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Biomedical subjects

M L Brown

Publications and source records attributed to M L Brown.

At least 19 recordsLinked to original sources
PubMed2001

Progress in cancer screening over a decade: results of cancer screening from the 1987, 1992, and 1998 National Health Interview Surveys.

BACKGROUND: Screening to detect cancer early, an increasingly important cancer control activity, cannot be effective unless it is widely used. METHODS: Use of Pap smears, mammography, fecal occult blood tests (FOBTs), sigmoidoscopy, and digital rectal examination (DRE) was evaluated in the 1987, 1992, and 1998 National Health Interview Surveys. Levels and trends in screening use were examined by sex, age, and racial/ethnic group. The effects of income, educational level, and health care coverage were examined within age groups. Logistic regression analyses of 1998 data were used to develop a parsimonious, policy-relevant model. RESULTS: Use of all screening modalities increased over the period examined; for mammography and DRE, the increase was more rapid in the first half of the decade; for the Pap test and sigmoidoscopy, the increase was more rapid in the second half of the decade. Levels of colorectal cancer screening (both sigmoidoscopy and FOBTs) in 1998 were less than the level that prevailed a decade earlier for mammography. Patterns of change for all screening modalities differed between age, sex, and racial/ethnic groups, but prevalence of use during the study, within recommended time intervals, was consistently lower among groups with lower income and less education. Logistic regression analyses indicated that insurance coverage and, to a greater extent, usual source of care had strong independent associations with screening usage when age, sex, racial/ethnic group, and educational level were taken into account. CONCLUSIONS: While cancer screening is generally increasing in the United States, usage is relatively low for colorectal cancer screening and among groups that lack health insurance or a usual source of care.

Adult↗
PubMed2001

Design, synthesis, and evaluation of novel A2A adenosine receptor agonists.

We have been interested in the design, synthesis, and evaluation of novel adenosine A2A agonists. Through the use of comparative molecular field analysis (CoMFA) we have generated a training model that includes 78 structurally diverse A2A agonists and correlated their affinity for isolated rat brain receptors with differences in their structural and electrostatic properties. We validated this model by predicting the activity of a test set that included 24 additional A2A agonists. Our CoMFA model, which incorporates the physiochemical property of dipole and selects against A1 receptor activity, generated a correlated final model (r2 = 0.891) that provides for enhanced A2A selectivity and predictability. Synthesis, pharmacological evaluation, and modeling of four novel ligands further validate the utility and predictive power (r2 = 0.626) of the CoMFA model.

Alkynes↗
PubMed2001

Selenium and mercury concentrations in brood-stock walleye collected from three sites on Lake Oahe.

A decline in the walleye Stizostedion vitreum sport fishery in lower Lake Oahe, South Dakota, was documented in the early 1980s and has been attributed to poor natural reproduction and/or recruitment. Contaminants were suspected of causing low natural reproduction/recruitment in lower Lake Oahe as well as low hatchability of eggs produced from broodstock walleyes taken from lower Lake Oahe. Concentrations of dissolved selenium in the Cheyenne River, which enters lower Lake Oahe, have increased considerably over the last 15 years. To determine whether selenium concentrations contributed to the reproduction problems in the lower Lake Oahe walleye population, adult walleye were collected during spawning operations in April 1994, 1995, and 1996 to obtain tissue samples. Muscle, liver, reproductive tissue, and unfertilized eggs were analyzed with a modified fluorometric method for determining selenium concentrations in plants. These tissues were also analyzed for mercury content using cold-vapor atomic absorption. No statistical differences (p < 0.05) in selenium or mercury concentrations among sites could be determined that would explain differential walleye egg hatchability. Correlation analysis determined significant inverse associations existed between the gonadal somatic index of male walleye and gonadal tissue selenium concentrations (r = -0.41, p = 0.0012). Both walleye sexes exhibited significant inverse associations between the hepatic somatic index (HSI) and liver selenium concentrations (males r = -0.33, p = 0.0095; and females r = -0.38, p = 0.0034). Positive relationships existed for female walleye selenium concentrations in the liver and the ovaries (r = 0.37, p = 0.003) and the liver and muscle tissue (r = 0.28, p = 0.027). Mercury concentrations in walleye ovaries were positively correlated with HSI (r = 0.30, p = 0.0012), length (r = 0.36, p = 0.0046), relative weight (r = 0.36, p = 0.0054), and muscle concentrations (r = 0.49, p = 0.0001). Mercury concentrations in male walleye muscle were correlated with age (r = 0.57, p = 0.0001), length (r = 0.79, p = 0.0001), and mercury concentrations in the testes (r = 0.43, p = 0.0006).

