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女性ホルモンであるエストロゲンの欠乏は女性の更年期症状を惹き起こし, QOL低下の要因となっている. 今回20歳から60歳未満の女性透析患者41名, 健常者38名を対象に閉経年齢, 血中FSH, E2値とクッパーマン指数 (更年期症状指数) およびQOL (WHO/QOL 26) との関連を調査した結果, 透析群の閉経年齢は健常者より若かった. 両群においてE2とFSHは有意の逆相関を示した. 透析患者においてはE2およびFSH値とクッパーマン指数の間に有意の関連がみられ, 閉経者のクッパーマン指数は高い. クッパーマン指数とQOLは逆相関した. クッパーマン指数とQOLについては対象全体でも有意の逆相関を示した. 以上のことから女性透析者においては, 早期に閉経, 高FSHを伴った更年期症状も早くから出現し, 症状も強い. それがQOLの低下にも影響を及ぼしていると考えられた.

BACKGROUND In vascular smooth muscle cells, α1-adrenergic stimulation increases DNA synthesis and cell proliferation via activation of p44/42 (ERK1/2) MAPK. We examined whether norepinephrine (NE) activates MAPK and stimulates the proliferation of prostatic epithelial and non-epithelial cells. METHODS Human prostatic epithelial cells, stromal cells, and smooth muscle cells were purchased from BioWhittaker (Walkersville, MD). After reaching a semi-confluent condition, the cells were cultured in RPMI-1640 without serum for 1 day. At 10 min after adding NE (10−6 or 10−7 M) to the medium, the cells were collected. Cell lysate was analyzed by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS–PAGE) followed by Western blot using anti-phospho-p44/42 and anti-p44/42 antibodies. The activation of p44/42 was estimated by the ratio of phospho-p44/42 to total p44/42. Cell proliferation was evaluated by 3H-thymidine uptake assay. After reaching a semi-confluent condition, the cells were cultured in RPMI-1640 containing 0.5% FCS with or without NE (10−6 or 10−7 M) for 16 hr followed by a 3H-thymidine uptake period (24 hr). RESULTS P44/42 MAPK was significantly activated by NE in non-epithelial cells (stromal cells and smooth muscle cells) while not in epithelial cells. The uptake of 3H-thymidine was significantly increased by NE in both non-epithelial cells, which was inhibited by α1-adrenoceptor antagonists. CONCLUSIONS These results suggest that NE may stimulate the proliferation of non-epithelial prostatic cells, which may be involved in the pathogenesis of BPH. Prostate 56: 313–318, 2003. © 2003 Wiley-Liss, Inc.

Background: The kidney eliminates the major fraction of plasma oxalate. It is well known that oxalate is freely filtered by glomeruli and secreted by the proximal tubules. However, the renal handling of oxalate in distal nephrons, which is considered as playing an important role in stone formation, remains obscure. Methods: At 15–180 min after intravenous injection of 14C-oxalate to rats, the intrarenal localization of radioactivity was quantitatively measured by the radioluminographic method using a bioimaging analyzer. Tissue radioactivity was compared with plasma, and urinary radioactivities were measured by a liquid scintillation counter. The control study was conducted with 14C-inulin. Results: The radioactivity of 14C-oxalate in the papilla was 10 times greater than in the cortex and eight times greater than in the medulla 180 min after injection when almost no radioactivity was present in the urine. In contrast, the radioactivity of 14C-inulin was nine times less in the papilla than in the cortex at the same time. Conclusion: Oxalate remains in the renal papilla for an extended period. This accumulation of oxalate may be attributed to calcium oxalate crystal fixation along the deep nephron which is considered to be the first step of stone formation.

Background. It is well known that a cadaver kidney transplant from an aged donor will result in lower graft survival. However, such marginal kidneys should not be easily given up, and it is important to explore ways to make the best use of them. Against this background, the present study was carried out to examine the relationship between recipient body mass and cadaver kidney transplant outcome. Methods. All 63 cadaver kidney transplant recipients at our institutions were studied. These patients were divided into two groups according to the age of the donor: group A (under age 60 years; n = 48) and group B (age 60 years and over; n = 15). Each of the groups was subdivided into two groups according to the mean body mass index (BMI) and body surface area (BSA) values, and the effects of BMI and BSA on graft survival were also studied. Results. There was no correlation between BMI and lowest serum creatinine (nadir S-Cr) in group A, but there was a positive correlation in group B. Similarly, there was a positive correlation between BSA and nadir S-Cr only in group B. In group A, there was no difference in graft survival between the recipients with a smaller BMI (BMI21.0) and larger BMI (BMI ≧ 21.0) or BSA. However, in group B, the 5-year graft survival of the recipients with a smaller BMI was 60.0%, and it was significantly better than that of the recipients with a larger BMI. Similarly, the 5-year graft survival of the recipients with a smaller BSA (BSA1.54 m(2)) was 62.5%, which was also significantly better than that of the recipients with a larger BSA (BSA ≧ 1.54 m(2)). Conclusions. In the recipients whose donor was aged 60 and over, recipient BMI and BSA affected posttransplant kidney function and graft survival. These results strongly suggest that the lower graft survival due to an aged donor can be improved if a recipient with a smaller body size can be selected.

