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Many studies have reported poor vital prognosis in hepatitis C virus (HCV)-infected dialysis patients. The rate of HCV-infected dialysis patients in Japan is as high as 9.8%, and antiviral therapy is believed to be important for improving vital prognosis. We conducted a multicenter study to examine the administration method for pegylated interferon α-2a (PEG-IFNα-2a) monotherapy in HCV-infected dialysis. We studied 56 patients: 14 with low viral loads (HCV RNA < 5.0 log IU/mL) were treated with 90 μg PEG-IFNα-2a weekly, 42 with high viral loads (HCV RNA ≥ 5.0 log IU/mL) were treated with 135 μg PEG-IFNα-2a weekly. We examined the sustained virological response (SVR), factors affecting the SVR, and treatment safety. The overall SVR rate was 39% (22/56); that for genotype 1, genotype 2, low viral loads, and high viral loads was 29%, 67%, 93%, and 21%, respectively. From receiver operating characteristic (ROC) analysis, the HCV RNA cutoff values likely to achieve SVR for genotypes 1 and 2 were

Although hepatitis C virus (HCV) infection is a persistent public health concern in hemodialysis patients, there seem to have been only a few reports on the prevalence of HCV at the start of hemodialysis. In this study we investigated whether patients starting on hemodialysis therapy are positive for anti-HCV antibody or not. The 400 patients who began regular hemodialysis between February 2003 and June 2007 were enrolled in this study. Clinical data such as age, anti-HCV antibody and primary cause of end-stage kidney disease (ESKD) were examined. As healthy controls we used 70,717 healthy blood donors in 2005 whose data were obtained from Tokyo Metropolitan Red Cross Blood Center. Anti-HCV antibody was used as an indicator of HCV infection. Since the prevalence of HCV infection is affected by age in Japan, we classified the patients by age group. The anti-HCV antibody prevalence rate among the patients who were new to hemodialysis was 7.3%, as opposed to 0.15% in the healthy volunteers. The prevalence of HCV in the 31–45-, 46–60-, and 61-year-old groups was significantly higher among the hemodialysis patients than among the healthy volunteers (P = 0.0209

症例1は29歳の女性. 1歳5か月にオルニチントランスカルバミラーゼ欠損症と診断された. 以後, 感染や疲労・ストレスで高アンモニア血症 (100～300μg/dL) をきたし入退院を繰り返していた. 平成13年3月23日, 嘔気があり当院外来を受診. アンモニア345μg/dLと上昇を認めL-アルギニン20g/日の点滴を施行した. しかし, 意識障害の改善なくアンモニア536μg/dLと上昇を認めたため血液濾過透析 (HDF) を施行した. 2日間のHDF施行でアンモニア72μg/dLと低下, 意識障害の改善を認めた. その後, 安息香酸ナトリウムの内服でアンモニアの上昇, 意識障害の出現なく退院となった. 症例2は筋緊張性ジストロフィーの28歳, 女性. 歩行困難, 脱力, 意識障害で入院となった. 入院翌日のアンモニアは717μg/dLと上昇し昏睡状態, 呼吸不全となった. 肝不全の所見なく原因不明の高アンモニア血症に対しHDFを施行した. 3日間のHDF施行でアンモニア40μg/dLに低下し意識状態の改善を認めた. 入院後の血漿アミノ酸分析により高シトルリン血症を認め, 成人発症2型シトルリン血症と診断した. L-アルギニンと安息香酸ナトリウムの投与を開始し, アンモニアの上昇, 意識障害の出現なく退院となった. 尿素サイクル異常症による昏睡を伴う高アンモニア血症にはL-アルギニンの経静脈投与が施行されている. 本症例のように急性期にL-アルギニンの投与が無効な症例, 昏睡を伴う原因不明の高アンモニア血症の症例には急性血液浄化の施行が有効と考えられた.

It is well known that heme oxygenase-1 (HO-1) as well as nitric oxide (NO) synthase expressed in tumor cell line and solid tumor. NO may be beneficial to the tumor growth, not only because enhanced vascular permeability in solid tumor is mediated by NO, but because the l -arginine-dependent NO pathway mediates angiogenic activity and vascular endothelial growth factor (VEGF) induces angiogenesis via formation of NO. However, NO has a powerful cytostatic action on tumor cells by inhibiting DNA synthesis and causing oxidative injury. While it has been suggested that induction of HO-1 may provide an important protective response by cells against oxidative damage, HO-1 expression in tumor cells is strongly enhanced by NO donor. Strong induction of HO-1 is observed in solid tumors after occlusion or embolization of the tumor-feeding artery, indicating that ischemic stress which may involve oxidative stress triggers HO-1 induction. In addition, it is of great importance that an HO inhibitor, zinc protoporphyrin IX, suppressed the tumor growth to a great extent. In conclusion, HO-1 expression in the solid tumor may confer resistance of tumor cells to hypoxic stress as well as to NO-mediated cytotoxicity.

