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Biomedical subjects

David M Umbach

Publications and source records attributed to David M Umbach.

At least 19 recordsLinked to original sources
PubMed2006

Pesticides and other agricultural factors associated with self-reported farmer's lung among farm residents in the Agricultural Health Study.

BACKGROUND: Farmer's lung, or hypersensitivity pneumonitis, is an important contributor to respiratory morbidity among farmers. METHODS: Using the 1993-7 enrolment data from the Agricultural Health Study, we conducted a cross-sectional study of occupational risk factors for farmer's lung among 50,000 farmers and farm spouses in Iowa and North Carolina using hierarchical logistic regression controlling for age, state, and smoking status. Participants provided information on agricultural exposures, demographic characteristics, and medical history via self-administered questionnaires. Approximately 2% of farmers (n = 481) and 0.2% of spouses (n = 51) reported doctor-diagnosed farmer's lung during their lifetime. We assessed farmers and spouses separately due to different information on occupational exposure history. Only pesticide exposures represented lifetime exposure history, all other farm exposures represented current activities at enrolment. RESULTS: Among farmers, handling silage (OR = 1.41, 95% CI 1.10 to 1.82), high pesticide exposure events (OR = 1.75, 95% CI 1.39 to 2.21), and ever use of organochlorine (OR = 1.34, 95% CI 1.04 to 1.74) and carbamate pesticides (OR = 1.32, 95% CI 1.03 to 1.68) were associated with farmer's lung in mutually-adjusted models. The insecticides DDT, lindane, and aldicarb were positively associated with farmer's lung among farmers. Current animal exposures, while not statistically significant, were positively associated with farmer's lung, particularly for poultry houses (OR = 1.55, 95% CI 0.93 to 2.58) and dairy cattle (OR = 1.28, 95% CI 0.86 to 1.89). The occupational data were more limited for spouses; however, we saw similar associations for dairy cattle (OR = 1.50, 95% CI 0.72 to 3.14) and organochlorine pesticides (OR = 1.29, 95% CI 0.64 to 2.59). CONCLUSION: While historic farm exposures may contribute to the observed associations with pesticides, these results suggest that organochlorine and carbamate pesticides should be further evaluated as potential risk factors for farmer's lung

Adult↗
PubMed2006

Antimutagenicity of cinnamaldehyde and vanillin in human cells: Global gene expression and possible role of DNA damage and repair.

Vanillin (VAN) and cinnamaldehyde (CIN) are dietary flavorings that exhibit antimutagenic activity against mutagen-induced and spontaneous mutations in bacteria. Although these compounds were antimutagenic against chromosomal mutations in mammalian cells, they have not been studied for antimutagenesis against spontaneous gene mutations in mammalian cells. Thus, we initiated studies with VAN and CIN in human mismatch repair-deficient (hMLH1(-)) HCT116 colon cancer cells, which exhibit high spontaneous mutation rates (mutations/cell/generation) at the HPRT locus, permitting analysis of antimutagenic effects of agents against spontaneous mutation. Long-term (1-3 weeks) treatment of HCT116 cells with VAN at minimally toxic concentrations (0.5-2.5mM) reduced the spontaneous HPRT mutant fraction (MF, mutants/10(6) survivors) in a concentration-related manner by 19-73%. A similar treatment with CIN at 2.5-7.5microM yielded a 13-56% reduction of the spontaneous MF. Short-term (4-h) treatments also reduced the spontaneous MF by 64% (VAN) and 31% (CIN). To investigate the mechanisms of antimutagenesis, we evaluated the ability of VAN and CIN to induce DNA damage (comet assay) and to alter global gene expression (Affymetrix GeneChip) after 4-h treatments. Both VAN and CIN induced DNA damage in both mismatch repair-proficient (HCT116+chr3) and deficient (HCT116) cells at concentrations that were antimutagenic in HCT116 cells. There were 64 genes whose expression was changed similarly by both VAN and CIN; these included genes related to DNA damage, stress responses, oxidative damage, apoptosis, and cell growth. RT-PCR results paralleled the Affymetrix results for four selected genes (HMOX1, DDIT4, GCLM, and CLK4). Our results show for the first time that VAN and CIN are antimutagenic against spontaneous mutations in mammalian (human) cells. These and other data lead us to propose that VAN and CIN may induce DNA damage that elicits recombinational DNA repair, which reduces spontaneous mutations.

