Biomedical subjects
Publications and source records attributed to M Warner.
A general review of the treatment of autoimmune diseases classified as pemphigus is presented and includes pemphigus vulgaris, pemphigus vegetans, pemphigus foliaceous, pemphigus erythematosus, druginduced pemphigus, IgA pemphigus, and paraneoplastic pemphigus. The nurse plays an essential role in educating patients and their families about local skin and oral care related to these diseases.
It is still an open question as to whether, upon administration of procarcinogens to rodents, development of cancers in extrahepatic tissues is due to activation of these chemicals in the liver or to in situ activation within the tissue. The low level of P450 in many tissues means that it is very difficult to demonstrate the formation of significant amounts of reactive metabolites when these tissues are incubated with procarcinogens in vitro. It is our contention that the importance of tissue-specific activation of procarcinogens can best be decided when the cells which harbour P450 have been identified and the isozyme profile in the cells defined. With this aim in view, we have begun to characterize the forms of P450 in the breast and brain. Perhaps not surprisingly, the P450s in the breast are regulated as a function of age and hormonal status of rats and most of the breast P450 can be accounted for by hepatic forms. The P450 content of the brain, on the other hand, is very responsive to environmental factors. The quantity of P450 as well as the isozyme profile is altered by drugs and chemicals in the environment. The P450s induced in the brain are similar to liver P450s, but the constitutive forms are not. P450s of the 1A family are inducible in both tissues and this indicates that heterocyclic amines can be activated in the brain and polycyclic aromatic hydrocarbons in the breast. The cells in which this activation can occur remain to be identified.
Idiopathic thrombocytopenic purpura (ITP) is a disorder characterized by increased platelet destruction in the setting of normal megakaryopoiesis. Approximately 20% of patients with ITP are refractory to corticosteroids and splenectomy. Recently, pulse high-dose dexamethasone was reported to be effective in the treatment of chronic ITP in adult patients. We treated 9 patients with severe chronic ITP with monthly high-dose dexamethasone. None of the 9 patients responded with a sustained increase in platelet count. Five of these patients were unable to tolerate the regimen. The failure of high-dose dexamethasone in our hands contrasts with the good results of an earlier publication and suggests that there could be a subset of responders who will require better identification.
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OBJECTIVE: To assess the prevalence of antibiotic resistance and serotype distribution among pneumococci in England and Wales in 1990 and 1995. DESIGN: Observational surveys in March 1990 and March 1995. During two weeks in each survey period all pneumococci isolated in public health laboratories in England and Wales were collected and assessed for sensitivity to antibiotics and the distribution of serogroups or serotypes. SETTING: The network of public health laboratories throughout England and Wales. SUBJECTS: 1127 individual patient isolates of Streptococcus pneumoniae obtained during the two surveys. MAIN OUTCOME MEASURES: Sensitivity or resistance to a range of antibiotics; serogroup or serotype. RESULTS: The prevalence of intermediate or full resistance to penicillin increased from 1.5% in 1990 to 3.9% in 1995 and resistance to erythromycin increased from 2.8% to 8.6%. About 92% of isolates belonged to serogroups or serotypes included in the currently available pneumococcal vaccine. CONCLUSION: Resistance to penicillin and erythromycin has increased among pneumococci in England and Wales. Continued surveillance to assess further increases in the prevalence of pneumococcal resistance to antibiotics is essential.
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Twenty-four hr after a single dose of the neuroleptic drug clozapine, cytochrome P4502D4 (P4502D4) immunoreactivity, which was barely detectable in the brains of untreated rats, was clearly evident in neurons of the substantia nigra pars compacta, ventral tegmental area, granular neurons of the olfactory bulb, and Purkinje and granular neurons of the cerebellum. Induction was maintained with daily administration for 3 weeks. The mRNA for P4502D4 was detected by Northern blotting and localized by in situ hybridization in neurons throughout the brain and in the Bergman glia in the cerebellum. There were no detectable changes in the distribution or quantity of P4502D4 mRNA after treatment with clozapine. The overall P450 content of the brain increased with daily administration to a approximately 7-fold induction by 3 weeks of clozapine treatment. No induction of 2D4 was observed with the dopamine D2 receptor blockers haloperidol, chlorpromazine, and sulpiride or with the serotonin receptor blocker mianserin. A clozapine-like induction of P4502D4 was obtained on administration of toluene to rats. The specificity of the induction of P4502D4 in the brain with respect to both the drugs that induce it and the cells in which it is induced suggests that induction of this enzyme could be involved in the therapeutic action of clozapine. The similarity of induction of P4502D4 elicited by clozapine and by the neurotoxin toluene suggests that more information is needed before a beneficial or toxicological role can be assigned to this isozyme.
