Search

The decomposition of the linear attenuation coefficient into photoelectric absorption and Compton scattering provides virtual monochromatic images (VMIs). The accuracy of the computed tomography (CT) number of VMI, which is obtained by decomposing the linear attenuation coefficient into photoelectric absorption and Compton scattering, was verified in the energy range of 40-200 keV. The possibility of improving the accuracy of CT numbers by using pre-energy-calibrated images as input was also investigated. The VMIs were generated in two groups of images: (i) dual-energy scanned images and (ii) high- and low-energy images generated by two-material decomposition (i.e., pre-energy-calibrated images). The object for analysis was solid iodine rods inserted in the center of the multi-energy CT phantom. The VMIs were generated from the dual-energy scanned images and pre-energy-calibrated images, and the theoretical and measured CT numbers of solid iodine rods were compared. Furthermore, the absolute error (AE) and relative error (RE) were calculated. With both images, the accuracy of the CT numbers was extremely high for regions close to the high- and low-tube-voltage X-ray energy or the high and low energy of the input images. By using the pre-energy-calibrated images, the maximum AE was reduced from 133 to 96 HU at an energy of 40 keV. Similarly, the maximum RE was reduced from 325 to 50% at an energy of 200 keV. The pre-energy-calibrated images reduced the overall error of the CT numbers and controlled the energy region where accurate CT numbers could be obtained.

We examined the effects of home-based walking on sedentary Japanese women's pregnancy outcomes and mood. A randomized controlled trial was conducted, involving 118 women aged 22-36 years. Participants were randomly assigned to walking intervention (n = 60) or control (n = 58) groups. The walking group was instructed to walk briskly for 30 min, three times weekly from 30 weeks' gestation until delivery. Both groups counted their daily steps using pedometers. Pregnancy and delivery outcomes were assessed, participants completed the Profile of Mood States, and we used the intention-to-treat principle. Groups showed no differences regarding pregnancy or delivery outcomes. The walking group exhibited decreased scores on the depression-dejection and confusion subscales of the Profile of Mood States. Five of the 54 women in the intervention group who remained in the study (9.2%) completed 100% of the prescribed walking program; 32 (59.3%) women completed 80% or more. Unsupervised walking improves sedentary pregnant women's mood, indicating that regular walking during pregnancy should be promoted in this group.

Introduction The effect of regular gum chewing on psychological status is unknown. The purpose of this study was to examine the effect of gum chewing for fourteen days on psychological status and physical and mental fatigue in healthy young adults. Methods We assigned 50 volunteers randomly to an intervention group (n = 26) and a control group (n = 24). Participants in the intervention group were requested to chew the gum twice per a day for fourteen days. The volunteers were required to complete a questionnaire related to lifestyle for baseline assessment. The State-Trait Anxiety Inventory (STAI), the Profile of Mood State (POMS), the World Health Organization Quality of Life 26, and assessment of physical and mental fatigue by visual analog scale were used at baseline, 2 weeks (after intervention), and 4 weeks (follow-up). Results At 2 weeks, the score of state anxiety was significantly lower in the intervention group than the control group. The intervention participants' scores of depression-dejection, fatigue and confusion in POMS were better than the control group scores. Mental fatigue were also relieved after the intervention. At 4 weeks, there were no significant differences between both groups. Conclusion Fourteen days' gum chewing may improve the levels of anxiety, mood and fatigue.

The purpose of this study was to examine the correlation of medical incidents and errors among nurses with factors describing their lifestyle, health, and work environment. We analyzed questionnaires completed by 6,445 female hospital nurses engaged in shift work in Japanese hospitals with general wards of more than 200 beds. Logistic regression analysis indicated that the risk for medical incidents/errors was predicted by being under treatment, absence due to sickness in the past 6 months, workplace, break times during night shift, bodily pain, and role (emotional). These results indicate that to prevent the occurrence of medical incidents/errors, it is necessary to regard current/recent illness, bodily pain, and role (emotional) as a nurse's personal problems and break times during the night shift and workplace as administrative problems.

To evaluate the long-term efficacy of entecavir in nucleoside-naïve chronic hepatitis B patients.One hundred and sixty-seven patients treated with entecavir 0.01mg, 0.1mg or 0.5mg for 24-52weeks in Phase II studies entered rollover study ETV-060 and received entecavir 0.5mg daily. Responses were evaluated among patients with available samples.After 96weeks in ETV-060 (120-148weeks total entecavir treatment time), 88% (127/144) of patients had HBV-DNA400 copies/ml; 90.1% (128/142) had alanine aminotransferase (ALT) 1x the upper limit of normal (ULN) among those with abnormal baseline ALT; and 26% (32/121) achieved HBe seroconversion among those HBeAg(+) at baseline. A subset of 66 patients received entecavir 0.5mg (approved dose) from Phase II baseline: at week 96 in ETV-060, 83% (48/58) had HBV-DNA400 copies/ml, 88% (52/59) had ALT 1x ULN, and 20% (10/49) achieved HBe seroconversion. Twenty-one out of 66 patients had paired baseline and on-treatment biopsies: 100% (21/21) and 57% (12/21) demonstrated histologic improvement, and improvement in fibrosis, respectively, over 3years. The 3-year cumulative probability of resistance was 3.3% for all patients and 1.7% for the 0.5mg subset.Long-term entecavir for nucleoside-naïve patients resulted in high rates of virological, biochemical, and histological response, with minimal resistance.

Purpose : The purpose of this research was to verify the effectiveness of a lecture, which programmed for the ability promotion of interpersonal relationship and autonomy in novice nurses, in order to prevent early resignation and to establish high-quality nursing. Methods : This intervention program consisted of a lecture and a self-check exercise, and it took for 2 hours. To evaluate their emotional changes after the educational intervention program, the participants were asked to answer self-reporting questionnaires including Emotional intelligence Quotient Scale (EQS) and Nursing Autonomy Scale (NAS). Results : Out of 3 areas of "self-effect", "human-relations" and "situation-reactions", a significantly higher increase was observed in "situation-reaction". Furthermore, out of 5 factors in NAS, each score of 4 factors except "Autonomic decision-making ability" and the total score significantly increased after the intervention. There was a significant correlation between the increases in scores of "Self-effect" of EQS and those in "Practice ability" of NAS after the intervention. Consideration : The lecture and self-check exercise were effective on self-understanding and autonomy in novice nurses.

