Use of loperamide hydrochloride in children.
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Child, Preschool↗
Biomedical subjects
J M Ward
Publications and source records attributed to J M Ward.
AIDS meningoencephalomyelitis. Pathogenesis and changing neuropathologic findings.
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Acquired Immunodeficiency Syndrome↗
Evaluation of cell proliferation in the kidneys of rodents with bromodeoxyuridine immunohistochemistry of tritiated thymidine autoradiography after exposure to renal toxins, tumor promoters, and carcinogens.
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Animals↗
Methyllycaconitine: a selective probe for neuronal alpha-bungarotoxin binding sites.
The ability of methyllycaconitine (MLA) to inhibit the binding of [125I]alpha-bungarotoxin to rat brain membranes, frog and human muscle extracts and the human muscle cell line TE671 has been measured. MLA showed a markedly higher affinity for the rat brain site (Ki 1.4 x 10(-9) M) than for the muscle receptors (Ki 10(-5)-10(-6) M). Structure modelling techniques were used to fit the structure of MLA to a nicotinic pharmacophore model. MLA is the first low molecular weight ligand to be shown to discriminate between muscle nicotinic receptors and their alpha-bungarotoxin-binding counterpart in the brain, and as such may be a useful structural probe for pursuing the structural and functional properties of the neuronal protein.
Aconitine↗
Naturally-occurring age-dependent glutathione S-transferase pi immunoreactive hepatocytes in aging female F344 rat liver as potential promotable targets for non-genotoxic carcinogens.
Naturally occurring basophilic foci (focal hepatocellular proliferative lesions) (FHPL) in the livers of aging female F344/NCr rats could not be promoted to grow or progress into tumors after phenobarbital (PB) exposure. Instead, PB induced new unique eosinophilic hepatocellular foci and adenomas much quicker in old rats than in young rats. We now report that these foci are immunoreactive for glutathione S-transferase pi (GSTP) and that they appear to arise from some naturally occurring single and double GSTP-reactive cells and foci which occur spontaneously in the liver of aging F344 rats in an age-related fashion. PB and other nongenotoxic chemicals may act as "carcinogens" by promoting the growth (clonal expansion) of some of these putative spontaneously-initiated cells and foci into tumors.
Aging↗
Pancreatic hepatocytes in Fischer and Wistar rats induced by repeated injections of cadmium chloride.
The effects of multiple sc injections of cadmium chloride (CdCl2) on the pancreas of two rat strains (Wistar [WF/NCr] and Fischer [F344/NCr]) were studied by histological and immunohistochemical examinations. A high incidence of hepatocytic foci occurred within the pancreata of both strains that was associated with this cadmium exposure. Although pancreatic hepatocytes (PH) were found in both strains, Wistar rats were more susceptible to cadmium-induced PH formation while showing more tolerance to cadmium in general. The highest incidence of PH was 93% in Wistar rats and 50% in Fisher rats. Dose-related increases in incidence of PH occurred at levels of 360-513 mumol Cd/kg. Number of PH foci/rat correlated well with PH incidence. By avidin-biotin immunohistochemistry, PH exhibited rat albumen and a gap junction protein (Connexin32) found in hepatocytes. PH were frequently seen along with pancreatic acinar atrophy (fatty replacement) and interstitial fibrosis. Thus, it appears that cadmium must be considered one of the most efficacious agents for production of PH within the rat pancreas. The ability of cadmium to induce this transdifferentiation is also clearly dose and strain related.
Animals↗
Beta-lactam antibiotic biosynthetic genes have been conserved in clusters in prokaryotes and eukaryotes.
A cosmid clone containing closely linked beta-lactam antibiotic biosynthetic genes was isolated from a gene library of Flavobacterium sp. SC 12,154. The location within the cluster of the DNA thought to contain the gene for delta-(L-alpha-aminoadipyl)-L-cysteinyl-D-valine synthetase (ACVS), the first step in the beta-lactam antibiotic biosynthetic pathway, was identified by a novel method. This DNA facilitated the isolation, by cross-hybridization, of the corresponding DNA from Streptomyces clavuligerus ATCC 27064, Penicillium chrysogenum Oli13 and Aspergillus nidulans R153. Evidence was obtained which confirmed that the cross-hybridizing sequences contained the ACVS gene. In each case the ACVS gene was found to be closely linked to other beta-lactam biosynthetic genes and constituted part of a gene cluster.
