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Biomedical subjects

M G Williams

Publications and source records attributed to M G Williams.

At least 37 records · Page 2Linked to original sources
PubMed1996

Kaolinosis in a cotton mill worker.

A 62-year-old white male employed for 43 years in the polishing room of a cotton textile mill was admitted to a tertiary care center with progressive dyspnea and productive cough that had not responded to therapy for tuberculosis. In spite of aggressive antibiotic therapy and respiratory support, the patient died as a consequence of respiratory failure. Small rounded and irregular opacities had been noted on the chest radiograph. Review of job-site spirometry demonstrated a worsening restrictive pattern over a 4-year period prior to his death. Additional occupational history revealed long-term exposure to kaolin in the polishing room, and pathologic examination of lung tissue confirmed extensive fibrosis and substantial quantities of kaolin. Kaolinosis is a disease typically found among individuals involved in mining or processing this material rather than in user industries. This case illustrates the importance of obtaining a complete occupational history in reaching a diagnosis. The clinicopathologic aspects of kaolinosis are also reviewed.

Fatal Outcome↗
PubMed1996

Simultaneous quantitation of pioglitazone and its metabolites in human serum by liquid chromatography and solid phase extraction.

A high-performance liquid chromatographic (HPLC) method for the simultaneous determination of pioglitazone (U-72107) and its potential metabolites (M-1 to M-6) in human serum was developed. The method involved a solid phase extraction (SPE) of pioglitazone, its metabolites, and the internal standard (U-92573) from serum using C18 SPE columns with an elution solvent of 0.5 ml of acetonitrile-water (35:65, v/v). Separation of the eight analytes was achieved within 20 min using a reversed-phase Zorbax RX-C8 analytical column (250 mm x 4.6 mm i.d., 5 microns particle size) with a mobile phase of acetonitrile-water (40:60, v/v) containing 3 ml acetic acid per liter mobile phase (apparent pH 5.5). An ultraviolet detector operated at 269 nm was used with a linear response observed from 0.02 to 2 micrograms ml-1 for these analytes except for M-4 which was best fitted with a polynomial regression. Limit of quantitation was found to be 0.02 microgram ml-1 for pioglitazone, M-3, M-5, and M-6; 0.04 microgram ml-1 for M-2 and M-4; and 0.5 microgram ml-1 for M-1 when using a 0.5 ml serum sample for extraction. Obtained from the method validation, intra- and inter-assay precision was < or = 9% and accuracy ranged from -8.2 to 13.4% for all analytes. The applicability of this method has been demonstrated by successfully analyzing clinical serum samples. The strategies in the HPLC characterization and in the SPE procedure development for this method are discussed as well.

Chromatography, High Pressure Liquid↗
PubMed1996

Occult ascending aortic rupture in the presence of an air bag.

A patient presented to the emergency department after a high-speed decelerating-type motor vehicle accident. Due to activation of his air bag device, the patient was without significant obvious injury. Upon evaluation in the emergency department he was also without any radiographic or physical signs of serious injury. In the ensuing 24 hours, severe chest pain developed, and subsequent aortography demonstrated a tear of his ascending aorta just distal to the root. Although occult injury to the aorta and great vessels does occur in a small percentage of patients, it is quite rare. However, with the advent of air bags, in the absence of associated injuries, signs, and symptoms, a high index of suspicion must be entertained in decelerating-type accidents to diagnose occult injury to the aorta and great vessels.

Accidents, Traffic↗
PubMed1996

Pharmacokinetics of the individual enantiomers of cis-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-benzamide monohydrochloride (U-54494A) in the dog.

U-54494A, a racemic mixture of two enantiomers, is being developed in racemic form as an anticonvulsant drug candidate. A comparative pharmacokinetic study with intravenous and oral administration of the two individual enantiomers to the dog was conducted to evaluate the potential enantioselective pharmacokinetics of U-54494. Following i.v. administration, the (-)- and (+)-enantiomers showed no significant differences in plasma clearance (0.84 +/- 0.11 versus 0.86 +/- 0.06 l/hr/kg) and terminal elimination half-life (11.2 +/- 2.7 versus 8.0 +/- 2.6 hr) for the parent drug. However, the AUC of intact drug was two-fold lower with two-fold shorter elimination half-life following the oral administration for the (+)-enantiomer as compared to the (-)-enantiomer. Higher plasma levels of the four metabolites were also observed for the (+)-than for the (-)-enantiomer, particularly after oral administration. These results suggested that the (+)-enantiomer appeared to be more extensively metabolized by first-pass effect than the (-)-enantiomer after oral dosing, and as a result, oral bioavailability for the (+)-enantiomer is only one half of that for its antipode (12.0 +/- 1.5% versus 26 +/- 9%).

