Biomedical subjects

D C Bruce

Publications and source records attributed to D C Bruce.

7 recordsLinked to original sources

PubMed1995

An integrated physical map of human chromosome 16.

We describe an integrated physical, genetic and cytogenetic map of human chromosome 16 comprising both a low-resolution megaYAC map and a high-resolution cosmid contig/miniYAC map, which provides nearly complete coverage of the euchromatic arms of the chromosome. The physical map is anchored to a high-resolution cytogenetic breakpoint map and is integrated with genetic and gene transcript maps of the chromosome by sequence-tagged sites and clone hybridizations.

Animals↗

PubMed1995

Efficient pooling designs for library screening.

We describe efficient methods for screening clone libraries, based on pooling schemes that we call "random k-sets designs." In these designs, the pools in which any clone occurs are equally likely to be any possible selection of k from the v pools. The values of k and v can be chosen to optimize desirable properties. Random k-sets designs have substantial advantages over alternative pooling schemes: they are efficient, flexible, and easy to specify, require fewer pools, and have error-correcting and error-detecting capabilities. In addition, screening can often be achieved in only one pass, thus facilitating automation. For design comparison, we assume a binomial distribution for the number of "positive" clones, with parameters n, the number of clones, and c, the coverage. We propose the expected number of resolved positive clones--clones that are definitely positive based upon the pool assays--as a criterion for the efficiency of a pooling design. We determine the value of k that is optimal, with respect to this criterion, as a function of v, n, and c. We also describe superior k-sets designs called k-sets packing designs. As an illustration, we discuss a robotically implemented design for a 2.5-fold-coverage, human chromosome 16 YAC library of n = 1298 clones. We also estimate the probability that each clone is positive, given the pool-assay data and a model for experimental errors.

Binomial Distribution↗

PubMed1994

Determination and metabolism of dithiol chelating agents. XVI: Pharmacokinetics of 2,3-dimercapto-1-propanesulfonate after intravenous administration to human volunteers.

The pharmacokinetics of 2,3-dimercaptopropane-1-sulfonate (DMPS), an effective chelating agent for mercury, were determined in five healthy adults after i.v. administration of 3.0 mg/kg of DMPS. DMPS is rapidly transformed to disulfide forms; 15 min after administration, only 12% of the total DMPS detected in blood was present as the parent drug. DMPS and its metabolites were eliminated primarily by the kidneys. By 96 hr after administration, 12% of the total DMPS found in the urine was excreted as the parent drug (10% of the administered dose) and 88% was excreted as disulfide metabolites (74% of the administered dose). The disposition of parent drug was described by a biexponential equation with an elimination half-life of 1.8 hr. By contrast, the elimination half-life of total DMPS was 20 hr. The oral bioavailability of the parent drug was found in a separate study to be 39%. Mercury excretion in healthy volunteers correlated well with the urinary excretion of both the parent drug (r2 = .94) and the disulfide metabolites (r2 = .96).

Adult↗

PubMed1992

Urinary mercury after administration of 2,3-dimercaptopropane-1-sulfonic acid: correlation with dental amalgam score.

There is considerable controversy as to whether dental amalgams may cause systemic health effects in humans because they liberate elemental mercury. Most such amalgams contain as much as 50% metallic mercury. To determine the influence of dental amalgams on the mercury body burden of humans, we have given volunteers, with and without amalgams in their mouth, the sodium salt of 2,3-dimercaptopropane-1-sulfonic acid (DMPS), a chelating agent safely used in the Soviet Union and West Germany for a number of years. The diameters of dental amalgams of the subjects were determined to obtain the amalgam score. Administration of 300 mg DMPS by mouth increased the mean urinary mercury excretion of the amalgam group from 0.70 to 17.2 micrograms and that of the nonamalgam group from 0.27 to 5.1 micrograms over a 9-h period. Two-thirds of the mercury excreted in the urine of those with dental amalgams appears to be derived originally from the mercury vapor released from their amalgams. Linear regression analysis indicated a highly significant positive correlation between the mercury excreted in the urine 2 h after DMPS administration and the dental amalgam scores. DMPS can be used to increase the urinary excretion of mercury and thus increase the significance and reliability of this measure of mercury exposure or burden, especially in cases of micromercurialism.

