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Biomedical subjects

L M Brown

Publications and source records attributed to L M Brown.

At least 55 records · Page 3Linked to original sources

Alcohol dehydrogenase 3 genotype and risk of oral cavity and pharyngeal cancers.

BACKGROUND: The consumption of alcoholic beverages is a strong risk factor for cancers of the oral cavity and pharynx (oral cancers). Alcohol dehydrogenase type 3 (ADH3) metabolizes ethanol to acetaldehyde, a carcinogen. We evaluated whether individuals homozygous for the fast-metabolizing ADH3(1) allele (ADH3[1-1]) have a greater risk of developing oral cancer in the presence of alcoholic beverage consumption than those with the slow-metabolizing ADH3(2) allele (ADH3[1-2] and ADH3[2-2]). METHODS: As part of a population-based study of oral cancer conducted in Puerto Rico, the ADH3 genotypes of 137 patients with histologically confirmed oral cancer and of 146 control subjects (i.e., individuals with no history of oral cancer) were determined by molecular genetic analysis of oral epithelial cell samples. Risks were estimated by use of multiple logistic regression analyses. RESULTS: Compared with nondrinkers with the ADH3(1-1) genotype, consumers of at least 57 alcoholic drinks per week with the ADH3(1-1), ADH3(1-2), and ADH3(2-2) genotypes had 40.1-fold (95% confidence interval [CI] = 5.4-296.0), 7.0-fold (95% CI = 1.4-35.0), and 4.4-fold (95% CI = 0.6-33.0) increased risks of oral cancer, respectively; the risk associated with the ADH3(1-1) genotype, compared with the ADH3(1-2) and ADH3(2-2) genotypes combined, was 5.3 (95% CI = 1.0-28.8) among such drinkers. Considering all levels of alcohol consumption, the risk of oral cancer per additional alcoholic drink per week increased 3.6% (95% CI = 1.9%-5.4%) for subjects with the ADH3(1-1) genotype and 2.0% (95% CI = 0.9%-3.0%) for subjects with the ADH3(1-2) or ADH3(2-2) genotype (two-sided P = .04). CONCLUSIONS: The ADH3(1-1) genotype appears to substantially increase the risk of ethanol-related oral cancer, thus providing further evidence for the carcinogenicity of acetaldehyde.

Aged↗

Cell cycle regulation of RPA1 transcript levels in the trypanosomatid Crithidia fasciculata.

Transcripts of both mitochondrial and nuclear DNA replication genes accumulate periodically during the cell cycle in Crithidia fasciculata. An octameric consensus sequence with a conserved hexameric core was found previously to be required for cycling of the TOP2 transcript, encoding the mitochondrial DNA topoisomerase. We show here that the rate of synthesis of the p51 protein, the large subunit of nuclear replication protein-A encoded by the RPA1 gene, varies during the cell cycle in parallel with RPA1 mRNA level. Plasmids expressing a truncated form of RPA1 (Delta RPA1 ) were used to identify cis elements required for cycling of the Delta RPA1 transcript. Sequences within the RPA1 5'-untranslated region (UTR) were found to be necessary for cycling of the Delta RPA1 transcript. These sequences also function when transposed 3'of the Delta RPA1 coding sequence. A 121 bp fragment of this sequence can confer cycling on a heterologous transcript, but is inactivated when two consensus octamers within the sequence are mutated. Mutation of these two octamers in the full-length 5'-UTR ofDelta RPA1 is insufficient to abolish cycling of the mRNA unless three additional octamers having single base changes within the hexameric core are also mutated. Thus, common octameric sequence elements are involved in periodic accumulation of both the TOP2 and RPA1 transcripts.

Animals↗

Drinking practices and risk of squamous-cell esophageal cancer among Black and White men in the United States.