Acrolein↗
PubMed2006

Inhibition of spontaneous mutagenesis by vanillin and cinnamaldehyde in Escherichia coli: Dependence on recombinational repair.

Vanillin (VAN) and cinnamaldehyde (CIN) are dietary antimutagens that effectively inhibit both induced and spontaneous mutations. We have shown previously that VAN and CIN reduced the spontaneous mutant frequency in Salmonella TA104 (hisG428, rfa, DeltauvrB, pKM101) by approximately 50% and that both compounds significantly reduced mutations at GC sites but not at AT sites. Previous studies have suggested that VAN and CIN may reduce mutations in bacterial model systems by modulating DNA repair pathways, particularly by enhancing recombinational repair. To further explore the basis for inhibition of spontaneous mutation by VAN and CIN, we have determined the effects of these compounds on survival and mutant frequency in five Escherichia coli strains derived from the wild-type strain NR9102 with different DNA repair backgrounds. At nontoxic doses, both VAN and CIN significantly reduced mutant frequency in the wild-type strain NR9102, in the nucleotide excision repair-deficient strain NR11634 (uvrB), and in the recombination-proficient but SOS-deficient strain NR11475 (recA430). In contrast, in the recombination-deficient and SOS-deficient strain NR11317 (recA56), both VAN and CIN not only failed to inhibit the spontaneous mutant frequency but actually increased the mutant frequency. In the mismatch repair-defective strain NR9319 (mutL), only CIN was antimutagenic. Our results show that the antimutagenicity of VAN and CIN against spontaneous mutation required the RecA recombination function but was independent of the SOS and nucleotide excision repair pathways. Thus, we propose the counterintuitive notion that these antimutagens actually produce a type of DNA damage that elicits recombinational repair (but not mismatch, SOS, or nucleotide excision repair), which then repairs not only the damage induced by VAN and CIN but also other DNA damage-resulting in an antimutagenic effect on spontaneous mutation.

Acrolein↗
PubMed2006

APE1 genotype and risk of bladder cancer: evidence for effect modification by smoking.

Apurinic/apyrimidinic (AP) sites are common mutagenic and cytotoxic DNA lesions that arise from the loss of normal bases. APE1, the major AP endonuclease of human cells, plays a central role in the repair of AP sites through both its endonuclease and phosphodiesterase activities. A common APE1 polymorphism, a T-->G transversion (Asp 148 Glu), was previously shown to be associated with risk of lung cancer, an association that was modified by cigarette smoking. To explore the association between APE1 genotype, smoking and bladder cancer risk, we examined data from an existing case-control study of bladder cancer patients (n = 239) and control individuals (n = 215) recruited from urology clinics at 2 hospitals in North Carolina. Genotype at the polymorphic site was determined using allele-specific primer extension reactions, followed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. We found no overall association between APE1 genotype and bladder cancer risk. In stratified analyses, however, a positive association with risk was observed with an increasing number of Glu alleles among never smokers, but not among smokers (p-value for interaction = 0.005). We can speculate that small allelic differences that are apparent in never smokers are obscured by the large amount of DNA damage found in smokers. Given the lack of established biological mechanisms, and suboptimal numbers of subjects in some exposure categories, our findings should be interpreted cautiously.

Aged↗
PubMed2006

Optimized mixed Markov models for motif identification.

