HOMA-IR > or = 2.5) and severe IR (HOMA-IR > or = 3.5) were present in 51.2% and 27.6%, respectively. Multivariate analysis identified body mass index (> or = 25 kg/m(2)) and hepatocyte steatosis (> or = 5%) as significant determinants of IR. Furthermore, multivariate analysis identified hepatocyte steatosis (> or = 5%), aa substitutions of the core region (Gln70 (His70) and/or Met91), and age (> or = 55 years) as significant determinants of severe IR. Especially, significantly lower proportions of patients with Gln70 (His70) and/or Met91 were noted among those without severe IR (59.6%) than those with severe IR (82.4%). The rates of sustained virological response in patients with IR (50.0%) were not significantly different from those without IR (52.9%). Furthermore, the rates of non-virological response in patients with IR (28.9%) were not significantly also different from those without IR (20.6%). In conclusion, the present study indicated that substitutions of HCV-1b core region were the important predictor of severe IR in patients without cirrhosis and diabetes mellitus, but HOMA-IR values might be not useful as predictors of 48-week PEG-IFN plus RBV therapy.

Development of Hepatocellular Carcinoma in Elderly Patients with Chronic Hepatitis C with or Without Elevated Aspartate and Alanine Aminotransferase Levels

Scandinavian Journal of Gastroenterology. 2009  |  Pubmed ID: 19521923

Hepatocellular carcinoma (HCC) in the elderly infected with hepatitis C virus (HCV) is expected to increase globally within the next two decades. The purpose of the study was to define the natural history of elderly patients with chronic hepatitis C needs in order to prevent HCC from arising in these patients.

Virological and Biochemical Features in Elderly HCV Patients with Hepatocellular Carcinoma: Amino Acid Substitutions in HCV Core Region As Predictor of Mortality After First Treatment

Intervirology. 2009  |  Pubmed ID: 19546575

We showed previously that amino acid (aa) substitutions in HCV genotype 1b (HCV-1b) core region are negative predictors of virological response to peginterferon + ribavirin therapy, and also risk factors of hepatocarcinogenesis. The aim of this study was to evaluate the impact of core aa substitutions on mortality in elderly patients.

Rapid Loss of Hepatitis C Virus Genotype 1b from Serum in Patients Receiving a Triple Treatment with Telaprevir (MP-424), Pegylated Interferon and Ribavirin for 12 Weeks

Hepatology Research : the Official Journal of the Japan Society of Hepatology. Nov, 2009  |  Pubmed ID: 19619256

Aim: To evaluate the efficacy and safety of the triple treatment with telaprevir (MP-424), pegylated interferon (PEG-IFN) and ribavirin during 12 weeks on-treatment. Methods: The triple treatment was given to 20 patients with chronic hepatitis C who had been infected with hepatitis C virus (HCV)-1b in high viral load (median: 6.8 log IU/mL [range: 5.5-7.2]), with a median age of 54 years (range: 36-65 years). They were followed for early dynamics of HCV RNA in serum during 12 weeks and side-effects. Results: HCV RNA levels decreased by 4.8 logs by 7 days and 5.5 logs by 14 days. HCV RNA disappeared in 50% (10/20) at 2 weeks, 79% (15/19) at 4 weeks, 88% (14/16) at 6 weeks, 94% (15/16) at 8 weeks and 100% (13/13) at 12 weeks. HCV RNA disappeared equally frequently in 10 treatment-naive patients, six non-responders to IFN monotherapy and four non-responders to PEG-IFN and ribavirin. It was no different in the patients with and without amino acid substitutions reducing the response to IFN. The treatment was withdrawn in seven (35%) patients, mostly due to reduced hemoglobin of less than 8.5 g/dL, of whom six (86%) remained clear of HCV RNA at 12 weeks. Conclusion: HCV RNA was lost from serum rapidly and universally in patients infected with HCV-1b in high viral loads by the triple treatment. Because an early loss of HCV RNA correlates with high rates of sustained virological response (SVR), it would increase SVR substantially, and merit the patients who have not responded to previous therapies.

Losartan Reduces the Onset of Type 2 Diabetes in Hypertensive Japanese Patients with Chronic Hepatitis C

Journal of Medical Virology. Sep, 2009  |  Pubmed ID: 19623665

The aim of this retrospective cohort study is to assess the cumulative development incidence and predictive factors for type 2 diabetes (T2DM) in HCV positive and hypertensive patients treated with losartan. Eighty Japanese patients were given 50 mg of losartan per day after diagnosis of hypertension (losartan group). Another 160 treated with spironolactone were selected as control (spironolactone group). Patients in spironolactone group were matched 1:2 with losartan group for age and sex. The mean observation period was 5.2 years in losartan group and 5.4 years in spironolactone group. An overnight (12 hr) fasting blood sample or a casual blood sample was taken for routine analyses during follow-up. The primary goal is the onset of T2DM. Evaluation was performed by using the Kaplan-Meier method and the cox proportional hazards analysis. Three patients in losartan group and 20 in spironolactone group developed T2DM. The 5th year cumulative appearance rates of T2DM were 5.4% in losartan group and 14.4% in spironolactone group. Multivariate cox proportional hazards analysis showed that T2DM development after the initiation of anti-hypertensive drugs occurred when anti-hypertensive drug was spironolactone (hazard ratio: 6.10; 95% confidence interval = 1.78-20.84; P = 0.004), histological staging was advanced (hazard ratio: 4.31; 95% confidence interval = 1.94-9.60; P < 0.001), fatty liver was present (hazard ratio: 3.28; 95% confidence interval = 1.47-7.27; P = 0.004), and patient had pre-diabetes (hazard ratio: 2.47; 95% confidence interval = 1.08-5.63; P = 0.032). Our results indicate losartan causes about 60% reduction of the onset of T2DM compared to patients treated with spironolactone.

N-Hexyl-4-aminobutyl Glycosides for Investigating Structures and Biological Functions of Carbohydrates

Organic & Biomolecular Chemistry. Nov, 2009  |  Pubmed ID: 19865710

The potential applications of N-hexyl-4-aminobutyl glycosides in the mass spectrometric investigation of glycan structure and in the investigation of glycan functions were studied. Under collision-induced dissociation (CID) conditions, sodiated glycosides carrying N-hexyl-4-aminobutyl groups effectively produced a hemiacetal species (C-ions), which is important in mass-spectrometry-based structural investigation. The usefulness of N-hexyl-4-aminobutyl glycosides in biological analysis was also confirmed by obtaining a binding constant for the binding of dipyrrometheneboron difluoride C3-labeled N-hexyl-4-aminobutyl beta-lactoside with an Erythrina cristagalli lectin, and by visualizing cellular organelles using a more hydrophobic BODIPY-labeled compound.

Influence of Amino-acid Polymorphism in the Core Protein on Progression of Liver Disease in Patients Infected with Hepatitis C Virus Genotype 1b

Journal of Medical Virology. Jan, 2010  |  Pubmed ID: 19950230

The substitution of amino acid (aa) 70 of arginine for glutamine and/or that of aa91 of leucine for methionine in the core protein in patients infected with hepatitis C virus (HCV) genotype 1b is associated with a poor response to pegylated interferon and ribavirin. Factors influencing these substitutions were sought in 1,097 patients infected with HCV-1b who had not received antiviral treatment. HCV variants with Arg70 and Leu91 (wild-type) decreased, while those with Gln70 and/or Met91 (mutant types) increased with age (P < 0.001). Of the 1,097 patients, 464 (42.3%) were infected with the Gln70 variant and the remaining 633 patients with the Arg70 variant. The proportion of patients with the Gln70 variant increased with the severity of liver disease (P < 0.001), elevated gamma-glutamyl transpeptidase (gamma-GTP) levels (P < 0.001) and a decrease in platelet count (P = 0.008). In univariate analysis patients with hepatocellular carcinoma, elevated aspartate aminotransferase (AST > or = 58 IU/L) and gamma-GTP (> or =61 IU/L), and decreased albumin levels (<3.9 g/dl) were more frequent in the patients with the Gln70 variant than the Arg70 variant (P = 0.003, 0.005, <0.001, and 0.031, respectively). In multivariate analysis HCC (odds ratio 1.829 [95% confidence interval 1.147-2.917]) and gamma-GTP > or =61 IU/L (1.647 [1.268-2.139]) increased the risk for the Gln70 variant. In conclusion, the substitution of amino aa70 of Arg for Gln in patients infected with HCV-1b increases with age, and it is associated with severe liver disease accompanied by elevated AST and gamma-GTP levels, as well as the development of hepatocellular carcinoma.

