Effect of 3-methylcholanthrene on atherosclerosis in two congenic strains of mice with different susceptibilities to methylcholanthrene-induced tumors.

Inbred mouse strains AKXL-38 and AKXL-38a are congenic strains that differ at the Ah locus, a gene which affects the inducibility of the cytochrome P-450 enzymes. The Ah-responsive strain, AKXL-38a, is more susceptible to 3-methylcholanthrene-induced tumors than the Ah-nonresponsive strain, AKXL-38. We previously reported that 3-methylcholanthrene (MC) increased the number and the size of atherosclerotic lesions in a dose-dependent fashion. We now demonstrate that the effect of MC is greater in Ah-responsive mice than in Ah-nonresponsive mice indicating that Ah-responsive mice not only are more susceptible to MC-induced cancer but also are more susceptible to MC-enhanced atherosclerosis. Mice that received atherogenic diet for 14 weeks but no MC had 1.3-1.4 lesions/mouse regardless of genetic type. When mice were treated with MC, the number of lesions increased to 2.1 +/- 0.1 (SE) in Ah-nonresponsive mice, 2.6 +/- 0.2 in Ah-responsive mice, and 2.3 +/- 0.2 in the F1 hybrid. The total area involved in lesions was 9.3-12.6 micron2 in untreated animals. When mice were treated with MC, the total lesion area increased to 23.5 +/- 5.2 micron2 in Ah-nonresponsive mice, to 43.9 +/- 6.6 micron2 in Ah-responsive mice, and to 36.2 +/- 4.8 micron2 in F1 hybrids. Thus MC increased the lesion area in both strains of mice, but the increase was significantly greater in Ah-responsive than in Ah-nonresponsive animals. High density lipoprotein levels were not significantly affected by MC treatment or Ah genotype. In order to determine whether the increased susceptibility to MC-induced atherosclerosis segregated with the Ah gene, AKXL-38 and AKXL-38a mice were mated and the F1 progeny were backcrossed to the Ah-nonresponsive parent. Backcross progeny were tested for Ah genotype by zoxazolamine sleeping time. Measurements of lesions showed that increased susceptibility to MC-enhanced atherosclerosis segregated with the Ah locus.

Comparison of atherosclerotic lesions and HDL-lipid levels in male, female, and testosterone-treated female mice from strains C57BL/6, BALB/c, and C3H.

In order to determine whether male and female mice differed in HDL-lipid levels or in atherosclerotic response to a high fat diet, we examined 3 inbred strains which differed in susceptibility to atherosclerosis; C57BL/6, BALB/c, and C3H. Mice were fed normal chow or an atherogenic diet containing 1.25% cholesterol, 15% fat, and 0.5% cholic acid. Lesion number and size were determined after 14 weeks on the diet; plasma HDL-lipid levels were determined at 0 and 4 weeks on the diet. For C3H, the most atherosclerosis-resistant strain, HDL-lipid levels were very high and not affected by sex or diet. For BALB/c, HDL-lipid levels were intermediate between the other two strains. Male levels were significantly higher than the females, and the atherogenic diet caused a drop in HDL-lipid levels of 14-27% depending on sex. For C57BL/6, the most atherosclerosis-susceptible strain, HDL-lipid levels were low compared to the other two strains. Males and females on normal chow did not differ in HDL-lipid, but females showed a 50% decrease in HDL when fed the atherogenic diet. For both BALB/c and C57BL/6, testosterone-treated females resembled the males. The HDL-lipid levels in mice on atherogenic diet differed over a 3-fold range among the nine groups. When HDL-lipid levels were compared to the number of atherosclerotic lesions or the total lesion area, a high degree of correlation was observed (r = -0.95 for lesion number and -0.93 for total lesion area). This suggests that HDL-lipid levels are important in determining atherosclerosis susceptibility in mice.

Quantitative assessment of atherosclerotic lesions in mice.

The well-defined genetic systems of the mouse are proving useful in experimental studies of atherosclerosis. Inbred mouse strains differ in atherosclerosis susceptibility, and several variants of apolipoproteins have been identified and mapped. This report explores the location and timing of lesion formation in the mouse in an effort to provide a basis for quantitatively comparing groups of mice. After 14 weeks on an atherogenic diet containing 1.25% cholesterol, 15% fat, and 0.5% cholic acid, C57BL/6J female mice had aortic lesions at each of the intercostal arteries, at the junction of the aorta to the heart, and in scattered areas covering 1.1% +/- 0.5 (SD) of the aortic surface. After 9 months on the atherogenic diet, those lesions near the heart and intercostal arteries were extensive, 8% +/- 3 (SD) of the remainder of the aorta was involved in lesions, and lesions were found in the coronary arteries. Results indicated that one suitable location for scoring lesions was in a 300 micron area of the aorta just beyond the aortic sinus. The mean number of lesions/mouse in the selected area after 14 weeks on the atherogenic diet was 1.1 +/- 0.3 (SD). The results were reproducible over 10 separate experiments. The number of lesions per mouse fit a Poisson distribution indicating that the presence of one lesion did not predispose the mouse to acquiring a second lesion. Lesion formation and cholesterol levels did not vary with the season of the year as demonstrated by 9 separate experiments over more than 12 months. Methods of evaluating the number and size of lesions were compared including sizing with a microscope eyepiece grid and computer-assisted planimetry. The resulting data provide reproducible methods of quantitatively comparing lesion formation in various strains or groups of mice, thereby increasing the usefulness of the mouse as an experimental system for atherosclerosis research.

