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Biomedical subjects

S Murray

Publications and source records attributed to S Murray.

At least 145 records · Page 8Linked to original sources
PubMed1993

Human hepatic CYP1A1 and CYP1A2 content, determined with specific anti-peptide antibodies, correlates with the mutagenic activation of PhIP.

Mono-specific antibodies targeted to human CYP1A1 and CYP1A2 have been produced by immunizing rabbits with protein conjugates of short synthetic peptides corresponding to residues 290-297 and 284-296 respectively, of these enzymes. The antibody targeted to CYP1A1 bound in immunoblotting to the recombinant protein expressed in yeast but did not bind to any human hepatic microsomal protein, whereas the antibody targeted to CYP1A2 bound only to this enzyme in immunoblotting of human hepatic microsomal fractions and did not recognize recombinant human CYP1A1. The intensity of hepatic microsomal CYP1A2 immunoreactivity (n = 5) correlated significantly with a number of activities characteristic of this enzyme: phenacetin O-deethylase (POD), ethoxyresorufin O-deethylase (EROD) and methoxyresorufin O-demethylase activities and the ability to activate the dietary carcinogen 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), to a mutagen. The anti-CYP1A2 anti-peptide antibody consistently inhibited both POD and EROD activities, but inhibition was incomplete (28%). In view of the known (> 90%) contribution of CYP1A2 to these activities and the correlation with antibody binding, this is consonant with an epitope for the anti-CYP1A2 anti-peptide antibody that forms the edge of a functionally important proinhibitory surface region previously identified in rat cytochromes CYP1A. CYP1A2 immunoreactivity determined by immunoblotting correlated significantly with the ability of human hepatic microsomal fractions to activate 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine (PhIP), another dietary carcinogen, to a mutagen. It is concluded that CYP1A1 is absent from human liver and that CYP1A2 is likely to be a major catalyst in the hepatic activation of PhIP.

Animals↗
PubMed1993

Cutaneous sarcoidosis and foreign bodies.

A histopathological diagnosis of sarcoidosis is, by convention, one of exclusion and is reached only when other potential causes of granulomatous disease, such as foreign bodies, are eliminated. We report herein three cases of systemic sarcoidosis with cutaneous manifestations of the disease, in which polarizable foreign particles were associated with the granulomata in the skin. We submit (a) that a granulomatous foreign body reaction and sarcoidosis are not mutually exclusive, (b) that particulate foreign matter may actually serve as a nidus for granuloma formation in sarcoidosis, and (c) that the occasional presence of extraneous material within the granulomata of sarcoidosis requires greater recognition by pathologists.

Adult↗
PubMed1993

Abuse of over-the-counter dextromethorphan by teenagers.

Dextromethorphan, the d-isomer of the opiate agonist levorphanol, has none of the analgesic or sedative effects associated with the opiates and is approved for over-the-counter use as an antitussive. It is available, in various combinations with other medications, in nonprescription cough suppressant and common cold formulations, and its availability in the United States is not controlled. In this paper we have reported two cases of recreational use of dextromethorphan-containing cough syrup by two unrelated teenage boys. Despite the safety of this medication when used at the recommended dosage, there have been cases of "recreational" use of dextromethorphan as well as death by overdose. Although usually thought to be nonaddictive, dextromethorphan produces a substance dependence syndrome, and physicians should be aware of its abuse potential, particularly by youths.

Adolescent↗
PubMed1993

The specificity of histopathology in erythroderma.

Conflicting views about the diagnostic value of skin biopsy in the investigation of erythrodermic patients are extant. The objective of the present study was to establish the frequency with which a correct diagnosis can be based on histopathological assessment alone. This was achieved by comparison of the "blinded" microscopic diagnosis with the final diagnosis (based on combined clinico-pathologic parameters and response to therapy). In a retrospective review of 56 skin biopsies from 40 patients with erythroderma, we found a positive correlation between the pathological diagnosis and the final diagnosis in 66%; furthermore, when the microscopic characteristics observed in different diagnostic categories were assessed, these proved to simulate those seen in conventional manifestations of the various underlying diseases but tended to be subtle in the setting of erythroderma. We conclude that, despite the homogeneity of the clinical expression of erythroderma, diagnostic histopathological features of the underlying disease are retained in the majority of cases.

Adult↗
PubMed1993

Study of dietetic knowledge among members of the primary health care team.

There is growing emphasis on health promotion in primary care. The success of this endeavour depends in part on the ability of members of the primary health care team to provide appropriate and practical advice and support, relating to lifestyle. A study of 58 primary health care professionals was carried out in the Grampian region of Scotland to assess their nutritional knowledge and their ability to provide practical dietary advice, particularly in relation to the prevention of coronary heart disease. Overall, the primary health care workers had a broad understanding of recommendations for healthy eating, but there was some confusion over specific aspects of these recommendations. Health professionals also found it difficult to translate knowledge into practical dietary advice tailored to an individual case. If health promotion in primary care is to work effectively, the infrastructure necessary for effective training and continuing education has to be addressed.

