It has been claimed that in vitro digestion of in vivo DNA-labeled gastric mucosa is suitable for evaluation of genotoxic effects of drugs or chemicals. This method was then used to show that omeprazole (a novel antiulcer drug) was potentially genotoxic. In this study we have examined the method used and the interaction of omeprazole and its derivatives with purified DNA. The method was shown to enrich for dividing cells (6.92 +/- 0.693%, N = 43, 2-hr labeling) in the digest from the intact tissue and was therefore unsuitable for estimating unscheduled DNA synthesis in the gastric mucosa induced by chemicals or drugs including omeprazole. It was further shown that neither omeprazole or its acid-activated product, a cationic sulfenamide, were able to react with isolated purified DNA from either a prokaryote (E. coli) or a eukaryote (salmon sperm). Hence any conclusions using this method attributing acute genotoxic effects to any chemical are based on unrecognized artifacts of the technique and are unsound. In addition, these results negate the suggestion that omeprazole or its gastric metabolites are genotoxic.

Animals↗

PubMed1990

The effect of variation in dietary protein or mineral supply on calcium and phosphorus metabolism in lactating ewes.

Two experiments are described in which changes in both nitrogen and mineral balance were monitored in ewes during lactation. In Expt 1, two groups (n 6) of ewes were fed on diets that were either high (15 g crude protein (N X 6.25; CP)/MJ metabolizable energy (ME)) or low (10 g CP/MJ ME) in protein content, and concurrent N and mineral balance studies were made at intervals during lactation with 45Ca and 32P being used to monitor faecal endogenous calcium and phosphorus losses. Ewes fed on the high-protein diet maintained a positive N balance during early lactation, whereas those fed on the low-protein diet were in negative N balance. Both groups, however, showed the same degree of negative Ca and P balance, with the amounts lost being directly related to milk yield. This indicates that loss of mineral from the skeleton at this time is not secondary to a loss of bone matrix due to a shortfall in dietary protein supply. In Expt 2, two groups of ewes (n 4) were fed on diets in late pregnancy that were either just adequate or generous in Ca and P supply relative to requirement (TCORN, 1990). After parturition both groups were fed on a diet which was formulated to meet their estimated Ca and P requirements for lactation. As in the previous experiment both groups were in negative Ca and P balance in early lactation and variation in dietary Ca and P supply during pregnancy had no effect on the extent of this loss. Alternative explanations for the cause of this loss of mineral from the skeleton are discussed.

Amino Acids↗

PubMed1990

Using lipid-lowering agents effectively. When diet is not enough.

Lipid-lowering agents can be used safely and effectively if the physician understands the nature of the patient's disorder and the mechanism of action of the various drugs. The benefits of altering lipid levels are manifested over years, not months. Without a long-term plan for periodic follow-up and intervention, short-term gains will accomplish very little.

Cholesterol, HDL↗

PubMed1990

Introduction of the activated N-ras oncogene into human fibroblasts by retroviral vector induces morphological transformation and tumorigenicity.

The introduction of activated N-ras cDNA into normal diploid human skin fibroblast cell cultures using the retroviral vector pZIPneo results in a spectrum of morphologies ranging from near normal to, in rare instances, dense piled-up colonies of morphologically transformed cells. However, none of the clones isolated were transformed as assessed by growth on agar or tumorigenicity in nude mice. Introduction of both c-myc and N-ras oncogene cDNAs into normal skin fibroblasts failed to produce transformation as assessed by growth on agar and tumorigenicity in nude mice, although c-myc infection alone conferred immortality and the resultant doubly infected cell line was immortal. Using the same construct, activated N-ras cDNA was shown to transform immortalized human fibroblasts to tumorigenicity. However, immortalization per se was shown not to guarantee 'co-operation' with an activated N-ras gene to give malignant transformation. Although numerical and structural chromosome aberrations (clonal and non-clonal) were observed in some of the cell strains isolated after retroviral infection, these were not directly associated with viral infection, the presence of the oncogenes or with the morphologically transformed phenotype.

Animals↗

PubMed1990

Coupling of H(+)-K(+)-ATPase activity and glucose oxidation in gastric glands.