Effects of prenatal cocaine on hearing, vision, growth, and behavior.

The illicit use of cocaine has increased dramatically over the last 10-12 years. There has been a corresponding increase in cocaine abuse among obstetric patients and in the number of "cocaine babies." According to some estimates, these children make up more than half of the drug-associated births. This problem is therefore a major public health concern. Consequently, our laboratory investigated the effects of prenatal cocaine exposure on hearing, vision, growth, and exploratory/stress behavior. This chapter summarizes the literature on animals and humans on these topics and presents new observations from our laboratory. In terms of maternal toxicity, prenatal cocaine exposure causes hypertension, placental abruption, spontaneous abortion, poor pregnancy weight gain, and undernutrition secondary to appetite suppression. Some offspring effects include in utero growth retardation, cephalic hemorrhage, fetal edema, altered body composition, congenital malformations, and even pre- and postnatal death. The offspring can also exhibit a variety of behavioral, visual, hearing, and language disorders. Differential effects of animal strain and late gestational cocaine exposure are discussed. Comparisons are made between prenatal cocaine, the fetal alcohol syndrome, and the effects of prenatal undernutrition. Recommendations for clinical assessment and intervention are made.

Multigeneration reproduction studies with carmoisine in rats.

Carmoisine (C.I. (1956) No. 14720) was fed at levels of 0, 0.35, 0.8 and 2.0% in the diet of rats throughout a multigeneration reproduction study. The dye had not untoward effects on reproduction capacity of any of the generations studied. Fertility, lactation and viability indices of all groups fed carmoisine did not differ significantly from controls at any stage of the study. These results indicate a maximum no-effect level of 2% in the diet. Data from an additional nine-week feeding study (dietary levels were 0, 2, 4, 6 and 8%) suggest that the no-effect level may in fact be even higher since 4% carmoisine in the diet was tolerated without evidence of overt toxicity.

A one year feeding study with carmoisine in rats.

Rat fed carmoisine (C.I. (1956) No. 14720) at 0.35, 0.8 or 2.0% in the diet for 52 weeks showed no adverse effects of the dye when compared to control animals. Mortality, weight gain, hematological values and relative organ weights were the same in control and treated animals. There was no increase in tumor incidence due to carmoisine treatment. Male rats fed 2.0% carmoisine showed an increased incidence of several mild subclinical conditions (minimal bronchitis and tracheal inflammation). Because of this occurrence, the maximum no-effect level after 1 year exposure appears to be 0.8%, equivalent to a daily intake of approx. 400 mg/kg.

Preoperative insurance status influences postoperative complication rates for gastric bypass.

One hundred morbidly obese patients who had gastric bypass surgery were studied to determine how various demographic and medical variables affected complication rates, weight loss, and reduction in comorbidities associated with obesity. During the follow-up period (range: 12 to 59 months), 42 patients developed at least 1 complication. Twenty-three patients developed postoperative medical complications, 9 developed psychiatric complications, and 24 developed complications related to food ingestion. No significant relationships were observed between outcome and age, sex, age of obesity onset, or associated medical disorders. Striking differences in outcome were noted, however, when patients were contrasted according to their preoperative insurance status. Patients dependent on medical assistance, social security disability, or workman's compensation (publicly funded group) (n = 40) developed significantly more medical and psychiatric complications than did those (n = 60) who had private medical insurance (p less than 0.02). Despite the higher complication rate, both groups had the same average weight loss (44.9 +/- 15.3 kg for the publicly funded group versus 43.1 +/- 12.9 kg for those with private insurance) and similar reductions in percent excess weight (66.0 +/- 18.4% versus 75.7 +/- 23.0%) during the first postoperative year. All patients also had similar reductions in medication requirements for hypertension, diabetes, and degenerative joint disease. Additionally, 45% of the publicly funded insurance group who either received public welfare (n = 26) or disability benefits (n = 14) preoperatively were able to attain either full-time or part-time employment postoperatively which allowed them to decrease their level of support (58% and 21%, respectively). Forty-six percent of women in the private insurance group who were not working outside the home also began part-time or full-time employment postoperatively. All patients who were working preoperatively continued to work. These data suggest that although the risks associated with gastric bypass surgery are greater in patients dependent on public funding, these patients benefit significantly from the surgery.