Administration, Oral↗
PubMed1995

The umpA gene of Escherichia coli encodes phosphatidylglycerol:prolipoprotein diacylglyceryl transferase (lgt) and regulates thymidylate synthase levels through translational coupling.

Using a combination of biochemical, physical, and genetic techniques, we have shown that the umpA gene of Escherichia coli is allelic with the lgt (phosphatidylglycerol:prolipoprotein diacylglyceryl transferase) of Salmonella typhimurium. These genes are essential for the viability of the respective organism and exhibit 92.8% sequence identity at the amino acid level. In E. coli, lgt and thyA (thymidylate synthase) form an operon. Thymidylate synthase levels are regulated by transcription from the lgt promoter and by translational coupling.

Amino Acid Sequence↗
PubMed1995

Trends in pediatric cardiac pacing.

OBJECTIVE: To review retrospectively a 31-year experience with pediatric cardiac pacing at the University of Toronto, with an emphasis on the changing trends in pacemaker implantation in infants and children. DATA SOURCE: Data were obtained from the pediatric pacemaker follow-up clinic at The Hospital for Sick Children, Toronto, Ontario or from the referring pediatric centre. Follow-up was normally continued until the death of the child or referral to an adult hospital at age 18 years. PATIENT SELECTION: The study comprised 397 children (under 18 years of age) who underwent initial pacemaker implantation at The Hospital for Sick Children between January 1962 and December 31, 1992. Follow-up was 99% complete (five children lost) and ranged from one month to 32 years (mean 6.5 years). DATA SYNTHESIS: The use of endocardial versus epicardial leads increased significantly over time (P < 0.001). In addition, significantly more children receiving pacemakers had sick sinus syndrome (P < 0.001). No difference in survival was found between children paced by endocardial versus epicardial leads or between children paced for sick sinus syndrome versus atrioventricular block. The frequency of exit block, by lifetable analysis, did not differ between children who received epicardial versus endocardial leads. CONCLUSIONS: Guidelines for permanent pacemaker implantation in children continue to evolve as developments in lead technology alter trends in pediatric cardiac pacing.

Adolescent↗
PubMed1994

First-pass effect of cis-3,4-dichloro-N-methyl-N-(2-(1-pyrrolidinyl)- cyclohexyl)-benzamide (U-54494) in rats--a model with multiple cannulas for investigation of gastrointestinal and hepatic metabolism.

A multiple cannulated rat model was utilized to investigate the relative contribution of the gut and liver as sites of first-pass metabolism of orally administered U-54494A, an anticonvulsant drug candidate. Each rat received a dose of U-54494A by oral, intraportal, and intravenous routes on three separate occasions. Intraportal and intravenous doses were administered through chronic cannulas surgically implanted in the portal vein and superior vena cava, respectively. Blood samples were collected over a 6-hr period from the superior vena cava cannula. The mean (n = 3) bioavailability of orally dosed U-54494A was 4.5 +/- 1.1%, while that dosed intraportally was 19.1 +/- 3.0%. The relative contribution of the gut and liver as sites of first-pass extraction and/or metabolism of orally administered drug was 69.9 +/- 14.0% and 24.5 +/- 12.2%, respectively. Approximately 35 to 40% of the total plasma clearance was attributeds to the liver. The plasma concentrations of the four known metabolites of U-54494A were apparently higher for the oral and intraportal routes compared to that after intravenous administration. This investigation confirms that the low oral bioavailability of U-54494A in the rat can be primarily attributed to both extensive intestinal and hepatic first-pass metabolism.

Administration, Oral↗
PubMed1994

Iron associated with asbestos bodies is responsible for the formation of single strand breaks in phi X174 RFI DNA.