To evaluate whether the fivefold greater incidence rate of squamous-cell esophageal cancer in Black compared with White men is due to type of alcoholic beverage consumed or to other qualitative differences in alcohol consumption, we conducted a population-based case-control study with 373 males diagnosed with squamous-cell esophageal cancer (124 Whites and 249 Blacks) and 1,364 male controls (750 Whites and 614 Blacks) from three geographic areas in the United States. Included were all histologically confirmed cases newly diagnosed from 1 August 1986 through 30 April 1989, among White and Black men aged 30 to 79 years. Risks varied to some extent according to type of alcohol used, with beer a stronger contributor in Whites, and wine and liquor stronger contributors in Blacks. However, most of the differences in the odds ratios by type of alcohol and race were eliminated after controlling for average weekly amount of total alcohol consumed. Thus, while alcohol use in all forms is an important risk factor for squamous-cell esophageal cancer in Whites and Blacks, type of alcoholic beverage used does not appear to account for the racial differences in incidence.

Adult↗

Multiple myeloma among Blacks and Whites in the United States: role of cigarettes and alcoholic beverages.

In the United States, the incidence rates of multiple myeloma in Blacks are more than twice those in Whites, but the etiology of this cancer is poorly understood. A population-based case-control interview study of 571 subjects (365 White, 206 Black) with multiple myeloma and 2,122 controls (1,155 White, 967 Black) living in three areas of the United States (Georgia, Michigan, New Jersey) offered the opportunity to investigate the relationship with smoking and alcohol drinking and to evaluate whether these factors might contribute to the excess risk of multiple myeloma in Blacks. For Blacks and Whites of either gender, there were no significantly elevated risks associated with ever use of cigarettes or alcoholic beverages and no consistent patterns with either intensity or duration of use. These data support previous studies indicating that smoking and drinking are not related causally to the risk of multiple myeloma, and thus cannot account for the racial disparity in incidence rates.

Adult↗

Cancer risk and mortality patterns among silicotic men in Sweden and Denmark.

Data from nationwide registry-based cohorts of patients hospitalized for silicosis in Sweden from 1965 to 1983 and Denmark from 1977 to 1989 were linked to national cancer registries in both countries and to mortality data in Sweden to evaluate the risk of cancer and other disorders among hospitalized silicotic patients. The overall cancer standardized incidence ratio (SIR) was 1.5 (95% confidence interval [CI], 1.3 to 1.7) in Sweden and 1.7 (95% CI, 1.2 to 2.3) in Denmark, primarily because of elevations in primary lung cancer in both Sweden (SIR, 3.1; CI, 2.1 to 4.2) and Denmark (SIR, 2.9; CI, 1.5 to 5.2). For Sweden, the all-causes standardized mortality ratio (SMR) was 2.0 (1.9 to 2.2). The SMR for all malignancies was 1.5 (1.2 to 1.7), primarily because of excesses of lung cancer (SMR, 2.9; CI, 2.1 to 3.9). The significant increase in mortality for all infectious and parasitic conditions (SMR, 11.2) was primarily due to tuberculosis (SMR, 21.8). Significant excesses in mortality from silicosis (SMR, 523), bronchitis (SMR, 2.6) and emphysema (SMR, 6.7) contributed to the elevation in nonmalignant respiratory deaths (SMR, 8.8), whereas excess mortality from musculoskeletal disorders (SMR, 5.9) was due to six deaths from autoimmune diseases. Despite limitations of the available data, our findings are consistent with previous reports indicating that silicotic patients are at elevated risk of lung cancer, nonmalignant respiratory diseases, tuberculosis, and certain autoimmune disorders.

Adult↗

Role of the matrixin MMP-2 in multicellular organization of adipocytes cultured in basement membrane components.

Primary rat adipocytes cultured in basement membrane component gels migrated and organized into large, three-dimensional, multicellular clusters. Gross morphological changes seen during this reorganization are described. The rate of cluster formation decreased with age of the rats and was stimulated by insulin in older, but not in younger rats. Echistatin, a disintegrin, partially inhibited the formation of multicellular clusters in a concentration-dependent fashion (50% inhibitory concentration approximately 10 nM). The original extracellular matrix was initially remodeled and eventually destroyed by the time large multicellular clusters were observed. This implied that one or more matrix-degrading protease(s) were being secreted. Adipocyte-conditioned medium was found to contain a divalent cation-sensitive gelatinase activity at approximately 72 and/or approximately 62 kDa. The elution profile of this activity from gelatin-Sepharose 4B was similar to matrix metalloproteinase 2 (MMP-2, a 72-kDa matrixin with a 62-kDa mature form), and the dimethyl sulfoxide eluant from these columns contained MMP-2 immunoreactivity. MMP-2 concentration and activity were greater in conditioned medium from young than from older animals; however, insulin did not affect the amount of MMP-2 in adipocyte-conditioned media. The matrixin inhibitor 1,10-phenanthroline not only blocked gelatinase activity in zymograms but also prevented extracellular matrix remodeling and destruction, as well as adipocyte migration and the formation of cell-cell contacts in adipocyte cultures. These observations are consistent with the hypothesis that the matrixin MMP-2 is secreted by adipocytes. Whereas matrixin activity alone may not be sufficient for the formation of multicellular clusters, the data indicate that it may have a requisite role in this process.

