Project Read--the importance of early learning. Rx: Read to your child.
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Age Factors↗
Biomedical subjects
M Smith
Publications and source records attributed to M Smith.
Predicting oscillation in arterial saturation from cardiorespiratory variables. Implications for the measurement of cerebral blood flow with NIRS during anaesthesia.
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Anesthesia↗
Immunogenicity of CD63 in a patient with melanoma.
CD63 is a member of the tetraspan family of molecules that is expressed in melanoma and which appears to be involved in regulation of motility and adhesion of melanoma cells. In the present study we have screened a cDNA library from a melanoma cell with antisera from a patient with melanoma and have shown that one of the antigens identified was CD63. The clone isolated contained a mutation in the transmembrane region, but this did not appear to be involved in immunogenicity of the molecule. Antisera from the patient showed weak reactivity with CD63 from melanoma and recombinant CD63 in Western blots. The latter studies showed marked variation in the fractions of CD63 identified with monoclonal antibodies to CD63 consistent with variable glycosylation of CD63. We suggest that glycosylation may account for its recognition by the human immune system. Further studies are required to assess the role of CD63 as an immunogen in melanoma.
Amino Acid Sequence↗
Methodologic considerations in the interpretation of postmortem carboxyhemoglobin concentrations.
The interpretation of postmortem carboxyhemoglobin (COHb) concentrations can have major implications even when COHb is not the direct cause of death. Much litigation may hinge on the length of time an individual was alive during the fire. Therefore, the reliability of an analytical method to measure COHb, ranging from low to sub-lethal levels, is critical to the proper interpretation of results. This study used 40 blood specimens from fire deaths and 15 blood specimens from non-fire deaths to compare COHb levels obtained from a spectrophotometric method (IL 482 CO-Oximeter; CO-Ox) with a reference gas chromatographic method (GC). Since spectrophotometric methods are influenced by the amount of total hemoglobin (Hb) present in the blood, multiple saline dilutions of specimens were performed to yield Hb as low as 1g/dl. For GC COHb concentrations < 5% and Hb > or = 4g/dl, the average and median ratios of CO-Ox COHb to GC COHb concentrations were 2.8 and 2.6 respectively. These ratios were 8.0 and 6.8 respectively when Hb < 4g/dl. At GC COHb levels ranging from 5 to 40% and Hb > or = 4g/dl, the average and median ratios were 1.6 and 1.0 respectively. These ratios were correspondingly 2.1 and 1.9 when Hb < 4 g/dl. These data clearly indicate COHb can be influenced by the analytical methods used.
Carbon Monoxide↗
Synergy in protein engineering. Mutagenic manipulation of protein structure to simplify semisynthesis.
Semisynthesis is a chemical technique of protein engineering that provides a valuable complement to directed mutagenesis. It is the method of choice when the structural modification requires, for example, a noncoded amino acid. The process involves specific and limited protein fragmentation, structural manipulation of the target sequence, and subsequent religation of fragments to give the mutant holoprotein. We suggested and demonstrated that mutagenesis and semisynthesis could be used synergistically to achieve protein engineering goals otherwise unobtainable, if mutagenesis was used to shuffle methionine residues in the yeast cytochrome c sequence (Wallace, C. J. A., Guillemette, J. G., Hibiya, Y., and Smith, M. (1991) J. Biol. Chem. 266, 21355-21357). These residues can not only be sites of specific cleavage by CNBr but also of spontaneous peptide bond synthesis between fragments in noncovalent complexes, which greatly facilitates the semisynthetic process. We have now used an informed "methionine scan" of the protein sequence to discover other useful sites and to characterize the factors that promote this extraordinary and convenient autocatalytic religation. Of eight sites canvassed, in a wide range of settings, five efficiently provoked peptide bond synthesis. The principal factor determining efficiency seems to be the hydropathy of the religation site. The mutants created have also provided some new insights on structure-function relationships in the cytochrome.
Chemical Phenomena↗
Treatment decision-making at the end of life: a survey of Australian doctors' attitudes towards patients' wishes and euthanasia.
