ABSTRACT
In this study, we assessed the effects of chronic prenatal ethanol exposure (CPEE) on spatial navigation in the water maze, conditioned responding using food-reinforced lever pressing, and amino acid neurotransmitter release from the hippocampus of the adult guinea pig. Pregnant guinea pigs were treated with ethanol (3 g/kg of maternal body weight/day), isocaloric-sucrose/pair-feeding, or water throughout gestation. Adult offspring were trained in two-lever operant chambers to respond for sucrose pellets, with one lever designated as the reward lever. There were no group differences in response acquisition or lever discrimination on a fixed-ratio 1 (FR-1) schedule. During extinction sessions, CPEE offspring maintained higher levels of responding on the previously reinforced lever, suggesting that CPEE increases perseveration and/or impairs response inhibition but does not affect operant responding for an appetitive reinforcer or the ability to discriminate rewarding from nonrewarding stimuli. In contrast, there was no effect of CPEE on performance in the water maze in the maternal ethanol regimen used in this study. CPEE did not alter electrically evoked glutamate or GABA release from hippocampal brain slices. However, when slices were tested after delivery of a tetanizing stimulation (five 5-s trains at 100 Hz), post-tetanic potentiation of electrically stimulated GABA release was greater in hippocampal slices obtained from CPEE offspring, whereas post-tetanic potentiation of electrically stimulated glutamate release was unaffected. These data suggest that conditioned learning is a sensitive behavioral measure of CPEE-induced brain injury. Increased activity-dependent potentiation of GABA release in the hippocampus may contribute to alterations in synaptic plasticity observed in CPEE offspring.
Subject(s)
Ethanol/pharmacology , Hippocampus/drug effects , Maze Learning/drug effects , Prenatal Exposure Delayed Effects , gamma-Aminobutyric Acid/metabolism , Animals , Biological Transport , Central Nervous System Depressants/pharmacology , Conditioning, Psychological/drug effects , Female , Guinea Pigs , Hippocampus/metabolism , Neurotransmitter Agents/metabolism , Pregnancy , Pregnancy OutcomeABSTRACT
Filiform squamous papillomas occur rarely on young sheep and correspond closely to those on cattle and other species; they lack the fibromatous component of papillomas reported previously. This paper describes microscopical, immunological and molecular evidence for the presence of a putative ovine papillomavirus in these lesions.
Subject(s)
Papilloma/veterinary , Papillomaviridae/isolation & purification , Sheep Diseases/pathology , Skin Neoplasms/veterinary , Tumor Virus Infections/veterinary , Animals , Female , Immunohistochemistry , Male , Microscopy, Electron , Papilloma/pathology , Papilloma/ultrastructure , Sheep , Skin Neoplasms/pathology , Skin Neoplasms/ultrastructure , Tumor Virus Infections/pathologyABSTRACT
Buthionine sulfoximine inhibits gamma-glutamylcysteine synthetase, the enzyme catalyzing the first reaction of glutathione (GSH) biosynthesis. GSH synthesis is blocked in animals or cultured cells exposed to buthionine sulfoximine, and GSH is substantially depleted in cells or tissues with moderate to high rates of GSH utilization. Studies reported to date have used DL-buthionine (SR)-sulfoximine or L-buthionine (SR)-sulfoximine, mixtures of four and two isomers, respectively. The present report describes a chiral solvent HPLC procedure for the analytical separation of the diastereomers of L-buthionine (SR)-sulfoximine and the separation of those isomers from the unresolved diastereomers of D-buthionine (SR)-sulfoximine. L-buthionine (R)-sulfoximine was isolated preparatively by repeated crystallization of L-buthionine (SR)-sulfoximine from water; L-buthionine (S)-sulfoximine was obtained by crystallization as the trifluoroacetate salt in ethanol/hexane mixtures. The absolute configuration, bond lengths and angles of L-buthionine (R)-sulfoximine were determined by X-ray diffraction. In vitro studies demonstrate that L-buthionine (R)-sulfoximine is a relatively weak inhibitor of rat kidney gamma-glutamylcysteine synthetase; binding is competitive with L-glutamate. L-buthionine (S)-sulfoximine is a tight-binding, mechanism-based inhibitor of the enzyme. Since L-buthionine sulfoximine is initially bound as a transition-state analogue, identification of the inhibitory diastereomer elucidates the steric relationships among ATP, glutamate, and cysteine within the active site. When administered to mice, L-buthionine (S)-sulfoximine (0.2 mmol/kg) was as effective as L-buthionine (SR)-sulfoximine (0.4 mmol/kg) in causing GSH depletion in liver, kidney, and pancreas. L-Buthionine (R)-sulfoximine (0.2 mmol/kg) did not cause significant GSH depletion in liver or pancreas. The L-(R)-diastereomer caused a modest GSH depletion in kidney that is tentatively attributed to interference with gamma-glutamylcyst(e)ine transport.
Subject(s)
Glutathione/biosynthesis , Methionine Sulfoximine/analogs & derivatives , Animals , Buthionine Sulfoximine , Chromatography, High Pressure Liquid , Glutamate-Cysteine Ligase/antagonists & inhibitors , Methionine Sulfoximine/chemistry , Methionine Sulfoximine/isolation & purification , Methionine Sulfoximine/pharmacology , Mice , Organ Specificity , Stereoisomerism , X-Ray DiffractionABSTRACT
Hypercalcemia is a common paraneoplastic syndrome complicating some varieties of lung cancer. It has rarely been reported with small-cell carcinoma of the lung. Seven cases of hypercalcemia complicating small-cell carcinoma of the lung are described; clinical features indicate that significant bone or bone marrow involvement is present in all cases. Parathormone assays were found to be generally in the normal range, though inappropriate for the levels of hypercalcemia.