Association of HLA-DR14 with the Treatment Response in Japanese Patients with Autoimmune Hepatitis

Digestive Diseases and Sciences. Jul, 2010  |  Pubmed ID: 20094777

Influence of human lymphocyte antigen (HLA) on the therapeutic response in autoimmune hepatitis (AIH) is not known.

Protective Effects of Cold Spinoplegia with Fasudil Against Ischemic Spinal Cord Injury in Rabbits

Journal of Vascular Surgery : Official Publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter. Feb, 2010  |  Pubmed ID: 20141964

Paraplegia remains a serious complication after surgical repair of thoracoabdominal aortic aneurysms. The aim of this study was to evaluate the neuroprotective efficacy of fasudil, a Rho kinase (ROCK) inhibitor, by reducing the number of infiltrating cells in the ventral horn and increasing the induction of eNOS against ischemic spinal cord injury in rabbits.

Nature and Duration of Growth Factor Signaling Through Receptor Tyrosine Kinases Regulates HSV-1 Latency in Neurons

Cell Host & Microbe. Oct, 2010  |  Pubmed ID: 20951966

Herpes simplex virus-1 (HSV-1) establishes life-long latency in peripheral neurons where productive replication is suppressed. While periodic reactivation results in virus production, the molecular basis of neuronal latency remains incompletely understood. Using a primary neuronal culture system of HSV-1 latency and reactivation, we show that continuous signaling through the phosphatidylinositol 3-kinase (PI3-K) pathway triggered by nerve growth factor (NGF)-binding to the TrkA receptor tyrosine kinase (RTK) is instrumental in maintaining latent HSV-1. The PI3-K p110α catalytic subunit, but not the β or δ isoforms, is specifically required to activate 3-phosphoinositide-dependent protein kinase-1 (PDK1) and sustain latency. Disrupting this pathway leads to virus reactivation. EGF and GDNF, two other growth factors capable of activating PI3-K and PDK1 but that differ from NGF in their ability to persistently activate Akt, do not fully support HSV-1 latency. Thus, the nature of RTK signaling is a critical host parameter that regulates the HSV-1 latent-lytic switch.

Performance of Extracorporeally Adjustable Ventricular Assist Device Inflow Cannula

The Annals of Thoracic Surgery. Nov, 2010  |  Pubmed ID: 20971290

This study evaluated the feasibility and efficacy of a newly developed adjustable left ventricular assist device inflow cannula in a short-term calf model.

Angiocrine Factors from Akt-activated Endothelial Cells Balance Self-renewal and Differentiation of Haematopoietic Stem Cells

Nature Cell Biology. Nov, 2010  |  Pubmed ID: 20972423

Endothelial cells establish an instructive vascular niche that reconstitutes haematopoietic stem and progenitor cells (HSPCs) through release of specific paracrine growth factors, known as angiocrine factors. However, the mechanism by which endothelial cells balance the rate of proliferation and lineage-specific differentiation of HSPCs is unknown. Here, we demonstrate that Akt activation in endothelial cells, through recruitment of mTOR, but not the FoxO pathway, upregulates specific angiocrine factors that support expansion of CD34(-)Flt3(-) KLS HSPCs with long-term haematopoietic stem cell (LT-HSC) repopulation capacity. Conversely, co-activation of Akt-stimulated endothelial cells with p42/44 MAPK shifts the balance towards maintenance and differentiation of the HSPCs. Selective activation of Akt1 in the endothelial cells of adult mice increased the number of colony forming units in the spleen and CD34(-)Flt3(-) KLS HSPCs with LT-HSC activity in the bone marrow, accelerating haematopoietic recovery. Therefore, the activation state of endothelial cells modulates reconstitution of HSPCs through the modulation of angiocrine factors, with Akt-mTOR-activated endothelial cells supporting the self-renewal of LT-HSCs and expansion of HSPCs, whereas MAPK co-activation favours maintenance and lineage-specific differentiation of HSPCs.

Clinical and Virological Effects of Long-term (over 5 Years) Lamivudine Therapy

Journal of Medical Virology. Apr, 2010  |  Pubmed ID: 20166170

Ideally, long-term lamivudine therapy should not induce tyrosine-methionine-aspartate-aspartate (YMDD) mutants (reverse transcription [rt]; rt M204I/V) in patients with chronic hepatitis B. There is little or no information on the clinical features of patients who do not develop such mutants. We analyzed 368 patients who received lamivudine therapy for more than 6 months between 1995 and 2003. Among them, 98 patients were negative for YMDD mutants during 5-year lamivudine therapy. Multivariate analysis identified hepatitis B e antigen (HBeAg) negativity, lack of cirrhosis, and high gamma glutamyltranspeptidase (GGTP) level as independent factors associated with lack of emergence of YMDD mutants during 5-year treatment. In these 98 patients, 21 patients developed YMDD mutants in the 5-year posttreatment follow-up. Old age was identified as the only factor associated with the emergence of YMDD mutants during that period. For all patients, 53 showed no elevation of alanine aminotransferase (ALT) or viral load after emergence of YMDD mutants during 5 years. Short latency to emergence of YMDD mutants, mixed (tyrosine-isoleucine-aspartate-aspartate (YIDD) [rtM204I] + tyrosine-valine-aspartate-aspartate (YVDD) [rtM204V]) type, and low ALT level were identified as independent factors associated with elevation ALT or viral load. HBeAg negativity, lack of cirrhosis, and high GGTP level were associated with lack of emergence of YMDD mutants during 5-year period. Young age protected against emergence of YMDD mutants over the 5-year period. Moreover, after the emergence of YMDD mutants, short latency to the emergence of YMDD mutant, mixed type mutants, and low baseline ALT level were associated with elevation of ALT or viral load.

Amino Acid Substitutions in the Hepatitis C Virus Core Region of Genotype 1b Affect Very Early Viral Dynamics During Treatment with Telaprevir, Peginterferon, and Ribavirin

Journal of Medical Virology. Apr, 2010  |  Pubmed ID: 20166188

Substitution of amino acid (aa) 70 and 91 in the core region of hepatitis C virus (HCV) genotype 1b can predict the response to pegylated interferon (PEG-IFN)/ribavirin combination therapy, but its impact on triple therapy of telaprevir/PEG-IFN/ribavirin is not clear. The aims of this study were to investigate the rate of HCV RNA loss following 12-week triple therapy, and determine the effect of aa substitutions on very early (within 48 hr) viral dynamics. Sixty-seven patients infected with HCV genotype 1b (HCV-1b) and high viral load who received 12-week triple therapy were studied. RNA loss could be achieved in 2%, 34%, 80%, 92%, 95%, 94%, and 90% of the patients after 1, 2, 4, 6, 8, 10, and 12 weeks of triple therapy, respectively. After 24-hr treatment, the proportion of patients with Arg70 and Leu91 substitutions with > or = 3.0 log fall in HCV RNA was significantly higher than those with < 3.0 log fall (P = 0.008). However, the aa substitution patterns in the core region did not influence the fall in HCV RNA after 48-hr treatment. Multivariate analysis identified substitutions of aa 70 and 91 (P = 0.014) and level of viremia at baseline (> or = 7.0 log IU/ml; P = 0.085) as independent parameters that determined the > or = 3.0 log fall in HCV RNA level after 24-hr triple therapy. It is concluded that 12-week triple therapy achieved high rates of loss of HCV RNA in Japanese patients infected with HCV-1b and high viral load, and that the aa substitution pattern in the core region seems to influence very early viral dynamics.