Objective: To examine the effectiveness of a simple behavioral intervention with an educational booklet on the modification of parenting behaviors and the prevention of sleep disturbance in 4-month-old infants. Design: A prospective cohort design with cluster sampling controls in a primary care setting. Participants: A total of 136 mothers with 4-month-old infants who visited a local health check-up clinic and responded to the 3-month follow-up survey. Methods: At the health check-up, an intervention group was provided with 10 minutes of group guidance and a simple educational booklet designed to encourage parents to promote favorable sleep patterns in their infants. A control group was provided with standard education alone. The two groups were questioned 3 months later through a survey sent by mail. Main measurements were parenting behaviors of parents and night waking of infants. Results: Two undesirable maternal behaviors that reinforce night waking in infants exhibited a significantly greater improvement in the intervention group than in the control group. “Feed or check diaper promptly” behavior and “hold and soothe immediately” behavior after “night waking” in the infant were significantly decreased in the intervention group. Conclusions: Our findings suggest that increased night waking in infants was prevented in the intervention group. Our results indicate that the proportion of infant night waking was significantly higher in the control group, and there was also a tendency toward an increase in the proportion of infants who woke frequently and cried. These infant behaviors were not changed in the intervention group at the 3-month follow-up stage.

The purpose of this paper is to study sender authenticated key agreements by a third party, which uses the received parameters to verify the fact that a sender of a message knows his long-term private key. In particular, we propose a standard model for the protocol among three entities for the first time. The security of this protocol depends on the difficulty of solving two new problems related to one-way isomorphisms and the decision co-bilinear Diffie-Hellman problem on multiplicative cyclic groups. It is the first time that the security of a key agreement has been formally proven by using negligible probability. We believe that our contribution gives many applications in the cryptographic community.

グリア代謝抑制時において99mTc-HMPAOの脳におけるretentionが変化するか否かについて，14C-N-イソプロピルパラヨードアンフェタミン(14C-IMP)とのダブルトレーサオートラジオグラフィ法により検討した。ラット右側線条体にフルオロクエン酸(FC，1nmol/μL，2μL)を微量注入し，4時間後に99mTc-HMPAO(74MBq)と14C-IMP(185kBq)とを同時に尾静脈より投与し，5分後に断頭した。迅速に冷凍切片を作成し，イメージングプレートに6時間コンタクトして99mTc-HMPAOのオートラジオグラムを得た。99mTcを減衰させた後，同一切片を再度1週間コンタクトして14C-IMPの画像を得た。画像上の左右の大脳皮質と線条体に関心領域を設定し，それぞれの部位における放射能濃度(PSL/mm2)を求めた。FC注入側の線条体では99mTc-HMPAO，14C-IMP共に対側と比較して約160％に集積が増加した。グリア細胞のTCAサイクルを完全に抑制しても99mTc-HMPAOのretentionには全く影響を与えないことが判明した。したがって，神経細胞において99mTc-HMPAOを極性化させる十分なグルタチオンが存在するものと推測される。各画像を20×25の小分画に分割し，各分画における99mTc-HMPAOと14C-IMPの放射能濃度をプロットした結果，正常部位においても，グリア代謝抑制部位においても両者の間に良好な相関関係を認めた。

The appearance of alpha-smooth-muscle-actin (alpha-smA)-positive cells during hepatic fibrosis was studied immunohistochemically in rat and human livers. In the normal rat liver, alpha-smA was observed only in vascular smooth muscle cells. With the progression of fibrosis induced by CCl4 injection, alpha-smA-positive cells appeared in the perisinusoidal space and the fibrous septa, and ultimately surrounded regenerative nodules. An increase of desmin-positive cells was recognized in the fibrotic areas and the perisinusoidal area. In the human liver, alpha-smA-positive cells appeared in the fibrotic area, whereas no desmin-positive cells were observed, except in vascular walls of the central vein and the portal tract, alpha-smA is a good marker for the detection of myofibroblast-like cells, and the appearance of alpha-smA in liver mesenchymal cells seems closely related to the process of hepatic fibrosis in both rat and man.

Entecavir (ETV) is a potent nucleoside analogue against hepatitis B virus (HBV), and emergence of drug resistance is rare in nucleoside-naive patients because development of ETV resistance (ETVr) requires at least three amino acid substitutions in HBV reverse transcriptase. We observed two cases of genotypic ETVr with viral rebound and biochemical breakthrough during ETV treatment of nucleoside-naive patients with chronic hepatitis B (CHB).Case 1: A 44-year-old HBeAg-positive man received ETV 0.1 mg/day for 52 weeks and 0.5 mg/day for 96 weeks consecutively. HBV DNA was 10.0 log(10) copies/ml at baseline, declined to a nadir of 3.1 at week 100, and rebounded to 4.5 at week 124 and 6.7 at week 148. Alanine aminotransferase (ALT) level increased to 112 IU/l at week 148. Switching to a lamivudine (LVD)/adefovir-dipivoxil combination was effective in decreasing HBV DNA. Case 2: A 47-year-old HBeAg-positive man received ETV 0.5 mg/day for 188 weeks. HBV DNA was 8.2 log(10) copies/ml at baseline, declined to a nadir of 2.9 at week 124, and then rebounded to 4.7 at week 148 and 6.4 at week 160. ALT level increased to 72 IU/l at week 172. The ETVr-related substitution (S202G), along with LVD-resistance-related substitutions (L180M and M204V), was detected by sequence analysis at week 124 in both case 1 and case 2.ETVr emerged in two Japanese nucleoside-naive CHB patients after prolonged therapy and incomplete suppression and in one patient after0.5 mg of dosing. ETV patients with detectable HBV DNA or breakthrough after extended therapy should be evaluated for compliance to therapy and potential emergence of resistance.

