Intestinal and hepatic cholesterogenesis in hypercholesterolemic dyslipidemia of experimental diabetes in dogs.

We previously reported that dog diabetes results in hypercholesterolemia and the accumulation of a high-density lipoprotein (HDL) subclass, HDL1. Hypercholesterolemic diabetic rodents exhibit hyperphagia, intestinal hypertrophy, and increased intestinal cholesterol synthesis and absorption; intestinal 3-hydroxy-3-methylglutaryl (HMG) CoA reductase activity is increased, whereas hepatic activity is unchanged or reduced. To determine whether similar mechanisms operate in the hypercholesterolemic diabetic dog, we measured hepatic and intestinal cholesterologenesis. Streptozocin-alloxan-induced diabetic dogs allowed access to food ad libitum were hyperphagic and hypercholesterolemic (10.1 vs. 4.47 mM) but normotriglyceridemic. Plasma HDL1 concentrations were markedly increased. Differences in renal and hepatic function were not statistically significant, except serum alkaline phosphatase, which was elevated 4-fold (P = 0.0003). Urinary mevalonate, an index of whole-body cholesterol synthesis, was increased 6-fold. Intestinal and hepatic weights were both increased, and direct measurements showed crypt and villus thickening. The activity of HMG CoA reductase per gram organ weight was increased 1.7-fold in liver and 2.1-fold in intestine. Calculated whole-organ activity in intestine was nearly twice that in liver. These observations provide strong evidence that intestinal cholesterogenesis is involved in the pathogenesis of hypercholesterolemia in dog diabetes and support the conclusion that increased cholesterol synthesis plays a role in the hypercholesterolemia of diabetes.

Geographic variation in the incidence of myocardial calcification associated with acute myocardial infarction.

There is reason to believe that calcium influx into heart muscle during acute myocardial infarction (AMI) can aggravate myocyte injury. Furthermore, the degree of such influx might correlate with the occurrence of microscopic myocyte calcification observed at autopsy. We have searched for evidence of myocyte calcification in hearts of patients found to have AMI at autopsy at the Veterans Administration Medical Center in Salt Lake City (SLCVA), a region with a low myocardial infection death rate, and at the George Washington University Medical Center in Washington, DC (GWUMC), a region with a high myocardial infection death rate. Of 23 consecutive cases examined under "blind" conditions at the GWUMC in which AMI was found, there were 15 instances of cardiac myocyte calcification observed in von Kossa-stained sections. Not a single example of myocyte calcification was found in 23 comparable cases at the SLCVA. The basis of this difference in myocyte calcification is unknown, but may be related to the fact that the Salt Lake City drinking water contains a higher level of magnesium, which is known to protect against soft tissue calcification, than does that of Washington, DC. This may be the basis for the apparent protection that dietary magnesium exerts against myocardial infarction death.

Generalized beta 2-microglobulin deposition. A preamyloidosis disorder?

Generalized beta 2-microglobulin deposition in the tissues of a 64-year-old man with idiopathic end-stage renal disease was determined post mortem by the use of immunoperoxidase and radial immunodiffusion techniques. He developed progressive organ failure secondary to beta 2-microglobulin deposition, requiring dialysis for the last two years of his life. His immediate cause of death was severe bronchopneumonia. The extensive tissular deposits were shown to be congophilic but not birefringent by alkaline Congo red stains. Immunochemical studies showed that the deposits were beta 2-microglobulin-positive but AA amyloid-, P-component-, prealbumin-, and kappa and lambda light chain-negative. We suggest that this patient had a primary beta 2-microglobulin dyscrasia in which beta 2-microglobulin deposited in tissues but did not undergo complete amyloidogenic change.

Endoscopic laser resection of atherosclerotic plaque in a live animal model. A preliminary report on some technical difficulties.

This study was designed to determine whether laser energy could be used effectively to resect atherosclerotic plaque through an endoscope in a live animal model. Twelve adult Yorkshire swine with infrarenal aortic atherosclerosis had a 2.5 mm and/or 3.2 mm diameter fiberscope passed into the aorta from the femoral artery after proximal aortic balloon occlusion. Endoscopic argon laser resection of the atherosclerotic plaque was then attempted in eight pigs with an argon laser fiber (60 to 400 microns). We were able to visualize the raised atherosclerotic plaque in all 12 pigs with the larger 3.2 mm diameter fiberscope, which was easily passed into the aortoiliac system from the 4 mm diameter femoral vessel. The articulating end feature enhanced maneuverability within the lumen and allowed laser fiber direction. The 2.5 mm endoscope did not allow adequate visualization in any pig since the vessel could not be cleared of blood. The 2.5 mm endoscope was also passed from the femoral artery distally into the hind limb and still did not allow adequate visualization of the vessel wall because of persistent luminal blood. The 3.2 mm endoscope enabled vessel wall visualization distal to the femoral artery when the proximal artery was occluded. No aortas were grossly perforated by the laser energy. In all pigs undergoing endoscopic laser resection, raised plaques were removed both grossly and histologically, although the plaque edges were carbonized and frayed as well as vaporized. With the small spot size of the argon fiber, channels were drilled through plaque, frequently with incomplete recanalization of the lumen.(ABSTRACT TRUNCATED AT 250 WORDS)

Apolipoprotein E-containing lipoproteins and lipoprotein remnants in experimental canine diabetes.