Extending Combination Therapy with Peginterferon Plus Ribavirin for Genotype 2 Chronic Hepatitis C Virological Responders: a Pilot Study of 7 Cases

Intervirology. 2010  |  Pubmed ID: 20197686

In treatment-resistant patients with genotype 2 chronic hepatitis C the suitable treatment duration is still unclear. The aims were to investigate extending combination therapy with peginterferon plus ribavirin for genotype 2.

Endothelial Cells Are Essential for the Self-renewal and Repopulation of Notch-dependent Hematopoietic Stem Cells

Cell Stem Cell. Mar, 2010  |  Pubmed ID: 20207228

Bone marrow endothelial cells (ECs) are essential for reconstitution of hematopoiesis, but their role in self-renewal of long-term hematopoietic stem cells (LT-HSCs) is unknown. We have developed angiogenic models to demonstrate that EC-derived angiocrine growth factors support in vitro self-renewal and in vivo repopulation of authentic LT-HSCs. In serum/cytokine-free cocultures, ECs, through direct cellular contact, stimulated incremental expansion of repopulating CD34(-)Flt3(-)cKit(+)Lineage(-)Sca1(+) LT-HSCs, which retained their self-renewal ability, as determined by single-cell and serial transplantation assays. Angiocrine expression of Notch ligands by ECs promoted proliferation and prevented exhaustion of LT-HSCs derived from wild-type, but not Notch1/Notch2-deficient, mice. In transgenic notch-reporter (TNR.Gfp) mice, regenerating TNR.Gfp(+) LT-HSCs were detected in cellular contact with sinusoidal ECs. Interference with angiocrine, but not perfusion, function of SECs impaired repopulation of TNR.Gfp(+) LT-HSCs. ECs establish an instructive vascular niche for clinical-scale expansion of LT-HSCs and a cellular platform to identify stem cell-active trophogens.

Early in Vivo Evaluation of Ventricular Assistance with a Miniature Centrifugal Blood Pump (TinyPump) in Rabbits

ASAIO Journal (American Society for Artificial Internal Organs : 1992). May-Jun, 2010  |  Pubmed ID: 20335798

We have developed an ultraminiature centrifugal pump, TinyPump, with a priming volume of 5 ml. The in vivo performance of TinyPump was compared with that of HPM-05 for left ventricular support. Each pump group included seven rabbits weighing 3.4-3.8 kg. One rabbit in the TinyPump group and two rabbits in the HPM-05 group died of unsuccessful cannulation. The remaining rabbits (six in the TinyPump group and five in the HPM-05 group) were instrumented and observed for 240 minutes. The pump flow was maintained at around 200 ml/min. The priming volumes of the entire circuits were 25 and 45 ml for TinyPump and HPM-05, respectively. TinyPump required a higher rotation speed (2214 +/- 47 vs. 1261 +/- 87 rpm, p < 0.05) because of its small priming volume but showed a similar plasma free hemoglobin level to HPM-05. The hematocrit values were kept higher in the TinyPump group during ventricular support (24.3 +/- 1.4% vs. 20.1 +/- 1.4% at 240 minutes, p < 0.05). The mean arterial pressure did not differ between the two groups. The biochemical parameters were also equivalent in the two groups. Overall, TinyPump exhibited a feasible in vivo performance. This ultraminiature device would offer promising outcomes for neonates and infants with intractable heart failure.

[Cost-effectiveness Analysis of Chemotherapy with GEM or S-1 for Patients with Non-resectable Pancreatic Cancer]

Gan to Kagaku Ryoho. Cancer & Chemotherapy. Apr, 2010  |  Pubmed ID: 20414022

To assess the cost-effectiveness of chemotherapy for patients with non-resectable pancreatic cancer, we compared two regimens containing either gemcitabine (GEM) or S-1.

Efficacy and Safety of Combination Therapy of Natural Human Interferon Beta and Ribavirin in Chronic Hepatitis C Patients with Genotype 1b and High Virus Load

Internal Medicine (Tokyo, Japan). 2010  |  Pubmed ID: 20519809

The aim of this study was to evaluate the efficacy of combination therapy of natural human interferon-beta and ribavirin in patients infected with hepatitis C virus (HCV) genotype 1b.

Efficacy and Safety of Combination Therapy of Natural Human Interferon Beta and Ribavirin in Chronic Hepatitis C Patients with Genotype 2 and High Virus Load

Internal Medicine (Tokyo, Japan). 2010  |  Pubmed ID: 20519810

The aim of this study was to evaluate the efficacy of combination therapy of natural human interferon-beta and ribavirin in patients infected with hepatitis C virus (HCV) genotype 2 and high virus load.

Efficacy of Switching to Entecavir Monotherapy in Japanese Lamivudine-pretreated Patients

Journal of Gastroenterology and Hepatology. May, 2010  |  Pubmed ID: 20546442

To assess the efficacy of switching Japanese chronic hepatitis B patients from lamivudine monotherapy to entecavir 0.5 mg/day.

Amino Acid Substitution in Hepatitis C Virus Core Region and Genetic Variation Near the Interleukin 28B Gene Predict Viral Response to Telaprevir with Peginterferon and Ribavirin

Hepatology (Baltimore, Md.). Aug, 2010  |  Pubmed ID: 20648473

Genetic variation near the IL28B gene and substitution of amino acid (aa) 70 and 91 in the core region of hepatitis C virus (HCV) genotype 1b can predict the response to pegylated interferon (PEG-IFN)/ribavirin combination therapy, but its impact on triple therapy of telaprevir/PEG-IFN/ribavirin is not clear. The aims of this study were to investigate the predictive factors of sustained virological response to a 12-week or 24-week regimen of triple therapy in 72 of 81 Japanese adults infected with HCV genotype 1. Overall, sustained virological response and end-of-treatment response were achieved by 61% and 89%, respectively. Especially, the sustained virological response was achieved by 45% and 67% in the 12- and 24-week regimens, respectively. Multivariate analysis identified rs8099917 near the IL28B gene (genotype TT) and substitution at aa 70 (Arg70) as significant determinants of sustained virological response. Prediction of response to therapy based on a combination of these factors had high sensitivity, specificity, and positive and negative predictive values. The efficacy of triple therapy was high in the patients with genotype TT, who accomplished sustained virological response (84%), irrespective of substitution of core aa 70. In the patients having genotype non-TT, those of Arg70 gained high sustained virological response (50%), and sustained virological response (12%) was the worst in patients who possessed both genotype non-TT and Gln70(His70). Conclusion: This study identified genetic variation near the IL28B gene and aa substitution of the core region as predictors of sustained virological response to a triple therapy of telaprevir/PEG-IFN/ribavirin in Japanese patients infected with HCV genotype 1b.