OBJECTIVE: To examine factors that influence medical practitioners' treatment decisions for patients with life-threatening or terminal illnesses. DESIGN: Postal survey, conducted between September and November 1995, of a self-administered questionnaire, describing four clinical case scenarios, to a random sample of 2172 Australian doctors in all States and Territories. Respondents were asked to prescribe treatment for the patients described in the scenarios. Patients' characteristics varied in terms of mental competence, illness severity, prognosis, the presence of advance directives, request for assisted death, and sociodemographic factors. The respondents' sociodemographic and medical training characteristics were also obtained. SETTING: Random national sample of all active medical practitioners. PARTICIPANTS: Hospital trainees, general practitioners, physicians, palliative care practitioners and surgeons were surveyed. A response rate of 73% was achieved. MAIN OUTCOME MEASURES: Frequency of prescription of supportive, acute or intensive treatment for patients in the four clinical scenarios based on respondents' sex, religion, medical training and country of medical degree. RESULTS: Three main findings were: (i) doctors did not make consistent decisions, but their decisions varied systematically by sociodemographic and medical training factors; (ii) doctors generally adhered to patient and family wishes when these were known; (iii) doctors did not generally adhere to a patient's request for assisted death. CONCLUSION: Treatment provided is significantly determined by the individual characteristics of the doctor and not solely by the nature of the medical problem. Participation in the informed-consent process and in the preparation of advance health care directives would enable practitioners to be familiar with patient and family wishes and could reduce variations of treatment related to sociodemographic and medical training factors. Stronger empirical data on the way that treatment decisions are made could provide the basis for an informed euthanasia policy.
Attitude of Health Personnel↗
Subcellular localization and analysis of apparent 180-kDa and 220-kDa proteins of the breast cancer susceptibility gene, BRCA1.
The breast cancer susceptibility gene BRCA1 encodes an 1863-amino acid protein that acts as a tumor suppressor. The biochemical function of BRCA1 is unknown, and there are conflicting results describing its subcellular location. We have identified a 220-kDa protein, which is reactive with three antibodies raised against the amino- and carboxyl-terminal regions of BRCA1. Immunoflourescence staining with an antibody to the carboxyl terminus of BRCA1 localized the protein to the nucleus of breast, ovarian, and cervical carcinoma-derived cell lines. A similar result was observed by biochemical subcellular fractionation that indicated that the 220-kDa protein was localized primarily to the nucleus of cell lines established from breast carcinomas. In addition to the 220-kDa protein, one antibody, C-20, also recognized a 180-kDa protein in MDA-MB-468 total cell lysates that was not detected by the other two antibodies. Several observations suggest the 180-kDa protein is the epidermal growth factor (EGF) receptor: (i) C-20 reacted avidly with a 180-kDa protein immunoprecipitated by an antibody to the EGF receptor; (ii) an EGF receptor antibody detected a 180-kDa protein immunoprecipitated by C-20; (iii) the affinity purified EGF receptor was both immunoprecipitated and detected on immunoblots by the C-20 antibody but not another BRCA1 antibody; (iv) similar phosphopeptide maps were generated from the EGF receptor and the 180-kDa protein immunoprecipitated by C-20, and this peptide map was distinct from the 220-kDa phosphoprotein; and (v) the C-20 immunizing peptide bears sequence identity to the EGF receptor. These results indicate that BRCA1 is a 220-kDa nuclear protein and that the 180-kDa protein reported previously may be unrelated to BRCA1.
Antibodies↗
Professional development support for community nurses.
This article presents the outline of a programme developed to support quality nursing care and provide professional development for staff nurses in a grade mixed, community nursing team. The initiative has been a joint venture between First Community Health NHS Trust and the University of Wolverhampton, School of Health Sciences, and shows the value of working together to establish a sound underpinning for practice.
Community Health Nursing↗
Tonic suppression of adrenal AP-1 activity by glucocorticoids.
The AP-1 transcription factor is a variable complex of Fos and Jun nuclear phosphoproteins that is induced in many cell types. AP-1 interacts with transcription factors of different classes, including the nuclear steroid hormone receptors, an interaction that is often mutually antagonistic and thereby serves to integrate different cellular signalling events. In addition to direct, molecular interactions between AP-1 and glucocorticoid receptor (GR), there is also evidence that the two signalling pathways may interact at different levels, but in vivo interactions of this nature have not been well characterized. We have investigated a unique cellular context for GR/AP-1 interactions, namely in the adrenal gland of the rat where the production of glucocorticoids leads to extremely high local levels of glucocorticoids, and where high constitutive AP-1 activity (as determined by in vitro DNA binding activity) has been demonstrated. We have now shown that depletion of glucocorticoid production in rats with the 11-beta-hydroxylase inhibitor, metyrapone, results in increased adrenal AP-1 activity. The demonstrated 5-fold increase is reversed by prior treatment with the glucocorticoid agonist, dexamethasone, and is largely localized to the adrenal medullary region. Further experiments have shown that c-Jun and JunD are the principal components of adrenal AP-1 in the basal state, but a change in jun-B expression appears to underly the metyrapone-induced increase in AP-1 activity. In situ hybridization analysis has shown that glucocorticoid depletion is associated with a dramatic increase in adrenal medullary junB mRNA, and using immunoblotting we have demonstrated a similar increase in nuclear levels of both the 43 kD JunB protein, and an associated phosphorylated JunB. Our use of a pharmacological intervention to demonstrate tonic suppression of adrenal medullary JunB expression by glucocorticoids has provided evidence of a nuclear mechanism that may have physiological relevance as an adaptive response to fluctuating levels of glucocorticoids.