The ability of amosite cored asbestos bodies isolated from human lungs to catalyse damage to phi X174 RFI DNA in vitro was measured and compared with that of uncoated amosite fibres with a similar distribution of length. Asbestos bodies (5000 bodies) suspended for 30 minutes in 50 mM NaCl containing 0.5 micrograms phi X174 RFI DNA, pH 7.5, did not catalyse detectable amounts of DNA single strand breaks. Addition of the reducing agent ascorbate (1 mM), however, resulted in single strand breaks in 10% of the DNA. Asbestos bodies in the presence of a low molecular weight chelator (1 mM) and ascorbate catalysed the formation of single strand breaks in 21% of the DNA with citrate or 77% with ethylenediamine tetra-acetic acid (EDTA), suggesting that mobilisation of iron may increase damage to DNA. Preincubation for 24 hours with desferrioxamine B, which binds iron (Fe (III)) and renders it redox inactive, completely inhibited the reactivity of asbestos bodies with DNA, strongly suggesting that iron was responsible. Amosite fibres (5000 fibres/reaction), with a similar length distribution to that of the asbestos bodies, did not catalyse detectable amounts of single strand breaks in DNA under identical reaction conditions. The results of the present study strongly suggest that iron deposits on the amosite core asbestos bodies were responsible for the formation of DNA single strand breaks in vitro. Mobilisation of iron by chelators seemed to enhance the reactivity of asbestos bodies with DNA. It has been postulated that the in vivo deposition of the coat material on to fibres may be an attempt by the lung defenses to isolate the fibre from the lung surface and thus offer a protective mechanism from physical irritation. These results suggest, however, that the iron that is deposited on asbestos fibres in vivo may be reactive, potentially increasing the damage to biomolecules, such as DNA, above that of the uncoated fibres.

Asbestos, Amosite↗
PubMed1993

Effect of glucose deprivation of GLUT 1 expression in 3T3-L1 adipocytes.

Elevated glucose transport rates during glucose deprivation are phenomena that have been observed in several different types of cells in culture. We show here that glucose transport rates in 3T3-L1 adipocytes increased by 10-fold within 18 h in response to glucose deprivation, confirming earlier work by Van Putten and Krans (Van Putten, J. P. M., and Krans, H. M. J. (1985) J. Biol. Chem. 260, 7996-8001). Mannose and 3-O-methylglucose (a nonmetabolizable glucose analog), but not fructose or galactose, blocked the increase in transport activity. Although the increase in transport was dependent on new protein synthesis, only a small and transient increase in GLUT 1 mRNA (less than 2-fold) was observed. In addition, the level of the normal isoform of GLUT 1 (46 kDa) did not increase. A lower molecular mass isoform (37 kDa) was observed but not until 15 h after glucose removal, the appearance of which was clearly not correlated with the increase in activity. Further, the extracellular glucose concentration required to elicit accumulation of this form (p37) was 2 orders of magnitude less than that required for transport stimulation (5 microM versus 500 microM glucose; p37 accumulation and transport activation, respectively). Interestingly, p37 was seen in the presence of galactose, but not fructose, despite elevated transport activity with either sugar. The p37 isoform was slightly larger than N-glycosidase F-treated GLUT 1 (36 kDa), implying that this form is still glycosylated, albeit incompletely. It is not known if p37 is functional, but the time- and sugar-dependent appearance of the lower isoform suggests that p37 is not responsible for starvation-induced transport but potentially represents an underglycosylated precursor of the normal, 46-kDa isoform of GLUT 1.

3T3 Cells↗
PubMed1993

Percutaneous transluminal coronary angioplasty in chronic coronary artery occlusion.

OBJECTIVES: This study was conducted to determine the procedural success rate, complication rate and long-term outcome of percutaneous transluminal coronary angioplasty in chronically occluded coronary arteries. BACKGROUND: Coronary angioplasty of chronically occluded vessels has a lower success rate than has angioplasty of nonoccluded vessels, but it is frequently considered safe because the target vessel is already occluded. The purpose of this study was to determine the reliability of these assumptions at our institution, with the objectives stated above. METHODS: We identified from the angioplasty data base at our institution 100 consecutive coronary angioplasty procedures performed between 1987 and 1991 for chronic total occlusion, defined as complete occlusion (Thrombolysis in Myocardial Infarction [TIMI] grades 0 and 1 flow) for > or = 3 months. The records of the 95 patients who underwent these procedures were reviewed to determine procedural outcome and medium-term results. RESULTS: Procedural success was obtained in 47 occluded vessels (47%). Significantly fewer successes were obtained in the right coronary artery (26.8%) than in either the left anterior descending (57.1%) or the left circumflex (45%) coronary artery (p < 0.05). A procedural failure without serious adverse consequences occurred in 45 procedures (45%), but in eight patients (right coronary artery in five, left anterior descending artery in three) attempted recanalization was complicated by extensive coronary dissection with acute myocardial ischemia, and one of these patients died. There were no emergency operations, but elective coronary artery bypass surgery was undertaken in 26 patients (in 3 after extensive dissection, in 7 after an apparently good result and in 16 in whom the procedure failed). At 12 months after the procedure, 64.1% of those with a procedural success were event free compared with 32.6% of those whose procedure was both unsuccessful and uncomplicated (p < 0.025) and 25% of those in whom it was unsuccessful and complicated by coronary dissection (p < 0.025). CONCLUSIONS: In this series of recanalization of chronically occluded coronary arteries, there was a low procedural success rate, particularly for the right coronary artery. However, when procedural success was obtained, the long-term outlook was good. The overall risk of coronary dissection was comparable to the risk in nonoccluded vessels but was particularly high in the right coronary artery (13%).

