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Tenofovir alafenamide (TAF) may be preferable to other nucleos(t)ide analogues (NA) regarding outcomes against chronic hepatitis B virus (HBV) infection.To evaluate the longer term virological/biochemical effectiveness of TAF and the renal safety of sequential therapy to TAF in real-world settings METHODS: This multi-centre, retrospective cohort study included consecutive adult patients who were switched from other NAs to TAF. We assessed the virological and biochemical responses up to 144 weeks. We performed sensitivity analyses for a subgroup with chronic kidney disease (CKD) at baseline.We analysed the data of 391 patients with chronic hepatitis B previously treated with entecavir (ETV) (n = 174), tenofovir disoproxil fumarate (TDF) (n = 116) or an NA combination (n = 101) for ≥ 24 months. HBV DNA 10 IU/ml at week 144 was found for 99% of patients, regardless of prior NA regimen or HBV DNA level at baseline. For patients who switched from TDF to TAF, total, low-density lipoprotein, high-density lipoprotein cholesterol and triglycerides were significantly increased after the switch. Patients who switched from a nucleotide analogue to TAF had an improved estimated glomerular filtration rate, although the rate of hypophosphataemia (2.5 mg/dl) remained 9.7% at week 144. The virological and biochemical responses of patients with CKD were similar to the overall results.Switching to TAF remained effective and safe for up to 3 years. Given the increasing comorbidities related to ageing, it will be important to carefully follow the change in the lipid levels of patients with a prior TDF-based regimen.

A Japanese woman in her 80s with rheumatoid arthritis (RA) was admitted for weakness, edema, and ascites. She was obese (148 cm in height, 60 kg in weight) and had a high gamma-glutamyltransferase level according to her laboratory findings before treatment. She had received methotrexate (MTX) at a dose of 6 mg/week for 1 year and 9 months. She had consumed large amounts of soft drinks (about 110 g of sugar/day) for a long time, but during the course of treatment for RA, she began drinking even more (170 g/day). Her condition improved with the discontinuation of MTX, adequate nutrition, and administration of diuretics. We diagnosed her with liver cirrhosis caused by both drug-induced hepatic injury due to MTX and by exacerbation of non-alcoholic steatohepatitis due to excessive sugar intake.

BACKGROUND AND AIM Direct-acting antivirals (DAAs) have contributed to the improvement of outcomes for all patients with chronic hepatitis C. The aim of this study was to evaluate the long-term hepatic benefits of hepatitis C virus (HCV) cure by DAAs in patients with compensated cirrhosis. METHODS This multicenter cohort study consisted of consecutive patients with compensated cirrhosis who initiated interferon-free DAA treatment before September 2016. The impact of treatment on long-term hepatic function was followed for at least 4 years after the end of treatment, and the progression to decompensation was evaluated. RESULTS The data of 394 patients were available for study. The median age was 70, and 41% had modified albumin-bilirubin (ALBI) grade 2b. During a short-term follow-up 1 year after the end of treatment, FIB-4 index and ALBI score significantly improved. The achievement rates of FIB-4

Background and AimsOutcome data of sequential hepatitis B virus treatment with tenofovir alafenamide (TAF) are limited. We aimed to assess the effectiveness and renal safety of TAF in chronic hepatitis B (CHB) patients who were previously treated with entecavir (ETV), tenofovir disoproxil fumarate (TDF), or nucleos(t)ide analog (NA) combination. MethodsThis multicenter, retrospective, cohort study included 458 consecutive CHB patients who switched to TAF monotherapy after at least two years of treatment with another NA. The longitudinal virological/laboratory responses were evaluated up to 96 weeks after switchover. Chronic kidney disease (CKD) was defined as an estimated glomerular filtration rate (eGFR)2. ResultsThe proportions of HBV DNA suppression (HBV DNAPP

Outcome data of sequential hepatitis B virus treatment with tenofovir alafenamide (TAF) are limited. We aimed to assess the effectiveness and renal safety of TAF in chronic hepatitis B (CHB) patients who were previously treated with entecavir (ETV), tenofovir disoproxil fumarate (TDF), or a nucleos(t)ide analogue (NA) combination.This multicenter, retrospective, cohort study included 458 consecutive CHB patients who switched to TAF monotherapy after at least 2 years of treatment with another NA. The longitudinal virological/laboratory responses were evaluated up to 96 weeks after switchover. Chronic kidney disease (CKD) was defined as an estimated glomerular filtration rate (eGFR) 60 mL/min/1.73 mThe proportions of complete viral suppression (CVS) (HBV DNA 20 IU/mL) at week 96 were 99.0%, 98.5%, and 98.4% in the prior ETV (n = 198), TDF (n = 137), and NA combination (n = 123) groups, respectively. Almost all patients with HBV DNA of 20-2000 IU/mL at baseline achieved CVS at week 96. On multivariable generalized estimated equation analysis, a low quantitative hepatitis surface antigen (qHBsAg) level at baseline was associated with a lower follow-up qHBsAg level (coefficient 0.81, p 0.001). The eGFR showed greater improvement in patients with CKD compared to those without (coefficient 21.7, p 0.001). However, the increase of eGFR reached a peak between weeks 24 and 48.Based on this longitudinal data analysis up to 96 weeks, sequential NA therapy with a switch to TAF is a good option to achieve high viral suppression and renal safety.

