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Biomedical subjects

C M White

Publications and source records attributed to C M White.

At least 91 records · Page 5Linked to original sources
PubMed1994

Assignment of a locus for mouse lung tumor susceptibility to proximal chromosome 19.

Previous studies have hypothesized that at least three genetic loci contribute to differences in pulmonary adenoma susceptibility between mouse strains A/J and C57BL/6J. One gene that may confer susceptibility to lung tumorigenesis is the Kras protooncogene. To identify other relevant loci involved in this polygenic trait, we determined tumor multiplicity in 56 randomly chosen N-ethyl-N-nitrosourea-treated (A/J x C57BL/6J) N1 x C57BL/6 backcross (AB6N2) progeny and correlated it with genotypes at 77 microsatellite markers spanning the genome. A correlation of lung tumor multiplicity phenotypes with genotypes of microsatellite markers on distal Chromosome (Chr) 6 in the Kras region (Pas1) was confirmed, and a new region on Chr 19 (designated Pas3) was identified that also contributes to susceptibility. Linkage analysis on Chr 19 with 270 AB6N2 mice localized the region flanked by D19Mit42 and D19Mit19 that is most closely associated with lung tumor susceptibility. The Pas3 locus may be an enhancer of the susceptibility locus on Chr 6.

Adenoma↗
PubMed1994

Low frequency of H-ras mutations in hepatocellular adenomas and carcinomas and in hepatoblastomas from B6C3F1 mice exposed to oxazepam in the diet.

Oxazepam has been the subject of recent toxicological and carcinogenesis studies because it is a commonly prescribed tranquilizer and has been shown to cause tumors in rodents. In this study, male and female B6C3F1 mice received 0, 125, 2500 or 5000 p.p.m. oxazepam in the diet for up to 2 years. Hepatocellular adenomas and carcinomas, as well as hepatoblastomas, which developed in these mice, were examined for the presence of activated ras proto-oncogenes. DNA was isolated from 20 or more tumors from each exposure group and analyzed by oligonucleotide hybridization, single-stranded conformation polymorphism analysis and direct sequencing of PCR-amplified H-ras gene fragments for codon 61 mutations. Thirteen of 37 (35%) hepatocellular adenomas and carcinomas from the 125 p.p.m. exposure group had mutations in codon 61, while mutations were detected in only 2 of 25 or 8% of the liver tumors from the 2500 p.p.m. exposure group and none of the 22 tumors from the 5000 p.p.m. group. This compares to 63% of 126 historical control liver tumors and 55% of 20 liver tumors from unexposed B6C3F1 mice in this study. In addition, 12 hepatoblastomas from the two high dose groups were examined for H-ras mutations at codon 61, but none were detected. No tumor DNAs from any of the exposure groups tested had mutations in codons 12, 13 or 117 of the H-ras gene or codons 12 or 13 of the K-ras gene, the other known hotspots for ras activation in mouse liver tumors. These results, together with those from the National Toxicology Program study showing no evidence of cytotoxicity or genotoxicity by oxazepam, suggest that oxazepam preferentially promotes cells that have activating lesions other than ras.

Adenoma↗
PubMed1993

Comparison of pulmonary O6-methylguanine DNA adduct levels and Ki-ras activation in lung tumors from resistant and susceptible mouse strains.

