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Biomedical subjects

D E Clark

Publications and source records attributed to D E Clark.

At least 19 recordsLinked to original sources
PubMed2000

Angiogenic growth factor expression in placenta.

New blood vessel growth is generally a rare event in the healthy adult. However, a notable exception to this is the female reproductive tract where cyclic angiogenesis occurs. Striking new vessel growth and remodeling also occurs during placentation; thus angiogenesis is essential for reproductive success. Vascular endothelial growth factor is a potent stimulator of this process and its production and action is tightly regulated. Indeed the placenta is a rich source of a soluble variant of the flt-1 receptor which seems to protect the placenta from the effects of excess vascular endothelial growth factor. The balance between new vessel growth (in the placental villi for example) and endothelial cell loss in the spiral arteries within the decidua is a delicate one. This is influenced by the local production of promotors and inhibitors of endothelial cell activation. Perturbation of this may lead to maternal pathology during pregnancy.

Angiogenesis Inducing Agents↗
PubMed2000

Effective dose from radiation absorbed during a panoramic examination with a new generation machine.

OBJECTIVES: The purpose of this investigation was to measure the tissue-absorbed dose and to calculate the whole-body effective dose (E) for a new generation panoramic machine (Planmeca PM 2002 CC Proline), operating in the panoramic examination mode. Comparisons could then be made with historical panoramic and intraoral radiographic dose measurement values and effective dose estimates. STUDY DESIGN: Thermoluminescent dosimeters were embedded in a humanoid, tissue-equivalent phantom at anatomically significant sites, representing key tissues. Absorbed dose measurements were obtained after every 5 panoramic exposures of a 25-exposure total. The measured average tissue-absorbed doses from a single panoramic exposure were used in the calculation of the whole-body E. RESULTS: The whole-body E for the PM 2002 CC Proline panoramic examination is 3.85 microSv. This is below the panoramic average of 6.7 microSv. The PM 2002 CC Proline panoramic examination delivers approximately 5% to 12% of the E of a complete mouth intraoral radiographic examination. CONCLUSIONS: The effective dose from the PM 2002 CC Proline examination is at the low end of the range for other panoramic machines and is far below either a D-speed or E-speed film intraoral radiographic examination.

Body Burden↗
PubMed1999

An indirect method for the estimation of osteoporotic fractures from injury and fracture profiles.

Study objective was to develop a valid epidemiological method for the estimation of osteoporotic fracture risk, using administrative databases and accounting for variable baseline risks of injury. Design is the secondary analysis of inpatient and outpatient utilization data. A baseline injury risk was estimated by the incidence of primary utilization of medical services for soft tissue injuries (ICD-9 diagnostic codes 910-929), and the risk profile was compared after normalization with the overall primary utilization rate for fractures (ICD-9 diagnostic codes 800-829). The setting is a county with approximately 100,000 inhabitants in the former East Germany. Participants were all inhabitants of the county who had a physician contact (inpatient or outpatient) during 1987-1988, as well as hospital inpatients for all of Germany in 1989. The number of fractures increased with age, especially in women, when compared to the number of fractures expected from the incidence of soft tissue injury. Similar patterns were identified in hospitalization data from East and West Germany. Estimating the prevalence of osteoporosis directly from certain "osteoporotic" fracture types associated with higher age is potentially biased, since it neglects the underlying risk of injury. Our model distinguished the osteoporotic fracture risk as the excess risk over an expected injury-related fracture risk for a given age and sex, and may allow a more valid quantification of osteoporotic fractures in different populations.

Adolescent↗
PubMed1999

Rapid calculation of polar molecular surface area and its application to the prediction of transport phenomena. 1. Prediction of intestinal absorption.

A method for the rapid computation of polar molecular surface area (PSA) is described. It is shown that consideration of only a single conformer when computing PSA gives an excellent correlation with intestinal absorption data-as good as previously reported methods employing multiple conformers. Circumventing a time-consuming conformational analysis opens the possibility of computationally screening large numbers of compounds for problems relating to absorption prior to synthesis. The robustness of the criterion for identifying poorly absorbed compounds (PSA >/= 140 A(2)) is illustrated through its application to a diverse test set of 74 drugs. The PSA-based method is also compared to an experimental method for absorption prediction recently described in the literature.

Chemical Phenomena↗
PubMed1999

Rapid calculation of polar molecular surface area and its application to the prediction of transport phenomena. 2. Prediction of blood-brain barrier penetration.

This paper describes the derivation of a simple QSAR model for the prediction of log BB from a set of 55 diverse organic compounds. The model contains two variables: polar surface area (PSA) and calculated logP, both of which can be rapidly computed. It therefore permits the prediction of log BB for large compound sets, such as virtual combinatorial libraries. The performance of this QSAR on two test sets taken from the literature is illustrated and compared with results from other reported computational approaches to log BB prediction.

