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Biomedical subjects

S Cox

Publications and source records attributed to S Cox.

At least 91 records · Page 5Linked to original sources
PubMed1996

Synergistic inhibition of human immunodeficiency virus isolates (including 3'-azido-3'-deoxythymidine-resistant isolates) by foscarnet in combination with 2',3'-dideoxyinosine or 2',3'-dideoxycytidine.

The combinations of foscarnet plus 2',3'-dideoxyinosine and foscarnet plus 2',3'-dideoxycytidine synergistically inhibit the replication of human immunodeficiency virus type 1 isolates, including two 3'-azido-3'-deoxythymidine-resistant isolates. The combination of 2',3'-dideoxyinosine plus 2',3'-dideoxycytidine showed additive inhibition of the majority of the human immunodeficiency virus isolates tested. All three combinations showed pronounced antagonistic cytotoxicity and thus were less toxic to the growth of peripheral blood mononuclear cells than the separate drugs.

Antiviral Agents↗
PubMed1996

Gay and lesbian identity development: a social identity perspective.

This paper critically examines models of identity development from the perspective of social identity theory. It is argued that recent perspectives on homosexual identity development have focused upon psychological processes of the individual and that a shift toward a more social psychological perspective is required. Extant models of homosexual identity development and associated relevant evidence are described, and criticisms of these models are discussed. Next, social identity theory is outlined, illustrating how such an approach can address the criticisms of the dominant approach to gay and lesbian identity development. An extension of social identity theory is then offered in an attempt to explain some of the identities which homosexuals have developed in reaction to being members of an oppressed group.

Female↗
PubMed1995

Kinetic analysis of cAMP-dependent protein kinase: mutations at histidine 87 affect peptide binding and pH dependence.

Mutation of His87 in the catalytic (C-) subunit of the cAMP-dependent protein kinase (cAPK) led to changes in the kinetic properties of this enzyme. The C-subunit is a bilobal structure, with catalysis occurring in the cleft between the two lobes. His87 lies at the edge of the cleft, making an interaction with phosphothreonine, 197. This is the only direct electrostatic or hydrogen-bonding interaction between the small and large lobes. Solvent viscosity studies of the His87Ala mutant of the C-subunit (rC[H87A]) revealed that binding of two peptides, LRRASLG and LRRASLG-NH2, was impaired relative to that of the wild-type C-subunit. Consistent with this, the Ki's for two inhibitor peptides, LRRAALG and LRRAALG-NH2, were 4 and 1.4 mM, respectively, 5- and 7-fold higher than the Ki's of the respective peptides for wild-type protein. Kinetic constants for three octapeptide substrates that differed only at the P+2 position suggested a direct interaction of His87 with residues at this site. The kcat for rC[H87A] was 2-3-fold higher than kcat for the wild-type enzyme, indicating an effect of the mutation on the rate-limiting step, product release. The pH dependence of kinetic parameters for rC[H87A] was also measured. A single pKa of 6.5 was observed in kcat/Kpeptide as compared to the two pKa's of 6.5 and 8.5 for the wild-type enzyme. These changes suggest a role for His87 in substrate recognition and in stabilization of the catalytically competent conformation of the enzyme.

Amino Acid Sequence↗
PubMed1995

The CEPH consortium linkage map of human chromosome 11.

The CEPH consortium framework map of chromosome 11 is presented. The map was generated from CEPH family DNAs with 181 probe/enzyme combinations contributed by 20 laboratories. Seventy-seven of the loci are defined by microsatellite polymorphisms that can be typed by the PCR. A total of 42 loci have been placed on the map with likelihood support of at least 1000:1. The female, male, and sex-average maps extend for 179.6, 110.8, and 145.3 cM, respectively. The largest interval on the sex-average map is less than 11 cM, and the average distance between uniquely placed loci is 4 cM. The genotypic data obtained for map construction have been used to identify the positions of crossovers on the chromosomes of CEPH family children, allowing the localization of new markers without computationally intensive likelihood models and providing a basis for efficient extension of the linkage map to higher resolution.

Adult↗
PubMed1995

AIDS research policy.

Explore the source record for details and available documents.

Acquired Immunodeficiency Syndrome↗
PubMed1995

High dose and standard dose adrenaline do not alter survival, compared with placebo, in cardiac arrest.