Coronary Disease↗
PubMed1993

Why do patients decline screening mammography?

Physician recommendation may not be sufficient to motivate patients to comply with health maintenance activities. During a physician visit, female patients over age 50 were reminded to schedule mammography; more than 10% overtly refused. A telephone questionnaire of 20 age-matched refusers and compliers was performed to assess knowledge, attitudes, behavior, and demographics. Refusers and compliers were similar in many respects; there was no significant difference in how the groups perceived their current health. Paradoxically, refusers had less knowledge of bad experiences with mammograms (p < .01). Refusers were more likely not to know if their insurance covered screening (p < .01), and were less likely to recall their physicians recommending screening even though recommendation was documented in the chart (p < .05). Refusers were less likely to have ever had a mammogram (p < .05). This subgroup of patients does not obtain mammograms, finds physician recommendation an insufficient stimulus for mammography, and considers insurance coverage a concern without investigating it.

Aged↗
PubMed1992

Intra- and interindividual variability in systemic exposure in humans to 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline and 2-amino-1-methyl- 6-phenylimidazo[4,5-b]pyridine, carcinogens present in cooked beef.

During the cooking of beef, the genotoxic heterocyclic aromatic amines 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx), and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) are formed. Little is known about the fate of these compounds in humans or the factors affecting it. We have developed assays based on capillary column gas chromatography-negative ion mass spectrometry capable of the simultaneous measurement of MeIQx, DiMeIQx, and PhIP in cooked meat and in human urine using stable isotope labeled analogues. Ten normal, healthy male volunteers were invited to consume a standard cooked meat meal (400-450 g lean beef, cooked as patties on a griddle hotplate) on four separate occasions over a period of 14 months. Following consumption of the test meals, urine was collected from 0 to 8 h, during which time all free amines were excreted and analyzed for MeIQx, DiMeIQx, and PhIP. Subjects ingested 240 +/- 9 (SEM) g cooked meat, which contained 2.2 +/- 0.2 ng MeIQx/g meat, 0.7 +/- 0.1 ng DiMeIQx/g meat, and 16.4 +/- 2.1 ng PhIP/g meat. The variability in relative systemic bioavailability was assessed from the percentage of ingested amine excreted unchanged in the urine. Subjects excreted 2.1 +/- 1.1% of MeIQx and 1.1 +/- 0.5% of PhIP ingested as unchanged amine in the urine. Levels of DiMeIQx in urine, if present, were below the sensitivity of our assay (20 pg/ml) and could not be detected in any of the samples analyzed. Irrespective of dose, urinary excretion of unchanged MeIQx or PhIP (expressed as a percentage of the ingested dose) remained constant for each individual subject. The intraindividual coefficients of variation for MeIQx (28.4%) and PhIP (23.7%) were low and the pooled interday (intrasubject) coefficients of variation for both compounds were only 19 and 3.4%, respectively. In contrast, inter-subject (intraday) variation was greater, with pooled coefficients of variation of 145% for MeIQx and 71% for PhIP. Based on these studies, it should be possible to use the percentage excretion of MeIQx and PhIP to assess the relative bioavailability of these compounds in humans.

Adult↗
PubMed1991

Identification of a functionally conserved surface region of rat cytochromes P450IA.

A region of rat cytochrome P450IA1 at residues 294-301 (Gln-Asp-Arg-Arg-Leu-Asp-Glu-Asn), equivalent to a proinhibitory region of cytochrome P450IA2, was identified by sequence alignment. Anti-peptide antibodies were successfully raised when the peptide was coupled through either its N- or its C-terminus to carrier protein, but no antibodies were produced against the so-called multiple peptide antigen, which consisted of eight copies of the peptide attached through its C-terminus to a synthetic base. Both of the anti-peptide antibodies bound specifically to cytochrome P450IA1 in the rat, as shown by e.l.i.s.a. and immunoblotting. They inhibited microsomal aryl hydrocarbon hydroxylase activity and the mutagenic activation of 2-acetylaminofluorene (these reactions are catalysed by cytochrome P450IA1), but not high-affinity phenacetin O-de-ethylation activity, which is catalysed by cytochrome P450IA2. However, there was differences in the properties of the two antisera in their binding to cytochromes P450IA1 in species other than the rat, their relative binding to the multiple peptide antigen, the yield of antibody following affinity purification using peptide coupled through its N-terminus to CNBr-activated Sepharose, and the binding of the purified preparations to N- and C-terminal-coupled peptide conjugates. These observations indicated that the antibodies were directed to the region of the peptide opposite to the end which was coupled to the carrier protein. Nevertheless, both of the antibody preparations bound equally well to the target cytochrome P450, thus indicating that, in the native protein, the whole of the peptide region is exposed on the surface of cytochrome P450IA1 and is available for binding by the antibodies. The role of this region appears to be the same in both cytochromes P450IA1 and P450IA2, despite the difference in its primary structure in the two cytochromes P450.

