Teaching cases from the Royal Marsden and St Mary's Hospitals case 19: pancytopenia following Hodgkin's disease.
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Biomedical subjects
Publications and source records attributed to C Coulter.
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Arginine metabolism plays an important role in many aspects of inflammation and wound healing. In this study, we tested the hypothesis that steroids and vitamin A have differential effects on arginine metabolism and thereby may provide a mechanism by which steroids impair wound healing, and vitamin A improves this impairment. Rats were treated with subcutaneous corticosterone pellets 2 days prior to wounding. Intraperitoneal injections of all-trans retinoic acid in peanut oil were administered at the same time and repeated 2 and 4 days later. Polyvinyl alcohol sponges were implanted subcutaneously through a dorsal incision. On Postwounding Days 1, 5, 10, and 15, wound fluid was recovered from the sponges and assayed for nitrite/nitrate (NOx), citrulline, arginine, and ornithine concentrations as well as arginase activity. Steroid treatment decreased the metabolism of arginine to nitric oxide in the early phase of wound healing, and retinoic acid did not change this relationship. Corticosterone also decreased metabolism of arginine to ornithine in the later wound. This depression was inhibited by concomitant administration of retinoic acid. Considering the importance of nitric oxide in host defense and ornithine as a precursor for polyamine and proline synthesis, these data provide a mechanism by which vitamin A improves wound strength, but does not improve wound infection rates in steroid-treated animals.
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O methylation of acetovanillone at 4 position by C2H3Cl and S-adenosyl[methyl-2H3]methionine was monitored in whole mycelia of Phanerochaete chrysosporium in the presence and absence of S-adenosylhomocysteine. Both the amount of the methylation product, 3,4-dimethoxyacetophenone, and the percent C2H3 incorporation into the 4-methoxyl group of the compound were determined. The results strongly suggest the presence of biochemically distinct systems for O methylation of acetovanillone utilizing S-adenosylmethionine and chloromethane, respectively, as the methyl donor. The S-adenosylmethionine-dependent enzyme is induced early in the growth cycle, with activity attaining an initial maximum after 55 h of incubation. Methylation by this enzyme is totally suppressed by 1 mM S-adenosylhomocysteine over almost the entire growth cycle. S-Adenosylmethionine-dependent O-methyltransferase activity is detectable in cell extracts, and the purification and characterization of the enzyme are described elsewhere (C. Coulter, J. T. Kennedy, W. C. McRoberts, and D. B. Harper, Appl. Environ. Microbiol. 59:706-711, 1993). The chloromethane-utilizing methylation system is absent in early growth but attains peak activity in the mid-growth phase after 72 h of incubation. The system is not significantly inhibited by S-adenosylhomocysteine at any stage of growth. No chloromethane-dependent O-methyltransferase activity is detectable in cell extract, suggesting that the enzyme is membrane bound and/or part of a multienzyme complex. Although the biochemical role of the chloromethane-dependent methylation system in metabolism is not known, one possible function could be the regeneration of veratryl alcohol degraded by the attack of lignin peroxidase.
Congenital malformations may present as meningitis caused by enteric organisms, but this is extremely rare and occurs almost exclusively in the paediatric population. We report an unusual case of a young man with chronic constipation presenting with spontaneous Gram-negative meningitis due to an underlying congenital spinal malformation known as the caudal regression syndrome.
OBJECTIVE: To report the successful treatment of Strongyloides stercoralis hyperinfection, which is usually lethal but in this case was diagnosed in its early stages. CLINICAL FEATURES: A 44-year-old woman, who had spent much of her life in Fiji and India, was treated with a high dose of prednisolone for rheumatoid arthritis complicated by gold lung. The onset of abdominal symptoms, an exacerbation of respiratory symptoms, and a persistent high eosinophil count and serum IgE level, led to the detection of numerous Strongyloides larvae in her faeces and sputum. INTERVENTION AND OUTCOME: She was treated with thiabendazole for five days, then mebendazole for one month, and the dose of prednisolone was reduced. Clinical symptoms and signs improved within days and after one week parasites could not be found in her faeces. After six months, enzyme-linked immunosorbent assay for Strongyloides infection gave a reading which was 40% of the initial level but still in the positive range. CONCLUSION: Steroid therapy in individuals with chronic, subclinical strongyloidiasis predisposes to the insidious development of hyperinfection syndrome, which has a high mortality rate. If detected early, this complication can be treated effectively. It can be prevented by actively seeking Strongyloides infection, by faecal microscopy and culture techniques and by serological tests, in high-risk individuals, such as immigrants from endemic areas.
