Failure of genetically selected miniature swine to model NIDDM

Ten young adult miniature swine from a line reported to be genetically selected for glucose intolerance and eight normal controls were obtained from Colorado State University. They were consecutively exposed to 4 mo of a high-fiber, low-fat standard swine diet; 4 mo of a high-sucrose, high-fat, low-fiber diabetogenic diet; and 4 mo of excess diabetogenic diet for obesification. Results of oral glucose tolerance and intravenous insulin tolerance tests conducted at the end of each regimen were compared. Hyperglycemia was not observed in any animals after any manipulation. Insulin sensitivity was also not influenced by diet. We conclude that F7 low-K miniature swine from this colony fail to model human non-insulin-dependent diabetes.     

Antidepressant-like effects of trazodone on a behavioral screen are mediated by trazodone, not the metabolite m-chlorophenylpiperazine

Trazodone is an atypical antidepressant drug (i.e. blocks neither monoamine uptake nor monoamine oxidase) which tests as an antidepressant drug on the differential-reinforcement-of-low-rate 72-s (DRL 72-s) schedule of reinforcement by increasing the reinforcement rate and decreasing the response rate. m-Chlorophenylpiperazine (m-CPP) is a 5-HT1B and 5-HT1C agonist, weak 5-HT2 antagonist, and trazodone metabolite. It has been suggested that formation of m-CPP is responsible for the antidepressant action of trazodone. Administration of m-CPP (1-10 mg/kg i.p.) 60, 30 or 10 min before the behavioral session did not mimic the reinforcement rate-increasing effects of trazodone (10-20 mg/kg i.p.) on rats performing under the DRL 72-s schedule of water reinforcement. Pretreatment with proadifen (50 mg/kg i.p.), an inhibitor of trazodone metabolism, caused a greater than 30-fold leftward shift in the dose-response curve for both the reinforcement rate and the response rate. These results suggest that the parent compound and not the trazodone metabolite m-CPP, mediates the antidepressant-like effects of trazodone on DRL 72-s behavior.     

Effects of acute thioridazine, metoclopramide and SCH 23390 on the basal activity of A9 and A10 dopamine cells

Extracellular single-unit recording techniques were employed to examine the effects of various dopamine (DA) antagonists on the basal activity of spontaneously active DA cells. Metoclopramide and thioridazine were both effective in reversing apomorphine-induced suppression of A9 and A10 DA cells. SCH 23390 produced only a partial reversal of this suppression. When the antagonists were given without any pretreatment, thioridazine preferentially increased the firing rate of A10 DA cells, and was relatively ineffective in altering A9 activity. Metoclopramide, on the other hand, increased the activity of most A9 DA cells, but was less effective in doing so with A10 cells. SCH 23390 did not significantly affect the basal activity of either cell subpopulation. These data support the hypothesis that the so-called 'atypical' antipsychotic drugs act preferentially on the A10 DA system. Taken together with previous results, they also suggest that the acute effects of DA antagonists on DA cell subpopulations coincide with their chronic effects.     

Effect of erythrocyte ingestion on macrophage antibacterial function.

Individuals with sickle cell anemia are subject to serious infections caused by a number of bacteria, including Salmonella species and Staphylococcus aureus. It has been suggested that in sickle cell anemia, extensive erythrophagocytosis by macrophages may interfere with their antibacterial function and thereby predispose to infection. As a means of investigating this possibility, we evaluated the effects of erythrocyte ingestion on the Killing of Salmonella typhimurium by peritoneal macrophages and of S. aureus by alveolar macrophages. Monolayers of rabbit macrophages were exposed to erythrocytes or latex particles immediately before and during bacterial challenge. Erythrophagocytosis markedly inhibited intracellular killing of S. typhimurium by peritoneal macrophages (bacterial survival was 181% of control) and of staphylococci by alveolar macrophages (bacterial survival was greater than 200% of control). Exposure to latex particles depressed the bactericidal activity of alveolar macrophages to a lesser degree. Next we investigated the possibility that erythrophagocytosis inhibits oxidative bactericidal mechanisms in macrophages. Hexose monophosphate shunt activity was stimulated by erythrocyte ingestion. However, zymosan-induced superoxide generation and chemiluminescence were suppressed by erythrocytes. Furthermore, a cell-free (hypoxanthine-xanthine oxidase) system for chemiluminescence generation was also depressed in the presence of erythrocytes (intact or lysate) or by purified hemoglobin. These studies reveal that erythrophagocytosis inhibits macrophage antibacterial function, probably because of interactions between erythrocyte components and reactive products of phagocyte oxygen metabolism. This host defense abnormality may predispose to bacterial infection in certain hemolytic anemias.     

Morphological and cytochemical alterations of the Golgi apparatus and GERL in rat parotid acinar cells during ethionine intoxication and recovery

The present electron microscopic cytochemical investigation was undertaken to characterize the alterations in the Golgi apparatus and GERL of rat parotid acinar cells during ethionine intoxication and recovery. Although the Golgi apparatus and GERL were reduced in size, and some broadening of the Golgi saccules occurred as the result of ethionine treatment, the relative localization of thiamine pyrophosphatase (TPPase) activity in the Golgi saccules, and acid phosphatase activity (AcPase) in GERL, remained unchanged. Shortly after ethionine treatment was stopped, a dramatic redistribution of enzyme activities was noted. Within the first 24 hours of recovery, the Golgi apparatus began to enlarge, and the content of secretory granules increased. By day 3 of recovery, cisternae morphologically identifiable as GERL and forming secretory granules possessed TPPase activity, while AcPase activity was virtually undetectable. After seven days of recovery, the Golgi apparatus and GERL appeared both morphologically and cytochemically normal. The enzyme modulation observed during recovery may be correlated with increased secretory granule production. Furthermore, the presence of TPPase activity in GERL and forming secretory granules lends support to the suggestion that GERL may be derived from the trans Golgi saccule.     

Pyridinyl imidazoles inhibit IL-1 and TNF production at the protein level

The mechanism by which SK&F 86002 and other pyridinyl imidazoles inhibit the production of IL-1 and TNF from LPS-stimulated human monocytes was examined. Inhibition of IL-1 and TNF production was found to depend on the time of addition of SK&F 86002, with diminishing effect when added more than 2 h after LPS stimulation. Analysis of Western blots confirmed that both intracellular IL-1β and extracellular TNF were significantly reduced in response to SK&F 86002, but these reductions were not paralleled by changes in IL-1 and TNF mRNA.³⁵S methionine pulse and pulse-chase studies on IL-1 biosynthesis suggest that significant inhibition by SK&F 86002 and related compounds occurs at the translational level.

     

A double-blind, placebo controlled trial of high-dose lecithin in Alzheimer''s disease.

The first long-term double-blind placebo controlled trial of high dose lecithin in senile dementia of the Alzheimer type is reported. Fifty one subjects were given 20-25 g/day of purified soya lecithin (containing 90% phosphatidyl plus lysophosphatidyl choline) for six months and followed up for at least a further six months. Plasma choline levels were monitored throughout the treatment period. There were no differences between the placebo group and the lecithin group but there was an improvement in a subgroup of relatively poor compliers. These were older and had intermediate levels of plasma choline. It is suggested that the effects of lecithin are complex but that there may be a "therapeutic window" for the effects of lecithin in the condition and that this may be more evident in older patients.