氨基胍对糖尿病大鼠肾脏非酶糖基化的抑制作用

目的 研究糖尿病大鼠肾脏高级糖基化终未产物(AGEs)的致病机制，探讨氨基胍对糖尿病大鼠肾脏的干预作用。方法将72只雄性Wistar大鼠随机分为A、B、C、D、E、F六组，用链脲佐菌素制做糖尿病大鼠模型，给予糖尿病大鼠氨基胍治疗24周，分别测定治疗8周、12周、24周时，糖尿病大鼠的血肌酐、血尿素氮、内生肌酐清除率、肾小球AGEs(GTE-AGEs)、肾小球基底膜厚度(GBMT)、肾小球系膜体积和24h尿蛋白定量，与其它各组治疗结果进行比较。结果治疗8周、12周、24周后，测得糖尿病大鼠血肌酐、血尿素氮、肾重／体重比值，肾小球AG-ES(GTE-AGEs)、肾小球基底膜厚度(GBMT)、肾小球系膜体积和24h尿蛋白定量均增高。氨基胍治疗组血肌酐、血尿素氮下降。结论AGEs在糖尿病肾病的发生发展中具有重要作用。氨基胍可通过抑制AGEs在糖尿病大鼠。肾脏的蓄积，降低尿蛋白排泄，抑制系膜增生及其它间接作用，发挥其对糖尿病肾病的防治作用，其抑制AGEs的作用大小与药物持续时间长短有关，与治疗时机无关。     

Effect of Nonenzymatic Glycosylation on the Titers of Circulating Autoantibodies in Pemphigus and Pemphigoid

Hyperglycemia is observed in some patients with autoimmune bullous diseases complicated by diabetes mellitus or treated with systemic corticosteroids. High concentrations of glucose can react with various proteins and change their structural and functional properties. We previously reported that nonenzymatic glycosylation of antibody can impair antigen-antibody binding. We ascertained whether glycosylation of autoantibody decreases the autoantibody titer by examining 30 sera from patients with pemphigus and pemphigoid. Nonenzymatic glycosylation in the physiological range was induced by incubation of sera with 1650 mM D-glucose at 4°C for 7 days. The titers of sera were determined by indirect immunofluorescence (IIF). In all cases, the immunofluorescence intensity of glycosylated sera was weaker than that of nonglycosylated sera. Glycosylated sera showed a lower antibody titer by 1 doubling dilution in 18 out of 30 cases, compared with nonglycosylated sera. The ten BP patients' sera were also analyzed by immunoblotting for reactivity with the BP180-GST fusion proteins, SΔ1 and 4575. All BP sera reacted with SΔ1, and 5 out of 10 BP sera reacted with both SΔ1 and 4575. In all the sera that reacted only with SΔ1, the glycosylated sera showed a 1 doubling dilution decrease in autoantibody titer. Interestingly, in 4 out of 5 sera that reacted with both SΔ1 and 4575, there were no differences in the antibody titer between glycosylated and nonglycosylated sera. These results indicate the possibility of a false decrease in autoantibody titers of sera from patients with autoimmune bullous diseases complicated with hyperglycemia. Although the false decrease in titers of autoantibodies induced by nonenzymatic glycosylation is not dramatic, it must be considered in order not to underestimate the disease activity of pemphigus in such cases.     

Glycosylated proteins of stratum corneum, nail and hair in diabetes mellitus: correlation with cutaneous manifestations

Nonenzymatic glycosylation of protein may play some role in the development of diabetic complications. To study the association of nonenzymatically glycosylated protein in keratinized tissues with the prevalence of cutaneous manifestations frequently observed in diabetics, we measured furosine values of stratum corneum, nail and hair from 61 diabetics and assessed their cutaneous manifestations. The manifestation most frequently found in this study was 10 cases of pigmented pretibial patches. We did not detect significant correlations between the prevalence of any cutaneous manifestations and furosine values of any keratinized tissues. However, 11 of the 17 patients with yellow nail showed high nail furosine values. Our data suggest that nonenzymatically glycosylated protein levels in the keratinized tissues do not correlate with the prevalence of cutaneous manifestations in diabetics, but do not exclude a role in the formation of yellow nail.     

