Search

To evaluate the clinical impact in knee osteoarthritis (OA) of coexisting patellofemoral (PF) joint OA (PFOA) in Japanese patients with medial tibiofemoral (TF) joint OA (TFOA). Patients with medial knee OA (n = 143) were enrolled. The radiographic severity of the TF and PF joints, anatomic axis angle of the TF joint, patellar alignment, trochlear morphology, patellar height, and passive range of motion (ROM) of the painful knee were evaluated. Additionally, the Japanese Knee Osteoarthritis Measure (JKOM) was used to investigate the association between the presence of PFOA and clinical symptoms. PFOA was present in 98 of 143 patients (68.5%) with medial knee OA. Quantile regression analysis revealed that coexisting PFOA was associated with the pain‐related subcategory of the JKOM. Furthermore, multiple logistic regression analysis showed that coexisting PFOA was associated with higher odds of reporting knee pain on using stairs while ascending (odds ratio [OR] 4.81 [95% confidence interval (95% CI) 1.73, 14.3]) and descending (OR 3.86 [95% CI 1.44, 10.8]). A more varus knee alignment and lower knee flexion ROM, which are features of patients with coexisting PFOA, were associated with knee pain while ascending/descending stairs. However, patellar alignment, trochlear morphology, and patellar height were not significantly associated with knee pain. PFOA coexisting with medial knee OA was associated with worse clinical symptoms, particularly while ascending/descending stairs, although patellar alignment did not contribute to reporting knee pain. Further studies that include evaluation of the PF joint are warranted to develop a basis for an optimal intervention based on compartmental involvement.

In congenital or acquired antithrombin III-deficient patients undergoing haemodialysis, coagulation or residual blood in the blood circuit and dialyser is commonly observed under anticoagulation with heparin. Argatroban, a synthetic thrombin antagonist, directly inhibits thrombin activity in a manner that is different from that of heparin, thereby displaying an anticoagulating effect without the activation of antithrombin III. For this reason, the anticoagulating effect of argatroban in haemodialysis patients with antithrombin III deficiency was investigated.

♦ Objectives To assess the efficacy and safety of icodextrin in Japanese patients and to investigate the relationship between net ultrafiltration (UF) during the long dwell and plasma oligosaccharides.♦ Design Open-labeled clinical trial involving patients on continuous ambulatory peritoneal dialysis (CAPD) receiving icodextrin during the 12-hour long dwell for 6 weeks, preceded by and followed by a 2-week baseline period and a follow-up period during which 1.36% glucose was used for the 8-hour long dwell.♦ Setting A prospective, randomized multicenter study done in tertiary medical centers.♦ Patients 18 stable patients on CAPD for 3 months or longer.♦ Main Outcomes Measures Net UF (in milliliters), UF rate (in milliliters per hour), plasma oligosaccharides, serum osmolarity (in milliosmoles per liter), peritoneal absorption of icodextrin, and peritoneal clearances of icodextrin, creatinine, and urea were assessed. Adverse events, laboratory findings, and vital signs were also monitored.♦ Results Long-dwell net UF (544.4 ± 96.7 mL at day 3, p< 0.001; 309.4 ± 60.7 mL at week 4, p< 0.001; and 391.7 ± 61.1 mL at week 6, p< 0.001) and UF rate (48.2 ± 38.8 mL/hour at day 3, p< 0.001; 26.9 ± 22.1 mL/hr at week 4, p< 0.002; and 35.3 ± 22.9 mL/hr at week 6, p= 0.0002) were significantly greater during the icodextrin period than at baseline (-25.9 ± 46.0 mL and -2.2 ± 22.1 mL/hr, respectively). Plasma oligosaccharides reached steady state within 2 weeks, remained stable during the treatment period, and returned to baseline level 2 weeks after discontinuation of icodextrin. Serum osmolarity increased during the use of icodextrin by approximately 5 mOsm/L. No statistically significant relationship was found between plasma oligosaccharides and net UF. Peritoneal absorption of icodextrin (36.3% ± 5.1% at day 3,42.2% ± 5.9% at week 4, and 38.0% ± 6.3% at week 6) and peritoneal clearance of icodextrin (10.1 mL/minute at day 3,10.1 mL/min at week 4, and 10.3 mL/min at week 6) showed no major change over time. Serum sodium and serum chloride both decreased by 5 mEq/L with icodextrin but remained within the normal range during the treatment period and returned to baseline levels immediately after discontinuation. No serious adverse events were observed during the study.♦ Conclusion The results of this study do not support the hypothesis that an increased blood oligosaccharide level and the concomitant elevation in serum osmolarity have a negative impact on peritoneal UF. Therefore, the increase in plasma oligosaccharides appears to be too small to be of clinical significance.

Posttransplant recurrence is frequent in patients who received renal transplantation for focal segmental glomerulosclerosis (FSGS). The recurrence has been ascribed to a circulating permeability factor or factors. We have used plasmapheresis (PP) to treat recurrent FSGS and also studied whether preoperative PP is effective in preventing recurrence of FSGS.

The present multicentral clinical study performed in 6 institutes demonstrated that the novel immunosuppressive agent, 15-deoxyspergualin (DSG), is very effective on rejection. In 34 cases of rejection, 30 were treated with DSG at 40 mg/m2(1 case), 80 mg/m2(7 cases), 120 mg/m2(9 cases), 180 mg/m2(9 cases), and 220 mg/m2(8 cases).

