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Biomedical subjects

D E Clark

Publications and source records attributed to D E Clark.

At least 55 records · Page 3Linked to original sources
PubMed1997

Computational methods for probabilistic decision trees.

Decision tree models may be more realistic if branching probabilities (and possibly utilities) are represented as distributions rather than point estimates. However, numerical analysis of such "probabilistic" trees is more difficult. This study employed the Mathematica computer algebra system to implement and verify previously described probabilistic methods. Both algebraic approximations and Monte Carlo simulation methods were used; in particular, simulations with beta, logistic-normal, and triangular distributions for branching probabilities were compared. Algebraic and simulation methods of sensitivity analysis were also implemented and compared. Computation required minimal programming and was reasonably fast using Mathematica on a standard personal computer. This study verified previously published results, including methods of sensitivity analysis. Changing the input distributional form had little effect. Computation is no longer a significant barrier to the use of probabilistic methods for analysis of decision trees.

Computer Simulation↗
PubMed1997

Blunt and penetrating trauma--has anything changed?

Management of abdominal trauma has changed significantly in the last decade. The next decade will also see significant change as imaging and minimally invasive surgical techniques evolve and more approaches are examined in well-designed prospective studies.

Abdominal Injuries↗
PubMed1997

A comparison of heuristic search algorithms for molecular docking.

This paper describes the implementation and comparison of four heuristic search algorithms (genetic algorithm, evolutionary programming, simulated annealing and tabu search) and a random search procedure for flexible molecular docking. To our knowledge, this is the first application of the tabu search algorithm in this area. The algorithms are compared using a recently described fast molecular recognition potential function and a diverse set of five protein-ligand systems. Statistical analysis of the results indicates that overall the genetic algorithm performs best in terms of the median energy of the solutions located. However, tabu search shows a better performance in terms of locating solutions close to the crystallographic ligand conformation. These results suggest that a hybrid search algorithm may give superior results to any of the algorithms alone.

Algorithms↗
PubMed1997

PRO_SELECT: combining structure-based drug design and combinatorial chemistry for rapid lead discovery. 1. Technology.

This paper describes a novel methodology, PRO_SELECT, which combines elements of structure-based drug design and combinatorial chemistry to create a new paradigm for accelerated lead discovery. Starting with a synthetically accessible template positioned in the active site of the target of interest, PRO_SELECT employs database searching to generate lists of potential substituents for each substituent position on the template. These substituents are selected on the basis of their being able to couple to the template using known synthetic routes and their possession of the correct functionality to interact with specified residues in the active site. The lists of potential substituents are then screened computationally against the active site using rapid algorithms. An empirical scoring function, correlated to binding free energy, is used to rank the substituents at each position. The highest scoring substituents at each position can then be examined using a variety of techniques and a final selection is made. Combinatorial enumeration of the final lists generates a library of synthetically accessible molecules, which may then be prioritized for synthesis and assay. The results obtained using PRO_SELECT to design thrombin inhibitors are briefly discussed.

Computer-Aided Design↗
PubMed1997

Isolation of macrophages (Hofbauer cells) from human term placenta and their prostaglandin E2 and thromboxane production.

Placental macrophages (Hofbauer cells) are located close to trophoblast cells and fetal capillaries, which makes them ideal candidates for involvement in regulatory processes within the villous core. Their production of various cytokines and prostaglandin (PG) synthesizing enzymes has previously been shown immunohistochemically. Hofbauer cells were isolated from human placenta after term deliveries by Ficoll and Percoll gradient centrifugation. Remaining trophoblast cells were removed with anti-epidermal growth factor (EGF)-receptor-coated Dynabeads followed by differential adherence. The identity of isolated cells was investigated by immunohistochemistry with anti-CD68, which showed that >90% cells were positive. After a 36 h recovery period in either 20% O2 or 5% O2, fresh medium was applied and PGE2 and thromboxane (TXA2) production analysed by enzyme immunoassay at 4, 8, and 24 h. PGE2 and TXA2 were both produced by placental macrophages with PGE2 synthesis being predominant. Concentrations of both could be stimulated by lipopolysaccharide with maximum effect after 24 h. Culture in low oxygen caused decreased PGE2 concentrations, whereas TXA2 production remained unchanged. In conclusion, the presented isolation protocol allows further study of Hofbauer cell function. This study also presents novel findings regarding the prostaglandin production of term Hofbauer cells under normal and hypoxic conditions.

