Mouse strains for chemical carcinogenicity studies: overview of a workshop.
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Animals↗
Biomedical subjects
J J Collins
Publications and source records attributed to J J Collins.
Studies on the short-term toxicity of theophylline in rats and mice.
The purpose of these studies was to evaluate the short-term toxicity of theophylline, a compound present in tea and used in a variety of clinical applications. Fourteen-day repeated-dose toxicity studies were conducted in B6C3F1 mice and F344 rats of both sexes. Theophylline was administered in feed (0, 500, 1000, 2000, 4000, and 8000 ppm) or by gavage in corn oil (12.5-twice daily, 25, 50, 50-twice daily, 100, 200, 200-twice daily, and 400 mg/kg). Dosed-feed exposure to theophylline at concentrations up to 8000 ppm induced no significant toxicity except for dose-related uterine hypoplasia in rats. Palatability problems at that level precluded administration of higher concentrations. In the gavage study, 400 mg/kg was acutely toxic for both species, but mice and rats differed in that this same daily dose administered as two separate doses of 200 mg/kg was acutely toxic in rats but not in mice. No dose-related weight gain depression was evident in mice; weight gain was depressed in the majority of dose levels in rats and was pronounced at the higher levels. Clinical signs in mice were squinting and distended testes in males, and in rats, rapid respiration (all doses), squinting, and hunching. Gross necropsies, organ weights, clinical pathology, and pathology identified no target organs in mice, while histopathologic observations in rats suggested heart and stomach as possible target organs. Histopathologic effects in a number of other tissues, including lung, thymus, bone marrow, spleen, and uterus, were considered to reflect agonal changes in treated rats, possibly related to inanition. The results suggest that both species and sex differences exist with respect to sensitivity to theophylline toxicity, with F344 rats being more sensitive than B6C3F1 mice and male rats being more sensitive than female rats.
Animals↗
Reproductive effects of theophylline in mice and rats.
Theophylline was administered by gavage in 13-week studies to B6C3F1 mice (0, 75, 150, 300 mg/kg/day) and F344 rats (0, 37.5, 75, 150 mg/kg/day) with significant reductions in male mouse terminal body and testicular weights. Male rats also displayed reduced testicular weight, as well as nonsignificant but dose-related decreases in body weight. There was a significant but non-dose-related decrease in female mouse body weight. In parallel studies of B6C3F1 mice and F344 rats, theophylline administered in the diet (0, 0.1, 0.2, 0.4%) produced significantly decreased terminal body weights in male and female mice, but not rats. In rats, cauda epididymis weight was reduced at the high dose compared to the control group, and there was an increase in abnormal sperm. These studies were followed by continuous breeding reproductive assays in CD-1 mice in which theophylline was administered in feed (0.0, 0.075, 0.15, and 0.30%; calculated doses of 0, 125, 265, and 530 mg/kg/day, respectively) to breeding pairs for 14 weeks. There was a dose-dependent decrease in the number of live pups produced per litter, a significant decrease in the number of litters produced per pair (0.30%) and in the adjusted live pup weight (0.30%), a decrease in the percentage of pups born alive (0.15 and 0.30%), and an increase in the number of days needed to produce each litter (0.30%). After 19 weeks of continuous treatment at 0.30%, a crossover mating trial indicated that females and males were adversely affected by theophylline, as judged by the decreased percentage of pups born alive, the decreased live pup weight, and the decreased number of live pups per litter relative to matings within the control group, but the effects in females were more extensive. Based on other studies, there is a suggestion that the observed changes in fertility may be partially attributed to embryotoxicity.
Animals↗
Comparative morbidity of mitral valve repair versus replacement for mitral regurgitation with and without coronary artery disease.
