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Biomedical subjects

D R Boswell

Publications and source records attributed to D R Boswell.

At least 19 recordsLinked to original sources
PubMed1995

Improved efficacy with nonsimultaneous administration of first doses of gentamicin and ceftazidime in vitro.

First doses of aminoglycoside and beta-lactam antibiotics, when used in combination, are usually given simultaneously; however, nonsimultaneous administration may be more efficacious. We used a dynamic in vitro model, which simulates in vivo serum kinetics, to assess the effect of spacing the first doses of gentamicin and ceftazidime used against Pseudomonas aeruginosa ATCC 27853 and two clinical isolates of P. aeruginosa, PA1 and PA2. The following dose regimens against P. aeruginosa ATCC 27853 were compared: (i) gentamicin given alone, (ii) ceftazidime given alone, (iii) gentamicin and ceftazidime given simultaneously, (iv) gentamicin followed by ceftazidime at 15 or 50 min or at 2, 4, or 8 h, and (v) ceftazidime which was followed by gentamicin at 4 h. The effects of regimen iii and the 4-h interval in regimen iv against PA1 and PA2 were also compared. Initial peak concentrations used were 8 mg/liter for gentamicin and 80 mg/liter for ceftazidime, with drug half-lives of 2.5 and 1.8 h, respectively. Compared with simultaneous administration, nonsimultaneous administration (regimens iv and v) produced greater overall bacterial killing and was associated with a delay in bacterial regrowth (p < 0.005) of up to 6.6 to 8.3 h, regardless of the order in which the drugs were given. The optimal interval between gentamicin and ceftazidime doses, which maximized initial bactericidal effect and the time before regrowth, appeared to be 2 to 4 h.

Ceftazidime↗
PubMed1994

Assessment of a computerized system for the diagnosis of iron deficiency.

The aim of this study was to develop a computer expert system that could reproduce a pathologist's diagnosis of iron deficiency from the data obtained from blood tests. 275 cases were collected for construction and testing of the expert system. The expert system used a combination of fuzzy set logic and cut-off points from 14 parameters to arrive at one of 5 diagnostic categories graded from "iron deficient" to "no evidence of iron deficiency". The agreement between pathologist and expert system was 0.91 (Spearman rank correlation coefficient) in the learning population; this dropped to 0.79 in the test population. Absolute agreement on diagnostic category was reached in 71% of cases. In no case was there disagreement by more than 3 grades.

Anemia, Hypochromic↗
PubMed1992

Elevated levels of acute phase plasma proteins in major depression.

Levels of acute phase and other plasma proteins were measured in 21 men with major depression, 28 men with alcohol dependence, and 12 men who acted as controls. The depressed men had significantly elevated levels of the acute phase proteins, haptoglobin and alpha-1-antichymotrypsin, and of immunoglobulin G. The elevations in haptoglobin and alpha-1-antichymotrypsin were highly correlated with each other, and were correlated with the severity of depression and negatively correlated with the thyroid stimulating hormone response to thyrotropin. The alcoholic men had elevated haptoglobin levels, but significantly decreased levels of immunoglobulin G. These findings provide further evidence for an inflammatory response during depression.

Acute-Phase Proteins↗
PubMed1992

Comparison of gentamicin dosing regimens using an in-vitro model.

An in-vitro model which simulates in-vivo pharmacokinetics was used to compare the efficacy against Pseudomonas aeruginosa of dosing regimens of gentamicin which achieve different peak/trough concentrations but use the same total dose over 24 h. First exposure to gentamicin produced a rapid bactericidal effect which was proportional to the initial peak concentration. Subsequent doses of gentamicin produced a smaller bactericidal effect. Regrowth occurred with all dosing regimens, even after very high initial concentrations (26 mg/L). The time to reach bacterial counts above starting values was prolonged in relation to peak concentrations. Regrowth was also demonstrated in continuous infusion experiments which maintained very high concentrations (26 mg/L), although an inhibitory effect was evident compared with single dose experiments and the experiments mimicking in-vitro pharmacokinetics. There was little evidence of a post-antibiotic effect. The data supports the use of larger initial and longer interval bolus dosing compared with current recommendations.

Drug Administration Schedule↗
PubMed1991

P1 variant antithrombins Glasgow (393 Arg to His) and Pescara (393 Arg to Pro) have increased heparin affinity and are resistant to catalytic cleavage by elastase. Implications for the heparin activation mechanism.