AbstractIschemia‐reperfusion injury by free radicals and lipid peroxides is observed in various organs. Ascorbic acid (AsA) or glutathione (GSH) in various doses (AsA:2,0.5, 0.1 mmol/kg, GSH:2 mmol/kg) was intraperitoneally administered to male Wistar rats. The entire small intestines were resected just before ischemia, after ischemia, and after 20 min of reperfusion (n= 7–10 at each time point). At each time point, the specimens were subjected to assays of lipid peroxides, GSH, and glutaminase activity of the tissues; they were also examined histologically. In the AsA group, the production of lipid peroxides after reperfusion was significantly suppressed in a dose‐dependent manner, and the ratio of oxidized GSH to total GSH was also significantly low. Tissue glutaminase activity decreased to a lesser extent, and the degree of injury was apparently less marked in the AsA group. This study indicates that AsA acts as an antioxidant against peroxidative tissue injury, possibly by scavenging radicals, preserving reduced GSH, and reducing the peroxidative reaction.

AbstractThe present study was designed to examine the in vivo effect of ebselen on reperfusion injury to the liver. Lipid peroxidation and glutathione (GSH) levels of the re‐perfused liver tissue, as well as hepatocellular damage (serum GOT, GPT, LDH, and histology) were examined. The production of thiobar‐bituric acid‐reactive substance did not increase in the 60‐min‐reper‐fused liver tissue in the ebselen group. Ebselen completely suppressed the increase in lipid hydroperoxide production in the reperfused liver tissue. After the tissue GSH level was reduced by buthionine sulphoximine, ebselen failed to suppress the lipid peroxidation of the reperfused liver tissue. Serum levels of GOT, GPT, and LDH, histological analysis, and the tissue level of GSH clearly showed that ebselen protects the reperfused liver tissue, both structurally and functionally. We conclude that ebselen's primary effect on ischemia‐reperfusion injury may be due to a GSH‐peroxidase‐like effect and/or the inhibitory effect of leukocyte infiltration.

AbstractSince June 1983, 27 kidneys have been shipped to the Kidney Center at the Tokyo Women's Medical College (TWMC) from the United States. These organs were divided into two groups, based on the years of their donation; 13 kidneys were assigned to group 1 and 14 to group 2. The differences between the two groups were as follows: donor age 19.8 ± 10.0 years vs 51.9 ± 14.5 years in group 2 (P <0.0001); total ischemic time 42 h 12 min in group 1 vs 65 h 42 min in group 2 (P= 0.0002); and Euro‐Collins preservation solution in group 1 vs University of Wisconsin (UW) solution in group 2. One hundred percent of the kidneys in group 1 and 85.7 % of those in group 2 recovered their function. The lowest serum creatinine levels averaged 96 + 38.4 µmol/l and 185.8 ± 101.0 umol/l, respectively (P= 0.01). The viability of 9 out of 14 grafts in group 2 were tested using 31P magnetic resonance spectroscopy (31P‐MRS). The results showed that all of the grafts having a monophosphate/inorganic phosphate (MP/Pi) ratio higher than 0.3 recovered their function and those lower than 0.2 did not. The problems associated with international organ sharing are discussed, along with the difficulties encountered at TWMC.

We investigated the preventive effect of pirfenidone (PFD), a newly developed anti-fibrotic agent, on experimental sclerosing peritonitis (sp) which we had established in rats. Male Wistar rats (150–250 g) were divided into the following two groups; 7 rats were treated with daily intraperitoneal (i. p.) injection of 0.1 % chlorhexidine gluconate (CH) and 15 % ethanol solved in 2 ml of saline for 26 days as a control of SP model (CH group) and 6 rats were treated daily with peroral (p. o.) administration of 350 mg/kg of PFD in addition to the daily i. p. injection of aforementioned CH-ethanol-saline solution for 26 days (CH + PFD group). Macroscopic intraperitoneal changes and histological fibrotic changes were graded by scoring in a blind manner.

Ischemia-reperfusion injury by free radicals and lipid peroxides is observed in various organs. Ascorbic acid (AsA) or glutathione (GSH) in various doses (AsA:2, 0.5, 0.1 mmol/kg, GSH:2 mmol/kg) was intraperitoneally administered to male Wistar rats. The entire small intestines were resected just before ischemia, after ischemia, and after 20 min of reperfusion (n= 7–10 at each time point). At each time point, the specimens were subjected to assays of lipid peroxides, GSH, and glutaminase activity of the tissues; they were also examined histologically. In the AsA group, the production of lipid peroxides after reperfusion was significantly suppressed in a dose-dependent manner, and the ratio of oxidized GSH to total GSH was also significantly low. Tissue glutaminase activity decreased to a lesser extent, and the degree of injury was apparently less marked in the AsA group. This study indicates that AsA acts as an antioxidant against peroxidative tissue injury, possibly by scavenging radicals, preserving reduced GSH, and reducing the peroxidative reaction.