This study examined the long-term effects of a brief behavioral intervention for sleep improvement. The program was designed as a complete self-help approach by correspondence, and consisted of self-assessments of sleep-related behavior, target-setting for behavior change, an educational booklet, self-monitoring of the behaviors for one month and reinforcement. The participants of the program at a Japanese worksite replied for a one-year followed up survey. Forty-seven poor sleepers whose sleep onset latency was 30 min or more and/or sleep efficiency was less than 85% were analyzed. Eight sleep parameters and nine sleep-related behaviors were evaluated using questionnaires at baseline, post-intervention and follow-up. At one year, total sleep time increased by 27 min, sleep onset latency shortened by 17.5 min and sleep efficiency improved by 6.9 points. Desirable changes were obtained in 4 sleep-related behavior including not being active before bedtime, not working or watching TV in the bedroom, not oversleeping on holidays and having a relaxed bath time. These results suggest that this brief behavioral intervention could improve sleep quality through the modification of sleep-related behavior.

Aim To verify the reliability and validity of a Japanese version of the Rathus Assertiveness Schedule in novice nurses to contribute to nursing management. Background An adequate scale is needed to measure the assertiveness and the effect of assertion training for Japanese nurses and to compare them with those in other countries. Methods Rathus Assertiveness Schedule was adapted to Japanese with back-translation and its validity was examined in 989 novice nurses. Results The Japanese version showed a high coefficient of reliability in a split-half reliability test (r = 0.76; P

We examined the effects of home-based walking on sedentary Japanese women's pregnancy outcomes and mood. A randomized controlled trial was conducted, involving 118 women aged 22-36 years. Participants were randomly assigned to walking intervention (n = 60) or control (n = 58) groups. The walking group was instructed to walk briskly for 30 min, three times weekly from 30 weeks' gestation until delivery. Both groups counted their daily steps using pedometers. Pregnancy and delivery outcomes were assessed, participants completed the Profile of Mood States, and we used the intention-to-treat principle. Groups showed no differences regarding pregnancy or delivery outcomes. The walking group exhibited decreased scores on the depression-dejection and confusion subscales of the Profile of Mood States. Five of the 54 women in the intervention group who remained in the study (9.2%) completed 100% of the prescribed walking program; 32 (59.3%) women completed 80% or more. Unsupervised walking improves sedentary pregnant women's mood, indicating that regular walking during pregnancy should be promoted in this group.

Aim: This prospective cohort study aimed to clarify the relationship between the level of assertiveness and the incidence of burnout in novice nurses in their first year at university hospitals and to obtain indices of assertion training in order for them to avoid burnout. Methods: The subjects were 1203 novice nurses working at 20 university hospitals in Japan who gave informed consent to participate in this research. The questionnaires were completed by 949 novice nurses in June 2003, and they were divided into two cohorts to observe the incidence of burnout, which was investigated in June 2004. Results: At the baseline, we obtained responses from 1030 novice nurses (85.6%) who had agreed to join the study. Ninety-two (20.5%) of the novice nurses experienced burnout and 43 (7.2%) experienced serious burnout. Both high and low levels of assertiveness score tended to high incidence rates of burnout. Multiple logistic regression analyses showed that the factors affecting burnout were lack of senior nursing staff support and very low and low levels of assertiveness, and those affecting serious burnout were male gender, hospital location in Tokyo, and very low and low levels of assertiveness. Conclusions: Novice nurses tend to burn out easily when their assertiveness scores are too low or too high. The ideal value of the assertiveness score seems to be medium.

The quantum SO(3)-invariants of ℚ-homology 3-spheres can be perturbatively expanded to the Ohtsuki invariant in number theory. On the other hand, it is known that the quantum SU(2)-invariants of 3-manifolds M admits a refinement involving a mod 2 cohomology class of M. A motivation of this paper is to study whether a perturbative expansion can be derived from the refinement. In this paper, we shall prove to be able to derive the perturbative expansion in the case of lens spaces by a concrete calculation, and shall define the perturbative invariant. Furthermore we obtain some properties for the perturbative invariant for covering spaces and connected sums of lens spaces.

Rapid turnover of novice nurses eventually results in a shortage of veteran nurses. This study aimed to clarify the factors affecting rapid turnover of novice nurses in a prospective manner. We carried out an investigation in 20 university hospitals whose directors of nursing service departments accepted our request to cooperate with our research program. These hospitals were selected from all of the 102 university hospitals listed in The Hospital Catalog of Japan. The subjects were 1,203 novice hospital nurses who gave their informed consent for participation in our study. The questionnaires, which dealt with burnout, assertiveness, stressful life events, reality shock, ward assignment preference, transfer preference, job satisfaction (workplace, salary, workload, and overtime), social support and coping mechanisms were completed by 923 novice nurses in June 2003. Then, their turnover was investigated in December 2003. Thirty-seven novice nurses (4.0%) quit during this period. Multiple logistic regression analysis showed that the factors affecting rapid turnover were 1) graduation from vocational nursing schools, 2) dissatisfaction with assignment to a ward contrary to their desire, and 3) no peers for support. Assignment of novice nurses to wards they choose as far as possible, avoidance of assigning novice nurses to wards alone, and establishment of a support system for nurses who graduate from vocational nursing schools seem to be important for preventing rapid turnover of novice nurses.

In hepatitis C virus (HCV) genotype 2b infection, viral eradication (sustained viral response; sVR) is obtained in about 40% by interferon monotherapy, whereas a considerable proportion of non-sVR patients exhibit sustained biochemical response (sBR) showing normal biochemical values despite persistent viraemia. However, the mechanism of sBR has not yet been established. In this study, we analysed serial changes in full-length sequences of HCV genotype 2b before and after interferon (IFN) therapy in five patients with sBR and five with no response (NR; persistent viraemia and abnormal biochemical values after IFN therapy). The overall substitution rate of amino acids in the full-length HCV genome was higher in the sBR group than in the NR group [2.22 +/- 0.48 (10(-3) changes/site/year) vs 1.04 +/- 0.30: P = 0.002]. When the genetic changes were analysed for individual HCV proteins, the sBR group had significantly higher substitution rates of amino acid in NS4A [8.82 +/- 2.80 (10(-3) changes/site/year) vs 0: P = 0.001]. These amino acid changes in sBR were mainly located in the binding motifs of HLA class I molecules including those frequently found in the Japanese population. These results demonstrated that the greater amino acid changes of HCV arising during interferon therapy are associated with the establishment of sBR. Although functional significance of these changes awaits further investigation, the finding that amino acid changes in NS4A in sBR patients are mainly located in the HLA class I binding motifs illustrated the potential roles of the escape mutations of HCV genome from CTLs in the decreasing activities of hepatitis in sBR.