The role of O6-methylguanine (O6MG) DNA adduct formation and persistence in the formation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumors from resistant C57BL/6 and susceptible A/J mice was investigated. In addition, the frequencies of pulmonary tumor formation and Ki-ras activation were defined in C57BL/6 mice treated with NNK or vinyl carbamate (VC), and the role of the p53 gene in pulmonary carcinogenesis in these resistant mice was examined. One day after treatment with 100 mg/kg NNK, O6MG adduct concentrations were twofold to eightfold higher in Clara cells and type II cells than in small cells or whole lungs from both mouse strains. The concentrations of O6MG in isolated cells decreased at a similar rate in the two strains of mice. Lung tumors were detected by 27 mo of age in 18% of the C57BL/6 mice after a single 100 mg/kg dose of NNK and in 46% of these mice after a single 60 mg/kg dose of VC. In contrast, the tumor incidence in untreated C57BL/6 mice was 4%. Only one of 22 lung tumors from C57BL/6 mice treated with NNK contained an activated Ki-ras gene that was associated with an O6MG DNA adduct, whereas previous studies detected activated Ki-ras oncogenes in most of the NNK-induced lung tumors analyzed from susceptible A/J and resistant C3H mice. The small differences in formation and persistence of the O6MG adduct in whole lung or isolated lung cells from A/J and C57BL/6 strains do not account for the differences in either susceptibility for tumor formation or activation of the Ki-ras gene between these strains. In contrast to the low number of NNK-induced tumors with Ki-ras mutations in the resistant mice, 11 of 20 lung tumors from VC-treated mice contained activated Ki-ras genes. Neither p53 tumor suppressor gene mutations nor overexpression of the p53 protein were detected in spontaneous or chemically induced lung tumors in C57BL/6 mice. Thus, although Ki-ras activation was detected in some tumors, pathways independent of ras activation and p53 inactivation also appear to be involved in lung tumorigenesis in this resistant mouse strain.

Animals↗
PubMed1992

Bone mineral density in 15- to 21-year-old eumenorrheic and amenorrheic subjects.

The purposes of this study were to compare the lumbar spine bone mineral density of eumenorrheic and amenorrheic white subjects aged 15 to 21 years, and to describe the femoral neck bone mineral density in the eumenorrheic subjects. Twenty-eight eumenorrheic females had lumbar bone mineral density (mean +/- SD) of 1.213 +/- 0.117 g/cm2, and femoral neck bone mineral density of 1.032 +/- 0.092 g/cm2 measured with dual energy x-ray absorptiometry. Bone mineral density at neither site was related to age, energy intake, or calcium intake. Femoral neck bone mineral density was related to energy expenditure. Body composition was measured with total body electrical conductivity, and bone mineral density at both sites was related to body weight as much as fat-free mass. Eight amenorrheic subjects had a lumbar spine bone mineral density of 1.057 +/- 0.113 g/cm2, which was lower than in the eumenorrheic group. However, when controlling for weight, this difference was not significant. Peak lumbar and femoral neck bone mineral density may be reached at midadolescence.

Absorptiometry, Photon↗
PubMed1991

Use of sex-linked minisatellite fragments to investigate genetic differentiation and migration of North American populations of the peregrine falcon (Falco peregrinus).

The M13 repeat detects different levels of genetic variation in falcons. First, this minisatellite probe reveals typically highly variant restriction fragments that show no apparent unequal distribution between the sexes. Secondly, the M13 repeat detects sets of fragments that are only present in DNAs from female falcons. The level of polymorphism displayed by the sex-linked fragments is greatly reduced relative to most autosomal minisatellites. In addition, the size of these fragments (in kilobase pairs) is species-specific among Mauritius kestrels (Falco punctatus) and peregrines (Falco peregrinus). Variation observed at one o of the sex-linked fragments in peregrines has proven to be useful in distinguishing a subset of the tundrius subspecies of this endangered raptor. This correlation has enabled a genetic test to be used to examine the representation of tundrius peregrines during mass migration.

Animals↗
PubMed1991

Gambling and pathological gambling among university students.

Students from six colleges and universities in five states in the U.S. (New York, New Jersey, Oklahoma, Texas, and Nevada) were surveyed concerning their gambling behavior and the rate of pathological gambling. Type of gambling varied by state, with students in the northeast and Nevada gambling more than students in Oklahoma and Texas. Over 90% of males and 82% of females had gambled. One third of the males and 15% of females gambled once a week or more. Rates of pathological gambling ranged from 8% in New York to 4% in Nevada. The incidence of pathological gambling was high among males, Hispanics, Asians, and Italian-Americans (compared with among other whites), students with non-traffic arrests, those with parents who have gambling problems, and those who abuse alcohol and other drugs. Pathological gambling was only weakly correlated with age, religion, lower grade point average in school, overeating, living in neighborhoods that are "poorer than most," family income, and parental drug use. It was not correlated with academic year in college, marital status, parental occupation, parental alcohol, and bulimic behavior. The implications of the findings for further research and social policy are discussed.