Mitral valve repair has been increasingly used at our hospital for mitral regurgitation with and without coronary disease. From January, 1984, to June, 1987, of 338 patients undergoing all forms of mitral valve surgery, 140 had first-time surgery for pure mitral regurgitation: 75 had valve repair, and 65 had valve replacement. Thirty-three of 75 (44%) had concomitant coronary bypass in the repair group, while 21 of 65 (32%) had coronary bypass in the replacement group. The mean functional class (3.4 versus 3.5), age (60 versus 61 years), and preoperative hemodynamics were similar in both groups. The cause of mitral regurgitation in the repair group was myxomatous change in 32 patients, ischemia in 27, rheumatic valve disease in 12, and endocarditis in 4. A Carpentier ring was used in 46, a Duran ring was used in 11, and none was used in 18. The operative mortality was 3 of 75 patients (4%) in the repair group, all with coronary artery bypass grafting, versus 2 of 65 patients (3%) in the replacement group, 1 of whom had undergone coronary artery bypass grafting. The mean postoperative functional class 15 months postoperatively was 1.12 in the repair group versus 1.15 in the replacement group. There were 7 late deaths in the replacement group and only 3 late deaths in the repair group. Actuarial survival at 30 months was 85 +/- 6% for the replacement group and 94 +/- 4% for the repair group. There were 5 late emboli (1 fatal, 4 nonfatal) after valve replacement and none after valve repair (p = 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Considerations in the surgical management of left atrial myxoma.
Myxomas are the most common tumors of the heart. They are frequently located in the left atrium and produce symptoms when they fragment and cause systemic emboli or when they interfere with cardiac valvular function and cause pulmonary congestion. Careful surgical management of these lesions should be curative with minimum early and late morbidity and mortality. Optimal operative technique emphasizes minimal manipulation of the heart before institution of cardiopulmonary bypass and aortic cross-clamping and careful examination of intracardiac chambers with meticulous removal of myxomatous debris. Using these techniques, 17 patients have been treated successfully at the Brigham and Women's Hospital. There were no operative deaths and no significant perioperative morbidity. Fifteen patients are asymptomatic, and one patient has minimal shortness of breath an average of 57 months after surgery. One patient died of leukemia 15 months postoperatively. No recurrent myxomas have been identified, and no patients have symptoms of other cardiac disease.
Adult↗
Surgical treatment of evolving and sustained myocardial infarction.
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Coronary Artery Bypass↗
Acute and chronic effects of alcohol use on violence.
While the empirical association of drinking and problem drinking to violence is well established, the etiological nature of the relationship is poorly understood. Using data collected from 1,149 convicted male felons, the acute (drinking just before the violent event) and chronic (a psychiatric diagnosis of alcohol abuse or dependence) effects of alcohol use on violence were analyzed. Logistic regression models were used to examine the relationship of acute and chronic alcohol effects to incarceration for a violent offense and arrest for a violent offense, with demographic and criminal history factors controlled. The acute effects of alcohol were found to be significantly associated with incarceration for a violent offense, but the net explanatory capacity of acute alcohol effects was not large. Chronic alcohol effects were not significantly associated with incarceration for a violent offense or arrest for a violent offense in the previous year. The findings were interpreted as being consistent with the hypothesis that alcohol effects violence directly, acting through the acute effects of use, rather than indirectly through the effects of underlying or mediating factors.
Adolescent↗
The costs of crime and the benefits of drug abuse treatment: a cost-benefit analysis using TOPS data.
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Ambulatory Care Facilities↗
The criminal justice client in drug abuse treatment.
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Adolescent↗
Antisocial personality and substance abuse disorders.
The relationship between antisocial personality (ASP) disorder and drug and alcohol disorders was examined using data from the Diagnostic Interview Schedule (DIS) gathered on a sample of 1,149 male prison inmates. The results of a linear canonical discriminant function analysis indicate differences among those with a DIS/ASP diagnosis that are related to the presence or absence of an accompanying substance abuse diagnosis: whites are more likely than nonwhites to receive the ASP diagnosis with a substance abuse diagnosis, and substance abuse appears to magnify ASP symptomatology. Diagnostic and clinical implications of findings are discussed.