As regulators of malignant cell behaviour and communication with stroma, cytokines have proved useful in understanding cancer biology and developing novel therapies. In renal cell carcinoma, patients with inflammatory reactions are known to have poor prognosis. In order to elucidate the relation between renal cell carcinoma and the host, serum levels of inflammatory cytokines, interleukin-6, tumour necrosis factor α, interleukin-1β, were measured. One hundred and twenty-two patients with renal cell carcinoma and 21 healthy control subjects were studied, and serum cytokine levels were measured using a highly sensitive ELISA kit. As a result, in the control group, interleukin-6, tumour necrosis factor α and interleukin-1β levels were 1.79±2.03, 2.74±0.94 and 0.16±0.17 pg ml−1, respectively. In the renal cell carcinoma patients, they were 8.91±13.12, 8.44±4.15 and 0.53±0.57 pg ml−1, respectively, and significantly higher. In the comparison of stage, interleukin-6 level was significantly higher in the stage IV group compared to the other stage groups including the control group, while tumour necrosis factor α level was significantly higher in each stage group compared to the control group. As for grade, interleukin-6 level was significantly higher in the grade 3 group compared to the control, grade 1 and grade 2 groups, while tumour necrosis factor α level was significantly higher in each grade group compared to the control group. All cytokines had a positive correlation with tumour size. In regard to the correlation with CRP, all cytokines had a positive correlation with CRP, while interleukin-6 had a particularly strong correlation. In conclusion, interleukin-6 may be one of the factors for the poor prognosis of patients with renal cell carcinoma. In addition, tumour necrosis factor α may be useful in the early diagnosis of renal cell carcinoma and post-operative follow-up. British Journal of Cancer (2002) 86, 1396–1400. DOI: 10.1038/sj/bjc/6600257 www.bjcancer.com © 2002 Cancer Research UK

Background/Aim: Investigators have reported that the nonmuscle myosin heavy chain B (SMemb) expression is enhanced in various types of glomerular diseases which develop into nephrosclerosis. In renal transplantation, transplant glomerulitis is often recognized during acute rejection. Therefore, we hypothesized that SMemb plays important roles in acute kidney rejection. To evaluate the role of SMemb in the development of kidney rejection, we examined its expression in rat kidney transplantation models. Methods: We used Lewis rats as recipients and Wistar rats as donors. Group I: controls; group II: isograft model; group III: allograft model; group IV: as group III +10 mg/kg/day of ciclosporin A (CsA), and group V: as group III + CsA administration for 5 days postoperatively. Histopathological and SMemb immunohistochemical studies were completed. Results: Clear enhancement of SMemb expression was found on day 3 in group III. In groups I, II, IV, and V, SMemb was faintly expressed in the glomerular cells. However, after termination of CsA treatment, the SMemb expression increased. The expression of SMemb was higher in the allograft model than in either isograft or CsA-treated models. Conclusions: Immunohistological investigations show that the SMemb expression was significant from an early stage at which histopathological reactions were hardly identifiable. This, therefore, could be useful for an earlier diagnosis of acute rejection.

Objective To compare the efficacy and safety of an incremental-dose regimen of terazosin (1–2 mg daily) and a fixed-dose regimen of tamsulosin (0.2 mg daily), on Japanese patients with symptomatic benign prostatic hyperplasia (BPH). Patients and methods This multicentre, single-blind, randomized trial compared terazosin and tamsulosin over 4 weeks, in 61 patients with symptomatic BPH randomly assigned to terazosin (n = 31) or tamsulosin (n = 30). Terazosin 0.5 mg twice daily was administered for 2 weeks, followed by 1 mg twice daily for 2 weeks. Tamsulosin (0.2 mg) was administered once daily for 4 weeks. Symptoms were evaluated using the International Prostate Symptom Score (IPSS), and quality of life (QOL) was assessed subjectively before treatment, and again after 2 and 4 weeks of treatment. Objective measurements taken before and after the treatment period were the maximum (Qmax) and average (Qave) urinary flow rates, and the percentage residual urine volume. Improvement was defined as a 25% decrease from baseline in IPSS, > 1 point increase in QOL score, and > 2.5 mL/s increase in Qmax. Adverse reactions potentially related to the study drugs were recorded throughout the treatment period. Results Both terazosin and tamsulosin produced statistically significant improvements in subjective and objective variables. Neither treatment affected systolic or diastolic blood pressure or pulse rate. Adverse reactions were noted in four patients (three in the terazosin group and one in the tamsulosin group). However, there was no statistically significant difference in the incidence of adverse effects between the groups. Conclusions Despite the limitations of small sample size and relatively short treatment periods, terazosin and tamsulosin were equally effective in the treatment of symptomatic BPH in Japanese patients, using relatively lower doses than those used in Western countries.

Summary In Japan, the number of patients seeking kidney transplants has declined in recent years. To investigate the reasons for this decline, a questionnaire was given to 73 haemodialysis patients treated at the Tokiwa-Tatsumi Clinic. The resulting data showed the percentage of patients seeking transplants declined from 61% in 1992 to 19.2% in 1999. The reasons given for not seeking transplants were the improvements of physical condition and resultant quality of life (QOL) due to progress in dialysis therapy, upgraded social welfare support, uncertainties of transplant medicine, loss of expectations due to limited availability of transplant kidneys and aging of patients. Meanwhile, the number of patients on dialysis continues to increase by approximately 10,000 a year, and the mean age of patients rises. To reduce this number, greater effort must be directed toward preventive medical care as well as educating the public regarding transplant medicine.

Hepatocyte growth factor (HGF) facilitates the regeneration of injured kidney in acute renal failure (ARF). HGF is produced as a single-chain precursor by cells of mesenchymal origin and is converted to a biologically active, heterodimeric molecule by proteolytic processing. We studied HGF mRNA and protein levels in systemic organs of glycerol-induced ARF rats, a model of crush syndrome. HGF protein concentration of tissue homogenate was measured by ELISA. Both mRNA and protein levels were increased in liver and spleen at 24 hours after the glycerol injection whereas HGF protein level was decreased in the injured kidney. Expression of HGF receptor/c-met mRNA was elevated only in the kidney. These results suggest that HGF supplied in an endocrine manner may play an important role in the regenerating process following ARF. Next, we measured serum HGF concentration by ELISA in 8 ARF patients caused by crush syndrome and the molecular size of serum HGF was determined by immunoblotting. Although serum HGF levels elevated in all patients, the HGF levels did not associate with their prognoses. While a single-chain molecule was predominantly observed in sera from chronic renal failure patients and healthy subjects, the majority of serum HGF was a heterodimeric form in 7 ARF patients. In one patient who developed disseminated intravascular coagulation syndrome and had a poor prognosis, a single-chain molecule was predominant although the serum HGF concentration was equivalent. These data suggest that the activity of proteolytic processing may be also an important factor for the expression of the biological function of HGF.