A trial of postoperative adjuvant combination chemo-immunotherapy for stage IV gastric carcinoma

A chemo-immunotherapy program was designed on the basis of our clinical findings, which revealed that the ability to generate cell-mediated cytotoxicity was remarkably augmented after adriamycin (AM) administration in cancer patients. Twenty patients with stage IV gastric carcinoma who had undergone noncurative resections were treated with the above regimen that consisted of active immunotherapy with autologous tumor cells, in combination with 30 mg of AM, given 7 days before the immunization, followed by long-term tegafur (FT) and immunomodulators. The survival of these patients was compared to that of 3 other groups of patients, namely; 30 patients treated with another chemo-immunotherapy regimen which comprised autologous tumor cells in combination with several anticancer drugs followed by long-term FT and immunomodulators (CCI1), 17 patients treated with mitomycin C followed by long-term FT and immunomodulators (CI), and 24 patients with comparable histories (HC). The first treatment group had significantly improved survival, as compared to the HC group (p<0.01) and the survival tended also to be more favorable, when compared to the CCIl group (p<0.2) or the CI group (p<0.2). Moreover, the survival rate at 9 months was significantly higher than that of either the CCI1 group (p<0.01) or the CI group (p<0.01).     

Heterogeneity of the haemoglobin-A1c-band in isoelectric focussing

Summary A double HbA_1c-band was demonstrated in isoelectric focussing of blood from diabetics with a fasting blood glucose above 11mmol/l. The same band-doubling was also demonstrated after incubation of erythrocytes in glucose/saline solutions. This finding may reflect the presence of the initial condensation product between haemoglobin and glucose, the Schiff-base intermediate.     

Glutathione S-Transferase-pi Expression in Prechemotherapy and Postchemotherapy Tumor Samples from Patients with Locally Advanced Breast Carcinomas

Abstract: Early local disease recurrence and distant metastasis remain major problems in the management of locally advanced breast carcinoma (LABC). Glutathione S-transferase of the pi class (GST-pi) has been implicated as a potential prognostic predictor for breast carcinomas, and its expression has been reported in 40–70% of untreated human primary breast cancers. We examined GST-pi expression by immunohistochemis-try technique in 45 prechemotherapy biopsy samples and 26 postchemotherapy resection samples from patients with LABC and evaluated its relationship with response to treatment, disease recurrence, and other known prognostic factors. GST-pi expression was present in 56% and 58% of prechemotherapy and postchemotherapy samples, respectively. Of 26 postchemotherapy tumor samples, 15 cases showed positive GST-pi staining; these 15 patients had shorter overall survival times compared with the 11 patients whose tissue samples showed negative staining (p = 0.053). Eight cases showed a marked increase (more than double) of GST-pi expression from prechemotherapy samples to postchemotherapy samples, however, the increase did not correlate with survival time, response rate, or relapse rate. Our findings suggest that evaluation of GST-pi expression after induction chemotherapy for LABC may allow selection of patients who might benefit from different chemotherapeutic regimens or adjuvant chemotherapy.?     

The effect of improved control on blood filtration properties and non-enzymatic glycosylation of erythrocyte proteins in type 2 diabetes

Abnormal blood flow in the microcirculation has been reported in diabetes and may be important in the pathogenesis of diabetic complications. The mechanism of this is not understood but non-enzymatic glycosylation of erythrocyte membrane or haemoglobin causing reduced erythrocyte deformability and a secondary change in filtration properties of blood have been suggested as possible factors. The relationship of non-enzymatic glycosylation of erythrocyte membrane and glycosylated haemoglobin to filtration time of blood was investigated during stabilization of diabetes with sulphonylurea therapy. Over an 8-month period, glycosylated haemoglobin, non-enzymatic glycosylation of erythrocyte membrane, and filtration time fell by 41%, 71%, and 53% of the initial value, respectively, but the rate of decline was slower for filtration time which did not change significantly until the last month. Due to the different time-course of improvement, no relationship was found between filtration time and glycosylated haemoglobin or non-enzymatic glycosylation of erythrocyte membrane whereas glycosylated haemoglobin and non-enzymatic glycosylation of erythrocyte membrane correlated significantly (r = 0.49, p less than 0.001). These results suggest that the abnormal filtration property of blood in diabetes is not a direct consequence of non-enzymatic glycosylation, and suggest that the erythrocytes made in the hyperglycaemic milieu are abnormally rigid. The filtration properties of blood are only improved when new generations of erythrocytes enter the circulation.     