Adult↗
Doppler echocardiographic evaluation of ring mitral valvuloplasty for pure mitral regurgitation.
Doppler echocardiographic studies were performed in 21 consecutive patients (mean age 56 +/- 11 years) to evaluate postoperative results of mitral ring anuloplasty. All patients were symptomatic and all had clinically severe isolated mitral regurgitation (MR). The origin of MR was myxomatous degeneration, coronary artery disease, rheumatic heart disease or congestive cardiomyopathy. In 20 patients ring anuloplasty was performed using the Carpentier ring and 1 patient using the Duran ring. Postoperative Doppler echocardiographic studies were performed to detect and semiquantitate residual MR by flow mapping and to identify left ventricular inflow or outflow obstruction. The severity of MR was assessed by flow mapping in the left atrium and graded from I to IV in increasing severity. Blood flow velocity spectra were recorded from the left ventricular outflow tract during systole and from the left ventricle subjacent to the mitral valve during diastole. Pressure half-time, mitral valve area and mitral valve gradient were derived from digitized mitral diastolic flow velocity spectra. After ring valvuloplasty, 9 patients had no MR and 6 had grade I, 3 grade II, 2 grade III and 1 patient grade IV MR. Peak diastolic mitral valve gradient was 8 +/- 4 mm Hg, mean diastolic gradient was 3 +/- 2 mm Hg and pressure half-time was 83 +/- 17 ms, representing a calculated mean mitral valve area of 2.9 +/- 0.8 cm. Peak velocity in the left ventricular outflow tract was 0.9 +/- 0.2 m/s, indicating no obstruction to outflow. Our study confirms that mitral ring valvuloplasty produces a significant reduction in severity of MR, and this is achieved without obstructing left ventricular inflow or outflow.
Adult↗
Nitrous oxide for blood pressure control after coronary artery surgery: a dose-response hemodynamic study in postoperative patients.
The inhaled anesthetic nitrous oxide is used for sedation in the coronary care unit and has been advocated as an antihypertensive agent in patients after a cardiac operation. To delineate the hemodynamic effects of nitrous oxide after cardiac surgery, we studied 11 patients with a mean age of 63 years who had undergone isolated coronary artery bypass grafting. All patients had major coronary artery disease and normal preoperative hemodynamic function. When patients were in stable condition in the intensive care unit, hemodynamic measurements were made at an inspired oxygen concentration of 40% with progressive doses of nitrous oxide (0, 10, 20, 40, and 60%). Measured and calculated hemodynamic data were compared using analysis of variance. Nitrous oxide caused significant decreases in mean arterial pressure in a dose-related fashion; pressure fell 6 mm Hg at 10% nitrous oxide and 11 mm Hg at 60% nitrous oxide (6 and 13% decreases). These changes were not associated with significant alteration in pulmonary artery pressure or cardiac index. Left ventricular stroke work index decreased significantly with the administration of nitrous oxide. We conclude that, in patients with normal hemodynamic and ventricular function, the administration of nitrous oxide for its sedative and antihypertensive effects is safe in the postoperative period and may be useful, especially in patients who are candidates for early extubation.
Aged↗
Toxicological evaluation of 4-vinylcyclohexene. I. Prechronic (14-day) and subchronic (13-week) gavage studies in Fischer 344 rats and B6C3F1 mice.