Background: Transurethral resection of the prostate (TURP) is the gold standard treatment for benign prostatic hyperplasia (BPH). Recently, less invasive transurethral laser prostatectomy, such as visual laser ablation (VLAP) or interstitial laser coagulation (ILCP), have been developed. Herein, we investigated the efficacy of VLAP and ILCP compared to TURP. Methods: A total of 80 patients with BPH were treated: 20 patients by VLAP, 30 patients by ILCP and 30 patients by TURP. All patients were followed up for 12 months after their operations. Treatment outcomes were evaluated by four different criteria: (i) the International Prostatic Symptom Score (I-PSS), (ii) the maximum flow rate (Qmax), (iii) postvoided residual urine volume before treatment and one, three, six and 12 months after treatment, and (iv) prostatic volume before operation and three and six months postoperatively. Results: The I-PSS, Qmax and residual urine volume were significantly improved compared to baseline levels and the improvement continued for 12 months in the three groups: for I-PSS (P < 0.001 in the VLAP group and P < 0.0001 in the ILCP and TURP groups), Qmax (P < 0.001 in the VLAP and ILCP groups, and P < 0.0001 in the TURP group), residual urine volume (P < 0.01 in the VLAP group and P < 0.0001 in the ILCP and TURP groups). Significant reduction of the prostatic volume was recorded only in the ILCP and TURP groups (P < 0.001). Conclusion: Visual laser ablation and ILCP can be good alternative treatments for BPH. Visual laser ablation provides good outcomes in patients with small-sized BPH and with risk factors such as heart disease or anticoagulation therapy.

Background. Growth factors such as insulin-like growth factor, epidermal growth factor, and hepatocyte growth factor have been reported to be effective in the treatment of acute renal failure, but their effectiveness in chronic renal failure has not been reported. Thymosin, a glycoprotein extract obtained from calf thymus, is also known to have growth factor-like activity. In this study, we investigated the protective effect of thymosin fraction 5 (TF5), isolated from thymosin, in mice and rats with experimentally induced uremia. Methods. Uremia was induced in mice by administering cis-Diammine-dichloroplatinum CDDP; 5 mg/kg, intraperitoneally once a week for 5 weeks. From the start of CDDP administration, mice in groups 1, 2 and 3, respectively, were given subcutaneous injections of saline or 1 mg/kg or 3 mg/kg of TF5 three times a week for 5 weeks. Uremia was induced in rats using the 5/6 renal ablation model. Rats in groups 1 and 2, respectively, were given subcutaneous injections of saline or 3 mg/kg of TF5 three times a week from the fifth to the twelfth week after removal of the right kidney, for a total of 8 weeks. Results. In uremic mice, 6 weeks after the start of CDDP administration, serum urea nitrogen (SUN) levels were 40.1 ± 16.4, 20.6 ± 6.6, and 20.2 ± 5.3 mg/dl in groups 1, 2, and 3, respectively, and the level was significantly lower in groups 2 and 3 than in group 1 (P < 0.05). In the uremic rats, 13 weeks after the removal of the right kidney, SUN levels were 105.2 ± 20.1 and 82.9 ± 11.6 mg/dl in groups 1 and 2, respectively, and serum creatinine levels were 2.22 ± 0.89 and 1.56 ± 1.06 mg/dl in groups 1 and 2, respectively, with a significant difference in both SUN and serum creatinine between groups 1 and 2 (P < 0.05). Conclusion. These results suggest the possibility that TF5 has a protective effect against progression of uremia.

Chemopreventive effects of bovine lactoferrin (bLF), which is found at high concentrations in colostrum, on rat bladder carcinogenesis were investigated using a rat bladder medium-term bioassay. In experiment 1, a total of 80 F344 male rats, 6 weeks old, were divided into 5 groups. Groups 1 and 2 were treated with 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in the drinking water for 8 weeks and after a 1-week interval, received dietary supplementation with 2% and 0.2% bLF, respectively. Group 3 received 0.05% BBN for 8 weeks and then no treatment. Group 4 was administered 2% bLF alone from week 9, without prior carcinogen exposure. Group 5 was maintained without any treatment throughout the experiment. All rats were killed at the end of week 36. Group 1 demonstrated a significantly decreased multiplicity of the bladder tumors (carcinomas and papillomas) as compared with group 3. Maximum cut surface areas of bladder tumors were also significantly decreased in groups 1 and 2 compared with group 3. No bladder tumors were observed in groups 4 or 5. In experiment 2, a total of 60 rats were divided into two groups (30 rats each); both were treated with 0.05% BBN for 4 weeks and after a 1-week interval, one received 2% bLF (group 1) and the other, basal diet (group 2) for 4 weeks. Group 1 demonstrated a tendency for decrease of the 5-bromo-2'-deoxyuridine (BrdU) labeling index. bLF was detected in the urine of rats fed bLF by ELISA as well as western blot analysis. The findings indicate that 2% bLF can inhibit BBN-induced rat bladder carcinogenesis, and that this may be due to bLF in the urine.