Achievement↗
PubMed1991

Response of hospitals, skilled nursing facilities, and home health agencies in Oregon to AIDS: reports of nursing executives.

To describe experience and readiness to provide care for persons with acquired immunodeficiency syndrome (AIDS), responses to a mailed survey from 86 percent of chief nursing executives of the 207 hospitals, skilled nursing facilities (SNFs) and home health agencies (HHAs) in Oregon were summarized. As of January 1989, 44 percent reported having provided care; even in low incidence counties, 64 percent of hospitals had provided care. Adequate resources were reported by 79 percent in hospitals, 26 percent in SNFs, and 69 percent in HHAs.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Dose-response relationship between O6-methylguanine formation in Clara cells and induction of pulmonary neoplasia in the rat by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone.

The relationship between the formation of O6-methylguanine (O6MG) and the induction of lung, liver, and nasal tumors in the Fisher 344 rat by the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) was examined in a dose-response study. Animals were treated for 20 wk (3 times/wk) with concentrations of NNK ranging from 0.03 to 50 mg/kg to induce tumors. Steady-state concentrations of O6MG were quantitated, and cytotoxicity was assessed in target cells and tissues after 4 wk of treatment with NNK. No cytotoxicity was detected in the lung during treatment with NNK. The formation of O6MG was greatest in Clara cells compared with macrophages, type II cells, small cells, and whole lung at all doses examined. The difference in adduct concentration between the Clara cell and other pulmonary cell types was most pronounced with low doses of carcinogen. The O6MG:dose ratio, an index of alkylation efficiency, increased 29-fold as the dose of NNK was decreased from 50 to 1 mg/kg of carcinogen. In contrast, only a small increase in alkylation efficiency was observed in type II cells and whole lung. A significant number of tumors were induced in the lung at doses of 0.1 to 50 mg/kg with incidences ranging from 10% at the lowest dose up to 87% in the group of animals which received 50 mg/kg of NNK. A linear relationship was observed when the concentration of O6MG in Clara cells as a function of dose was plotted against the corresponding tumor incidence. This relationship was not observed using DNA adduct concentrations in type II cells or whole lung. The development of pulmonary tumors appeared to involve the formation of alveolar hyperplasias which progressed to adenomas and finally to carcinomas. The majority of adenomas were solid, whereas carcinomas were mainly papillary. Examination of the ultrastructure of the hyperplasias, adenomas, and carcinomas revealed morphological structures (e.g., lamellar bodies, tubular myelin) which are associated with type II cells. Thus, these data suggest that the majority of neoplasms in the lung begin as type II cell proliferations with progression to adenomas and carcinomas within the areas of hyperplasia. The lack of agreement between biochemical and morphological findings makes it difficult to hypothesize a cell of origin for the pulmonary neoplasms. In contrast to the lung, tumors were induced in the liver and nasal passages only after exposure to high doses of NNK. Moreover, both the formation of DNA adducts and cytotoxicity appear obligatory for the generation of tumors in these tissues.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1990

Child sexual abuse and premarital intercourse among high-risk adolescents.

This study examined the extent to which child sexual abuse was associated with an increased likelihood of premarital sex among adolescents at high risk of sexual abuse. The sample consisted of 177 teenage girls who, because of evidence of family dysfunction, had become part of a public child welfare system. Half the sample had been placed in a foster home and the remainder were receiving protective services in their own home. About 40% of the teens in both groups had been sexually abused, although teens still living at home were less likely to have reported abuse. Victims of sexual abuse were found to be more likely to have engaged in voluntary sexual intercourse, even after background factors were controlled. Teens in foster home were somewhat less likely to be sexually active than the teens who remained at home.

