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K G Brown

Publications and source records attributed to K G Brown.

At least 19 recordsLinked to original sources
PubMed2001

In vivo ultrasonic measurement of tissue vibration at a stenosis: a case study.

It is known that bruits often can be heard downstream from stenoses. They are thought to be produced by disturbed blood flow and vessel wall vibrations. Our understanding of bruits has been limited, though, to analysis of sounds heard at the level of the skin. For direct measurements from the stenosis site, we developed an ultrasonic pulse-echo multigate system using quadrature phase demodulation. The system simultaneously measures tissue displacements and blood velocities at multiple depths. This paper presents a case study of a severe stenosis in a human infrainguinal vein bypass graft. During systole, nearly sinusoidal vessel wall vibrations were detected. Solid tissue vibration amplitudes measured up to 2 microm, with temporal durations of 100 ms and frequencies of roughly 145 Hz and its harmonics. Cross-axial oscillations were also found in the lumen that correlate with the wall vibrations, suggesting coupling between wall vibration and blood velocity oscillation.

Blood Flow Velocity↗
PubMed1999

The effect of queuosine on tRNA structure and function.

Computational modeling was performed to determine the potential function of the queuosine modification of tRNA found in wobble position 34 of tRNAasp, tRNAasn, tRNAhis, and tRNAtyr. Using the crystal structure of tRNAasp and a tRNA-tRNA-mRNA complex model, we show that the queuosine modification serves as a structurally restrictive base for tRNA anticodon loop flexibility. An extended intraresidue and intramolecular hydrogen bonding network is established by queuosine. The quaternary amine of the 7-aminomethyl side chain hydrogen bonds with the base's carbonyl oxygen. This positions the dihydroxycyclopentenediol ring of queuosine in proper orientation for hydrogen bonding with the backbone of the neighboring uridine 33 residue. The interresidue association stabilizes the formation of a cross-loop hydrogen bond between the uridine 33 base and the phosphoribosyl backbone of the cytosine at position 36. Additional interactions between RNAs in the translation complex were studied with regard to potential codon context and codon bias effects. Neither steric nor electrostatic interaction occurs between aminoacyl- and peptidyl-site tRNA anticodon loops that are modified with queuosine. However, there is a difference in the strength of anticodon/codon associations (codon bias) based on the presence or lack of queuosine in the wobble position of the tRNA. Unmodified (guanosine-containing) tRNAasp forms a very stable association with cytosine (GAC), but is much less stable in complex with a uridine-containing codon (GAU). Queuosine-modified tRNAasp exhibits no bias for either of cognate codons GAC or GAU and demonstrates a lower binding energy similar to the wobble pairing of guanosine-containing tRNA with a GAU codon. This is proposed to be due to the inflexibility of the queuosine-modified anticodon loop to accommodate proper positioning for optimal Watson-Crick type associations. A preliminary survey of codon usage patterns in oncodevelopmental versus housekeeping gene transcripts suggests a significant difference in bias for the queuosine-associated codons. Therefore, the queuosine modification may have the potential to influence cellular growth and differentiation by codon bias-based regulation of protein synthesis for discrete mRNA transcripts.

Anticodon↗
PubMed1999

Lung cancer and environmental tobacco smoke: occupational risk to nonsmokers.

The principal epidemiologic evidence that environmental tobacco smoke (ETS) increases the risk of lung cancer in (lifelong) nonsmokers is from studies of nonsmoking women married to smokers. This article estimates exposure-response curves for 14 studies (1, 249+ cases, 7 countries) with data on lung cancer categorized by the number of cigarettes/day smoked by the husband. The pooled results from the five U.S. studies alone are extrapolated to ETS levels in the workplace using measures of serum cotinine and nicotine samples from personal monitors as markers of exposure to ETS. It is predicted that the increase in lung cancer risk for nonsmoking women from average ETS exposure at work (among those exposed at work) is on the order of 25% (95% confidence interval (CI) = 8, 41) relative to background risk (i.e., with no ETS exposure from any source). This compares to an estimate of 39% (95% CI = 5, 65) for nonsmoking women whose husbands smoke at the adult male smoker's average of 25 cigarettes/day. At the 95th percentiles of exposure, the estimate from spousal smoking is 85% (95% CI = 32, 156), compared to 91% (95% CI = 34, 167) from workplace ETS exposure. Subject to the validity of the assumptions required in this approach, the outcome supports the conclusion that there is a significant excess risk from occupational exposure to ETS. The excess risk from ETS at work is typically lower than that from spousal smoking, but may be higher at the 95th percentiles of exposure.