Multifocal synchronous or metachronous tumor development is a common observation in human urothelial cancer cases. However, the underlying mechanism has remained obscure. We have employed a new tool to investigate the p53 gene status, the yeast p53 functional assay, in combination with immunohistochemistry in a total of 50 tumor samples from 32 cases with urothelial cancers, including 8 with multiple synchronous tumor development and 2 demonstrating metachronous tumors. p53 mutations were found in 13 cases (9 with missense mutations, 3 with deletion, 1 with splicing mutation) by the yeast p53 functional assay. p53 protein overexpression was seen in all 9 cases with missense mutations, but in only one of the 4 cases with nonsense mutations. Two tumors without p53 mutation also showed positive p53 immunoreactivity. Overall, p53 abnormalities including mutations and/or protein overexpression were found in 15 (47%) cases. p53 abnormalities were significantly more frequent in non-papillary and in high grade tumors. Loss of the wild type allele in addition to a p53 mutation was suggested in 8 of the 15 (53%) cases. All 4 cases with mutations in multiple synchronous tumors had identical p53 mutations in the separate urothelial cancers, strongly suggestive of monoclonality. The one case with multiple metachronous tumors, in contrast, was characterized by variation in the p53 status, indicative of different clonal origins. In conclusion, combined assessment for p53 status as used here (yeast p53 functional assay plus immunohistochemistry) may provide insights into the molecular mechanisms of urothelial carcinogenesis.

Background: The flexible cystoscope has not been as widely accepted in the field of urology as in other fields. The results of this investigation provided implications for determining the reasons for the under-use of flexible cystoscopy as well as for the drawbacks of the flexible cystoscope. Methods: We performed an investigation by sending a questionnaire to urologists asking them to compare the flexible cystoscope with the rigid cystoscope in order to determine why use of the former lags behind that of the latter. Results: We received answers from 420 urologists. We classified the urologist into four groups according to their years of experience. We also classified patients, for whom flexible cystoscopy was carried out, into four groups. The majority of the urologists in all groups thought that the flexible cystoscope provided a small field of vision and rough images. Urologists thought that the flexible cystoscope was inferior to the rigid cystoscope in terms of manipulability in biopsy. However, doctors who examined many patients using flexible cystoscopy believed that it was advantageous in terms of decreasing the patients’ pain and they have experienced no problem in clinical practice. Conclusions: Lack of experience in using the flexible cystoscope appears to be the main reason for the negative impression it generates. The flexible cystoscope can be routinely used in place of the rigid counterpart for urological investigations and it is recommended that it be used more widely for the benefit of the patients.

5′-Deoxy-5-fluorouridine (5′-dFUrd) is a prodrug of 5-fluorouracil (5-FUra) activated by pyrimidine nucleoside phosphorylase (PyN Pase), mainly by uridine phosphorylase (Urd Pase) in rodents and by thymidine phosphorylase (TdR Pase) in humans, which is preferentially located in tumor tissues compared to normal tissues. It has been reported that PyN Pase is induced by cytokines such as tumor necrosis factor (TNF), interleukin-1α (IL-1α) and interferon (IFN). Thymosin is a glycoprotein extract obtained from the calf thymus and is a potent immunopotentiating preparation. In this study, the antiproliferative activity of 5′-dFUrd used in combination with thymosin fraction 5 (TF5) was investigated in mouse bladder cancer cell line MBT-2 in vitro and in vivo. In vitro TF5 enhanced the activity of 5′-dFUrd by up to 4.11-fold, whereas the activity of other cytostatics such as 5-FUra, mitomycin C, adriamycin, cis -platinum, etoposide, vinblastine and methrotrexate was not changed. In vivo when the effects of combination therapy with 5′-dFUrd and TF5 in C3H/HeN mice implanted with MBT2 were studied, tumor growth was not suppressed by TF5 alone while tumor growth was suppressed to some degree by 5′-dFUrd alone. However, tumor growth suppression was enhanced when 5′-dFUrd was used in combination with TF5. In order to investigate this mechanism, Urd Pase in MB2 was measured, and it was found that TF5 increased enzyme activity by up to 1.8-fold in MBT2. This increased susceptibility might be a result of the induction of Urd Pase, which is the essential enzyme for the conversion of 5′-dFUrd to 5-FUra. These results suggested that the therapeutic benefit of 5′-dFUrd would be improved by its use in combination with TF5 and the modulation of converting enzymes for antitumor prodrugs could be a novel therapeutic strategy for treating human cancers.

BACKGROUND In an androgen-dependent manner, the androgen receptor (AR) binds to the androgen-responsive element (ARE) in the regulatory region of target genes. We hypothesize that an “ARE decoy,” a double-stranded oligonucleotide containing the same DNA sequence as ARE, can inhibit prostatic proliferation by competitive inhibition of AR transcriptional activity. METHODS We synthesized a 23-mer ARE decoy based on the deduced ARE sequence at the promoter region of the human prostate-specific antigen (PSA) gene. The nuclear extract was prepared from LNCaP cells, and DNA-protein interactions were examined by gel shift assay. Then the antiandrogen effect of the ARE decoy was studied in LNCaP cells transfected with the ARE decoy by lipofection. After 24-hr incubation with 10−9 M dihydrotestosterone (DHT), induction of apoptosis was examined by DNA fragmentation. RESULTS The gel shift assay demonstrated specific binding of the ARE decoy to the LNCaP nuclear protein which is most likely AR. The transfection experiment showed DNA fragmentation in the ARE decoy-transfected cells despite the presence of DHT, though not in the cells transfected with the control decoy. CONCLUSIONS The ARE decoy had an antiandrogen effect and induced apoptosis in LNCaP cells. This ARE decoy may become a potential therapeutic tool for prostate cancers when combined with a highly efficient transfection method. Prostate 41:121–126, 1999. © 1999 Wiley-Liss, Inc.