Primary biliary cirrhosis (PBC) is one of the most important autoimmune liver diseases but the etiology and pathogenesis remain unknown. In this study, we analyzed differential mRNA expression in the liver of a patient with PBC using suppression subtractive hybridization to identify overexpressed genes. Overexpression of mRNA transcripts from mitochondrial DNA was observed in the PBC liver, compared to normal liver. To explore the mechanism of increased mitochondrial transcription, we investigated the mRNA levels of nuclear DNA-encoded regulator molecules of mitochondrial gene expression in 60 liver biopsy samples from various diseases, including PBC, using competitive RT-PCR. Increased expression of mitochondrial transcriptional factor A (mtTFA) and mitochondrial nuclear respiratory factor 1 (NRF-1) mRNA was demonstrated in PBC liver compared to other liver diseases, while NRF-1 coactivator 1, PGC-1 was suppressed. Mitochondrial DNA-encoded mRNA molecules are overexpressed in the PBC liver, and this is associated with up-regulation of mitochondrial transcription factor mtTFA and its transactivator NRF-1. Further studies are needed to focus on the relevance of this perturbation of mitochondrial gene expression in the pathogenesis of PBC.

Hepatitis C virus (HCV) subgenomic replicon has been reported to replicate efficiently and continuously in human hepatoma Huh-7 cells. To extend the previous results to other isolated HCV clones, we constructed another HCV replicon from HC-J4, one of chimpanzee-infectious HCV clones. An HCV replicon derived from HC-J4 (RpJ4) consists of HCV-5' untranslated region, neomycin phosphotransferase gene, the encephalomyocarditis virus internal ribosomal entry site, HCV nonstructural region, NS3 to NS5B, and HCV-3' untranslated region. The adaptive mutations known to be required for HCV-Con1 replicon were introduced in RpJ4 replicon, aa.(amino acids number according to HC-J4) 2197 serine to proline, deletion of serine at aa.2201, and aa.2204 serine to isoleucine (RpJ4-S2197P, RpJ4-S22001del, and RpJ4-S2204I). RpJ4/ISDR mutant and RpJ4-S2201del/ISDR mutant were also constructed by introducing six amino acid mutations into the interferon sensitivity determining region (ISDR). After transfection into Huh-7 cells and G418 selection, RpJ4 and RpJ4/ISDR mutants did not produce any colony. In contrast, G418-resistant cells were transduced efficiently by RpJ4-S2197P, RpJ4-S2204I, RpJ4-S2201del and RpJ4-S2201del/ISDR mutant, with the RpJ4-S2201del/ISDR mutant being most efficient. Hence the HCV replicon derived from HC-J4 can replicate efficiently following the introduction of adaptive mutations into the upstream region of ISDR. Moreover, additional introduction of mutations into ISDR further enhanced its replication. These findings demonstrate that the genetic structure of the NS5A domain is critical in HCV replications.

Sjogren's syndrome has been suspected to be an extrahepatic manifestation of chronic hepatitis C virus (HCV) infection. To evaluate the association of sialadenitis with HCV infection, serum levels of salivary amylase (s-isoamylase) and antibodies to Ro (SS-A) and La (SS-B) were analyzed in 114 patients with chronic hepatitis C. Serum s-isoamylase levels were monitored before and after HCV was eradicated by interferon therapy. Immunohistochemistry and Western blotting using anti-HCV antibodies, and in situ hybridization of HCV-RNA were performed in the salivary gland. Serum s-isoamylase levels were elevated in patients with chronic hepatitis C (P

The correlation between hepatitis C virus (HCV) genomic sequences and circulating HCV RNA levels was assessed to investigate the genetic elements affecting viral load. The interferon sensitivity-determining region (ISDR) sequence and the serum viral load were strongly correlated in 226 patients examined. Analysis of the entire HCV genome from six patients (three with a high and the others with a low viral load) with similar ISDR sequences identified several candidate residues associated with viral load. The amino acid (aa) sequences of these candidate residues and flanking regions in 67 additional patients revealed that only the residue at aa 962 varied significantly between the HCV patients with low and high serum loads (P = 0.042). At this position, alanine was observed more frequently in the patients with a high viral load. In conclusion, our results strongly suggest that serum HCV RNA loads are inversely correlated with amino acid substitutions in the ISDR, and aa 962 was identified as a possible second determinant of serum HCV RNA load.

Human umbilical cord blood (UCB) cells have many advantages as grafts for cell transplantation because of the immaturity of newborn cells compared with adult cells. In contrast to their hematopoietic and mesenchymal potential, it remains unclear whether UCB cells have endodermal competence. Here, with a view to utilize UCB cells for cell transplantation into injured liver, we investigated the hepatic potential of UCB cells both in vitro and in vivo. We determined the most efficient conditions leading UCB cells to produce albumin (ALB). In a novel primary culture system supplemented with a combination of growth/differentiation factors, about 50% of UCB cells in 21-day cultures expressed ALB, and the ALB(+) cells coexpressed hepatocyte lineage markers. The ALB-expressing cells were able to proliferate in the culture system. Moreover, in the cell-transplantation model into liver-injured severe combined immunodeficient mice, inoculated UCB cells developed into functional hepatocytes in the liver, which released human ALB into the sera of the recipient mice. In conclusion, this study demonstrates that human UCB is a source of transplantable hepatic progenitor cells. Our findings may have relevance to clinical application of UCB-derived cell transplantation as a novel therapeutic option for liver failure.