Amino Acid Sequence↗
PubMed1991

Combined assay for phenacetin and paracetamol in plasma using capillary column gas chromatography-negative-ion mass spectrometry.

A gas chromatographic-mass spectrometric assay has been developed for the measurement of phenacetin and its major metabolite paracetamol in plasma. Phenacetin and unconjugated paracetamol are analysed in a single chromatographic run while total paracetamol is measured separately after enzymatic hydrolysis. The two compounds, and the deuterated analogues used as internal standards, are analysed as their trifluoroacetyl derivatives and the mass spectrometer is operated in the electron-capture negative-ion chemical ionisation mode. The negative-ion mass spectra of the derivatives contain fragment ions, formed by loss of an acetyl group from the respective molecular ions, which are the base peaks in the spectra. When these ions are specifically monitored, amounts of derivative equivalent to 1 pg of parent compound can be detected. This allowed the development of an assay for phenacetin, unconjugated paracetamol and total paracetamol in plasma having a precision of 2.6, 1.4 and 2.4%, respectively, and preliminary results for a subject given a 100-mg oral dose of phenacetin are reported.

Acetaminophen↗
PubMed1991

Gas chromatographic-mass spectrometric assay to measure urinary N tau-methylhistamine excretion in man.

An assay has been developed for N tau-methylhistamine, a major metabolite of the autocoid histamine, based on gas chromatography-electron-capture negative-ion chemical ionisation mass spectrometry. N tau-Methylhistamine was extracted from urine by cation-exchange chromatography and converted to its di-(3,5-bistrifluoromethylbenzoyl) derivative. The latter has good chromatographic properties and gives a negative-ion mass spectrum with the molecular ion (M., m/z 605) as base peak. A commercially available trideuterated analogue of N tau-methylhistamine was used as internal standard. Basal urinary excretion of N tau-methylhistamine in five normal subjects was found to be 0.21 +/- 0.05 mumol/h (289 +/- 74 mumol/mol of creatinine). This value was not significantly altered in these subjects following the infusion of a subpharmacological dose of histamine. In eight atopic volunteers, basal urinary excretion of N tau-methylhistamine was also not significantly changed following challenge with inhaled allergen.

Adult↗
PubMed1991

The measurement of MeIQx adducts with mouse haemoglobin in vitro and in vivo: implications for human dosimetry.

We have investigated covalent binding of radiolabelled [14C]2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) to mouse haemoglobin in vitro and in vivo. Furthermore, we report the development of a capillary column gas chromatography negative ion mass spectrometry (GC-MS) assay capable of detecting MeIQx liberated from haemoglobin after acid or base hydrolysis. Following microsomal activation, the amount of radiolabelled material associated with haemoglobin in vitro increased with incubation time to 0.67 +/- 0.15 nmol/mg haemoglobin at 2 h (initial concentration 0.47 mM [14C]MeIQx, mean +/- SD, n = 6). Hydrolysis of these samples with acid revealed that 47-60% of the radiolabelled material covalently bound to haemoglobin was acid labile. Of this, 7.2-9.8% was recovered as MeIQx as determined by GC-MS. This liberated fraction should reflect the amount of sulphinic acid amide present which is formed when N-hydroxy-MeIQx reacts with sulphydryl-containing amino acids present in haemoglobin. In vivo, no radiolabelled material bound to haemoglobin could be detected in animals treated with the lowest dose of MeIQx (0.2 mg/kg). At higher doses, there was a dose-dependent increase in the covalent binding of radiolabel to haemoglobin (2.0-200 mg/kg). However, the GC-MS assay for hydrolysable adducts of MeIQx yielded detectable quantities of MeIQx (32.2 +/- 17.5 fmol MeIQx/mg haemoglobin) only at the highest dose used. Application of the GC-MS assay to human haemoglobin samples showed that acid-labile adducts of MeIQx, if present, were below the limit of detection of the assay. These results show that levels of sulphinamide adducts of the dietary aromatic amine MeIQx, with haemoglobin, are very low and the implications for future human dosimetry of this carcinogen are discussed.

Animals↗
PubMed1991

Epidemiology of sharps accidents in general surgery.

A prospective study was carried out of all general surgical operations in one theatre of a teaching hospital over a 6-week period to identify the predisposing factors involved in the occurrence of sharps accidents and their relative importance. Although various predisposing factors have been intimated, the relative importance has never been ascertained. Glove puncture was used as an objective measure of a sharps accident and this was compared with subjective reporting of needlestick injury. The overall rate of sharps accidents per surgeon per operation was 23%. The position at the operating table and medical rank of operator affected the rate of accidents more than duration of operation. The group at most risk of sharps accidents was junior surgeons acting as the principal operator. It is important to recommend inoculation against hepatitis B in this group before starting surgical training. Another method of minimizing the risk to junior surgeons would be compulsory training on surgical rigs. Operations on patients with AIDS or hepatitis B should be carried out by the most senior surgeon available to reduce the risk of sharps injury and disease transmission.

Accidents, Occupational↗