Adult↗
PubMed1997

Skin cancer and inorganic arsenic: uncertainty-status of risk.

The current U.S. EPA standard for inorganic arsenic in drinking water is 50 ppb (microgram/L), dating to the National Interim Primary Drinking Water Regulation of 1976. The current EPA risk analysis predicts an increased lifetime skin cancer risk on the order of 3 or 4 per 1000 from chronic exposure at that concentration. Revision of the standard to only a few ppb, perhaps even less than 1 ppb, may be indicated by the EPA analysis to reduce the lifetime risk to an acceptable level. The cost to water utilities, and ultimately to their consumers, to conform to such a large reduction in the standard could easily reach several billion dollars, so it is particularly important to assess accurately the current risk and the risk reduction that would be achieved by a lower standard. This article addresses the major sources of uncertainty in the EPA analysis with respect to this objective. Specifically, it focuses on uncertainty and variability in the exposure estimates for the landmark study of Tseng and colleagues in Taiwan, analyzed using a reconstruction of the their exposure data. It is concluded that while the available dataset is suitable to establish the hazard of skin cancer, it is too highly summarized for reliable dose-response assessment. A new epidemiologic study is needed, designed for the requirements of dose-response assessment.

Arsenic↗
PubMed1997

Inorganic arsenic: a need and an opportunity to improve risk assessment.

This paper presents views on the current status of (inorganic) arsenic risk assessment in the United States and recommends research needed to set standards for drinking water. The opinions are those of the Arsenic Task Force of the Society for Environmental Geochemistry and Health, which has met periodically since 1991 to study issues related to arsenic risk assessment and has held workshops and international conferences on arsenic. The topic of this paper is made timely by current scientific interest in exposure to and adverse health effects of arsenic in the United States and passage of the Safe Drinking Water Act Amendment of 1996, which has provisions for a research program on arsenic and a schedule mandating the EPA to revise the maximum contaminant level of arsenic in drinking water by the year 2001. Our central premise and recommendations are straightforward: the risk of adverse health effects associated with arsenic in drinking water is unknown for low arsenic concentrations found in the United States, such as at the current interim maximum contaminant level of 50 microg/l and below. Arsenic-related research should be directed at answering that question. New epidemiological studies are needed to provide data for reliable dose-response assessments of arsenic and for skin cancer, bladder cancer, or other endpoints to be used by the EPA for regulation. Further toxicological research, along with the observational data from epidemiology, is needed to determine if the dose-response relationship at low levels is more consistent with the current assumption of low-dose linearity or the existence of a practical threshold. Other recommendations include adding foodborne arsenic to the calculation of total arsenic intake, calculation of total arsenic intake, and encouraging cooperative research within the United States and between the United States and affected countries.

Arsenic↗
PubMed1996

Does self-regulation require cognitive resources? Evaluation of resource allocation models of goal setting.

The resource allocation model of goal setting (R. Kanfer & P.L. Ackerman, 1989) maintains that self-regulation initiated through goal setting requires attentional resources that could be more productively applied to skill acquisition and complex task performance. The current study questioned this hypothesis because attentional resources had not been directly manipulated or measured in studies supporting the model. Thus, alternative explanations that are based on other complex task goal-setting models cannot be excluded. As a direct test of the resource allocation hypothesis, dual task methodology was used to measure the attentional resource requirements of self-regulation. Even at the limits of human information processing, participants who were assigned difficult, specific goals performed at least as well on the secondary task as did individuals with do-your-best goals. These findings suggest that self-regulation does not necessarily require attentional resources. Implications for theory and practice are discussed.

Adolescent↗
PubMed1996

Gene disruptions indicate an essential function for the LmmCRK1 cdc2-related kinase of Leishmania mexicana.

