No abstract

Hepatocellular vacuolation can be a diagnostic challenge since cytoplasmic accumulations of various substances (lipid, water, phospholipids, glycogen, and plasma) can have a similar morphology. Cytoplasmic accumulation of phospholipids following administration of cationic amphiphilic drugs (CAD) can be particularly difficult to differentiate from nonphosphorylated lipid accumulations at the light microscopic level. Histochemical methods (Sudan Black, Oil Red-O, Nile Blue, etc.) can be used to identify both nonphosphorylated and/or phosphorylated lipid accumulations, but these techniques require non-paraffin-embedded tissue and are only moderately sensitive. Thus, electron microscopy is often utilized to achieve a definitive diagnosis based upon the characteristic morphologic features of phospholipid accumulations; however, this is a low throughput and labor intense procedure. In this report, we describe the use of immunohistochemical staining for LAMP-2 (a lysosome-associated protein) and adipophilin (a protein that forms the membrane around non-lysosomal lipid droplets) to differentiate phospholipidosis and lipidosis, respectively in the livers of rats. This staining procedure can be performed on formalin-fixed paraffin embedded tissues, is more sensitive than histochemistry, and easier to perform than ultrastructural evaluation.

-The antidiabetic agent troglitazone was given to groups of 4 cynomolgus monkeys per sex at 300, 600, or 1200 mg/kg daily by gavage for 52 weeks. A group of 4 monkeys per sex received vehicle alone and served as controls. Emesis and soft stool or diarrhea occurred sporadically in all troglitazone-treated groups, but did not compromise animal health. There were no effects on body weight or food consumption, or ophthalmologic, electrocardiographic, or echocardiographic parameters. Erythrocyte count, hemoglobin, and hematocrit decreased 8% to 16% in males at all doses and serum cholesterol decreased 30% to 46% in both sexes at all doses. Urinary ketones were increased in several animals at 600 and 1200 mg/kg. Absolute and relative liver weights increased at all doses in both sexes by 40% to 71%. The only microscopic change attributable to troglitazone treatment was minimal to mild bile duct hyperplasia in males at all doses and in females at 600 and 1200 mg/kg. No differences in systemic exposure were apparent between sexes. Over the dose range tested, AUC values were 27 to 102 µg·hr/ml of troglitazone, 401 to 2060 µg·hr/ml of its sulfate conjugate, and 34 to 312 µg·hr/ ml of its quinone metabolite. Therefore, oral administration of troglitazone to monkeys at 300, 600, and 1200 mg/kg for 52 weeks resulted in significant systemic exposure, with only minimal gastrointestinal, hematologic, and hepatic effects.

Eight stress-susceptible and eight normal pigs were used in the first portion of the study. Urine samples were collected for 24 hr over 4 consecutive days while the pigs were kept in metabolism cages. Each 24-hr sample was assayed for epinephrine, norepinephrine and dopamine. Urinary levels of dopamine were lower (P < .01) in the stress-susceptible pigs. No significant differences in urinary epinephrine or norepinephrine were observed. The second portion of the study evaluated the catecholamines in the caudate nucleus of the brain. Six stress-susceptible and six control pigs were examined. Immediately after exsanguination, caudate nuclei were excised and frozen in liquid nitrogen. The caudate nuclei were assayed for catecholamines within 2 to 3 days of freezing. Caudate nuclei dopamine levels were lower (P < .01) in stress-susceptible pigs (5,961 ng/g) than in control pigs (10,878 ng/g). No significant differences in norepinephrine levels of the caudate nuclei were observed between the two groups.

No abstract