The cyclin-dependent kinase (CDK) inhibitor p27(KIP1) exerts its growth suppressive effects by targeting the cyclin-CDK complexes. Reduced protein levels of p27(KIP1) have been reported in numerous human cancers and this has been attributed to increased degradation. However, few reports have addressed the significance of p27(KIP1) expression in chemical carcinogenesis of rodents. In a rat two-stage urinary bladder carcinogenesis model, with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) initiation followed by promotion with sodium L-ascorbate (Na-AsA), we evaluated the expression of p27(KIP1) protein using immunohistochemistry during various stages of urinary bladder carcinogenesis. In addition, we evaluated the mRNA expression profiles for p27(KIP1), p21(WAF1/Cip1) and p53 in tumors. Fisher 344 rats were initiated with 0.05% BBN in the drinking water for 4 weeks and then administered 5% Na-AsA in the diet. Immunohistochemical examination revealed p27(KIP1) protein to be constitutively expressed in normal urothelium, simple hyperplasia and in most papillary and nodular (PN) hyperplasias and small papillomas, but diminished or absent in large papillomas and in transitional cell carcinomas. An inverse correlation between expression of p27(KIP1) and cell proliferation was generally observed. Quantitation of mRNA by multiplex reverse transcription-PCR showed a significant downregulaton of p27(KIP1), p21(WAF1/Cip1) and p53 mRNA in tumors. More than 50% reduction in p27(KIP1) mRNA expression was observed in 42 and 47% of tumors at weeks 18 and 24, respectively; similar reduction in p21(WAF1/Cip1) mRNA expression was observed in 58 and 73% of tumors at weeks 18 and 24, and in p53 mRNA expression in 50 and 73% of tumors at weeks 18 and 24, respectively. None of the 25 tumors we examined by PCR-single-strand conformational polymorphism analysis had p53 mutations. These data imply that abnormal down-regulation of p27(KIP1), p21(WAF1/Cip1) and/or p53 in tumor cells may contribute to the malignant progression of tumors during rat two-stage bladder carcinogenesis.

We investigated the combination therapy of local radiation of lung metastasis and vaccination with autologous tumor cells that produced interleukin (IL)-2, interferon-gamma (IFN-gamma), and granulocyte-macrophage colony-stimulating factor (GM-CSF) using the mouse Renca pulmonary metastasis model. Wild-type Renca (W/Renca) were transfected with pEF-BOS vector incorporating cDNAs for IL-2, IFN-gamma, or GM-CSF to express these cytokines. W/Renca, IL-2-producing Renca (Renca/IL-2), and IFN-gamma-producing Renca (Renca/IFN-gamma) produced subcutaneous tumor at the injection site in eight of eight, one of eight, and two of eight mice, respectively. No tumors were found in the GM-CSF-producing Renca (Renca/GM-CSF) group (zero of eight). Renca/IFN-gamma produced subcutaneous (s.c.) tumors in all Balb/c nude mice, but Renca/IL-2 and Renca/GM-CSF did not. To test the elicitation of antitumor activity, Balb/c mice were injected intravenously with 1 x 10(5) W/Renca on day 0, vaccinated, s.c., with 1 x 10(6) cells each of 5,000 rad preirradiated Renca/IL-2, Renca/IFN-gamma, and Renca/GM-CSF or 3 x 10(6) cells of preirradiated W/Renca on days 1, 7, and 14, and radiated with 300 rad to both lungs on day 5. The animals were killed on day 21 and tumor nodules in the lungs were enumerated. Neither local irradiation alone nor the combination of lung radiation and multiple vaccination with irradiated W/Renca significantly reduced the number of lung tumors. In contrast, the combination of lung radiation and the multiple vaccinations with cytokine-producing Renca cells significantly reduced the number of lung tumors. This regimen was more effective than the multiple vaccinations with cytokine-producing Renca cells alone. These studies demonstrate the efficacy of vaccination with autologous tumor cells expressing these cytokines and sensitization of the tumor target with radiation.

Pierisin, a protein purified from pupae of the cabbage butterfly, Pieris rapae , exhibits cytotoxic effects against the human gastric cancer TMK-1 cell line, inducing apoptosis. The present study was performed to determine whether pierisin might exert a similar influence on nine other human cancer cell lines and human umbilical vein endothelial cells (HUVECs). Pierisin showed cytotoxic effects in all the human cells tested, with IC 50 values ranging from 0.043 ng/ml to 150 ng/ml. Among the target cells, the cervical carcinoma cell line, HeLa, was the most sensitive to pierisin, showing a 1000-fold less IC 50 value than that of HUVECs. While pierisin clearly induced apoptotic cell death in most cancer cell lines and HUVECs, the pathway appeared to be probably different from that involving anti-Fas, TNF-α and p53. Pierisin may thus be a promising new candidate for cancer therapy.

Background: Patients with benign prostatic hyperplasia (BPH) have a wide range of concentrations of PSA. However, it is not known what factors influence the concentration of serum PSA other than the prostate volume. BPH is composed of an enlarged transition zone (TZ) and other zones (nonTZ). The TZ is thought to play a more important role than the non TZ in determining the concentration of serum PSA in BPH patients. Methods: We investigated the individual glandular zone volume, the amount of PSA produced by each zone and the PSA density in each zone in 23 patients with histologically-confirmed BPH. The PSA density in the TZ was calculated by dividing the difference between the serum PSA before and after surgical resection by the specimen weight. We examined the influence of these parameters on the concentration of serum PSA in BPH patients. Results: The serum PSA concentration correlated with the amount of PSA produced by the TZ (r= 0.90, P< 0.01), but not the nonTZ (r= 0.25, P= 0.29). The concentration of serum PSA also showed a significant correlation with the TZ volume (r= 0.67, P

FK506, a major immunosuppressive agent, often causes nephrotoxicity accompanied by renal vasoconstriction. It is recognized that endothelin (ET) plays a role in the cyclosporin A-induced nephrotoxicity, but the involvement of ET in the FK506-induced renal dysfunction is still poorly understood. We elicited nephrotoxicity by daily administration of FK506 in spontaneously hypertensive rats, and we examined the renal gene expression of ET and its receptors and the effects of an ET receptor antagonist on FK506-induced renal dysfunction. FK506 administration (4 mg/kg/day, i.m.) for 14 days induced nephrotoxicity, including a renal vasoconstriction and a decrease in glomerular filtration rate. The renal dysfunction was accompanied by an increase in ET-1 mRNA levels, while ETB-receptor mRNA was unaffected. Continuous administration of an ETA/ETB antagonist, TAK-044 (3 mg/day, s.c.), which effectively blocked systemic and renal vascular responses to exogenously administered ET-1, partially attenuated the FK506-induced renal vasoconstriction. However the reduced glomerular filtration rate were not affected by TAK-044. Thus, although enhanced gene expression of ET-1 in the kidney is involved in the renal vasoconstriction, ET does not play a major role in the FK506-induced renal dysfunction.