The management of interferon (IFN) therapy for histologically severe chronic hepatitis C virus genotype 1b (HCV-1b [F3]) is controversial. A decision analysis using the Markov decision analysis model was performed for 6 disease management strategies by using clinical data from a Japanese teaching hospital and available published data. The results of base case analyses showed that IFN monotherapy was considered favorable for patients aged 40 to 60 years with HCV-1b (F3). For the sensitivity analyses, to support the results of base case analyses, HCV-1b (F3) patient quality-of-life (QOL) score must be 0.5 or greater for those 40 to 50 years old and 0.4 to 0.5 or greater for those 60 years old. When patients with HCV-1b (F3) were judged as nonresponsive (NR) after IFN monotherapy, the transition probabilities of liver diseases at 40, 50, and 60 years of age had to be such that the progression of liver diseases was controlled at an annual rate of 7.51% to 8.82% or lower, 7.77% to 8.27% or lower, and 6.39% to 6.60% or lower, respectively, and the sustained virologic response (SVR) rate for IFN monotherapy must be 3.0% to 5.51% or greater, 5.57% to 5.93% or greater, and 10.6% to 11.21% or greater, respectively. It is likely that IFN monotherapy could be applied to patients with HCV-1b (F3) aged 40 years at a dose of at least 432 MU. However, IFN monotherapy did not appear useful for patients with HCV-1b (F3) aged 50 and 60 years if they had no amino acid mutation in NS5A 2209 to 2248 and HCV RNA levels exceeded 1.0 mEq/mL. In conclusion, use of decision analysis models can help in therapeutic decisions for patients with HCV-1b.

Embryonic stem (ES) cells have a potential to differentiate into various progenitor cells. Here we investigated the differentiation capacity of mouse ES cells into hepatocytes both in vitro and in vivo. During the culture of embryoid bodies (EBs) derived from ES cells, albumin (ALB) messenger RNA (mRNA) was expressed within 12 days after removal of leukemia inhibitory factor, and α-fetoprotein (AFP) mRNA was observed within 9 days without additional exogenous growth factors. In ES cells and early EBs, by contrast, neither ALB mRNA nor AFP mRNA was observed. ALB protein was first detected at day 15 and the level increased with the culture period. The differentiation of EBs facilitated the synthesis of urea with the culture period, whereas early EBs and ES cells produced no urea. These results suggest that cultured EBs contain hepatocytes capable of producing ALB and urea. ES cells and the isolated cells from EBs were transplanted through portal vein to the liver after 30% partial hepatectomy of female mice pretreated with 2-acetylaminofluorene. Four weeks after transplantation with isolated cells from day-9 EBs, ES-derived cells containing Y-chromosome in the liver were positive for ALB (0.2% of total liver cells), whereas teratoma was found in mice transplanted with ES cells or EBs up to day 6. The incidence of teratoma was decreased with the culture duration and no teratoma was observed in the liver transplanted with isolated cells from day-9 EBs. In conclusion, our in vitro and in vivo experiments revealed that cultured EBs contain functional hepatocytes or hepatocyte-like cells. (HEPATOLOGY 2002;36:22-29.)

Cytotoxic T cells (CTLs) are believed to play an important role in the pathogenesis of chronic hepatitis C based on histological findings of the liver and in vivo experiments. Fas-ligand-Fas and perforin dependent pathways are two major killing systems when CTLs induce their target-cell death. Thus, the present study attempts to determine whether these pathways are activated, and if they are, how they are related in chronic hepatitis C. To investigate the expression of Fas-ligand and perforin, we performed double immunofluorescent staining of liver biopsy specimens from patients with chronic hepatitis C. Fas-ligand and perforin expression was observed in mononuclear cells, and the partial coexistence of the two proteins was observed. Cells expressing both proteins were positive for CD45RO(+) T cells (active T cells), whereas cells expressing perforin were negative for CD68 (macrophages). In the cases which had sustained negative HCV-RNA over 6 months after interferon treatment, Fas-ligand was not expressed, although perforin was slightly detectable. To quantitatively assess the balance of these pathways, hepatic mRNAs of Fas-ligand and perforin were measured by quantitative RT-PCR. The ratio of Fas-ligand-mRNA/perforin-mRNA was significantly correlated with serum alanine aminotransferase (ALT) levels (r=0.913). These results suggest that both pathways are activated in chronic hepatitis C and that Fas-ligand-Fas pathway may be predominant in active inflammation.

The genetic basis of hepatocellular carcinoma (HCC) has not yet been fully understood. Although various methods have been developed to detect differentially expressed genes in malignant diseases, efficient analysis from clinical specimens is generally difficult to perform due to the requirement of a large amount of samples. In the present study, we analysed differentially expressed genes with a small amount of human HCC samples using suppression subtractive hybridization (SSH). Total RNA were obtained from the hepatitis C virus-associated HCC and adjacent non-HCC liver tissues. cDNA was synthesized using modified RT-PCR, and then tester cDNA was ligated with 2 different kinds of adaptors and hybridized with an excess amount of driver cDNA. Tester specific cDNA was obtained by suppression PCR and the final PCR product was subcloned and sequenced. We identified 7 known genes (focal adhesion kinase, deleted in colon cancer, guanine binding inhibitory protein α, glutamine synthetase, ornithine aminotransferase, M130, and pepsinogen C) and 2 previously unknown genes as being overexpressed in HCC, and 1 gene (decorin) as suppressed in HCC. Quantitative analysis of gene expression using quantitative RT-PCR demonstrated the differential expression of these genes in the original and other HCC samples. These findings demonstrated that it is possible to identify the previously unknown, differential gene expression from a small amount of clinical samples. Information about such alterations in gene expression could be useful for elucidating the genetic events in HCC pathogenesis, developing the new diagnosic markers, or determining novel therapeutic targets. © 2001 Cancer Research Campaign http://www.bjcancer.com

Aim: The aim of this study was to examine the effectiveness and toxicity of radiation therapy in combination with transcatheter arterial chemoembolization (TACE) for hepatocellular carcinoma (HCC) with extensive portal vein tumor thrombus (PVTT). Methods: The combined therapy was performed in 24 HCC patients with extensive PVTT. External radiation targeted for PVTT (50 Gy in 2 Gy fractions) was performed in combination with repetitive TACE for intralobar lesions using 30–60 mg epirubicin every 3 months, and associations of the following variables with the survival rate were evaluated: gender, age, viral etiology, Child’s class, performance status, extrahepatic metastasis, size and number of HCC, and location of PVTT. Results: The local response confined to PVTT was complete response (CR) in four patients, partial response (PR) in eight patients, no change (NC) in eight patients, and progressive disease (PD) in four patients. By using the stepwise Cox’s regression analysis, only Child’s class was associated with the survival rate. The survival rates after 1 and 2 years were 73 and 21% in Child’s A, 10 and 0% in Child B or C, and 61 and 21% in patients in whom the local response was CR or PR, and 19 and 9% in those in whom the local response was NC or PD, respectively. By using the multiple logistic regression analysis, Child’s class was the only factor associated with the local response (P = 0.006). Conclusions: The combined therapy is feasible and may be useful to reverse PVTT in patients with good hepatic function reserve.

