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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
PubMed1995

The use of gene tests to detect hereditary predisposition to cancer: economic considerations.

Several mutations recently have been shown to be associated with hereditary nonpolyposis colon cancer (HNPCC) in families displaying unusually strong predisposition to colorectal cancer. Laboratory tests to detect such gene mutations soon will be commercially available, raising the possibility for population-wide screening. The purpose of this study was to explore the economic implications of conducting a population-wide screening for HNPCC compared with restricted screening among members of the families at high risk. An exploratory analysis was performed to determine which factors are most important in determining the cost-effectiveness of such a testing program. The base-case analysis focuses on current uncertainty about the population prevalence of the HNPCC genotype and phenotype. The uncertainty with regard to parameters related to the cost-effectiveness of screening and preventive interventions for HNPCC were explored, using additional sensitivity analyses. Cost-effectiveness is achieved for population-wide screening only when assumptions most favorable to that outcome are made regarding the HNPCC prevalence, the cost and effectiveness of screening, and preventive intervention. Information on the population prevalence of HNPCC genotypes and the penetrance of these genotypes is essential for making policy decisions. Additional information is needed regarding the determinants of the cost of genetic testing and counseling, the efficacy of preventive regimens for individuals at high risk, and the accuracy and cost of alternative methods of identifying families at risk.

Adult↗
PubMed1995

A method for characterizing transition concertedness from polymer dynamics computer simulations.

A statistical method based on classifying the transitions among a set of dihedral angles within an "energy transfer window" is developed, and used to analyze Brownian (BD) and molecular dynamics (MD) simulations of the acyl chains in a lipid bilayer, and MD of neat hexadecane. It is shown for the BD simulation that when a transition of the dihedral angle in the center of the chain occurs, a transition of a particular next nearest neighbor (or angle 2-apart) will follow concertedly with a probability of approximately 0.10 within a time window of approximately 3 ps. The MD bilayer simulations, which are based on a more flexible model of the hydrocarbon chains, yield corresponding concerted transition probabilities of approximately 0.083 and window sizes of 1-2 ps. An analysis of angles 4-apart yields concerted transition probabilities of 0.03 and 0.04 for the BD and MD bilayer simulations, respectively, and window sizes close to those of the corresponding 2-apart cases. Statistical hypothesis testing very strongly rejects the assertion that these follower transitions are occurring at random. Similar analysis reveals marginal or no evidence of concertedness between 1-apart (nearest neighbor) and between 3-apart dihedral angle transitions. The pattern of concertedness for hexadecane is qualitatively similar to that of the lipid chains, although concertedness is somewhat stronger for the 3-apart transitions and somewhat weaker for those 4-apart. Finally, it is suggested that the diffusion of small solute molecules in membranes is better facilitated by nonconcerted transitions, which are associated with relatively large displacements of the chains, than by concerted transitions, which do little to change the chain shape.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1995

15-Hydroxyeicosatetraenoic acid and diabetic endothelial dysfunction in rabbit aorta.

We examined the effects of diabetes on eicosanoid metabolism and endothelium-dependent relaxation in isolated aorta from alloxan-induced diabetic rabbits and that from normal rabbits incubated in increased concentrations (44 mM) of glucose in vitro for 6 h. Immunoreactive 15-hydroxyeicosatetraenoic acid (HETE) was assayed in the incubation media of isolated aortic segments. Basal and acetylcholine (ACh)-stimulated release of 15-HETE was significantly greater in aorta of diabetic animals as compared with those of normal rabbits. Incubation of aortic segments from normal rabbits in increased concentrations of glucose caused a significant increase in basal and ACh-stimulated release of 15-HETE; and the release was significantly greater in aortic segments with endothelium than in segments without endothelium. Basal and ACh-stimulated release of 15-HETE was inhibited by indomethacin, a cyclooxygenase inhibitor. 15-HETE caused contractions of aortic rings that were inhibited by the prostaglandin H2 (PGH2) thromboxane A2 (TXA2) receptor blocker SQ-29548, but not by the TXA2 synthase inhibitor carbethoxyhexyl imidazole or indomethacin. Treatment of aortic rings with subthreshold concentrations of 15-HETE impaired ACh-induced relaxation; this was prevented by treatment with SQ-29548. Thus, abnormal release of endothelium-derived 15-HETE may play a role in endothelial cell dysfunction and increased vasoconstriction in diabetes by a mechanism that involves interaction with PGH2/TXA2 receptors.