A phase 1-2 trial of 90Y-labelled monoclonal antibody, HMFG1 administered intraperitoneally to 30 patients with ovarian carcinoma is presented. The problems encountered with myelotoxicity are described, and the steps which have so far been taken to overcome this and to increase the dose of 90Y to an estimated tumouricidal level. Bone deposition of free 90Y limits the dose which can be administered without severe bone marrow toxicity. The intravenous use of a chelating agent, Ledclair (EDTA) has allowed the dose to be increased from 18 to 30 mCi without causing severe myelotoxicity. 90Y-DTPA MAb is an unstable immunoconjugate in vivo and in vitro. The use of a more stable linkage such as a macrocycle should enable the administered dose to be increased without increasing the amount of free 90Y which becomes available to be deposited in bone. This would be expected to reduce toxicity and increase therapeutic efficacy.
Each B-cell lymphoma expresses a surface immunoglobulin that contains unique antigenic determinants (idiotypes). We have produced 199 murine monoclonal antibodies reactive with the idiotypes isolated from 67 patients with follicular small-cleaved-cell lymphoma. These antiidiotype antibodies were analyzed for their ability to react with lymphoma cells from patients other than the one against which each antibody was made. Twenty of the 199 antiidiotype antibodies were reactive with lymphoma cells from more than one patient. Depending on the antibody, the frequency of idiotype sharing ranged from 0.6 to 6.2 percent of B-cell lymphoma tumors evaluated. Tumors could be grouped into distinct families on the basis of their reactivity with these antibodies. In the aggregate, the 20 antibodies reacted with a total of 49 of 150 B-cell lymphomas (33 percent), including 30 of 110 follicular small-cleaved-cell lymphomas (27 percent). Many of these shared idiotypes were expressed by more than one histopathological subtype of lymphoma. We conclude that a panel of antibodies reactive with shared idiotypes can be produced for patients with B-cell lymphoma, obviating the need to produce an antiidiotype antibody for each patient.
In an attempt to correlate the ability to activate transcription with affinity for single-stranded DNA, both wild-type and temperature-sensitive pseudorabies virus immediate-early proteins were tested for the ability to bind to single-stranded DNA columns. Wild-type and temperature-sensitive immediate-early proteins bound to nonspecific single-stranded DNA columns with similar affinities at both 0 and 40 degrees C. There did not seem to be a direct correlation between the ability to activate transcription and the ability to bind to single-stranded DNA. To study further the interactions that are involved in binding to single-stranded DNA, we expressed the immediate-early protein in an Escherichia coli expression vector. In this system the expressed immediate-early protein was not phosphorylated, nor could it be complexed with mammalian cell factors. The first trp construct did not express a soluble form of the immediate-early protein, presumably due to the insoluble nature of the trp leader. We deleted a large segment of the trpE gene and found that the immediate-early fusion protein was soluble. We tested this protein for its affinity for single-stranded DNA by passage over single-stranded DNA cellulose columns. The bacterially expressed immediate-early protein bound single-stranded DNA at least as well as did the wild-type protein. Affinity for single-stranded DNA did not appear to be dependent on the phosphorylation state nor on the presence of mammalian cell factors.
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Local tissue concentrations of glucocorticoids are modulated by the enzyme 11beta-hydroxysteroid dehydrogenase which interconverts cortisol and the inactive glucocorticoid cortisone in man, and corticosterone and 11-dehydrocorticosterone in rodents. The type I isoform (11beta-HSD1) is a bidirectional enzyme but acts predominantly as a oxidoreductase to form the active glucocorticoids cortisol or corticosterone, while the type II enzyme (11beta-HSD2) acts unidirectionally producing inactive 11-keto metabolites. There are no known clinical conditions associated with 11beta-HSD1 deficiency, but gene deletion experiments in the mouse indicate that this enzyme is important both for the maintenance of normal serum glucocorticoid levels, and in the activation of key hepatic gluconeogenic enzymes. Other important sites of action include omental fat, the ovary, brain and vasculature. Congenital defects in the 11beta-HSD2 enzyme have been shown to account for the syndrome of apparent mineralocorticoid excess (AME), a low renin severe form of hypertension resulting from the overstimulation of the non-selective mineralocorticoid receptor by cortisol in the distal tubule of the kidney. Inactivation of the 11beta-HSD2 gene in mice results in a phenotype with similar features to AME. In addition, these mice show high neonatal mortality associated with marked colonic distention, and remarkable hypertrophy and hyperplasia of the distal tubule epithelia. 11Beta-HSD2 also plays an important role in decreasing the exposure of the fetus to the high levels of maternal glucocorticoids. Recent work suggests a role for 11beta-HSD2 in non-mineralocorticoid target tissues where it would modulate glucocorticoid access to the glucocorticoid receptor, in invasive breast cancer and as a mechanism providing ligand for the putative 11-dehydrocorticosterone receptor. While previous homologies between members of the SCAD superfamily have been of the order of 20-30% phylogenetic analysis of a new branch of retinol dehydrogenases indicates identities of > 60% and overlapping substrate specificities. The availability of crystal structures of family members has allowed the mapping of conserved 11beta-HSD domains A-D to a cleft in the protein structure (cofactor binding domain), two parallel beta-sheets, and an alpha-helix (active site), respectively.
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