HBcrAg is a Predictor of Post-treatment Recurrence of Hepatocellular Carcinoma During Antiviral Therapy

Liver International : Official Journal of the International Association for the Study of the Liver. Nov, 2010  |  Pubmed ID: 20840396

The recurrence rate of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) is high even in patients receiving curative therapy. In this study, we analysed the risk factors for tumour recurrence after curative therapy for HBV-related HCC while under treatment with nucleot(s)ide analogues (NAs) by measuring serum HBcrAg and intrahepatic covalently closed circular DNA (cccDNA) levels to elucidate the viral status associated with HCC recurrence.

Correlation of YMDD Mutation and Breakthrough Hepatitis with Hepatitis B Virus DNA and Serum ALT During Lamivudine Treatment

Hepatology Research : the Official Journal of the Japan Society of Hepatology. Feb, 2010  |  Pubmed ID: 19788696

Aim: Continuous lamivudine treatment is associated with high frequency of drug resistance. We analyzed the incidence of tyrosine-methionine-aspartate-aspartate (YMDD) motif mutant and breakthrough hepatitis (BTH) in hepatitis B virus (HBV) DNA positive patients receiving lamivudine for > 1 year and correlated it with HBV DNA and alanine aminotransferase (ALT) levels to evaluate if these measurements can provide a practical option for monitoring patients in clinical practice and define early switch from lamivudine therapy. Methods: Of the 929 patients receiving lamivudine for > 1 year, 359 patients who maintained an ALT level of /= 3 years. Results: The incidence of YMDD motif in patients receiving lamivudine for < 3 years was 27% in patients with ALT

Sustained Virological Response in a Patient with Chronic Hepatitis C Treated by Monotherapy with the NS3-4A Protease Inhibitor Telaprevir

Journal of Clinical Virology : the Official Publication of the Pan American Society for Clinical Virology. Jan, 2010  |  Pubmed ID: 19857995

Here, we describe for the first time a case of sustained virological response (SVR) achieved in a patient with chronic hepatitis C (CH-C) by monotherapy with a NS3-4A protease inhibitor, telaprevir, without interferon therapy. A 59-year-old treatment-naïve Japanese man was enrolled in a phase II trial of telaprevir by repeat oral administration at a dose of 750mg every 8h for 24 weeks. At the start of treatment, he exhibited a low-level viremia with genotype 1b of the hepatitis C virus (HCV). After the first week of treatment with telaprevir, serum HCV RNA was undetectable, and negativity remained until the end of treatment. Moreover, he was evaluated as having a SVR after the post-treatment 24-week follow-up program. Two characteristics may explain the strong antiviral activity of telaprevir in the present case. First, although pre-treatment PCR-direct sequencing and cloning for the N-terminal in the NS3 region showed a protease inhibitor-resistant variant (T54A) in 1 of 32 independent clones, the T54A substitution has only a low-level resistance to protease inhibitors and his viral load was low. Second, when compared to a consequence sequence of 35 treatment-naïve patients with HCV genotype 1b, R130K and Q195K substitutions were unique to the present case. Although it is presently unknown whether the R130K and Q195K substitutions are related to SVR, this case suggests that long-term telaprevir monotherapy may be effective in CH-C patients with genotype 1 and a low viral load.

Rapid Detection of Drug-resistant Mutations in Hepatitis B Virus by the PCR-Invader Assay

Journal of Virological Methods. Jan, 2011  |  Pubmed ID: 20950650

Early detection of resistant mutations of hepatitis B virus (HBV) is important for patients on nucleos(t)ide analog therapy. An assay based on the PCR-Invader technology was developed to detect resistant mutations with high sensitivity. The assay specifically detects mutations at codons 180, 181, 184, 202, 204, and 250 of the HBV polymerase reverse transcriptase domain. These mutations result in resistance to lamivudine and entecavir. In mixtures of plasmids containing wild-type and resistant mutants, fold-over-zero values for resistant mutations were detected in 2% of the total. Seventy-five serum samples from patients, whose treatment had been switched from lamivudine to entecavir, were examined by the PCR-Invader assay and direct sequencing. The PCR-Invader assay detected all resistant mutations that were detected by direct sequencing and even detected the presence of mutants that direct sequencing could not. Cloning sequencing confirmed those mutations found by the PCR-Invader assay and not by direct sequencing. The PCR-Invader assay is a useful tool for the early detection of drug-resistant mutations.

HCV Substitutions and IL28B Polymorphisms on Outcome of Peg-interferon Plus Ribavirin Combination Therapy

Gut. Feb, 2011  |  Pubmed ID: 21068134

A number of recent studies have shown that human polymorphisms near the IL28B type III interferon (IFNλ) gene influence the response to peg-interferon plus ribavirin combination therapy for infection with chronic hepatitis C virus (HCV). Viral polymorphisms, including substitutions within the HCV core and NS5A proteins, have also been shown to influence treatment outcome, but it is not known whether these factors act independently of the IL28B polymorphism or if they reflect the same or a different underlying mechanism. Multiple logistic regression was used to determine whether host and viral polymorphisms independently predict sustained virological response (SVR).

Accuracy of Oral Mucosal Thickness Measurements Using Spiral Computed Tomography

Journal of Periodontology. Jun, 2011  |  Pubmed ID: 21073331

Assessment of oral mucosal thickness is important in implant surgery; however, examining the soft tissue three dimensionally is difficult. A reamer method is invasive, and a non-invasive ultrasonic method produces only low-resolution images depending on anatomic variations. The emerging technology of spiral computed tomography (CT) is an alternative to the conventional methods. Spiral CT has been a useful diagnostic tool in implant surgery. Although it delivers high radiation doses, spiral CT provides three-dimensional imaging of low-contrast structures. The purpose of the present study is to assess the accuracy of oral mucosal measurements using spiral CT.

Influence of ITPA Polymorphisms on Decreases of Hemoglobin During Treatment with Pegylated Interferon, Ribavirin, and Telaprevir

Hepatology (Baltimore, Md.). Feb, 2011  |  Pubmed ID: 21246582

Polymorphisms of the inosine triphosphatase (ITPA) gene influence anemia during pegylated interferon (PEG-IFN) and ribavirin (RBV) therapy, but their effects during triple therapy with PEG-IFN, RBV, and telaprevir are not known. Triple therapy for 12 weeks, followed by PEG-IFN and RBV for 12 weeks, was given to 49 patients with RBV-sensitive (CC at rs1127354) and 12 with RBV-resistant (CA/AA) ITPA genotypes who had been infected with hepatitis C virus (HCV) of genotype 1. Decreases in hemoglobin levels were greater in patients with CC than CA/AA genotypes at week 2 (-1.63 ± 0.92 vs. -0.48 ± 0.75 g/dL, P = 0.001) and week 4 (-3.5 ± 1.1 vs. -2.2 ± 0.96, P = 0.001), as well as at the end of treatment (-2.9 ± 1.1 vs. -2.0 ± 0.86, P = 0.013). Risk factors for hemoglobin <11.0 g/dL at week 4 were female gender, age >50 years, body mass index (BMI) <23, and CC at rs1127354 by multivariate analysis. RBV dose during the first 12 weeks was smaller in patients with CC than CA/AA genotypes (52 ± 14% vs. 65 ± 21% of the target dose, P = 0.039), but the total RBV dose was no different between them (49 ± 17% and 54 ± 18% of the target, P = 0.531). Sustained virological response (SVR) was achieved in 70% and 64% of them, respectively (P = 0.724). CONCLUSION: ITPA polymorphism influences hemoglobin levels during triple therapy, particularly during the first 12 weeks while telaprevir is given. With careful monitoring of anemia and prompt adjustment of RBV dose, SVR can be achieved comparably frequently between patients with CC and CA/AA genotypes.