4-Vinylcyclohexene (VCH), a dimer of 1,3-butadiene present in the gases discharged during tire curing, was examined for its toxic effects in Fischer 344 (F344) rats and B6C3F1 mice by 14-d prechronic and 13-wk subchronic testing. In the 14-d studies, VCH was administered orally by gavage in corn oil at doses of 0 (vehicle control), 300, 600, 1250, 2500, or 5000 mg/kg body weight to groups of five F344 rats and B6C3F1 mice of each sex, while the doses for the 13-wk studies (10 animals/group; 5 d/wk) were 0 (vehicle control), 50, 100, 200, 400, or 800 mg/kg body weight for rats and 0 (vehicle control), 75, 150, 300, 600, or 1200 mg/kg body weight for mice. All rats and most mice in the 14-d studies died when administered doses greater than or equal to 1250 mg/kg, although no compound-related gross or histopathologic effects were observed. In the 13-wk studies, extensive mortality was observed only in mice dosed at 1200 mg/kg. Final body weights were reduced in the 13-wk studies in male rats receiving doses greater than or equal to 400 mg VCH/kg, in female rats receiving 800 mg/kg, and in female mice receiving 600 mg/kg. Compound-related histopathologic effects in the 13-wk studies included hyaline droplet degeneration of the proximal convoluted tubules of the kidney in dosed male rats, the severity of which was dose-related, and a reduction in the number of primary follicles and mature graafian follicles in the ovaries of female mice receiving 1200 mg VCH/kg. No compound-related gross or histopathologic effects were evident in dosed female rats or male mice in the 13-wk studies.
Administration, Oral↗
Toxicological evaluation of 4-vinylcyclohexene. II. Induction of ovarian tumors in female B6C3F1 mice by chronic oral administration of 4-vinylcyclohexene.
4-Vinylcyclohexene (VCH), a dimer of 1,3-butadiene present in the gases discharged during tire curing, was examined for its toxic and carcinogenic effects in Fischer 344 (F344) rats and B6C3F1 mice by 2-yr chronic testing. VCH was administered orally by gavage in corn oil at doses of 0 (vehicle control), 200, or 400 mg/kg body weight to groups of 50 F344 rats and B6C3F1 mice of each sex for 103 wk (5 d/wk). Because the studies of VCH in male and female rats and in male mice were considered to be inadequate studies of carcinogenicity due to the extensive and early mortality at the high dose or both doses tested, as well as the lack of conclusive evidence of a carcinogenic effect, the present article focuses on the results of the 2-yr study of VCH in female B6C3F1 mice. Survival of high-dose female mice was lower (p less than 0.001) than that of the vehicle controls, whereas survival of low-dose and survival of vehicle control female mice were comparable. Mean body weights of high-dose female mice were generally slightly lower than those of the vehicle controls, whereas the mean body weights of low-dose female mice were generally greater than or comparable to those of the vehicle controls. Oral administration of VCH by gavage to female B6C3F1 mice was associated with an increased incidence of a number of nonneoplastic lesions, including mild acute inflammatory lesions and epithelial hyperplasia of the forestomach, congestion of the lungs and adrenal glands at the high dose, and cytologic alteration of the adrenal cortex at both doses. However, the most striking finding was the markedly increased (p less than 0.01) incidences of uncommon ovarian neoplasms, including mixed benign tumors, granulosa-cell tumors, and granulosa-cell tumors or carcinomas (combined), in both groups of dosed female mice. In addition, the increased incidence of adrenal-gland capsular adenomas in high-dose female mice may have been compound-related.
Administration, Oral↗
Time course of resolution of pulmonary hypertension and right ventricular remodeling after orthotopic cardiac transplantation.
Most patients with severe congestive heart failure have secondary pulmonary hypertension (PHT). Elevation of pulmonary vascular resistance (PVR) to greater than 480 dynes.sec.cm-5 (6 Wood units) is currently the principle hemodynamic contraindication to orthotopic cardiac transplantation. We performed serial two-dimensional Doppler echocardiographic examinations and right heart catheterizations in 24 recipients (21 men, 14-58 years old) of orthotopic cardiac transplants to determine the time course of resolution of PHT and the concomitant remodeling of the donor right ventricle. Right and left heart filling pressures declined in parallel and reached the upper normal range at 2 weeks after the transplant procedure and remained unchanged at 1 year follow-up. Mean pulmonary arterial pressure (mm Hg) decreased from 38 +/- 9 preoperatively to 22 +/- 5 at 2 weeks and was 19 +/- 5 at 1 year after the transplantation procedure. At 1 year after surgery, PVR had decreased from 202 +/- 89 dynes.sec.cm-5 preoperatively to 99 +/- 36 dynes.sec.cm-5 (p less than .001), while cardiac output increased from 3.7 +/- 1.2 to 6.3 +/- 1.5 liters/min (p less than .001). Echocardiographic analysis showed that transplant recipients had an enlarged right ventricle on day 1 after surgery, and a volume overload contraction pattern and tricuspid regurgitation was present in the majority. This increase in right ventricular size was maintained at 1 year follow-up while the incidence of tricuspid regurgitation decreased. We conclude that there is rapid resolution of moderately elevated pulmonary arterial pressures after cardiac transplantation.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Early and late results of coronary bypass surgery. Evolution and the influence of cardioplegia.