We herein report the case of a woman in her 80s with a recurrent hepatocellular carcinoma (HCC) tumor that rapidly increased in size during direct-acting antiviral (DAA) treatment. She suffered from HCC at her initial visit to our department and underwent hepatectomy. Thereafter, she underwent DAA treatment for chronic hepatitis C; however, her alpha-fetoprotein (AFP) level rapidly increased, and a liver tumor of > 1 cm in diameter was observed that had not been seen immediately before DAA treatment. She underwent hepatectomy again and moderate to poorly differentiated HCC was diagnosed. The patient’s AFP level showed a rapid increase immediately after the start of DAA treatment; however, the increase ceased after the first month, and the influence from the surrounding environment of the tumor was considered to be temporary.

Hepatitis C virus (HCV) RNA values measured with two real-time PCR methods (Cobas Ampliprep/Cobas TaqMan, CAP/CTM, and the Abbott real-time PCR test, ART) vary among patients with genotype 1. We investigated HCV RNA values measured by two real-time PCR assays during pegylated interferon plus ribavirin (PEG-IFN/RBV) therapy. We evaluated 185 cases of chronic hepatitis C patients, among which 97 patients received the PEG-IFN/RBV therapy. HCV RNA values of CAP/CTM for genotype 1 were significantly higher than those of ART (p0.05) The difference in HCV RNA values (CAP/CTM minus ART) of genotype 1 was significantly higher than those in genotype 2 (p0.0001). The positive rate (0) of the difference of HCV RNA values in genotype 1 was 100 % (55/55), which was significantly higher than the 78.6 % (33/42) of genotype 2 (p0.001). There was no difference between TT and TG/GG genotype groups in terms of difference of HCV RNA values (CAP/CTM minus ART). After PEG-IFN/RBV therapy was administered, reduction of HCV measurements was observed from day 1 for both assays regardless of genotype. The HCV value of CAP/CTM during PEG-IFN/RBV therapy was consistently higher than the value of ART, although the difference in these two values gradually became smaller during the course of therapy, and eventually no significant difference was observed near the detection level. No correlation was observed between the sustained virological response (SVR) rate and the difference between the CAP/CTM HCV values and the ART HCV value before treatment.

Background and Aim: The inosine triphosphatase (ITPA) genotype is associated with ribavirin-induced anemia and pegylated interferon α (PEG IFN-α)-induced platelet reduction during PEG IFN-α plus ribavirin combination therapy. Natural IFN-β plus ribavirin therapy is associated with increases in platelet counts during treatment. We investigated decreases in platelet counts according to ITPA genotype during natural IFN-β/ribavirin therapy to determine if patients with low platelet counts were eligible for this combination therapy. Methods: A total of 187 patients with chronic hepatitis C received PEG IFN-α/ribavirin or natural IFN-β/ribavirin therapy. Decreases in platelet counts based on ITPA genotype were investigated during treatment through 24 weeks. Results: Platelet counts decreased during week 1 of PEG IFN-α/ribavirin therapy, but increased during week 2, after which platelet counts decreased gradually. Platelet counts decreased until week 4 of natural IFN-β/ribavirin therapy, after which platelet counts increased. Platelet counts after week 8 were higher relative to pretreatment platelet counts. Patients with the ITPA-CC genotype showed a smaller decrease in platelet counts during natural IFN-β/ribavirin therapy than those with the ITPA-CA/AA genotype; platelet counts after week 8 of this therapy were higher than pretreatment platelet counts, regardless of pretreatment platelet counts. Multivariate logistic regression analyses showed that natural INF-β/ribavirin therapy was the only significant independent predictor for an increase in platelets through week 8. Conclusion: Natural IFN-β/ribavirin therapy is safe for patients with the ITPA-CC genotype, even if their pretreatment platelet counts are low.