Animals↗
PubMed2001

Statistical test to assess rank-order imaging studies.

RATIONALE AND OBJECTIVES: Rank-order experiments often provide a reasonable method of determining whether a large-scale receiver operating characteristic study can be justified. The authors' purpose was to formalize a proposed method for analyzing rank-order imaging experiments and provide methods that can be used in determining sample sizes for both cases and raters. MATERIALS AND METHODS: Simulations were conducted to determine the adequacy of the normal approximation of a statistic used to test the null hypothesis of random ordering. For a multireader experiment, formulas are presented and guidelines are provided to enable investigators to determine the number of required readers (raters) and cases for a specific study. RESULTS: When there are at least five ordered images per case, 10 cases are sufficient to test a random rank order. When there are only three or four images for a case, 20 cases are required. The authors constructed tables of statistical power for selected numbers of ordered images, numbers of cases, and degrees of trend, and they also provide an approximation for use in situations that are not tabled. CONCLUSION: The statistical methods for analyzing rank-order experiments and estimating sample sizes for study planning are relatively simple to implement. The derived formulas for sample size estimation, when applied to typical imaging experiments, indicate that modest numbers of cases and readers are required for rank-order studies.

Humans↗
PubMed2001

Bowel surveillance patterns after a diagnosis of colorectal cancer in Medicare beneficiaries.

BACKGROUND: Postoperative colon surveillance has been recommended for patients with a diagnosis of local/regional colorectal cancer. The extent to which these recommendations are followed in practice is poorly characterized. Patterns of surveillance after surgery for colorectal cancer were determined by using a large population-based database. METHODS: This is a retrospective cohort study with cancer registry data linked to Medicare claims. Identified were 52,283 patients treated for local/regional colorectal cancer between 1986 and 1996, and surveillance patterns through 1998 were determined. Surveillance patterns were analyzed by using survival analysis and by computing the proportion of surviving patients who underwent procedures during 4 time periods after treatment: 2 to 14 months, 15 to 50 months, 51 to 86 months and more than 87 months. RESULTS: Median times to first through fifth surveillance events were 20, 14, 15, 15, and 15 months, respectively. For 17% of the cohort there was no surveillance event. Younger patients were more likely to undergo surveillance. Surveillance patterns were not affected by stage. The proportions of the cohort that underwent no surveillance during the 4 respective time periods were 54%, 52%, 60%, and 69%. The percentages of patients who underwent surveillance annually or more frequently in the latter 3 time periods, respectively, were 19%, 10%, and 5%, or 11% overall, treating the data for the 3 events as a whole. Over the period from 1986 to 1998, the proportion of patients who had no surveillance procedures gradually decreased, whereas the proportion of those who underwent procedures annually or more frequently remained relatively constant. CONCLUSIONS: During the period from 1986 to 1998 there was low utilization of postdiagnosis colon surveillance in a substantial proportion of elderly patients with a diagnosis of local/regional colorectal cancer. Over time there was a trend toward increasing receipt of any surveillance procedures. The percentages of patients undergoing surveillance annually or more frequently did not change between earlier and later periods.

Aged↗
PubMed2001

The burden of illness of cancer: economic cost and quality of life.

Cancer is a major public health issue and represents a significant burden of disease. In this chapter, we analyze the main measures of burden of disease as relate to cancer. Specifically, we review incidence and mortality, years of life lost from cancer, and cancer prevalence. We also discuss the economic burden of cancer, including cost of illness, phase-specific and long-term costs, and indirect costs. We then examine the impact of cancer on health-related quality of life as measured in global terms (disability-adjusted life years and quality-adjusted life years) and using evaluation-oriented applications of health-related quality of life scales. Throughout, we note the relative strengths and weaknesses of the various approaches to measuring the burden of cancer as well as the methodologic challenges that persist in burden-of-illness research. We conclude with a discussion of the research agenda to improve our understanding of the burden of cancer and of illness more generally.

Cost of Illness↗
PubMed2000

The scid recombination-inducible cell line: a model to study DNA-PK-independent V(D)J recombination.