Background and Aim: It has been a conflicting issue whether TT virus (TTV), a newly isolated DNA virus from a patient with liver injury of unknown cause, is a causative agent of acute and/or chronic hepatitis. TT Virus DNA titers were shown to be 10–100-fold greater in liver tissue than in serum, whereas the majority of TTV-positive cases had no biochemical or histological evidence of significant liver damage. We therefore attempted in situ hybridization to investigate whether TTV is hepatotropic. Methods: Because of the marked divergence in TTV genome types, a template for TTV-DNA (coding region for N22 clone) was amplified and labeled with digoxigenin-dUTP by using hemi-nested PCR from the serum, then DNA probes were applied to the liver sections of the same case. After hybridization, the probes were visualized immunohistochemically. Besides TTV-DNA-negative cases, competitive inhibition experiments with unlabeled probes were performed to confirm the specificity. Results There were no positive signals in the negative controls, and the intensity of positive signals was markedly diminished in the competitive inhibition experiments. No cross-hybridization with different genotype probes also confirms the specificity. Under the optimal conditions, the positive signals were located in the cytoplasm of the hepatocytes in eight of nine TTV-DNA-positive cases. The signals were not seen in non-parenchymal cells of the liver. Conclusion: TT Virus is proved to be hepatotropic by in situ hybridization.

In this paper, we shall give a general formula for the quantum SU(2) -invariant of Seifert fibered rational homology spheres over a 2-sphere associated with the trivial first cohomology class modulo two, based on the linear skein theory. We shall derive the Casson–Walker invariant from the formula. Also, we shall give a formula for a second coefficient of the perturbative invariant associated with the trivial first cohomology class modulo two, which is a topological invariant. We shall give a relation between the second coefficient and the Ohtsuki invariant. We shall show that the second coefficient for Seifert fibered integral homology spheres belongs to 3 Z .

As a part of the defense mechanism of the host to viral infection, interferons induce the transcription of several genes. These interferon-inducible genes contribute to the eradication of the viruses. Whereas some studies suggested the participation of a dsRNA-dependent protein kinase in the host reaction to hepatitis C virus infection, the involvement of other interferon-inducible genes has not been evaluated. Furthermore, there has been no analysis on the expression profile of multiple interferon-inducible genes. The aim of this study was to clarify the hepatic mRNA expression profile of interferon-inducible genes with a special concern to chronic hepatitis C. A total of 76 liver biopsy samples (28 with chronic hepatitis C, 10 with chronic hepatitis B, 9 with alcoholic liver disease, 14 with autoimmune hepatitis, 10 with primary biliary cirrhosis, and 5 of normal liver) were enrolled. The expression of the following genes was quantified by competitive reverse transcription-polymerase chain reaction and was compared according to the etiology; dsRNA-dependent protein kinase (PKR), 2′,5′-oligoadenylate synthetase (2,5-AS), latent cellular endoribonuclease (RNase L), RNase L inhibitor, and MxA. As a result, PKR mRNA was significantly overexpressed in the liver of chronic hepatitis C compared with those of other etiologies (P= .0178), and it correlated significantly with serum alanine transaminase values (r = .51, P = .0054). Also, the expression of the RNase L inhibitor showed a significant reduction in chronic hepatitis C (P = .0184). The expressions of 2,5-AS, RNase L, and MxA were not different significantly irrespective to the etiology. In conclusion, hepatic overexpression of PKR and reduced expression of RNase L inhibitor seem to contribute to the anti-HCV mechanism characteristically. (Hepatology 2000;32:1089-1095.)

Two patients with hepatocellular carcinoma (HCC) were treated with transjugular intrahepatic portosystemic stent-shunt (TIPS) and followed for 22 and 58 months thereafter. HCC was well controlled by transcatheter arterial chemoembolization. Hepatic failure or metastasis, especially in the lung, was not observed in the long-term observation. TIPS seems to be useful even in patients with HCC, provided HCC is controlled.

BACKGROUND Gap junctions contain intercellular channels through which contacting cells communicate directly. The expression of connexin 32, a major gap junction protein in the liver, during the progression of chronic liver diseases has not yet been clarified. METHODS Immunohistochemical staining was performed using anti-connexin 32 antibody on 6 specimens of normal human liver, 7 of chronic viral hepatitis, and 7 of liver cirrhosis. RESULTS The number of gap junction plaques in chronic viral hepatitis and liver cirrhosis was significantly smaller than that in normal liver (10350+/-2180 and 7550+/-3040 vs 22560+/-3700 spots/mm2, p

Mechanisms determining the chronicity or the pattern of clinical course of hepatitis C virus (HCV) infections have not been clarified. Recently, CD81 was reported to bind the E2 protein of HCV and was suggested to function as a cellular receptor for HCV. Accordingly, the hypothesis was examined that CD81 polymorphism, if it exists, might correlate with certain clinical courses of HCV infection. CD81 cDNA sequences were determined from peripheral blood mononuclear cells (PBMCs). Twenty-four Japanese subjects were enrolled initially as follows: patients with chronic hepatitis C without cirrhosis (n = 3), patients with cirrhosis (n = 3), patients with cirrhosis complicated by hepatocellular carcinoma (HCC) (n = 3), patients with persistent HCV viremia without ALT elevation (n = 3), those with positive anti-HCV antibodies without evidence of HCV viremia (n = 3), and healthy volunteers (n = 9). In all PBMCs samples analyzed, no polymorphism was found in the CD81 cDNA sequence. The sequence was different, however, from the one reported previously at three nucleotide positions: a transversion to thymine instead of cytosine at nt 1130, a deletion at nt 1206, and a guanine insertion at nt 71. Subsequently, CD81 cDNA sequences from PBMCs and HCC tissue were compared among the other 6 patients with chronic hepatitis C bearing HCC. A comparative study of the CD81 sequences from HCC and PBMCs revealed that various nucleotide mutations existed only in the HCC samples in 3 out of 6 patients. Several mutations in the 3' non-coding region of CD81 cDNA were observed exclusively in HCC tissue suggesting its possible role in hepatocarcinogenesis. Because of the absence of polymorphisms, however, CD81 is unlikely to affect the progression of chronic hepatitis C in terms of chronicity, hepatitis activity, or disease stage.