Algorithms↗
PubMed1999

Localization of leukemia inhibitory factor and its receptor in human placenta throughout pregnancy.

Mice in which the gene that encodes the receptor (R) for leukemia inhibitory factor (LIF) has been deleted show abnormal growth and development of the placenta. This indicates that LIF plays an important role in placental development. The expression of LIF-R and LIF was examined in human trophoblast and decidua using in situ hybridization and immunocytochemistry. LIF-R mRNA and immunoreactivity was localized in villous and extravillous trophoblast throughout pregnancy, and in endothelial cells of the fetal villi. Strong expression of mRNA encoding LIF was detected in decidual leukocytes, which are abundant at the implantation site. Extravillous trophoblast, which invades the maternal decidua, therefore expresses LIF-R as it moves past decidual leukocytes, which express LIF mRNA. The effect of LIF on cultured human trophoblast was examined in vitro. Recombinant human LIF had no effect on [3H]thymidine incorporation by purified extravillous trophoblast, nor on expression of integrins alpha1, alpha5, or beta1 by isolated trophoblast. These results identify fetal endothelial cells and all cells of the trophoblast lineage as targets for the action of LIF in human placenta. Although its effects on trophoblast are not yet clear, LIF appears to mediate interactions between maternal decidual leukocytes and invading trophoblast. LIF may also play a critical role in controlling angiogenesis in the placental villi, since human fetal endothelial cells express LIF-R, and mice lacking a functional LIF receptor gene show altered vascular development in the placenta.

Cell Division↗
PubMed1999

Hospital trauma registries linked with population-based data.

BACKGROUND: We sought to obtain more reliable population-based data for injury epidemiology and trauma system evaluation by linking several sources. METHODS: In the state of Maine, probabilistic computer methods were used to link data from hospitals contained in a trauma registry for 1995 to 1996 to data from the same years contained in death certificates, ambulance run reports, and hospital discharge abstracts. The most reliable data available from each source were merged to form a standard record for each identifiable case of acute trauma. RESULTS: A total of 8,924 cases of serious injury were identified that either were in the registry, had a death certificate, or had both an ambulance run report and a hospital discharge abstract. Only 74% of the Trauma Center cases and 33% of the cases overall were contained in the registry. Only 84% of fatal hospitalized cases matched to a death certificate. Incompleteness of the registry and occasional failures to match records from one source to another were attributable to intentional omissions and a variety of human data management problems. CONCLUSIONS: Combining sources of data for injury victims can produce a resource more descriptive than any single source alone. However, computer-assisted record linkage still requires human review and corrections. Feedback of discrepancies to the individual data sources should further improve the quality of data available for linkage.

Databases, Factual↗
PubMed1999

Predicting regional variations in mortality from motor vehicle crashes.

OBJECTIVE: To show that the previously-observed inverse relationship between population density and per-capita mortality from motor vehicle crashes can be derived from a simple mathematical model that can be used for prediction. METHODS: The authors proposed models in which the number of fatal crashes in an area was directly proportional to the population and also to some power of the mean distance between hospitals. Alternatively, these can be parameterized as Weibull survival models. Using county and state data from the U.S. Census, the authors fitted linear regression equations on a logarithmic scale to test the validity of these models. RESULTS: The southern states conformed to a different model from the other states. If an indicator variable was used to distinguish these groups, the resulting model accounted for 74% of the variation from state to state (Alaska excepted). After controlling for mean inter-hospital distance, the southern states had a per-capita mortality 1.37 times that of the other states. CONCLUSIONS: Simply knowing the mean distance between hospitals in a region allows a fiarly accurate estimate of its per-capita mortality from vehicle crashes. After controlling for this factor, vehicle crash mortality per capita is higher in the southern states, for reasons yet to be explained.

Accidents, Traffic↗
PubMed1999

Alternative splicing of vascular endothelial growth factor (VEGF)-R1 (FLT-1) pre-mRNA is important for the regulation of VEGF activity.