This trial compared blinded 10 mg aliquots of adrenaline with placebo in 194 cardiac arrest patients treated in hospital using American Heart Association guidelines. In-hospital and out-of-hospital arrests were included. Of the 339 eligible patients a large proportion (145 (45%)) were not randomised and received open 1 mg aliquots of adrenaline. This group is also analysed. Supervising physicians gave significant preference for males, patients with no previous cardiac history and without multiple organ disease to be given open 1 mg adrenaline. Patients in asystole at the time of consideration for entry were preferentially placed in the trial group (114 (69%) vs. 170 (88%)) and patients in ventricular fibrillation were preferentially given open 1 mg adrenaline (31 (21%) vs. 24 (12%) P < 0.03). The most beneficial rhythm changes which led to survival were sinus rhythm and ventricular tachycardia. Analysis of rhythm changes resulting from the dosing showed a significant (P = 0.01) change to a beneficial rhythm with 10 mg adrenaline but not for 1 mg adrenaline or placebo. This was not reflected by an improvement in immediate survival. No significant differences in immediate survival (IS) or hospital discharge (HD) exists between open 1 mg adrenaline (IS 14 (9.7%), HD 3 (2%)) or the 10 mg adrenaline (IS 9 (9.6%), HD 0) vs. placebo (IS 7 (7%), HD 0) trial arms. Patients reaching the point of use of adrenaline have a uniformly poor immediate survival (8.8%) and hospital discharge rate (0.9%). Dosing with 10 mg or 1 mg adrenaline does not influence outcome compared with placebo.

Aged↗
PubMed1995

Intracellular activation and cytotoxicity of three different combinations of 3'-azido-3'-deoxythymidine and 2',3'-dideoxyinosine.

We measured the intracellular activation and cytotoxicity of 3'-azido-3'-deoxythymidine (zidovudine, ZDV) and 2',3'-dideoxyinosine (ddI) when combined at three different clinically relevant combinations of 1:1, 1:10, and 10:1 (ZDV:ddI). The activation of ddI to ddA-TP was increased in all three combinations with ZDV, compared to ddI alone. A maximum twofold increase in ddA-TP was observed, which could not be further increased by raising the concentration of ZDV in the combination. On the other hand, the concentration of ZDV in the combination could be reduced to one-tenth while retaining increased activation of ddI. We also examined the cytotoxicity of these combinations in CEM cells, phytohemagglutinin (PHA)-stimulated and resting human peripheral blood mononuclear cells (PBMCs). CEM cells were the least sensitive overall to the drugs. ZDV showed greater cytotoxicity in stimulated PBMCs than resting PBMCs, whereas the reverse was true for ddI. This could be explained by the different activation pathways of these two drugs. The 1:1 and 10:1 ZDV:ddI combinations showed reduced toxicity compared to the separate drugs. These results indicate that ZDV and ddI need not necessarily be combined together at a ratio of ZDV:ddI of 1:1, but that some alteration in the dosages of ZDV or ddI in patients could be possible without loss of the benefits of combined ZDV:ddI therapy.

Antiviral Agents↗
PubMed1995

Pharmacokinetics of phenytoin in children with acute neurotrauma.

OBJECTIVE: To determine the pharmacokinetics of intravenous phenytoin in critically ill infants and children with acute neurologic injury. DESIGN: A prospective, descriptive study. SETTING: A pediatric intensive care unit. PATIENTS: Sixteen children, 0.5 to 16 yrs of age (mean 7.6), with various types of acute neurologic injuries, receiving intravenous phenytoin therapy. INTERVENTIONS: Blood samples were collected to measure total and free phenytoin concentrations in plasma. A 24-hr urine collection was made to determine the concentrations of the major metabolite of phenytoin. MEASUREMENTS AND MAIN RESULTS: In 12 children who survived the acute illness, a lower-than-predicted Michaelis-Menten constant (Km) and higher-than-predicted maximum rate of metabolism (Vmax) were observed. Initial free phenytoin fractions ranged between 0.08 and 0.15. In the eight patients who had additional free fractions measured, six patients demonstrated an increase (9.1% to 34% increase) in free fraction, while two patients demonstrated a decrease (1.8% and 19.8% decrease) in free fraction. The ratio of amount of phenytoin to phenytoin plus 5-(p-hydroxyphenyl)-5-phenylhydantoin excreted in the urine in a 24-hr urine collection demonstrated a wide inter-patient variability. There was no correlation in the difference between the predicted and calculated Km and Vmax values and Glasgow Coma Score, circulating albumin concentration, or concomitant medications. CONCLUSION: Based on the average Km and Vmax values of the children enrolled in our study, it appears that children with neurologic injury between the ages of 0.5 and 9 yrs may require dosages of at least 8 to 10 mg/kg/day, and children aged 10 to 16 yrs may require 6 to 8 mg/kg/day to attain therapeutic phenytoin concentrations.

