Toxic shock syndrome and enterotoxin C.
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Bacterial Toxins↗
Biomedical subjects
R M Brown
Publications and source records attributed to R M Brown.
A testis-specific form of the human pyruvate dehydrogenase E1 alpha subunit is coded for by an intronless gene on chromosome 4.
The pyruvate dehydrogenase (PDH) complex converts pyruvate to acetyl CoA, an essential step in aerobic glucose metabolism. We have previously shown that the gene for the E1 alpha subunit of this complex, expressed in somatic tissues, is located on band p22.1 of the human X chromosome. This gene, PDHA1, contains 10 introns and spans approximately 17 kb. An autosomal locus, PDHA2, showing significant cross-hybridization with a PDH E1 alpha cDNA probe, was detected on chromosome 4, in the region q22-q23. We here report the isolation of human testis-specific PDH E1 alpha cDNA clones. The similarity with the X chromosome-linked cDNA coding sequence at the nucleotide level is 84%. Specific amplification using the polymerase chain reaction confirmed the presence of a testis-specific mRNA and indicated that postmeiotic spermatogenic cells express this subunit. In situ hybridization with a unique probe from the 3' untranslated region of the testis-specific cDNA showed that the gene for this form of PDH E1 alpha is localized on chromosome 4 in the region q22-q23. The autosomal human gene was isolated from a chromosome 4-specific genomic library. The transcribed region of this gene is identical to the testis-specific cDNA sequence. It completely lacks introns and possesses characteristics of a functional processed gene.
Amino Acid Sequence↗
Differential methylation of the hypervariable locus DXS255 on active and inactive X chromosomes correlates with the expression of a human X-linked gene.
Consistent differences in methylation of particular cytosine residues in the DNA of active and inactive X chromosomes can be used for rapid, direct analysis of X-inactivation patterns in different female tissues. We have studied methylation of the highly polymorphic DXS255 locus in tissues from patients with deficiency of the E1 alpha subunit of the pyruvate dehydrogenase complex in whom the results can be correlated directly with total enzyme activity, levels of immunoreactive protein, and patterns of cell mosaicism. The results confirm that methylation of the DXS255 locus correlates with X-chromosome expression. In patients and normal controls, the pattern of X inactivation varied widely from tissue to tissue and often deviated markedly from a 50:50 proportion. These deviations are likely to reflect small numbers of tissue-specific stem cells at the time of random X inactivation and cannot be taken alone as evidence for selection or "nonrandom" inactivation.
Dosage Compensation, Genetic↗
Oxidation and dispersion of HT in the environment: the August 1986 field experiment at Chalk River.
The short-range environmental dispersion and oxidation of a release of tritiated hydrogen (HT) to the atmosphere has been studied in a field experiment. Emphasis was placed on the processes leading to the appearance of tritiated water (HTO) vapor in the atmosphere because HTO is much more radiotoxic than HT. The following conclusions were reached: No evidence was found for the rapid conversion of HT to HTO in the atmosphere; HTO observed in air, during and after the release, arose mainly from HT oxidation in the soil followed by emission of HTO; HT deposition velocities to soil ranged from 0.041 cm s-1 to 0.13 cm s-1, consistent with previous chamber measurements; the rate of HTO loss from soil, averaged over 21 d, was less than 1% h-1; and HTO concentrations in vegetation water initially increased with time after the release, then by 48 h decreased exponentially at a rate similar to soils.
Air Pollutants, Radioactive↗
Human metabolism of arsenobetaine ingested with fish.
1. Six volunteers ingested 74As-labelled arsenobetaine with a fish meal. The retention and distribution of the tracer were studied by body radioactivity measurements. 2. The tracer became rapidly dispersed in soft tissues, with no major concentration in any localized organ or region. 3. In all subjects less than 1% of the ingested activity remained in the body after 24 days. 4. Any losses from the skin were minor in relation to those by other routes of excretion.
Adult↗
Pyruvate dehydrogenase deficiency caused by deletion of a 7-bp repeat sequence in the E1 alpha gene.
A 7-bp deletion in the X-chromosomal pyruvate dehydrogenase (PDH) E1 alpha gene was characterized in a female patient with the "cerebral" form of PDH deficiency. The mutation was localized using the chemical cleavage method and further characterized by application of the polymerase chain reaction and DNA sequencing. This 7-bp sequence is found in the normal gene as a direct tandem repeat. The deletion causes a change in the reading frame. Results have shown that the level of normal sized PDH E1 alpha in the fibroblast sample was approximately 30% of that of normal controls. This is consistent with normal transcription from the X chromosome carrying the nonmutated form of the E1 alpha subunit, as this chromosome is active in approximately 30% of this patient's cells. The severity of PDH E1 alpha deficiency in affected females is to a large extent dependent on the X-chromosome inactivation pattern in the brain. The clinical picture might therefore vary significantly between patients with the same mutation. We show that the 7-bp deletion must be a de novo mutation, because it is not present in the parent's X chromosomes. Furthermore, the deletion was not detected in chorionic villus samples in two subsequent pregnancies.
