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Biomedical subjects

A D Jones

Publications and source records attributed to A D Jones.

143 records · Page 8Linked to original sources
PubMed1981

Static electrification of airborne asbestos: a study of its causes, assessment and effects on deposition in the lungs of rats.

The paper describes a series of experiments carried out in the laboratory to investigate how asbestos fibres might become electrostatically charged during the process of being made airborne, the magnitude and polarity of the charge per fibre, and the effect on lung deposition in rats. Measurements of the penetration of fibres through an electrostatic elutriator enabled the magnitude and distribution of charge in a cloud of fibres to be quantitatively assessed. Thus it was found that a typical fibre of UICC amosite, as dispersed in a typical animal exposure chamber, carried a net charge of magnitude equivalent to about 60 electrons. The distribution of charge was bimodal, suggesting that two charging mechanisms were taking place, the main one producing net negative charge and the lesser one producing net positive charge. These were attributed to materials in the dust dispenser used and with which the fibres came into contact during dispersal. It was found that the magnitude of charge on a typical fibre could be significantly reduced by the introduction of equal numbers of positive and negative gaseous ions from an a.c. corona discharge ioniser. Finally it was found that enhancement by up to 40% of the dust deposited into the slowest clearing part of the respiratory tract of experimental rats was brought about by the electrostatic charge on the airborne fibres. The implications of this finding in the field of occupational hygiene are briefly discussed.

Animals↗
PubMed1977

Medical practice and tribal communities.

Recent studies are discussed of societies in which medical procedures, involving injections and other modern techniques, are carried out by unqualified practitioners. These practitioners are discussed from the point of view of the sociology of health care.

Allied Health Personnel↗
PubMedDate not supplied

Pulmonary and intraperitoneal inflammation induced by cellulose fibres.

The inflammatory effects of respirable cellulose fibres were studied in two short-term animal models: intraperitoneal injection in mice, and inhalation in rats. The mouse peritoneal cavity is particularly sensitive to fibrous compared to non-fibrous particles. Both cellulose fibres and the positive control fibre, crocidolite asbestos, were administered in doses ranging from 10(4) to 10(8) fibres and caused marked, dose-dependent recruitment of inflammatory cells to the mouse peritoneal cavity, which was highest 1 day following injection. Crocidolite was much more active than cellulose, despite the mass dose of cellulose being 66 times greater for an equivalent number of fibres. Crocidolite at the higher doses caused inflammation to persist through 7 days. For the inhalation study, rats were exposed daily, 5 days per week, to aerosols of cellulose dust for ca. 3 weeks at a concentration of 1000 fibres ml(-1). Inhalation exposure induced an early inflammatory response in rat lungs, as determined by bronchoalveolar lavage, which peaked at 1 day following the start of inhalation and thereafter declined, despite a further 13 days of exposure over a period of 18 calendar days. In vitro production of the pro-inflammatory cytokine tumour necrosis factor alpha (TNF-alpha) by lavaged alveolar macrophages was markedly depressed by the end of the exposure period in cellulose-exposed animals, compared to sham-exposed controls, and this effect was still present in rats that had been allowed to recover for 28 days beyond the end of exposure. We conclude that the cellulose material studied is less inflammogenic than crocidolite and that the extent of the inflammatory response within the lung appears to reduce with continued exposure over a 14-day period.

Administration, Inhalation↗
PubMedDate not supplied

Synthesis of the protein cutting reagent iron (S)-1-(p-bromoacetamidobenzyl)ethylenediaminetetraacetate and conjugation to cysteine side chains.

Convenient methodology for preparation and conjugation of the protein-cutting iron chelate iron (S)-1-(p-bromoacetamidobenzyl) ethylenediaminetetraacetate (Fe-BABE) is given. This formulation of the reagent can be handled in a manner analogous to many other protein-labeling reagents, such as fluorescent probes or cross-linkers. By taking advantage of the recently discovered peptide hydrolysis reaction, the chelate may be tethered to a single site (e.g., a cysteine side chain) and used to map its proximity to individual peptide bonds by automated Edman sequencing of the protein fragments produced. The method is illustrated by conjugation of Fe-BABE to the carboxy terminal domain (amino acid residues 234-329) of the Escherichia coli RNA polymerase alpha subunit. The molecular mass of the protein conjugate was confirmed by electrospray ionization mass spectrometry.