Amino Acid Substitution in HCV Core Region and Genetic Variation Near the IL28B Gene Affect Viral Dynamics During Telaprevir, Peginterferon and Ribavirin Treatment

Intervirology. Feb, 2011  |  Pubmed ID: 21325786

Objectives: Genetic variation near the IL28B gene and substitution of aa 70 and 91 in the core region of HCV-1b are useful as predictors of treatment efficacy to telaprevir/pegylated interferon (PEG-IFN)/ribavirin, but its impact on viral dynamics is not clear. Methods: This study investigated predictive factors of viral dynamics during 12- or 24-week regimen of triple therapy in 80 Japanese adults infected with HCV-1b. Results: After 24 h of commencement of treatment, the proportion of patients with Arg70 and Leu91 substitutions in the core region who showed ≥3.0 log drop in HCV RNA level was significantly higher than that of patients with Gln70 (His70) and/or Met91. At 8 and 12 weeks, HCV RNA loss rate of patients with rs8099917 genotype TT near IL28B gene was significantly higher than that of patients with non-TT. Multivariate analysis identified substitution of aa 70 and 91 as a predictor of ≥3.0 log fall in HCV RNA level at 24 h (Arg70 and Leu91) and SVR (Arg70), and rs8099917 (TT) as a predictor of HCV RNA loss at 12 weeks and SVR. Conclusions: This study identified genetic variation near IL28B gene and aa substitution of the core region as predictors of viral dynamics during triple therapy.

Efficacy and Safety in Sitagliptin Therapy for Diabetes Complicated by Chronic Liver Disease Caused by Hepatitis C Virus

Hepatology Research : the Official Journal of the Japan Society of Hepatology. Jun, 2011  |  Pubmed ID: 21435130

Aim:  Diabetes is present in patients with chronic liver disease caused by hepatitis C virus (HCV). The aim of this case-control study is to assess the efficacy and safety of dipeptidyl peptidase-4 inhibitor (sitagliptin) for type 2 diabetes mellitus (T2DM) with chronic liver disease caused by HCV. Methods:  Sixteen HCV positive patients with T2DM treated by sitagliptin were retrospectively enrolled. These patients were given sitagliptin between December 2009 and January 2010. Another 16 HCV patients with T2DM treated only with diet and excise for 48 weeks were selected as the control group. Serum levels of fasting plasma glucose (FPG), hemoglobin A1C (HbA1C), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were measured before and 12, 24, 36 and 48 weeks after the initiation of treatment. Results:  In the sitagliptin group, the average HbA1C level decreased approximately 0.8% at 48 weeks after the initiation of sitagliptin. Next, the average FPG level decreased approximately 20 mg/dL during follow up after the initiation of sitagliptin. All the patients were able to take sitagliptin of 50 mg/day without reduction because of sitagliptin-related side-effects. On the other hand, in the control group, the average HbA1C and FPG level did not change with statistical significance during follow up of 48 weeks. Regarding aminotransferase, there were no significant changes of average AST and ALT level during follow up of 48 weeks in both the sitagliptin group and control group. Conclusion:  Our results indicate that sitagliptin is effective and safe for the treatment of T2DM complicated with HCV positive chronic liver disease.

Amino Acid Substitutions in Hepatitis C Virus Core Region Predict Hepatocarcinogenesis Following Eradication of HCV RNA by Antiviral Therapy

Journal of Medical Virology. Jun, 2011  |  Pubmed ID: 21503914

Substitution of amino acid (aa) 70 and/or 91 in the core region of HCV genotype 1b (HCV-1b) is an important predictor of hepatocarcinogenesis, but its impact on the development of hepatocellular carcinoma (HCC) following eradication of HCV RNA by antiviral therapy is not clear. 1,273 patients with HCV-related chronic liver disease, with sustained virological response, defined as negative HCV RNA at 24 weeks after cessation of interferon monotherapy or interferon plus ribavirin combination therapy, were included in a follow-up study to evaluate the impact of aa substitution in the core region on hepatocarcinogenesis. Twenty six patients developed HCC during the follow-up. The cumulative rates of new HCC were 3.2%, 4.8%, and 8.6% at the end of 5, 10, and 15 years, respectively. The rates in patients infected with HCV-1b/Gln70(His70) [glutamine (histidine) at aa 70] were significantly higher than in patients infected with HCV-1b/Arg70 (arginine at aa 70) (P = 0.007; log-rank test) and HCV-2a/2b (P < 0.001; log-rank test). The rates in patients infected with HCV-1b/Arg70 were not significantly higher than in those infected with HCV-2a/2b (P = 0.617; log-rank test). Multivariate analysis identified HCV-1b/Gln70(His70) (HR 10.5, P < 0.001), advanced fibrosis (HR 9.03, P = 0.002), and old age (HR 3.09, P = 0.066) as determinants of hepatocarcinogenesis. In conclusion, aa substitution in the core region of HCV-1b at the start of antiviral therapy is an important predictor of HCC following eradication of HCV RNA. This study emphasizes the importance of detection of aa substitutions in the core region before antiviral therapy.

Common Genetic Polymorphism of ITPA Gene Affects Ribavirin-induced Anemia and Effect of Peg-interferon Plus Ribavirin Therapy

Journal of Medical Virology. Jun, 2011  |  Pubmed ID: 21503919

An association between a single nucleotide polymorphism (SNP) in the inosine triphosphate pyrophosphatase (ITPA) gene and reduction of hemoglobin during peg-interferon plus ribavirin combination therapy for patients with chronic hepatitis C virus (HCV) infection has been reported. However, the effect of the SNP on outcome of therapy has not been fully elucidated. Factors associated with anemia during combination therapy, including rs1127354 genotype, were analyzed in 1,002 treated patients. The effect of the SNP on outcome of therapy was analyzed in a subset of 830 patients with genotype 1. A rapid initial decrease in hemoglobin levels was observed in patients with rs1127354 genotype CC compared with a slow decrease in non-CC patients. Cumulative reduction of ribavirin was significantly more frequent in genotype CC patients than non-CC patients (odds ratio 1.928, P = 8.6 × 10(-8) ). The frequency of patients who received at least the recommended 80% of scheduled ribavirin was significantly lower among genotype CC patients, especially among those who had pretreatment hemoglobin levels between 13.5 and 15 g/dl (P < 0.03), and the sustained viral response rate was significantly lower in this group of patients. Independent predictive factors for sustained virological response included a SNP in the IL28B locus (rs809991), age, fibrosis, ITPA SNP rs1127354 as well as pretreatment hemoglobin levels. Our data suggests that measures to prevent anemia should be considered for patients who have pretreatment hemoglobin levels less than 13.5 g/dl or who have rs1127354 genotype CC and pretreatment hemoglobin levels between 13.5 and 15 g/dl.

