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Biomedical subjects

N Rothman

Publications and source records attributed to N Rothman.

At least 109 records · Page 6Linked to original sources
PubMed1994

p53 mutations in human bladder cancer.

Mutations in the tumor suppressor gene p53 play an important role in carcinogenesis and tumor progression. To assess the status of p53 from genomic DNA from bladder cancer samples a two stage polymerase chain reaction was employed. The technique provided material for subsequent detection of mutations by Single Strand Conformation Polymorphism (SSCP) analysis followed by DNA sequence analysis. SSCP analysis of exons 5 to 9 of p53 was performed using fragments from PCR end-labeled with 32P followed by autoradiography using an electrophoresis system with temperature control. This SSCP method improved resolution of mutations in exons 5, 7, and 8 and the sharpness of bands in exons 6 and 9. Bands with altered migration patterns were excised from the dried SSCP gels, reamplified by PCR, and sequenced. Mutations in conserved exons 5, 6, 7, 8, and 9 of the p53 gene were analyzed from bladder tumor biopsies. Our results are consistent with the literature in that mutations in p53 are predominantly found in high grade bladder cancer (Odds Ratio = 4.05, Fisher Exact P = 0.104); however, the results were not statistically significant due to small numbers. Eight of 35 (23%) tumor samples examined showed mutations in p53 (including two double mutations). Six of 13 (46%) grade III and IV tumors had p53 mutations vs. 2 of 17 (12%) grade I and II tumors. Normal individuals carried no p53 mutations. We found no correlation between pack years of smoking and mutation in p53. The spectrum of mutations confirmed a high proportion of G:C C:G transversions as well as the occurrence of double mutations.

Autoradiography↗
PubMed1994

Identification of 1-hydroxypyrene glucuronide as a major pyrene metabolite in human urine by synchronous fluorescence spectroscopy and gas chromatography-mass spectrometry.

Humans are exposed to polycyclic aromatic hydrocarbons (PAHs) from various occupational, environmental, medicinal and dietary sources. The measurement of specific PAH metabolites, particularly 1-hydroxypyrene, in human urine treated with deconjugating enzymes (e.g. beta-glucuronidase) has been extensively used as a means of assessing recent exposure to PAHs. We have examined pyrene metabolites in human urine prior to enzymatic deconjugation in order to determine the relative proportions of conjugated and unconjugated pyrene metabolites. The analytical method utilized immunoaffinity chromatography, high performance liquid chromatography (HPLC) and the complementary techniques of synchronous fluorescence spectroscopy (SFS) and gas chromatography-mass spectrometry (GC-MS) to measure pyrene-containing metabolites. SFS analysis of immunoaffinity-purified urine samples showed fluorescence spectra characteristic of the pyrene moiety (using wavelength differences of 34 nm, 54 nm and 102 nm). These spectra are produced by several PAHs containing the pyrene moiety. HPLC analysis with fluorescence detection indicated that the major fluorescent metabolite in immunoaffinity-purified urine was much more polar than simple hydroxylated metabolites of pyrene (1-hydroxypyrene) or benzo[a]pyrene (benzo[a]pyrene-diols or -tetrols). Following digestion with beta-glucuronidase, this metabolite co-chromatographed with authentic 1-hydroxypyrene and exhibited fluorescence spectra characteristic of 1-hydroxypyrene, suggesting that the major metabolite was a glucuronide conjugate of 1-hydroxypyrene. This was subsequently confirmed by GC-MS analysis of trimethylsilyl derivatives of the major metabolite; both 1-hydroxypyrene and glucuronic acid were detected independently as derivatized products. Since 1-hydroxypyrene glucuronide is approximately 5-fold more fluorescent than 1-hydroxypyrene, it may provide a more sensitive biomarker for assessing exposure to pyrene in mixtures of PAHs.

Chromatography, High Pressure Liquid↗
PubMed1993

N-acetylation phenotype and genotype and risk of bladder cancer in benzidine-exposed workers.

Several studies in subjects occupationally exposed to arylamine carcinogens have shown increased risks for bladder cancer associated with the slow acetylator phenotype. To follow up these reports, a case-control study of N-acetylation and bladder cancer risk was carried out among subjects occupationally exposed to benzidine, in benzidine dye production and use facilities in China. Thirty-eight bladder cancer cases and 43 controls from these factories were included for study of acetylation phenotype, by dapsone administration, and for polymorphisms in the NAT2 gene, by a polymerase chain reaction (PCR)-based test. In contrast to previous studies, no increase in bladder cancer risk was found for the slow N-acetylation phenotype (OR = 0.3; 95% CI = 0.1-1.3) or for slow N-acetylation-associated double mutations in NAT2 (OR = 0.5; 95% CI = 0.1-1.8). Examination of specific mutations and adjustment for age, weight, city and tobacco use did not alter the results. When examined by level of benzidine exposure in the cases, the bladder cancer risks associated with low (OR = 0.3, 95% CI = 0.0-2.2), medium (OR = 0.7, 95% CI = 0.1-4.5) and high (OR = 0.6, 95% CI = 0.1-3.5) exposure showed no interaction between genotype and benzidine exposure, within the range of exposures experienced by subjects in this study. This study, which is the first to incorporate phenotypic and genotypic analyses, provides evidence that the NAT2-related slow N-acetylation polymorphism is not associated with an increased risk of bladder cancer in workers exposed to benzidine, and may have a protective effect.

