Effects of the kappa opioid agonist U50,488 and the kappa opioid antagonist nor-binaltorphimine on choice between cocaine and food in rhesus monkeys

Rationale Selective kappa opioid receptor agonists usually decrease cocaine self-administration in procedures that use rate-based measures of reinforcement; however, the rate-altering effects of kappa agonists complicate interpretation of these findings.Objectives To evaluate the effects of the selective kappa agonist U50,488 and the selective kappa antagonist nor-binaltorphimine (nor-BNI) on concurrent choice between cocaine and food in rhesus monkeys. The concurrent-choice procedure provides a rate-independent measure of the relative reinforcing effects of cocaine in comparison with food.Methods Four rhesus monkeys were trained to respond under a concurrent-choice schedule for food (1-g pellets) or cocaine (0–0.1 mg/kg per injection). Saline and increasing doses of U50,488 (0.0032–0.1 mg/kg per h) were administered by pseudo-continuous i.v. infusion (one infusion every 20 min) during sequential 3-day blocks. In a separate experiment, monkeys were treated with nor-BNI (3.2 mg/kg, i.v.), and cocaine choice was re-determined during pseudo-continuous infusion with saline or U50,488 (0.1 mg/kg per h).Results During saline treatment, cocaine maintained a dose-dependent and monotonic increase in cocaine choice. Monkeys responded primarily for food when low cocaine doses were available (0–0.01 mg/kg per injection) and primarily for cocaine when higher cocaine doses were available (0.032–0.1 mg/kg per injection). U50,488 produced a dose-dependent increase in cocaine choice, manifested as leftward shifts in the cocaine-choice, dose–effect curve. U50,488 also dose-dependently decreased overall response rates. Nor-BNI did not alter cocaine choice, but it attenuated the effects of U50,488.Conclusions These results suggest that continuous treatment with U50,488 produces a kappa receptor-mediated increase in the relative reinforcing effects of cocaine in comparison with food.     

Analysis of opioid receptor subtype antagonist effects upon mu opioid agonist-induced feeding elicited from the ventral tegmental area of rats

The present study examined opioid receptor(s) mediation of feeding elicited by mu opioid agonists in the ventral tegmental area using general or selective opioid antagonist pretreatment. Naltrexone as well as equimolar doses of selective mu and kappa, but not delta opioid antagonists in the ventral tegmental area significantly reduced mu agonist-induced feeding, indicating a pivotal role for these receptor subtypes in the full expression of this response.     

AUGMENTATION OF IMMUNE FUNCTIONS AND AUTOLOGOUS TUMOR-KILLING ACTIVITY BY KAPPA-SELENOCARRAGEENAN IN MICE BEARING SARCOMA 180

Ｗｉｔｈｉｎｃｒｅａｓｉｎｇｋｎｏｗｌｅｄｇｅｏｆｔｕｍｏｒｉｍｍｕｎｉｔｙａｎｄｃａｎｃｅｒｂｉｏｔｈｅｒａｐｙ，ｉｔｈａｄｂｅｎｃｏｎｃｅｎｔｒａｔｅｄｔｈａｔｈｏｓｔｉｍｍｕｎｅｆｕｎｃｔｉｏｎｓｍａｒｋｅｄｌｙａｆｅｃｔｔｈｅｏｃｕｒｅｎｃｅ...     

Differential effects of systemically administered nor-binaltorphimine (nor-BNI) on κ-opioid agonists in the mouse writhing assay