The effectiveness of steroid hormone metabolites as sedatives and anesthetics has been known for many years. More recently, their interaction with neurotransmitter receptors has helped to elucidate their mechanism of action, but their physiological functions and their role in disturbances of behavior, anxiety, and sleep/wakefulness have yet to be elucidated. Until 1981 it was assumed that metabolites of steroid hormones arose from the adrenals and gonads and that their action on neurotransmitter receptors was a mechanism of communication between the brain and the periphery. The evidence that the brain could accumulate steroids independently of the adrenals and gonads in 1981 and later the evidence for the presence of the cholesterol side chain cleavage enzyme (P450scc) in the brain have challenged this concept and stimulated a great deal of interest in the possibility that the brain could be making its own steroids from cholesterol for some as yet undefined purpose. In this review we examine the data pertaining to the role of brain P450 in the synthesis and degradation of neurosteroids. We summarize the data on the presence of P450scc in the brain and try to answer the following questions: (1) Does P450scc in the brain contribute significantly to the synthesis of GABAA receptor active steroids? (2) Can the P450scc in the brain account for the accumulation of pregnenolone in the brain? (3) Is there evidence for special functions of the pregnenolone synthesized in the brain? (4) Is there a role for other forms of brain P450 in neurosteroid action?
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Cytochrome P450 was partially purified from rat breast tissue from 1-, 2-, 3-, 6-, 9-, and 15-week-old pregnant, lactating, or 3-week postlactation rats. The detergent-solubilized P450 was spectrally quantified, and the P450 isozyme pattern in the different samples was characterized by Western blot analysis with antibodies against cytochromes P450 1A1, 1A2, 2A, 2B, 2D4, 3A, 4A, 2E, and 19. The yield of P450 was 5-60 pmol/g wet weight tissue, with the highest yields in 1- and 2-week-old pups and lactating rats. The cytochromes P450 expressed in the breast can be divided into six main groups on the basis of their pattern of regulation: (a) those present in all samples (4A, 2E1, and 2D4), (b) those highly expressed in 1- to 3-week-old rats (2D4 and 3A), (c) those expressed only after 9 weeks of age [P450 19 (aromatase)], (d) those induced in pregnancy and maintained during lactation (1A1), (e) those induced in pregnancy and not maintained during lactation (2A), and (f) those induced 3 weeks after lactation (2B, 2A, and 3A). Reverse transcription-polymerase reaction amplification was used to confirm the presence of P450 isoforms in the breast. The mRNAs of cytochromes P450 1A1, 2A1, 2B1-3, 2D1, 2D3, 2D4, 2E1, and 4A3 were detected on analysis of total breast RNA. The mRNA of CYP 3A1 was not convincingly detected in untreated rat breast but was inducible by treatment with pregnenolone-16-alpha-carbonitrile. The presence of these various forms of P450 in the breast and their regulation by age and endocrine status may have implications for in situ metabolism of steroids and steroid antagonists and for activation of procarcinogens.
The possible relationship between cytochrome P450 (P450) in brain and degenerative diseases of the central nervous system prompted an investigation into the members of the 2D subfamily in rat brain. The mRNA for P450 2D4 was much more abundant than those for 2D1 and 2D5, which are major hepatic forms. 2D2 and 2D3 mRNAs, which are also abundant forms in liver, were not detectable in brain. To evaluate the quantitative significance of 2D4 protein in brain, specific antibodies were raised. The full length 2D4 cDNA was cloned from brain mRNA by reverse transcription-polymerase chain reaction amplification and was translated, in a reticulocyte lysate system, into a protein of approximately 50 kDa. A [35S]methionine-labeled protein of 50 kDa could be immunoprecipitated from in vitro translated 2D4 mRNA. In Western blots, no signals were obtained with brain microsomes. However, with P450 extracted from brain a band of 50 kDa could be detected when 60 pmol or more were loaded in each lane. There was no detectable developmental regulation of the 2D4 mRNA and no change during pregnancy, during lactation, or after treatment with ethanol, conditions under which the P450 content of brain increases. In Dark Agouti rats, which do not express P450 2D1 mRNA in liver, 2D4 mRNA in brain was as abundant as in Wistar rats. We conclude that 2D4 is expressed as a stable protein in the brains of untreated rats, where it represents < 5% of the total P450.