Amino acid mutations in the interferon sensitivity determining region (ISDR) are closely associated with the response to interferon in patients with hepatitis C virus genotype 1b (HCV-1b) infection. In this study, 36 patients chronically infected with HCV-1b, with no history of interferon therapy with respect to ISDR changes in HCV were studied. Two serum samples were obtained from each patient, with an average interval of 3.5 years, and predominant nucleotide and amino acid sequences of the ISDR at initial and subsequent time points were compared for each patient. Three of 12 patients with the wild type ISDR (no amino acid mutation in the ISDR compared to the consensus sequence) changed to the intermediate type (1 to 3 mutations) at later time points, whereas the other 9 still had the wild type. Similarly, 2 of 18 patients with the intermediate type changed to the wild type, whereas the other 16 patients continued to have the intermediate type. One of 6 patients with the mutant type (4 or more mutations) changed to the intermediate type, and the other 5 continued to have the mutant type. Although ISDR nucleotide changes/site/year were not significantly different among the 3 groups of patients, percentages of non-synonymous nucleotide changes were greater in the mutant type (63%) than the wild (9%) or the intermediate type (20%) (P < 0.05). These results show that mutations in the ISDR do not occur frequently, suggesting that interferon sensitivity does not change greatly during the natural course of the disease in each patient.

透析医療における感染の現況を把握し感染防止の実態の調査を行った. 郵送によるアンケート法により, 日常的に慢性血液透析を行っている本邦の医療施設2910施設を対象とした. アンケート回収は1681施設57.8%と良好だった. 回答率の偏りは, 私的施設の回答率 (44.8%) がその他の施設の回答率 (51.7%) より低かったが, 地域, 施設規模別では差がなく, おおむね偏りのない調査が行われた.81.6%の施設が, 感染対策マニュアルを自施設で作成しており, 施設の74.5%に感染対策委員会が設置され, その3分の2の施設で感染対策委員会が毎月開かれているなど, 多くの施設で, 院内感染予防に対する積極的な対策が講じられていることが明らかにされた.HBs抗原の測定率は施設の94.3%, 患者の97.1%の, HCV抗体測定率は施設の93.3%, 患者の98.9%と良好だった. 患者陽性率はHBs抗原で2.84%, HCV抗体では22.4%だった.HBs抗原, HCV抗体施設陽性率は7地域間で異なり (p=0.00515, p

The activity of hepatitis varies in chronic hepatitis C virus (HCV) infection. Some patients show persistently normal serum alanine aminotransferase (ALT) values, whereas the others show high-ALT values and progress to liver cirrhosis or hepatocellular carcinoma. However, virological mechanisms causing hepatitis have not fully been elucidated. We analyzed serial changes in full-length HCV sequences in 10 patients with various profiles of hepatitis activity. In the nonstructural 5A (NS5A) and NS5B, the rate of amino acid changes, as well as the proportion of nonsilent ones, was low in patients with normal ALT values compared with those with abnormal ALT (for the rate of amino acid changes, 0 × 10 −3 vs 3.19 × 10 −3 changes/site/year ( P = 0.037) in NS5A and 0 × 10 −3 vs 1.22 × 10 −3 changes/site/year ( P = 0.023) for NS5B, for the proportion of nonsilent changes, 4 vs 22% ( P = 0.017) in NS5A and 0 vs 16% ( P = 0.039) in NS5B). Also, the flare-up of hepatitis coincided with higher nucleotide/amino acid substitution rates in NS5B. In conclusion, the genomic structures of the NS5A and NS5B regions may correlate with hepatitis activity in chronic hepatitis C.

A close correlation was reported between amino acid mutations in the nonstructural protein 5A (interferon [IFN] sensitivity-determining region [ISDR]) of hepatitis C virus (HCV)-1b and the response to IFN therapy. The dynamic change of ISDR quasispecies during IFN treatment was investigated in 22 patients. In 18 nonresponders, the number of ISDR mutations in major quasispecies decreased after therapy (P =.039). In each nonresponder, the percentage of wild-type (no mutations in the ISDR) quasispecies increased after treatment (P =.008), whereas the percentages of intermediate- (1-3 mutations) and mutant-type (≥4 mutations) quasispecies decreased (P =.037 and P =.043, respectively). No mutant-type quasispecies were detected after therapy. Four complete responders had only quasispecies with ≥3 mutations before therapy. Thus, HCVs have fewer mutations in the ISDR after IFN therapy than those before therapy. These IFN-resistant HCVs were already present before therapy as minor quasispecies and were selected by IFN in nonresponders.

Although endoscopic clipping is used widely for the treatment of bleeding gastroduodenal ulcers, clinical trials on its efficacy are scarce. The aim of this study is to assess the efficacy and safety of endoscopic clipping for hemostasis from bleeding gastroduodenal ulcers.The present study was designed as a retrospective study using historical controls. One hundred consecutive patients with bleeding gastroduodenal ulcers were treated by endoscopic clipping. The preceding 91 consecutive patients treated by endoscopic pure ethanol injection were regarded as controls. Forty-nine of the clipping group and 41 of the ethanol group had lesions at sites difficult to perform endoscopic manipulation. Hemostatic rates, rebleeding rates, amounts of blood transfusion, and durations of hospital stay were analyzed.The hemostatic rate was 96% in both clipping and ethanol groups, whereas the rebleeding rate was lower (15% vs 29%, p = 0.023) in the former than the latter. In technically difficult cases, the hemostatic rate was comparable (96 vs 90%).In patients with bleeding gastroduodenal ulcers, endoscopic clipping may be a choice of therapy because of a low rebleeding rate compared with pure ethanol injection.

