Studies of cholesterol and bile acid metabolism, and early atherogenesis in hamsters fed GT16-239, a novel bile acid sequestrant (BAS).

The purpose of this study was to compare the efficacy of GT16-239, an alkylated, cross-linked poly(allylamine) bile acid sequestrant with cholestyramine on cholesterol and bile acid metabolism, and early aortic atherosclerosis in hypercholesterolemic male F1B Golden Syrian hamsters. In this controlled study, 42 hamsters were divided into six groups and were fed a chow-based hypercholesterolemic diet supplemented with a 10% oil blend (55% coconut/45% corn), 0.1% cholesterol (w/w) (control) and either 0.9 or 1.2% cholestyramine or 0.2, 0.4 or 0.6% GT16-239 for 13 weeks. Laboratory analyses included evaluating plasma lipoprotein cholesterol and triglyceride concentrations, hepatic HMG-CoA reductase and 7 alpha-hydroxylase activities, fecal excretion of bile acids and neutral sterols, hepatic cholesterol concentrations, and early atherosclerosis (aortic fatty streak area). Relative to the control diet, the 0.6% GT16-239 versus the 1.2% cholestyramine significantly inhibited the elevation of plasma lipoprotein total cholesterol (TC) (-69% vs -40%), high density lipoprotein-cholesterol (HDL-C) (-49% vs -30%), and non-HDL-C (-81 vs -48%) concentrations; increased the activities of both HMG-CoA reductase (1492% vs 62%) and 7 alpha-hydroxylase (175% vs 86%); lowered the concentration of hepatic cholesteryl ester (-94% vs -59%); increased fecal cholesterol concentration (+28% vs -10%); and decreased aortic fatty streak area (-100% vs -86%). Unexpected findings of this comparison were increased fecal concentrations of cholic acid (533%) and chenodeoxycholic acid (400%) and the reduction in lithocholic acid (-50%) in the 0.6% GT16-239 compared to the 1.2% cholestyramine group. In summary, GT16-239 had a greater impact on cholesterol metabolism and early atherosclerosis in hypercholesterolemic hamsters than cholestyramine.

DiGeorge anomaly with renal agenesis in infants of mothers with diabetes.

We report on 2 infants with the DiGeorge anomaly born to diabetic mothers treated with insulin. Both infants had unilateral renal agenesis. One of the mothers has manifestations suggestive of velo-cardio-facial syndrome (VCFS). Cytogenetic studies on both patients and the mother with apparent VCFS were normal. Molecular studies utilizing probes from the DiGeorge critical region did not demonstrate a 22q11 microdeletion in either patient or the mother with apparent VCFS. We conclude that maternal diabetes is a pathogenetic factor in the DiGeorge anomaly, and infants of diabetic mothers who have this anomaly should also be screened for renal agenesis.

The hypocholesterolemic and antiatherogenic effects of Cholazol H, a chemically functionalized insoluble fiber with bile acid sequestrant properties in hamsters.

Cholazol H (Alpha-Beta Technology, Worcester, MA), a chemically functionalized, insoluble dietary fiber with bile acid sequestrant properties, was studied in 30 male F1 B Golden Syrian hamsters for its effect on plasma lipid concentrations and early atherogenesis in experiment 1. In experiment 2, 30 male Golden Syrian hamsters were studied for the effects on plasma lipids and fecal excretion of bile acids. In experiment 1, three groups of 10 hamsters each were fed a chow-based hypercholesterolemic diet supplemented with 5% coconut oil and 0.1% cholesterol for 6 weeks. After 6 weeks, hamsters were continued on the diet with either 0% drug (hypercholesterolemic diet [HCD]), 0.5% cholestyramine (CSTY), or 0.5% Cholazol H for 8 weeks. Fasting plasma lipids were measured at weeks 6, 10, and 14, and early atherosclerosis (fatty streak formation) was measured at week 14. Relative to HCD, CSTY and Cholazol H significantly lowered plasma total cholesterol (TC) (-37%, P < .03, and -30%, P < .04, respectively) and plasma very-low and low-density lipoprotein-cholesterol (nonHDL-C) (-45%, P < .02, and -36%, P < .03, respectively) with no significant effects on plasma HDL-C or triglycerides (TG). Despite similar reductions in nonHDL-C, only Cholazol H significantly prevented early atherosclerosis (-38%, P < .02) relative to HCD. In experiment 2, three groups of 10 hamsters each were fed a chow-based hypercholesterolemic diet supplemented with 10% coconut oil and 0.05% cholesterol and either 0% drug HCD, 0.5% CSTY, or 0.5% Cholazol H for 4 weeks. Fasting plasma lipids were measured at weeks 2 and 4, and fecal bile acids were measured at week 4. Both Cholazol H and CSTY were equally effective in significantly lowering plasma TC (-16%, P < .003, and -13%, P < .01, respectively) and nonHDL-C (-22%, P < .004, and -18%, P < .02, respectively), with no significant effect on HDL-C and TG relative to HCD. Cholazol H and CSTY produced a significantly greater concentration of fecal total bile acids (39%, P < .001, and 28%, P < .002, respectively) relative to HCD. Also, there was a 48% (P < .002) and 65% (P < .001) greater fecal concentration of cholic acid (CA) for Cholazol H-treated hamsters compared with HCD- and CSTY-treated hamsters, respectively. Cholazol H also significantly increased fecal concentration of deoxycholic acid (DCA; 56%, P < .02) compared with HCD. In summary, Cholazol H is as effective as CSTY for prevention of diet-induced hypercholesterolemia and early atherosclerosis in hamsters.