Analysis of crashes of air taxi and commuter flights explored the controversial issue of "accident proneness." There were 20 pilots who had 2 or more crashes during 1983-88. These pilots (repeaters) and their 42 crashes were compared with 534 pilots who were each involved in a single air taxi or commuter crash during the same period (nonrepeaters). Unexpectedly, repeaters were more experienced pilots with a mean total flight time of 7016 h vs. 5321 for nonrepeaters. Repeaters did not differ from nonrepeaters in the overall proportion of crashes in which pilot performance appeared to be a major factor. Repeaters differed significantly from nonrepeaters as to flight hours during the past 90 d (mean 215 vs. 183 h) and the proportion of their crashes that occurred in Alaska (48% vs. 24%). Alaska repeaters differed from non-Alaska repeaters with regard to the proportion of crashes on takeoff (40% vs 14%) and airport conditions as a factor (50% vs. 18%). The high proportion of repeaters involved in crashes in Alaska, where environmental conditions make flying more hazardous, and the substantially greater recent flight time suggest that the intensity and amount of occupational exposure are major determinants of pilot involvement in more than one crash.
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After a single dose of ethanol (0.8 ml/kg) administered intraperitoneally, the P450 content of the rat brain increased from 62 +/- 19 to 230 +/- 97 pmol/g (wet weight) of tissue (mean +/- SD, n = 5). Most of this increase could be accounted for by a 10- to 20-fold increase in the olfactory lobes and hypothalamic preoptic area. The P450s were identified by Western blot analysis and by microsequencing of the N-terminal ends after resolution of the proteins on SDS gels. They were identified as P450 2C7, 2C11, 2E1, 4A3, 4A8, and a member of the P450 2D family. In P450 extracted from the brains of control rats, P450 2C and 4A were also detectable but at a much lower concentration. P450 1A1, 2A1, 2B1, or 3A was not detected in the brains of either control or ethanol-treated rats. Oral administration of the same dose of ethanol resulted in a similar increase in the whole brain but smaller effects in the olfactory lobes. This effect of ethanol on the P450 in the brain has implications for the mechanism of toxicity and the development of tolerance to ethanol and for the effects of other drugs and environmental pollutants that act on the central nervous system.
Members of the P450 4A subfamily are key enzymes in the synthesis and degradation of metabolites of arachidonic acid, which are of physiological importance in the brain. In the rat, four members of this subfamily, 4A1, 4A2, 4A3, and 4A8, have been described. In this study, the expression of members of the 4A subfamily in the rat brain has been examined by PCR amplification, by western and northern blotting, and by protein N-terminal sequencing. With PCR all four members of the subfamily were detectable in the liver and kidney. P450 4A1 was found exclusively in the liver and kidney, whereas P450 4A2 was detectable in all the tissues tested, including the lung, seminal vesicles, prostate, cerebral cortex, hypothalamic preoptic area, cerebellum, and brainstem. The tissue distribution of P450 4A3 was similar to that of 4A2 except that it was not detectable in seminal vesicles. A P450 4A8-specific fragment was amplified from the kidney, liver, and prostate and weakly from the cerebral cortex but not from other brain regions. Despite the evidence of their presence by PCR, no members of the 4A family were detectable on northern blots with mRNA from the brain. On western blots a P450 4A-specific antiserum recognized a band in P450 fractions prepared from the brain. The intensity of the signal with 30 pmol of P450 from the brain was similar to that with 10 pmol of liver microsomal P450. The brain P450 was extracted from 1 g of brain, whereas the 10 pmol of liver P450 is the equivalent of 1 mg of liver.(ABSTRACT TRUNCATED AT 250 WORDS)
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