The opioid antagonist effects of systemically administered nor-binaltorphimine (nor-BNI) were evaluated against the kappa agonists CI-977, U69,593, U50,488, ethylketocyclazocine (EKC), Mr2034 and bremazocine, the mu agonist morphine and the alkaloid delta agonist BW-373U86 in the acetic acid-induced writhing assay in mice. All eight agonists completely and dose-dependently inhibited writhing. Antagonism of CI-977 was apparent 1 h after administration of 32 mg/kg nor-BNI, peaking after 4 h and was maintained for at least 4 weeks; no antagonist effects of nor-BNI were apparent after 8 weeks. Nor-BNI (32 mg/kg) caused little or no antagonism of morphine or BW-373U86 at 1 h and none at 24 h after nor-BNI administration. Subsequently, dose-effect curves for CI-977, U50,488, U69,593, EKC, Mr2034 and bremazocine were determined 24 h after pretreatment with 3.2, 10 and 32 mg/kg nor-BNI. Pretreatment with 3.2 mg/kg nor-BNI produced significant antagonism of all six kappa agonists, suggesting that their antinociceptive effects were mediated at least in part by nor-BNI-sensitive kappa receptors. At higher doses, nor-BNI dose-depend-ently shifted the agonist dose-effect curves of CI-977, U50,488, U69,593 and bremazocine, but not those of EKC and Mr2034, suggesting that the latter compounds may be producing effects via nor-BNI-insensitive receptors. Mu receptor involvement was demonstrated following a 24 h pretreatment with 32 mg/kg-FNA in combination with nor-BNI, which significantly increased the degree of antagonism of Mr2034 and EKC from that seen with nor-BNI alone. Hence, SC administered nor-BNI selectively antagonized agonist activity mediated through kappaopioid receptors without differentiating between kappa subtypes. Nor-BNI also enabled the mu agonist activity of proposed kappa agonists to be measured.A preliminary report of these findings was made at the International Narcotic/Research/Conference in Keystone, CO, June, 1992. This work was supported by USPHS grant DA 00254. Animals used in these studies were maintained in accordance with the University Committee on Use and Care of Animals, University of Michigan, and guidelines of the Committee on Care and Use of Laboratory Animal Resources, National Research Council (Department of Health, Education and Welfare, Publication No. (NIH) 85-23, revised 1983)     

Kappa Light Chain Nodular Glomerulosclerosis with Conspicuous Crescent Formation and Tubulointerstitial Injury

We describe a 39-year-old man who developed kappa light chain nodular glomerulosclerosis with superimposed conspicuous crescent formation and extensive tubulointerstitial injury. The clinical picture was characterized by nephrotic syndrome and rapidly progressive glomerulonephritis. Incessantly progressive loss of renal function culminated in irreversible renal failure 7 weeks after initial manifestation of renal insufficiency. The patient has since been maintained on thrice weekly hemodialysis with chemotherapy for five years. At the time of pathologic diagnosis by renal biopsy, there was no evidence of multiple myeloma, and no serum M-component or Bence-Jones proteinuria was detected. An initial bone marrow aspirate revealed the presence of 0.6% atypical lymphocytes as the sole abnormality, although these were later identified as atypical plasma cells. These cells had also infiltrated the renal interstitium. Crescentic kappa light chain nodular glomerulosclerosis lacking evidence of plasma cell dyscrasia should be included in the differential diagnosis of rapidly progressive glomerulonephritis.     

Consistency achieved by 23 European pathologists from 12 countries in diagnosing breast disease and reporting prognostic features of carcinomas

 A detailed analysis of the consistency with which pathologists from 12 different European countries diagnose and classify breast disease was undertaken as part of the quality assurance programme of the European Breast Screening Pilot Network funded by the Europe against Cancer Programme. Altogether 107 cases were examined by 23 pathologists in 4 rounds. Kappa (κ) statistics for major diagnostic categories were: benign (not otherwise specified) 0.74, atypical ductal hyperplasia (ADH) 0.27, ductal carcinoma in situ (DCIS) 0.87 and invasive carcinoma 0.94. ADH was the majority diagnosis in only 2 cases but was diagnosed by at least 2 participants in another 14, in 9 of which the majority diagnosis was benign (explaining the relatively low κ for this category), DCIS in 4 (all low nuclear grade) and invasive carcinoma (a solitary 1-mm focus) in 1. The histological features of these cases were extremely variable; although one feature that nearly all shared was the presence of cells with small, uniform, hyperchromatic nuclei and a high nucleo-cytoplasmic ratio. The majority diagnosis was DCIS in 33 cases; κ for classifying by nuclear grade was 0.38 using three categories and 0.46 when only two (high and other) were used. When ADH was included with low nuclear grade DCIS there was only a slight improvement in κ. Size measurement of DCIS was less consistent than that of invasive carcinoma.The majority diagnosis was invasive carcinoma in 57 cases, the size of the majority being 100% in 49. The remainder were either special subtypes (adenoid cystic, tubular, colloid, secretory, ductal/medullary) or possible microinvasive carcinomas. Subtyping was most consistent for mucinous (κ, 0.92) and least consistent for medullary carcinomas (κ, 0.56). Consistency of grading using the Nottingham method was moderate (κ=0.53) and consistency of diagnosing vascular invasion, fair (κ=0.38). There was no tendency for consistency to improve from one round to the next, suggesting that further improvements are unlikely without changes in guidelines or methodology.     