To investigate the molecular mechanisms of the variable (diversity) joining (V(D)J) recombination process at an endogenous gene locus, recombination-inducible cell lines were made from both bcl-2-bearing severe combined immune deficiency (scid) homozygous and scid heterozyous (s/ + ) mice by transforming pre-B cells with the temperature-sensitive Abelson murine leukemia virus (ts-Ab-MLV). These transformants can be induced to undergo immunoglobulin light-chain gene rearrangements by incubating them at the non-permissive temperature. In the case of transformed scid cells, a significant amount of hairpin coding ends are accumulated during recombination induction, but few coding joints are generated. After being shifted to the permissive temperature. however, these cells are capable of opening hairpin ends and forming coding joints. Thus, ts-Ab-MLV transformed scid cells can be readily manipulated for both recombination cleavage and end resolution. However, unlike the rapid coding joint formation in s/ + cells that have the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs), the process for resolving coding ends in scid cells is slow and error prone, and also appears to be correlated with a reduction in the RAG1/2 expression. Apparently, this process is mediated by a DNA-PK-independent pathway. The fact that the activity of this pathway can be manipulated in vitro makes it possible to delineate the mechanisms in end opening, processing and joining. Therefore, these ts-Ab-MLV transformed scid cell lines offer a model to study the molecular nature as well as the regulation of the DNA-PK-independent pathway in coding end resolution.

Animals↗
PubMed2000

A macrophage receptor for apolipoprotein B48: cloning, expression, and atherosclerosis.

We have cloned a human macrophage receptor that binds to apolipoprotein (apo)B48 of dietary triglyceride (TG)-rich lipoproteins. TG-rich lipoprotein uptake by the apoB48R rapidly converts macrophages and apoB48R-transfected Chinese hamster ovary cells in vitro into lipid-filled foam cells, as seen in atherosclerotic lesions. The apoB48R cDNA (3,744 bp) encodes a protein with no known homologs. Its approximately 3.8-kb mRNA is expressed primarily by reticuloendothelial cells: monocytes, macrophages, and endothelial cells. Immunohistochemistry shows the apoB48R is in human atherosclerotic lesion foam cells. Normally, the apoB48R may provide essential lipids to reticuloendothelial cells. If overwhelmed, foam cell formation, endothelial dysfunction, and atherothrombogenesis may ensue, a mechanism for cardiovascular disease risk of elevated TG.

Amino Acid Sequence↗
PubMed2000

Metabolism of recombination coding ends in scid cells.

V(D)J recombination cleavage generates two types of dsDNA breaks: blunt signal ends and covalently sealed hairpin coding ends. Although signal ends can be directly ligated to form signal joints, hairpin coding ends need to be opened and subsequently processed before being joined. However, the underlying mechanism of coding end resolution remains undefined. The current study attempts to delineate this process by analyzing various structures of coding ends made in situ from recombination-inducible pre-B cell lines of both normal and scid mice. These cell lines were derived by transformation of B cell precursors with the temperature-sensitive Abelson murine leukemia virus. Our kinetic analysis revealed that under conditions permissive to scid transformants, hairpin coding ends could be nicked to generate 3' overhangs and then processed into blunt ends. The final joining of these blunt ends followed the same kinetics as signal joint formation. The course of this process is in sharp contrast to coding end resolution in scid heterozygous transformants that express the catalytic subunit of DNA-dependent protein kinase, in which hairpin end opening, processing, and joining proceeded very rapidly and appeared to be closely linked. Furthermore, we demonstrated that the opening of hairpin ends in scid cells could be manipulated by different culture conditions, which ultimately influenced not only the level and integrity of the newly formed coding joints, but also the extent of microhomology at the coding junctions. These results are discussed in the context of scid leaky recombination.

Animals↗
PubMed2000

Endoscopic colorectal cancer screening: a cost-saving analysis.

BACKGROUND: Comprehensive analyses have shown that screening for cancer usually induces net costs. In this study, the possible costs and savings of endoscopic colorectal cancer screening are explored to investigate whether the induced savings may compensate for the costs of screening. METHODS: A simulation model for evaluation of colorectal cancer screening, MISCAN-COLON, is used to predict costs and savings for the U.S. population, assuming that screening is performed during a period of 30 years. Plausible baseline parameter values of epidemiology, natural history, screening test characteristics, and unit costs are based on available data and expert opinion. Important parameters are varied to extreme but plausible values. RESULTS: Given the expert opinion-based assumptions, a program based on every 5-year sigmoidoscopy screenings could result in a net savings of direct health care costs due to prevention of cancer treatment costs that compensate for the costs of screening, diagnostic follow-up, and surveillance. This result persists when costs and health effects are discounted at 3%. The "break-even" point, the time required before savings exceed costs, is 35 years for a screening program that terminates after 30 years and 44 years for a screening program that continues on indefinitely. However, net savings increase or turn into net costs when alternative assumptions about natural history of colorectal cancer, costs of screening, surveillance, and diagnostics are considered. CONCLUSIONS: Given the present, limited knowledge of the disease process of colorectal cancer, test characteristics, and costs, it may well be that the induced savings by endoscopic colorectal cancer screening completely compensate for the costs.