Mechanics of edematous lungs.

Using the parenchymal marker technique, we measured pressure (P)-volume (P-V) curves of regions with volumes of approximately 1 cm3 in the dependent caudal lobes of oleic acid-injured dog lungs, during a very slow inflation from P = 0 to P = 30 cmH2O. The regional P-V curves are strongly sigmoidal. Regional volume, as a fraction of volume at total lung capacity, remains constant at 0.4-0.5 for airway P values from 0 to approximately 20 cmH2O and then increases rapidly, but continuously, to 1 at P = approximately 25 cmH2O. A model of parenchymal mechanics was modified to include the effects of elevated surface tension and fluid in the alveolar spaces. P-V curves calculated from the model are similar to the measured P-V curves. At lower lung volumes, P increases rapidly with lung volume as the air-fluid interface penetrates the mouth of the alveolus. At a value of P = approximately 20 cmH2O, the air-fluid interface is inside the alveolus and the lung is compliant, like an air-filled lung with constant surface tension. We conclude that the properties of the P-V curve of edematous lungs, particularly the knee in the P-V curve, are the result of the mechanics of parenchyma with constant surface tension and partially fluid-filled alveoli, not the result of abrupt opening of airways or atelectatic parenchyma.

Model for a pump that drives circulation of pleural fluid.

Physical and mathematical models were used to study a mechanism that could maintain the layer of pleural fluid that covers the surface of the lung. The pleural space was modeled as a thin layer of viscous fluid lying between a membrane carrying tension (T), representing the lung, and a rigid wall, representing the chest wall. Flow of the fluid was driven by sliding between the membrane and wall. The physical model consisted of a cylindrical balloon with strings stretched along its surface. When the balloon was inflated inside a vertical circular cylinder containing a viscous fluid, the strings formed narrow vertical channels between broad regions in which the balloon pressed against the outer cylinder. The channels simulated the pleural space in the regions of lobar margins. Oscillatory rotation of the outer cylinder maintained a lubricating layer of fluid between the balloon and the cylinder. The thickness of the fluid layer (h), measured by fluorescence videomicroscopy, was larger for larger fluid viscosity (mu), larger sliding velocity (U), and smaller pressure difference (delta P) between the layer and the channel. A mathematical model of the flow in a horizontal section was analyzed, and numerical solutions were obtained for parameter values of mu, U, delta P, and T that matched those of the physical model. The computed results agreed reasonably well with the experimental results. Scaling laws yield the prediction that h is approximately (T/delta P)(microU/T)2/3. For physiological values of the parameters, the predicted value of h is approximately 10(-3) cm, in good agreement with the observed thickness of the pleural space.

Addition of guar gum and soy protein increases the efficacy of the American Heart Association (AHA) step I cholesterol-lowering diet without reducing high density lipoprotein cholesterol levels in non-human primates.

The aim of this study was to determine whether the addition of soy protein and guar gum to the American Heart Association (AHA) Step I diet would increase its efficacy compared with the typical "Average American Diet" (AAD) in a non-human primate model. Twenty adult female cynomolgus monkeys (Macaca fascicularis) were fed one of three diets for 6 wk. The AAD contained 36% energy from fat; the standard Step I diet contained 30% energy from fat; and the modified AHA Step I diet contained 30% energy from fat with the addition of soy protein isolate (10% of total energy) and guar gum (5.8 g/d). Plasma samples were collected from food-deprived monkeys at 4, 5 and 6 wk of dietary treatment for analyses of plasma total cholesterol (TC), lipoprotein cholesterol and triacylglycerol (TAG) concentrations. Plasma TC, LDL-C, HDL-C and TAG concentrations were not significantly different in wk 4, 5 and 6 within any of the diet periods; thus the three measurements were averaged. After 6 wk of dietary treatment, monkeys fed the standard Step I diet had lower plasma TC (-19%) (P < 0.05) and LDL cholesterol (LDL-C) (-24%) (P < 0.09) than when they were fed the AAD, with no effect on HDL cholesterol (HDL-C), the lipoprotein cholesterol profile or TAG. Beyond the effect of the standard Step I diet, the modified AHA Step I diet further reduced plasma TC and LDL-C (-24% and -40%) (P < 0. 05) and the TC/HDL-C and LDL-C/HDL-C ratios (-37% and -52%) (P < 0. 05) with no significant changes in plasma HDL-C or TAG. The primary conclusions of this study are that the efficacy of the AHA Step I cholesterol-lowering diet can be increased with the addition of soy protein and guar gum and provide a more favorable lipoprotein cholesterol profile. Whether the cholesterol-lowering effect is the result of soy protein or guar gum or a synergistic effect of both remains to be determined.