Acute Disease↗
PubMed1995

Development of a panel of monochromosomal somatic cell hybrids for rapid gene mapping.

We have assembled a panel of monochromosomal somatic cell hybrids for use in gene mapping. DNA from each individual hybrid was used as a probe on normal human metaphases to identify the human chromosome and any fragments by reverse painting. To test the efficiency of the panel PCR amplification of DNA from the monochromosomal somatic cell hybrid panel was used in combination with human specific oligonucleotide primers to assign alpha-catenin (CTNNA1) and p21/WAF1 to chromosomes 5 and 6 respectively. These genes were localized further using hybrids containing specific translocations to 5q11-qter and 6p21 respectively. We also developed primers to enable us to assign 17 ESTs sequenced by the HGMP Resource Centre. The hybrid panel was developed with support of the UK HGMP and the DNA is available to all registered users.

Base Sequence↗
PubMed1995

Integrated genetic map of human chromosome 2.

A framework genetic map of human chromosome 2 is described, integrating data from the Centre d'Etude du Polymorphisme Humain (CEPH) version 6 database, the CEPH chromosome 2 consortium database, the National Institute of Health (NIH)/CEPH Collaborative Mapping group and other laboratories. A comprehensive map is also presented, showing regional locations of a large number of additional loci. The framework map is used to identify an informative set of meiotic breakpoints within the CEPH families, and the utility of this information for mapping new markers is discussed. The degree of typing error within the data set is estimated, as are the sex-specific interference parameters. A location database for these genetic and additional cytogenetic data is constructed using algorithms which map genetic distances on to a physical scale, and the potential for this approach to aid the integration of genetic and physical data is examined.

Chromosome Mapping↗
PubMed1994

Holoenzyme interaction sites in the cAMP-dependent protein kinase. Histidine 87 in the catalytic subunit complements serine 99 in the type I regulatory subunit.

Two mutations of the catalytic (C) subunit of the cAMP-dependent protein kinase where His87 was changed to Ala and Asp were expressed in Escherichia coli and purified. These mutants were phosphorylated at Thr197 and were catalytically active, although some changes in their kinetic parameters were observed. The most striking differences were in their interaction with the physiological inhibitors. Both mutants were inhibited by protein kinase inhibitor with Ki values below 50 nM. Both mutants were defective in their interaction with the type I regulatory (RI) subunit as measured by (i) the rate of holoenzyme formation with cAMP bound RI-subunit and (ii) the apparent Kd with the cAMP-free RI-subunit. The rate of holoenzyme formation was impaired both in the presence and absence of ATP with the His to Asp mutant showing the greatest effect. The mutant C-subunits were also combined with RI-subunits that contained mutations in the autoinhibitor sequence at Arg94 (P-3) and Ser99 (P + 2). Complementarity between His87 and Ser99 was established, but not between His87 and Arg94. Holoenzyme formation with a Ser99-->Lys mutant RI-subunit was less dependent on ATP when combined with either of the C-subunit mutants than when it was combined with the wild-type C-subunit. The apparent Kd values in the presence of ATP for the mutant combinations were also measured. The Ser99-->Lys mutant was compensated for by both His87 mutants. The His87-->Ala C-subunit mutant was unable to form an inhibited holoenzyme complex with a mutant RI-subunit which was defective in cAMP binding to the A-site. This indicated that this R-subunit was defective in C-subunit recognition as well as in cAMP binding. The roles of His87 on the C-subunit and Ser99 and Arg209 on the RI-subunit in R-C interactions are discussed.

Alanine↗
PubMed1994

High-performance liquid chromatographic determination of intrathecally administered [D-Ala2-D-Leu5]-enkephalin concentrations in canine cerebrospinal fluid.

A rapid and useful method for high-performance liquid chromatographic analysis of exogenous [D-Ala2-D-Leu5]-enkephalin (DADLE) in cerebrospinal fluid (CSF) is described. CSF (0.5 ml) samples were filtered using a 0.22-micron Co-Star filter. Chromatography was performed on a mu Bondapak C18 column using a mobile phase of A, 0.05 M sodium phosphate (monobasic, pH 6.0) and B, 60% acetonitrile in 0.05 M sodium phosphate (pH 6.0) with a flow-rate of 1 ml/min. Absorbance at 210 nm was measured. The procedure produced a linear curve for the concentration range 1-10 micrograms/ml. The development of the assay produced rapid, repeatable and accurate results for CSF analysis of DADLE at concentrations achieved with therapeutic administration of the peptide. This method could also be used in the future for analysis of compounds like DADLE.

