Selective delivery of chemotherapeutic agents with a new catheter system

A new catheter system was used in ten patients (16 infusions) for infusion of chemotherapeutic agents to the sites of malignant gliomas. Thirteen infusions to the supraophthalmic region were successful, as were three infusions to the posterior cerebral region. There were no complications after the infusions. A neurologic complication occurred in one patient in whom two successful supraophthalmic infusions were previously carried out. In this patient the guide wire separated during catheter placement into the posterior cerebral artery.     

Actions of buspirone in a putative model of anxiety in the mouse

In a two-compartment box divided into a dark area and a brightly illuminated white area, mice taken from a dark environment showed aversion to the light and exhibited preference for exploratory rearings and line crossings in the black area. The peripheral administration of buspirone, and its injection into the dorsal raphe nucleus, lead to an increased time spent in the white area associated with enhanced exploratory behaviour with a decreased incidence of rearings and line crossings in the black section. In contrast, the injection of 5-hydroxytryptamine and 2-methyl-5-hydroxytryptamine into the dorsal raphe nucleus increased exploratory behaviour in the black section with decreased activity in the white area: the effects of 2-methyl-5-hydroxytryptamine were antagonized by buspirone administered peripherally. Ritanserin, methysergide, metergoline and cyproheptadine failed, in non-sedative doses, to influence exploratory behaviour in the two-compartment system and ritanserin and methysergide also failed to antagonize the effects caused by 2-methyl-5-hydroxytryptamine. It is concluded that in the mouse model the ability of buspirone to reduce the aversive response to a brightly illuminated area may reflect an anxiolytic action, that the dorsal raphe nucleus may be an important locus of action, and that the effects of buspirone may reflect an interaction at 5-hydroxytryptamine receptors.     

The effects of ondansetron, a 5-HT3 receptor antagonist, on cognition in rodents and primates

The selective 5-HT3 receptor antagonist, onansetron, has been assessed in three tests of cognition in the mouse, rat and marmoset. In a habituation test in the mouse, ondansetron facilitated performance in young adult and aged animals, and inhibited an impairment in habituation induced by scopolamine, electrolesions or ibotenic acid lesions of the nucleus basalis magnocellularis. Arecoline failed to improve basal performance in young adult mice but inhibited the impairment caused by scopolamine and lesions of the nucleus basalis magnocellularis. In the T-maze reinforced alternation task in rats, ondansetron and arecoline antagonised a scopolamine-induced impairment. In an object discrimination and reversal learning task in the marmoset, assessed using a Wisconsin General Test Apparatus, ondansetron improved performance in a reversal learning task. We conclude that ondansetron potently improves basal performance in rodent and primate tests of cognition and inhibits the impairments in performance caused by cholinergic deficits.     

Piecemeal degranulation of mast cells in the inflammatory eyelid lesions of interleukin-4 transgenic mice. Evidence of mast cell histamine release in vivo by diamine oxidase-gold enzyme-affinity ultrastructural cytochemistry

We used light and electron microscopy to analyze the eyelid inflammation that develops in transgenic mice that overexpress interleukin-4 (IL-4; Tepper et al, Cell 62:457, 1990). Analysis of alkaline Giemsa-stained plastic sections examined by light microscopy (Dvorak et al, J Exp Med 132:558, 1970), as well as by routine transmission electron microscopy, indicated that the mast cells in the inflammatory eyelid lesions were undergoing piecemeal degranulation, a form of secretion in which the cells' cytoplasmic granules exhibit characteristic morphologic changes that are thought to be associated with the prolonged, vesicle-mediated release of the granules' constituents. Moreover, by using a newly reported enzyme affinity-gold method, which stains histamine based on binding to diamine oxidase-gold (Dvorak et al, J Histochem Cytochem 41:787, 1993), we show that these activated mast cells had released much of their histamine content. The eyelid lesions also exhibited increased numbers of mast cells; interstitial fibrosis, particularly around cutaneous nerves and blood vessels; activated fibroblasts; focal axonal damage; venules with endothelial cells containing numerous vesiculo-vacuolar organelles; and infiltrates of neutrophils and eosinophils. Our findings illustrate that overexpression of the IL-4 gene in vivo can result in eyelid lesions associated with piecemeal degranulation of mast cells, as well as tissue fibrosis and a variety of other pathologic changes. These results also represent the first direct morphologic evidence for histamine secretion by mast cells in vivo.     

Activation of the CPP32 protease in apoptosis induced by 1-beta-D- arabinofuranosylcytosine and other DNA-damaging agents

The response of human myeloid leukemia cells to treatment with 1-beta- arabinofuranosylcytosine (ara-C) includes the induction of apoptosis. Ara-C induced apoptosis is associated with proteolytic cleavage of poly(ADP-ribose) polymerase (PARP) and protein kinase C (PKC) delta. However, the signals involved in this response are unknown. The present studies show that ara-C treatment of U-937 cells is associated with induction of a protease activity that cleaves the tetrapeptides Ac-DEVD- pNA and Ac-DMOD-pNA found at the cleavage sites of PARP and PKC delta, respectively. The ara-C-induced protease activity was sensitive to overexpression of the anti-apoptotic protein Bcl-xL and the baculovirus protein p35. By contrast, overexpression of the cowpox virus protein CrmA blocked apoptosis induced by engagement of the Fas receptor but not that induced by ara-C. CrmA overexpression also had no detectable effect on ara-C-induced cleavage of PKC delta. The results further show that ara-C induces activation of the CPP32 protease by a CrmA- insensitive and p35-sensitive mechanism. Similar results were obtained with cisplatinum, etoposide, and camptothecin. These findings indicate that ara-C and other DNA-damaging agents activate a CrmA-insensitive apoptotic pathway involving CPP32 and that these signals differ from those associated with apoptosis induced by the Fas receptor.