The Development of Chronic Kidney Disease in Japanese Patients with Non-alcoholic Fatty Liver Disease

Internal Medicine (Tokyo, Japan). 2011  |  Pubmed ID: 21576832

Objective Chronic kidney disease (CKD) is present in patients with nonalcoholic fatty liver disease (NAFLD). The aim of this retrospective study was to assess the cumulative development incidence and predictive factors for new onset of CKD in Japanese patients with NAFLD. Methods A total of 5,561 NAFLD patients without CKD were enrolled. CKD was defined as either an estimated glomerular filtration rate of <60 mL/min/1.73 m(2) or dipstick proteinuria (≥+1). A blood sample and a urine sample were taken for routine analyses during follow-up. The mean observation period was 5.5 years. The primary goal is the new development of CKD. Independent factors associated with new development of CKD were analyzed by using the Kaplan-Meyer method and the Cox proportional hazards model. Results Of 5.561 NAFLD patients, 263 patients developed CKD. The cumulative development rate of CKD was 3.1% at the 5th year and 12.2% at the 10th year. Multivariate Cox proportional hazards analysis showed that CKD development in patients with NAFLD occurred when patient had low level of GFR of 60-75 mL/min/1.73 m(2) [hazard ratio:2.75; 95% confidence interval (CI)=1.93-3.94; p<0.001], age of ≥50 years (hazard ratio: 2.67; 95% CI=2.06-3.46; p<0.001), diabetes (hazard ratio: 1.92; 95% CI=1.45-2.54; p<0.001), hypertension (hazard ratio: 1.69; 95% CI=1.25-2.29; p<0.001), and elevated serum gamma-glutamyltransferase of ≥109 IU/L (hazard ratio: 1.35; 95% CI=1.02-1.78; p=0.038). Conclusion Our retrospective study indicates that the annual incidence of CKD in Japanese patients with NAFLD is about 1.2%. Five factors of low eGFR level, aging, type 2 diabetes, hypertension, and elevated gamma-glutamyltransferase, increases the risk of the development of CKD.

In Vivo Evaluation of the "TinyPump" As a Pediatric Left Ventricular Assist Device

Artificial Organs. May, 2011  |  Pubmed ID: 21595723

Pediatric patients with end-stage heart failure require mechanical circulatory support (MCS) just as adults do. In order to meet the special requirements for neonates' and infants' MCS, pediatric circulatory support devices must be compact with low priming volume, easily controllable with low flow, less traumatic for blood cells and tissues, and biocompatible with minimum anticoagulation. We have designed and developed a miniature rotary centrifugal blood pump, "TinyPump," with a priming volume of 5 mL, which has already demonstrated its controllable performance for low flow and durability in vitro. To evaluate the feasibility of the TinyPump as a left ventricular assist device (LVAD) suitable for neonates and infants, we have examined the biocompatibility and hemodynamic performance of the TinyPump in a pediatric animal model using Shiba goats. The TinyPump is a miniaturized centrifugal pump weighing 150 g comprising a disposable pump head with a 30-mm diameter impeller having six straight-vanes and a reusable motor driver. The impeller in the pump head is supported by a hydrodynamic bearing at its center and is driven by radial magnetic force coupled to the motor driver. TinyPump implantations were performed in 22 Shiba goats (17 female and 5 male), with body weights ranging from 8.4 to 27.2 kg. Under gas anesthesia, via left lateral thoracotomy, a 22 Fr inflow cannula was inserted through the left ventricular apex, while a 6-mm outflow graft was anastomosed to the descending aorta, which were then connected to a TinyPump mounted on the animal's back. Postoperative hemodynamic monitoring included heart rate, arterial and central venous pressure, pump flow, and rotation speed. Target pump flow in all animals was maintained at 0.9 ± 0.1 L/min, which is approximately half the normal pulmonary artery flow measured in control animals. Blood samples were collected to evaluate peripheral organ functions, hemolysis, and thrombosis. Goats were divided into three groups-acute phase (6 h; n = 4), subchronic phase (6 h 2 postoperative days [POD]; n = 11), and chronic phase (3 POD-16 POD; n = 8)-based on their survival duration. In the early experiments, hemolysis and thrombi formation at the impeller bearing resulted in termination of the study. Subsequent modifications of the bearing design, pump housing design, and magnetic coupling force helped to minimize the hemolysis and thrombi formation, prolonging the survival duration of the Shiba goats to 2 weeks with minimum adverse effects on the blood components and organ functions. With further experiments and improvements in pump durability and hemocompatibility, the TinyPump can serve as a suitable circulatory support device for neonates and infants bridging to heart transplantation as well as to heart recovery.

IL28B but Not ITPA Polymorphism is Predictive of Response to Pegylated Interferon, Ribavirin, and Telaprevir Triple Therapy in Patients with Genotype 1 Hepatitis C

The Journal of Infectious Diseases. Jul, 2011  |  Pubmed ID: 21628662

Pegylated interferon, ribavirin, and telaprevir triple therapy is a new strategy expected to eradicate the hepatitis C virus (HCV) even in patients infected with difficult-to-treat genotype 1 strains, although adverse effects, such as anemia and rash, are frequent.

In Vivo Evaluation of a New Surfactant Polymer Coating Mimicking the Glycocalyx of Endothelial Cells

ASAIO Journal (American Society for Artificial Internal Organs : 1992). Sep-Oct, 2011  |  Pubmed ID: 21869616

The purpose of this study was to demonstrate that a proprietary surfactant polymer (SP) coating does not adversely affect the hemodynamic performance of cardiopulmonary bypass (CPB) or gas exchange in oxygenators. The new coating was applied to a CPB circuit including cannulae, reservoir, oxygenator, and blood pump implanted into 12 pigs, divided into groups with either coated or noncoated pumps. CPB flow was maintained at a fixed level of approximately 2.4 L/min for 6 hours with full heparinization. Hemodynamic data and pump performance were recorded every hour, and blood samples were taken every 2 hours. After sacrifice, the CPB circuit and major organs were macroscopically examined. There was no significant difference in the oxygen transfer rate between the two groups. The coating did not adversely affect oxygenator inlet or outlet pressures. There was no significant difference between the two groups in microthrombi seen in the oxygenators. No thromboemboli were noted in the major organs on gross or histologic examination. In conclusion, this new SP coating did not decrease gas exchange performance, and its biocompatibility evaluations revealed no differences between coated and noncoated groups under aggressive heparin use.

Development Rate of Chronic Kidney Disease in Hepatitis C Virus Patients with Advanced Fibrosis After Interferon Therapy

Hepatology Research : the Official Journal of the Japan Society of Hepatology. Oct, 2011  |  Pubmed ID: 21883737

Aim:  The aim of this retrospective cohort study is to assess the development incidence and predictive factors for chronic kidney disease (CKD) after the termination of interferon therapy in hepatitis C virus (HCV) positive Japanese patients with liver cirrhosis. Methods:  A total of 650 HCV positive, liver cirrhotic patients who were treated with interferon and showed an estimated glomerular filtration rate (eGFR) of ≥60 mL/min per 1.73 m(2) after the termination of interferon therapy were enrolled. CKD was defined as an eGFR of <60 mL/min per 1.73 m(2) . End-stage-CKD was defined as an eGFR of <15 mL/min/1.73 m(2) . The primary goal is the new development of CKD and end-stage-CKD. Results:  Eighty-five patients developed CKD, and six patients progressed to end-stage-CKD. The development rate of CKD was 5.2% at the 5th year, 14.5% at the 10th year and 30.6% at the 15th year. Multivariate Cox proportional hazards analysis showed that CKD occurred when patients had age increments of 10 years (hazard ratio: 2.32; 95% confidence interval [CI] 1.61-3.35; P < 0.001), eGFR decrements of 10 mL/min per 1.73 m(2) (hazard ratio: 1.66; 95% CI 1.27-2.16; P < 0.001), hypertension (hazard ratio: 2.00; 95% CI 1.13-3.53; P = 0.017), diabetes (hazard ratio: 1.79; 95% CI 1.02-3.14; P = 0.042), and non-clearance of HCV (hazard ratio: 2.67; 95% CI 1.34-5.32; P = 0.005). The development rate of end-stage-CKD was 0.4% at the 5th year, 1.6% at the 10th year and 2.8% at the 15th year. Conclusions:  The annual incidence for CKD among cirrhotic patients with HCV was determined to be about 1.0-1.5%. In addition, the annual incidence for end-stage-CKD is one order of magnitude lower than that of CKD.