Adrenal Glands↗
Mechanistic and structural contributions of critical surface and internal residues to cytochrome c electron transfer reactivity.
The influence of mutations in two conserved regions of yeast iso-1-cytochrome c believed to be critical to the mechanism of cytochrome c electron transfer reactions has been investigated. The variants Asn52Ala, Tyr67Phe, Ile75Met, and Thr78Gly involve perturbation of critical hydrogen-bonding interactions with an internal water molecule (Wat166) and have been studied in terms of their electrochemical properties and the kinetics with which they are reduced by Fe(EDTA)2- and oxidized by Co(phen)3(3+). In parallel studies, the Co(phen)3(3+) oxidation kinetics of Tyr, Leu, Ile, Ala, Ser, and Gly variants of the phylogenetically conserved residue Phe82 have been studied and correlated with previous electrochemical and kinetic results. To assist mechanistic interpretation of these results, the three-dimensional structures of the Asn52Ala and Ile75Met ferrocytochrome c variants have been determined. The reduction potentials of the variants modified in the region of Wat166 were at least 33 mV (pH 6, 25 degrees C, and mu = 0.1 M) lower than that of the wild-type protein. Electron transfer reactivity of this family of variants in both the oxidation and reduction reactions was increased as much as 10-fold over that of the wild-type cytochrome. On the other hand, the reactivity of the position-82 variants in both oxidation and reduction depended on the structural characteristics of the oxidation-reduction reagent with which they reacted, and this reactivity was related to the nature of the residue at this position. These findings have been interpreted as demonstrating that the principal influence of modification at position-82 arises from changes in the nature of reactant-protein interaction at the surface of the protein and in maintaining the high reduction potential of the cytochrome while the principal influence of internal modifications near Wat166 results from alteration of the reorganization energy for the oxidation state-linked conformational change defined by crystallographic analysis of the wild-type protein.
Cytochrome c Group↗
Telomere shortening, ageing, and chromosome damage.
A relationship between telomere shortening and ageing has been established. A series of young and elderly healthy donors. Alzheimer disease patients, young and old Down's syndrome individuals were cytogenetically analyzed. No preferential damage in distal bands was seen in age-related chromosome instability.
Aging↗
Disorder and persistent photoconductivity in ZnxCd1-xSe semiconductor alloys.
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Journal Article↗
Providing intensive care. For neurosciences, proposals are "too little too late".
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Hospital Bed Capacity↗
A neuroimmune hypothesis for the aetiopathology of viral illness and manic depression: a case report of an adolescent.
This paper explores the unifying aetiopathology between disorders of the immune system and the CNS, using a case example. An adolescent had a 2-year history of chronic-active Epstein-Barr virus infection and recurrent acute pancreatitis that resolved following a course of immunotherapy. Subsequently, she redeveloped acute symptoms of infectious mononucleosis and pancreatitis, along with manic depression, and then made a complete recovery with combination of lithium carbonate and electroconvulsive therapy. On follow-up, lithium carbonate effectively controlled the previous neuroimmune dysfunction.
Acute Disease↗
Epinephrine-induced changes in serum potassium and cardiac repolarization and effects of pretreatment with propranolol and diltiazem.