BACKGROUND: Identifying functional elements, such as transcriptional factor binding sites, is a fundamental step in reconstructing gene regulatory networks and remains a challenging issue, largely due to limited availability of training samples. RESULTS: We introduce a novel and flexible model, the Optimized Mixture Markov model (OMiMa), and related methods to allow adjustment of model complexity for different motifs. In comparison with other leading methods, OMiMa can incorporate more than the NNSplice's pairwise dependencies; OMiMa avoids model over-fitting better than the Permuted Variable Length Markov Model (PVLMM); and OMiMa requires smaller training samples than the Maximum Entropy Model (MEM). Testing on both simulated and actual data (regulatory cis-elements and splice sites), we found OMiMa's performance superior to the other leading methods in terms of prediction accuracy, required size of training data or computational time. Our OMiMa system, to our knowledge, is the only motif finding tool that incorporates automatic selection of the best model. OMiMa is freely available at 1. CONCLUSION: Our optimized mixture of Markov models represents an alternative to the existing methods for modeling dependent structures within a biological motif. Our model is conceptually simple and effective, and can improve prediction accuracy and/or computational speed over other leading methods.

Algorithms↗
PubMed2006

Pesticides associated with wheeze among commercial pesticide applicators in the Agricultural Health Study.

Pesticides are potential risk factors for respiratory disease among farmers, but farmers are also exposed to other respiratory toxicants. To explore the association of pesticides with wheeze in a population without other farming exposures, the authors analyzed data from 2,255 Iowa commercial pesticide applicators enrolled in the Agricultural Health Study. Controlling for age, smoking status, asthma and atopy history, and body mass index, the authors calculated odds ratios for the relationship between wheeze and 36 individual pesticides participants had used during the year before enrollment (1993-1997). Eight of 16 herbicides were associated with wheeze in single-agent models; however, the risk was almost exclusively associated with the herbicide chlorimuron-ethyl (odds ratio (OR) = 1.62, 95% confidence interval (CI): 1.25, 2.10). Inclusion of chlorimuron-ethyl in models for the other herbicides virtually eliminated the associations. The odds ratios for four organophosphate insecticides (terbufos, fonofos, chlorpyrifos, and phorate) were elevated when these chemicals were modeled individually and remained elevated, though attenuated somewhat, when chlorimuron-ethyl was included. The association for dichlorvos, another organophosphate insecticide, was not attenuated by chlorimuron-ethyl (OR = 2.48, 95% CI: 1.08, 5.66). Dose-response trends were observed for chlorimuron-ethyl, chlorpyrifos, and phorate; the strongest odds ratio was for applying chlorpyrifos on more than 40 days per year (OR = 2.40, 95% CI: 1.24, 4.65). These results add to the emerging literature linking organophosphate insecticides and respiratory health and suggest a role for chlorimuron-ethyl.

Adolescent↗
PubMed2006

Smoking is associated with increased telomerase activity in short-term cultures of human bronchial epithelial cells.

Telomerase plays an important role in the maintenance of telomere ends in normal and tumor cells and ectopic expression can immortalize human bronchial epithelial (HBE) cells. We assessed telomerase activation, growth properties and methylation status in the hTERT promoter in a panel of HBE cell cultures in relation to smoking and previous lung cancer history. HBE cells were obtained from a total of 26 subjects, six of whom were lifelong non-smokers, while 20 subjects had a smoking history, including seven who had lung carcinoma. Telomerase activity was determined using the telomeric repeat amplification protocol (TRAP). Maximum passage number and time to senescence were also determined through extended culturing. The distribution of the telomerase activity between ever-smokers and never-smokers was significantly different (P=0.03, F-test), and there was a strong correlation between telomerase activity and the number of pack-years smoked (P=0.0012, F-test for slope). A small difference in telomerase activity was observed according to lung cancer status (P=0.02, F-test). Telomerase activity was not correlated with maximum passage number after extended culturing or with time to senescence. None of the HBE cultures demonstrated methylation of the hTERT promoter. Our results indicate an association between tobacco carcinogen exposure and telomerase activity in normal bronchial epithelium, although a causative role of tobacco smoking in the (re)activation of telomerase can not be proven. An increase in telomerase activity in normal bronchial epithelium might extend the lifespan of cells at risk for malignant transformation, and thus contribute to lung carcinogenesis.

Adolescent↗
PubMed2006

Optimal sampling of rat liver tissue for toxicogenomic studies.