Adipocytes↗

Temporal variability in immunological parameters: peripheral blood mononuclear cell subsets, serum immunoglobulins, and soluble markers of immune system activation.

T-cell subsets and soluble factors of immune system activation are increasingly used as biologic markers of disease and predictors of disease progression. For example, changes in CD4 cells and CD4:CD8 ratio, sIL-2R, B2M, neopterin, and IgA have been used in predicting AIDS onset and progression. We examined the temporal variability of T-cell subsets, monocytes, natural killer cells, B cells, immunoglobulins, soluble interleukin-2 receptor (sIL-2R), neopterin, and beta-2 microglobulin (B2M) among 135 adults tested at two time points approximately 3 months apart. The purpose of the study was two-fold: (1) to assess the stability of these measures at two points in time, and (2) to investigate which parameters tend to track together over time, i.e., show significant longitudinal correlation. Mean population values for these immunologic parameters remained remarkably stable over the 3-month period. However, individual subjects exhibited significant temporal variability for many parameters. Unlike observations in patients with AIDS, changes in immunoglobulins and other soluble factors were not significantly correlated with changes in cellular subsets over the same period. However, change in B2M was correlated with change in neopterin (r = .35, p < or = .0001), and change in IgA was correlated with changes in IgG and IgM (r = .44, r = .54, P < or = .001 for both). Characterizing this temporal variability in a healthy population provides important information for researchers applying these tests in clinical and epidemiological studies.

Adult↗

Alcohol use and prostate cancer risk in US blacks and whites.

Prostate cancer is the most common malignancy in US men (more than 165,000 cases per annum) and occurs substantially more frequently in blacks than in whites. The causes of this disease are, however, poorly understood. Alcohol consumption, which has been clearly related to malignancies of the upper aerodigestive tract, may also increase risk of cancer at other sites, including the prostate. The authors investigated alcohol use as a risk factor for prostate cancer among US blacks and whites. A population-based, case-control study was carried out among 981 men (479 blacks and 502 whites) with pathologically confirmed prostate cancer diagnosed between August 1, 1986, and April 30, 1989, and 1,315 controls (594 blacks and 721 whites) who resided in Atlanta, Georgia; Detroit, Michigan; and 10 counties in New Jersey, geographic areas covered by three population-based cancer registries. In-person interviews elicited information on alcohol use and other factors possibly related to prostate cancer. Compared with never-users, risk for prostate cancer increased with amount of alcohol drunk (chi2 (trend), p < 0.001), with significantly elevated risks seen for those who had 22-56 drinks per week (odds ratio = 1.4; 95% confidence interval 1.0-1.8) and 57 or more drinks per week (odds ratio = 1.9; 95% confidence interval 1.3-2.7). The finding was consistent among blacks (chi2 (trend), p < 0.01) and whites (chi2 (trend), p < 0.05), and among young and old subjects; it was not restricted to a specific type of alcoholic beverage. In this first large study among US blacks and whites, increased risk for prostate cancer was associated with increased alcohol use. The risk was similar for whites and blacks and could not be attributed to tobacco use or to a number of other potential confounders.

Adult↗

Cancer risks among iron and steel workers in Anshan, China, Part I: Proportional mortality ratio analysis.

