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Biomedical subjects

S Freer

Publications and source records attributed to S Freer.

8 recordsLinked to original sources
PubMed2000

Patient education and emergency room visits.

Patients visit emergency rooms for urgent and non-urgent care. Because emergency room visits are more costly than visits to primary care clinics and are less likely to involve preventive care, third party payers and institutions have always tried to shift patients away from the emergency room and towards primary care clinics where appropriate. Hypothesizes that an intervention based in an adult primary care clinic might enable this, especially if it involved patients who used both the clinic and the emergency room. Surveys patients to determine why they used the emergency room and to identify barriers to using the primary care clinic instead. Based on the survey results, an intervention was developed to facilitate use of the primary care clinic. Discusses the methodology used in the survey and analyses results. Concludes that it is difficult to change patient behaviour to fit the demands of the health care system. Possibly, it would be better to change the system to fit the behaviour patterns of the patients.

Adult↗
PubMed1999

Glutathione peptidomimetic drug modulator of multidrug resistance-associated protein.

The peptidomimetic drug gamma-glutamyl-S-(benzyl)cysteinyl-R-(-)-phenyl glycine diethyl ester (TER199) is an analog of glutathione designed to be an isozyme-specific inhibitor of GSTP1-1 protein1-1. This compound (and the de-esterified moiety) is shown to be an effective inhibitor of multidrug resistance-associated protein1 (MRP1)-mediated drug resistance. Kinetic analyses revealed that gamma-glutamyl-S-(benzyl)cysteinyl-R-(-)-phenyl glycine reversibly inhibits the transport of 2,4-dinitrophenyl-S-glutathione with a K(i) of 752 microM. TER199 reversed the accumulation deficit of daunorubicin in MRP1-transfected NIH3T3 fibroblasts and maintained intracellular levels for >2 h after daunorubicin removal. Cytotoxicity assays revealed that TER199 significantly reversed the resistance of MRP1-transfected NIH3T3 cells for vincristine, doxorubicin, etoposide, and mitoxantrone. HL-60 cells made resistant to TER199 by chronic, long-term selection had increased mRNA and protein levels of multidrug resistance-associated protein, MRP1, and gamma-glutamyl cysteine synthetase heavy and light subunits (the rate-limiting enzyme in GSH synthesis). In spite of increased gamma-glutamyl cysteine synthetase, their glutathione content was reduced approximately 35% from that of parental HL-60 cells. These cells also exhibited a drug resistance profile commensurate with the previously described MRP1 overexpressing phenotype, with resistance to Vinca alkaloids, epipodophyllotoxins, and anthracyclines; additional cross-resistance to paclitaxel (Taxol), mitoxantrone, and 5-fluorouracil was observed.

3T3 Cells↗
PubMed1990

Stereochemical mechanism of action for thymidylate synthase based on the X-ray structure of the covalent inhibitory ternary complex with 5-fluoro-2'-deoxyuridylate and 5,10-methylenetetrahydrofolate.

The structure of the Escherichia coli thymidylate synthase (TS) covalent inhibitory ternary complex consisting of enzyme, 5-fluoro-2'-deoxyuridylate (FdUMP) and 5,10-methylene tetrahydrofolate (CH2-H4PteGlu) has been determined at 2.5 A resolution using difference Fourier methods. This complex is believed to be a stable structural analog of a true catalytic intermediate. Knowledge of its three-dimensional structure and that for the apo enzyme, also reported here, suggests for the first time how TS may activate dUMP and CH2-H4PteGlu leading to formation of the intermediate and offers additional support for the hypothesis that the substrate and cofactor are linked by a methylene bridge between C-5 of the substrate nucleotide and N-5 of the cofactor. By correlating these structural results with the known stereospecificity of the TS-catalyzed reaction it can be inferred that the catalytic intermediate, once formed, must undergo a conformational isomerization before eliminating across the bond linking C-5 of dUMP to C-11 of the cofactor. The elimination itself may be catalyzed by proton transfer to the cofactor's 5 nitrogen from invariant Asp169 buried deep in the TS active site. The juxtaposition of Asp169 and bound tetrahydrofolate in TS is remarkably reminiscent of binding geometry found in dihydrofolate reductase where a similarly conserved carboxyl group serves as a general acid for protonating the corresponding pyrazine ring nitrogen of dihydrofolate.

Binding Sites↗
PubMed1980

Correlation between anti-RANA and anti-EBNA titers in normal subjects with and without HLA-DRw4.

We have determined the relationship of antibody titers to the rheumatoid arthritis nuclear antigen (RANA) and of antibody titers to the Epstein-Barr nuclear antigen (EBNA) to each other and to the DRw4 B cell alloantigen in the sera of 34 normal white adults. By a sensitive indirect immunofluorescence (IF) assay, 76% had RANA antibody, compared to 23% by a micro-immunodiffusion assay. The correlation coefficient for the tube dilution titers of anti-RANA and anti-EBNA was 0.61 (P < 10(-4)). The 14 DRw4-positive subjects and the 20 DRw4-negative subjects did not differ with respect to anti-RANA titers (P = 0.51) or anti-EBNA titers (P = 0.89). We conclude that: 1) most normal adults have RANA antibody by IF; 2) anti-RANA and anti-EBNA titers are closely related; 3) the titers of these antibodies cannot be related to the presence of the DRw4 determinant in normal persons.

Antibodies, Antinuclear↗