Different degrees of a toxic response between and within the various lobes of the liver have been observed in rodents following treatment with acetaminophen. This study was designed to compare 2 sampling methods of the rat liver for gene-expression analysis. Ten male Fischer 344/N rats, 12-14 weeks of age, were treated with vehicle (0.5% aqueous ethyl cellulose) or acetaminophen (APAP, 1500 mg/kg) and sacrificed 24 hours following dose administration. Two representative sections were collected from the left liver lobe, stained with hematoxylin and eosin (H&E), and evaluated independently by 2 pathologists. The central core of the left lobe was cubed and frozen. Five random cubes were conserved, while the remaining left lobe core was pulverized. From each of the 10 animals, 2 random cubes and 2 samples from the homogeneous, pulverized samples were prepared for microarray analysis. Histopathologic evaluation revealed a variable response of centrilobular necrosis within the left lobe. Multiple methods used to analyze the microarray data indicated that sampling technique was not a major contributor to the variability observed in the gene expression data; however, only the powdered samples clustered for all animals, even those with disparate histopathologic results. Additionally, a powdered sample provided the advantages of a homogenous sample pool and the ability to use sample aliquots for other analyses to include proteomics, metabonomics, and other molecular techniques.

Acetaminophen↗
PubMed2006

Pesticides and adult respiratory outcomes in the agricultural health study.

In the 1700s, Bernardino Ramazzini was among the first to describe respiratory disease among agricultural workers. Since then, farmers continue to have higher rates of respiratory illnesses, even as changes occur in occupational and environmental exposures on farms. While grain and animal exposures have been well studied for their role in agricultural lung diseases, pesticide exposures have not. Using the Agricultural Health Study, a prospective cohort study of approximately 89,000 licensed pesticide applicators and their spouses in Iowa and North Carolina, we are currently assessing the association of pesticides with respiratory outcomes, including wheeze, adult asthma, farmer's lung, and chronic bronchitis. At enrollment (1993-1997), 19% of farmers and 22% of commercial pesticide applicators reported wheeze in the previous year. Using logistic regression models adjusted for age, state, smoking status, and body mass index, we evaluated the association of 40 individual pesticides with wheeze within these two groups separately. In both groups, we observed strong evidence of an association of organophosphates with wheeze. For farmers, the organophosphates chlorpyrifos, malathion, and parathion were positively associated with wheeze; for the commercial applicators, the organophosphates chlorpyrifos, dichlorvos, and phorate were positively associated with wheeze. Chlorpyrifos was strongly associated with wheeze in a dose-dependent manner in both groups; use of chlorpyrifos for at least 20 days per year had an odds ratio of 1.48 (95% confidence interval [CI] = 1.00-2.19) for farmers and 1.96 (95% CI = 1.05-3.66) for commercial applicators. Our wheeze results are consistent with recent animal models that support a role for organophosphates and respiratory outcomes.

Adult↗
PubMed2005

Accurate anchoring alignment of divergent sequences.

MOTIVATION: Obtaining high quality alignments of divergent homologous sequences for cross-species sequence comparison remains a challenge. RESULTS: We propose a novel pairwise sequence alignment algorithm, ACANA (ACcurate ANchoring Alignment), for aligning biological sequences at both local and global levels. Like many fast heuristic methods, ACANA uses an anchoring strategy. However, unlike others, ACANA uses a Smith-Waterman-like dynamic programming algorithm to recursively identify near-optimal regions as anchors for a global alignment. Performance evaluations using a simulated benchmark dataset and real promoter sequences suggest that ACANA is accurate and consistent, especially for divergent sequences. Specifically, we use a simulated benchmark dataset to show that ACANA has the highest sensitivity to align constrained functional sites compared to BLASTZ, CHAOS and DIALIGN for local alignment and compared to AVID, ClustalW, DIALIGN and LAGAN for global alignment. Applied to 6007 pairs of human-mouse orthologous promoter sequences, ACANA identified the largest number of conserved regions (defined as over 70% identity over 100 bp) compared to AVID, ClustalW, DIALIGN and LAGAN. In addition, the average length of conserved region identified by ACANA was the longest. Thus, we suggest that ACANA is a useful tool for identifying functional elements in cross-species sequence analysis, such as predicting transcription factor binding sites in non-coding DNA. AVAILABILITY: ACANA software and test sequence data are publicly available at http://BioMedEmpire.org/

Algorithms↗
PubMed2005

Retinal degeneration and other eye disorders in wives of farmer pesticide applicators enrolled in the agricultural health study.