Animals↗
PubMed1994

Comparison of extraction procedures for high-performance liquid chromatographic determination of cellular deoxynucleotides.

For the determination of cellular deoxynucleoside triphosphates (dNTPs) by high-performance liquid chromatography, the choice of extracting agent and periodate oxidation procedure is important for accurate results. Different extraction methods were compared using either cold methanol or trichloroacetic acid for extraction of dNTPs from lymphoblastoid cells. The recoveries of the dNTPs varied with the different extraction methods. A modification of the periodate oxidation procedure for degrading ribonucleoside triphosphates to their bases was also compared with the original method. Both methods gave accurate results when trichloroacetic acid was used as extracting agent, but when methanol was used interfering peaks were present on the chromatogram when the original method was used. These peaks were absent when the modified periodate procedure was used.

Chromatography, High Pressure Liquid↗
PubMed1994

Large linkage analysis in 100 families with autosomal recessive spinal muscular atrophy (SMA) and 11 CEPH families using 15 polymorphic loci in the region 5q11.2-q13.3.

The autosomal recessive proximal spinal muscular atrophy (SMA) gene was mapped to the region 5q11.2-q13.3 in 1990. Here, we present a large genetic linkage study of 100 SMA families and 11 CEPH families using 14 polymorphic simple sequence repeats (SSRs) and one RFLP in the region 5q11.2-q13.3. The genetic interval between the closest SMA flanking loci D5S435 and D5S557 comprises 1 cM at zmax = 27.94. Two recombinants were identified between the SMA gene and the closest telomeric marker D5S557 (theta = 0.02 at zmax = 8.63). The first places the SMA gene centromeric to this marker; the second suggests a double recombinant at D5S557, which is very unlikely. More likely explanations are discussed in the paper. No recombinant was found between D5S435 and the SMA gene (theta = 0.00 at zmax = 25.36). We localized a recently described polymorphic marker, D5S351 (Hudson et al., 1992), close to the SMA (theta = 0.00 at zmax = 19.01) and the 3'MAP1B gene (theta = 0.01 at zmax = 38.76). Due to its high PIC value of 0.70, it represents a very useful marker for prenatal diagnosis. In addition, we developed a new reverse primer for the nearest centromeric locus D5S435 (Soares et al., 1993), a useful marker for prenatal diagnosis, which has been very difficult to amplify in the past. Three of the markers presented here are newly developed polymorphic SSRs (one tetranucleotide repeat, D5S507/W15CATT, and two dinucleotide repeats, D5S544/C88.2GT and D5S682/C88.3GT). These markers are too far from the SMA gene to be relevant for cloning; nevertheless, as part of the human genome project, they are contributing to the fine genetic mapping of the region 5q11.2-q13.3. The most likely order of the loci based on two-point and multipoint linkage analyses as well as on specific recombination events and physical mapping studies is D5S76-D5S507- D5S6-D5S125-D5S680-D5S435-SMA-D5S557- D5S351-5'MAP1B-3'MAP1B-JK53CA1/2-(D5S127- D5S39)-(D5S544-D5S682). In general, the genetic distances obtained from the SMA and CEPH families are comparable.

Base Sequence↗
PubMed1994

Preoperative evaluation of abnormal mammographic findings to avoid unnecessary breast biopsies.

OBJECTIVE: To prospectively evaluate a program of additional mammographic views, interval follow-up, and stereotactic biopsy in the management of abnormalities detected on mammograms. METHODS: From June 1988 to September 1991, 267 consecutive women who were referred for surgical consultation because of an abnormal mammographic finding were evaluated. Mammographic abnormalities were assessed as benign or as requiring interval follow-up, stereotactic biopsy, open surgical biopsy, or additional views. Women having additional mammographic views were reassigned to the preceding groups. The mean follow-up for women who did not have a biopsy was 37 months. RESULTS: Only 129 (48%) of the women who were sent for surgical consultation underwent open biopsy, and 46 (36%) of the biopsy specimens revealed carcinoma. Forty-one (89%) of the cancers were ductal carcinoma in situ or stage I lesions. Of the 117 women who were assigned to follow-up, six (5%) subsequently required biopsy and two cancers were identified. CONCLUSION: Rigorous mammographic evaluation and the use of stereotactic biopsy for selected lesions can prevent breast biopsy for low-suspicion mammographic abnormalities while still allowing the detection of early-stage breast cancer.

Adult↗