Efficacy and Safety of Combination Therapy of Natural Human Interferon Beta and Ribavirin in Chronic Hepatitis C Patients

Internal Medicine (Tokyo, Japan). 2011  |  Pubmed ID: 21963723

The aim of this study was to evaluate the efficacy and safety of combination therapy of natural human interferon-beta and ribavirin for patients for whom prior interferon therapy was discontinued due to depression induced by interferon-alpha.

Combination of Hepatitis B Viral Antigens and DNA for Prediction of Relapse After Discontinuation of Nucleos(t)ide Analogs in Patients with Chronic Hepatitis B

Hepatology Research : the Official Journal of the Japan Society of Hepatology. Feb, 2012  |  Pubmed ID: 22103237

Aim:  The factors associated with hepatitis recurrence after discontinuation of nucleos(t)ide analogs (NAs) in patients with chronic hepatitis B were analyzed to predict the risk of relapse more accurately. Methods:  A total of 126 patients who discontinued NA therapy were recruited retrospectively. The clinical conditions of a successful discontinuation were set as alanine aminotransferase (ALT) below 30 IU/L and serum hepatitis B virus (HBV) DNA below 4.0 log copies/mL. Results:  Relapse of hepatitis B were judged to occur when maximal serum ALT became higher than 79 IU/L or when maximal serum HBV DNA surpassed 5.7 log copies/mL following NA discontinuation since these values corresponded with mean values of ALT (30 IU/L) and HBV DNA (4.0 log copies/mL), respectively. At least 90% of patients with either detectable hepatitis B e antigen or serum HBV DNA higher than 3.0 log copies/mL at the time of NA discontinuation relapsed within one year. In the remaining patients, higher levels of both hepatitis B surface and core-related antigens at the time of discontinuation, as well as a shorter course of NA treatment, were significantly associated with relapse by multivariate analysis. Conclusions:  It appears that negative results for hepatitis B e antigen and serum HBV DNA lower than 3.0 log copies/mL are essential for successful NA discontinuation, which may be attained by a longer treatment period. Levels of hepatitis B surface and core-related antigens are also significant factors independently associated with relapse of hepatitis.

Difference in Malignancies of Chronic Liver Disease Due to Non-alcoholic Fatty Liver Disease or Hepatitis C in Japanese Elderly Patients

Hepatology Research : the Official Journal of the Japan Society of Hepatology. Mar, 2012  |  Pubmed ID: 22175908

Aim:  Malignancies that include hepatocellular carcinoma often occurred in patients with chronic liver disease. The aim of this retrospective match control study was to assess the cumulative development incidence and predictive factors for total malignancies in elderly Japanese patients with non-alcoholic hepatic diseases (NAFLD) or hepatitis C virus (HCV). Methods:  A total of 1600 NAFLD patients with age of ≥60 years were enrolled, and 1600 HCV patients with age of ≥60 years were selected as control by matching 1:1 with NAFLD group for age, sex, and follow-up period. The primary goal is the first development of malignancies. Evaluation was performed by the use of the Wilcoxon rank sum test, the Kaplan-Meier method, and Cox proportional hazard model. The mean observation period is 8.2 years in both NAFLD and HCV group, respectively. Results:  The number of patients with the development of malignancies was 167 in the NAFLD group and 395 in the HCV group. The 10th development rate of malignancies was 13.9% in the NAFLD group and 28.2% in the HCV group (risk ratio 2.27; P < 0.001). The incident rates of hepatocellular carcinoma in all the malignancies were 6.0% (10/167) in the NAFLD group and 67.6% (267/395) in the HCV group (P < 0.001). The malignancies in the NAFLD group were observed in the following order: gastric cancer 34 cases (20.4%) > colon cancer 31 cases (18.6%) > prostate cancer 21 cases (12.6%). Conclusions:  The incident rates of hepatocellular carcinoma in all the malignancies were approximately 6% in the NAFLD group and two-thirds in the HCV group.

Prevalence and Predictive Factors of Diabetes in Hepatitis Virus Positive Liver Cirrhosis with Fasting Plasma Glucose Level of <126 mg/dL

Hepatology Research : the Official Journal of the Japan Society of Hepatology. Jan, 2012  |  Pubmed ID: 22236146

Aim:  The aim of this study was to evaluate the prevalence and predictive factors of diabetes in hepatitis virus positive liver cirrhotic patients with fasting plasma glucose (FPG) level of <126 mg/dL. Methods:  A total of 263 patients with hepatitis C virus (HCV) or hepatitis B virus (HBV) positive liver cirrhosis, FPG level of <126 mg/dL, and had diabetes status evaluated by the use of 75-g oral glucose tolerance test (OGTT), were enrolled in this study. Plasma glucose and insulin levels were analyzed periodically for 3 h after oral glucose loading. Diabetes was defined as a 2-h post-load glucose on the OGTT of ≥200 mg/dL. The prevalence of diabetes by use of OGTT and predictive factors for diabetes were evaluated by the use of the Mann-Whitney U-test, Fisher's exact probability test or multivariate analysis by logistic regression. Hypoalbuminemia was defined as serum albumin level of <3.9 g/dL. Elevated indocyanine green retention rate at 15 min (ICG( R) 15) was regarded as ≥ 25%. Results:  Out of 263 patients, 44 (16.7%) were diagnosed as having diabetes. Multivariate analysis showed that diabetes occurred when patients had hypoalbuminemia of <3.9 g/dL (odds ratio [OR] 2.33; 95% confidential interval [CI] = 1.04-5.24; P = 0.040) and ICG( R) 15 of <25% (OR 2.36; 95%CI = 1.01-5.58). Conclusions:  Hypoalbuminemia and elevated ICG( R) 15 in hepatitis virus related cirrhotic patients with FPG level of <126 mg/day enhance diabetes pattern after OGTT with significant difference.

Long-term Efficacy of Interferon Therapy in Patients with Chronic Hepatitis B Virus Infection in Japan

Journal of Gastroenterology. Feb, 2012  |  Pubmed ID: 22361865

BACKGROUND: Few studies have investigated the long-term effects of interferon (IFN) therapy for chronic hepatitis B (CHB). In this retrospective study, we investigated the efficacy of and predictors of response to IFN therapy in CHB patients. METHODS: We analyzed data for 615 Japanese CHB patients (hepatitis B e antigen [HBeAg]-positive 414, HBeAg-negative 201) treated with IFN, and conducted follow up for a median duration of 8.1 years (range 0.5-23.2). Responders were defined as patients who showed continuously normalized alanine transaminase (ALT) levels, HBeAg clearance, and low hepatitis B virus (HBV) DNA levels at 6 months post-treatment or for a span of more than 6 months until each test point at 1, 3, 5, and 10 years. RESULTS: The IFN response rates of all patients were 21, 18, 21, 23, and 25% at 6 months and 1, 3, 5, and 10 years, respectively. On multivariate analysis, significant determinants of the outcome of IFN therapy were as follows: at 6 months and 1 year, young age, low HBV DNA levels, and long duration of treatment; at 3 years, long duration of treatment, young age, and high level of albumin; at 5 years, high level of albumin, female, and pretreated with IFN; and at 10 years, HBeAg-negative. Sixty-nine of the 615 patients (11%) achieved seroclearance of hepatitis B surface antigen (HBsAg). On multivariate analysis, age ≥30 years, HBV genotype A, and male were all independent factors predicting the achievement of HBsAg seroclearance. CONCLUSION: HBeAg, HBV DNA level, age, sex, albumin, duration of treatment, pretreatment with IFN, and HBV genotype were important factors in determining long-term response to IFN therapy.