Adult↗
PubMed1993

Quantitative determination of cis-3,4-dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzamide and three of its metabolites in plasma by high-performance liquid chromatography.

A sensitive HPLC method was developed for simultaneous quantitation of cis-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-benzamide and three of its metabolites in dog plasma. The method involved selective solid-phase extraction of the compounds of interest from dog plasma and HPLC separation of the analytes on a cyano column. Absorbance of the column effluent was monitored at 230 nm by a UV detector. The analytical procedure has a linear range of 10 ng/mL to 20 micrograms/mL, with a low limit of quantitation of 10 ng/mL for each analyte. The accuracy and intra- and interassay precision for each compound were < or = 11% in the concentration range evaluated. Applicability of this method to the quantitation of 1 and its metabolites was assessed in a preclinical pharmacokinetic study.

Animals↗
PubMed1992

Asbestos in organs and placenta of five stillborn infants suggests transplacental transfer.

Digests of lungs, liver, and placenta from five stillborn infants of 22 to 38 weeks gestational age were examined for asbestos and other fibers using light and electron microscopy, energy dispersive X-ray analysis, and selected area diffraction analysis. Uncoated chrysotile asbestos fibers were found in the digests of at least one of the three tissues examined from each stillborn infant. The asbestos fiber burdens ranged from 71,000 to 357,000 fibers/g wet tissue. Most of the fibers were small, with the mean length ranging from 0.83 to 2.53 microns. While appreciable numbers of uncoated chrysotile fibers were present, no coated asbestos fibers were found in any of the stillborns. Both coated and uncoated nonasbestos fibers were found in at least one of the tissue digests of all five stillborns. The uncoated nonasbestos fibers were characterized as aluminum silicates, diatomaceous earth fragments, or other fibers. The coated nonasbestos fibers or ferruginous bodies were consistent with being formed on diatomaceous earth fragments, black carbon cores, or sheet silicate cores. Since the placenta is the only route of communication between the fetus and the outside environment, our findings strongly suggest a transplacental transfer of asbestos and other fibers in humans.

Asbestos↗
PubMed1990

Prevention of central nervous system toxicity of the antitumor antibiotic acivicin by concomitant infusion of an amino acid mixture.

Acivicin is an investigational amino acid antitumor antibiotic currently being evaluated in Phase II clinical trials. In humans acivicin causes reversible, dose-limiting central nervous system (CNS) effects including somnolence, ataxia, personality changes, and hallucinations. We have observed and reported previously that acivicin-treated cats exhibit symptoms (ataxia, sedation, somnolence) resembling CNS toxicity reported in humans. We hypothesized that if acivicin uptake into brain were mediated by a saturable transport system common to endogenous amino acids, drug uptake and CNS toxicity might be blocked by elevation of normal amino acid concentrations in circulating plasma. To test this hypothesis, cats received constant-rate i.v. infusions of either saline or Aminosyn, 10% (a commercially available mixture of 16 amino acids not containing glutamine, glutamate, aspartate, or cysteine) for 4 h prior to and 18 h subsequent to administration of acivicin at a dose producing marked behavioral changes in control cats. Presence or absence of ataxia and sedation were noted at intervals after acivicin treatment. Results showed that Aminosyn infusion prevented CNS symptoms in six of eight cats. Subsequent experiments showed that acivicin levels in brain tissue of Aminosyn-treated cats were 13% of the drug levels in saline-infused cats. Acivicin levels in most peripheral tissues were also decreased significantly by Aminosyn infusion but not to the extent observed in brain. Decreased brain uptake was shown to be due to a combination of amino acid blockade of drug transport into that organ and of increased total body clearance of drug. Concomitant Aminosyn treatment did not alter the efficacy of acivicin in mice bearing L1210 leukemia or MX-1 human mammary carcinoma. Further studies demonstrated that a solution containing only four large neutral amino acids (leucine, isoleucine, phenylalanine, and valine) could also protect cats from acivicin-induced CNS toxicity, apparently without increasing acivicin total body clearance. However, a mixture of several other amino acids contained in Aminosyn (alanine, arginine, tyrosine, histidine, proline, serine, and glycine) failed to prevent CNS toxicity. We conclude that cotreatment with Aminosyn or a mixture of large neutral amino acids could protect cancer patients from acivicin-induced CNS toxicity without ablating antitumor efficacy.