Aim: The onset of depression symptoms during pegylated interferon α plus ribavirin (PEG-IFN/RBV) combination therapy has led to treatment discontinuation in some cases. In the present study, we conducted a questionnaire survey during treatment to determine whether natural human interferon β plus ribavirin (IFNβ/RBV) therapy is associated with a lower incidence of depression symptom onset compared with PEG-IFN/RBV therapy. Methods: Seventy-seven patients with chronic hepatitis C received PEG-IFN/RBV (PR) or IFNβ/RBV (FR) therapy. A questionnaire survey was administered at the start of treatment, and at 4 and 12 weeks, using the Beck Depression Inventory II (BDI-II) and the Pittsburgh Sleep Quality Index (PSQI). Results: BDI-II scores in the PR group increased at 4 and 12 weeks, but remained unchanged in the FR group. At 12 weeks, the mean BDI-II score and incidence of abnormalities with a BDI-II score of ≥14 were significantly lower in the FR group than in the PR group. BDI-II scores during IFNβ/RBV therapy in 11 patients currently using antidepressants remained unchanged up to 12 weeks. None of these 11 patients required addition or dose increases of antidepressants, and there was no evidence of worsened depression symptoms. Nine PR patients had BDI-II scores of ≥14 and PSQI scores of ≥11 at 12 weeks. Conclusions: IFNβ/RBV therapy was associated with a lower incidence of depression symptom onset during treatment. In patients already diagnosed with depression, there was no evidence that IFNβ/RBV therapy caused any worsening of symptoms, indicating that IFNβ/RBV therapy is safe for patients with depression.

2008年8月から10月にかけて4名の患者がC型急性肝炎を発症し九州厚生年金病院に入院した．いずれの患者も同年4月から5月にかけて同院に入院したことがあり，院内感染の可能性ありと判断し，調査委員会を設置し調査を開始した．4名中3名でウイルス遺伝子の一致を認めた．4名中2名でウイルスは自然に消失し，1名はインターフェロン治療で治癒，1名は慢性化した．感染から数カ月経過していたと考えられ感染経路は特定できなかったが，感染防止対策としてスタンダード・プリコーションの徹底，作業内容・作業環境の見直しなどを行った結果，以降新たな感染者は見られなかった．C型肝炎の院内感染を防止するためには，サーベイランスを含めた院内全体の取り組みが必要である．

We report a case of pulmonary tumor embolism due to hepatocellular carcinoma (HCC). A woman in her 60s was treated with sorafenib 800 mg daily for HCC with lymph node metastasis. Approximately 50 days after taking sorafenib, she experienced dyspnea and was admitted to the hospital on account of hypoxia. Although her oxygen saturation levels deteriorated, we could find no obvious cause for the hypoxia; despite artificial respiration and oxygenation, she died of respiratory failure on the fourth day of admission. Tissue samples revealed that the HCC cells had infiltrated her lung arterioles; therefore, we concluded that multiple tumor microembolisms from the HCC to the lungs had caused death via respiratory failure. Cases of hypoxia caused by multiple invisible embolisms from HCCs are rarely reported. We believe that infiltration into the lymphatic system may have been related to the development of pulmonary tumor microembolisms.

This paper proposes near-field sound-source localization based on crosscorrelation of a signed binary code. The signed binary code eliminates multibit signal processing for simpler implementation. Explicit formulae with near-field assumption are derived for a two microphone scenario and extended to a three microphone case with front-rear discrimination. Adaptive threshold for enabling and disabling source localization is developed for robustness in noisy environment. The proposed sound-source localization algorithm is implemented on a fixed-point DSP. Evaluation results in a robot scenario demonstrate that near-field assumption and front-rear discrimination provides almost 40% improvement in DOA estimation. A correct detection rate of 85% is obtained by a robot in a home environment.

ASK (activator of S phase kinase) is an activation subunit for mammalian Cdc7 kinase. We have generated mutant ES cell lines in which ASK can be conditionally inactivated. Upon loss of the ASK genes, the mutant ES cells rapidly cease cell growth. In keeping with its expected roles in activation of the essential S phase kinase, DNA synthesis is arrested and significant cell death is eventually induced in ASK-deficient cells, demonstrating essential roles of ASK for viability of ES cells. Using these mutant cells, we have set up a system where ASK molecules can be functionally dissected. In keeping with previous results from yeasts, conserved motif-M and motif-C were shown to be essential for in vivo functions of ASK, whereas a long C-terminal tail, found only in ASK-related molecules in higher eukaryotes, is not required. Unexpectedly, the motif-N, related to the BRCT motif and dispensable for viability in yeasts, is essential for the viability of ES cells. Further characterization reveals that motif-N is required for the maximum phosphorylation of MCM in cells, whereas the autophosphorylation activity of Cdc7 is not significantly affected by its loss. These results may suggest that motif-N of ASK may facilitate recruitment of substrates for Cdc7 kinase.

