Chemotherapeutic options in HIV infection.
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Analysis of Variance↗
Biomedical subjects
S Cox
Publications and source records attributed to S Cox.
Domain movements in protein kinases.
Structural studies of the catalytic subunit of the cAMP-dependent protein kinase, both by crystallographic methods and in solution, reveal two conformations. Crystal structures of several other protein kinases have also been solved in the past year. With this combined information we can begin to define mobile domains and subdomains within the conserved catalytic core.
Animals↗
Dinucleotide repeat polymorphism at D14S542.
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Alleles↗
Phenytoin age-dose-concentration relationship in children.
A list (n = 423) of phenytoin steady-state concentrations from children taking phenytoin alone or in combination with other drugs (n = 308) was obtained from our therapeutic drug monitoring database (1984-1990). Only 43% of concentrations were within the commonly accepted "therapeutic" or "reference" range (10-20 mg/L). Age-dose-concentration relationships showed that while occasional concentrations were above 20 mg/L, many patients receiving commonly recommended pediatric phenytoin doses (4-8 mg/kg/day) achieved concentrations below the reference range, especially children under 3 years of age. Michaelis-Menten pharmacokinetic parameters, maximal elimination rate (Vmax) and Michaelis constant (Km), were evaluated for patients with at least two steady-state concentrations measured for two or more different daily doses. Comedication with other drugs had no effect on either Vmax or Km for phenytoin. Vmax appeared to decrease significantly with age, but there was no age relationship for Km.
Adolescent↗
Report and abstracts of the Third International Workshop on Human Chromosome 2 Mapping 1994. Aarhus, Denmark, June 24-26, 1994.
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Base Sequence↗
Proceed with care: direct predictive testing for Huntington disease.
The cloning of the Huntington disease (HD) gene allows highly accurate predictive testing using direct analysis of the CAG repeat. This new test provides results with almost complete certainty but poses unique counseling issues related to direct testing for an adult-onset disease. These include testing individuals who are at 25% risk, without the need for blood from a 50% at risk relative; the assessment of symptomatic individuals; the need for ongoing counseling despite simplification of laboratory procedures; and counseling of persons from families who represent a new mutation for HD. This paper describes protocols for direct predictive testing for adult and prenatal assessment, on the basis of the experience of the Canadian Collaborative Study on Predictive Testing (CCSPT). Over the past 8 years, we have provided > 400 results by using linked markers and, more recently, 416 results by using direct assessment of CAG expansion in the HD gene. The vast majority (86%) of requests for direct predictive testing have been from persons who have not previously received results by using linked markers. Despite the ability to now directly assess for the mutation associated with HD, we still recommend assessment of DNA from an affected relative, as this may significantly enhance the accuracy of information to be provided to the at-risk individual. Distance from a genetics center has previously limited the availability of testing, and therefore we have developed approaches to providing predictive testing in the patient's own community.
Adult↗
SCH 38057: a picornavirus capsid-binding molecule with antiviral activity after the initial stage of viral uncoating.
The activity of a new water-soluble molecule, SCH 38057, against picornaviruses is described. SCH 38057 inhibited plaque formation of selected entero- and rhinoviruses in a range of 10.2 to 29.1 microM (50% endpoint) and had a therapeutic index of 10 against poliovirus type 2 (polio 2) in HeLa cells. When administered orally or subcutaneously, SCH 38057 protected mice infected with either coxsackievirus B3 (CVB3) or echovirus-9 from mortality. The molecule provided a low level of protection against thermal inactivation of virus, indicating that SCH 38057 interacts with the picornavirus capsid. Binding studies with [3H]SCH 38057 revealed that the molecule binds to CVB3 and human rhinovirus 14 (HRV14) in a ratio of 29 and 19 molecules per viral particle, respectively. The affinity constant for SCH 38057 binding to CVB3 was 7.0 x 10(-4) M. When added to cultures of infected cells at 3 h after infection, SCH 38057 markedly inhibited viral RNA synthesis. This finding with lack of inhibition of attachment and loss of infectious virus after attachment were interpreted to indicate that, although SCH 38057 binds to the viral capsid, the molecule exerts its antiviral effect after the initial stage of picornavirus uncoating, i.e., after conversion of the 156S infectious viral particle to smaller subviral species.
Animals↗
Audit of theophylline plasma level monitoring in a pediatric hospital.