Acetylation↗
PubMed1993

Detection of metabolites of polycyclic aromatic hydrocarbons in human urine.

A non-invasive assay has been developed for the recovery of r-7,t-8,t-9,c-10-tetrahydroxy-7,8,9,10-tetrahydrobenzo[alpha]-pyrene (BP-7,10/8,9-tetrol) from human urine. This tetrol is excreted as a metabolite of benzo[alpha]pyrene (BP) in a process catalyzed by cytochrome P450 enzymes and epoxide hydrolases. Urine was hydrolysed to release activated benzo[alpha]-pyrene-diol-epoxides covalently bound to macromolecular species or conjugated tetrols. The relatively non-polar organic molecules from urine hydrolysates were collected on octadecasilane chromatography columns (Sep-Paks). Materials eluted in solvent (80% CH3OH), were further purified on immunoaffinity columns with antibodies raised against anti-N2-[10(7,8,9-trihydroxy-7,8,9,10-tetrahydrobenzo [alpha]pyrenyl)]-guanosine. HPLC was then used to isolate BP-7,10/8,9-tetrol, which was quantitated by synchronous fluorescence spectroscopy (SFS). This assay detected 0.24-3.12 pmol BP-7,10/8,9-tetrol per ml urine (limit of detection 0.01 pmol/ml, given 10 ml urine), in four study subjects. Reproducibility was assessed by adding tritium labeled BP-7,10/8,9-tetrol (1500 fmol) to a urine sample previously identified to contain the tetrol at levels below the limit of detection of the fluorescence assay; a recovery of > 30% of the added radioactivity was achieved (510 +/- 64 fmol, mean +/- SD, n = 3). Because HPLC alone was not sufficient to isolate materials for quantitation by SFS directly from human urine, immunoaffinity chromatography was found to be a necessary preparatory step in BP-7,10/8,9-tetrol isolation. These data demonstrate the presence of tetrahydrotetrol metabolites of BP in human urine and suggest that measurement of BP-7,10/8,9-tetrol and other polycyclic aromatic hydrocarbon-tetrols may prove to be valuable dosimeters of human internal exposure to polycyclic aromatic hydrocarbons.

Benzo(a)pyrene↗
PubMed1993

Correlation between N-acetyltransferase activity and NAT2 genotype in Chinese males.

Eighty-four healthy Chinese male control subjects derived from an occupation-based case-control study of bladder cancer were evaluated for hepatic N-acetyltransferase activity by dapsone and for NAT2 genotype using allele-specific amplification of peripheral leukocyte DNA by the polymerase chain reaction. Fifty-nine percent of the overall variation in acetylation activity was explained by genotype (p < 0.0001). The remaining variation in acetylation was not associated with dapsone N-hydroxylation activity, age, current smoking status, or weight in the study population, or within any genotype subgroup. Although acetylation activity in the homozygous mutant group did not overlap with the other genotype categories, there was moderate overlap in acetylation between the heterozygous mutant and wildtype groups, and substantial variation in acetylation within them. Considering all subjects with the identical NAT2 genotype as phenotypically similar and all subjects with differing NAT2 genotypes as phenotypically distinct may result in misclassification of metabolic risk factors in epidemiological investigations. As such, it would seem prudent, where possible, to collect both acetylation phenotype and NAT2 genotype data, since the advantages and limitations of these two sources of information complement, and serve to assess the accuracy of each other.

Aged↗
PubMed1993

Association of PAH-DNA adducts in peripheral white blood cells with dietary exposure to polyaromatic hydrocarbons.

Previous investigations suggest that dietary sources of polycyclic aromatic hydrocarbons (PAHs) contribute to the PAH-DNA adduct load in peripheral white blood cells (WBCs). In the current study, we measured PAH-DNA adducts by enzyme-linked immunosorbent assay in WBCs obtained from 47 California wildland (forest) firefighters at two time points (early and late) during an active forest fire season. PAH-DNA adduct levels were not associated with recent firefighting activity, but were positively associated with frequency of charbroiled food consumption in the previous 2 weeks. In addition, adduct levels declined with time since last ingestion of charbroiled food. These studies indicate that recent consumption of charbroiled food contributes to the PAH-DNA adduct load in peripheral WBCs.