Chromatography, High Pressure Liquid↗
PubMedDate not supplied

Determination of atrazine metabolites in human urine: development of a biomarker of exposure.

Enzyme-linked immunosorbent assays (ELISAs) are reported for the detection of atrazine and its principle metabolite in human urine. The ELISAs can be used with crude urine or following extraction and partial purification by methods described in this report. GC, MS, and HPLC techniques were used to confirm and complement the ELISA methods for qualitative and quantitative detection of urinary metabolites. A series of samples from workers applying this herbicide confirmed a mercapturic acid conjugate of atrazine as a major urinary metabolite. The mercapturate was found in concentrations at least 10 times that of any of the N-dealkylated products or the parent compound. Atrazine mercapturic acid was isolated from urine using affinity extraction based upon a polyclonal antibody for hydroxy-s-triazines and yielded products sufficiently pure for structure confirmation by MS/MS. In a pilot study monitoring applicators, a relationship between cumulative dermal and inhalation exposure and total amount of atrazine equivalents excreted over a 10-day period was observed. On the basis of these data, we propose that an ELISA for the mercapturate of atrazine could be developed as a useful marker of exposure.

Acetylcysteine↗
PubMedDate not supplied

Rapid screening of fentanyl (China White) powder samples by solid-phase radioimmunoassay.

We report the use of a solid-phase radioimmunoassay (RIA) to rapidly screen powder samples for various illicit fentanyl analogs. A 10-mg sample is dissolved in water, serial dilutions are made over a range of 1:10 to 1:100,000, and then duplicate 50-microL aliquots are analyzed by RIA. This method was verified by analyzing 18 "China White" samples, first by RIA and then by gas chromatography/mass spectrometry (GC/MS) with the spectrometrist blind to the results of the RIA. Of the samples, 11 were positive by radioimmunoassay and all were confirmed by GC/MS and found to contain fentanyl, alpha-methylfentanyl, fluorofentanyl, cis- and trans-3-methylfentanyl, thienylfentanyl, or cis- and trans-3-methylthienylfentanyl. The seven samples that were negative by RIA contained a variety of substances typically found in street drug samples--caffeine, codeine, and heroin--but none of the fentanyls. Differences in fentanyl concentration between samples were quite large, up to 300-fold; however, the drug seems to be uniformly distributed within a single sample. Thus, accidental overdose is more likely to result from the large intersample variability in drug concentration rather than the "clumping" of fentanyl within a sample. This solid-phase RIA provides a simple, rapid, and reliable screening method for detecting fentanyl and its illicit analogs in powder samples.

Dose-Response Relationship, Drug↗
PubMedDate not supplied

An evaluation of sample preparation techniques for the GC/MS analysis of urinary mercapturic acid conjugates.

Recovery rates of four different techniques for the preparation of human urine samples spiked with N-acetyl-S-benzyl-L-cysteine (BMA) were compared at three different spiking levels. At concentrations of 1,000 ppm and 1 ppm in the urine, recoveries of BMA were greatest (80-96%) using an ion pair phase transfer technique and a C18 solid-phase extraction (C18) technique while an acidic ethyl acetate extraction method yielded 67-69% recoveries and a quaternary amine solid-phase extraction technique showed poor recoveries (5-7%). At 10 ppb, quantitative recovery could only be determined for the C18 technique due to interferences from samples prepared using the other three techniques. The results indicate that the C18 sample preparation technique followed by GC/MS analysis using stable isotopically labeled internal standards provides a rapid and accurate method for quantitation of mercapturic acids at low-ppb levels in the urine.

Acetylcysteine↗
PubMedDate not supplied

[14C]monocrotaline kinetics and metabolism in the rat.

