Monocyte activation following systemic administration of granulocyte-macrophage colony-stimulating factor.

Twenty-four patients with solid malignancies were treated with granulocyte-macrophage colony-stimulating factor (GM-CSF) on a Phase 1b trial. The objective of the study was to evaluate the effects of GM-CSF on peripheral blood monocyte activation. GM-CSF was administered by subcutaneous injection daily for 14 days. Immune parameters measured were monocyte cytotoxicity against the human colon carcinoma (HT29) cell line, serum tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta, and in vitro TNF-alpha and IL-1 beta induction. All patients were evaluable for toxicity. Fifteen patients were evaluable for immunologic response. Treatment with GM-CSF led to a statistically significant enhancement in direct monocyte cytotoxicity against HT29 cells. There was no increase in serum TNF-alpha or IL-1 beta and no consistent in vitro induction of TNF-alpha or IL-1 beta from monocytes posttreatment. Treatment was well tolerated overall. We conclude that treatment with GM-CSF can lead to enhanced monocyte cytotoxicity. Further studies are in progress to evaluate the effect of GM-CSF on other parameters of monocyte functions.

Experimental pneumococcal otitis media: longitudinal studies in the gerbil model.

In order to ascertain that the Mongolian gerbil, Meriones unguiculatus, is an acceptable model for studying the development of chronic from acute otitis media, we used previously published methods for experimental otitis media in a longitudinal study of the acute disease and sequellae. The gerbil was found to be susceptible to as few as 30 viable Streptococcus pneumoniae type 3 cells, indicating that only a few viable pathogens are able to cause the disease. Untreated experimental infections with S. pneumoniae type 23 resulted in a mild, self-limiting disease with little permanent sequellae, while S. pneumoniae type 3 produced severe disease characterized by an acute phase of from 2 to 3 weeks, followed by the development of new bone formation and a vascularized granulation tissue which persisted throughout the 13-week study. Viable pneumococci could be recovered from the middle ears for only two weeks. We conclude that the gerbil is a useful model for otitis media.

Longitudinal studies of experimental otitis media with Haemophilus influenzae in the gerbil.

Haemophilus influenzae non-typable strain 119 was found to cause severe otitis media with sequellae when inoculated into the middle ear cavities of the Mongolian gerbil, Meriones unguiculatus. Acute inflammation was followed by the development of highly vascular granulation tissue and formation of new bone within the middle ear bulla. These changes persisted throughout the 14-week study in the untreated animals. The gerbil was variably susceptible to otitis media caused by inoculating 30-3000 bacterial cells and 100% susceptible to greater than 3000 cells. The susceptibility of the gerbil to common etiological agents of otitis media allows its use as an appropriate model of the disease.

Dimethyl sulfoxide: inhibition of acetylcholinesterase in the mammalian heart.

The heart rate of the isolated, perfused, working rat heart was significantly and equally depressed by 1 X 10(-6)M acetylcholine (ACh) and by 6 X 10(-5)M 4-ketoamyltrimethylammonium (4K), a cholinomimetic agonist. Dimethyl sulfoxide (DMSO) (10 microliter/ml, 140 mM) strongly potentiated the effect of ACh but did not alter the effect of 4K. DMSO (10 microliter/ml, 140 mM) strongly potentiated the effect of ACh but did not alter the effect of 4K. DMSO (10 microliter/ml, 140 mM final concentration) alone had no significant effect upon heart rate when added to the perfusate in incremental additions of 1 microliter X (ml perfusate)-1 X min-1 over a 10-min period. The specific activity of atrial homogenate cholinesterase was 48.8 +/- 3.46 nmoles X min-1 X (mg protein)-1 (mean +/- S.E.M.), 38.2 +/- 1.60 for butyrylcholinesterase, and 11.2 +/- 0.86 for acetylcholinesterase (AChE). True AChE activity (measured in the presence of a maximally effective concentration of tetraisopropylpyrophosphoramide) had a Vmax of 13.4 +/- 0.17 nmoles X min-1 X mg protein)-1 and an apparent Km value of 1 X 10(-4)M acetylthiocholine. At this Km substrate concentration, DMSO inhibited atrial AChE activity (I50 = 9 microliter/ml). At the concentration tested, DMSO inhibited atrial AChE and potentiated ACh effects.