Cell Separation↗
PubMed1997

Modeling injury outcomes using time-to-event methods.

BACKGROUND: Mortality is an important measurement of injury outcomes, but measurements reflecting disability or cost are also important. Hospital length of stay (LOS) has been used as an outcome variable, but reduced LOS could be achieved either by improved care or by increased mortality. A solution to this statistical problem of "competing risks" would enable injury outcomes based on LOS to be modeled using time-to-event methods. METHODS: Time-to-event methodology was applied to 2,106 cases with complete data from the 1991-1994 registry of a regional trauma center. LOS was used as the outcome variable, modified by assigning an arbitrarily long LOS to any fatal case. A combination of proportional hazards and logistic regression models was used to explore the effects of potential predictive variables, including Trauma Score (TS), Injury Severity Score (ISS), components of TS or ISS, age, sex, alcohol use, and whether a patient was transferred. RESULTS: The "TRISS" combination of TS, ISS, and age previously shown to predict mortality also predicted "modified LOS" (Wald p value less than 0.001 for each variable). Models using only age and certain components of ISS or TS fit our data even better, with fewer parameters. Other variables were not predictive. Modified Kaplan-Meier plots provided easily interpreted graphical results, combining both mortality and LOS information. CONCLUSIONS: With a simple modification to allow for competing risks, time-to-event methods enable more informative modeling of injury outcomes than binary (lived/died) methods alone. Such models may be useful for describing and comparing groups of hospitalized trauma patients.

Female↗
PubMed1997

A comparison of health information on Florida's free-nets.

In the popular rush to provide electronic consumer health information, particularly via the Internet, one system has been largely overlooked-the free-net. Free-nets are often text-based systems from which users choose topics from "menus." While the World Wide Web can be more graphically appealing, it can also be overwhelming. Medical information resources are available to diverse populations through free-nets, which are convenient, free services. The amount of information and range of topics they offer are vast. A study of Florida's free-nets during a six-month period involved five free-net systems. Survey items included user demographics, interlibrary loan services, attitudes toward providing medical advice, and availability of medical librarian expertise. Comparisons include the number of user queries on medical and health-related free-net menus, user-friendliness, and the type of health information provided.

Computer Communication Networks↗
PubMed1997

Expression and localization of the vascular endothelial growth factor family in ovarian epithelial tumors.

Vascular endothelial growth factor (VEGF) is an angiogenic factor secreted by various tumors, including epithelial tumors of the ovary, and is involved in tumor progression and maintenance. The significance and function of other members of the VEGF family in the ovary has not yet been elucidated. In the present study, we have defined the expression of mRNA encoding VEGF-B, VEGF-C, and placenta growth factor (PIGF), compared with that of VEGF mRNA, in normal ovary and a range of ovarian epithelial tumors. Analysis by reverse transcription-PCR indicated that mRNA encoding VEGF (isoforms 121 and 165), VEGF-B (isoforms 167 and 186), and VEGF-C, but not PIGF, were present in all ovarian tissues examined. By in situ hybridization, neither VEGF-C nor PIGF transcripts were detected in any of the samples. The expression pattern of VEGF-B mRNA was generally similar to that of VEGF mRNA, in that transcripts were readily detected in the epithelial cells of all histologic types of ovarian carcinoma, but could not be detected in normal or benign tumor epithelium. Specific differences in the expression of the two genes were noted in areas of tumor necrosis, in which the expression of VEGF mRNA, but not VEGF-B mRNA, was further enhanced, and in a sample in which VEGF-B mRNA was strongly expressed in tumor-associated macrophages that did not hybridize with the riboprobe to VEGF mRNA. These results imply that a second member of the VEGF family, VEGF-B, may play a significant role in the angiogenesis, progression, and maintenance of ovarian carcinomas.

Adult↗
PubMed1996

Moose-motor vehicle collisions. An increasing hazard in northern New England.