Can morbidly obese patients safely lose weight preoperatively?

BACKGROUND: Preoperative weight loss is often suggested as a means of reducing operative risk in obese patients requiring laparotomy but there are no large studies documenting that this is feasible or helpful. Although several commercial products are available that provide high levels of protein with low levels of carbohydrates in convenient liquid preparations, recommendations regarding the extent to which weight loss can be pursued preoperatively are not available. PURPOSE: To determine whether it is practical and safe to have obese patients lose weight preoperatively. PATIENTS AND METHODS: We asked 100 severely obese patients requesting gastric bypass surgery to diet before their operations. Seventy patients agreed to diet by consuming a 420 Kcal, 70 g protein liquid diet daily for at least 1 month. RESULTS: Forty-seven patients lost at least 7.5 kg (mean +/- SD 17.1 +/- 0.7). The patients who successfully lost weight preoperatively (dieters group) were significantly heavier than patients (nondieters group) who did not lose weight (251% +/- 45% of ideal body weight [IBW] versus 229% +/- 33% IBW, respectively; P < 0.01), had a significantly higher ratio of men to women, and had psychiatric evaluations and psychological test scores that suggested significantly more psychopathology. Other biosocial and medical characteristics were similar. Postoperatively, the dieters and nondieters had similar rates for morbidity. Dieters and nondieters had no differences in wound-healing complications, and subgroups who had collagen deposition measured experimentally had similar amounts of hydroxy-proline accumulation in their wounds. CONCLUSION: These results suggest that a preoperative diet program appeals more to certain subgroups of severely obese patients than to others. An aggressive preoperative weight loss program that encourages patients to lose an average of 17 kg is safe and can be accomplished practically using available commercial products.

Prenatal cocaine, alcohol, and undernutrition differentially alter mineral and protein content in fetal rats.

Alcohol exposure and undernutrition during pregnancy have been associated with altered fetal body composition. Recent observations suggest that cocaine exposure during pregnancy may impair delivery of nutrients to the fetus and could thereby alter body growth and composition. Such effects are important because they can adversely influence physical and neural development. Consequently, we investigated the dose-dependent effects of cocaine on fetal body composition in an animal (rat) model and compared such effects with those caused by prenatal alcohol exposure and undernutrition. Pregnant Sprague-Dawley rats received either 20, 30, 40, or 50 mg/kg cocaine HCl (SC) twice daily from gestation days 7 through 19. Pair-fed (undernutrition) and untreated control groups and a group receiving 3.0 g/kg alcohol (PO) twice daily served as comparison groups (n = 11 to 14/group). Females were sacrificed on gestation day 20. One male and one female fetus was removed from each dam. The fetuses were minced, dehydrated, defatted, and analyzed for content of protein and the minerals Zn, Ca, Fe, Mg, K, and Na. In terms of concentration per unit of fat-free dry solids, male fetuses in the cocaine groups showed significant decreases in protein compared to untreated controls (15+/-3 to 20+/-2 mg/g vs. 24+/-4 mg/g, p = 0.01). There was a significant treatment effect for Ca (p < 0.05), reflecting a trend for decreased Ca concentrations in the fetuses of the cocaine and undernutrition groups. Male fetuses in the alcohol group had significantly elevated Mg levels compared to male fetuses in the other groups (3.0+/-0.8 vs. 1.0+/-0.2 to 2.3+/-0.7 mg/g, p < 0.05). There were some sex differences, with female fetuses having significantly lower concentrations of Mg, Fe, K, and higher protein concentrations than male fetuses. Although the effects were few and modest, these results suggest that prenatal cocaine, alcohol, and undernutrition can differentially alter fetal body weight and composition and, therefore, adversely influence fetal development.

Interactive effects of prenatal alcohol and cocaine exposures on postnatal mortality, development and behavior in the Long-Evans rat.

Polydrug abuse has increased substantially in recent years amongst obstetric patients. One of the most common drug combinations is alcohol and cocaine. To better understand the adverse consequences of this drug combination on pregnancy and the offspring, alcohol (2 g/kg, b.i.d.) and cocaine HCl (30 mg/kg, b.i.d.) were administered individually and in combination to separate groups of pregnant Long-Evans rats from gestation days 7-20. The pregnant dams were evaluated for maternal weight gain, food and water consumption, mortality, and gestational length. The offspring were evaluated for physical maturation, mortality, and behavior. The drug combination was found to have greater effects regarding decreased birth weight, increased postnatal mortality, and delayed physical maturation than either drug alone. Drug treatments also influenced activity monitor behavior in that prenatal cocaine exposure was associated with hypoactivity while the alcohol and the alcohol-plus-cocaine treatments were associated with hyperactivity in periweanling pups. Drug treatments had no significant effects on passive or active avoidance behaviors. These results suggest that combining alcohol and cocaine increases the risk to the offspring.