A standardized proportional mortality ratio (SPMR) study of 8,887 deaths during 1980-1989 among male workers in a large integrated iron-steel complex in Anshan, China, was conducted to provide clues to occupational risk factors. Accidents and cancer accounted for a higher proportion of deaths among the iron-steel workers than among the general male population (SPMR = 1.21; 95% CI = 1.12-1.31 and 1.14; 95% CI = 1.10-1.18, respectively). Among all workers, SPMRs were significantly elevated for stomach, lung, and colorectal cancers (SPMR = 1.37, 1.37, 1.38, respectively), but not other cancers. Risks of stomach cancer appeared to be highest among workers employed in jobs with exposure to iron and coal dust, whereas significant increases in colorectal cancer were seen for loading and other dusty jobs and for administrative and sedentary jobs without dust exposure. Risks of lung cancer appeared increased for a variety of jobs throughout the complex, especially those with probable high levels of exposure to polycyclic hydrocarbons and asbestos. Risk of esophageal cancer was significantly elevated for fire-resistant brick makers, and risk of nonmalignant respiratory disease was significantly elevated for those employed as furnace workers, foundry workers, and fire-resistant brick makers.

Accidents, Occupational↗

Cancer risks among iron and steel workers in Anshan, China, Part II: Case-control studies of lung and stomach cancer.

Nested case-control interview studies of lung cancer (610 incident cases), stomach cancer (292 incident cases), and 959 controls were conducted to follow up leads from a proportional mortality analysis of deaths among male workers in a large integrated iron-steel complex in Anshan, China. For lung cancer, after adjusting for the significant non-occupational risk factors (smoking, other pulmonary disease, family history of lung cancer, and low consumption of fruit or tea), risks were significantly elevated for those employed for 15 or more years in smelting and rolling (OR = 1.5, CI = 1.1-2.2), in the fire-resistant brick factory (OR = 2.9, CI = 1.4-5.9), in general loading (OR = 2.5, CI = 1.0-6.1), and as coke oven workers (OR = 3.4; CI = 1.4-8.5). For stomach cancer, after adjusting for consumption of pickled vegetables, prior gastric diseases, family history of stomach cancer, low intake of fruits and vegetables, and education, risks were significantly elevated for those employed for 15 or more years in ore sintering and transportation (OR = 2.1, CI = 1.0-4.4), in the fire-resistant brick factory (OR = 2.5, CI = 1.1-5.8), in general loading (OR = 3.2, CI = 1.2-8.9), as boilerworkers and cooks (OR = 2.6, CI = 1.2-5.6), and as coke oven workers (OR = 5.4, CI = 1.8-16.0). For both lung and stomach cancers, significant dose-response gradients were observed for exposure to total dust and benzo(a)pyrene, but not for specific chemical components of dust. Overall, long-term steel workers with exposure to workplace pollutants had a 40% increased risk of both lung and stomach cancers. These case-control studies confirm many of the occupational findings reported in the proportionate mortality analysis, and suggest avenues for further work to evaluate the carcinogenicity of individual components of dust.

Adult↗

The effects of anticonvulsant drugs on long-term potentiation (LTP) in the rat hippocampus.

In hippocampal CA1 area, there are at least two forms of long-term potentiation (LTP): one is N-methyl-D-aspartate (NMDA) receptor-dependent LTP (NMDA LTP), which is induced with a 25 Hz tetanus and blocked by 50 microM 2-amino-5-phosphonovaleric acid (APV); the other is NMDA receptor-independent LTP (VDCC LTP), which is induced by 200 Hz tetanus stimulation in the presence of APV and blocked by nifedipine, a voltage-dependent Ca++ channel (VDCC) blocker, or by the intracellular injection of 1,2-bis(2-Aminophenoxoy)ethane-N,N,N',N'-tetraacetic acid (BAPTA). The effects of anticonvulsant drugs phenobarbital, phenytoin, and valproic acid on both NMDA LTP and VDCC LTP were investigated in rat hippocampal slices. The results showed that 0.1 mg/ml valproic acid significantly altered baseline population spike amplitude by 34.6%, but the other drugs had no significant effect on the baseline population spike amplitude. Phenobarbital (0.025 mg/ml) potently blocked NMDA LTP and inhibited VDCC LTP. Phenytoin (0.02 mg/ml) had no effect on NMDA LTP but reduced VDCC LTP. Valproic acid did not inhibit VDCC LTP, but it abolished the expression of NMDA LTP in a similar manner as H-7, a nonspecific protein kinase C inhibitor. These data suggest that the anti-convulsant effects of these three drugs may be via different cellular mechanisms.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

Alcohol and pancreatic cancer in blacks and whites in the United States.