OBJECTIVE: To analyze the epidemiology and epizootiology of moose-motor vehicle collisions (MMVC) and outcomes in severely injured patients to identify variables that might be modified to reduce the impact of this mutually deleterious interspecies interaction. DESIGN: Wildlife and Traffic Safety databases permitted retrospective, population-based assessment of MMVC epidemiology. A case series compiled from hospital trauma registries characterized morbidity and mortality from MMVC. SETTING: New Hampshire and Maine area. PATIENTS: All victims of MMVC (1980 through 1991) were included in population-based analyses. Twenty-three patients hospitalized at three rural trauma centers (January 1990 through June 1994) were included in the case series. MAIN OUTCOME MEASURES: Location, time of day and seasonal occurrence of MMVC were determined. Injury patterns and Injury Severity Scores were analyzed in 23 representative patients. Maine's 1991 traffic and medical data were linked, and factors predictive of injury from MMVC were identified using multivariate logistics. RESULTS: Most MMVC occur from April through October after dark. Of 23 subjects, 70% sustained head and/or face injuries and 26%, cervical spine injuries. Mortality was 9%. Mean Injury Severity Score was 15.7 (SD=9.0). Safety belt use, rear seat location, and light truck occupancy were associated with reduced injury (p<.05). CONCLUSIONS: Moose-motor vehicle collisions are increasing in rural regions. Prevention programs should emphasize defensive driving and seat belt use, especially during high-risk periods. Injury patterns in MMVC suggest a need for automobile design modifications that better protect the passenger compartment form direct impact.

Accidents, Traffic↗
PubMed1996

Active-site-directed 3D database searching: pharmacophore extraction and validation of hits.

Two new computational tools, PRO_PHARMEX and PRO_SCOPE, for use in active-site-directed searching of 3D databases are described. PRO_PHARMEX is a flexible, graphics-based program facilitating the extraction of pharmacophores from the active site of a target macromolecule. These pharmacophores can then be used to search a variety of databases for novel lead compounds. Such searches can often generate many 'hits' of varying quality. To aid the user in setting priorities for purchase, synthesis or testing, PRO_SCOPE can be used to dock molecules rapidly back into the active site and to assign them a score using an empirical scoring function correlated to the free energy of binding. To illustrate how these tools can add value to existing 3D database software, their use in the design of novel thrombin inhibitors is described.

Binding Sites↗
PubMed1996

Evolutionary algorithms in computer-aided molecular design.

In recent years, search and optimisation algorithms inspired by evolutionary processes have been applied with marked success to a wide variety of problems in diverse fields of study. In this review, we survey the growing application of these 'evolutionary algorithms' in one such area: computer-aided molecular design. In the course of the review, we seek to summarise the work to date and to indicate where evolutionary algorithms have met with success and where they have not fared so well. In addition to this, we also attempt to discern some future trends in both the basic research concerning these algorithms and their application to the elucidation, design and modelling of chemical and biochemical structures.

Algorithms↗
PubMed1996

Maternal plasma levels of vascular endothelial growth factor in normotensive pregnancies and in pregnancies complicated by pre-eclampsia.

We have measured the level of vascular endothelial growth factor (VEGF) in maternal plasma during normotensive pregnancy and in pregnancies complicated by pre-eclampsia. VEGF was measured using a competitive enzyme immunoassay. Plasma VEGF was significantly elevated (P < 0.0001) in the pre-eclamptic group (median value 32.7 ng mL-1, range 10.3-64.0), compared with the normotensive group (median value 11.7 ng mL-1, range 6.3-24.3). VEGF is a potent regulator of endothelial cell function. The increased level found in women with pre-eclampsia indicates that VEGF may be involved in the maternal endothelial cell dysfunction associated with this condition. An increase in VEGF, a potent regulator of microvascular permeability, may also contribute to the extravasation of plasma proteins and the subsequent development of proteinuria, both characteristic features of pre-eclampsia.

Adolescent↗
PubMed1996

Localization of VEGF and expression of its receptors flt and KDR in human placenta throughout pregnancy.

Vascular endothelial growth factor (VEGF) is a potent secreted angiogenic growth factor. Its action is mediated through the tyrosine kinase receptors flt and KDR. We here examine, in detail, the distribution of this ligand and its receptors in human placentae throughout gestation. In the first trimester, in-situ hybridization revealed uneven distribution of flt mRNA around the villous trophoblast indicating spatial regulation. Temporal regulation of flt was observed with no flt mRNA expression detected in villi from mid-gestational placenta, while low levels were found in term villi. Extravillous trophoblast was found to contain both mRNA encoding flt and flt-like immunoreactivity throughout pregnancy. In contrast, KDR mRNA was found only in association with endothelial cells. Within the decidua the anti-flt antibody stained multiple cell types during the first trimester of pregnancy but only the extravillous trophoblast later in gestation. VEGF immunoreactivity tended to co-localize with the staining for flt. These results indicate that VEGF may exert an important role within both the placental villi and the maternal decidua in relation to the growth, differentiation and migration of trophoblast and that this is mediated primarily through the spatial and temporal regulation of the flt receptor rather than the KDR receptor.