Many studies have reported poor vital prognosis in hepatitis C virus (HCV)-infected dialysis patients. The rate of HCV-infected dialysis patients in Japan is as high as 9.8%, and antiviral therapy is believed to be important for improving vital prognosis. We conducted a multicenter study to examine the administration method for pegylated interferon α-2a (PEG-IFNα-2a) monotherapy in HCV-infected dialysis. We studied 56 patients: 14 with low viral loads (HCV RNA5.0 log IU/mL) were treated with 90 μg PEG-IFNα-2a weekly, 42 with high viral loads (HCV RNA ≥ 5.0 log IU/mL) were treated with 135 μg PEG-IFNα-2a weekly. We examined the sustained virological response (SVR), factors affecting the SVR, and treatment safety. The overall SVR rate was 39% (22/56); that for genotype 1, genotype 2, low viral loads, and high viral loads was 29%, 67%, 93%, and 21%, respectively. From receiver operating characteristic (ROC) analysis, the HCV RNA cutoff values likely to achieve SVR for genotypes 1 and 2 were5.7 log IU/mL (SVR rate: 64% 9/14) and6.5 log IU/mL (SVR rate: 88% 7/8), respectively. If there was HCV RNA negativation at 4 weeks (rapid virological response), the SVR rate was 94% (16/17), whereas it was 6% (1/16) if there was HCV RNA positivity at 24 weeks. The rate of treatment discontinuation from adverse events or aggravated complications was 25% (14/56). High SVR rates can potentially be achieved with PEG-IFN monotherapy by identifying the target patients, based on virus type and viral load before initiating treatment and by modifying therapy during treatment according to responsiveness.

alpha(1)-Protease inhibitor (alpha(1)PI), the most abundant serine protease inhibitor found in human plasma (at 30-60 microM), is a glycoprotein (53 kDa) having a single cysteine residue at position 232 (Cys(232)). We have found that Cys(232) of human alpha(1)PI was readily S-nitrosylated by nitric oxide (NO) without affecting inhibitory activity to trypsin or elastase. S-nitrosylated alpha(1)PI (S-NO-alpha(1)PI) not only retained inhibitory activity against these serine proteases, but also gained thiol protease inhibitory activity against a Streptococcus pyogenes protease; the parental alpha(1)PI did not have this activity. Furthermore, S-NO-alpha(1)PI exhibited bacteriostatic activity against Salmonella typhimurium at concentrations of 0.1-10 microM, which were 20- to 3000-fold stronger than those of the other NO-generating compounds or S-nitroso compounds such as S-nitrosoalbumin and S-nitrosoglutathione. NO appears to be transferred into the bacterial cells from S-NO-alpha(1)PI via transnitrosylation, as evidenced by electron spin resonance spectroscopy with an NO spin trap. Thus, we conclude that S-NO-alpha(1)PI may be generated from the reaction between alpha(1)PI and NO under inflammatory conditions, in which production of both is known to increase. As a result, new functions, i.e., antibacterial and thiol protease inhibitory activities of alpha(1)PI, were generated.

Induction of haem oxygenase-1 (HO-1) as well as nitric oxide (NO) biosynthesis during tumour growth was investigated in an experimental solid tumour model (AH136B hepatoma) in rats. An immunohistochemical study showed that the inducible isoform of NO synthase (iNOS) was localized in monocyte-derived macrophages, which infiltrated interstitial spaces of solid tumour, but not in the tumour cells. Excessive production of NO in the tumour tissue was unequivocally verified by electron spin resonance spectroscopy. Tumour growth was moderately suppressed by treatment with either Nω-nitro-L-arginine methyl ester (L-NAME) or S-methylisothiourea sulphate (SMT). In contrast, HO-1 was found only in tumour cells, not in macrophages, by in situ hybridization for HO-1 mRNA. HO-1 expression in AH136B cells in culture was strongly enhanced by an NO (NO+) donor S-nitroso-N-acetyl penicillamine. HO-1 mRNA expression in the solid tumour in vivo decreased significantly after treatment with low doses of NOS inhibitors such as L-NAME and SMT (6–20 mg kg−1). However, the level of HO-1 mRNA in the solid tumour treated with higher doses of NOS inhibitor was similar to that of the solid tumour without NOS inhibitor treatment. Strong induction of HO-1 was also observed in solid tumours after occlusion or embolization of the tumour-feeding artery, indicating that ischaemic stress which may involve oxidative stress triggers HO-1 induction in the solid tumour. Lastly, it is of great importance that an HO inhibitor, zinc protoporphyrin IX injected intra-arterially to the solid tumour suppressed the tumour growth to a great extent. In conclusion, HO-1 expression in the solid tumour may confer resistance of tumour cells to hypoxic stress as well as to NO-mediated cytotoxicity. © 1999 Cancer Research Campaign

A consensus conference for the Guidelines for the Management of Secondary Hyperparathyroidism in Chronic Dialysis Patients was conducted in the general meeting of the Japanese Society for Dialysis Therapy (JSDT) in June 2006, and the guidelines were proposed in the Journal of JSDT in 4 months later. The aim of this study was performed on the status of observance with the data, based on 6 months later proposal of the guidelines. Only 48.9% stayed within the range specified by the calcium and phosphorus guideline. Moreover, only 12% of patients were able to remain within the ranges specified by all three guidelines (calcium, phosphorus, and PTH), 6 months later proposal of the guidelines. In our institution, compliance with the JSDT guidelines was inadequate. Major reasons were the special characteristics of the medical care system and patients in our institution as a university hospital. Further improvement in the contents and method of the use of the guidelines is necessary alongside observation of the present situation in Japan.