The pyrrolizidine alkaloid monocrotaline (MCT) has been shown to cause hepatic necrosis and pulmonary hypertension in the rat. To better understand the mechanism of action, tissue distribution and covalent binding studies were conducted at 4 and 24 hr following administration of [14C]MCT (60 mg/kg, 200 microCi/kg, sc). For the 4 hr study, the levels of MCT equivalents were 85, 74, 67, 36, and 8 nmol/g of tissue for red blood cells (RBC), liver, kidney, lung, and plasma, respectively, while the covalent binding levels were 125, 132, 39, 64, 44 pmol/mg of protein for tissues as listed above. The 24-hr tissue distribution levels were 49, 25, 9, 10, 2 nmol/g of tissue for RBC, liver, kidney, lung, and plasma, respectively, while covalent binding was 74, 28, and 55 pmol/mg of protein for liver, kidney, and lung, respectively. We also studied the kinetics of [14C]MCT (60 mg/kg, 10 microCi/kg, iv), which demonstrated rapid elimination of radioactivity with approximately 90% recovery of the injected radioactivity in the urine and bile by 7 hr. The plasma levels of radioactivity dropped from 113 nmol/g of MCT equivalents to 11 nmol/g at 7 hr while RBC levels decreased from 144 to only 81 nmol/g at the same time point. The apparent retention of MCT equivalents in the RBC suggests that this organ may act as the carrier of metabolites from the liver to other organs including the lung and may play a role in the pulmonary toxicity.

Animals↗
PubMedDate not supplied

Metabolism of [14C]monocrotaline by isolated perfused rat liver.

The metabolism of the pyrrolizidine alkaloid [14C]monocrotaline [( 14C]MCT) was examined using the in situ isolated perfused rat liver. Hepatic tissue was perfused in a recirculatory fashion for 90 min and the distribution of metabolites between the bile and perfusate was analyzed. Monocrotalic acid (MCA) was found to be the major acidic metabolite of [14C]MCT, with trace amounts of 1-formyl-7-hydroxy-6,7-dihydro-5H-pyrrolizine, 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP), and 1-hydroxymethyl-7-oxo-6,7-dihydro-5H-pyrrolizine (tentative assignment) being identified in the perfusates using GC/MS. MCT N-oxide was also identified but represented less than 4% of the perfusate 14C. The simple necine base retronecine was not present at detectable levels in the perfusion medium. A large portion of the 14C recovered from both the bile and perfusate was not extractable, under acidic or basic conditions, into organic solvents. Using fast atom bombardment MS/MS, a portion of this material was identified as a glutathione conjugate of DHP. In addition, this nonextractable material retained a portion of the radioactivity that was equivalent to the acidic fraction. Given these findings and the absence of retronecine, the major pathway for the metabolism of MCT could potentially involve the production of MCT pyrrole, which subsequently reacts with cellular nucleophiles producing MCA in addition to highly water-soluble conjugated pyrroles and possibly macromolecular adducts.

Animals↗
PubMedDate not supplied

In vivo metabolism of isomeric naphthalene oxide glutathione conjugates.

We have examined the fate of glutathione conjugates derived from naphthalene metabolism at various dose levels (5-80 mg/kg) in an effort to explore the potential use of urinary mercapturic acids as biomarkers of exposure to naphthalene and as indicators of the activity and stereoselectivity of cytochrome P-450-dependent naphthalene epoxidation. This approach extends previous studies which demonstrated a high degree of stereoselectivity in the formation of (+)-1R,2S-naphthalene oxide from naphthalene in target tissue microsomes (mouse lung), but not in microsomal preparations isolated from nontarget tissues such as mouse liver. To validate the use of mercapturic acids as indicators of epoxide formation in vivo, individual naphthalene oxide glutathione adduct isomers were administered iv to mice, and urinary metabolites were identified and quantified. Mercapturates accounted for 69-75% of the administered dose in the 8-hr urines of animals treated with trans-1-(S)-hydroxy-2-(S)-glutathionyl-1,2-dihydronaphthalene (adduct 1) and 76-84% for trans-1-(R)-hydroxy-2-(R)-glutathionyl-1,2-dihydronaphthalene (adduct 2). Only 39-57% of the dose of trans-1-(R)-glutathionyl-2-(R)-hydroxy-1,2-dihydronaphthalene (adduct 3) administered to mice was excreted as the mercapturic acid derivative; however, two additional metabolites were detected which were not present in the urine of animals treated with adducts 1 or 2. The first metabolite, accounting for 2-4% of the dose of adduct 3, was not identified. The second metabolite, isolated by HPLC and identified by mass spectrometry as (hydroxy-1,2-dihydronaphthalenylthio)pyruvic acid, accounted for 14-25% of the administered dose of adduct 3.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcysteine↗
PubMedDate not supplied