The generation of homozygous null mutants for the crk1 Cdc2-Related Kinase of Leishmania mexicana was attempted using targeted gene disruption. Promastigote mutants heterozygous for crk1 were readily isolated with a hyg-targeting fragment, but attempts to create null mutants by second-round transfections with a bie-targeting fragment yielded two classes of mutant, neither of which was null. First, the transfected fragment formed an episome; second, the cloned transfectants were found to contain wild-type crk1 alleles as well as hyg and ble integrations. DNA-content analysis revealed that these mutants were triploid or tetraploid. Plasticity in chromosome number following targeting has been proposed as a means by which Leishmania avoids deletion of essential genes. These data support this theory and implicate crk1 as an essential gene, validating CRK1 as a potential drug target. L mexicana transfected with a Trypanosoma brucel homologue, tbcrk1, was shown to be viable in an immcrk1 null background, thus showing complementation of function between these trypanosomatid genes. The expression of crk1 was further manipulated by engineering a six-histidine tag at the C-terminus of the kinase, allowing purification of the active complex by affinity selection on Nl(2+)-nitriloacetic acid (NTA) agarose.

Alleles↗
PubMed1995

Significance of exposure assessment to analysis of cancer risk from inorganic arsenic in drinking water in Taiwan.

The primary source of evidence that inorganic arsenic in drinking water is associated with increased mortality from cancer at internal sites (bladder, liver, lung, and other organs) is a large ecologic study conducted in regions of Southwest Taiwan endemic to Blackfoot disease. The dose-response patterns for lung, liver, and bladder cancers display a nonlinear dose-response relationship with arsenic exposure. The data do not appear suitable, however, for the more refined task of dose-response assessment, particularly for inference of risk at the low arsenic concentrations found in some U.S. water supplies. The problem lies in variable arsenic concentrations between the wells within a village, largely due to a mix of shallow wells and deep artesian wells, and in having only one well test for 24 (40%) of the 60 villages. The current analysis identifies 14 villages where the exposure appears most questionable, based on criteria described in the text. The exposure values were then changed for seven of the villages, from the median well test being used as a default to some other point in the village's range of well tests that would contribute to smoothing the appearance of a dose-response curve. The remaining seven villages, six of which had only one well test, were deleted as outliers. The resultant dose-response patterns showed no evidence of excess risk below arsenic concentrations of 0.1 mg/l. Of course, that outcome is dependent on manipulation of the data, as described. Inclusion of the seven deleted villages would make estimates of risk much higher at low doses. In those seven villages, the cancer mortality rates are significantly high for their exposure levels, suggesting that their exposure values may be too low or that other etiological factors need to be taken into account.

Adult↗
PubMed1994

Statistical issues on the no-observed-adverse-effect level in categorical response.

The determination of the value of the no-observed-adverse-effect level (NOAEL) when observed responses can be categorized by severity (categorical data) and sample sizes are small is discussed. The common situation of only two categories, where only the presence or absence of an effect is observed, is addressed first (dichotomous data). Three tests for dichotomous data are critically examined, including the Brown-La Vange test, a modified version of that test, and Dunnett's multiple comparison test. Although the modified test is an improvement, all three procedures have shortcomings in determining the value of the NOAEL, particularly when the sample size is small. An alternative method is suggested, based on the Akaike information criterion (AIC), which performs well. This method is extended to severity data with an arbitrary number of categories. Use of a dose-response curve for the NOAEL is discussed.

Data Interpretation, Statistical↗
PubMed1991

Cyclical disturbance of diabetic control in girls before the menarche.

Seven diabetic girls who presented with cyclical disturbance of diabetic control before the menarche are described. In six girls cyclical hyperglycaemia occurred and in one cyclical hypoglycaemia. The index case is described in detail, and is then included in a description of the main clinical features of all seven cases. Cyclical disturbance of diabetic control may present in diabetic girls from age 9 years onwards. Home blood glucose monitoring records may reveal cyclical disturbance, usually hyperglycaemia, and usually occurring at 21-34 day intervals and lasting for two to five days. Serious illnesses and hospital admission can be averted by educating parents to make appropriate changes to insulin regimen or diet. Our hypothesis is that the disturbance of diabetic control is caused by the onset of cyclical hormonal changes, a 'menstrual' cycle before menstruation. The precise mechanism for the changes in carbohydrate tolerance is unknown.

Adolescent↗
PubMed1989

Statistical uncertainty in the no-observed-adverse-effect level.