The effects of diabetes on plasma lipoproteins were examined in a cohort of control and streptozocin-alloxan diabetic beagles fed either standard rations or an atherogenic cholesterol-supplemented diet. Lipoprotein cholesterol, triglyceride, and retinyl ester concentrations were measured in fractions separated by density gradient ultracentrifugation. Individual lipoprotein classes and apolipoproteins were assessed by electrophoresis. Postheparin plasma lipoprotein triglyceride lipase activities were also examined. In the absence of added dietary cholesterol, diabetic animals became hypercholesterolemic with relatively increased low-density (LDL) and decreased high-density (HDL) lipoprotein cholesterol concentrations. Apolipoprotein E-containing beta- to alpha 2-migrating HDL1 (HDLc) appeared in rho = 1.020-1.080 g/ml subfractions, whereas alpha 1-migrating typical HDL (rho = 1.06-1.21 g/ml) was reduced. In comparison to nondiabetic cholesterol-fed animals, diabetic cholesterol-fed animals had increased cholesterol (but not triglyceride) concentrations in very-low- and intermediate-density classes. These classes contained retinyl esters and low-molecular-weight apolipoprotein B (components of intestinal lipoprotein remnants) as well as apolipoprotein E and high-molecular-weight apolipoprotein B. These findings could not be explained by decreased postheparin plasma lipoprotein lipolytic activities. Increased plasma concentrations of HDLc in poorly controlled diabetic dogs may reflect a pathologic disturbance in the excretory limb of cholesterol transport from peripheral cells to the liver. In addition, exaggerated retention of lipoprotein remnants in cholesterol-fed diabetic dogs may contribute to increased delivery of cholesterol to extrahepatic tissues. This model appears to be suitable for physiologic studies of the effects of diabetes on reverse cholesterol transport.

The frequency of fungal involvement in abnormal vocal cord biopsy specimens.

Finding an unsuspected fungal infection of the true vocal cord prompted a retrospective study of abnormal vocal cords received as surgical specimens. Of 30 cases initially diagnosed histologically as either inflammation or hyperkeratosis, two (in addition to the index case) contained fungal elements visible on special stains. None of the patients had systemic mycoses on examination or on follow-up. Local excision apparently cured all lesions. Fungi may cause more vocal cord lesions than previously recognized and cannot be well visualized on routine sections.

The effect of neurotensin on the concentration of cholesterol and bile acids in the guinea pig.

In guinea pigs, total plasma cholesterol concentrations increased above the control values after single intravenous injections and after 3 days of continuous subcutaneous administration of neurotensin (NT). A high dose of NT (125 pmol/100 g body weight) induced tachycardia and severe respiratory distress; the lowest dose (1.25 pmol/100 g body weight) had the greatest hypercholesterolemic effect 15 min after the injections. The bulk of the total plasma cholesterol was in low density lipoprotein fractions. Cholesterol increased in the same fractions after intravenous administrations of NT. NT induced a decrease in the cholesterol content in the ileum but did not affect significantly the cholesterol content in the liver, kidneys or adrenals. In 48-hr fasted controls, plasma cholesterol concentration and cholesterol content in the liver, kidneys, adrenals and terminal ileum increased; after intravenous injections of NT, plasma cholesterol concentration further increased but cholesterol content of the liver, kidneys and ileum decreased. In fed animals, the concentration of the biliary taurochenodeoxycholic acid increased above the control values 5 and 35 min after the intravenous injections of NT. In fasted controls, the total concentration of bile acids was higher than in fed controls, but only the concentration of taurochenodeoxycholic acid further increased after the injections of NT. Proportionately more taurochenodeoxycholic acid than cholesterol was present in bile after the intravenous injections of NT. These data are consistent with the hypothesis that NT has a regulatory role in intestinal cholesterol transport.

Aortic and renal lesions in hypercholesterolemic adult, male, virgin sprague-dawley rats.

Male, virgin Sprague-Dawley rats received for periods of from 2 to 80 weeks 1 of the 3 following diets: Commercial rat chow (control diet), commercial rat chow supplemented with cholesterol (cholesterol diet) or commercial rat chow supplemented with cholic acid and taurine in equimolar amounts (cholic acid diet). Plasma cholesterol concentration was elevated in all rats kept on the cholesterol or on the cholic acid diets. Three of 8 rats kept on the control diet also developed hypercholesterolemia 80 weeks after beginning the experiment. Intimal plaques in the aorta and glomerulosclerosis were observed in all rats with plasma cholesterol concentrations above 150 mg/100 ml, including the three hypercholesterolemic controls. Cholesterol concentrations in the aorta and kidneys of the rats with these lesions were not increased above the control values while hypercholesterolemia was common to all the rats with these lesions regardless of the type of the diet.

Effect of neurotensin on specific activity of plasma cholesterol following intravenous administration of cholesterol-4-14C.

In order to investigate the source of the additional circulating cholesterol in hypercholesterolemia induced by neurotensin (NT), 12.5 pmol/100 g body weight NT was injected into the tail veins of rats which received by the same route 1 X 10(6) dpm/100 g body weight cholesterol-4-14C 24 hours earlier. Fifteen minutes later the concentration of the labeled plasma cholesterol was the same in the treated animals and in the controls. However, specific activity of plasma cholesterol significantly decreased in rats that received NT, while it remained unchanged in the controls. These data suggest that the additional circulating cholesterol after the intravenous administration of NT was either newly formed or originated in some tissue where equilibrium between endogenous and exogenous cholesterol has not yet been established.

The effect of neurotensin on the plasma cholesterol levels in the rat.

The effect of the hypothalamic tridecapeptide neurotensin (NT) on the plasma cholesterol levels was studied in the rat. 15 min after the intravenous administration of 1.25 pmol/100 g body weight NT, the concentration of the total plasma cholesterol was increased about 25% above the control values (P less than 0.001) and remained at about the same level 30 min after the injection. The hypercholesterolemic response to the intravenous administration of NT increased dose dependently (12.5 and 125 pmol). Adrenalectomy and hypophysectomy did not modify the hypercholesterolemic effect of NT. The data suggest that NT may have a role in cholesterol transport.