UDP-glucuronosyltransferase1A1 (UGT1A1) catalyses glucuronidation of bilirubin (the final break down product of heme which is produced mainly in the spleen and liver) and is located on the lumen of the endoplasmic reticulum (ER). To identify partner UGTs that form hetero-oligomers with UGT1A1, or other proteins that bind directly to UGT1A1, yeast two-hybrid screening was performed using UGT1A1 as bait. From these studies, cDNA clones specific for human serum albumin (HSA) were unexpectedly isolated. The direct interaction between UGT1A1 and albumin was confirmed in vitro by a pull-down assay. FITC-albumin uptake into HepG2 and Huh7 cells was observed only when bilirubin are present in the culture medium. Furthermore, the endocytosis inhibitor phenylarsine oxide (PAO) prevented albumin uptake into the cells, suggesting that the albumin/bilirubin complex is internalized through receptor-mediated endocytosis. From these studies, it would appear that production of large amounts of toxic bilirubin might use different uptake pathways for entry into hepatocytes.

Background and Aim: Interferon and ribavirin combination therapy for chronic hepatitis C produces hemolytic anemia. This study was conducted to identify the factors contributing to ribavirin-induced anemia. Methods: Eighty-eight patients with chronic hepatitis C who received interferon-α-2b at a dose of 6 MU administered intramuscularly for 24 weeks in combination with ribavirin administered orally at a dose of 600 mg or 800 mg participated in the study. A hemoglobin concentration of

OBJECTIVE The sustained virological response (SVR) rate has improved to >70% for patients with hepatitis C virus genotype 1 treated with the triple therapy of telaprevir (TVR), pegylated interferon (PEG-IFN)-α, and ribavirin (RBV). However, this therapy has various adverse effects, although there have been no reports of it decreasing body weight. METHODS A total of 175 patients with chronic hepatitis C received one of three IFN-based regimens (35 received the PEG-IFN/RBV/TVR (PRT) regimen, 70 received the PEG-IFN/RBV (PR) regimen, and 70 received the IFN-β/RBV (FR) regimen) and body weight was followed for 12 weeks. RESUTS Decreases in body weight up to week 12 were significantly greater in the PRT group than in the PR or FR groups (p

A study evaluating the iron loss of a developed iron powder core under DC bias conditions with sinusoidal and square magnetizing voltage waveforms was conducted. It was found that the iron loss of the powder core decreases when the DC bias magnetic flux density increases. Also, the variation in the iron loss of the core material caused by the difference in the magnetizing voltage waveform is smaller than that of a conventional steel core. Hence, the developed core material is suitable for applications such as inductors used in power converters.

Background Terminal deoxynucleotidyltransferase (TdT) is a DNA polymerase that enhances Ig and TcR gene diversity in the N region in B- and T-cells. TdT is found as a member of a large protein complex in the lysate of the thymocytes. To elucidate the molecular mechanism of the synthesis of the N region, we first attempted to isolate the genes with products that are interacting directly with TdT. Results Using a yeast two-hybrid system, we isolated a cDNA clone encoding a novel nuclear protein that interacts with TdT. This protein was designated as TdT interacting factor 1 (TdIF1). TdIF1 has a high degree of homology to the transcription factor p65, which belongs to the nuclear receptor superfamily. TdIF1 contains HMG-I and HMG-Y DNA binding domains (AT-hooks) and can bind to single- and double-stranded DNA. TdT and TdIF1 were co-eluted at position 232 kDa by gel filtration of MOLT4 lysate. TdIF1 can enhance TdT activity fourfold in vitro assay system using oligo(dT)16 as primers. Conclusions TdIF1 binds directly to TdT, both in vitro and in vivo. TdIF1 and TdT exist as the members of a 232 kDa protein complex. TdIF1 can enhance TdT activity maximum fourfold in vitro assay system, suggesting that it positively regulates the synthesis of the N region during V(D)J recombination in the Ig and TcR genes.

A rare case of an inflammatory pseudotumor (IPT) of the liver with reactive arthritis (ReA) is herein described. A 34-year-old woman presented with post-infectious ReA in the bilateral knees and foot joints. As the primary infected site for ReA could not be determined, a systemic survey revealed an IPT in her liver, which was diagnosed histologically. The arthritis and the tumor regressed simultaneously after being treated by indomethacin farnesil 400 mg/day. Although the exact etiology of IPT or ReA still remains unknown, it is hypothesized that the same pathogenetic mechanisms may be involved in the development of IPT and ReA.

A 21-year-old woman was diagnosed as having Graves' disease in April, 1995. Thiamazole was administered; about a month later the patient had a skin rash and propylthiouracil (PTU) was given instead. Two months after commencing PTU, she rapidly developed jaundice, accompanied by severe liver damage. The drug-induced lymphocyte stimulating test was positive for PTU and she was diagnosed as having severe hepatitis induced by PTU. After pulse therapy with 500 mg of methylprednisolone was given for 3 days, liver function test results were gradually improved, and became normalized 1 1/2 months after admission. The pathology findings of the liver biopsy sample taken before administration of corticosteroid showed necrosis of hepatocytes predominantly around the central veins (i.e., zone 3 necrosis), and moderate to severe infiltration of lymphocytes and neutrophils in portal areas and lobules. Severe hepatic damage due to PTU is rare; 25 cases have been reported so far in the English-language literature. When we use PTU for patients with hyperthyroidism, we should keep in mind that severe liver damage induced by PTU can be fatal, and we should therefore diagnose it earlier by liver biopsy and lymphocyte stimulating test.