Chromosome Deletion↗
Child sexual abuse presenting as organic disease.
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Child Abuse, Sexual↗
Cellulose biogenesis in bacteria and higher plants is disrupted by magnetic fields.
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Acetobacter↗
X-chromosome localization of the functional gene for the E1 alpha subunit of the human pyruvate dehydrogenase complex.
The functional gene locus for the E1 alpha subunit of the human pyruvate dehydrogenase complex has been localized to the p22.1-22.2 region of the X chromosome by in situ hybridization and analysis of somatic cell hybrids with various human X-chromosome rearrangements. Another locus showing significant cross-hybridization with an E1 alpha cDNA probe was detected on chromosome 4, in the region q22. The X-chromosome localization of the pyruvate dehydrogenase E1 alpha subunit gene provides a number of possible explanations for the clinical and biochemical variability which is a major feature of human pyruvate dehydrogenase deficiency.
Animals↗
Gentamicin and low dose piperacillin in febrile neutropenic patients.
One hundred and twenty-seven febrile neutropenic patients were randomized to receive empirical antibiotic therapy with intravenous gentamicin and 12 g/day or 8 g/day piperacillin. Despite a high incidence of Hickman catheter infections by antibiotic-resistant bacteria, there was an overall response in 56% of patients and no difference in the numbers responding to each antibiotic regimen. In addition, the duration of fever was not significantly different in the two groups of patients. The majority of the unresponsive patients responded to the addition of further antibiotics and there were only two infection related deaths. The results suggest that high dose antibiotics are not essential for the initial empirical therapy in febrile neutropenic patients.
Adult↗
The clinical and biochemical spectrum of human pyruvate dehydrogenase complex deficiency.
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Cells, Cultured↗
The polarization of fibroblasts in early primary cultures is independent of microtubule integrity.
Fibroblasts in culture apparently require an intact system of microtubules in order to adopt and maintain a polarized morphology. In contrast, the polarization of a number of epithelial cell types has been shown to be microtubule-independent. Reconciliation of these apparently contradictory data is difficult, however, because the epithelial cells were studied in short-term primary cultures while the fibroblasts were studied in secondary or longer-term cultures. To clarify the situation we have examined the effects of the microtubule-disrupting drugs, colcemid and nocodazole, on the polarization of a single cell type, the chick heart fibroblast (HF), maintained in both primary (1 degree) and secondary (2 degree) cultures. Immunofluorescence observations of both types of culture showed that in control medium the cells contained abundant microtubules, which were absent if the cells were cultured in medium containing either colcemid or nocodazole. The effects of microtubule-disrupting drugs on the polarization of the cells were quantified using two measures of cell shape, elongation and dispersion, both of which increase with increasing polarization. The results show that microtubule-disrupting drugs do not have a significant effect on the polarization of HF spreading in 1 degree culture but significantly reduce the polarization of HF spreading in 2 degree cultures. The effects of microtubule disruption on HF that had been maintained in 1 degree culture for 6 h, 24 h or 48 h were also quantified.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Effects of chronic delta-9-tetrahydrocannabinol (THC) administration on neurotransmitter concentrations and receptor binding in the rat brain.
THC is the major psychoactive constituent of marijuana and is also known as an hallucinogenic compound. Numerous reports have shown that large doses of THC produce significant alterations in various neurotransmitter systems. The present study was designed to determine whether chronic exposure to THC produces significant alterations in selected neurotransmitter systems (dopamine, serotonin, acetylcholine, GABAergic, benzodiazepine, and opiate) in the rat brain. In Experiment 1, male Sprague-Dawley rats were gavaged with vehicle, 10 or 20 mg THC/kg body weight daily, 5 days/week for 90 days. Animals were killed either 24 hours or two months after the last dose. Brains were dissected into different regions for neurochemical analyses. Two months after the cessation of chronic administration, there was a significant decrease in GABA receptor binding in the hippocampus of animals in the high dose group. However, no other significant changes were found in neurotransmitter receptor binding characteristics in the hippocampus or in neurotransmitter concentrations in the caudate nucleus, hypothalamus or septum after chronic THC administration. In an attempt to replicate the GABA receptor binding changes and also to determine the [35S]TBPS binding in hippocampus, we designed Experiment 2. In this experiment, we dosed the animals by gavage with 0, 5, 10 or 20 mg THC/kg daily, 5 days/week or with 20 mg THC/kg Monday through Thursday and 60 mg/kg on Friday for 90 days. Results from this experiment failed to replicate the dose-dependent effect of THC on GABA receptor binding in hippocampus. Modulation of [35S]TBPS binding by GABA or 3 alpha-OH-DHP or inhibition by cold TBPS in frontal cortex did not show any significant dose-related effects. Results from these experiments suggest that chronic exposure to THC does not produce significant alterations in catecholamine or indoleamine neurotransmitter systems or in opiate or GABA receptor systems in the rat brain.