Adolescent↗
PubMed1990

Amenorrhea, osteopenia, and the female athlete.

Athletic amenorrhea is a problem because it is associated with an increased risk of injuries and potentially an increased risk of osteoporosis in later life. This article gives suggestions for the evaluation of the athlete with amenorrhea and for treatment protocols. Primary care physicians should routinely screen female adolescent athletes for amenorrhea and, if athletic amenorrhea is present, initiate treatment or referral for treatment for this important problem with short- and long-term complications.

Adolescent↗
PubMed1989

Cell specificity for the pulmonary metabolism of tobacco-specific nitrosamines in the Fischer rat.

The activity and distribution of the metabolic pathways of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), its major metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and the structurally related nitrosamine, N'-nitrosonornicotine (NNN) were examined in pulmonary cells from F344 rats in order to investigate the mechanisms by which NNK and NNAL, but not NNN, cause lung tumors. The tritium labeled nitrosamines were incubated with Clara cells, alveolar macrophages, alveolar type II cells, or small cells and metabolites were analyzed by HPLC. O6-Methyl-guanine (O6MG) formation was also quantified in the cells incubated with NNK. Clara cells metabolized all compounds more extensively than the other cell types. Total alpha-hydroxylation, carbonyl reduction to NNAL, and pyridine N-oxidation in cells incubated with NNK, as well as concentrations of O6MG in DNA were higher in Clara cells than in other cell types. Carbonyl reduction of NNK predominated over the other metabolic pathways in all cell types. The high activity for alpha-hydroxylation of NNK in Clara cells is consistent with previous studies which proposed that the cell specificity for O6MG formation and the accumulation of this adduct during low-dose exposure to NNK may stem from the presence of a high affinity pathway in Clara cells for NNK activation. Metabolism of NNAL by alpha-hydroxylation, and by reconversion to NNK followed by alpha-hydroxylation were observed. Total alpha-hydroxylation of NNAL was less extensive than alpha-hydroxylation of NNK. NNN was metabolized by both the 2'- and 5'-alpha-hydroxylation pathways. 2'-Hydroxylation of NNN produces the same DNA pyridyloxobutylating agent as does methyl hydroxylation of NNK. However, NNN is not a methylating agent and does not induce lung tumors in rats. Metabolism of NNN by 2'-hydroxylation was, depending on cell type, 41-85% as extensive as total alpha-hydroxylation of NNK, indicating that the rates of formation of the DNA pyridyloxobutylating agent were similar from NNN and NNK. The results of this study demonstrate that Clara cells have a high capacity to metabolically activate NNK, NNAL and NNN and provide further support for the hypothesis that DNA methylation of pulmonary cells is important in NNK carcinogenesis.

Alkylation↗
PubMed1988

Cell specific differences in O6-methylguanine-DNA methyltransferase activity and removal of O6-methylguanine in rat pulmonary cells.

Previous studies have demonstrated that cell specificity exists for the alkylation of DNA from lung cells following treatment of rats with the tobacco specific carcinogen 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK). The concentration of the promutagenic adduct O6-methylguanine (O6MG) was found to be greatest in Clara cells followed by macrophages, type II cells and alveolar small cells. The purpose of this study was to measure the activity of the repair protein O6-methylguanine-DNA methyltransferase (O6MGMT) and to determine whether differences exist for the removal of O6MG among pulmonary cell types. Constitutive activity of O6MGMT was 2-fold greater in macrophages and type II cells than alveolar small cells and Clara cells. Treatment for 4 days with NNK (10 mg/kg/day) had no effect on O6MGMT activity in macrophages, but decreased activity in alveolar small cells and type II cells by 57 and 84%, respectively. O6MGMT activity was reduced to below limits of detection in Clara cells following treatment with NNK. The effect of NNK on O6MGMT activity was consistent with rates of removal of O6MG in macrophages and Clara cells. The loss of O6MG from DNA of macrophages followed first order kinetics (t1/2 = 48 h) while very little loss of this adduct was observed in Clara cells over an 8 day period following cessation of carcinogen treatment. Even though O6MGMT activity was reduced in alveolar small cells and type II cells, approximately 90% of the O6MG bound to DNA in these cell types was removed within 8 days after treatment was discontinued. The loss of O6MG from pulmonary cells appears to result largely from the removal of this adduct by O6MGMT since rates of cell turnover were very low (0.5-1.5%/day) in the lung and were not affected by treatment with NNK. This study indicates that the activity of O6MGMT and the rate of resynthesis of this repair enzyme differ considerably among pulmonary cells following the methylation of DNA. The high concentration of O6MG in Clara cells and the low rate of repair of this promutagenic adduct may be critical factors in the potent pulmonary carcinogenicity induced by the tobacco specific carcinogen NNK.