Anti-Bacterial Agents↗
Evidence that HIV-1 gag precursor shares antigenic sites with the major capsid protein of human cytomegalovirus.
A rabbit antiserum prepared against disrupted sucrose-banded HIV-1 virus (strain FRE-3) reacted with antigens present in nuclear inclusions, pathognomonic for human cytomegalovirus (HCMV). This cross-reactivity was observed in autopsy specimens from individuals infected with CMV, in the presence or absence of co-infection with HIV-1. A Towbin immunoassay showed that the serum reacted specifically with the HCMV major capsid protein (MCP, 153 kDa), both in the nuclear fraction of infected cells and in virions. Direct evidence that these proteins share antigenic determinants was provided by the two-way cross-reactivity of affinity-selected antibodies (i.e., anti-MCP with HIV-1 gag precursor Pr55; anti-Pr55 with MCP). All four strains of HCMV tested showed this reactivity, but the counterpart proteins of simian CMV and herpes simplex virus type 1 did not, indicating that the determinant is not common to all herpes group viruses.
Antigens, Viral↗
Applications of immunohistochemistry in rodent tumor pathology.
Immunohistochemistry can serve as a valuable adjunct to rodent tumor pathology. Specific antigens may be localized to cells and tissues in normal organs, preneoplastic lesions, and benign and malignant tumors. The immunoreactivity of polyclonal and monoclonal antibodies to these antigens provide a more accurate basis for tumor diagnosis and aid in understanding pathogenesis. Ultimately, the application of more precise understanding of tumor histogenesis and diagnosis will lead to more accurate interpretations of tumor incidence data for safety assessment in toxicology.
Animals↗
Renal tubular cell or hepatocyte hyperplasia is not associated with tumor promotion by di(2-ethylhexyl)phthalate in B6C3F1 mice after transplacental initiation with N-nitrosoethylurea.
B6C3F1 mice of both sexes that had been exposed transplacentally on day 18 of gestation to 0.5 mmole N-nitrosoethylurea (NEU) were fed either normal diets or diets containing di(2-ethylhexyl)phthalate (DEHP) at 6,000 ppm beginning at 6 wk of age and continuing to 78 wk of age. At 52 and 78 wk of age, 6-26 mice from each group received a single injection of 5-bromo-2'-deoxyuridine (Brdu) at 200 mg/kg i.p. and were sacrificed 1 h later for determination of the levels of renal and hepatic DNA synthesis by the Brdu immunohistochemical technique. No differences occurred in incidences of gross or microscopic renal tubular cell tumors between the NEU (males 15%, females 21%) and NEU-DEHP groups (males 10%, females 15%) at 78 wk. The labelling index (LI) of renal cortical tubular cells was significantly increased at 78 wk (22.3 +/- 3.7/mm2 for males, 21.8 +/- 1.2 for females) in mice given NEU and DEHP as compared with NEU alone (9.7 +/- 1.0 for males, 6.9 +/- 0.7 for females). The number and sizes of focal hepatocellular proliferative lesions (FHPL), including hyperplastic foci, hepatocellular adenomas and carcinomas, were quantified by image analysis and stereology. DEHP significantly enhanced the mean volume and volume % of FHPL, including liver tumors, but not numbers of FHPL/liver. Hepatocyte LI was also not affected, at least as detected by the technique used, while FHPL had significantly increased LI (14.5-48.3) as compared with normal hepatocytes (0.5-2.4). This study provides some evidence that enhanced chronic cell replication in the kidney may not always be associated with renal carcinogenesis of tumor promotion, while tumor promotion in liver may be a consequence of increased DNA synthesis in initiated or focus cells rather than in nonproliferative parenchymal hepatocytes, which may not be target cells of some tumor promoters.
Animals↗
Amelioration of sodium barbital-induced nephropathy and regenerative tubular hyperplasia after a single injection of streptozotocin does not abolish the renal tumor promoting effect of barbital sodium in male F344/NC4 rats.