Acetylcholine↗
PubMed1995

Relationship between glycocalyx and povidone-iodine resistance in Pseudomonas aeruginosa (ATCC 27853) biofilms.

Biofilm-embedded bacteria are generally more resistant to antimicrobial agents than are planktonic bacteria. Two possible mechanisms for biofilm resistance are that the glycocalyx matrix secreted by cells in a biofilm reacts with and neutralizes the antimicrobial agent and that the matrix creates a diffusion barrier to the antimicrobial agent. This study was therefore conducted to examine the relationship between glycocalyx and enhanced povidone-iodine resistance in biofilms of Pseudomonas aeruginosa (ATCC 27853). Biofilms were generated by inoculation of polycarbonate membranes with broth-grown cells and incubation of them on the surfaces of nutrient agar plates. The quantities of glycocalyx material per cell were found not to be significantly different between biofilm and planktonic samples. Transmission electron microscopy showed that the distributions of glycocalyx material around cells differed in biofilm and in planktonic samples. Addition of alginic acid to planktonic cell suspensions resulted in a slight increase in resistance to povidone-iodine, suggesting some neutralizing interaction. However, the iodine demands created by biofilm and planktonic samples of equivalent biomass were not significantly different and, therefore, do not explain the contrast in resistance observed between biofilm and planktonic samples. Examination of the relationship between cell death and biomass detachment from the glycocalyx matrix revealed that most cell death occurred in the fraction of biomass that detached from a biofilm during treatment. The overall rate of iodine diffusion through biofilms was not different from that of planktonic cells collected on a polycarbonate membrane.(ABSTRACT TRUNCATED AT 250 WORDS)

Biofilms↗
PubMed1995

U.S. screening mammography services with mobile units: results from the National Survey of Mammography Facilities.

PURPOSE: To investigate elements of mobile facilities for mammography in the United States. MATERIALS AND METHODS: The prevalence and performance of mobile facilities for mammography in the United States were studied with regard to cost, price, quality assurance, and access. Data were acquired from the National Cancer Institute's National Survey of Mammography Facilities, conducted in 1992. RESULTS: Of the 1,057 facilities surveyed, 2.4% were identified as mobile and accounted for 3% of mammography examinations performed. All mobile facilities reported accreditation by the American College of Radiology, and 92% were in Statistically Metropolitan Areas. Most were affiliated with community hospitals or private radiology practice and were more likely to be associated with lower fees, convenient operating hours, batch interpretation, and computerized reporting than were their stationary counterparts. CONCLUSION: Mobile mammography facilities compare favorably with stationary facilities. The use of these mobile units in the United States, however, has been limited.

Accreditation↗
PubMed1995

Imaging systems evaluation: effect of subtle cases on the design and analysis of receiver operating characteristic studies.

OBJECTIVE: Large-scale receiver operating characteristic (ROC) studies are expensive and time-consuming. If most of the difference in diagnostic accuracy occurs in a subset of subtle cases, considerable effort could be saved by restricting comparisons to this subset. We investigate the effect of subtle cases on diagnostic accuracy, the magnitude of error that can occur because of an imbalance of subtle cases in two groups, and the potential for sample size reductions if only subtle cases are used. METHODS: Data from a previous study of posteroanterior chest radiographs were reanalyzed separately for subsets of typical cases and subsets of subtle cases. Actually positive and actually negative cases were classified as subtle or typical and as difficult or easy for diagnosis of the specific abnormality. The area under the ROC curve (Az) was used as the measure of diagnostic accuracy. Pairwise comparisons were done among three techniques and for the detection of nodules and interstitial disease. RESULTS: The performance index (Az) was significantly (> or = 25%) lower for the subset of subtle cases as compared with the subset of typical cases. The difference in observer performance between two techniques was more often greater in the subset of subtle cases than in the subset of typical cases. CONCLUSION: The difference in diagnostic accuracy between the subset of typical cases and the subset of subtle cases is large enough that a difference in the proportion of subtle cases in two samples could result in clinically significant false differences in observer performance. Furthermore, the generally larger difference observed in the group of subtle cases suggests that sample sizes for some experiments could be reduced by 45-90% if the experiment were restricted to subtle cases.