Stereoselectivity of naphthalene epoxidation by mouse, rat, and hamster pulmonary, hepatic, and renal microsomal enzymes.

Previous studies have demonstrated the formation of three glutathione conjugates during the hepatic and pulmonary microsomal metabolism of naphthalene in the presence of reduced glutathione and cytosolic enzymes containing the glutathione transferases. These glutathione conjugates now have been identified by negative ion fast atom bombardment mass spectrometry, by proton NMR spectroscopy, and by chemical synthesis from the (1S,2R)- and (1R, 2S)-naphthalene 1,2-oxide enantiomers as isomeric hydroxyglutathionyldihydronaphthalene derivatives. All three glutathione adducts yielded prominent mass spectral ions at m/z 450 (M-H)-, 432 (dehydration product), and 306 (glutathionyl moiety) which were consistent with the monoglutathionyl derivatives of hydroxydihydronaphthalene. Signals in the proton NMR spectra at 3.60 and 4.95 ppm (adduct 1) and 3.60 and 4.95 ppm (adduct 2) indicated that these conjugates were diastereomers of 1-hydroxy-2-glutathionyl-1,2-dihydronaphthalene. Corresponding signals for H1 and H2 at 4.22 and 4.45 ppm for adduct 3 showed that this isomer was generated from attack of glutathione at the 1 position of the naphthalene 1,2-oxide. Incubation of synthetic (1S, 2R)-naphthalene 1,2-oxide with glutathione in the presence of glutathione transferases resulted in the formation of adducts 1 and 3 in approximately equal proportions; under identical conditions, glutathione conjugate 2 was formed from (1R, 2S)-naphthalene 1,2-oxide. Incubation of naphthalene, glutathione, and glutathione transferases with pulmonary, hepatic, or renal microsomal preparations from mouse, rat, and hamster resulted in the formation of all three glutathione conjugates. Substantial differences in the rates of formation of the individual conjugates were observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Distribution of trans-4-hydroxy-2-hexenal and tandem mass spectrometric detection of its urinary mercapturic acid in the rat.

The distribution of trans-4-hydroxy-2-hexenal (t-4HH), a pyrrolizidine alkaloid metabolite and a lipid peroxidation product, was studied following the injection of [3H]t-4HH into the hepatic portal vein of male Sprague-Dawley rats. Less than 3% of the tritium label remained in the liver 24 hr after administration with levels in the other major organs correspondingly lower. The majority of recovered radioactivity (77-83%) appeared in the urine with 60-69% appearing within 8 hr after administration. Most of the urinary radioactivity (75%) was recovered in an acidic fraction following acid/base extraction. A tandem mass spectrometry technique using negative ion fast atom bombardment (FAB) ionization in combination with Mass-analyzed Ion Kinetic Energy Spectrometry verified that a C-3 mercapturic acid conjugate of trans-4-hydroxy-2-hexenal was produced as a urinary metabolite. This compound presumably forms via a Michael addition of glutathione at C-3 of t-4HH followed by hydrolysis of glutamate and glycine and acetylation to yield the mercapturic acid. While Michael additions of glutathione to t-4HH-related compounds have been observed in vitro, these results provide in vivo evidence of this mechanism.

Acetylcysteine↗