The renal tumor promoting activity of barbital sodium (BBNa) and the role of renal tubular cell hyperplasia in tumor promotion following initiation with streptozotocin (STZ) was investigated. Six week old male F344/NCr rats were given STZ as a single i.p. injection of 50 mg/kg body wt and beginning 2 weeks later were fed diets containing 0 or 4000 p.p.m. of BBNa until they were killed at 33, 52 or 72 experimental weeks for histological evaluation and determination of levels of renal DNA synthesis by bromodeoxyuridine (Brdu) immunohistochemistry. A promoting effect on renal carcinogenesis was found by 72 weeks, but not at 33 or 52 weeks, confirming that prolonged administration of BBNa is necessary to promote renal tubular cell neoplasms. The promoting effect was evident as a higher incidence of large renal tubular tumors after 52 weeks, rather than an increase in number of dysplastic tubules, putative preneoplastic lesions. These findings suggest that the targets for the promoting activity of BBNa may be dysplastic lesions which may progress to tumors. Detailed examination by the step section technique through the entire kidneys revealed that STZ or BBNa administration induced a high incidence of putative preneoplastic renal tubular lesions (dysplasias) which seemed to be derived from the P1 or P2 segment of the nephron, also a site of high Brdu labeling index (LI) associated with BBNa toxicity. STZ administration was also associated with attenuation of BBNa-induced nephropathy and with diabetes from pancreatic islet degeneration and atrophy. The reduction in severity of nephropathy was correlated with a reduction in the LI of the renal cortical and medullary tubules, but not with the renal tumor incidence. These results indicate that decreased DNA synthesis in target cells does not eliminate tumor promoting activity in renal tubular epithelium. In addition, BBNa alone induced papillomas of the transitional epithelium of the renal pelvis and renal tubular cell adenomas.
Adenoma↗
H-ras activation and ras p21 expression in bladder tumors induced in F344/NCr rats by N-butyl-N-(4-hydroxybutyl)nitrosamine.
Bladder tumors were induced in male F344/NCr rats by administration of N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) at 500 p.p.m. in their drinking water for 12 weeks. Twenty-one bladder tumors that developed between 25 and 50 weeks after BBN administration was begun were evaluated for immunoreactivity with polyclonal or monoclonal antibodies raised against ras p21, for amplification of ras genes by Southern blotting, and for activating point mutations in ras genes by selective oligonucleotide hybridization of products from polymerase chain reaction (PCR). Increased expression of ras p21 was detected by avidin-biotin immunohistochemistry in 18/21 (85%) of the neoplastic bladder lesions. By Southern analysis, there was no significant amplification of H-ras, K-ras or N-ras in any of the tumors except one that showed a 5-fold amplification of K-ras. Point mutations in ras genes were detected by selective oligonucleotide hybridization of the products of PCR. Of the 21 bladder tumors, three tumors were shown to have mutations in codon 12 (GGA----GAA), six tumors in codon 61 (two CAA----CTA, four CAA----CGA), and one in both codon 12 (GGA----GAA) and codon 61 (CAA----CGA), all in H-ras. Thus 10 of 21 tumors has ras gene mutations in a portion of the tumor cells. The variable pattern of point mutation in H-ras suggests that these mutations may not all be a direct consequence of interaction of BBN metabolites with H-ras. Enhanced expression of ras p21 was always focal and was not necessarily associated with transforming ras mutations. It is therefore suggested that tumorigenesis in BBN-initiated bladder cells might involve H-ras activation as part of a multistep pathway; however, H-ras involvement is not obligatory for tumor development.
Animals↗
Differential effects of renal carcinogens and tumor promoters on growth promotion and inhibition of gap junctional communication in two rat renal epithelial cell lines.
To evaluate the effects of renal carcinogens and tumor promoters on gap junctional intercellular communication (IC) and colony formation, two rat kidney epithelial cell lines were examined in vitro. The NRK-52E line was obtained from the American Type Culture Collection and the NK-4 line was established by us from male F344/NCr rats. The NRK-52E line was co-cultured on a confluent monolayer of lethally irradiated NRK-52E cells to determine colony-forming ability (cloning efficiency) and clonal expansion (average surface area of the colonies, SA) and the NK-4 line was cultured on collagen gel. Streptozotocin (STZ), a renal carcinogen, and trisodium nitrilotriacetate monohydrate (NTANa3), a renal carcinogen and tumor promoter, showed mild growth-enhancing effects on both cell lines, as determined by significant increases in SA, but not in cloning efficiency (CE). Sodium barbital (BBNa), a renal tumor promoter, had similar effects, while phenobarbital sodium (PBNa), a non-renal tumor promoter, lacked such activity. The effects of these compounds on gap junctional function were investigated by the Lucifer Yellow dye transfer microinjection assay using monolayers of NRK-52E and NK-4 cells. We found that STZ, NTANa3 and BBNa inhibited IC in NRK-52E cells, in accordance with their reported tumorigenic and/or tumor-promoting activity in vivo, while PBNa did not. Thus, we could present these findings in NRK-52E cells as an in vitro model to examine the potential tissue-specific effects of renal carcinogens and tumor promoters in vitro. We found, however, that other growth control mechanisms beside IC may play a role, because although the NK-4 line did not possess normal IC, the tumor promoters studied had identical growth-promoting effects on colony formation and expansion in both this cell line and the NRK-52E line.
