Metabolism, sister chromatid exchanges, and DNA single-strand breaks induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and their modulation by vitamin A in vitro

The nicotine-derived N-nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1- butanone (NNK) is abundant in smokeless tobacco and tobacco smoke and is hepatocarcinogenic in F344 rats. We have investigated how vitamin A modulates sister chromatid exchanges and DNA single-strand breaks induced by NNK. In V79 cells, vitamin A at concentrations ranging from 34.9 to 139.6 microM inhibited sister chromatid exchange frequencies induced by 20 mM NNK activated by primary rat hepatocytes. Sister chromatid exchanges were inhibited by 24, 44, and 55% when cells were cotreated with 34.9, 69.8, and 139.6 microM vitamin A, respectively. DNA single-strand breaks induced by NNK in rat hepatocytes were also inhibited by vitamin A. After 9 h of elution, DNA single-strand breaks induced by 1, 5, and 10 mM NNK were inhibited by 13, 5, and 3.5% in the presence of 69.8 microM vitamin A, respectively. This protective effect by vitamin A was associated with a reduction of alpha-carbon hydroxylation, an activation pathway of NNK. This pathway was inhibited by 50% when cells were cotreated with 3.49 microM vitamin A. The reduction in the hepatic microsomal aminopyrine N-demethylase, aniline hydroxylase, and N,N-dimethyl aniline N-demethylase in the presence of vitamin A (0.035 to 0.35 microM) suggests that vitamin A could reduce NNK genotoxicity by inhibiting the enzymes involved in the activation process.     

Metabolism and DNA damage induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in fetal tissues of the Syrian golden hamster

The nicotine derived N-nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a potent respiratory tract carcinogen in adult Syrian golden hamsters. In this study, the metabolism and genotoxicity of NNK was investigated in fetal hamster trachea and lung tissues. Fetal lung and tracheal explants were cultured in vitro with [5-3H]NNK, and metabolites released into the culture medium were assayed by high-performance liquid chromatography-scintigraphy. Activation of NNK by alpha-carbon hydroxylation and deactivation by pyridine N-oxidation increased from Day 12 to 15 of fetal development. In lung tissues, at Day 12 of fetal development, carbonyl reduction of NNK to 4-(methylnitrosamino)-1-(3-pyridyl)butan-1-ol was the major metabolic pathway. When adult and fetal lung explants were cultured in vitro with [methyl-3H] NNK, explant DNA was methylated at the O6- and N-7 guanine sites. When hamsters were injected i.p. with NNK (0-200 mg/kg) on Day 14 of gestation, chromosome aberrations were observed in epithelial cells established from lung and tracheal explant outgrowths. Most aberrations in lung and tracheal cells were of chromatid types. High frequency of chromatid exchange was observed in tracheal cells. After injection of NNK (200 mg/kg) to 14-day pregnant hamsters, NNK was detected in lung (0.39 +/- 0.16 nmol/mg), placenta (0.72 +/- 0.48 nmol/mg protein) and amniotic fluids (34.07 +/- 7.62 nmol/ml). These results demonstrated that NNK can cross the placental barrier in pregnant hamsters and be activated to genotoxic intermediates in tracheal and lung tissues and suggest that NNK is a transplacental carcinogen in this species.     

Open-heart surgery after 70 years of age. Results in 136 patients

Between 1975 and 1983, 136 patients aged over 70 underwent open heart surgery: aorto-coronary by-pass in 67 cases, valve replacement in 46 cases, combined valve and coronary surgery in 20 cases, resection of a left ventricular aneurysm in 2 cases and closure of a ruptured septum in 1 case. There were 13 deaths in the short-term (9.6%). Operative mortality for aorto-coronary by-pass was 4.5%, and that of valve replacement 4.4%, whereas for the combined procedures it was 35%. Non-fatal post-operative complications were frequent, occurring in 40% of patients. Life-table analysis showed 77% survival at 5 years. Of the 111 patients who left hospital, only one was lost to follow-up. At an average follow-up of 26 months, there were 84 patients in functional class I, 17 in class II and 9 in class III. Complications related to the presence of a prosthetic valve occurred in only 3 patients, none of whom required reoperation during the follow-up period. In the elderly, open heart surgery can therefore be carried out at relatively low risk, except where combined procedures are concerned. The long term history, together with the degree of functional improvement achieved, justify cardiac surgery even in the elderly.     

A reexamination of the effects of intracerebroventricular glucocorticoids in adrenalectomized rats

Several investigators have reported that many of the behavioral and metabolic effects of ADX can be reversed by appropriate levels of glucocorticoids administered either peripherally or centrally. The present studies were conducted to offer a comparison of the effects of orally administered corticosterone (CORT) with ICV glucocorticoids [CORT, CORT acetate, or dexamethasone (DEX)]. Of particular interest were the effects of glucocorticoid treatment on body weight gain and on macronutrient self-selection. Adult male Sprague-Dawley rats were fitted with ICV cannulae and either bilaterally ADX or given sham operations. In the first experiment, ADX animals were initially treated systematically with CORT (20 micrograms/ml in their drinking water). After a wash-out period during which no steroids were administered, ADX rats were given daily ICV CORT injections (100 micrograms/day in 10 microliters). Systemic CORT treatment promotes weight gain and normal food choice patterns in ADX rats. ICV injections failed to promote weight gain in ADX rats, and daily injection of the vehicle promoted a weight loss in sham-operated controls. Four additional experiments were conducted. ADX, glucocorticoid-treated animals and ADX, vehicle-treated controls as well as sham-operated, vehicle-treated controls were used to assess the effects of both steroid and vehicle on body weight gain and dietary selection patterns. ADX ICV-glucocorticoid-treated animals typically failed to gain weight at the rate observed when ADX rats are treated with CORT systematically. Under one condition, ADX-CORT-treated animals gained weight at a rate comparable to untreated controls, but their ICV-injected control group failed to gain weight.(ABSTRACT TRUNCATED AT 250 WORDS)     

Practical and technical considerations in establishing an intraoperative radiation therapy program in the community practice

The Radiation Oncology Center in Sacramento, California, has developed a procedure for establishing an intraoperative radiation therapy facility in a community practice. The logistics pertaining to personnel, equipment, physical measurements, and quality assurance are presented. Particular emphasis is given to the most effective means of acquiring the large quantity of data needed to ensure a program of acceptable quality.