Amino Acids↗
PubMed1990

Cloning of a lactate dehydrogenase gene from Clostridium acetobutylicum B643 and expression in Escherichia coli.

A lactate dehydrogenase (LDH) gene of Clostridium acetobutylicum B643 was cloned on two recombinant plasmids, pPC37 and pPC58, that were selected by complementation of Escherichia coli PRC436 (acd), a fermentation-defective mutant that does not grow anaerobically on glucose. E. coli PRC436(pPC37) and PRC436(pPC58) grew anaerobically and fermented glucose to mostly lactate. When pPC37 and pPC58 were transformed into E. coli FMJ39 (ldh pfl), an LDH-deficient strain, the resulting strains grew anaerobically on glucose and produced lactate. Crude extracts of E. coli FMJ39(pPC37) and FMJ39(pP58) contained high LDH activity only when assayed for pyruvate reduction to lactate, and the LDH activity was activated 15- to 30-fold by the addition of fructose 1,6-diphosphate (FDP). E. coli FMJ39 had no detectable LDH activity, and E. coli LDH from a wild-type strain was not activated by FDP. Maxicell analysis showed that both plasmids pPC37 and pPC58 expressed a protein with an apparent Mr of 38,000 in sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Restriction endonuclease mapping of pPC37 and pPC58 and DNA hybridization studies indicated that a 2.1-kb region of these two clones of C. acetobutylicum DNA encodes the FDP-activated LDH.

Cloning, Molecular↗
PubMed1990

Asbestos content of lung tissue, lymph nodes, and pleural plaques from former shipyard workers.

Autopsy samples from eight former shipyard workers were collected from lung parenchyma, tracheal lymph nodes, and pleural plaques. The tissue from each respective area was prepared by a modified bleach digestion technique, and the residue was collected on a 0.2-micron pore polycarbonate or 0.22-micron mixed cellulose ester filter. Quantitation of ferruginous bodies and uncoated fibers was done by light and transmission electron microscopy, respectively. Differences in the asbestos burden were noted for each site. Ferruginous bodies were observed in both parenchyma and nodes but not in plaques. Three subjects were found to have more ferruginous bodies per gram dry weight in their lymph nodes than in their lung parenchyma. Likewise, all subjects were found to have more uncoated fibers per gram in the nodes than in the parenchyma. Amphibole and chrysotile fibers were noted in the lung and extrapulmonary sites, with chrysotile being the predominant asbestiform in plaques. The majority of the uncoated fibers in both the nodes and the plaques were less than or equal to 5 microns in length. However, some fibers with dimensions conforming to the "Stanton hypothesis" reached both areas. These residual patterns most likely reflect the impact of clearance on lung burden as opposed to the eventual accumulation and stasis in the extrapulmonary areas.

Aged↗
PubMed1990

Clinical outcome following coronary balloon angioplasty in 100 consecutive patients with multivessel coronary artery disease.

Prompted by current uncertainties regarding the precise role of percutaneous transluminal coronary balloon angioplasty (PTCA) in patients with multivessel disease, we reviewed the records of 100 such patients undergoing their first PTCA at our centre between 1 March 1987 and 23 March 1989. Thirty had three-vessel coronary disease (stenoses greater than or equal to 70% in all three major coronary artery territories), 51 had a previous myocardial infarction and 25 had undergone previous coronary bypass surgery. The mean number of lesions of greater than or equal to 70% per patient was 2.7 (0.8) [mean (SD)]. Successful angioplasty was achieved in 88 of these 100 patients. One year following successful angioplasty, the overall event-free rate [freedom from death, myocardial infarction, need for further revascularisation by either aortocoronary bypass graft surgery or repeat angioplasty, and recurrence of severe (class III/IV) angina] was 73%. These data suggest that, in patients with multivessel disease, angioplasty may be an effective technique for short-term symptomatic management. Definitive guidelines regarding the role of PTCA in such patients must await the results of ongoing large-scale clinical trials.

Adult↗