To characterize the role of phosphodiesterase type 4 (a cAMP-specific and rolipram-sensitive phosphodiesterase) among phosphodiesterases in the regulation of the intracellular cAMP level in cortical neurons, we investigated the effects of phosphodiesterase inhibitors on the intracellular cAMP levels in primary cultured rat cortical neurons. Selective inhibitors of phosphodiesterase type 4 and type 2 significantly enhanced beta-adrenoceptor-mediated cAMP increase. Selective inhibitors of phosphodiesterase type 1, type 3 and type 5/6 had no effect on the cAMP level. Rolipram enhanced the beta-adrenoceptor-mediated cAMP increase in cortical neurons, astrocytes and vascular smooth muscle cells at different minimum effective concentrations (10, 100 and 1000 nM, respectively). These findings indicate that phosphodiesterase type 4, showing a high-sensitivity to rolipram, plays a major role in regulating cAMP in the cortical neurons, and that rolipram at low doses enhances the intracellular cAMP increase in the cortical neurons selectively.

Aim This study aims to evaluate the efficacy and safety of interferon-beta plus ribavirin therapy in older Japanese patients. Patients and methods This study enrolled 132 older patients (age, ≥65 years) with chronic hepatitis C who received 24–48 weeks of interferon-beta plus ribavirin (FR; n = 66) or pegylated interferon-alpha plus ribavirin (PR; n = 66) therapy. Results Patients with the ITPA genotype (CA/AA) in the PR group had significantly greater decreases in hemoglobin levels than those in the FR group at or after week 8. The proportions of patients with a dose reduction of interferon-beta and ribavirin in the FR group were significantly lower than those in the PR group. A significantly higher proportion of patients completed treatment in the FR group than in the PR group. The sustained virological response (intention-to-treat analysis) rate of naive patients with genotype 1 was 29% (6 of 21) in the PR group and 29% (6 of 21) in the FR group. The sustained virological response (intention-to-treat) rate of those with genotype 2 was 67% (12 of 18) in the PR group and 72% (13 of 18) in the FR group. Conclusion Interferon-beta plus ribavirin therapy was safe in elderly patients, with lower proportions of patients with a dose reduction of interferon-beta or ribavirin and treatment discontinuation. In treatment-naive patients, the sustained virological response rate was similar between interferon-beta plus ribavirin therapy and pegylated interferon-alpha plus ribavirin therapy, regardless of whether the patients had hepatitis C virus genotype 1 or 2.

We report a case of double liver cancer in an elderly woman with chronic hepatitis C. The patient was diagnosed with two liver tumors when she was in her 70s, and she underwent hepatectomy for the same. Histopathological examination determined that the two tumors were distinct. One was a well-to-moderately differentiated hepatocellular carcinoma (HCC) and the other was a combined hepatocellular carcinoma and mucinous cholangiocarcinoma (ChC). The HCC component was positive for cytokeratin 19, and it infiltrated into the portal vein and artery and the gall bladder. The ChC component was positive for hepatocyte paraffin 1 (HepPar1) staining and infiltrated into the bile duct. There has been no cancer recurrence at 6 months after surgery. Double cancer of the liver with these histological types is extremely rare and interesting, given the origin and differentiation of liver cancer.

The MAGE-1 gene, originally isolated from a human melanoma cell line, directs the expression of a potential tumor-rejection antigen, MZ2-E. This antigen is recognized by autologous cytotoxic T lymphocytes in association with a major histocompatibility complex class I molecule (HLA-A1), and has provided a basis for specific immunotherapy for melanoma patients. Here we show a high frequency of expression of the MAGE-1 gene in hepatocellular carcinoma (HCC). We examined the expression of the MAGE-1 gene in cell lines originated from hepatoma cells and in tumor and nontumor tissues of livers with HCC by reverse-transcription polymerase chain reaction (RT-PCR) and subsequent Southern blotting. MAGE-1 messenger RNA (mRNA) was expressed in three of four HCC cell lines (75%) and in 16 of 20 (80%) resected HCCs though none was detected in nontumor tissues. The high frequency expression of MAGE-1 gene in HCCs suggests the possibility as a target for tumor-specific immunotherapy for HCC patients.

