Nicholas J. Rencricca

Effect of drinking pattern on plasma lipoproteins and body weight

The effect of drinking pattern on plasma lipoproteins and body weight was examined in three groups of squirrel monkeys: (1) controls fed isocaloric liquid diet; (2) regular drinkers given liquid diet containing ethanol (EtOH) substituted isocalorically for carbohydrate at 12% of calories daily; and (3) binge drinkers fed 6% EtOH calories daily for a four-day period followed by three days of 20% EtOH to mimic a weekend bout drinking cycle. The number of calories offered per day was the same for all groups, and the average weekly EtOH consumption (12% calories) was identical for the two alcohol treatments. The entire study lasted six months. There were no significant differences in plasma cholesterol, triglyceride or liver function tests. Regular drinkers had the highest high density lipoprotein2/high density lipoprotein3 (HDL2/HDL3) protein and apolipoprotein A-I/B ratios of any group and exhibited a significant elevation in the molar plasma lecithin:cholesterol acyltransferase (LCAT) rate (nmol/min/ml). Binge drinking produced a selective increase in low density lipoprotein (LDL) cholesterol and apolipoprotein B, and a depression in the fractional LCAT rate (% esterified/min). During the course of the study, controls ate 92% of their diet while the alcohol groups each consumed 95% of the liquid diet. Despite this difference, body weight and Quetelet index (weight/height2) decreased progressively in the order controls greater than regular drinkers greater than binge drinkers. Results from our study indicate that moderate, regular daily consumption of EtOH at 12% of calories causes a modest reduction in body weight and produces a coronary protective lipoprotein profile (increases HDL2/HDL3, increases apolipoprotein A-I/B, low LDL cholesterol). By contrast, when this same average weekly dose is concentrated in a binge cycle, unfavorable alterations in lipoprotein composition (increases LDL cholesterol, increases apolipoprotein B) and metabolism (decreases LCAT activity) occur along with weight loss and depletion of body fat. These studies point to the value of the squirrel monkey model in evaluating both favorable and pathophysiological effects of chronic EtOH intake.

Alcohol Produces Dose-Dependent Antiatherogenic and Atherogenic Plasma Lipoprotein Responses

Abstract A comprehensive assessment of lipoprotein compositional/metabolic response to incremental caloric ethanol (EtOH) doses ranging from low to moderate to high was undertaken using male squirrel monkeys. Control monkeys were maintained on a chemically defined, isocaloric liquid diet, while experimental primates were fed increasing doses of alcohol (6, 12, 18, 24, 30, and 36% of energy) substituted isocalorically for carbohydrate at 3-month intervals. Liver function tests and plasma triglyceride were normal for all animals. Plasma cholesterol showed a transient increase at the 12% caloric dose that was attributed solely to an increase in high density lipoprotein (HDL). A more pronounced increase in plasma sterol, beginning at 24% and continuing to 36% EtOH, was the result of increments in both HDL and low density lipoprotein (LDL) cholesterol, although the contribution by the latter was substantial primarily at the 36% dose. Plasma apolipoprotein elevations (HDL apolipoprotein A-1, LDL apolipoprotein B) generally accompanied the lipoprotein lipid increases, although the first atherogenic response for LDL became manifest as a significant increase in apolipoprotein B at 18% EtOH calories. Postheparin plasma lipoprotein lipase was not affected by dietary alcohol, whereas hepatic triglyceride lipase activity showed significant increases at higher (24 and 36%) EtOH doses. Plasma lecithin-cholesterol acyltransferase activity was normal at the 6 and 12% EtOH doses, but exhibited a significant reduction beginning at 18% and continuing to 36% EtOH. Alterations in these key lipoprotein regulatory enzymes may represent the underlying metabolic basis for the observed changes in lipoprotein levels and our earlier findings of HDL2/HDL3 subtraction modifications. Results from our study indicate that in squirrel monkeys, moderate (12%) EtOH caloric intake favors an antiatherogenic lipoprotein profile (↑HDL, normal LDL levels, and lecithin-cholesterol acyltransferase activity), whereas higher doses (24–36%) produce both coronary-protective (↑HDL) and atherogenic (↑LDL) responses. Moreover, the 18% EtOH level represents an important transition dose which signals early adverse alterations in lipoprotein composition (↑apolipoprotein B) and metabolism (↓lecithin-cholesterol acyltransferase).