Theophylline assays performed in a children's hospital were audited, focusing particularly on distribution of plasma concentration values, interpretation of the assay result, appropriateness of the advice conveyed to the physician, and the response to this advice. Assays performed by a multidisciplinary therapeutic drug monitoring (TDM) service during a 1-month period in 1988 and again in 1992 were chosen for review. Theophylline concentration in plasma was quantified by fluorescence polarization immunoassay. Medical technologists interpreted results and made specific recommendations concerning dose changes and/or need for follow-up assays on 48.5 (1988 survey) and 37.9% (1992 survey) of results. Review of these recommendations revealed that only approximately 1% could have been improved or were incorrect. Physician compliance with dose change recommendations was similar in both surveys (chi 2 = 0.16, p = 0.7), with recommendations being followed on 75.9 (1988) and 73.3% (1992) of occasions. Compliance with recommendations for ordering additional samples at specific times also was similar between the two surveys (chi 2 = 2.06, p = 0.15), with recommendations being followed on 75 (1988) and 87.2% (1992) of occasions. Overall, combining the data for both surveys, (a) significantly more out-patients than in-patients (69.2 versus 27.8%, respectively) were subtherapeutic, (b) significantly fewer out-patients than in-patients (27.6 versus 70.2%, respectively) were within the therapeutic range (chi 2 = 33.7, p < 0.001), but (c) numbers (2-4%) of potentially toxic results within the two groups were similar.
Asthma↗
Report and abstracts of the Second International Workshop on Human Chromosome 2 Mapping.
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Base Sequence↗
Occupational health: control and monitoring of psychosocial and organisational hazards at work.
This paper considers the conceptualizations which underpin the traditional approach to occupational health and offers a critique; much of which points up the importance of psychosocial and organizational issues. It then explores the possible development of a new 3 factor model of concern - organisational health - based on health, work and organisation. It takes as its thesis the need to address the problems posed by psychosocial and organisational hazards at work and the argument that these can be managed effectively within the framework of practice that has proved successful for the more tangible workplace hazards.
Conflict of Interest↗
The effects of liver and renal disease on stereoselective serum binding of flurbiprofen.
Stereoselectivity in the serum binding of flurbiprofen, a non-steroidal anti-inflammatory drug which is highly bound to albumin, was studied in patients with liver and renal disease. Subjects with renal disease or liver disease with ascites had significantly lower serum albumin concentrations than normals, resulting in higher free fractions of both the R(-) and S(+) enantiomers of flurbiprofen as determined by equilibrium dialysis. The ratio (+/- s.d.) of R/S-flurbiprofen free fractions was lower in the subjects with ascites (0.714 +/- 0.298) than in those without ascites (0.796 +/- 0.090) (P < 0.05).
Adult↗
Assay of intracellular thymidylate synthetase activity and inhibition by 5-fluoro-2'-deoxyuridine in lymphocytes.
Thymidylate synthetase catalyses the formation of thymidine monophosphate from deoxyuridine monophosphate. Purified thymidylate synthetase can be assayed radiochemically using labelled deoxyuridine monophosphate as substrate, but cells are impervious to deoxyuridine monophosphate and so intracellular thymidylate synthetase activity cannot be assayed in this way. In this paper we describe the assay of intracellular thymidylate synthetase activity in intact cells using labelled 2'-deoxyuridine. The assay showed linear kinetics with respect to time, concentration of 2'-deoxyuridine, and cell concentration. 5-fluoro-2'-deoxyuridine inhibited intracellular thymidylate synthetase activity measured with this assay by 50% at 5 nM. Cell growth was inhibited by 50% at 6 nM 5-fluoro-2'-deoxyuridine. The assay was specific for thymidylate synthetase and enabled measurement of thymidylate synthetase activity in situ in intact cells.
Cells, Cultured↗
The human IL-1 receptor antagonist gene (IL1RN) maps to chromosome 2q14-q21, in the region of the IL-1 alpha and IL-1 beta loci.
The IL-1 receptor antagonist (IL-1RN) is a protein that binds to IL-1 receptors and inhibits the binding of IL-1 alpha and IL-1 beta. As a consequence, the biological activity of these two cytokines is neutralized in physiological and pathophysiological immune and inflammatory responses. In this study, using a panel of somatic rodent-human cell hybrids, we show that the gene for the human interleukin-1 receptor antagonist (IL1RN) maps to the long arm of chromosome 2. Previously, we described a length variation polymorphism within the second intron of the IL-1RN gene (Steinkasserer et al., 1991, Nucleic Acids Res. 19: 5095). Segregation of this, together with an IL-1 alpha polymorphism, was followed in a panel of five CEPH families. Linkage analysis permitted the mapping of the IL-1RN gene to band q14-q21 in the region for the IL-1 alpha and IL-1 beta loci. This study supports the view that an early gene duplication event resulted in the creation of an interleukin-1 gene family.
Chromosome Mapping↗
The CEPH consortium linkage map of human chromosome 2.
This paper describes the Centre d'Etude du Polymorphisme Humain (CEPH) consortium linkage map of chromosome 2. The map contains 36 loci defined by genotyping generated from the CEPH family DNAs. A total of 73 different markers were typed by 14 contributing laboratories; of these, 36 loci are ordered on the map with likelihood support of at least 1000:1. Markers are placed along the length of the chromosome but no markers were available to anchor the map at either telomere or the centromere. Multilocus linkage analysis has produced male, female, and sex-averaged maps extending for 261, 430, and 328 cM, respectively. The sex-averaged map contains five intervals greater than 15 cM and the mean genetic distance between the 36 uniquely placed loci is 9.1 cM.