Adolescent↗

PubMed1992

Human studies with the chelating agents, DMPS and DMSA.

Meso-2,3-dimercaptosuccinic acid (DMSA) is bound to plasma albumin in humans and appears to be excreted in the urine as the DMSA-cysteine mixed disulfide. The pharmacokinetics of DMSA have been determined after its administration to humans po. For the blood, the tmax and t1/2 were 3.0 h + 0.45 SE and 3.2 h + 0.56 SE, respectively. The Cmax was 26.2 microM + 4.7 SE. To determine whether dental amalgams influence the human body burden of mercury, we gave volunteers the sodium salt of 2,3-dimercaptopropane-1-sulfonic acid (DMPS). The diameters of dental amalgams of the subjects were determined to obtain the amalgam score. Administration of 300 mg DMPS by mouth increased the mean urinary mercury excretion of subjects over a 9 h period. There was a positive correlation between the amount of mercury excreted and the amalgam score. DMPS might be useful for increasing the urinary excretion of mercury and thus increasing the significance and reliability of this measure of mercury exposure. DMSA analogs have been designed and synthesized in attempts to increase the uptake by cell membranes of the DMSA prototype chelating agents. The i.v. administration of the monomethyl ester of DMSA, the dimethyl ester of DMSA or the zinc chelate of dimethyl DMSA increases the biliary excretion of platinum and cadmium in rats.

Adult↗

PubMed1991

Binding of polonium-210 to liver metallothionein.

The interactions of 210Po at the molecular level in biological systems have received little study even though this alpha-emitting radionuclide occurs widely in nature. Polonium-210 was given subcutaneously to rats and found to be incorporated into liver metallothionein as judged by a number of criteria including heat stability, acetone precipitation, and chromatography. In vitro studies confirmed this binding. The binding of 210Po to metallothionein has implications that may help explain some of the radiation damage 210Po causes intracellularly.

Animals↗

PubMed1989

Determination and metabolism of dithiol chelating agents. VI. Isolation and identification of the mixed disulfides of meso-2,3-dimercaptosuccinic acid with L-cysteine in human urine.

Virtually nothing is known about the biotransformation of the heavy metal chelating agent, meso-2,3-dimercaptosuccinic acid (DMSA). Two fasted, normal, young men were given 10.0 mg DMSA/kg po, and their urines were collected over a 14-hr period. Urine samples were analyzed, before and after electrolytic reductive treatment, for DMSA and its biotransformants using bromobimane derivatization, HPLC separation, and fluorescence detection. Metabolites were isolated by HPLC, ion-pairing extraction, ion-exchange extraction, and TLC. By 14 hr after DMSA administration, 87% of the total DMSA and 95% of the total L-cysteine found in urine consisted of altered forms of these compounds. The urinary excretion of altered DMSA, at 1, 2, 4, 6, 9, and 14 hr after administration of DMSA, when compared to the urinary excretion of altered L-cysteine had a correlation coefficient of 0.952 and p less than 0.003. Approximately 90% of the altered DMSA excreted in the 2- to 4-hr urine was found in disulfide linkage with L-cysteine. The remaining 10% was found as cyclic disulfides of DMSA. Of the mixed disulfides found in 4- to 6-hr urine, 97% consisted of two L-cysteine residues per one DMSA and the remaining 3% consisted of one L-cysteine per one DMSA. The 2:1 mixed disulfides (97%) were isolated as three distinct species by TLC, consisting of 77, 12, and 8% of the total mixed disulfides found. In addition to the novelty of these biotransformants of DMSA, the DMSA-cysteine mixed disulfides indicate a thiol-disulfide interchange between DMSA and L-cystine. The discovery of the formation of these water soluble DMSA-cysteine mixed disulfides should encourage the evaluation of DMSA in the treatment of cystinuria.

Adult↗