Although increases in serum epinephrine are known to cause hypokalemia, the epinephrine dosages and concentrations at which this effect occurs, and the electrocardiographic consequences, have not been evaluated. Because epinephrine infusion is now being used to provoke arrhythmias in some patients, we have determined the physiologic effects of a range of dosages of epinephrine. The effects of pretreatment with propranolol and diltiazem on these indexes of epinephrine effect were also evaluated. Epinephrine dose ranging started at 10 ng/kg/min, with doubling of the dose every 10 minutes until a predetermined end point was reached. At the end of each dosage level, serum electrolytes, catecholamines, and an electrocardiogram were recorded. Whereas even the lowest dosage of epinephrine significantly increased heart rate, serum glucose levels increased and serum potassium decreased only when dosages of 160 to 320 ng/kg/min were administered. Plasma concentrations of epinephrine at these dosages were mean +/- SD 1,328 +/- 902 pg/ml, comparable to those observed in these subjects during maximal exercise (1,003 +/- 527 pg/ml). The major electrocardiographic effect of epinephrine infusion was a dose-related increase in QTc, but pretreatment with propranolol blunted this effect and tended to shorten QTc. At an epinephrine dose of 40 ng/kg/min, QTc prolongation persisted and was inhibited by diltiazem. These data suggest that the major electrocardiographic effect of epinephrine infusion is mediated by increased calcium current. At dosages > 80 ng/kg/min, plasma epinephrine concentrations are comparable to those observed with severe stress, and hypokalemia is common. The use of epinephrine as an electrophysiologic provoker at dosages > 80 ng/kg/min results in both a direct effect, as well as an indirect effect due to hypokalemia.
Adrenergic beta-Antagonists↗
Randomised controlled trial of general practitioner versus usual medical care in an urban accident and emergency department: process, outcome, and comparative cost.
OBJECTIVE: To see whether care provided by general practitioners to non-emergency patients in an accident and emergency department differs significantly from care by usual accident and emergency staff in terms of process, outcome, and comparative cost. DESIGN: A randomised controlled trial. SETTING: A busy inner city hospital's accident and emergency department which employed three local general practitioners on a sessional basis. PATIENTS: All new attenders categorised by the triage system as "semiurgent" or "delay acceptable." 66% of all attenders were eligible for inclusion. MAIN OUTCOME MEASURES: Numbers of patients undergoing investigation, referral, or prescription; types of disposal; consultation satisfaction scores; reattendance to accident and emergency department within 30 days of index visit; health status at one month; comparative cost differences. RESULTS: 4684 patients participated. For semiurgent patients, by comparison with usual accident and emergency staff, general practitioners investigated fewer patients (relative difference 20%; 95% confidence interval 16% to 25%), referred to other hospital services less often (39%; 28% to 47%), admitted fewer patients (45%; 32% to 56%), and prescribed more often (41%; 30% to 54%). A similar trend was found for patients categorised as delay acceptable and (in a separate analysis) by presenting complaint category. 393 (17%) patients who had been seen by general practitioner staff reattended the department within 30 days of the index visit; 418 patients (18%) seen by accident and emergency staff similarly reattended, 435 patients (72% of those eligible) completed the consultation satisfaction questionnaire and 258 (59% of those eligible) provided health status information one month after consultation. There were no differences between patients managed by general practitioners and those managed by usual staff regarding consultation satisfaction questionnaire scores or health status. For all patients seen by general practitioners during the study, estimated marginal and total savings were Ir1427 pounds and Ir117,005 pounds respectively. CONCLUSION: General practitioners working as an integral part of an accident and emergency department manage non-emergency accident and emergency attenders safely and use fewer resources than do usual accident and emergency staff.
Adult↗
In vivo study of the mutagenicity of biperidine, pipotiazine, chlorpromazine, and haloperidol.
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Adult↗
Skeletal matrices, muci, and the origin of invertebrate calcification.
The sudden appearance of calcified skeletons among many different invertebrate taxa at the Precambrian-Cambrian transition may have required minor reorganization of preexisting secretory functions. In particular, features of the skeletal organic matrix responsible for regulating crystal growth by inhibition may be derived from mucous epithelial excretions. The latter would have prevented spontaneous calcium carbonate overcrusting of soft tissues exposed to the highly supersaturated Late Proterozoic ocean [Knoll, A. H., Fairchild, I. J. & Swett, K. (1993) Palaios 8, 512-525], a putative function for which we propose the term "anticalcification." We tested this hypothesis by comparing the serological properties of skeletal water-soluble matrices and mucous excretions of three invertebrates--the scleractinian coral Galaxea fascicularis and the bivalve molluscs Mytilus edulis and Mercenaria mercenaria. Crossreactivities recorded between muci and skeletal water-soluble matrices suggest that these different secretory products have a high degree of homology. Furthermore, freshly extracted muci of Mytilus were found to inhibit calcium carbonate precipitation in solution.
Journal Article↗