Determinants of the Clinical Outcome of Patients with Severe Acute Exacerbation of Chronic Hepatitis B Virus Infection

Journal of Gastroenterology. Feb, 2012  |  Pubmed ID: 22370817

BACKGROUND: Severe acute exacerbation of chronic hepatitis B can sometimes occur and lead to hepatic failure and death. The objective of this study was to elucidate the predictors of progression to hepatic decompensation during severe acute exacerbation. METHODS: We prospectively analyzed 37 consecutive patients with acute exacerbation of chronic hepatitis B (accompanied by jaundice and coagulopathy) for clinical outcome and factors that influenced the development of severe acute exacerbation, including viral kinetics. RESULTS: Fourteen (37.8%) patients progressed to severe acute exacerbation (accompanied by encephalopathy). Multivariate analysis identified serum bilirubin (>5 mg/dl, P = 0.002) as a significant determinant of progression to hepatic failure and prothrombin activity (<45%, P = 0.028) and as a determinant of liver-related death. The hepatitis B virus (HBV) DNA level before therapy was measured in 25 patients. HBV DNA levels increased or did not change from before commencement of treatment in all 11 patients who progressed to severe acute exacerbation. On the other hand, HBV DNA levels did not change or increased in 8 of 14 patients (57%) with acute exacerbation (P = 0.02). CONCLUSIONS: Serum bilirubin and prothrombin activities were significant predictors of clinical outcome in patients with severe acute exacerbation of chronic hepatitis B. Viral kinetics until commencement of therapy can predict the severity of acute exacerbation of chronic hepatitis B.

Functional Mitral Regurgitation: Modern Concepts for Ventricular Geometry Reshaping

Expert Review of Medical Devices. Mar, 2012  |  Pubmed ID: 22404774

Functional mitral valve regurgitation (MR), a condition affecting millions of primarily elderly patients worldwide, is associated with poor clinical outcomes. Functional MR has traditionally been considered a disorder of regional or global left ventricular (LV) remodeling secondary to myocardial disease, in which anatomically normal leaflets fail to coapt adequately. The primary mechanisms of MR are mitral annular dilatation and leaflet restriction secondary to LV remodeling. Although annuloplasty is commonly used to correct valve incompetence, the effects of altered ventricular mechanics on MR need to be specifically addressed. This review focuses on current concepts of geometric reconfiguration of the LV and mitral-ventricular apparatus to reduce MR.

Association of Two Polymorphisms of the IL28B Gene with Viral Factors and Treatment Response in 1,518 Patients Infected with Hepatitis C Virus

Journal of Gastroenterology. Mar, 2012  |  Pubmed ID: 22438096

BACKGROUND: Two nucleotide polymorphisms of the interleukin-28B (IL28B) gene, at rs8099917 and rs12979860, influence the response to interferon (IFN)-based therapies in patients infected with hepatitis C virus (HCV) of genotype 1. We aimed to investigate whether these polymorphisms showed complete linkage in Japanese patients. METHODS: A total of 1,518 Japanese patients infected with HCV were genotyped for the two IL28B loci, and the two sets of genotypes were compared. RESULTS: TT at rs8099917 and CC at rs12979860 were detected in 77.7 and 76.8%, respectively, of the 1,518 patients and TG/GG and CT/TT were detected in 22.3 and 23.2%. These two sets of IL28B genotype stood in strong linkage disequilibrium (r (2) = 0.98). Discordance between the two IL28B polymorphisms occurred in 16 (1.1%) patients, and 13 (0.9%) of them possessed IFN-sensitive TT at rs8099917 and IFN-resistant CT at rs12979860. Three of these 13 patients had HCV of genotype 1b and had received pegylated-interferon and ribavirin, and none of them gained a sustained virological response. At rs8099917, IFN-resistant TG/GG were more frequent in patients infected with HCV of genotype 1 than in those infected with HCV of genotype 2 [258/1,046 (24.7%) vs. 75/441 (17.0%), p = 0.001]. The response to pegylated-interferon/ribavirin in 279 patients who were infected with HCV-1 and the response to IFN monotherapy in 361 patients who were infected with HCV-1 , was higher in those with TT than in those with TG/GG at rs8099917, as well as being higher in those with CC than in those with CT/TT at rs12979860 (p < 0.001). CONCLUSIONS: Linkage disequilibrium between two IL28B polymorphisms at rs8099917 and rs12979860 is strong in Japanese HCV patients, but there are some discrepancies between the two sets of genotypes.

Hemodynamic Differences Between the Awake and Anesthetized Conditions in Normal Calves

Journal of Artificial Organs : the Official Journal of the Japanese Society for Artificial Organs. Mar, 2012  |  Pubmed ID: 22447313

There is insufficient information in the literature about baseline circulatory parameters in normal calves in the anesthetized versus postoperative awake conditions under which a large volume of medical research is conducted. Eleven calves (mean body weight, 78.1 ± 14.3 kg) were implanted with a flow probe and fluid-filled pressure lines to measure cardiac output (CO), aortic (AoP), central venous (CVP), pulmonary arterial (PAP), and left atrial pressures (LAP). Systemic (SVR) and pulmonary vascular resistance (PVR) were also calculated. We obtained the above hemodynamic data (n = 11) and epicardial echocardiography (n = 7) during open-chest surgery under isoflurane anesthesia. After full recovery from surgery, animals were evaluated in the awake condition on postoperative days 6-9 using transthoracic echocardiography (n = 7) and the hemodynamic monitoring lines and probes noted (n = 11). CO, AoP, and PAP levels in the anesthetized condition were significantly lower than in the awake condition. Other hemodynamic parameters (CVP, LAP, SVR, and PVR) were not significantly different. In conclusion, data from this study quantify changes in CO, AoP, and PAP in anesthetized calves that may affect the hemodynamic response to experimental therapeutics such as new cardiac assist devices, prosthetic valves, and surgical interventions. Our study also provides baseline data for the translation of the hemodynamic data obtained in acute in vivo calf studies to that of an awake subject.

Long-term Clinical Evaluation of Implant over Denture

Journal of Prosthodontic Research. Jan, 2012  |  Pubmed ID: 21705295

The use of implants to treat edentulous jaws has become a well-established and accepted contemporary clinical method. The aim of this study was to analyze information about the implants used, patients, denture modality, and complications after denture insertion in partially and fully edentulous patients with implant overdentures placed.

Amino Acid Substitution in HCV Core/NS5A Region and Genetic Variation Near IL28B Gene Affect Treatment Efficacy to Interferon Plus Ribavirin Combination Therapy

Intervirology. 2012  |  Pubmed ID: 21734353

Objective: To evaluate predictive factors of treatment efficacy to interferon (IFN)/ribavirin in patients infected with HCV genotype 1b (HCV-1b). Methods: This study investigated pretreatment predictors, including viral- (aa substitutions in core aa 70/91 and NS5A-ISDR/IRRDR) and host-related factors (genetic variation near IL28B gene), to 48-week IFN/ribavirin in 490 Japanese adults infected with HCV-1b. Results: The proportion of patients who showed end-of-treatment response (ETR), sustained virological response (SVR), and SVR after ETR was 76, 54, and 76%, respectively. There was a significant positive correlation between the number of aa substitutions in ISDR and those in IRRDR. Concerning the substitution of core aa 91, the number of aa substitutions in ISDR/IRRDR of patients with Leu91 was significantly higher than that of patients with Met91. Furthermore, levels of viremia were influenced by aa substitutions in core aa 91 and ISDR/IRRDR. By multivariate analysis, rs8099917 genotype was an important predictor of ETR and SVR. With regard to viral factors, core aa 70/91 was an important predictor of ETR, and SVR after ETR. ISDR was an important predictor of SVR, and SVR after ETR. Conclusion: aa substitution in core/NS5A region and genetic variation near IL28B were important predictors of treatment efficacy to IFN/ribavirin.