Hepatocyte growth factor (HGF) facilitates the regeneration of injured kidney in acute renal failure (ARF). Here we investigated the HGF production in glycerol-induced ARF rats. HGF mRNA expression levels were elevated in liver, spleen, and lung 6-24 h after glycerol injection. Tissue HGF protein levels determined by an enzyme-linked immunosorbent assay also increased in liver and spleen, whereas they decreased in the injured kidney 24 h after injection. Immunohistochemical studies showed that the number of HGF-producing cells did not increase in the liver. HGF receptor/c-Met mRNA levels were elevated only in the kidney. These results indicate that HGF supplied in an endocrine manner may play an important role in the regenerating process following ARF.

Silkworm larvae plasma (SLP) 法はpeptidoglycan (PG) とβ-glucan (BG) を測定できる新しい方法である. したがって, 従来までのlimulus amebocyte Iysate (LAL) 法とBGの測定法と組み合わせることで, PGの汚染状態を測定することができる. そこで, これらの方法を用いて透析液汚染を検討した. さらに, PG刺激に対するヒト末梢血単核球 (PBMC) の各種サイトカイン産生に及ぼす影響をin vitroで検討した. その際PGとしてはmuramyl dipeptide (MDP) を使用した. 透析液は9透析施設より透析供給システムの4箇所1) 逆浸透装置, 2) 多人数用透析液供給装置, 3) 多人数用コンソール末端, 4) 個人用コンソール末端の計54箇所より無菌的に採取し, LAL (C) 法, LAL (G) 法, SLP法を用いて測定した. 次に健常人, 血液透析患者各10名のPBMCを採取し, lipopolysaccaride (LPS), MDP, LPS+MDPおよび汚染透析液で刺激し, 24時間培養後interleukine-1 receptor antagonist (IL-1 Ra), interleukine-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α) をELISA法にて測定した. PGは1), 2) においては検出されなかった. しかし, 末端の透析液においては3) 4.1±6.1 (N=3, 検出率17%), 4) 3.3±4.6ng/ml (N=7, 検出率39%) と汚染が認められ, PGの単独汚染やendotoxin (ET) との混合汚染も認められた. また, PBMCのIL-1 Ra, IL-1β, TNF-αの産生は, MDPの濃度依存性に増大し, MDPおよびETが相乗的に作用して, それぞれ単独刺激の場合よりもサイトカイン産生が5-10倍有意に増幅された. 以上より, 従来からET汚染が認められていた透析液にはPGも含まれていた可能性がある. また, ETとPGは相乗作用を示しサイトカイン産生を誘導する. したがって, 透析液汚染はETだけでなく, PGに対しても十分に注意する必要がある.

Hepatocyte growth factor (HGF) facilitates recovery from tissue injuries. We previously reported that serum HGF levels were elevated in chronic renal failure (CRF) patients. In the present study Western blot analysis of CRF patients' sera showed the majority of their serum HGF was a single-chain precursor molecule. In CRF rats developed by 5/6 nephrectomy or high adenine diet, both HGF mRNA expression levels and tissue HGF concentrations were increased in liver and spleen. The results suggest that HGF production increases in CRF, which may be a response to chronic progressive renal injuries in an endocrine manner.

Hepatocyte growth factor (HGF) is a mesenchymal-derived growth factor which predominantly targets various epithelial and endothelial cells. We here investigated the biological function of HGF in rat dorsolateral prostatic tissue. HGF stimulated proliferation and DNA synthesis of prostatic epithelial cells in primary culture. c-Met/HGF receptor mRNA was specifically expressed in isolated epithelial cells. An immunohistochemical study revealed that HGF is located in prostatic stromal cells. When stromal cells were isolated and cultured, they produced significant amounts of HGF, which was further stimulated by prostaglandin E2, 12-O-tetradecanoylphorbol-13-acetate, and dibutyryl cyclic AMP, but not by testosterone. These results indicate that HGF is a stromal-derived potent mitogen for dorsolateral prostatic epithelial cells which may function as a paracrine regulator for growth of the prostatic glands.

BACKGROUND Sixteen patients with invasive bladder cancer were received neoadjuvant methotrexate, vinblastine, pirarubicin and cisplatin chemotherapy on our planning protocol. METHODS The tumor was evaluated after 1 course of chemotherapy by radiographic examination, urine cytology, cystoscopy and random biopsy. If the response is CR or PR, one more course of chemotherapy was performed, and cystectomy was carried out. If the response is NC or PD, cystectomy was immediately carried out. Twelve of them were underwent cystectomy and four were preserved bladder. Clinical response was evaluated by echo, CT, MRI, urinary cytology, cystoscopy and random biopsy. RESULTS Clinical CR was observed in 25% and PR was 37.5%. Pathological CR was observed in 31.3% and PR was 37.5%. The different rate between clinical and pathological evaluations was 31.3% and the result suggests that we should find the method of more accurate staging evaluation. Four patients who were evaluated clinical CR were selected bladder-preserving. However, two of them (50%) had recurred; one had grade 3 tumor was treated by total cystectomy and the other had multiple tumors was treated by one course of M-VAC and TUR-Bt. CONCLUSION We should consider which cases are possible to preserve bladder by investigating the tumor characteristics.