Adult pig pancreatic endocrine cells were harvested by autodigestion without added enzymes. The isolated, crude cells were purified by mono-poly resolving medium (MPRM). The purity of the harvested cells was determined by dithizone staining and the number of pancreatic endocrine cells was counted. A large number of the cells were stained red with dithizone and showed a high viability and a good insulin secretory response to glucose stimulation. The average number of cells purified by MPRM was 3.40 ± 1.32 X 105cells/g pancreas and the number of dithizone-stained cells was 2.81 ± 1.09 X 105cells/g pancreas. The insulin secretion from the pancreatic endocrine cells was maintained throughout a 40-day observation period and high glucose stimulation induced an increase in insulin secretion from the cultured cells. In the cells purified by MPRM, light and electron microscopic studies showed the cells to be typical pancreatic endocrine cells. The present purification method using MPRM allowed us quickly to obtain a large amount of adult pig pancreatic endocrine cells from the unpurified preparations. It is thought to be useful for transplantation and biochemical or biological studies of adult pig pancreatic endocrine cells.

The comparative pharmacokinetics of doxorubicin (DOX) were investigated in five hemodialysis (HD) and eight non-hemodialysis (non-HD) patients who were infused with a 40- to 60-mg dose of DOX at a constant rate over 30 min. A significant difference was observed in the total body clearance (Cl tot) of DOX between HD and non-HD patients. The area under the curve (AUC) for both DOX and doxorubicinol (DOXol), an active metabolite, showed increases of approximately 1.5 and 3 times in HD patients as compared with non-HD patients. Although these differences were not statistically significant (P<0.1), the mean residence time (MRT) of DOX and DOXol in HD patients showed a 2-fold increase in comparison with those in non-HD patients. Compartmental analysis indicated that the greater AUC values and longer MRT of DOX and DOXol in HD patients resulted from the lesser DOXol formation and disappearance of rate constants. As a consequence of the decrease in Cl tot for DOX and the marginal hemodialysis clearance of both DOX and DOXol, the present study suggests that the exposure to DOX and DOXol obtained in HD patients greater that achieved in non-HD patients. Careful attention should therefore be paid to HD patients receiving DOX.

A randomized clinical trial of combination chemotherapy for adult acute lymphoblastic leukemia (ALL) with doxorubicin, vincristine and prednisolone with and without L-asparaginase (AdVP vs L-AdVP) was conducted, involving 58 institutions throughout Japan. After reaching complete remission (CR), patients were treated with the same regimen for more than 2 years. Among 166 evaluable cases of the 198 cases enrolled, CR rates were 63.1% (53/84) with AdVP and 64.6% (53/82) with L-AdVP (P = 0.837). Median survival times and 7-year survival rates were 12.7 months and 21.2% with AdVP, and 16.0 months and 22.3% with L-AdVP ( P = 0.955 by generalized Wilcoxon test [GW], P = 0.952 by log-rank test [LR]). Median disease-free survival times and 7-year survival rates were 13.5 months and 23.8% with AdVP and 17.0 months and 30.6% with L-AdVP, showing some increments for L-AdVP but no statistical significance ( P = 0.141 by GW, P = 0.300 by LR). Among the cases of extramurally confirmed FAB subtypes, CR rates were 75.9% (63/83) for the L1 subtype and 51.3% (39/76) for the L2 subtype ( P = 0.001). As to adverse effects, pancreatitis was complicated more frequently in L-AdVP than in AdVP ( P = 0.039). Other side effects such as hyperbilirubinemia, diabetes mellitus, diarrhea and hypofibrinogenemia were observed more frequently with L-AdVP, but with no statistical significance. Thus, addition of a single course of L-asparaginase in the induction phase of combination chemotherapy with doxorubicin, vincristine and prednisolone did not significantly enhance the effect of antileukemic treatment of adult ALL.

Liblomycin (NK313) is a bleomycin analog that has proved to be associated with less pulmonary toxicity and with more potent antitumor activity than bleomycin in animal tumors. In a phase I study, pulmonary toxicity was not observed, whereas myelosuppression was the dose-limiting factor. The maximum tolerated dose was 140 mg/m2 given once a week for 4 weeks. In the present phase II study, patients with malignant lymphomas received liblomycin at 80 or 100 mg/m2 by intravenous infusion over 15 min once a week for 4 weeks. A total of 39 patients were entered, and 31 [4 with Hodgkin's disease (HD) and 27 with non-Hodgkin's lymphoma (NHL)] were evaluable. The median age of the patients was 52 years (range, 22–74 years), and their performance status ranged from 0 to 3. In all, 28 of the patients had a history of intensive anticancer chemotherapy. Responses were evaluated according to WHO criteria. We obtained 1 complete remission and 9 partial remissions (PRs), for an overall response rate of 37%, in the 27 patients with NHL, whereas 1 PR was achieved in the 4 patients with HD. In all, 9 PRs (32.1%) were obtained in patients who has been exposed to prior chemotherapy, including 4 PRs (33.3%) in 12 patients who had previously been treated with bleomycin. Myelosuppression and nausea and vomting were the major toxicities, which occurred in about 50% of the patients, and myelosuppression was severe in two patients treated at a dose of 100 mg/m2. We concluded that liblomycin demonstrated significant antitumor activity against malignant lymphomas.