Adolescent↗
PubMed1993

Operationalizing the Corbin & Strauss Trajectory Model for elderly clients with chronic illness.

A research team of six nursing faculty at Thomas Jefferson University College of Allied Health Sciences collaborated to develop a research proposal to provide nursing care to a selected population of chronically ill elderly persons. The Corbin and Strauss Nursing Model for Chronic Illness Management (1991) was selected as the organizing framework to guide research and care delivery. While conceptual models offer direction for nursing practice, specific guidelines for providing care can only be identified when major concepts of the model are operationalized (Fawcett, 1989). This article describes the first step in operationalizing the Corbin and Strauss Trajectory Model undertaken by the research team which resulted in the development of eight "Phase-specific protocols." Two of the eight phase-specific protocols are presented.

Aged↗
PubMed1992

Acute high dose exposure to benzene in shipyard workers.

Fifteen degassers were acutely exposed over several days to high concentrations (> 60 ppm) of benzene during removal of residual fuel (degassing) from shipboard fuel tanks. Medical surveillance evaluation mandated by the Occupational Safety and Health Administration's (OSHA) Benzene Standard initially revealed 11 workers (73%) reporting neurotoxic symptoms while degassing. Workers with more than 2 days (16 hours) of acute exposure were significantly more likely to report dizziness and nausea than those with 2 or fewer days of acute exposure. Repeated laboratory analyses performed over a 4-month period after the acute exposure revealed at least one hematologic abnormality consistent with benzene exposure in 9 (60%) of these degassers. One year later, 6 workers (40%) had persistent abnormalities; an additional worker with normal hematologic parameters at the time of our initial evaluation subsequently developed an abnormality consistent with benzene exposure. Numerous large granular lymphocytes were observed on 6 (40%) of the peripheral blood smears. Despite these laboratory findings, there were no significant associations between the presence of hematologic abnormalities and either the number of hours of acute benzene exposure or the duration of employment as a degasser. Volatilization of benzene from the residual fuel was the suspected source of benzene in the headspace of tanks. Confined space exposure to petroleum products may be exposing workers to benzene at levels above the OSHA Short-Term Exposure Limit (STEL). This situation warrants further study.

Adult↗
PubMed1992

Occupational exposures in California wildland fire fighting.

Industrial hygiene measurement of exposures to wildland fire fighters was conducted in northern California during three consecutive fire seasons (1986-1989) in conjunction with three separate health effects studies. Chemicals that were monitored included carbon monoxide, total and respirable particulates, polyaromatic hydrocarbons (PAHs), crystalline silica, aldehydes, and benzene. Measurements were taken at both wildland fires and prescribed (planned) burns. A variety of collection methods were employed--colorimetric detector tubes and a CO monitor were used for direct-reading area measurements; colorimetric diffusion tubes, filter cassettes, sorbent tubes, and passive vapor monitors were used for determining personal time-weighted average exposures. A new screening method (National Institute for Occupational Safety and Health Method 2539) was used to identify the presence of specific aldehydes. Results show that wildland fire fighters may at times be exposed to concentrations of carbon monoxide, total or respirable particulates, or silica at levels near or higher than recommended occupational exposure limits, although group means were generally well below the limits. Time-weighted average formaldehyde levels, measured in a few instances above 0.37 mg/m3 (0.3 ppm), indicate a potential for formaldehyde-induced eye or respiratory irritation under these conditions. Certain characteristics of the work such as high altitude, temperature, and breathing rate; extended work shifts; and additional off-shift exposures suggest that adjustment of 8-hr exposure limits may be necessary to provide adequate protection. In part, because of the rigors of performing industrial hygiene measurements under fire fighting conditions, data are limited and could not be considered representative of the full range of exposures fire fighters may encounter.(ABSTRACT TRUNCATED AT 250 WORDS)

Air Pollutants, Occupational↗
PubMed1991

Anti-tick saliva antibody: a biologic marker of tick exposure that is a risk factor for Lyme disease seropositivity.