The no-observed-adverse-effect level (NOAEL) is a dose value that U.S. EPA reduces by uncertainty factors (UF) and modifying factors (MF) to obtain a reference dose (RfD) for input to regulatory decision making. Whether the true added risk at the NOAEL is below an acceptable level, however, is a source of statistical uncertainty itself. As several authors have previously noted, the probability that added risk at the NOAEL is not negligibly small increases as sample sizes decrease. This is because the definition of the NOAEL statistically controls for the chance of a false-positive error, but not for a false-negative error. The false-positive rate is the test level set by the user in testing for a statistically significant dose effect, typically 0.05. When it is held fixed, the increase in statistical uncertainty as sample size decreases produces an increase in the false-negative rate. Hence, the fewer data available for statistical inference, the higher the expected value of the NOAEL and the less toxic an agent is likely to appear. The solution lies in calculating the probability that a statistical procedure used will detect the maximum added risk acceptable for health regulation (the "power" at that added risk). If the observed response in a dose group is not significantly elevated relative to the control group, and the power for detecting a difference is low as well, then the statistical evidence is inconclusive. In such a case, additional data or other sources of information are needed for evaluating added risk. These concepts are illustrated for examples from the literature with dichotomous (quantal response) data and categorical (severity) data, using a new statistical procedure.

Research Design↗
PubMed1989

A dose-response analysis of skin cancer from inorganic arsenic in drinking water.

A study of the prevalence of skin cancer among 40,421 persons consuming arsenic-contaminated drinking water in Taiwan was used for a cancer dose-response assessment of ingested arsenic. The numbers of persons at risk over three dose intervals and four exposure durations were estimated from the data in order to apply the method of maximum likelihood to a multistage-Weibull time/dose-response model. A constant exposure level since birth for each of the exposure categories was assumed. It was found that the cumulative hazard increases as a power of three in age, and is linear or quadratic (with a linear coefficient) in dose. Observations from a smaller epidemiologic survey in Mexico were similar to what would be predicted from the model of the Taiwan data. Assuming that the skin cancer risk from ingested arsenic in the American population would also be similar to the Taiwan population, an American male would have a lifetime risk of developing skin cancer of 1.3 x 10(-3) (3.0 x 10(-3] if exposed to 1 microgram/kg/day for a 76-year lifespan (median lifespan in the U.S.).

Adult↗
PubMed1987

Effect of vitamin D supplementation during pregnancy on the vitamin D status of ewes and their lambs.

Pregnant ewes were injected intramuscularly with 300,000 iu of vitamin D3 in a water miscible vehicle either 10, seven or four weeks before the expected lambing date and the effects on plasma concentrations of 25-hydroxyvitamin D3 were monitored. The concentrations increased quickly and remained high at parturition but at no time were they outside the normal physiological range. The concentrations in the plasma of the newborn lambs were higher than in uninjected controls and were well correlated with the concentrations in their mothers. Dosing pregnant ewes with 300,000 iu of vitamin D3 in a rapidly available form, approximately two months before lambing, provided a safe means of increasing the vitamin D status of the ewe and the newborn lamb by preventing the seasonally low concentrations of 25-hydroxyvitamin D3.

Animals↗
PubMed1987

Altitude, radiation, and mortality from cancer and heart disease.

The variation in background radiation levels is an important source of information for estimating human risks associated with low-level exposure to ionizing radiation. Several studies conducted in the United States, correlating mortality rates for cancer with estimated background radiation levels, found an unexpected inverse relationship. Such results have been interpreted as suggesting that low levels of ionizing radiation may actually confer some benefit. An environmental factor strongly correlated with background radiation is altitude. Since there are important physiological adaptations associated with breathing thinner air, such changes may themselves influence risk. We therefore fit models that simultaneously incorporated altitude and background radiation as predictors of mortality. The negative correlations with background radiation seen for mortality from arteriosclerotic heart disease and cancers of the lung, the intestine, and the breast disappeared or became positive once altitude was included in the models. By contrast, the significant negative correlations with altitude persisted with adjustment for radiation. Interpretation of these results is problematic, but recent evidence implicating reactive forms of oxygen in carcinogenesis and atherosclerosis may be relevant. We conclude that the cancer correlational studies carried out in the United States using vital statistics data do not in themselves demonstrate a lack of carcinogenic effect of low radiation levels, and that reduced oxygen pressure of inspired air may be protective against certain causes of death.