We investigated the possibility of shortening the interval between courses of the commonly prescribed 28-day MVP (mitomycin C, vindesine, and cisplatin) regimen in patients with non-small-cell lung cancer (NSCLC). We conducted a nonrandomized phase II study using recombinant human granulocyte colony-stimulating factor (G-CSF, Chugai) to explore the possibility of shortening the cycle length to 21 days and compared the results with those obtained in historical controls who had received the standard 28-day regimen. A total of 40 patients, 37 of whom were evaluable, were entered in the 21-day treatment group of the trial and were compared with 38 historical controls who had received standard 28-day cycles of MVP at our institution. Patients in the 21-day group received mitomycin C at 8 mg/m2 on day 1, vindesine at 3 mg/m2 on days 1 and 8, and cisplatin at 80 mg/m2 on day 1, with the schedule being repeated every 21 days. Controls had received the same regimen, albeit at 28-day intervals. G-CSF was given s. c. to the patients in the 21-day group at a daily dose of 2 µg/kg from day 2 to day 21 of every MVP cycle. The administration of G-CSF to these patients accelerated neutrophil recovery as compared with that observed in the historical controls. Significant differences were found between the two groups in terms of mean neutrophil nadirs (2666/µl in the first cycle and 1369/µl in the second for the G-CSF group vs 416/µl in the first cycle and 685/µl in the second cycle for the control group;P<0.0001) and the mean duration of neutropenia (=1000/µl; 1.0 day in the first cycle and 1.7 days in the second for the G-CSF group vs 8.0 days in the first cycle and 6.9 days in the second for the control gruop;P<0.0001). This enabled 32 (86%) of 37 patients in the G-CSF group to complete =2 cycles on schedule. In 10 patients, the bone marrow aspirates taken after G-CSF administration showed increases in band neutrophil and myelocyte percentages. In conclusion, MVP treatment of patients with NSCLC at 21-day intervals is possible with the support of G-CSF.

A procedure to measure a polarized triplet–triplet absorption spectrum using a stretched polymer film was described, and this method was applied to determine the polarizations of the triplet–triplet transitions of phenanthrene.

A phase I study of NKT-01 (deoxyspergualin), which is a derivative of an antitumor antibiotic, spergualin, was performed by a cooperative study group. NKT-01 was given intravenously by 3-h infusion. The effect of single administration was studied prior to evaluation of daily administration for 5 consecutive days. In all, 5 and 33 patients with various malignancies, including leukemia, were entered into the trials of single and daily administration, respectively. In the single-administration study, all patients were evaluable and no clear adverse effect was observed at doses ranging from 20 to 320 mg/m2. In the daily-administration study, 28 evaluable patients (16 men and 12 women; median age, 55.5 years) were treated with a daily dose of 20–500 mg/m2. Toxicities such as myelosuppression, mild nausea/vomiting, anorexia, alopecia, tongue and perioral numbness, and hypotension were observed dose-dependently during or after the treatment. Grade 2 leukopenia, thrombocytopenia, and anemia were experienced at a dose of 500 mg/m2. These usually recovered to normal values by approximately 3 weeks after treatment. A pharmacokinetic analysis of single administration revealed rapid plasma clearance, with mean half-lives for the a and ß phases being 28 min and 6.9 h, respectively. Approximately 12% of the infused dose was excreted into the urine in unmetabolized form. The pharmacokinetic parameters obtained after 5-day administration were similar to those recorded after single administration. Concerning treatment response, a transient but significant reduction in the number of leukemic cells was observed in one patient with adult T-cell leukemia. In this study, perioral numbness, hypotension, and hematological toxicity were concluded to be dose-limiting, with the maximal acceptable dose being 500 mg/m2. The recommended dose for a phase II study of NKT-01 against solid tumors was judged to be 400 mg/m2 given daily by 3-h infusion for 5 days, every 3 weeks. In hematological malignancies, however, higher myelosuppressive schedules of administration should be investigated.

The effects of recombinant granulocyte colony-stimulating factor (rG-CSF) on the myelosuppression, especially neutropenia, induced by cancer chemotherapy in patients with urogenital cancer were investigated in a randomized, controlled clinical study. In this study, rG-CSF was given subcutaneously at a dose of 2 µg/kg per day for 14 consecutive days. Changes in neutrophil counts were compared between the first (no rG-CSF) and second cycles (rG-CSF treatment period) of chemotherapy. rG-CSF administration was found to be effective in reducing the duration of neutropenia, in elevating the neutrophil nadir, and in reducing recovery time. Based on comparisons between the randomized rG-CSF treatment group (with rG-CSF) and the control group, treatment with rG-CSF resulted in the moderation or prevention of neutropenia and the acceleration of recovery. These results demonstrate that in chemotherapy of patients with urogenital cancer, in which neutropenia is a dose- or schedule-limiting factor, the concomitant use of rG-CSF may enable an increase in the dose (higher single dose or increased dose per unit of time) or shorten the chemotherapy period.

UFT is a compound in which futraful (FT) and uracil are combined at a ratio of 1:4. UFT was given orally at a daily dose of 300–600 mg in a phase II study. Pooled data on a UFT phase II study of 438 evaluable patients, at 104 institutions revealed a response in carcinoma of the stomach (27.7%), pancreas (25.0%), gallbladder and bile duct (25.0%), liver (19.2%), colon and rectum (25.0%), breast (32.0%), and lung (7.0%). The mainly gastrointestinal toxicity resulted in anorexia (24.3%), nausea and vomiting (12.5%), and diarrhea (11.8%). On the other hand, hematological toxicity was rare and mild. To analyze the lifeprolonging effect of the therapy, a cohort study was carried out in 438 cases collected in the UFT phase II study 5 years after the commencement of the therapy. The 50% survival time for 185 patients with gastric cancer was 185 days. The corresponding times in 54 patients with colorectal cancer and 49 with breast cancer were 227 and 505 days, respectively. A historical comparative study of UFT and FT, which was administered in the same institutions for equal evaluation, revealed that UFT had a significantly better effect than FT without more pronounced side effects with the equivalent dose schedule. In conclusion, UFT can be considered a useful agent against cancers over a broad spectrum, especially in gastrointestinal cancer.