Acetates↗
Cloning and expression of an alpha-amylase gene from Streptomyces thermoviolaceus CUB74 in Escherichia coli JM107 and S. lividans TK24.
A gene coding for a thermostable extracellular alpha-amylase, carried by a 5.7 kb BamHI chromosomal DNA fragment isolated from Streptomyces thermoviolaceus strain CUB74, was cloned into Escherichia coli JM107 using, as a cloning vector, the high-copy-number plasmid pUC8. E. coli containing a recombinant plasmid pQR300 expressed the amylase gene and exported the enzyme into the periplasmic space and the culture medium. The amylase protein expressed by E. coli had the same molecular mass (50 kDa) as that expressed by the Streptomyces parent strain, which suggests that the enzyme is processed similarly by both strains. The amylase gene was also cloned into Streptomyces lividans TK24 using pIJ702 as vector. The enzyme was stable at 70 degrees C when CaCl2 was present.
Cloning, Molecular↗
Evaluation of the Craig Lipreading Inventory.
Responses to the Craig Lipreading Inventory have not been subjected to rigorous statistical analysis. No normative data currently exist. The purposes of this study were to evaluate the internal validity and interest reliability and to obtain normative data. The inventory was administered to 150 children, ages 3 to 8 yr. The internal consistency was very high for each subtest. Significant correlations were obtained among the subtests. Significant differences in scores were noted for the three age groups, indicating the need for standards at each age group. Preliminary Z-scores and percentile ranks were computed for each age group. It was concluded that the inventory is a valuable, reliable tool of lipreading evaluation in children.
Child↗
Pathology of tumours in laboratory animals. Tumours of the rat. Tumours of the haematopoietic system.
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Animals↗
Strain-dependent effects of phenobarbital on liver tumor promotion in inbred mice.
Inbred strains of mice were found to differ significantly in their susceptibility to liver tumor promotion by PB. The susceptibility to promotion of hepatocarcinogenesis by this drug was a dominant trait in crosses between the sensitive DBA and resistant C57 mice. The reciprocal F1 hybrids responded similarly to tumor promotion by PB. PB promoted the development of hepatoblastomas in D2B6F1 males but not in B6D2F1 mice. Female mice of the D2B6F1 cross, similarly exposed to PB, failed to develop hepatoblastomas. These results suggested a sex-linked differential response to the development of hepatoblastomas in reciprocal F1 hybrids that are genetically identical except for the reverse origin of their X and Y chromosomes. Differences in the promoting effects of PB between C57 and DBA mice appeared to correlate with differences in the metabolism/detoxification of this drug. In conclusion, mouse strains that differ in susceptibility to two-stage liver carcinogenesis provide excellent opportunities to investigate the genetic and/or biochemical mechanisms responsible for these differences. Understanding these mechanisms may lead to the identification of factors that affect liver tumor development not only in mice but in other species as well.
Adenoma↗
Liver tumor promoters and other mouse liver carcinogens.
Mouse liver tumors are important end points for safety assessment of chemicals in rodent carcinogenicity assays. The mechanisms of induction of these tumors, whether by chemicals with significant genotoxic activities or by chemicals without such activities, remain unknown. If test mice have spontaneous tumors of high or low background incidence, the promotion of these tumors or of spontaneously initiated or susceptible cells may provide a basis for carcinogenesis induced by these compounds. Likewise, chronic toxicity and its associated target cell hyperplasia may also lead to promotion of these tumors. Experimental systems have been developed to study the mechanisms of tumor promotion in mouse liver. These models should significantly advance research into mechanisms of hepatocarcinogenesis and tumor promotion in mouse liver and may subsequently be used for human risk assessment.
Age Factors↗