An assessment of the validity of reporting by proxy to women's health questionnaire: a pilot study

OBJECTIVE: The quality of proxy reports provided by husbands regarding women's health, when the index case (the wife) cannot be interviewed, is controversial. STUDY DESIGN: Fourteen husbands and wives at menopause were interviewed separately using the same pre-constructed questionnaire. The extent of agreement between their reports was assessed. RESULTS: Higher agreement was noted for questions regarding physiognomy, number of live children, age at menopause and general health problems. Lesser agreement was observed regarding obstetric history. CONCLUSIONS: In light of these preliminary observations, the use of husbands as proxy for women's health questionnaire at midlife should be carefully considered and may be limited to questions regarding general health issues rather than reproductive health.     

不同化学发光分析系统检测丙型肝炎病毒抗体的性能评价

目的 评价罗氏Cobas e601及雅培Architect i2000两种化学发光免疫分析系统检测抗-HCV的分析性能和一致性.方法 按照CLSI推荐的方法对两台分析仪检测抗-HCV的精密度、检出限、阴阳性符合率等性能进行验证试验;两台仪器分别检测120例有反应性血清样本及30例无反应性样本,用Kappa检验评价检测结果的一致性.结果 两台仪器的精密度良好;检出限均为0.3NCU;阴阳性符合率为100％;两个分析系统检测抗-HCV总体符合率为70.67％,无反应性、e601 S/CO≥15.0、i2000 S/CO≥6.0样本结果的符合率为100％,e601 S/CO为1.01 ～5.0和i2000 S/CO为1.01 ～2.0样本结果的符合率为0和44.4％:经统计分析κ=0.35在Kappa系数区段中一致性程度属于弱(κ=0.35,P＜0.05).结论 两个分析系统检测抗-HCV的分析性能均良好,适用于临床标本的常规检测,对于两台仪器检测结果不一致的样本,尤其是e601 S/CO 1 ～ 15及i2000 S/CO 1～6的样本,建议进行补充实验(RIBA,NAT)来明确诊断.     

黄芩苷对脂多糖诱导的巨噬细胞Toll样受体4表达的影响

目的 研究黄芩苷对脂多糖诱导的小鼠巨噬细胞Toll样受体4和其下游信号分子抑制蛋白kB以及效应分子肿瘤坏死因子α表达的影响.方法 分别用脂多糖(终浓度1 mg/L)或脂多糖+黄芩苷(终浓度10、50和100 μmol/L)处理生长良好的小鼠巨噬细胞RAW264.7,逆转录聚合酶链反应和Western Blot检测细胞Toll样受体4表达情况和抑制蛋白kB含量变化,酶联免疫吸附法检测细胞上清液中肿瘤坏死因子α的浓度.结果 脂多糖刺激RAW264.7细胞可导致Toll样受体4表达增高,促进抑制蛋白kB降解,上调肿瘤坏死因子α表达;黄芩苷预处理能降低脂多糖诱导的Toll样受体4表达增高,降低抑制蛋白kB降解,下调肿瘤坏死因子α分泌.结论 黄芩苷可通过抑制Toll样受体4表达和降低抑制蛋白kB降解,影响Toll样受体4/抑制蛋白kB-核因子kB炎症信号途径,阻碍炎症因子肿瘤坏死因子α的生成,发挥抗炎作用,这可能是其抗动脉粥样硬化的作用机制之一.