In the present study, genetic changes in the polymerase gene were analyzed in seven patients after 4 weeks of short-term lamivudine therapy, and those in the entire HBV genome were also investigated in one incomplete responder during 24 weeks of long-term therapy. During short-term therapy, serum HBV-DNA levels decreased rapidly in all seven patients, but were still detectable in four patients at the end of the therapy. In three of these four patients, one to five amino acid substitutions were observed in the polymerase gene other than YMDD. In contrast, no genetic changes were found in three patients who became negative for HBV-DNA by the end of therapy. In one incomplete responder to long-term therapy, eight amino acid substitutions were detected during lamivudine therapy throughout the entire HBV genome including the X, surface and core genes as well as the polymerase gene but not YMDD. In conclusion, HBV mutations other than YMDD motif or even outside the reverse transcriptase gene were found after lamivudine therapy, suggesting their contribution to reduced sensitivity to lamivudine. YMDD mutations seem to be rare during short-term therapy in immunocompetent chronic hepatitis B patients.

致死量をこえる黄リンを服用し, 肝機能障害とビタミンK不応性の凝固障害をきたしながら, N-acetylcysteine (以下NAC) の早期経口投与により救命しえた1例を経験した. 症例は56歳, 女性. 自殺目的にて“猫イラズ”1/2本以上 (黄リン800mg相当以上) をジュースに溶解し服用約2時間後, 嘔吐を主訴に受診した. 服薬状況より致死的と判断し, 同意を得たうえで服用9時間30分後にNACを胃管より投与した. 投与量は急性アセトアミノフェン中毒に準じた. 凝固因子はビタミンK投与にかかわらず, 第4病日にはPT43%, トロンボテスト18%まで低下した. GPTは第5病日に 191IU/lとピークに達したが, 黄疸は認めなかった. 回復期の肝生検では, 肝細胞内のリポフスチンの増加やクッパー細胞の腫大等を認め, 電顕上はrERの減少を認めた. 抗酸化剤のNACには内因性NOの産生・活性化作用が知られており, 黄リンによる急性肝不全を軽減しうる可能性が示唆された.

症例は17歳, 女性. 既往歴, 家族歴に特記すべきことなし. 1997年1月下旬より咽頭痛, 38℃台の発熱が続き, 肝障害, 腹部エコーにて肝及び脾に多発性の腫瘤性病変を認めたため精査目的にて入院. 入院時に著明な肝脾腫を認めた. 末梢血像は正常であったが, 肝腫瘍生検にて著明な小円形細胞の腫瘍性増殖を認めた. 骨髄穿刺にてリンパ球表面マーカーはCD10, CD19, CD20, CD34陽性でありALL (L1) に合致した所見であった. その後末梢血中に腫瘍細胞が出現し, 化学療法にて肝腫瘤像の著明な改善を認めた. 白血病細胞は高頻度に肝に浸潤するが, 重症肝障害を来すことは稀とされる. 本例は入院時に肝障害を認め, 診断時において末梢血像に腫瘍細胞の出現なく, 多発性の肝腫瘤を契機にALLの診断に至った. 白血病においては一般的に肝生検などによる診断は禁忌な場合が多いとされるが, 早期に肝生検を施行し診断できた貴重な症例と思われ報告した.

高齢者の肝細胞癌 (HCC) 症例に対する化学塞栓療法 (TACE) 反復施行例の成績について, 若年者症例を対照として検討した。2回以上のTACEを主たる治療として行ったHCC症例のうち, 初回治療時の年齢が70歳以上の28例を高齢者群 (O群), 55歳以下の23例を若年者群 (Y群) とした。TACEはlipidol TAI (またはlipiodol TAE) を3か月に1回行うことを原則とし, 各群全症例におけるのべ施行回数はO群で157回, Y群で186回だった。両群で性, Child分類, performance status, 病因, 飲酒歴, 肝硬変の合併, 主腫瘍径, Stageに差はみられなかった。TACEの施行回数は, O群5.6±4.2, Y群8.1±7.0で差がなかった。O群とY群において抗癌剤の種類および1回あたりの動注量には差がなかった。PR以上の効果が1回以上得られた症例は, O群で28例中10例で, Y群で23例中13例だった (NS)。O群ではのべ6回重篤な副作用 (骨髄抑制2, 十二指腸潰瘍1, 胸水1, 脳症1, 敗血症1) がみられたのに対し, Y群ではみられなかった (P

An 82-year-old male patient was admitted for liver dysfunction. Laboratory test showed the following data; aspartate aminotransferase (AST) 79 IU/ι, alanine aminotransferase (ALT) 28 IU/ι, total bilirubin (T. Bil) 0.9 U, zinc sulfate turbidity test (ZTT) 48.9 U, γ-globulin 4.9 g/dl, immunoglobulin G (IgG) 5, 046 mg/dl, anti-nuclear antibodies×320, anti-niitochondrial antibodies (-), hepatitis B virus surface antigen (HBsAg) (-), HBcAb (-), anti-hepatitis C virus (anti-HCV) (-), hepatitis C virus (HCV-RNA) (-), anti-hepatitis G virus (anti-HGV) (-), α-fetoprotein 306.8 ng/ml, carcinoembryonic antigen (CEA) 2.3 ng/nil, carbohydrate antigen (CA) 19-9 77.2 U/ml. Abdominal ultrasonography and computed tomography showed a large mass occupying most of the right lobe and portal thrombosis in the liver. Liver biopsy revealed cirrhosis with inactive hepatitis in the nontumorous lesion and well-differentiated hepatoceliular carcinoma in the tumorous lesion. We report a rare case of an aged male patient with autoimmune hepatitis complicated by hepatoceliular carcinoma.(Internal Medicine 38: 422-425, 1999)

This study examined the relation between the bedtime of 4-month-old infants and their daily weight gain, using health check-up data and a questionnaire. The infants, totalling 155 in number, were divided into a late group (109 infants; LG) whose mothers had taken them to bed after 22.00 hours and a control group (46 infants; CG) whose bedtime was earlier than 22.00 hours. The daily weight gain was significantly lower in the LG than the CG and this was related to bedtime by multiple regression analysis.