Deoxyspergualin (DSG), an analogue of spergualin produced by B. laterosporus, has a strong immunosuppressive effect in various transplantation models. We have investigated the mechanism of donor-specific prolongation of survival time in rat kidney grafting by donor-specific blood transfusion (DST) and a short course of DSG. Lewis (LEW) kidney allografts were transplanted into fully allogeneic BN rats. Fresh, whole LEW blood 1.0 ml, was injected i.v. into BN rats 2 days prior to transplantation. Then, DSG, 6 mg/kg per day, was administered by i.m. injection on days 0, 1, and 2 after transplantation. The recipients were divided into five groups: group 1 (n=6) no treatment: group 2 (n=6) DST only; group 3 (n=7) DSG only; group 4 (n=7) DST and DSG; and group 5 (n=6), third party (ACI rats) blood transfusion and DSG. Lymphocytes (cervical lymph nodes) and serum were harvested from BN recipients on day 7 postgrafting. For suppressor cell assays, lymphocytes from BN recipients in each group were added as a third cell to the mixed lymphocyte reaction (MLC) between nontransplanted BN lymphocytes (responder) and LEW or other third party (PVGC, ACI, WKA rats) lymphocytes (stimulator). Antidonor lymphocytotoxic antibody (ADLA) was checked by microcytotoxicity assays. Median survival times (MST) for each group were: group 1, 10 days; group 1, 10 days; group 3, 13 days; group 4, 75 days; and group 5, 13 days. Remarkable prolongation of MST was only noted in group 4. In the suppressor cell assay, group 4 showed significant suppression (40%; P<0.05); the other groups did not show any suppression. This suppressive activity in group 4 was effective only during the MLC between BN and LEW, not during the MLC of third party-BN combinations. Thus, suppressor cells from DST/DSG-treated BN recipients appear to be donor-specific. In the microcytotoxicity assay, the only group that showed any ADLA was group 2, which was not treated with DSG. These results clearly show that both induction of donor-specific suppressor cells and inhibition of ADLA production are associated with the remarkable donor-specific prolongation of kidney allograft survival in DST/DSG-treated recipients.

Mammalian S‐adenosylmethionine (AdoMet) synthetase exists as two isozymes, liver‐type and kidney(non‐hepatic)‐type enzymes. The developmental expression of these two isozyme proteins has been investigated in rat liver using immunohistochemical techniques. The liver‐type AdoMet synthetase is expressed only in adult liver, but not in fetal liver. On the other hand, the kidney‐type AdoMet synthetase is predominantly expressed in fetal liver and faintly detected in adult liver. It was also found that both isozymes were localized to the hepatocytes of rat liver. These results clearly show that AdoMet synthetase isozymes are developmentally regulated within hepatocytes. In addition, in rat kidney we have shown that the kidney‐type AdoMet synthetase is predominantly localized to the distal tubule.

Deoxyspergualin (DSG), an analogue of spergualin produced by Bacillus laterosporus, has a strong immunosuppressive effect in various transplantation models. In this study, we investigated the effect of DSG on vascular rejection in canine kidney transplantation.

Without Abstract:

The present study was designed to examine the in vivo effect of ebselen on reperfusion injury to the liver. Lipid peroxidation and glutathione (GSH) levels of the reperfused liver tissue, as well as hepatocellular damage (serum GOT, GPT, LDH, and histology) were examined. The production of thiobarbituric acid-reactive substance did not increase in the 60-min-reperfused liver tissue in the ebselen group. Ebselen completely suppressed the increase in lipid hydroperoxide production in the reperfused liver tissue. After the tissue GSH level was reduced by buthionine sulphoximine, ebselen failed to suppress the lipid peroxidation of the reperfused liver tissue. Serum levels of GOT, GPT, and LDH, histological analysis, and the tissue level of GSH clearly showed that ebselen protects the reperfused liver tissue, both structurally and functionally. We conclude that ebselen's primary effect on ischemia-reperfusion injury may be due to a GSH-peroxidase-like effect and/or the inhibitory effect of leukocyte infiltration.

Numerous studies have been reported in the field of vascular graft in recent years. The main interest in these studies has focused on produc ing either a small diameter arterial graft or prosthesis for veins. Polyurethane polymers are emerging because of their superior mechanical, chemically stable and biocompatible nature. Above all, the prominent blood compatibility and elasticity has attracted many investigators to investigate the material for vascular grafts with small diameter.Although several difficulties still remain to be solved, important factors such as anti-thrombogenicity of materials, compliance in long term, porosity, sur face microstructure, and permeability are discussed on the basis of many ex perimental results.In addition, our basic as well as clinical examination of polyurethane graft as a blood access for hemodialysis are presented along with future prospects and difficulties to overcome.