Comparison of 1085 patients having coronary bypass surgery without cardioplegia from Jan. 1970 to Aug. 8, 1977 with 1060 patients operated upon with cardioplegia from Aug. 9, 1977 to Dec. 31, 1980 suggests that improved myocardial protection afforded by cardioplegia combined with profound topical hypothermia has its principal impact in those patients requiring urgent or emergency operations by reducing the probability of intraoperative left ventricular failure after coronary bypass. The need for postoperative balloon pumping and the risk of intraoperative death were significantly lower in patients operated upon with hypothermia + cardioplegia myocardial protection. In patients who survived 30 days after operation there was no significant improvement in long-term survival, incidence of myocardial infarction, or recurrence of angina pectoris in the cardioplegia group despite a greater average number of grafts per patient and a smaller number of ungrafted but obstructed coronary arteries.
Adult↗
Performance of a fabricated trileaflet porcine bioprosthesis. Midterm follow-up of the Hancock modified-orifice valve.
The fabrication of the Hancock modified-orifice valve raised questions about its long-term durability. Since 1976, 315 patients (206 male, 109 female) with a mean age of 63 years underwent aortic valve replacement with 21 mm (n = 120), 23 mm (n = 153), 25 mm (n = 36), and 27 mm (n = 6) Hancock modified-orifice valves. There were five operative deaths (1.6% mortality). Two hundred sixty-two patients are alive 2 to 117 (mean 53) months postoperatively. Actuarial probability of survival at 96 months was 78% +/- 3%. Two hundred twenty-two survivors are in Functional Class I or II. Forty-three patients have had valve-related complications: thromboembolism in 25 (1.9%/pt-yr), primary valve dysfunction in eight (0.6%/pt-yr), and endocarditis in 11 (0.8%/pt-yr). Twelve patients have required reoperation (0.8%/pt-yr) for primary valve dysfunction (four patients), for endocarditis (five patients), and for perivalvular leak (three patients). At 96 months the actuarial probability of freedom from thromboembolism was 87% +/- 3%, from primary valve dysfunction 97% +/- 2%, and from endocarditis 92% +/- 3%. The probability of freedom from all valve-related complications was 78% +/- 4% and from reoperation 94% +/- 2%. The performance of this prosthesis justifies its continued use for aortic valve replacement.
Adult↗
Long-term survival of more than 2,000 patients after coronary artery bypass grafting.
Among 2,004 patients who underwent their first coronary artery bypass graft operation between January 1970 and December 1980 without concomitant valve replacement or aneurysmectomy, life-table survival was 89% at 5 years and 80% at 8 years after surgery. In a multivariate Cox model analysis, the independent correlates of long-term survival were emergent operation with cardiogenic shock (multivariate mortality rate ratio [RR] = 14.0), use of a postoperative intraaortic balloon pump (RR = 3.9), ejection fraction less than 50% (RR = 2.4), preoperative history of congestive heart failure (RR = 2.2), cardiopulmonary bypass time (RR = 1.4 for each 30-minute increment), uncorrected mitral regurgitation (RR = 1.5 for each increment of angiographic gradation), left main coronary artery narrowing (RR = 1.7) and diabetes (RR = 1.6). After controlling for these factors, age, sex and the percentage of narrowings that were bypassed were not independent correlates of long-term survival.
Adult↗