Retinal degeneration is the leading cause of visual impairment in older adults. An association between retinal degeneration and fungicide use was observed previously among farmer pesticide applicators in the Agricultural Health Study, a large study of farm families from Iowa and North Carolina. The objective of this investigation was to determine whether wives of these farmer pesticide applicators were at increased risk of retinal degeneration. Self-reported cross-sectional data obtained via questionnaire between 1993 and 1997 from 31,173 wives were used. Associations of specific pesticides and groups of pesticides based on function (fungicides, herbicides, insecticides, and fumigants) or chemical structure (organophosphates, organochlorines, and carbamates) with eye disorders were evaluated using logistic and hierarchical logistic regression analyses. Self-reported retinal degeneration was associated with the wife's fungicide use (odds ratio = 1.9, 95% confidence interval: 1.2, 3.1) after adjustment for age and state of residence. Specific fungicides that appeared to drive this association were maneb or mancozeb and ziram. No associations between pesticide use and other eye disorders were found. Although these findings for retinal degeneration are based solely on self-reported disease, they are consistent with those reported for farmer pesticide applicators. These findings suggest that exposure to some fungicides and other pesticides may increase the risk of retinal degeneration and warrant further investigation.

Adult↗
PubMed2004

A random-periods model for expression of cell-cycle genes.

We propose a nonlinear regression model for quantitatively analyzing periodic gene expression in studies of experimentally synchronized cells. Our model accounts for the observed attenuation in cycle amplitude by a simple and biologically plausible mechanism. We represent the expression level for each gene as an average across a large number of cells. For a given cell-cycle gene, we model its expression in each cell in the culture as following the same sinusoidal function except that the period, which in any individual cell must be the same for all cell-cycle genes, varies randomly across cells. We model these random periods by using a lognormal distribution. The variability in period causes the measured amplitude of the cyclic expression trajectory to attenuate over time as cells fall increasingly out of synchrony. Gene-specific parameters include initial amplitude and phase angle. Applying the model to data from Whitfield et al. [Whitfield, M. L., Sherlock, G., Saldanha, A. J., Murray, J, I., Ball, C. A., et al. (2002) Mol. Biol. Cell 13, 1977-2000], we fit the trajectories of 18 well characterized phase-marker genes and find that the fit does not suffer when a common lognormal distribution is assumed for all 18 genes compared with a separate distribution for each. We then use the model to identify 337 periodically expressed transcripts, including the 18 phase-marker genes. The model permits estimation of and hypothesis testing about biologically meaningful parameters that characterize cycling genes.

Gene Expression↗
PubMed2004

Mini-and microsatellite mutations in children from Chernobyl accident cleanup workers.

Knowledge about possible genotoxic effects of low-dose radiation on the human germline is limited and relies primarily on extrapolations from high-dose exposures. To test whether ionizing radiation can cause paternal genetic mutations that are transmitted to offspring, we enrolled families of 88 Chernobyl cleanup workers exposed to ionizing radiation. We analyzed DNA isolated from lymphocytes for mutations via DNA blotting with the multi-locus minisatellite probes 33.6 and 33.15 and via PCR in a panel of six tetranucleotide repeats. Children conceived before and children conceived after their father's exposure showed no statistically significant differences in mutation frequencies. We saw an increase in germline microsatellite mutations after radiation exposure that was not statistically significant. We found no dependence of mutation rate on increasing exposure. A novel finding was that the tetranucleotide marker D7S1482 demonstrated germline hypermutability. In conclusion, our results do not support an increased level of germline minisatellite mutations but suggest a modest increase in germline mutations in tetranucleotide repeats. Small sample size, however, limited statistical power.