Altitude↗
PubMed1986

Atomic and Raman spectroscopy of the dipalmitoylphosphatidic acid-calcium complex and phase transitions.

Calcium binding measurements by atomic absorption spectroscopy and temperature-dependent phase transitions studies by Raman spectroscopy were combined in order to investigate the effect of Ca2+ binding on dipalmitoylphosphatidic acid (DPPA) dispersed in CaCl2 solutions of varying concentration at pH 7. The peak heights for the Raman CH stretch bands observed at 2885 cm-1 and 2935 cm-1 were used as a measure of hydrocarbon chain randomization and aggregate ultrastructure. Two transitions were observed for both pure DPPA and DPPA-Ca2+ mixtures. Ca2+ binding caused greatly increased DPPA chain rigidity in the melted state above Tm, but had much less effect on the solid phases below Tm. The increase in rigidity in the fluid state was observed to vary linearly with the molar ratio of bound Ca2+ to total DPPA throughout the range 0 to 1. The results of the Raman and Ca2+ binding measurements are explained by a model in which two populations of DPPA co-exist in the fluid state when Ca2+ binding has not reached saturation. One population consists of the Ca2+-bound DPPA complex with stoichiometric 1:1 binding ratio (determined from an atomic absorption Ca2+ binding study), and the second population is free DPPA. We propose that Ca2+-induced clustering and separation of the two components occurs chiefly because of differences in chain fluidity of the two components.

Calcium↗
PubMed1986

Statistical modeling of animal bioassay data with variable dosing regimens: example--vinyl chloride.

We consider animal bioassay experiments with variable dosing regimens in which groups of animals are dosed beginning at different ages and for varying durations. Two response models are discussed and then applied to data from an experiment on vinyl chloride exposure of F-344 rats, B6C3F1 and Swiss CD-1 mice, and Syrian Golden hamsters. The multistage model of Armitage and Doll, as extended by Whittemore, Day and Brown, and Crump and Howe, is used to estimate the dose effect on the ordered stages of tumor development. The data for all endpoints and species/strains examined consistently indicate a predominant effect on the first stage, suggesting that vinyl chloride is primarily a tumor initiator. This is consistent with evidence from two-stage experiments on this chemical. The second response model, new to this article, adjusts for survival nonparametrically. It is used to test for an age difference in susceptibility, to evaluate alternative exposure durations, and to compare the effectiveness of alternative dosing regimens for detecting carcinogenicity.

Animals↗
PubMed1985

Risk assessment of laboratory rats and mice chronically exposed to formaldehyde vapors.

Experimental data from the Chemical Industry Institute of Toxicology (CIIT) are used to estimate the risk of squamous cell carcinoma of the nasal cavity in Fischer 344 (F344) rats over a range of ambient air concentrations of formaldehyde that includes current exposure guidelines for the workplace and home. These values are presented as a best estimate envelope obtained from five mathematical dose-response formulation. The response of Sprague-Dawley (SD) rats dosed at 15 ppm in a separate study at New York University is consistent with the predicted lifetime response for F344 rats at a slightly lower concentration (13-14 ppm). A dose-related mortality effect beyond what is attributable to the occurrence of nasal carcinomas is found in F344 rats at all CIIT exposure levels (2, 6, and 15 ppm). There is no evidence of a mortality effect in B6C3F1 mice of the CIIT study, and data for SD rats of the NYU experiment are inconclusive. In the CIIT study, rats exposed to 15 ppm exhibited a high incidence of nasal cavity squamous cell carcinomas and polypoid adenomas. Polypoid adenomas were also observed with increased incidences at 2 ppm and 6 ppm. Statistical comparisons with matched controls, and the low historical rate of spontaneous occurrence both suggest that polypoid adenomas may be a risk to F344 rats at exposure levels below the current Occupational Safety and Health Administration (OSHA) standard of 3 ppm. Squamous cell carcinomas were observed in two mice exposed to 15 ppm. This finding may be biologically significant since this tumor is rare and has not been previously reported in 4932 untreated B6C3F1 mice from recent National Toxicology Program (NTP) feeding studies.

Animals↗