現在の日本における移植医療特に腎移植については, 欧米と比較すると非常に遅れていることは明らかである. このことは, 現在の日本においては移植医療そのものが特殊な治療として考えられていることが一つの要因となっている. そこで本研究では, 透析患者からみた移植医療の位置付けを明らかにし, 今後の移植医療の発展の方向性に寄与することを目的とした.結果: 1. 血液透析患者は腎移植療法を必要以上に危険な治療であると考えている. 2. 腎移植療法についての知識が非常に不足している. 3. 腎移植数が少ないために自分が腎移植を受けることをあきらめている. 4. 将来的には腎不全の治療の中心に腎移植療法がなることを希望している.結論: 腎移植療法に対する適切な情報を腎不全患者に提供することが腎移植を一般的な治療とするためには必要であると考える.

Seventy-nine patients with benign prostatic hyperplasia (BPH) were treated with cernitin pollen extract. Patient ages ranged from 62 to 89 years (mean, 68 years). Mean baseline prostatic volume was 33.2 cm3. Cernitin pollen extract was administered in a dosage of 126 mg (2 tablets, 63 mg each), three times a day, for more than 12 weeks. Symptom scores, based on a modified Boyarsky scoring scale, uroflowmetry, prostatic volume, residual urine volume, and urinalysis results were examined before and after administration of cernitin pollen extract. Symptom scores significantly decreased from baseline, and the favorable results continued during the treatment period. Urine maximum flow rate and average flow rate increased significantly from 9.3 mL/s to 11 mL/s and from 5.1 mL/s to 6 mL/s, respectively. Residual urine volume decreased significantly from 54.2 mL to less than 30 mL. There was no change in prostatic volume. However, 28 patients treated for more than 1 year showed a mean decrease of prostatic volume to 26.5 cm3. No adverse reactions were observed. Clinical efficacy at 12 weeks was rated excellent, good, satisfactory, and poor in 11%, 39%, 35%, and 15% of patients, respectively. Overall clinical efficacy was 85%. In conclusion, cernitin pollen extract showed a mild beneficial effect on prostatic volume and urination variables in patients with symptomatic BPH.

血液透析患者では肺外結核が多く, 抗酸菌の塗抹検査や分離培養による菌の検出は困難であり, また細胞性免疫能の低下のためツベルクリン反応は特異性が低く, 診断には苦慮する. そこで新しい結核の血清診断法であるtrehalose-6,6'-dimycolate (TDM) 血清診断法を血液透析患老の結核症に応用し検討を行った. 活動性結核の疑われる症例および結核の既往 (非活動性結核) のある症例8例, 非結核症例5例と健康成人5例を検討した. その結果, 活動性結核を疑われた血液透析患者3例の血清IgG分画に抗TDM抗体を検出し, 活動性結核と診断しえた.さらにTDM血清診断法にて診断しえた微熱の持続する71歳, 女性の臨床経過を検討したところ, SM, INH, RFPの三者併用療法にて微熱は消失し, 白血球の正常化およびCRPの低下に伴い抗TDM抗体価は次第に減少した.以上よりTDM血清診断法は血液透析患者の結核症においても有用であり, 抗TDM抗体価は患者の病状を反映し推移するため治療を決定するうえでの重要性が示唆された.

皮膚〓痒症, 湿疹・皮膚炎を合併した186例の透析患者を対象に塩酸アゼラスチン2mg/日を投与し, 〓痒, 皮膚症状に対する臨床効果を検討した. 〓痒は, 発現時期別に日中, 夜間, 透析中の3つに分け観察し, その程度は白取の「〓痒重症度の基準」に準じて5段階に分類・判定した. 〓痒に対する塩酸アゼラスチンの効果は, 投与8週後まで投与期間に比例して高まっていった. この傾向は, 日中, 夜間, 透析中のすべての〓痒感に共通しており, 投与8週目まで〓痒重症度の症状なし, 軽微の患者が徐々に増加していった. 週別改善度においても投与7週目まで週を追う毎に改善度の上昇が見られ, 投与8週後の最終全般改善度は, 著明改善14.2%, 中等度改善29.0%, 軽度改善27.9%という成績であった. 副作用および血液検査の異常は10例, 5.4%に認められ, その主なものは, 眠気, 味覚異常, 口渇などであった.以上の成績から, 塩酸アゼラスチンは, 透析患者の皮膚〓痒症に優れた効果を示し, 安全性も高く有用な薬剤と考えられる.

急性腎不全(ARF)においては腎機能が回復するまで何らかの方法で腎機能を代行しなければならない.それが各種血液浄化法である. ARFは病因により患者の状態が異るので,それに応じて治療計画を立て,治療計画に適した血液浄化法を選ばなければならない.単なる循環不全から来た利尿薬抵抗性浮腫にはCAVHを,腎不全のみで他に合併症がない場合には間歇的なHD, HDFやHFが適応される.腎不全に感染,消化管出血等が合併したり,多臓器不全で循環動態が不安定かつ異化亢進が強く,溶質除去と共に大量の輸液を必要とする場合には持続的腎補助であるCHDやCHDFが適応となる.この際用いる透析液,補充液の組織に留意が必要でアシドーシスの補正には重炭酸塩が望ましい.

The serum levels of hepatocyte growth factor (HGF) were determined in chronic renal failure (CRF) patients. Nondialysis patients with renal insufficiency had significantly higher serum HGF than normal subjects (0.34 +/- 0.10 ng/ml, n = 21 vs. 0.19 +/- 0.05 ng/ml, n = 15; p0.001), and the elevated serum HGF correlated with their serum creatinine levels. Hemodialysis (HD) patients treated for 5-10 years showed higher serum HGF than those receiving HD for 1 year or less (0.45 +/- 0.14 ng/ml, n = 8 vs. 0.33 +/- 0.11 ng/ml, n = 9; p0.05). Continuous ambulatory peritoneal dialysis patients also showed elevated serum HGF levels comparable to those of HD patients. There was no difference in serum HGF levels in HD patients with or without acquired cystic disease of kidney. Consequently, serum HGF is elevated in CRF, which may be attributed to the increased production of HGF in response to the chronic renal injury, the effect of heparin, or reduced removal of serum HGF in CRF patients.