Prediction of postoperative complications after elective aortic surgery using stepwise logistic regression analysis.

Perioperative risk factors that contribute to postoperative morbidity have been identified for various forms of vascular disease, but it is not clear to what degree each type of disease contributes to morbidity when these diseases are seen in combination. We used stepwise logistic regression analysis to determine the relative importance of 25 risk factors in predicting postoperative complications in 100 consecutive patients undergoing elective intra-abdominal aortic surgery (59% aneurysmal disease, 37% occlusive disease, 26% renal artery lesions). Thirty-one patients developed postoperative complications, including three deaths. The most common complication was deterioration in renal function (17 patients, 24% of those at risk) followed by the need for prolonged endotracheal intubation (> 48 hours, 8%). All other events occurred uncommonly (4% or less). Stepwise logistic regression demonstrated four criteria that were significantly associated with complications. In descending order of importance these were: renal artery occlusive disease, intraoperative blood replacement, the preoperative APACHE II score, and a history of heavy smoking. Since both physiologic status and comorbid conditions contribute to morbidity and costs of elective vascular surgery, outcome studies must be adjusted to account for these preoperative characteristics. Additionally, since two-thirds of patients who have renal artery occlusive disease develop complications that prolong hospitalization, our current methods of protecting the kidney during ischemia should be improved to potentially reduce this cause of morbidity.

Bridging the two cultures of dual diagnosis: research and service.

Common goals for research and service in dual diagnosis are identified. Three major barriers to the integration of research and service are explored: (a) differences in culture, (b) negative history, and (c) competition for limited resources. Applied research concerning diagnosis, treatment, behavioral recording, and organization and management development can encourage greater cooperation. To promote the integration of the research and service, joint conferences and publications are recommended as well as graduate training programs and agencies that emphasize both research and service. A vigorous policy initiative is needed to obtain private and public support for integrating research and service in dual diagnosis.

The use of noncontingent escape to reduce disruptive behaviors in children with speech delays.

Noncontingent escape (NCE) was used to reduce disruptive behavior in 3 children during regularly scheduled speech therapy sessions. Results showed rapid decreases in disruptive behavior and accompanying increases in compliance across children. Findings suggest that speech therapists with little expertise in behavior analysis can effectively implement NCE.

Hypoxic-ischaemic brain injury: imaging and neurophysiology abnormalities related to outcome.

BACKGROUND: The outcome for patients with hypoxic-ischaemic brain injury (HIBI) is often poor. It is important to establish an accurate prognosis as soon as possible after the insult to guide management. Clinical assessment is not reliable and ancillary investigations, particularly imaging and EEG, are needed to understand the severity of brain injury and the likely outcome. METHODS: We undertook a retrospective study of 39 patients on an intensive therapy unit (ITU) with HIBI who were referred for MRI. The patients were seen consecutively >57 months. HIBI was due to a variety of insults causing cardiac arrest, hypoperfusion or isolated hypoxia. RESULTS: The outcome was poor, 29 patients died, 7 were left severely disabled and only 3 made a good recovery. Characteristic imaging changes were seen on MRI. These included extensive changes in the cortex and the deep grey matter present on diffusion-weighted imaging (DWI) and T2-weighted imaging within 6 days of the insult. In other patients, different patterns of involvement of the cortex and basal ganglia occurred. There was no significant difference in the outcome or imaging appearances according to aetiology. A poor prognosis was consistently associated with a non- or poorly responsive EEG rhythm and the presence of periodic generalized phenomena with a very low-voltage background activity. CONCLUSION: In this retrospective study of patients with HIBI, MRI and EEG provided valuable information concerning prognosis.

A model-based assessment of the effects of projected climate change on the water resources of Jordan.

This paper is concerned with the quantification of the likely effect of anthropogenic climate change on the water resources of Jordan by the end of the twenty-first century. Specifically, a suite of hydrological models are used in conjunction with modelled outcomes from a regional climate model, HadRM3, and a weather generator to determine how future flows in the upper River Jordan and in the Wadi Faynan may change. The results indicate that groundwater will play an important role in the water security of the country as irrigation demands increase. Given future projections of reduced winter rainfall and increased near-surface air temperatures, the already low groundwater recharge will decrease further. Interestingly, the modelled discharge at the Wadi Faynan indicates that extreme flood flows will increase in magnitude, despite a decrease in the mean annual rainfall. Simulations projected no increase in flood magnitude in the upper River Jordan. Discussion focuses on the utility of the modelling framework, the problems of making quantitative forecasts and the implications of reduced water availability in Jordan.