The production of 14CO2 from uniformly labeled glucose was shown to account for the entire increase in histamine-stimulated O2 consumption in rabbit gastric glands when no other substrate was added to the medium. The increased production of CO2 was correlated to the increase in O2 consumption and the accumulation of [14C]-aminopyrine (AP) after stimulation with several secretagogues. Inhibitors of H(+)-K(+)-ATPase reduced the secretagogue-induced increase in CO2 production by greater than 90%, showing that the activity of this enzyme was responsible for the greater part of gastric gland metabolism under stimulated conditions. In contrast to AP accumulation, inhibition of CO2 production by omeprazole, an acid-activated inhibitor of the H(+)-K(+)-ATPase, was not reversed by washing. The reversal of AP accumulation after omeprazole treatment and washing was most likely due to a recruitment of residual pumps bordering a nonacidic space, which had not previously been inhibited by omeprazole. These residual pumps slowly generate a pH gradient and hence AP uptake. Adding NH4+ to gastric glands resulted in a concentration-dependent increase of CO2 production up to the maximal stimulated level but without formation of the pH gradient as measured by AP uptake and loss of the omeprazole inhibition of glucose oxidation. As NH4+ can act as a K+ surrogate for H(+)-K(+)-ATPase, and as NH3 is membrane permeant, full stimulation of CO2 production is evidence that the major mechanism of H(+)-K(+)-ATPase activation in situ is an increase in the KCl permeability of the pump membrane.

Adenosine Triphosphatases↗

PubMed1990

Cell digestion and genotoxicity assessment in gastric mucosa.

It has been claimed that the in vivo incubation of rat gastric mucosa with a test drug, followed by labelling with tritiated thymidine and selective in vitro digestion is a suitable method for evaluating genotoxic potential. However, the method rests on the assumptions that the radiolabel released on digestion has been incorporated into damaged DNA which has undergone repair (i.e. unscheduled DNA synthesis, UDS) and that the results are not confounded by the presence of dividing cells (scheduled DNA synthesis). This study examined the method by repeating the digestion procedure on rat gastric mucosa which had been labelled with bromodeoxyuridine in vivo, to mimic the 3H-TdR experiments previously reported. Results showed that the cell digest contained a mixture of cells, including parietal cells, and that there was a 6.9 +/- 0.69% (n = 43) contamination with dividing cells over a 2-hour period of labelling. This represents a 10-fold enrichment of dividing cells as compared to intact tissue. It is concluded that measurements of total radioactivity in DNA made using this digestion method cannot be related solely to UDS, but are related to a variety of unrecognized artifacts.

Animals↗

PubMed1990

Omeprazole and the gastric mucosa.

The potential for either omeprazole or its sulphenamide to interact with DNA was investigated by incubating tritiated omeprazole at either neutral or acidic pH with either purified prokaryotic (Escherichia coli) or purified eukaryotic (salmon sperm) DNA. Each incubation was carried out for 30 min. The DNA was separated on agarose gels, stained with ethidium bromide, and the radioactivity in the DNA determined. No radioactivity was associated with the DNA on the gel with either prokaryotic or eukaryotic DNA or with either protocol. No interaction with the DNA was found, thus excluding the possibilities of base modification, DNA strand breakage or intercalation. It was concluded that neither omeprazole nor its gastric metabolites are genotoxic.

Animals↗

PubMed1990

Stability of morphine sulfate in infusion devices and containers for intravenous administration.

The stability of morphine sulfate in one brand of polyvinyl chloride (PVC) container, one brand of glass syringe, and two brands of disposable infusion devices was determined. Solutions of morphine sulfate 2 and 15 mg/mL were used to fill the PVC containers and drug administration devices. Stability was determined for both concentrations of morphine sulfate at room temperature (23-25 degrees C) and 4 degrees C in the PVC containers, glass syringes, and disposable infusion devices; stability was also determined at 31 degrees C in the disposable infusion devices. At 0, 1, 2, 4, 7, 12, and 15 days, portions of the solutions were removed and assayed in triplicate by a stability-indicating high-performance liquid chromatographic method. At each time point the drug-infusion fluid combinations were inspected visually for color changes and the presence of particulate matter, and pH was measured. Morphine sulfate 2 and 15 mg/mL remained stable for at least 12 days in all the containers and devices at each temperature tested. No substantial changes in the pH or physical appearance of the solutions were observed. Morphine sulfate can be repackaged in the disposable glass syringe, PVC container, and both disposable infusion devices for routine clinical use.