Adenoma↗
PubMed2000

Comparative molecular field analysis of colchicine inhibition and tubulin polymerization for combretastatins binding to the colchicine binding site on beta-tubulin.

A molecular modeling study using Comparative Molecular Field Analysis (CoMFA) was undertaken to develop a predictive model for combretastatin binding to the colchicine binding site of tubulin. Furthermore, we examined the potential contribution of lipophilicity (log P) and molecular dipole moment and were unable to correlate these properties to the observed biological data. In this study we first confirmed that tubulin polymerization inhibition (IC50) correlated (R2 = 0.92) with [3H]colchicine displacement. Although these data correlated quite well, we developed two independent models for each set of data to quantify structural features that may contribute to each biological property independently. To develop our predictive model we first examined a series of molecular alignments for the training set and ultimately found that overlaying the respective trimethoxyphenyl rings (A ring) of the analogues generated the best correlated model. The CoMFA yielded a cross-validated R2 = 0.41 (optimum number of components equal to 5) for the tubulin polymerization model and an R2 = 0.38 (optimum number of components equal to 5) for [3H]colchicine inhibition. Final non-cross-validation generated models for tubulin polymerization (R2 of 0.93) and colchicine inhibition (R2 of 0.91). These models were validated by predicting both biological properties for compounds not used in the training set. These models accurately predicted the IC50 for tubulin polymerization with an R2 of 0.88 (n = 6) and those of [3H]colchicine displacement with an R2 of 0.80 (n = 7). This study represents the first predictive model for the colchicine binding site over a wide range of combretastatin analogues.

Bibenzyls↗
PubMed1999

Comparative molecular field analysis of hydantoin binding to the neuronal voltage-dependent sodium channel.

Comparative molecular field analysis (CoMFA), a 3-D QSAR technique, is widely used to correlate biological activity with observed differences in steric and electrostatic fields. In this study, CoMFA was employed to generate a model, based upon 14 structurally diverse 5-phenylhydantoin analogues, to delineate structural and electrostatic features important for enhanced sodium channel binding. Correlation by partial least squares (PLS) analysis of in vitro sodium channel binding activity (expressed as log IC50) and the CoMFA descriptor column generated a final non-cross-validated model with R2 = 0.988 for the training set. The final CoMFA model explained the data better than a simpler correlation with log P (R2 = 0.801) for the same training set. The CoMFA steric and electrostatic maps described two general features that result in enhanced binding to the sodium channel. These include a preferred 5-phenyl ring orientation and a favorable steric effect resulting from the C5-alkyl chain. This model was then utilized to accurately predict literature sodium channel activities for hydantoins 14-20, which were not included in the training set. Finally the hydantoin CoMFA model was used to design the structurally novel alpha-hydroxy-alpha-phenylamide 21. Synthesis and subsequent sodium channel evaluation of compound 21 (predicted IC50 = 9 microM, actual IC50 = 9 microM), a good binder to the sodium channel, established that the intact hydantion ring is not necessary for efficient binding to this site. Thus alpha-hydroxy-alpha-phenylamides may represent a new class of ligands that bind with increased potency to the sodium channel.

Amides↗
PubMed1999

Formation of coding joints in V(D)J recombination-inducible severe combined immune deficient pre-B cell lines.

Characterization of the severe combined immune deficient (scid) defect in the recombination process has provided many insights into the underlying mechanisms of variable (diversity) joining recombination. By using recombination-inducible scid pre-B cell lines transformed with the temperature-sensitive Abelson-murine leukemia virus, we show that large quantities of recombination intermediates can be generated, and their resolution can be followed during further cell culture. In this study, we demonstrate that the ability of these scid pre-B cell lines to resolve coding ends depends on the cell culture temperature. At the nonpermissive temperature of 39 degreesC, scid pre-B cell lines fail to form coding joints and contain mostly unresolved hairpin-coding ends. Once the cell culture is returned to the permissive temperature of 33 degreesC, these same cells make a significant amount of coding joints concomitant with the disappearance of hairpin-coding ends. Thus, the scid cells are capable of resolving coding ends under certain culture conditions. However, the majority of the recovered coding joints contains extensive deletions, indicating that the temperature-dependent resolution of coding ends is still scid-like. Our results suggest that the inability of scid cells to promptly nick hairpin-coding ends may lead to aberrant joining in these cells.

Animals↗