Autourethrography (A-UG), a new method of retrograde urethrography was developed, in which the patient injects the contrast medium by himself under fluoroscopical observation by urologists out side of the room. For clinical study of A-UG, comparative study between A-UG and the conventional retrograde urethrography (C-UG) was performed on 20 patients with benign prostatic hypertrophy. The mean age was 68.8 years (range 49-85 years) in A-UG and 69.4 years (range 61-86 years) in C-UG. We evaluated complications of A-UG, compared with these of C-UG. Opacification of the posterior urethra was achieved in all but one in A-UG. None of these patients in A-UG experienced pain during the examination of A-UG. On the other hand, all patient experienced pain in C-UG. Urethral bleeding occurred in only one of 19 patients in A-UG, compared with eighteen of 20 patients in C-UG. Extravasation occurred in one of 19 patients in A-UG, compared with three patients of 20 patients in C-UG. A-UG left the urologists free from the radiological exposure. It is concluded that A-UG is highly useful examination for patients and urologists.

We retrospectively studied clinical problems for 55 patients with primary hyperparathyroidism who were operated on at our hospital. The chance to discovery of primary hyperparathyroidism and its accompanied symptoms were various. Other than classical symptoms, hypertension was noted in 12 patients and malignant tumors in 9. Forty-four percent of patients who had no bone related symptoms were found to have decreased bone mineral density (BMD). Even the patients with normal BMD were seen to increase the BMD, postoperatively. We thought that the parathyroidectomy was indicated for the asymptomatic patients with normal BMD. Biochemical investigation showed that positive rate were 50% for PTH-C, 94% for PTH-HS, 78% for intact PTH, 87% for serum total calcium and 98% for serum ionized calcium. Serum ionized calcium and intact PTH were useful for the diagnosis of patients who had normocalcemia or slight elevation of serum calcium. The sensitivity was 61% for ultrasound sonography (US) and 49% for computer tomography (CT) and scintigram, respectively. The detection rate of US and CT was positively related to the size of the parathyroid glands, but scintigram was not. The rate with which the parathyroid glands can be recognized during operation increased from 30% in the former group to 52% in the later group. As a result, 11% of the patients with adenoma had too much surgery and 29% of the patients with hyperplasia had too little surgery.

Fourteen hundred seventeen patients with a single stone under either general or epidural anesthesia were treated by one session of ESWL using the Dornier HM3 while 255 cases by one session of ESWL using the Dornier MPL9000 under no anesthesia but only with some analgesics, with 3 months' follow up available in all patients. The ratio of stone location in the kidney vs ureter was 7 to 3 in the Dornier HM3 and 5 vs 6 in the Dornier MPL9000. The overall success rate (stone free and residual stone fragments of less than 4 mm, 3 months after ESWL) was 58% (591 cases/1016 cases) for kidney stones with the Dornier HM3 and 35% (41/117) with the Dornier MPL9000. On the other hand, the overall success rate for ureter stones was 61% (245/401) with the Dornier HM3 and 70% (96/138) with the Dornier MPL9000. The overall success rate for stones of more than 10 mm, was poor when treated by the Dornier MPL9000 compared with the Dornier HM3.

蛍光眼底造影は, 眼科領域では網脈絡膜疾患の診断, 治療効果の判定に不可欠な検査法である. しかしその造影剤として用いられるフルオレッセイン-ナトリウム (NaFI) による副作用発現は稀ではなく, また透析患者におけるNaFIの薬物動態は知られていない. そこでまず基礎的検討として比色法によるNaFIの濃度測定法を検討し, 次に血液透析 (HD) 患者におけるNaFlの透析性を調べた. NaFIはHDにより速やかに除去され, 血中濃度は透析4時間で前値の17.5%, 5時間で14%に低下した. NaFIのクリアランス (Mean±SD) は1時間値20.2±20.1ml/min, 2時間値30.8±19.1ml/minであった. またNaFIのHD患者における非透析時の半減期は約21時間で健常者では約1.1時間であった. 以上よりNaFIは比較的良好な透析性を有すること, 非透析時は半減期が極めて長いこと, 副作用も稀ではないことなどからHD患者の蛍光眼底造影後は, NaFIの残存を防ぐ意味からも速やかにHDを行いNaFIを除去することが望ましいと考えられた.

1990年1月1日から12月31日の1年間に大阪府下で維持透析を受けた慢性腎不全患者を対象に後天性多嚢胞化萎縮腎 (acquired cystic disease of the kidney, ACDK) の発生率ならびに腎癌併発件数に関する調査を行った. 大阪府下で維持透析を実施している施設は133施設で総患者数は7,379名であった. ACDKの調査に回答のあった施設は118施設で, 回収率は88.7%であった. 118施設中59施設 (50%) がACDKの有無についての検査を年1-2回 (平均1.6回) 行っていた. 検査方法は59施設すべてが超音波検査を行い, 1施設を除いた58施設がCT検査を併用していた.59施設の総患者 (3,271名) を対象にACDK発生率ならびに腎摘除術の件数の調査では3,271名中, ACDKは男性501名, 女性257名, 計758名 (23.2%) であった. 男女比は約2:1で男性に多く, ACDK発生率は透析歴の長期化とともに経年的に増加し10-12年で44%のピークに達した. 12年を超えるとむしろ発生率は34-36%に低下した. ACDKの患者15例に腎癌の併発があり (男性15例, 女性0例), 腎摘除術を受けていた. 透析歴が長くなるほど腎癌の合併率が高くなる傾向にあった.