Myeloma complicated by alpha 1-antitrypsin deficiency.
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Biomedical subjects
Publications and source records attributed to J B Day.
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Radiolabeled verruculogen was detected in a wide range of body tissues 6 min after intravenous administration, but after a further 20 min it was mainly being excreted via the biliary route. In isolated liver perfusion, [14C]verruculogen was rapidly taken up by the liver and metabolized completely, principally to the related tremorgen TR-2 but also to a desoxy derivative of verruculogen. In addition, a smaller amount of an isomer of TR-2 was detected. These metabolic products were excreted in the bile.
In surface culture of Penicillium simplicissimum, verruculogen was shown to be biosynthesized from the intact carbon skeletons of tryptophan and proline, isoprenoid derivatives of mevalonic acid, and a methyl group donated by methionine. Selected radiolabeled precursors (1 mCi) pulse-fed at the optimum stage of fermentation yielded verruculogen (specific activity, 5.89 X 10(2) microCi mmol-1) labeled in the prolyl and isoprenyl regions of the molecule and suitable for metabolic studies.
The moulds Penicillium simplicissimum and P crustosum and the tremorgenic mycotoxins, verruculogen and penitrem A, isolated from them, were given to sheep and pigs to compare their potencies. Pigs were generally less susceptible and in both species penitrem A was less potent than verruculogen. Five-month-old lambs seemed more susceptible to mycelium containing verruculogen than were 15-month-old sheep given a similar oral dose relative to bodyweight. Repeated daily dosing of lambs and sheep for five days with P simplicissimum failed to enhance the effect, indicating that verruculogen toxicity was not cumulative. Long and short acting barbiturate anaesthesia blocked the effects of lethal doses of tremorgens. Sedation with diazepam diminished, but did not block, mycotoxin-induced tremors suggesting that there was no specific action of this anticonvulsant sedative on tremorgens.
Two new indolic metabolites were isolated from Penicillium crustosum and separated from other penitrem mycotoxins by high-performance liquid chromatography. Penitrem D is a deoxy-penitrem A. Penitrem E is dechloro-penitrem A and was shown to be tremorgenic in mice, although it has only one-third of the activity of penitrem A. Roquefortine was also shown, for the first time, to be an important metabolic product of P. crustosum.
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A spectrofluorometric assay for the estimation of the tremorgenic mycotoxin verruculogen in crude mycelial extract has been devised and used to determine concentrations as low as 0.2 microgram ml-1. Verruculogen production by Penicillium estinogenum has been extended from surface culture to submerged culture in 60 1 stirred fermenters, in which the maximum cell-associated mycotoxin yield [5 mg (100 ml culture)-1] was obtained within 7 d. It was found necessary to supplement the medium (Czapek Dox broth plus 0.5% yeast extract) with calcium chloride (2%) to induce profuse sporulation (2 X 10(7) conidia ml-1).
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