A population-based, case-control study of pancreatic cancer based on direct interviews with 307 white and 179 black incident cases and 1164 white and 945 black population controls was conducted in three areas of the United States to determine the role alcohol drinking plays as a risk factor for pancreatic cancer and to estimate the extent to which it may explain the higher incidence of pancreatic cancer in blacks compared to whites. Our findings indicate that alcohol drinking at the levels typically consumed by the general population of the United States is probably not a risk factor for pancreatic cancer. Our data suggest, however, that heavy alcohol drinking may be related to pancreatic cancer risk. Among men, blacks and white who drank at least 57 drinks/week had odds ratios (ORs) of 2.2 [95% confidence interval (CI) = 0.9-5.6] and 1.4 (95% CI = 0.6-3.2), respectively. Among women, blacks who drank 8 to < 21 drinks/week had an OR of 1.8 (95% CI = 0.8-4.0), and those who drank at least 21 drinks/week had an OR of 2.5 (95% CI = 1.02-5.9), but whites with the same levels of alcohol intake experienced no increased risk. Compared to whites, blacks had significantly higher ORs associated with heavy alcohol drinking (> or = 57 drinks/week) in men (P = 0.04) and with moderate-to-heavy drinking (> or = 8 drinks/week) in women (P = 0.03). Additional research is needed to determine whether heavy alcohol drinking is causally related to pancreatic cancer and whether the risk of alcohol-related pancreatic cancer is greater in blacks than in whites.

Adult↗

Prostate cancer risk in U.S. blacks and whites with a family history of cancer.

Prostate cancer occurs more frequently in U.S. blacks than whites. A population-based case-control study which investigated the association with family history of cancer was carried out among 981 men (479 black, 502 white) with pathologically confirmed prostate cancer, diagnosed between August 1, 1986, and April 30, 1989, and 1,315 controls (594 black, 721 white). Study subjects, aged 40-79, resided in Atlanta, Detroit, and 10 counties in New Jersey, geographic areas covered by population-based cancer registries. Prostate cancer risk was significantly elevated among those who reported a history of prostate cancer in first-degree relatives (O.R. = 3.2; 95% C.I.: 2.0-5.0), with blacks and whites having similarly elevated risks. These risks were unchanged by statistical adjustment for job-related socio-economic status, education, income, and marital status. Overall, the ORs associated with history of prostate cancer in fathers and brothers were 2.5 (95% C.I.: 1.5-4.2) and 5.3 (95% C.I.: 2.3-12.5), respectively. Risks associated with a family history of prostate cancer were consistently elevated among younger and older subjects. Only small non-significant excesses of prostate cancer risk were associated with a family history of breast, colorectal, or other cancers. While familial occurrence is a key risk factor for prostate cancer and likely to be genetically based, the similar familial risks among blacks and whites suggest that the ethnic disparity in incidence is influenced by environmental factors.

Adult↗

Adenocarcinoma of the esophagus: role of obesity and diet.

BACKGROUND: In the United States, the incidence of adenocarcinoma of the esophagus, including the esophagogastric junction, has been increasing rapidly over the past two decades. Except for an association with Barrett's esophagus, little is known about the etiology of these cancers. PURPOSE: Our purpose was to investigate dietary and nutritional risk factors for adenocarcinoma of the esophagus. METHODS: A population-based, case-control interview study of 174 white men with adenocarcinoma of the esophagus and 750 control subjects living in three areas of the United States was conducted during 1986 through 1989. RESULTS: Risk was significantly elevated for subjects in the heaviest quartile compared with the lightest quartile of body mass index (odds ratio [OR] = 3.1; 95% confidence interval [CI] = 1.8-5.3). No significant associations were seen with total calories from food, number of meals eaten per day, level of fat intake, or consumption of coffee and tea. Risks were highest for those consuming the least amount of vegetables, with some evidence of a dose response for the subcategories of cruciferous vegetables (P for trend < .001) and vegetables consumed raw (P for trend = .10). A significantly elevated risk was also seen for those consuming the least amount of raw fruit (P for trend = .05). No clear associations were reported for intake of particular micronutrients overall or in supplements, but a significant protective effect was associated with increasing intake of dietary fiber (P for trend = .004). CONCLUSIONS: The findings of an increased risk with obesity and decreased risks with intake of raw fruits and vegetables and dietary fiber provide useful directions to pursue in further investigations of this malignancy. IMPLICATIONS: The finding with respect to obesity is particularly noteworthy, since it may explain at least a portion of the recent epidemic increases reported in the incidence of this tumor.