Chromosome Mapping↗
Pharmacokinetics and pharmacodynamics of ibuprofen isomers and acetaminophen in febrile children.
The pharmacokinetics of racemic ibuprofen and its stereoisomers have been described in adults, but little has been reported for children. The pharmacodynamics of acetaminophen and ibuprofen have not been well described in either adults or children. Children (N = 39; age range, 11 months to 11 1/2 years) were randomly selected to receive a single dose of either 6 mg/kg of liquid ibuprofen or 10 to 15 mg/kg of liquid acetaminophen (mean +/- dose given, 11.6 +/- 0.7). Pharmacokinetic and pharmacodynamic analyses were performed with temperature as the effect parameter and mean acetaminophen, total ibuprofen, and ibuprofen stereoisomer concentrations over time. Time of maximum serum concentrations for ibuprofen was 54.05 minutes versus 27.0 minutes for acetaminophen, time to maximum temperature decrease was 183 minutes for ibuprofen and 133 minutes for acetaminophen. Temperature reduction for the ibuprofen dose was significantly different than that of the acetaminophen dose at later time points (240, 300, 360, 420, and 480 minutes). Further pharmacokinetic-pharmacodynamic studies with use of individual ibuprofen stereoisomers and other dosing regimens are indicated.
Acetaminophen↗
Expression of the phosphorylase kinase gamma subunit catalytic domain in Escherichia coli.
The catalytic subunit of phosphorylase b kinase (gamma) and an engineered truncated form (gamma-trc, residues 1-297) have been expressed in Escherichia coli. The truncated protein included the entire catalytic domain as defined by sequence alignment with other protein kinases but lacked the putative calmodulin binding domain. Full-length protein was produced in insoluble aggregates. Some activity was regenerated by solubilization in urea and dilution into renaturating buffer but the activity was found to be associated with a smaller molecular weight component. Full-length protein could not be refolded successfully. The truncated gamma subunit was produced in the soluble fraction of the cell as well as in inclusion bodies. The insoluble protein was refolded by dilution from urea and purified to homogeneity, in a one step separation on DEAE-Sepharose to give a protein mol. wt 32,000 +/- 2000 with a high sp. act. of 5.3 mumol 32P incorporated into phosphorylase b(PPB)/min/nmol. Kinetic parameters gave Km for ATP 46 +/- 3 microM and Km for PPb 27 +/- 1 microM. The sp. act. and the Km values are comparable to those observed for the activated holoenzyme and indicate that the gamma-trc retains the substrate recognition and catalytic properties. The ratio of activities at pH 6.8/8.2 was 0.84. gamma-trc was inhibited by ADP with a Ki of 52 microM and was sensitive to activation by Mg2+ and inhibition by Mn2+, properties that are characteristic of the holoenzyme and the isolated gamma subunit. Calmodulin which confers calcium sensitivity on the isolated gamma subunit had no effect on the enzymic properties of gamma-trc.(ABSTRACT TRUNCATED AT 250 WORDS)
Adenosine Diphosphate↗
Dynamic changes in HIV-1 quasispecies from azidothymidine (AZT)-treated patients.
The emergence of azidothymidine (AZT)-resistant human immunodeficiency virus (HIV) variants in clinical samples was studied by a direct genomic sequencing method. Sequential lymphocyte samples from four patients, who had been treated with AZT for up to 27 months, were shown to gradually accumulate multiple nucleotide changes, some of which are known to be associated with AZT resistance. Several samples were shown to contain mixtures of wild-type and mutated genomes, indicating gradual rather than sudden changes in the HIV-1 quasispecies. These results demonstrate for the first time that automated solid-phase DNA sequencing is a rapid and useful tool for investigation of antiviral drug resistance and suggest that DNA sequencing may be important in routine clinical diagnostics in the future.
Acquired Immunodeficiency Syndrome↗
Persistence of azidothymidine-resistant human immunodeficiency virus type 1 RNA genotypes in posttreatment sera.
The rate of reversion from azidothymidine (zidovudine; AZT) resistance was studied by direct sequencing of human immunodeficiency virus type 1 (HIV-1) virion RNA in sera from four patients who discontinued long-term treatment. Before cessation of treatment, all four patients harbored HIV-1 with multiple mutations reported to confer AZT resistance. In three patients, slow reversions of these mutations starting after 9, 9, and 18 months were detected. The slow reversions indicate that AZT-resistant HIV-1 variants are likely to have an unaltered replicative capacity and pathogenic potential. Furthermore, there were discrepancies between the in vivo RNA sequences and the sequences of virus isolates, indicating that the isolation procedure may select for nonrepresentative virus variants.
Acquired Immunodeficiency Syndrome↗