Mitoxantrone as first-line chemotherapy in advanced breast cancer: results of a collaborative European study

Summary Mitoxantrone (Novantrone^®; dihydroxyanthracenedione) is a substituted anthraquinone with a spectrum of activity similar to doxorubicin in experimental tumors.One hundred and seventy three patients with advanced breast cancer and no prior cytotoxic therapy for advanced disease entered a phase II study of mitoxantrone, 14 mg/m² i.v. repeated every 3 weeks. At the time of this analysis 116 patients were evaluable. Eight patients achieved a complete response and 27 a partial response, the overall response rate being 30% (95% confidence limits: 22–39%). The median time until response was recorded was 15 weeks. The median duration of response was 74+ weeks and the median time to progression or death for all 116 patients was 22+ weeks.Mitoxantrone was well tolerated with myelosuppression as the dose-limiting toxicity. The most frequent non-haematological toxicities were nausea and vomiting (65%) but they were rarely severe. Total alopecia occurred in only 6% of the patients. Four patients developed clinically significant evidence of cardiotoxicity after cumulative mitoxantrone doses of 174–256 mg/m².Thus, mitoxantrone offers comparable efficacy and less acute toxicity than the most active single agents currently available in the treatment of advanced breast cancer.     

The combination of cisplatin and vinorelbine with concurrent thoracic radiation therapy for locally advanced stage IIIA or IIIB non-small-cell lung cancer

Aims: The aims of this study were to assess the efficacy and toxicity of concurrent chemoradiotherapy with divided schedule of cisplatin and vinorelbine in patients with locally advanced non-small-cell lung cancer (NSCLC). Methods: Patients with previously untreated, unresectable, and stage IIIA or IIIB NSCLC were eligible if they had a performance status of 0 or 1, were 75 years or younger, and had adequate organ function. Twenty-six patients (24 men and 2 women; median age, 66 years; age range, 42–75 years) were enrolled. Both cisplatin (40 mg/m²) and vinorelbine (20 mg/m²) were given on days 1 and 8 every 3 weeks. Beginning on day 2 of chemotherapy, thoracic radiotherapy was given for approximately 6 weeks (2 Gy per fraction; total dose, 60 Gy). Results: Five of the 26 patients achieved a complete response, and 16 achieved a partial response for an overall response rate of 80.8% (95% confidence interval, 60.6–93.4%). The median survival time was 23 months (range, 4–43 months). Overall survival rates at 1 and 2 years were 80 and 56%, respectively. Hematologic toxicities included grade 3–4 neutropenia in 84.6% of patients, grade 3–4 thrombocytopenia in 3.8%, and grade 3–4 anemia in 61.5%. Two patients (7.7%) had grade 3 radiation esophagitis that resolved completely without dilation. Grade 3–4 radiation pneumonitis occurred in two patients (7.7%) and was treated with corticosteroids. Both patients had a good partial resolution of symptoms and radiographic abnormalities. There were no treatment-related deaths. The actual delivered dose intensities for both cisplatin and vinorelbine were 79.5%. Radiotherapy was completed in 96% of patients. Conclusion: Concurrent chemoradiotherapy with cisplatin and vinorelbine administered on a divided schedule is effective and well tolerated in patients with locally advanced NSCLC.     

Phase I trial of cetuximab in combination with capecitabine, weekly irinotecan, and radiotherapy as neoadjuvant therapy for rectal cancer

PURPOSE: To establish the feasibility and efficacy of chemotherapy with capecitabine, weekly irinotecan, cetuximab, and pelvic radiotherapy for patients with locally advanced rectal cancer. METHODS AND MATERIALS: Twenty patients with rectal cancer (clinical Stage uT3-T4 or N+) received a standard dosing regimen of cetuximab (400 mg/m(2) on Day 1 and 250 mg/m(2) on Days 8, 15, 22, and 29) and escalating doses of irinotecan and capecitabine according to phase I methods: dose level I, irinotecan 40 mg/m(2) on Days 1, 8, 15, 22, and 29 and capecitabine 800 mg/m(2) on Days 1-38; dose level II, irinotecan 40 mg/m(2) and capecitabine 1000 mg/m(2); and dose level III, irinotecan 50 mg/m(2) and capecitabine 1000 mg/m(2). Radiotherapy was given to a dose of 50.4 Gy (45 Gy plus 5.4 Gy). Resection was scheduled 4-5 weeks after termination of chemoradiotherapy. RESULTS: On dose level I, no dose-limiting toxicities occurred; however, Grade 3 diarrhea affected 1 of 6 patients on dose level II. Of 5 patients treated at dose level III, 2 exhibited dose-limiting toxicity (diarrhea in 2 and nausea/vomiting in 1). Therefore, dose level II was determined as the recommended dose for future studies. A total of 10 patients were treated on dose level II and received a mean relative dose intensity of 100% of cetuximab, 94% of irinotecan, and 95% of capecitabine. All patients underwent surgery. Five patients had a pathologically complete remission and six had microfoci of residual tumor only. CONCLUSION: Preoperative chemoradiotherapy with cetuximab, capecitabine, and weekly irinotecan is feasible and well tolerated. The preliminary efficacy is very promising. Larger phase II trials are ongoing.