Angiogenesis is essential for normal mammalian development and is controlled by the local balance of pro- and antiangiogenic factors. Here we describe a novel mouse cDNA sequence encoding sFLT-1 that is a potent antagonist to vascular endothelial growth factor (VEGF) and show for the first time its in vivo production. In situ hybridization and Northern blot analysis with probes specific for sFLT-1 or FLT-1 showed that the relative abundance of their mRNAs changed markedly in spongiotrophoblast cells in the placenta as gestation progressed. On day 11 of pregnancy, sFLT-1 mRNA was undetectable but FLT-1 readily apparent, and by day 17 sFLT-1 mRNA was abundant but FLT-1 barely detectable. sFLT-1 was identified in conditioned medium of cultured placenta from day 17 pregnant mice and likely to be present in the circulation, as there is a substantial increase of VEGF-binding activity in the serum from day 13 of pregnancy, which coincides with the abundant sFLT-1 expression in placenta. Expression of sFLT-1 was also observed in adult lung, kidney, liver, and uterus. These data suggest a novel mechanism of regulation of angiogenesis by alternative splicing of FLT-1 pre-mRNA. Treatment of pregnant mice with exogenous VEGF from day 9 to 17 of pregnancy, which alters the ratio of VEGF to sFLT-1, resulted in an increase in the number of resorption sites and fibrin deposition in the placenta of ongoing pregnancies. These findings have important implications for understanding placental function and may be relevant in a range of disease states.

Alternative Splicing↗
PubMed1999

Digital radiography and California third parties.

Acceptance of digital radiography is increasing but has not yet progressed to the mainstream. A key factor in widespread use of this advancement is acceptance--both theoretical and technological--by dental health plans for claim submissions. This article details a survey of California third parties to examine their practices, concerns, and plans regarding digital dental radiography.

Humans↗
PubMed1998

Flexible docking using Tabu search and an empirical estimate of binding affinity.

This article describes the implementation of a new docking approach. The method uses a Tabu search methodology to dock flexibly ligand molecules into rigid receptor structures. It uses an empirical objective function with a small number of physically based terms derived from fitting experimental binding affinities for crystallographic complexes. This means that docking energies produced by the searching algorithm provide direct estimates of the binding affinities of the ligands. The method has been tested on 50 ligand-receptor complexes for which the experimental binding affinity and binding geometry are known. All water molecules are removed from the structures and ligand molecules are minimized in vacuo before docking. The lowest energy geometry produced by the docking protocol is within 1.5 A root-mean square of the experimental binding mode for 86% of the complexes. The lowest energies produced by the docking are in fair agreement with the known free energies of binding for the ligands.

Algorithms↗
PubMed1998

Hepatocyte growth factor levels during normal and intra-uterine growth-restricted pregnancies.

Hepatocyte growth factor (HGF), also known as scatter factor, binds the c-met receptor. It has been shown to be involved in mesenchyme-epithelial interactions. HGF is produced by the villous mesenchyme of the placenta throughout pregnancy and its receptor located on the villous cytotrophoblast cells. In this study the levels of HGF were measured in consecutive samples of plasma taken from pregnant women. Normal pregnancies were compared with intrauterine growth restricted (IUGR) pregnancies (below the third centile). In both groups, the levels of HGF were found to increase significantly as pregnancy progressed and then fall post partum. There was a considerable amount of variation found between individual women but no significant difference (P=0.65) between the normal and IUGR pregnancies.

Adult↗
PubMed1998

Monitoring hospital trauma mortality using statistical process control methods.

BACKGROUND: We sought to develop a simple and effective way to monitor trends in trauma mortality, using objective clinical categories and methods of statistical process control. STUDY DESIGN: Control charts and Pareto analysis were applied to trauma mortality data at the Maine Medical Center. We collected data prospectively on patients who died in our hospital after acute injury during 1985-1996 (and retrospectively for 1975-1984) to identify cases requiring medical quality review. We excluded from this study patients older than 80 years, those whose Glasgow Coma Scale motor component was never > 3 at any time after admission, and those with pathologic fractures, carcinomatosis, high quadriplegia, or severe burns. The remaining deaths were classified as resulting from inability to resuscitate (mostly hemorrhage), neurologic deterioration, or organ failure. The annual numbers in each of these categories were evaluated under the hypothesis of stationary Poisson processes with mean values equal to those seen from 1975-1984. RESULTS: After the exclusions, annual mortality from trauma has remained within control limits consistent with the Poisson model. Death from neurologic deterioration has shown a trend consistent with significant improvement in the process mean. Transient peaks in the other categories did not exceed control limits, but Pareto analysis prompted detailed studies of aortic and liver trauma. CONCLUSIONS: Process control methodology is easy to apply and potentially useful in monitoring hospital trauma mortality.

Cause of Death↗
PubMed1998

A vascular endothelial growth factor antagonist is produced by the human placenta and released into the maternal circulation.