Chromatography, High Pressure Liquid↗

PubMed1990

Stability of heroin hydrochloride in infusion devices and containers for intravenous administration.

The stability of heroin hydrochloride in various drug-administration devices was studied. Heroin hydrochloride was supplied as the bulk powder by the National Institute on Drug Abuse and in the formulated dosage form by Evans Medical, Ltd. Stability was determined at concentrations of 1 and 20 mg/mL at room temperature (23-25 degrees C) and at 4 degrees C in a polyvinyl chloride (PVC) bag, a disposable glass syringe, and two disposable infusion devices. Studies at both concentrations also were conducted at 31 degrees C in the disposable infusion devices. All experiments were conducted in triplicate. A validated, stability-indicating, high-performance liquid chromatography assay was used. Heroin hydrochloride remained stable for a minimum of 15 days in the PVC bag and the Infusor infusion device at the tested temperatures and concentrations. In the glass syringe, heroin hydrochloride was shown to be stable for a minimum of 15 days at both 1 mg/mL and 20 mg/mL if refrigerated at 4 degrees C, whereas at room temperature it was stable for a minimum of 7 days at 1 mg/mL and for 12 days at 20 mg/mL. In the Intermate 200 infusion device, heroin hydrochloride was stable for a minimum of 15 days at both concentrations and all temperatures except for the 1 mg/mL concentration at 31 degrees C. In the latter case, stability was for a minimum of two days. No substantial changes in physical appearance or pH were observed in any of the containers under the conditions studied. Heroin hydrochloride can be repackaged in the disposable glass syringe, PVC bag, and each of the disposable infusion devices for routine clinical use.

Chromatography, High Pressure Liquid↗

PubMed1990

Illness and the workplace: a study of physicians and employers.

Seven million patients with work-related injuries are seen annually in the United States, the majority by primary care physicians. The number of such patients seen in a typical community practice may be significant but has never been studied. Most community-based physicians have little or no formal training in occupational health care. This study consisted of a survey of practicing physicians and major industrial employers in a city of 39,000 with a strong manufacturing base. The purpose was to assess physician skills, attitudes, and practices that might influence the optimal management of patients with work-related conditions, and to assess employer attitudes about this management. Eighty-three percent of physicians and 68% of employers responded to the written surveys. Low numbers of patients with work-related conditions were reported except by orthopedists and a neurologist. Few physicians communicated directly with employers, citing time and confidentiality as factors. Twenty-five percent were unaware of specific legal guidelines for such contact. Administrative and legal complexities were cited by 97% of the respondents as barriers to effective management of such cases. Eight percent of employers sought more contact with physicians, including site visits and more detailed work restriction guidelines. The education of primary care physicians may improve their understanding of work-related conditions and the optimal management and rehabilitation of these patients.

Communication↗

PubMed1989

Chromosomal analyses of human lymphocytes exposed in vitro to caprolactam.

Caprolactam was tested for the induction of chromosomal aberrations in cultured human lymphocytes from one male donor and one female donor. At 7.5 mg/ml, caprolactam-treated cells from the male showed a small but significant increase in the frequency of aberrations. No effect was observed in cells from the female if gaps are excluded.

Adult↗

PubMed1989

Complications of imaging procedures in six elderly patients.

Explore the source record for details and available documents.

Aged↗

PubMed1989

Micronuclei: origins, applications and methodologies--a workshop sponsored by the Health and Safety Executive held in Manchester, May 23-25, 1988.

Explore the source record for details and available documents.

Animals↗

PubMed1989

Application of the anthropometric discriminant functions in estimation of carrier probabilities in Martin-Bell syndrome.

A method of estimating the likelihood ratio and the risk of an individual being affected with Martin Bell syndrome (MBS) from anthropometric measurements is described. The procedure is based on the discriminant functions (one for each sex), generated in our previous study in order to separate the individuals with MBS from the normal individuals. The procedure is illustrated by the examples of estimating the likelihood and the likelihood ratio in four individuals of either sex, belonging to MBS families, where the discriminant score value obtained from each individual is compared with the empirical (normalized) distribution of discriminant scores from the known MBS and normal subjects of a corresponding sex. The ways in which the risk of an individual being MBS is estimated in the general population or in members of the MBS families are indicated. The limitations of the discriminant diagnosis based on body measurements, as well as its particular applications in studies of the Martin-Bell syndrome, are discussed.

Anthropometry↗