Altered Erythropoiesis during the Course of Virulent Murine Malaria

Summary Peripheral, medullary, and splenic erythroid parameters were quantitatively assessed in mice during the course of virulent malarial (P. berghei) infection. Mice became progressively anemic, with circulating erythrocytes, hematocrit, and hemoglobin levels declining to approximately 20% of control by Day 21. The anemia was further characterized by a 34% increase in mean corpuscular volume, a 16% elevation in mean corpuscular hemoglobin, and a 14% decrease in mean corpuscular hemoglobin concentration by Day 21. A meager 1.5-fold reticulocytosis was noted on Day 7, which declined thereafter. Tibial nucleated cellularity was depressed to 85 and 72% of control values on Days 7 and 21, respectively, while erythroid precursor numbers remained at 74% of control levels throughout the course of infection. In contrast, splenic nucleated cells were elevated 2-fold on Day 7 and increased approximately 4-fold on Days 14 and 21. Although nearly 20-fold elevations in erythroid precursor levels were apparent, these increases were below what one might expect in noninfected mice with a similar degree of anemia. These data support the contention that the erythropoietic capability of mice infected with malaria is impaired. Accordingly, it is suggested that this situation contributes to the severe anemic status of malarial mice, in addition to the well-documented mechanisms leading to the destruction of parasitized and nonparasitized erythrocytes. The research participation of P. Desrochers, R. Gundersen, M. Hardy, M. Haviland, D. Lynch, S. McGinnis, and M. Parlee is greatly appreciated.

Effect of ethanol on low density lipoprotein and platelet composition

The present study was designed to investigate the effect of ethanol (EtOH) dose on low density lipoprotein (LDL) and platelet composition. Male squirrel monkeys were divided into three groups designated Control, Low, and High EtOH, and fed isocaloric liquid diets containing 0%, 12%, and 24% of calories as EtOH, respectively. After four months of treatment, monkeys fed the 12% alcohol dose had LDL and platelet cholesterol concentrations similar to Controls. By contrast, platelet membranes from High EtOH animals contained significantly more cholesterol which was associated with higher levels of plasma LDL cholesterol and apolipoprotein B. Blood platelet count, size, and mass were similar for all groups and circulating platelet aggregates were absent in the two alcohol cohorts. Despite elevations in platelet cholesterol mass and thromboxane A2 (TXA2) precursor, phospholipid arachidonate, platelet responsiveness, measured as thromboxane formed in response to a collagen challengein vitro, and the cholesterol/phospholipid molar ration, were not significantly altered by high dose alcohol. Normal platelet activity in High EtOH monkeys may have resulted from a significant increase in the platelet phospholipid polyunsaturated/saturated fatty acid ratio and a non-significant increase in platelet phospholipid mass, both of which would have a fluidizing effect on platelet membranes. Our data indicate that low EtOH intake has no effect on platelet composition and function while unfavorable platelet cholesterol enrichment following consumption of high dose ethanol may arise from elevations in plasma LDL. Potentially thrombogenic (TXA2 formation, platelet aggregate formation) consequences of increased platelet cholesterol in squirrel monkeys fed high levels of alcohol may be averted by compensatory physicochemical changes in platelet membrane lipid composition although persistent elevations in circulating LDL may contribute to increased risk of cardiovascular disease.

Androgen suppression of circulating immune complexes and enhanced survival in murine malaria.

Abstract The role of sex hormones as modulators of autoimmune expression, including immune complex deposition and host survival has received considerable attention. In this study BALB/c female mice received 20 mg of depotestosterone cypionate 5 days before and 5 days after infection with the malarial parasite Plasmodium herghei. On Day 15 of the infection, surviving mice were monitored for levels of erythrocytes, hematocrits, absolute parasitemias, and circulating immune complexes (CIC). CIC were determined in serum samples by polyethylene glycol insolubilization and direct measurement by helium—neon laser nephelometry. Treated mice showed a 44% reduction in the quantity of CIC, in contrast to infected controls which received cottonseed oil. Mice given the hormone were afforded protection as evidenced by 100% survival on Day 15 of the infection, versus 68% survival for the infected control group. The circulating erythroid and parasitemic levels did not differ significantly between experimental and control groups. We conclude that androgens suppress CIC levels during malaria and further suggest their involvement in the differential host survival noted herein.

Depressed splenic t lymphocyte numbers and thymocyte migratory patterns in murine malaria.

Summary The results obtained in this study show that a progressive depression in the splenic T-cell population occurs in P. berghei-infected mice and that T-cell migration is abnormal also. Since the thymus and lymph nodes involute in P. berghei-infected mice (10), it is likely that the total T-cell pool is depleted in the infected mouse. The decreased ability of transplanted thymus cells to seed into the infected spleen and the decreased T-cell population may indicate that infected mice have an environment hostile to T-cell viability.