Animals↗
PubMed1987

Cell selective alkylation of DNA in rat lung following low dose exposure to the tobacco specific carcinogen 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone.

The molecular dosimetry of O6-methylguanine (O6MG) in DNA from lung and specific cell populations isolated from lung was determined during multiple administrations of the tobacco specific carcinogen 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) to Fischer 344 rats. O6MG accumulated with doses of NNK ranging from 0.1 to 100 mg/kg/day. The dose response for NNK was nonlinear; the O6MG to dose ratio, an index of alkylation efficiency, increased dramatically as the dose of carcinogen decreased. These data suggest that low and high Km pathways may exist for activation of NNK to a methylating agent. Marked differences in O6MG concentration were observed in specific lung cell populations. The Clara cell, one of the suggested progenitor cells for nitrosamine-induced neoplasia, was found to possess the greatest concentration of O6MG. Moreover, as the dose of NNK was decreased from 100 to 0.3 mg/kg, the alkylation efficiency in this cell population increased 38-fold. The high level of DNA adduct formation in Clara cells following low dose exposure to NNK was supported by autoradiographic studies. Four h after treatment with 1 mg/kg [3H]NNK, silver grains were more heavily concentrated over Clara cells than over other cell types in the lung. Comparative studies on dimethylnitrosamine, a weak carcinogen in the rat lung, did not demonstrate this cell specificity for DNA alkylation. Thus, the presence of a high affinity pathway in the Clara cell for activation of NNK may contribute to the carcinogenicity of this tobacco specific carcinogen.

Alkylation↗
PubMed1987

DNA adducts as a dosimeter for risk estimation.

The dose response for O6-methylguanine (O6MG) formation and cytotoxicity was determined in lung and nasal mucosa from Fischer 344 rats during multiple dose administration of the tobacco-specific nitrosamine-4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK). O6MG accumulated in the lung following treatment for 12 days with doses of NNK from 0.3 to 100 mg/kg/day. The dose response for NNK was nonlinear; the O6MG-to-dose ratio, an index of alkylation efficiency, increased dramatically as the dose of carcinogen decreased. These data suggest that low- and high-Km pathways may exist for activation of NNK to a methylating agent. Marked differences in O6MG concentration were observed in specific lung cell populations. The Clara cell, one of the suggested progenitor cells for nitrosamine-induced neoplasia, was found to possess the greatest concentration of O6MG. Moreover, as the dose of NNK was decreased from 100 to 0.3 mg/kg, the alkylation efficiency in this cell population increased 38-fold. The presence of a high-affinity pathway in the Clara cell for activation of NNK may contribute to the potent carcinogenicity observed following low-dose exposure to this tobacco-specific carcinogen. The dose response for O6MG formation differed considerably between the respiratory and olfactory mucosa from the nasal passages of the rat. The dose response was nonlinear in respiratory mucosa but linear in olfactory mucosa. The alkylation efficiency increased dramatically only in the respiratory mucosa as the dose of NNK was decreased. These studies suggest that a low Km pathway for NNK activation is also present in the nose and that this pathway is localized predominantly in the respiratory region.(ABSTRACT TRUNCATED AT 250 WORDS)

Alkylation↗