Animals↗
Selective idiotype suppression of an adoptive secondary antiacetylcholine receptor antibody response by immunotoxin treatment before transfer.
Acetylcholine receptor (AChR)-immune lymph node cells were treated with Id-specific immunotoxin before their transfer and antigenic challenge in adoptive recipient rats. In contrast to untreated, AChR-immune lymph node cells that, when challenged, produced high titers of serum anti-AChR antibody, in vitro anti-Id-ricin A chain treatment significantly inhibited anti-AChR antibody responses upon adoptive transfer. The inhibition was specific in that control lymph node cells immune to keyhole limpet hemocyanin were unaffected and totally responsive after treatment by the same immunotoxin. Furthermore, evidence is presented by isoelectric focusing analysis that the anti-Id antibody preparation used in this study contains all of the specificities required to eliminate the entire spectrum of AChR-reactive B cell clones.
Acetylcholine↗
Potential of inductively coupled plasma mass spectrometry for trace element metabolism studies in man.
A new inorganic mass spectrometric technique is described which allows sensitive, rapid and economic determination of trace element concentrations and isotope ratios in aqueous samples. This paper illustrates the potential of the technique in one particular application area, namely the measurement of strontium isotope ratios in human blood and urine following ingestion of an enriched stable strontium isotope. The data from a human volunteer experiment illustrate the viability of the analytical method, with measurement precisions of +/- 0.2% (1 sigma) achieved for the isotope ratio in urine samples, which contained approximately 300 ng 86Sr in the volume required for analysis. Measurement precision is limited by counting statistics.
Humans↗
Clonotypic analysis of the antibody response to the acetylcholine receptor in experimental autoimmune myasthenia gravis.
Autoreactive B cells reactive with the acetylcholine receptor (AChR), and the antibodies produced by them, are proposed to play a primary role in the immunopathology of myasthenia gravis and its animal models. Therefore, the anti-AChR antibody response induced in rats was characterized for the clonotypic heterogeneity, isotype distribution, and affinity by isoelectric focusing (IEF) and affinity immunoblotting. It was determined that the rat anti-AChR serum antibody was relatively heterogeneous, reflecting the oligoclonality of the response. Furthermore, isotypic dominance by IgG2a was observed in that the majority of clonal products detected by IEF were of this isotype in both primary and secondary responses. Lastly, the clonotypic anti-AChR antibodies were of relatively low affinity (avidity) when compared to antibodies reactive with the highly immunogenic protein antigen, keyhole limpet hemocyanin; anti-AChR antibody avidity did not appear to increase when the antibodies in the secondary response were compared to antibodies in the primary response. These antibody characteristics are discussed in terms of their role in disease induction.
Animals↗
A comparison of referrals to primary-care and hospital out-patient clinics.
All referrals from two general practices to psychiatrists in hospital and primary-care out-patient clinics were examined. Women in all diagnostic groups were preferentially referred to the primary-care clinics, which provided especially for psychotic and chronic illnesses, and at which attendance rates on first and subsequent appointments were substantially higher than at the hospital clinics. The hospital crisis-intervention clinic dealt particularly with acute psychosis and personality disorder. Patients referred to the traditional hospital out-patient service were those with the less common neuroses and personality disorder. These results are reviewed in the context of the criticism that psychiatric clinics in primary care serve only the "worried well".
Adult↗
The shape of cultured epithelial cells does not depend on the integrity of their microtubules.
Fibroblasts are thought to require an intact system of cytoplasmic microtubules in order both to adopt and to maintain a polarized morphology in culture, but whether the same is true for epithelial cells is not clear. We therefore compared the effects of the microtubule-disrupting drugs, colcemid and nocodazole, on the morphology of isolated embryonic chick heart fibroblasts (HF), corneal epithelial (CE) and epidermal epithelial (EE) cells. Immunofluorescence observations showed that all three cell types contained abundant microtubules when cultured in control medium and that these were absent from cells cultured in medium containing either colcemid or nocodazole. Qualitative observations suggested that these drugs inhibited the polarization of spreading HF but had no effect on the morphology of either of the epithelial cell types. We confirmed this observation quantitatively using two measures of cell shape, elongation and dispersion, both of which increase with increasing polarization. Our measurements show that microtubule-disrupting drugs significantly reduce both the elongation and dispersion of spreading HF but do not have a significant effect on either of these measures for the epithelial cell types. We quantified in a similar way the effects of microtubule-disrupting drugs on the morphology of all three cell types that had previously spread in control medium. We found that transferring spread HF to colcemid-containing medium significantly reduced both the elongation and dispersion of these cells but that the same treatment had no effect on these measures for either of the epithelial cell types. Our observations suggest that, unlike the fibroblasts, the epithelial cell types we have studied do not require microtubules either to adopt or to maintain a polarized morphology.
Animals↗