An integrated memory array processor (IMAP) ULSI with 64 processing elements and a 2 Mb SRAM has been developed to build a compact real-time image processing system. The chip attains a 3.84 GIPS peak performance through the use of SIMD parallel processing and 1.28 GByte/s on-chip processor-memory bandwidth. The IMAP is capable of parallel indexed addressing, which increases applications for parallel algorithms. Created using 0.55 μm BiCMOS double layer metal process technology, the IMAP contains 11 million translators in a 15.1 x 15.6 mm 2 die area.

We have fabricated a high yield integrated memory array processor (IMAP) LSI, which features a high memory bandwidth (1.28-GB/s) and low power consumption (4-W max.) and which contains a 2-Mb SRAM with 1.28-I/O's and 64 processor elements (PE's) in one chip. A high-bandwidth and low-power memory circuit design is the key technology to realize the IMAP-LSI. We adopted following new designs for memory circuit. (1) Memory access time is designed to be twice as fast as PE execution time (2) Employment of dynamic power control mode, which reduces the memory power consumption down to 30% of maximum power without a loss in access-speed (3) Simplified synchronization with PE's (4) 4-way block redundancy. These design techniques are suitable for future system integrated ULSI's. >

The inosine triphosphatase (ITPA) genotype is associated with ribavirin-induced anemia and pegylated interferon α (PEG IFN-α)-induced platelet reduction during PEG IFN-α plus ribavirin combination therapy. Natural IFN-β plus ribavirin therapy is associated with increases in platelet counts during treatment. We investigated decreases in platelet counts according to ITPA genotype during natural IFN-β/ribavirin therapy to determine if patients with low platelet counts were eligible for this combination therapy.A total of 187 patients with chronic hepatitis C received PEG IFN-α/ribavirin or natural IFN-β/ribavirin therapy. Decreases in platelet counts based on ITPA genotype were investigated during treatment through 24 weeks.Platelet counts decreased during week 1 of PEG IFN-α/ribavirin therapy, but increased during week 2, after which platelet counts decreased gradually. Platelet counts decreased until week 4 of natural IFN-β/ribavirin therapy, after which platelet counts increased. Platelet counts after week 8 were higher relative to pretreatment platelet counts. Patients with the ITPA-CC genotype showed a smaller decrease in platelet counts during natural IFN-β/ribavirin therapy than those with the ITPA-CA/AA genotype; platelet counts after week 8 of this therapy were higher than pretreatment platelet counts, regardless of pretreatment platelet counts. Multivariate logistic regression analyses showed that natural INF-β/ribavirin therapy was the only significant independent predictor for an increase in platelets through week 8.Natural IFN-β/ribavirin therapy is safe for patients with the ITPA-CC genotype, even if their pretreatment platelet counts are low.

This paper describes a real-time vision system (RVS) architecture and performance and its use of an integrated memory array processor (IMAP) prototype. This prototype integrates eight 8-bit processors and a 144-kbit SRAM on a single chip. The RVS was developed with 64 IMAP prototypes connected in series in a 512 processor-system configuration. A host workstation can access the memory on the IMAP prototypes directly through a random access port. Images are inputted and outputted at high speed through serial access ports. The RVS performance is shown in real-time road-image processing and in a neural network simulation, as well as in low-level image processing algorithms, such as filtering, histograms, discrete cosine transform (DCT), and rotation. The RVS image processing is shown to be much faster than the video rate.

An integrated memory array processor (IMAP) LSI has peak performance of 3.84 GIPS and is suitable for high-speed, low-level image processing (LIP). Keys to performance are: integration of 64 simple processing elements (PEs) and 2 Mb SRAM with 128 b I/O, and single-instruction stream multiple-data stream (SIMD) parallel processing by use of 1.28 GB/s on-chip processor-memory bandwidth. A large number of active sense amplifiers ordinarily used in a wide memory bandwidth creates the problem of large power consumption. The number of active sense amplifiers here is reduced by a factor of 4 by accessing half of each word at a time, but accessing it at twice the speed of the PE clock. This keeps power consumption low. Each memory block can perform indexed addressing within its pages. This capability contributes to IMAP flexibility and efficiency in LIP. To raise yield, the architecture employs 4-way block replacement redundancy. IMAP is fabricated in 0.55 /spl mu/m BiCMOS 2-layer metal process technology. >