Anti-tick saliva antibody (ATSA) has potential as a biologic marker of exposure to tick bites. In 1989, we conducted a cross-sectional study of 304 outdoor workers in Monmouth County, New Jersey, to evaluate associations between self-reported tick exposure, ATSA status, and Lyme disease antibody status. ATSA levels 1) were correlated with an index of tick exposure on the basis of three self-reported measures of tick exposure and outdoor hours worked per week (p = 0.01); 2) were consistently higher in pet owners compared with persons without pets (p = 0.03); and 3) when examined by duration since last tick bite, peaked at 3-5 weeks after tick bite and then declined (p = 0.06). ATSA levels dichotomized at the 75th percentile (approximately two standard deviations above the mean ATSA optical density of 25 subjects who denied recent tick exposure) were associated with self-reported tick exposure: adjusted odds ratios for high ATSA levels were 4.2 (95% confidence interval (CI) 0.9-18.9) for moderate (versus none) tick exposure and 5.8 (95% CI 1.2-27.2) for high (versus none) tick exposure. Finally, high ATSA levels were associated with Lyme disease seropositivity, with an adjusted odds ratio of 3.2 (95% CI 1.3-7.6). The data suggest that ATSA is a biologic marker of tick exposure that is a risk factor for Lyme disease seropositivity.

Adolescent↗
PubMed1991

Pulmonary function and respiratory symptoms in wildland firefighters.

We studied cross-seasonal changes in pulmonary function and respiratory symptoms in 52 wildland firefighters in Northern California. The mean cross-seasonal change in forced expiratory volume in 1 second (FEV1) was -1.2% (95% confidence interval [CI] -0.5%, -2.0%) with a corresponding mean change in forced expiratory volume (FVC) of -0.3% (95% CI 0.4%, -1.0%). Decreases in FEV1 and FVC were most strongly associated with hours of recent fire-fighting activity (P = .002 and .01, respectively). When the study group was divided into three categories based on recent fire-fighting activity, firefighters in the high activity category (mean +/- SE, 73 +/- 7 hours of fire-fighting in previous week) had a -2.9% (130 mL) change in FEV1 and a -1.9% (102 mL) change in forced vital capacity (FVC). There was a significant cross-seasonal increase in most respiratory symptoms evaluated. Several symptoms (eye irritation, nose irritation, and wheezing) were associated with recent fire-fighting. These findings suggest that wildland firefighters experience a small cross-seasonal decline in pulmonary function and an increase in several respiratory symptoms. Research is under way to identify the fire conditions and specific components of exposure that produce pulmonary irritants, and to examine the potential reversibility of acute pulmonary change.

Adolescent↗
PubMed1990

Solvent-associated decrements in olfactory function in paint manufacturing workers.

To assess the effects of low-level organic solvent exposure on olfactory function, a cross-sectional study in paint manufacturing workers was undertaken. Workers in two paint manufacturing facilities (N = 187) were tested using the University of Pennsylvania Smell Identification Test (UPSIT), a standardized, quantitative test of olfactory function. Industrial hygiene air samples over the past 13-15 years revealed that average solvent exposures in these plants were 2-40% of the existing threshold limit values for the three chemicals measured. Stratification by smoking status revealed evidence of dose-related decrements in olfactory function (p = .01) only in non-smokers. Furthermore, those nonsmoking workers in the highest exposure category had UPSIT scores below the fifth percentile for their age. These results suggest that solvents may cause nervous system dysfunction at lower levels than previously suspected, and that the olfactory system may be a critical target organ for the neurotoxic effects of solvents and other chemicals.

Adult↗
PubMed1990

Formation of polycyclic aromatic hydrocarbon-DNA adducts in peripheral white blood cells during consumption of charcoal-broiled beef.

The effect of ingesting charcoal-broiled (CB) beef on polycyclic aromatic hydrocarbon (PAH)-DNA adduct levels in nucleated peripheral white blood cells (WBCs) was examined in four healthy, non-smoking males who consumed an average of 280 g CB beef daily for 7 days. PAH-DNA adducts were quantitated by enzyme-linked immunosorbent assay. During the week of CB beef consumption, two individuals exhibited a 3- to 6-fold increase in PAH-DNA adducts above baseline levels observed during the month prior to CB beef consumption. In contrast, PAH-DNA adduct levels in the two other subjects did not increase. Thus, dietary sources of PAH can contribute to the PAH-DNA adduct load in peripheral WBCs in some individuals.

Adult↗
PubMed1982

Role of glnA-linked genes in regulation of glutamine synthetase and histidase formation in Klebsiella aerogenes.

We isolated mutants of Klebsiella aerogenes with insertions of transposon Tn5 linked to the structural gene for glutamine synthetase, glnA. We found that K. aerogenes, like Escherichia coli and Salmonella typhimurium, contains a regulatory gene, glnG, which is closely linked to but distinct from glnA. The product of glnG is essential for normal regulation of the synthesis of glutamine synthetase and histidase. We analyzed two mutations which affected the regulation of the formation of these enzymes and appeared to be outside glnG. The results of our studies suggest the presence in K. aerogenes of at least two regulatory genes located in the glnA region, namely, glnG and another gene, the transcription of which can be initiated at the promoter of glnA.

Ammonia-Lyases↗