Humans↗
PubMed1995

Screening mammography in community practice: positive predictive value of abnormal findings and yield of follow-up diagnostic procedures.

OBJECTIVE: The purpose of this study was to gather from 50 community mammography practices that were included in the National Survey of Mammography Facilities data concerning abnormal findings on screening mammograms to determine the frequency of various recommendations made for patients who had abnormal findings and to compare these recommendations with the frequency with which the procedures were actually performed. We also determined the positive predictive value of screening mammograms (the number of cancers detected per 100 abnormal findings) and the yield (the number of cancers detected per 100 procedures done) of various diagnostic procedures done because of abnormal findings. MATERIALS AND METHODS: We identified 1717 screening mammograms done in the last half of 1991 that had abnormal findings. Radiologic recommendations and follow-up procedures, including repeat standard (screening) mammography, additional mammographic views, sonography, clinical breast examination, needle aspiration, needle biopsy, and open biopsy, were identified for all of the cases from the radiologic records, and follow-up data were obtained from referring physicians. The positive predictive value and yield in the National Survey of Mammography Facilities were compared with data from the mammography screening practice of the University of California at San Francisco (UCSF), a facility noted for its clinical efficiency. RESULTS: We estimate that 11% of all screening mammograms resulted in a recommendation for further diagnostic procedures. These 1717 mammograms with abnormal findings led to the following recommendations and procedures: repeat standard (screening) mammography, 610 (recommended)/635 (performed); additional mammographic views, 785/707; sonography, 400/345; biopsy, 189/229; and needle aspiration, 21/51. More procedures were done than were recommended in some cases because the results of certain procedures often led to the performance of other, additional procedures. The positive predictive value for screening examinations with abnormal findings was 3.5%, and the yield for open biopsy was 21%. In the UCSF data base, the positive predictive value for examinations with abnormal findings was 10%, and the yield for open biopsy was 34%. CONCLUSION: The positive predictive value for examinations with abnormal findings and the yield for diagnostic procedures performed as a result of abnormal findings in 50 community radiologic facilities were higher than those reported in some earlier studies, a fact that raised concern about the induced cost of screening mammography. However, these values were low compared with those in the UCSF data base. This fact was particularly true of repeat standard (screening) mammography.

Adult↗
PubMed1995

Relationship between the Bracken Basic Concept Scale and the Differential Ability Scales with an at-risk sample of preschoolers.

This study investigated the relationship between the Bracken Basic Concept Scale and the Differential Ability Scales with 35 at-risk preschoolers between the ages 3-6 and 5-11. A Pearson product-moment correlation coefficient of .70 was obtained between the Bracken Basic Concept Scale Total Test scores and the General Conceptual Ability scores of the Differential Ability Scales. This association supports the use of the Bracken scale to predict intelligence if replicated with a larger sample and specific handicaps. In addition, support for the administration of the more brief Bracken School Readiness Composite compared to using the Bracken Total Test score in the prediction of the Differential Ability Scales General Conceptual Ability score was found.

Aptitude↗
PubMed1994

Bicyclic hydantoins with a bridgehead nitrogen. Comparison of anticonvulsant activities with binding to the neuronal voltage-dependent sodium channel.