Endothelial Growth Factors↗
PubMed1996

County wide employment and population growth: an analysis of the 1980s.

"Regional scientists remain interested in studying interregional differences in the growth rates of population and employment. Following the earlier work of Carlino and Mills, this paper examines growth trends at the county level in the U.S. during the period 1981-1989. Five major sectors of employment are examined. A partial adjustment model is developed that captures intercounty differences in amenities, business and fiscal conditions, demography, employment structure, and relative location. Some evidence is given that population and employment growth was simultaneous, although feedback effects apparently were not strong."

Americas↗
PubMed1996

Personal and location-specific characteristics and elderly interstate migration.

"The purpose of this paper is to investigate the impact of locational and individual characteristics upon interstate retiree migration, particularly in state-level public policy variables. Data regarding the characteristics of individual movers are drawn from the 1990 U.S. Census of Population and Housing 5% Public Use Microdata Sample. The household data are merged with location-specific attributes including both natural amenities and local fiscal variables." Three alternative models are developed, involving push factors, pull factors, and differences in site characteristics experienced by migrants. "The results indicate that both personal and locational characteristics are important factors determining the decision of elderly migrants to change their state of residence. While there is some limited support for the push and pull specifications, the difference model is found to provide the best overall fit."

Adult↗
PubMed1996

Localization of mRNA encoding c-kit during the initiation of folliculogenesis in ovine fetal ovaries.

The c-kit protein is a transmembrane tyrosine kinase receptor that binds the growth factor stem cell factor. Mutant alleles of the genes coding for both the receptor (c-kit) and its ligand (stem cell factor) affect gametogenesis, development of melanoblasts and some aspects of haematopoiesis. The aim of this study was to examine expression of the c-kit gene during folliculogenesis in fetal sheep ovaries using in situ hybridization. A 422 bp cDNA encoding the extracellular domain of the c-kit protein was amplified from sheep ovarian RNA using reverse-transcription-polymerase chain reaction (RT-PCR), cloned and sequenced. Riboprobes transcribed from the ovine cDNA encoding c-kit were used to detect the presence of mRNA encoding c-kit within the ovaries of fetal sheep on days 90, 100, 120 and 135 of gestation (term = 147 days). In day 90 and 100 fetal ovaries, mRNA encoding c-kit was not detected in association with oogonia during the period of meiosis (to prophase I) but was present in some of the isolated oocytes. In ovaries from day 90 to day 135, mRNA encoding c-kit was detected in the oocytes at every stage of follicular growth--primordial through to antral follicles. This pattern of localization is consistent with that demonstrated in mice.

Animals↗
PubMed1996

Hepatocyte growth factor/scatter factor and its receptor c-met: localisation and expression in the human placenta throughout pregnancy.

Hepatocyte growth factor (HGF), also known as scatter factor, acts via the c-met receptor resulting in pronounced effects on certain epithelial cells. We hypothesised that HGF would be important in placental development where the trophoblast represents a specialised barrier of epithelial origin. In this paper we examine the expression and production of HGF and its receptor in the human placenta throughout pregnancy. In addition, RT-PCR was undertaken on human embryos to ascertain whether pre-implantation embryonic or trophoblast cells were under the influence of this growth factor. In samples from the first trimester of pregnancy in situ hybridisation with a c-met antisense probe detected message expression in villous cytotrophoblast and in decidual glands but not in extravillous trophoblast. Some c-met expression was detected in cytotrophoblast from the second trimester placentae; this declined to negligible levels by term. Staining with an anti c-met antibody largely confirmed these findings but found relatively strong staining of cytotrophoblast at term. HGF was confined to the villous core throughout pregnancy when examined by both in situ hybridisation and immunohistochemistry. Trophoblast was consistently negative for HGF. Pre-implantation embryos examined by RT-PCR were negative for both c-met and HGF mRNA. These results indicate that the HGF may exert an important influence on cytotrophoblast throughout the process of placental formation and growth.

Blastocyst↗