The onset of depression symptoms during pegylated interferon α plus ribavirin (PEG-IFN/RBV) combination therapy has led to treatment discontinuation in some cases. In the present study, we conducted a questionnaire survey during treatment to determine whether natural human interferon β plus ribavirin (IFNβ/RBV) therapy is associated with a lower incidence of depression symptom onset compared with PEG-IFN/RBV therapy. Seventy-seven patients with chronic hepatitis C received PEG-IFN/RBV (PR) or IFNβ/RBV (FR) therapy. A questionnaire survey was administered at the start of treatment, and at 4 and 12 weeks, using the Beck Depression Inventory II (BDI-II) and the Pittsburgh Sleep Quality Index (PSQI). BDI-II scores in the PR group increased at 4 and 12 weeks, but remained unchanged in the FR group. At 12 weeks, the mean BDI-II score and incidence of abnormalities with a BDI-II score of ≥14 were significantly lower in the FR group than in the PR group. BDI-II scores during IFNβ/RBV therapy in 11 patients currently using antidepressants remained unchanged up to 12 weeks. None of these 11 patients required addition or dose increases of antidepressants, and there was no evidence of worsened depression symptoms. Nine PR patients had BDI-II scores of ≥14 and PSQI scores of ≥11 at 12 weeks. IFNβ/RBV therapy was associated with a lower incidence of depression symptom onset during treatment. In patients already diagnosed with depression, there was no evidence that IFNβ/RBV therapy caused any worsening of symptoms, indicating that IFNβ/RBV therapy is safe for patients with depression.

This paper presents architectural features and performances for an Integrated Memory Array Processor (IMAP) LSI, which integrates a large capacity memory and a one-dimensional SIMD processor array on a single chip. The IMAP has a conventional memory interface, almost the same as a dual port video RAM with operational input extension. SIMD processing is carried out on the IMAP chip, using an internal processor array, while other higher level processing is concurrently accomplished with external processors through the random access memory port. In addition to the basic IMAP architecture, this paper describes orthogonal IMAP, which has an extended IMAP architecture. The basic IMAP uses a conventional memory cell, while the orthogonal IMAP uses an orthogonal memory for holding images.

Background & Aims ME3738 (22β-methoxyolean-12-ene-3β, 24-diol), a derivative of soyasapogenol B, attenuates liver disease in several animal models of acute and chronic liver injury. ME3738 is thought to inhibit replication of hepatitis C virus (HCV) by enhancing interferon (IFN)-β production, as determined using the HCV full-length binary expression system. We examined the effect of ME3738 combined with IFN-α on HCV replication using the genotype 1b subgenomic replicon system and an in vivo mouse HCV model. Methods HCV replicon cells (ORN/3-5B/KE cells and Con1 cells) were incubated with ME3738 and/or IFN-α, and then intracellular IFN-stimulated genes (ISGs) and HCV RNA replication were analyzed by reverse-transcription-real time polymerase chain reaction and luciferase reporter assay. HCV-infected human hepatocyte chimeric mice were also treated with ME3738 and/or IFN-α for 4 weeks. Mouse serum HCV RNA titer, HCV core antigen, and ISGs expression in the liver were measured. Results ME3738 induced gene expression of oligoadenylate synthetase 1 and inhibited HCV replication in both HCV replicon cells. The drug enhanced the effect of IFN to significantly increase ISG expression levels, inhibit HCV replication in replicon cells, and reduce mouse serum HCV RNA and core antigen levels in mouse livers. The combination treatment was not hepatotoxic as evident histologically and did not reduce human serum albumin in mice. Conclusions ME3738 inhibited HCV replication, enhancing the effect of IFN-α to increase ISG expression both in vitro and in vivo , suggesting that the combination of ME3738 and IFN might be useful therapeutically for patients with chronic hepatitis C.

A derivative of soyasapogenol, 22beta-methoxyolean-12-ene-3beta, 24(4beta)-diol (ME3738), ameliorates liver injury induced by Concanavalin A in mice. We examined whether ME3738 has independent antiviral effects against hepatitis C virus (HCV) using an established HCV replication model that expresses the full-length genotype 1a HCV complementary DNA plasmid (pT7-flHCV-Rz) under the control of a replication-defective adenoviral vector expressing T7 polymerase. Hepatocellular carcinoma (HepG2) cells, human hepatoma (Huh7) cells, or monkey kidney (CV-1) cells were transfected with pT7-flHCV-Rz, and infected with adenoviral vector expressing T7 polymerase. ME3738 or interferon-alpha (IFN-alpha) was added thereafter and then protein and RNA were harvested from the cells at 9 days after infection. HCV-positive and HCV-negative strands were measured by real-time reverse-transcription polymerase chain reaction and HCV core protein expression was measured using an enzyme-linked immunosorbent assay. The messenger RNA levels of innate antiviral response-related genes were assessed using real-time reverse-transcription polymerase chain reaction. ME3738 dose-dependently reduced HCV-RNA and core protein in hepatocyte-derived cell lines. The antiviral effect was more pronounced in HepG2 than in Huh7 cells. ME3738 increased messenger RNA levels of interferon-beta (IFN-beta) and of IFN-stimulated genes (2'-5' oligoadenylate synthetase, myxovirus resistance protein A [MxA]). Interferon-beta knockdown by small interfering RNA abrogated the anti-HCV effect of ME3738. Moreover, the anti-HCV effects were synergistic when ME3738 was combined with IFN-alpha.ME3738 has antiviral effects against HCV. The enhancement of autocrine IFN-beta suggests that ME3738 exerts antiviral action along the type I IFN pathway. This anti-HCV action by ME3738 was synergistically enhanced when combined with IFN-alpha. ME3738 might be a useful anti-HCV drug either with or without IFN-alpha.