A total of 55 arteriosclerosis obliterans (ASO) patients with hypercholesterolemia (total cholesterol [TC] ≥ 220 mg/dL or low density lipoprotein cholesterol [LDL-C] ≥ 140 mg/dL) were treated with LDL-apheresis. A follow-up questionnaire was sent to 39 of these patients by mail. Reported herein are effects of the LDL-apheresis and prognosis in 26 patients (17 men and 9 women) who undertook the LDL-apheresis and responded to the follow-up questionnaire. The subjective symptoms reported were investigated at three stages: before the treatment, immediately after the final LDL-apheresis, and at the follow- up observation time (March, 1993). An LDL-cholesterol level was reduced from 171 ±30 (mean ±SD) to 83 ±39 mg/dL by 10 ±3 applications of the apheresis. No aggravation in clinical symptoms was observed in any patient. Improvement rates of the clinical symptoms immediately after the final LDL-apheresis in these particular patients were as follows: foot chillness 52%, foot numbness 58%, foot dullness 81%, intermittent claudi cation 62%, foot pain at rest 75%, and ulcer at toes 100%. According to analysis of the questionnaire, these improvements in the clinical symptoms have been maintained at relatively high rates such as 69% in foot chillness, 91% in foot numbness, 100% in foot dullness, 81% in intermittent claudication, 89% in foot pain at rest, and 100% in ulcer at toes for 1.2 ± 0.8 (0.1 to 2.4) years of the observation period. The improvements are suggested to be due to the amelioration in peripheral blood flow as evidenced by devel opment of new collaterals observed on arteriograms.

Abstract: Nephrotic syndrome due to focal segmental glomerulosclerosis (FGS) frequently recurs even after renal transplantation and may cause renal allograft failure. From January 1983 though April 1995, 11 adult recipients with primary FGS received 11 kidney transplants at our institution, and 3 of them were treated with pretransplant plasma exchange (PE). Other patients did not receive any preoperative PE, and 4 patients lost their grafts due to recurrent FGS (50%). PE was completed 3 times before the transplantation to prevent posttransplant recurrence of FGS. Two recipients did not have any proteinuria or graft dysfunction without posttransplant PE. One patient had mild proteinuria immediately after transplantation, and histological examination showed recurrent FGS. The patient has been undergoing PE once a month (2 years posttransplant). Her renal function is excellent (sCr 1.2 mg/dl), and her FGS is being well controlled by PE. PE seems to be effective for the prevention of the recurrence of FGS following renal transplantation.—

A phase I clinical and pharmacokinetic study of recombinant human tumor necrosis factor (rH-TNF) was conducted in a single dose schedule in 33 patients with advanced cancer. rH-TNF was given by i.v. infusion over 30 min with a starting dose of 1x105 units/m2. The dose was escalated up to 16x105 units/m2 according to the modified Fibonacci scheme. Toxic effects were similar but not identical to those reported with interferons and interleukin-2, and included fever, rigors, nausea and vomiting and anorexia in a non-dose-dependent manner, and hypotension, leukocytosis, thrombocytopenia and transient elevation of transaminases (SGOT and SGPT) in an approximately dose-dependent manner. DIC syndrome was observed in one patient who had received 16x105 units/m2. The dose-limiting toxicities were hypotension, thrombocytopenia and hepatotoxicity, and the maximum tolerated dose in a single i.v. infusion of rH-TNF appeared to be 12x105 units/m2 when thrombocytopenia and elevation of SGOT and SGPT were taken as the dose-limiting toxicities. However, if hypotension was included, the maximum safely tolerated dose appeared to be 5x105 units/m2.

Elevations of serum lipid peroxide levels were demonstrated in mice after an equitoxic dose of doxorubicin. When BDF1 mice were injected with doxorubicin (20 mg/kg body weight, IP), lipid peroxide levels in sera were elevated 1 day after the injection and the levels declined on subsequent days. 5-Fluorouracil (400 mg/kg body weight, IP) never changed the peroxide levels in serum. Furthermore, it was found that the co-administration of [dl]-a-tocopheryl acetate or coenzyme Q10 IM strongly inhibited the doxorubicin-induced elevation of lipid peroxides in serum.

In a cooperative randomized control study of immunotherapy with bestatin in combination with chemotherapy in adults with acute nonlymphocytic leukemia (ANLL), 101 patients (48 in the bestatin group and 53 in the control group) out of 115 patients registered were evaluated as eligible. The bestatin group achieved a statistically significant prolongation of survival compared with the control group in overall ANLL and acute myelogenous leukemia. In the analysis of patient age, the bestatin group achieved a statistically significant prolongation of both the remission duration and survival in patients aged 50 to 65 years, while the differences were not significant in the 15 to 49 age group. The bestatin group tended to achieve a higher rate of reinduction of remission in patients who had recurrence of leukemia. Side effects developed in only 5 (9.6%) of 52 patients treated with bestatin. None of these side effects were particularly serious in nature. It is concluded that bestatin is useful for prolongation of survival of adult patients with ANLL, making for a longer remission duration especially in elderly patients and with few side effects.

We examined 960 urine specimens from 12 renal transplant patients for the presence of thymus-derived rosette-forming cells as a post-transplant study. Active T-rosette-forming cells appeared in the urine before or simultaneously with an increase in serum creatinine during all 14 acute rejection crises. Moreover, the active urinary T-rosette-forming cells disappeared promptly after pulse treatment with large doses of methylprednisolone in 11 rejection crises, which resolved completely, while in patients with continued detection of active T-rosette-forming cells in the urine rejection crises recurred within a few weeks.