Adenocarcinoma↗

Racial differences in serum immunoglobulin levels: relationship to cigarette smoking, T-cell subsets, and soluble interleukin-2 receptors.

To investigate the influence of race, cigarette smoking, and immunologic parameters on serum immunoglobulins, we analyzed serum IgG, IgA, and IgM levels in 455 healthy adults. The study population ranged in age from 20 to 69 years, including 282 whites and 173 blacks, 181 never-smokers, 93 ex-smokers, and 181 current smokers. Race and smoking were independently associated with alterations in serum IgG levels. Blacks had significantly higher IgG levels than whites (1,587 vs. 1,209 mg/dl; P < 0.001), and never smokers had significantly higher levels than current smokers (1,426 vs. 1,287 vs. mg/dl; P < 0.001). IgA and IgM levels were unrelated to race or smoking. Serum IgG was also found to be directly related to the proportion of HLA-DR+ cells and the level of soluble interleukin-2 receptors (sIL-2R) and inversely related to the proportion of CD4+ cells. Investigation of this racial heterogeneity may provide insights into the pathogenesis of immunologic diseases that exhibit unexplained racial variation.

Adult↗

High bladder cancer mortality in rural New England (United States): an etiologic study.

An interview study of next-of-kin of 325 persons who died of bladder cancer and 673 individuals who died of other causes in Vermont and New Hampshire (United States) was conducted to assess reasons for the persistent pattern of elevated bladder cancer mortality for both genders in rural New England. There are some evidence of elevated risks for both leather and textile workers that rose to over twofold for workers who also lived near these industries and for persons with French-Canadian ancestry. Occupational exposures in the textile and leather industry may explain at least a portion of the excess bladder cancer risk in rural New England.

Case-Control Studies↗

Biased attention in childhood anxiety disorders: a preliminary study.

This study provides preliminary tests of two hypotheses: (1) Anxiety-disordered children show an attentional bias toward emotionally threatening stimuli, and (2) normal controls show an attentional bias away from emotionally threatening stimuli. Twelve children, 9 to 14 years of age, with primary diagnoses of anxiety disorder were compared with 12 normal controls matched for age, gender, vocabulary level, and reading ability. Subjects completed a reaction time task that measured visual attention toward threatening versus neutral words. The anxious group showed the predicted attentional bias toward threat words. However, controls did not show the predicted bias away from threat words. These results are the first showing that biased attentional processing occurs among clinically anxious children. The potential role of such an attentional bias in childhood anxiety disorders and future direction for research are discussed.

Adolescent↗

Brain regional differences in glycine reversal of ethanol-induced inhibition of N-methyl-D-aspartate-stimulated neurotransmitter release.

The present study investigated the interaction between glycine and ethanol on N-methyl-D-aspartate (NMDA)-stimulated neurotransmitter release in hippocampal, cerebrocortical, and striatal slices from rat brain. Some, but not all, previous studies have shown that glycine may reverse the inhibitory effect of ethanol on NMDA receptors. Hippocampal or cortical slices were prepared and prelabelled with [3H]norepinephrine, and striatal slices were labelled with [3H]dopamine. Stimulation of the slices with 500 microM NMDA for two minutes caused a significant release of [3H]neurotransmitter in each brain region above basal. Ethanol (60 mM) significantly inhibited the NMDA-stimulated release of neurotransmitter from all brain regions. Addition of glycine (0.3-3 microM) to the buffer bathing the slices had no effect on the inhibitory effect of ethanol in hippocampus or cortex. However, in striatal slices, 0.3 and 1.0 microM glycine added to the buffer reversed the inhibitory effect of ethanol on NMDA-stimulated [3H]dopamine release without having any effect on either basal or NMDA-stimulated release by itself. These results show that the interaction between ethanol and glycine varies in different brain regions. Therefore interpretation of the potential inhibitory effect of ethanol on NMDA receptor function in vivo should consider brain region and local concentrations of glycine.

Animals↗