Vascular endothelial growth factor (VEGF) is a potent secreted factor that promotes angiogenesis and maintains the integrity of the endothelium. Levels of VEGF are increased in many tumors and are elevated in women with pre-eclampsia, a serious disease of pregnancy. Here we show by in situ hybridization that the trophoblast contains the mRNA encoding a soluble version of the VEGF receptor known as Flt-1 (sFlt-1: initially described by Kendall and Thomas, PNAS 90:10705-10709). Binding assays and Western blotting of villus-conditioned media confirmed the production of sFlt-1. Serum from pregnant women was found to contain a VEGF-binding protein that was not present in serum from men or nonpregnant women. As determined by heparin affinity, column fractionation, and cross-linking, this protein was identical to sFlt-1. Taken together, these results show that the placenta secretes sFlt-1, which would be expected to be a VEGF antagonist. This is the first report of production of the sFlt-1 receptor in vivo, and it reveals a new mechanism for naturally regulating this potent angiogenic agent. The presence of such an antagonist suggests that regulation of VEGF action is essential to successful pregnancy. This has important implications for the activity of VEGF locally and systemically in other conditions.

Blotting, Western↗
PubMed1998

Hypertonic saline resuscitation of patients with head injury: a prospective, randomized clinical trial.

BACKGROUND: Experimental and clinical work has suggested that hypertonic saline (HTS) would be better than lactated Ringer's solution (LRS) for the resuscitation of patients with head injuries. No clinical study has examined the effect of HTS infusion on intracranial pressure (ICP) and outcome in patients with head injuries. We hypothesized that HTS infusion would result in a lower ICP and fewer medical interventions to lower ICP compared with LRS. METHODS/DESIGN: Prospective, randomized clinical trial at two teaching hospitals. RESULTS: Thirty-four patients were enrolled and were similar in age and Injury Severity Score. HTS patients had a lower admission Glasgow Coma Scale score (HTS: 4.7+/-0.7; LRS: 6.7+/-0.7; p = 0.057), a higher initial ICP (HTS: 16+/-2; LRS: 11+/-2; p = 0.06), and a higher initial mean maximum ICP (HTS: 31+/-3; LRS: 18+/-2; p < 0.01). Treatment effectively lowered ICP in both groups, and there was no significant difference between the groups in ICP at any time after entry. HTS patients required significantly more interventions (HTS: 31+/-4; LRS: 11+/-3; p < 0.01). During the study, the change in maximum ICP was positive in the LRS group but negative in the HTS group (LRS: +2+/-3; HTS: -9+/-4; p < 0.05). CONCLUSION: As a group, HTS patients had more severe head injuries. HTS and LRS used with other therapies effectively controlled the ICP. The widely held conviction that sodium administration will lead to a sustained increase in ICP is not supported by this work.

Adult↗
PubMed1998

Expression and localization of the Th2-type cytokine interleukin-13 and its receptor in the placenta during human pregnancy.

PROBLEM: To investigate the expression of the Th2-type cytokine interleukin (IL)-13 and its receptor in human placenta during gestation. METHOD OF STUDY: Expression of IL-13 and its receptor was analyzed by reverse transcriptase (RT)-polymerase chain reaction (PCR), in situ hybridization and immunohistochemistry using human placental samples. RESULTS: IL-13 mRNA was detected by RT-PCR in placental extracts from all stages of gestation. In situ hybridization revealed IL-13 mRNA in first trimester cytotrophoblast and syncytiotrophoblast. Few positive cells were found within decidual sections from the same pregnancy. Immunohistochemistry revealed a similar pattern to in situ hybridization. This was largely absent in second- and third-trimester placentae. IL-13 receptor alpha chain (IL-13R alpha) was detected by immunofluorescence on the surface of leukocytes in first-trimester villous core and decidua. CONCLUSIONS: The expression of IL-13 is spatially and temporally regulated in the placenta, and associated with the close proximity of a receptor-bearing target leukocyte population.

DNA, Complementary↗
PubMed1998

Comparison of expression patterns for placenta growth factor, vascular endothelial growth factor (VEGF), VEGF-B and VEGF-C in the human placenta throughout gestation.

Angiogenesis and vascular transformation are important processes in the normal development of the placenta. Vascular endothelial growth factor (VEGF) is a potent angiogenic growth factor and is thought to be important for placental development. Recently several new members of this family have been described. In this study we used in situ hybridisation to localise which cells in the placenta expressed mRNA for VEGF, placenta growth factor (PlGF), VEGF-B and VEGF-C. We were unable to find any message for either VEGF-B or VEGF-C in the placenta, suggesting that only low levels are produced which this method was unable to detect. The mRNA encoding VEGF was found to be produced by cells within the villous mesenchyme, decidual macrophages and decidual glands but, in contrast to our previous findings, not by trophoblast. The mRNA encoding PlGF was produced in large amounts by villous cytotrophoblast, syncytiotrophoblast and extravillous trophoblast. The mRNAs encoding VEGF and PlGF were thus not co-localised and it appears that there is unlikely to be any significant production of VEGF/PlGF heterodimer in the placenta.

Blotting, Northern↗