Measurements of a polarized triplet–triplet absorption spectrum using stretched polymer films have been attempted at liquid nitrogen temperature. The polarizations of the triplet–triplet transitions of diphenylacetylene were determined, and the molecular structure in the excited triplet state was discussed.

The study of the current status of renal replacement therapy in Japan is based on the analysis of data from the registry reports for regular dialysis therapy and kidney transplantation. The total number of patients receiving regular dialysis therapy was 123,926 at the end of 1992: 117,809 (95.1%) on hemodialysis and 6,117 (4.9%) on peritoneal dialysis. The primary diseases of newly accepted patients were chronic glomerulonephritis (42.2%), diabetic nephropathy (28.4%), nephrosclerosis (5.9%), polycystic kidney disease (2.7%), chronic pyeronephritis (1.6%), and others. The number of kidney transplant patients in Japan was 8,384 at the end of 1991: 6,154 (73.4%) received a living donor transplantation and 2,230 (26.9%) received a cadaver donor transplantation. Overall 5-year survival rates of dialysis patients were 60.4%: 69.7% for chronic glomerulonephritis, 41.7% for diabetic nephropathy, 39.6% for nephrosclerosis, 73.6% for diffuse polycyustic kidney disease, and 66.6% for chronic pyeronephritis. The causes of death of dialysis patients were heart failure (31.1%), cerebrovascular accident (13.6%), infectious dieases (11.3%), malignancies (7.1%), cahexia/uremia (6.7%), myocardial infarction (5.8%), and others. The gross mortality rate of dialysis patients was increased in cases of less than 4 hours of the average length of each dialysis session, less than 4% and more than 9% of the average weight loss during each dialysis session, less than 1.0 of Kt/V, and less than 0.9 and more than 1.7 g/kg/d of protein catabolic rate. Overall 5-year patient and graft survival rates of kidney transplant patients since 1964 were 82.7% and 60.3%: 84.4% and 65.0% in living donor cases, and 77.4% and 46.2% in cadaver donor case, respectively. Those since 1983 were 90.1% and 68.2%: 91.3% and 72.6% in living donor cases, and 87.8% and 59.3%, respectively. Graft survival rates were superior in cases treated with combined steroid, cyclosporine and azathioprine or mizoribine, to those treated with other immunosuppressive regimens, and they decreased as the number of HLA-A, -B and -DR increased.

A phase I study ofN4-palmitoyl-1-β-d-arabinofuranosylcytosine (PLAC) was conducted in 88 patients; 36 with solid tumors and 52 with hematological malignancies, using 2 different schedules. Schedule 1 employed a single oral administration and Schedule 2, 5-day consecutive daily oral administration. In Schedule 1, the daily dose was initiated with 1 mg kg−1which was escalated up to 24 mg kg−1according to the modified Fibonacci’s method. Side effects included nausea, vomiting and skin rashes, but myelosuppression was not seen within this dose range. In Schedule 2, the daily dose was started with 1 mg kg−1which was escalated up to 24 mg kg−1. Major side effects were nausea, vomiting and amorexia, and mild myelosuppression was noted at 12 mg kg−1or more. The dose-limiting toxicity was gastrointestinal toxicity, which appeared at 3.3 mg kg−1or more and became frequent at 7 mg kg−1or more. Pharmacokinetic study revealed that the plasma concentrations of PLAC and ara-C, obtained by the oral intake of 3.3 mg kg−1or more of PLAC, were sufficient for these compounds to exert cytotoxic effects on various human leukemia cellsin vitro. Based on these observations and plausible mechanism of action of PLAC, further clinical study should be carried out in a treatment schedule of considerably prolonged administration period with 3.3–6 mg kg−1day−1of PLAC.

HEMORRHAGE from the cut surface is inevitable in the partial resection of liver, pancreas, kidney and spleen. In partial hepatectomy and in partial pancreatectomy the leak of the bile or the pancreatic juice further complicates the cut surface. If the leak continues persistently after operation, it is detrimental to the peritoneum. The use of needles and sutures for stopping the hemorrhage and the leak of the bile or the pancreatic juice may cause additional hemorrhage and the retardation of operation time. To solve this problem, an adhesive, 98% ethyl cyanoacrylate monomer, was used. We have reported that the replacement of methyl radical by the ethyl in the side chain of cyanoacrylate monomer significantly lessens histotoxicity1,2 and that n-butyl, 2-ethylhexyl and isopropyl monomers have no less histotoxicity than ethyl monomer on histologic examination.3 EXPERIMENTAL SURGERY MATERIALS AND METHODS. —Experimental animals were 12 mongrel dogs. The right lobe of the

Direct infusion of ethyl cyanoacrylate monomer into the viscerocutaneous tubular fistula was curative when the fistula was narrower than 5 mm in diameter. A piece of flat rubber or silicone gauze was fixed by cyanoacrylate adhesive on the cutaneous opening of the wide tubular fistula. Gradually the diameter of the fistula shrank from 10 mm or greater to 5 mm or less. Thereafter, direct infusion of ethyl cyanoacrylate monomer into the fistula was curative. Covering of mucosal lips of the labial fistula with a flat rubber piece or silicone gauze by means of ethyl cyanoacrylate monomer or dimethylpolysiloxane failed to cure the labial fistula but relieved local dermatitis, dehydration, and electrolyte imbalance preoperative ly.