Adult↗
PubMed2004

Diesel exhaust, solvents, and other occupational exposures as risk factors for wheeze among farmers.

Farmers engage in activities that result in exposure to diesel exhaust, solvents, welding fumes, and other respiratory irritants. Using the Agricultural Health Study, a cohort of pesticide applicators in Iowa and North Carolina, we evaluated the odds of wheeze associated with nonpesticide occupational exposures. We used logistic regression models controlling for age, state, smoking, and history of asthma or atopy to evaluate odds of wheeze in the past year among the 20898 farmers who provided complete information on all covariates. Driving diesel tractors was associated with elevated odds of wheeze (odds ratio = 1.31; 95% confidence interval = 1.13, 1.52); the odds ratio for driving gasoline tractors was 1.11 (95% confidence interval = 1.02, 1.21). A duration-response relationship was observed for driving diesel tractors but not for driving gasoline tractors. Activities involving solvent exposure, including painting and use of solvents for cleaning, were associated with an increased odds of wheeze in a duration-dependent fashion. The highest odds of wheeze for farm activities were for daily painting (odds ratio = 1.82; 95% confidence interval = 0.89, 3.73), an indication of daily solvent exposure. These results add to the growing body of evidence of adverse respiratory effects of diesel exposure on the lung and suggest exposure to solvents may contribute as well.

Adolescent↗
PubMed2004

Application of the GA/KNN method to SELDI proteomics data.

SUMMARY: Proteomics technology has shown promise in identifying biomarkers for disease, toxicant exposure and stress. We show by example that the genetic algorithm/k-nearest neighbors method, developed for mining high-dimensional microarray gene expression data, is also capable of mining surface enhanced laser desorption/ionization-time-of-flight proteomics data. AVAILABILITY: The source code of the program and documentation on how to use it are freely available to non-commercial users at http://dir.niehs.nih.gov/dirbb/lifiles/softlic.htm

Algorithms↗
PubMed2004

Analytical and statistical methods to evaluate microsatellite allelic imbalance in small amounts of DNA.

Microsatellite analysis is a powerful tool for the assessment of genetic instability and loss of heterozygosity in cancer cells. However, most human tumors harbor significant numbers of normal cells, which may contribute to false-negative results. Recent techniques based on fluorescently labeled primers and semiautomated capillary electrophoresis of polymerase chain reaction (PCR) products allow a reliable quantitative assessment of (PCR) products while requiring very small numbers of cells. We report a highly sensitive protocol for the semiautomated analysis of allelic imbalance based on time-release PCR and capillary electrophoresis. With this protocol, as few as 100 cells can be used to reliably assess allelic imbalance (AI) in DNA samples. Using a panel of seven microsatellite markers, we determined allelic variation in a large set of heterozygous lymphocyte DNA samples and examined the use of different statistical analysis techniques. Using these statistical approaches, we describe a calibration method to evaluate AI from microsatellite results. Using a simple formula, cutoff points at preset confidence levels are used to decide whether allelic imbalance exists in a given sample at the loci under investigation. Our method allows the reliable detection of AI with very small amounts of DNA, and is sufficiently quantitative to assess allelic ratios in nonclonal tissue specimens.

Allelic Imbalance↗
PubMed2004

Patterns of pesticide use and their determinants among wives of farmer pesticide applicators in the Agricultural Health Study.

Pesticide exposure among farmers' wives is poorly characterized. Using questionnaire data from a cohort study of licensed pesticide applicators and their spouses, we investigated patterns of pesticide use among farmers' wives (n = 31,173). Wives reported a wide range of pesticide use: 36% never used pesticides during their lifetimes, whereas the heaviest pesticide users (10%) reported lifetime use of 3 or more agricultural pesticides plus commonly used residential pesticides. We identified 5 ordinal pesticide-use categories and studied factors associated with each category through polytomous logistic regression. Engaging in field work and household hygiene practices that could increase exposure were associated with pesticide use, and associations appeared to strengthen with increasing pesticide use category. Farm women reporting the heaviest pesticide use could exacerbate their exposure by engaging in practices that could increase pesticide contact.

Adolescent↗