The anticonvulsant activity of diphenylhydantoin (DPH or phenytoin) is consistent with its actions on the neuronal voltage-dependent sodium channel. To further elucidate the binding requirements for this site, we synthesized several hydantoin analogs and evaluated these in in vitro sodium channel-binding and/or in vivo whole animal anticonvulsant assays. 5-Pentyl-5-phenylhydantoin (8), the most potent binder to the sodium channel in this study, had the same affinity as DPH (IC50 = 40 microM), revealing that one phenyl ring is sufficient for good interactions. Since our previous studies with monophenyl-substituted bicyclic 2,4-oxazolidinediones suggested that N3-alkylation and the conformational constraint of a 5-alkyl substituent over one face of the oxazolidinedione ring improved activity, we synthesized two examples of analogous bicyclic hydantoins. However, the bicyclic hydantoins were much less potent binders to the neuronal voltage-dependent sodium channel than their monocyclic counterparts. The binding activity for the more potent bicyclic hydantoin, 1,8-diaza-9,10-dioxo-7-phenylbicyclo[5.2.1]decane (4) (IC50 = 427 microM), was comparable to that of the ring-opened, N3-methylated monocyclic hydantoin model, 5-butyl-3-methyl-5-phenylhydantoin (9) (IC50 = 285 microM), and these were 8-11 times less potent than the monocyclic model 8, which contains a free imide NH. Furthermore, 5-butyl-5-phenylhydantoin (7; IC50 = 103 microM) was less potent than 8, suggesting that increased log P may enhance binding. Thus, unlike 2,4-oxazolidinediones, N3-alkylation of hydantoins dramatically decreases sodium channel-binding activity. Bicyclic hydantoin 4 was nevertheless a good anti-MES anticonvulsant in mice (ED50 = 86 mg/kg), although this activity likely results from mechanisms other than interactions at the neuronal voltage-dependent sodium channel. Compound 4 was also relatively neurotoxic (TD50 = 124 mg/kg). These results suggest that the binding of hydantoins to the sodium channel may be enhanced by (a) a free imide NH group and (b) an increased log P. Furthermore, 2,4-oxazolidinediones and hydantoins must either orient differently in the same binding site or interact with different sites on the neuronal voltage-dependent sodium channel.

Alkylation↗
PubMed1994

The radiation dosimetry and normal value study of 99mTc-HMPAO-labeled leukocytes.

RATIONALE AND OBJECTIVES: Indium-111 (111In)-labeled leukocyte scanning has been used frequently in patients suspected of having infections. Recently, technetium-99m hexamethylpropylene amine oxime (99mTc-HMPAO) has been used to label leukocytes. This study was undertaken to determine the distribution and dosimetry of 99mTc-HMPAO leukocytes in healthy subjects. METHODS: Five healthy volunteers had leukocytes labeled with 99mTc-HMPAO. After injection of the labeled leukocytes, whole body images and blood and urine samples were obtained at multiple time points. RESULTS: Visual interpretation of the images demonstrated significant bowel activity as early as 2 hours and increasing with time such that one the 8- and 24-hour images, the amount of bowel activity would preclude using 99mTc-HMPAO leukocyte scanning for abdominal processes. The dosimetry for this study is similar to that of other studies and is in an acceptable diagnostic range. CONCLUSIONS: 99mTc-HMPAO leukocyte studies are an acceptable alternative to 111In-labeled leukocyte studies in terms of dosimetry. Use of such studies in the abdomen should be limited to early images, usually before 2 hours, to avoid confusion with the normal route of excretion in the bowel.

Female↗
PubMed1994

Physical fatigue in high and very high frequency manual materials handling: perceived exertion and physiological indicators.

This paper presents the results of a preliminary laboratory study undertaken to determine the perceived exertion and physiological responses of highly trained and experienced workers to high (up to 16 repetitions/min) and very high frequency (above 16 repetitions/min) manual lifting, lowering, and carrying/turning tasks. The results indicate that workers engaged in such highly repetitive and physically demanding tasks may operate at psychophysical workloads that may clearly be considered physically fatiguing and unacceptable according to the current physiological design criteria. In this study subjects performing lifting and lowering tasks, on the average, operated at 57% and 52% of their uphill treadmill aerobic capacity, respectively. For carrying and turning tasks, the average metabolic energy expenditure rate corresponded to 43% of subjects' aerobic capacity. The overall heart rates of the study subjects were 155 beats per minute (bpm) for lifting, 144 bpm for lowering, and 142 bpm for carrying and turning. These physiological responses, when compared with recommended physiological design criteria, are excessively high. The ratings of perceived exertion (RPE) for the shoulder, back, and whole body were highest for lifting (range, 10.20-15.50) and least for carrying and turning (range, 10.30-13.40; carrying and turning activities also included RPE of arms). Generally workers perceived the associated physical exertions as acceptable.