The heparin affinity of normal and two P1 variants of antithrombin-III (AT) was studied by gradient elution with NaCl in Tris buffer on heparin-Sepharose. At pH 7.4 normal AT eluted at [Na+] 0.78 mol/l and the variants both showed increased affinity with AT Pescara eluting at [Na+] 0.86 mol/l and AT Glasgow at [Na+] 0.92 mol/l. We have earlier proposed a model for heparin activation in which the native state of AT maintains a salt bridge involving the P1 Arg-393 residue. Binding of heparin induces a higher heparin affinity conformation in which the salt bridge is disrupted to reveal the reactive centre for inhibition of thrombin. The Glasgow and Pescara variants, lacking a reactive centre P1 basic residue, would be unable to form this salt bridge, and we suggested that the high affinity conformation which they adopt as their native state would resemble the heparin induced conformation. To examine this model, we measured the heparin induced fluorescence of two P1 variants and tested the susceptibility of their reactive loops to catalytic cleavage. Both variants had fluorescence spectra indistinguishable from normal AT. In the absence of heparin, neither variant was more susceptible than normal to catalytic cleavage by human neutrophil elastase. These findings suggest that the conformation of these P1 variants is different to that of fully heparinized normal AT.

Antithrombin III↗
PubMed1991

Antimicrobial effects of lomefloxacin in vitro.

The MIC of lomefloxacin was determined for 554 isolates from the urinary tract. Some of the more resistant strains of Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, and Pseudomonas aeruginosa were studied in a dynamic in-vitro model in order to study dosing strategies. The model simulated, in Mueller-Hinton broth, the profile of plasma lomefloxacin concentrations in volunteers. Bacteria were exposed to a range of lomefloxacin concentration profiles achievable by oral dosing. The first dose of lomefloxacin was rapidly bactericidal in a dose-dependent manner for all strains. On re-exposure, a dose-dependent inhibitory effect was observed. Drug-resistant mutants were readily isolated from all bacteria tested on lomefloxacin-containing plates. These occurred at a high frequency in P. aeruginosa (10(-1)), but less frequently in K. pneumoniae (10(-3)). P. mirabilis (10(-5)), and E. coli (10(-6)). The number of resistant mutants isolated tended to be lower with use of higher drug concentrations. The results suggest that lomefloxacin dosing regimens ensuring maintenance of a high serum concentration: MIC ratio will result in maximal antibacterial effects and minimal problems with resistant strains.

4-Quinolones↗
PubMed1991

Prediction of the site of signal peptidase cleavage in normal and variant human preproalbumin.

We describe the use of a template for the recognition site of signal peptidase to give score predictions for cleavage at normal and aberrant sites in human and chicken preproalbumin. As expected, the highest score obtained for human preproalbumin was at the normal cleavage site between -7 Ser and -6 Arg. The mutation in preproalbumin Kaikoura (-2 Arg----Cys) introduced an aberrant cleavage site in the propeptide between the new -2 Cys and -1 Arg. Although the new site had a lower template score (6.88) than the normal site (9.99), it is cleaved in vivo about five times faster. The presence of minor proportions of des-Asp and des-Asp-Ala-albumin in normal human plasma was not found to correlate with possible aberrant signal peptidase cleavage. These truncated albumin species, therefore, appear to be generated through cleavage of mature albumin in circulation. Chicken preproalbumin had only one probably signal peptidase cleavage site, the one utilised in vivo. Template scores should be regarded as qualitative predictions rather than definitive quantitative indicators.

Algorithms↗
PubMed1989

Novel human proalbumin variant with intact dibasic sequence facilitates identification of its converting enzyme.

We describe here the identification of a new genetic variant of human proalbumin with an N-terminal sequence of Arg-Gly-Val-Phe-Arg-Arg-Val-Ala-His-Lys-. Proalbumin Blenheim (10%) and mature albumin Blenheim (38%) with an initial sequence of Val-Ala-His-Lys-make up nearly half the serum albumin in affected individuals. Despite retaining an intact dibasic processing site, proalbumin Blenheim (1 Asp----Val) enters the circulation unprocessed. The observed ratio of proalbumin to albumin can be accounted for by proteolysis in the periphery. Employed as a potential substrate, proalbumin Blenheim provides a unique means of identifying the physiologically relevant proalbumin convertase. In vitro studies showed that the variant is readily cleaved by trypsin. However, it is not cleaved by the proposed proalbumin convertase, a membrane-bound Ca2+-dependent proteinase prepared from rat liver Golgi vesicles, which gives authentic cleavage of normal human proalbumin.