Aim: The aim of this study was to examine the preventive effects of ME3738 on hepatic fibrosis induced by bile duct ligation (BDL) in rats. Methods: ME3738 (20 mg/day) was administered orally for 21 days immediately after BDL. Fibrosis was assessed by measuring hepatic hydroxyproline (Hyp) content. Activated hepatic stellate cells (HSCs) were assessed by α-smooth muscle actin (α-SMA) immunostaining. Hepatic thiobarbituric acid-reactive substance (TBARS), 4-hydroxy-2-nonenal (4-HNE) and 8-hydroxy-2-deoxyguanosine (8-OHdG) immunostaining were used to analyze oxidative stress. The gene expressions of collagen-I, transforming growth factor-β1 (TGF-β1), tissue inhibitor of metalloproteinases-1 (TIMP-1), interleukin-6 (IL-6) and heme oxygenase-1 (HO-1) in the liver were examined by real-time reverse transcriptase polymerase chain reaction (RT–PCR). Results: Hepatic Hyp content and the area of hepatic fibrosis in BDL rats treated with ME3738 were reduced by 24% and 39% compared with non-treated BDL rats (hepatic Hyp, 9.40 ± 2.85 vs. 12.39 ± 3.91 mg/liver; P = 0.036; area of hepatic fibrosis, 13.1 ± 3.8 vs. 21.5 ± 10.9; P = 0.045). Furthermore, α-SMA-positive cells were significantly reduced by 40% (22.3 ± 14.8 vs. 37.6 ± 14.2; P = 0.011), collagen-I mRNA by 83% (6.5 ± 2.2 vs. 38.3 ± 9.1; P = 0.002), HO-1 mRNA by 58% (4.13 ± 1.22 vs. 9.73 ± 1.80; P = 0.018) and hepatic HO-1 content by 26% (2.13 ± 0.80 vs. 2.87 ± 0.19; P = 0.01) following ME3738 treatment. The hepatic expression of TBARS, 4-HNE, 8-OHdG and mRNA levels of TGF-β1, TIMP-1 and IL-6 in the liver were unchanged by ME3738 treatment. Conclusion: Oral ME3738 administration may prevent the progression of hepatic fibrosis in BDL rats through suppression of the activation and collagen synthesis of HSC and, in part, oxidative stress. ME3738 has potential as a therapeutic drug for cholestatic liver fibrosis.

Recently, in ordor that rotational speed of DC machines may become faster, conditions on commutation are strict more than ever. In these cases, it is important to evaluate the performance of carbon brush materials accurately.This paper describes the new method evaluating brush materials and experimental results based on the new proposed method.Performance of brush materials has been evaluated by the tests obtaining characteristics of sliding contact and of commutation. However, a tendency of results obtained by these tests has not agreed with that of experimental results by using DC machines.In this paper, the authors propose a new method to evaluate characteristics of commutation and sliding contact. The features of a proposed method are as follows:(1) ‘Degree of contact disturbance’ is used as a way of estimations for sliding contact characteristics. The degree is time-dependent fluctuation of sliding contact voltage.(2) Performance of commutation is reviewed by using a new expression of the spark region.In order to realize these evaluation, testing machine for observation of flash was produced. The tendencies between obtained characteristics by produced testing machine and experimental results tested by DC machine, show good agreement. The validity of these evaluating method is confirmed.

Serotonin (5-hydroxytryptamine; 5-HT) 2C receptors and the downstream melanocortin pathway are suggested to mediate the appetite-suppressing effects of 5-HT drugs such as m-chlorophenylpiperazine (mCPP) and fenfluramine. Here, we report that fluvoxamine (3-30 mg/kg), a selective serotonin reuptake inhibitor (SSRI), in the presence of SB 242084 (1-2 mg/kg), a selective 5-HT2C receptor antagonist, exerts appetite-suppressing effects while fluvoxamine or SB 242084 alone has no effect. The appetite-suppressing effects were attenuated in the presence of SB 224289 (5 mg/kg), a selective 5-HT1B receptor antagonist. Moreover, CP 94253 (5-10 mg/kg), a selective 5-HT1B receptor agonist, exerted appetite-suppressing effects and significantly increased hypothalamic pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) gene expression and decreased hypothalamic orexin gene expression. These results suggest that fluvoxamine and inactivation of 5-HT2C receptors exert feeding suppression through activation of 5-HT1B receptors, and that 5-HT1B receptors up-regulate hypothalamic POMC and CART gene expression and down-regulate hypothalamic orexin gene expression in mice.