Adult↗
PubMed1994

Stage of cancer at diagnosis for Medicare HMO and fee-for-service enrollees.

OBJECTIVES: Health maintenance organizations (HMOs) with Medicare contracts often provide cancer screening and preventive services not covered under fee-for-service. This study compared cancer patients in HMOs and fee-for-service on stage at diagnosis. METHODS: The study examined stage at diagnosis for aged Medicare enrollees in HMOs and fee-for-service, using information from the Surveillance, Epidemiology, and End Results program, linked with Medicare enrollment files. Twelve cancer sites were investigated, and demographics, area of residence, year of diagnosis (1985 to 1989), and education at the census tract level were controlled. RESULTS: HMO enrollees were diagnosed at earlier stages for cancers of the female breast, cervix, colon, and melanomas and at later stages for stomach cancer. There were no differences for cancers of the prostate, rectum, buccal cavity and pharynx, bladder, uterus, kidney, and ovary. HMO effects were strongest in areas with large, mature HMOs. CONCLUSIONS: Compared with fee-for-service enrollees, HMO enrollees were diagnosed at earlier stages for cancer sites for which effective screening services are available. The earlier detection of certain cancers among HMO enrollees may result from coverage of screening services and, perhaps, promotion by HMOs of such services.

Aged↗
PubMed1994

Quality assurance audits of community screening mammography practices: availability of active follow-up for data collection and outcome assessment.

OBJECTIVE: Routine and periodic mammography audit studies, the systematic evaluation of clinical follow-up procedures and outcomes subsequent to screening mammography reports of abnormal findings, have been advocated as an important component of quality assurance in screening mammography. This study assessed the degree to which mammography facilities in community practice maintain reporting and record-keeping systems and ascertain sufficient clinical follow-up data to facilitate the practice of mammography audit studies. MATERIALS AND METHODS: As part of a national survey of 1057 mammography facilities, data were collected from a stratified subsample of 50 facilities on facility information systems, and facility records were systematically abstracted to determine the degree of completeness of clinical follow-up data to screening mammography examinations with abnormal findings. Facilities were assisted in obtaining additional information through active data follow-up, and this information also was entered into the study's database. RESULTS: The nature of mammography information systems and the degree of data completeness varied widely. Computerized systems were used at relatively few facilities (12%). The organization of records and data varied widely and was generally not designed to accommodate routine systematic analysis. Screening examinations could be identified without reading the actual text of the mammography report at 94% of the facilities, but reports had to be read at the majority of facilities to identify examinations with abnormal findings (70%). Before active data follow-up, records were incomplete in about 40% of all cases. After active data follow-up, this decreased to 16%. Forty-two facilities achieved an average completeness of more than 90%, whereas the remaining eight lagged significantly behind this level. CONCLUSION: At the time of this study (late 1992 to early 1993), only about 20% of the facilities surveyed had informational systems and sufficient ascertainment of data to support the practice of mammography audit studies. After active data follow-up, more than 80% of the facilities were willing and able to achieve a high degree of data completeness with the assistance of our data abstracters. The results of this study suggest that, with the advent of standardized mammography data collection and analysis systems and increased emphasis on clinical outcomes assessment as a standard of care, the practice of performing mammography audits, although not currently widespread, is feasible for most facilities.

Breast Neoplasms↗
PubMed1994

The price of mammography in the United States: data from the National Survey of Mammography Facilities.

Data from the National Survey of Mammography Facilities are used to explore the efficiency of service delivery by mammography facilities. Screening mammography generally costs $100 or more. This study outlines principles recommended to lower unit costs of screening mammography and examines the extent to which facilities surveyed employed them. It reports charges, volume, and other facility characteristics, comparing them with the assumptions regarding these features in a study by the Physician Pricing Review Commission. That study, sponsored by the federal government, concluded that screening mammography can be delivered for around $60; however, only 14 percent of the facilities achieved the requisite volume of 15 or more mammograms per day. Facilities must become more efficient in order to charge the lower rates. This case study may have relevance for other potentially expensive preventive measures and medical procedures.