Adult↗
PubMed1989

Molecular characterization of antithrombin Barcelona-2: 47 arginine to cysteine.

The molecular characterization of antithrombin Barcelona-2 is reported. The abnormal antithrombin was isolated from plasma by chromatography on heparin-Sepharose at pH 6.0, and ion exchange on DEAE-Sephadex at pH 8.6 and 6.0. The tryptic peptides were mapped by reverse-phase HPLC and amino acid sequencing and mass spectrometry showed arginine-47 to be replaced by cysteine. The affinity of Barcelona-2 for heparin is dramatically decreased. The new cysteine does not form a mixed disulphide with DTNB, implying it is present as a disulphide with some other available thiol molecule such as cysteine. This extra bulk at position 47 accounts for the low heparin affinity compared with two other mutations (Rouen-1 47 His; Rouen-2 47 Ser) at this residue. These results confirm the view that Arg-47 is an important residue in heparin binding. No dimers of Barcelona-2 were observed suggesting that steric hindrance of the new cysteine at residue 47 prevents dimerisation.

Amino Acid Sequence↗
PubMed1989

Alpha thalassaemia in the Maori: a family study.

Twelve members of a Maori family were investigated for alpha-thalassaemia after a provisional diagnosis of thalassaemia had been made on the basis of chronic hypochromic microcytic red cell indices. Ten family members were shown to have the 3.7 kb deletion form of alpha-thalassaemia; two of these were homozygous for this deletion (-alpha/-alpha); eight had the single deletion (-alpha/alpha alpha). While anaemia was not a significant finding, the degree of hypochromicity and microcytosis correlated well with the alpha globin gene status of individual family members. This and other studies provide evidence that alpha-thalassaemia is a significant contributor to the chronic mild anaemia of the Maori.

Adolescent↗
PubMed1989

A cross-reference table between the Protein Data Bank of macromolecular structures and the National Biomedical Research Foundation-Protein Identification Resource amino acid sequence data bank.

The National Biomedical Research Foundation-Protein Identification Resource (NBRF-PIR) and the Protein Data Bank at Brookhaven National Laboratory (PDB) both contain protein sequences. We have prepared a cross-reference index of the sequences in these data banks, and compared the data. Of the 270 cases of sequences of the same protein appearing in both data bases, for only 31% are the sequences identical. This is often the result of a difference in the state of maturation of the proteins rather than experimental error. Nevertheless is useful to be aware that the sequence information in these two data archives should not be regarded as redundant.

Amino Acid Sequence↗
PubMed1988

The outline structure of the T-cell alpha beta receptor.

From an analysis of the immunoglobulins of known structure we derive a list of 40 sites crucial for the conserved structure of the variable domains. We show that, with marginal exceptions, the sequences of the T-cell alpha beta receptors contain, at sites homologous to these 40, the same or very similar residues. Thus the V alpha-V beta dimer has a framework structure very close to that of the immunoglobulins. Further comparisons show that parts of the surface of the V alpha-V beta framework are hypervariable. They also show that the loops that form the antigen-binding site are similar in size to those commonly found in the immunoglobulins but have different conformations. Only limited sequence variations occur in the first loop of the antigen-binding site in both V alpha and V beta. This, and their geometrical arrangement, suggest that they mainly interact with the MHC proteins.

Amino Acid Sequence↗
PubMed1988

The quality of performance of the fructosamine test.

The performance of fructosamine assays in 35 laboratories was assessed over a six month period in 1987. While agreement between laboratories was poor in the range expected in diabetic patients, most laboratories were internally consistent. The interlaboratory differences are largely attributed to the calibration methods used for this test. Fructosamine results from any one laboratory must not be interpreted by comparison with data from other laboratories or the literature. Other common biochemical tests were found to suffer from similar problems, but to a less serious extent.

Calibration↗
PubMed1988

A program for template matching of protein sequences.

The matching of a template to a protein sequence is simplified by treating it as a special case of sequence alignment. Restriction of the distances between motifs in the template controls against spurious matches within very long sequences. The program using this algorithm is fast enough to be used in scanning large databases for sequences matching a complex template.

Algorithms↗