RENOVASCULAR hypertension is usually treated with an implantation of either bypass graft or patch graft. This method has been successful to some extent.1 However, we are not completely satisfied with it. The failures seem to have arisen from the fact that the renal artery lies deep in retroperitoneal space. Especially on the right side, the renal artery runs behind the inferior vena cava and this hinders delicate surgical manipulation. Not rarely the failure to establish sufficient blood flow in the renal artery ultimately leads to nephrectomy. Needless to say, reconstruction of the artery necessitates a precise technique. It is not recommended that such a maneuver be performed in a restricted surgical field or even behind the inferior vena cava which is vulnerable to factitial injury.Recent advancement in renal homotransplantation has shown that the nephrectomized kidney functions well after transplantation.2 It therefore occurred to us that the kidney

Transplantation of pancreaticoduodenal allografts was done in 30 totally pancreatectomized dogs. Ten hosts served as a control group and the remaining 20 were treated with azathioprine for immuno-suppression. Excepting two hosts (one in each group) which died of anastomotic complications, the control hosts lived for 3–20 days (averaging 10 days) and the azathioprine-treated hosts for 7–63 days (averaging 22 days). In both groups, hyperglycemia occurred rarely and only after a preponderance of islets were destroyed by rejection; it was therefore considered a terminal event. Serum amylase increased sharply at the start of rejection in control hosts and decreased rapidly to the preoperative level once the initial phase of rejection had passed. In azathioprine-treated hosts, small retarded rises in serum amylase were observed. Histologically the rejection patterns in the allografts were either acute or chronic. A chronic rejection pattern was found only in such allografts as stayed for more than 3 weeks in azathioprine-treated hosts. In the transplanted pancreas, there was no difference between the resistance of acinar cells and that of islet cells against the host's immunological attack. Different parts of the allograft showed different susceptibilities to the host reaction. The parenchyma of the pancreas and of the duodenum, as organs, succumbed readily to the immunological attack. Some lymph nodes were relatively resistant. Nerves and blood vessels maintained their histologic integrity longer than other tissues of the allograft.

The polarized absorption spectrum of the conjugate base of 2-naphthoic acid was measured in a stretched PVA sheet. By comparing the polarized absorption spectrum with the results of the PPP calculations including a VESCF and variable β methods, we discussed the electronic structure of the conjugate base.

Purpose We wanted to clarify, in a large population, the reasons that peritoneal dialysis (PD) was interrupted and to propose appropriate strategies that might prolong the use of PD as a renal replacement therapy.Patients and Methods We enrolled 5 391 patients from 439 centers into the study. Each center used a worksheet to report details about patients who either transferred to hemodialysis (HD) or died on continuous ambulatory peritoneal dialysis (CAPD) over a 6-month period from 1 April 2000, to 30 September 2000.Results We collected 252 drop-out cases from 141 centers. Of the 252 cases, 170 (67.5%) involved transfer to HD, and 82 (32.5%) involved death while on PD. Primary renal diseases were chronic nephritis (CN: 51.6%), diabetic nephropathy (DM: 26.6%), nephrosclerosis (4%), and unspecified or other condition (15.8%). Mean duration on PD in drop-out cases was 4.47 years. The age of patients at transfer to HD was younger (53.7 years) than the age of patients at death on PD (65.2 years). Patients with CN remained on PD significantly longer than did patients with DM (5 years vs 2.4 years). The three main reasons for PD discontinuation were overhydration because of ultrafiltration failure (UFF) or poor compliance with salt and fluid restrictions (34.1%); peritonitis (30.1%); and preference of the physician, patient, or family (6.5%). The proportional share represented by those three major reasons varied with the number of years since PD initiation (from 1 year to more than 8 years). Patients who had been on PD for a longer time were more likely to drop out because of UFF and less likely to drop out because of peritonitis. The three major causes of death on CAPD were cerebrovascular accident (22%), ischemic heart disease (14.6%), and sudden death (9.8%).Conclusion Approximately 10% of patients drop out from PD programs annually in Japan. To prolong PD treatment, new solutions that better preserve peritoneal function need to be developed, and patients and caregivers alike need to receive intensive education in preventing and treating peritonitis.

Human lymphoblastoid interferon alpha was administered intramuscularly at a dose of 3 times 106units per day to 25 patients with advanced renal cell carcinoma. Six patients (24.0per cent) showed objective responses, including 2 with complete regression of tumors. Nine patients (37.5per cent) showed disease stabilization, while the disease progressed in 9 others (37.5per cent). All tumor responses (2 complete, 4 partial and 2 mixed responses) were seen in lung, skin and liver metastases in patients whose primary tumors had been removed. Mean time to response was 87 ± 74 days (range 28 to 240 days) and mean duration of response was 6.5 ± 6.4 months (range 1 to greater than 20 months). Human lymphoblastoid interferon alpha was a potential active antitumor agent in patients with advanced renal cell carcinoma.

We report on a trial of partial kidney transplantation performed on a low body weight child with impaired cardiac function due to mitral valve stenosis and uremic cardiomyopathy. The weight of the donated kidney was successfully reduced by one-third using bench surgery in order to obtain sufficient graft perfusion and function. Our procedure is justified when a graft is too large to be adequately perfused in a recipient suffering from cardiac failure.