Data Collection↗
PubMed1993

Prostate cancer screening: what we know and what we need to know.

OBJECTIVE: To critically evaluate the evidence for recommending the screening of asymptomatic men for prostate cancer with a blood test to detect a prostate-specific antigen (PSA). DATA SOURCES: Relevant articles on screening for prostate cancer were identified from MEDLINE searches, from the authors' files, and from the bibliographies of identified articles. STUDY SELECTION: In the absence of controlled prospective trials, the studies are primarily retrospective and contain information about the sensitivity, specificity, and predictive values of tests used to screen for prostate cancer; the natural history of untreated prostate cancer; the morbidity, mortality, and costs of definitive treatment; and reviews of screening study biases. DATA EXTRACTION: Potential treatment-related mortality and costs that could be incurred by screening were estimated using defined assumptions. RESULTS: Although screening for prostate cancer has the potential to save lives, because of possible overdiagnosis, screening and subsequent therapy could actually have a net unfavorable effect on mortality or quality of life or both. Given the performance characteristics of the test, widespread screening efforts would probably cost billions of dollars. CONCLUSIONS: The net benefit from widespread screening is unclear. A randomized prospective study of the effect of screening on prostate cancer mortality has therefore been initiated by the National Cancer Institute.

Aged↗
PubMed1992

Elevated glucose alters A23187-induced release of arachidonic acid from porcine aortic endothelial cells by enhancing reacylation.

Cultured porcine aortic endothelial cells were conditioned in normal (5.2 mM) and elevated (15.6 mM) glucose, prelabeled with [14C]arachidonic acid and stimulated with ionophore A23187. Elevated glucose cultures released less radiolabeled products and less [14C]arachidonic acid. Analysis of cellular lipids revealed that elevated glucose reduced net loss of radiolabel from diacylphosphatidylethanolamine, did not affect early phosphatidylinositol hydrolysis, and increased net loss from diacylphosphatidylcholine and alkenylacylphosphatidylethanolamine. Uptake of radiolabel upon stimulation was examined to measure the role of reacylation on the diminished net release of radiolabel in elevated glucose cultures. Enhanced acylation of [3H]arachidonic acid into cellular lipids, especially PI, was observed in stimulated and resting cultures with elevated glucose. Further, pretreatment of the cultures with an acyltransferase inhibitor, thimerosal, prior to A23187 stimulation in radiolabeled cultures, abolished the effects of glucose on eicosanoid and arachidonic acid release. Differences in the ionophore-induced net loss of radiolabel from diacylphosphatidylethanolamine and phosphatidylinositol of the two glucose treatments were diminished by thimerosal exposure, while net loss of radiolabel from diacylphosphatidylcholine and alkenylacylphosphatidylethanolamine were unaffected. The data indicate that elevated glucose alters deacylation and enhances reacylation of arachidonic acid into endothelial cells and particularly into phosphatidylinositol. Enhanced reacylation may explain some of the altered lipid pathways that have been observed in experiments that elevate glucose concentrations or involve diabetes.

Acylation↗
PubMed1992

Specialized role for a murine class I-b MHC molecule in prokaryotic host defenses.

Although nonclassical (class I-b) gene products represent the majority of murine major histocompatibility complex (MHC) genes, the role of these relatively nonpolymorphic molecules remains uncertain. Recently, one such protein, H-2M3 (formerly designated Hmt), was shown to bind and specifically present N-formylated peptides to cytotoxic T lymphocytes. Because N-formylation is characteristic of prokaryotic proteins, this MHC molecule may be especially adapted for a role in the mammalian defense against bacterial attack. The current studies demonstrate that an MHC molecule, indistinguishable from H-2M3, presents antigens derived from the intracellular pathogen Listeria monocytogenes to Listeria-specific CD8+ cells.

Animals↗