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D E Clark

Publications and source records attributed to D E Clark.

At least 73 records · Page 4Linked to original sources
PubMed1995

PRO-LIGAND: an approach to de novo molecular design. 1. Application to the design of organic molecules.

An approach to de novo molecular design, PRO-LIGAND, has been developed that, in the environment of a large, integrated molecular design and simulation system, provides a unified framework for the generation of novel molecules which are either similar or complementary to a specified target. The approach is based on a methodology that has proved to be effective in other studies--placing molecular fragments upon target interaction sites-but incorporates many novel features such as the use of a rapid graph-theoretical algorithm for fragment placing, a generalised driver for structure generation which offers a large variety of fragment assembly strategies to the user and the pre-screening of library fragments. After a detailed description of the relevant modules of the package, PRO-LIGAND's efficacy in aiding rational drug design is demonstrated by its ability to design mimics of methotrexate and potential inhibitors for dihydrofolate reductase and HIV-1 protease.

Computer Simulation↗
PubMed1995

PRO_LIGAND: an approach to de novo molecular design. 6. Flexible fitting in the design of peptides.

This paper describes the further development of the functionality of our in-house de novo design program, PRO_LIGAND. In particular, attention is focused on the implementation and validation of the 'direct tweak' method for the construction of conformationally flexible molecules, such as peptides, from molecular fragments. This flexible fitting method is compared to the original method based on libraries of prestored conformations for each fragment. It is shown that the directed tweak method produces results of comparable quality, with significant time savings. By removing the need to generate a set of representative conformers for any new library fragment, the flexible fitting method increases the speed and simplicity with which new fragments can be included in a fragment library and also reduces the disk space required for library storage. A further improvement to the molecular construction process within PRO_LIGAND is the inclusion of a constrained minimisation procedure which relaxes fragments onto the design model and can be used to reject highly strained structures during the structure generation phase. This relaxation is shown to be very useful in simple test cases, but restricts diversity for more realistic examples. The advantages and disadvantages of these additions to the PRO_LIGAND methodology are illustrated by three examples: similar design to an alpha helix region of dihydrofolate reductase, complementary design to the active site of HIV-1 protease and similar design to an epitope region of lysozyme.

Amino Acids↗
PubMed1995

PRO-LIGAND: an approach to de novo molecular design. 3. A genetic algorithm for structure refinement.

Recently, the development of computer programs which permit the de novo design of molecular structures satisfying a set of steric and chemical constraints has become a burgeoning area of research and many operational systems have been reported in the literature. Experience with PRO-LIGAND-the de novo design methodology embodied in our in-house molecular design and simulation system PRO-METHEUS-has suggested that the addition of a genetic algorithm (GA) structure refinement procedure can 'add value' to an already useful tool. Starting with the set of designed molecules as an initial population, the GA can combine features from both high- and low-scoring structures and, over a number of generations, produce individuals of better score than any of the starting structures. This paper describes how we have implemented such a procedure and demonstrates its efficacy in improving two sets of molecules generated by different de novo design projects.

Algorithms↗
PubMed1995

PRO_LIGAND: an approach to de novo molecular design. 4. Application to the design of peptides.

In some instances, peptides can play an important role in the discovery of lead compounds. This paper describes the peptide design facility of the de novo drug design package, PRO_LIGAND. The package provides a unified framework for the design of peptides that are similar or complementary to a specified target. The approach uses single amino acid residues, selected from preconstructed libraries of different residues and conformations, and places them on top of predefined target interaction sites. This approach is a well-tested methodology for the design of organics but has not been used for peptides before. Peptides represent a difficulty because of their great conformational flexibility and a study of the advantages and disadvantages of this simple approach is an important step in the development of design tools. After a description of our general approach, a more detailed discussion of its adaptation to peptides is given. The method is then applied to the design of peptide-based inhibitors to HIV-1 protease and the design of structural mimics of the surface region of lysozyme. The results are encouraging and point the way towards further development of interaction site-based approaches for peptide design.

Amino Acid Sequence↗
PubMed1995

Comparison of probabilistic and deterministic record linkage in the development of a statewide trauma registry.

We have been working to develop a statewide injury surveillance system using not only hospital-based trauma registries but also other sources of data (including ambulance run reports, hospital discharge abstracts, and death certificates). For this purpose, a commercially available probabilistic matching program was compared to the deterministic program described previously. Using the same data preprocessing and linkage strategy, we programmed the probabilistic software to perform the matching step and compared the results with those obtained from the previously tested program. The outcomes using our data were similar, but we expect the probabilistic program to be more adaptable for general use, especially if large amounts of data must be linked.

Databases, Factual↗
PubMed1994

PRO_LIGAND: an approach to de novo molecular design. 2. Design of novel molecules from molecular field analysis (MFA) models and pharmacophores.

A computational approach for molecular design, PRO_LIGAND, has been developed within the PROMETHEUS molecular design and simulation system in order to provide a unified framework for the de novo generation of diverse molecules which are either similar or complementary to a specified target. In this instance, the target is a pharmacophore derived from a series of active structures either by a novel interpretation of molecular field analysis data or by a pharmacophore-mapping procedure based on clique detection. After a brief introduction to PRO_LIGAND, a detailed description is given of the two pharmacophore generation procedures and their abilities are demonstrated by the elucidation of pharmacophores for steroid binding and ACE inhibition, respectively. As a further indication of its efficacy in aiding the rational drug design process, PRO_LIGAND is then employed to build novel organic molecules to satisfy the physicochemical constraints implied by the pharmacophores.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1994

Temporal changes to uterine collagen types I, III and V in relation to early pregnancy in the rat.

Uterine tissues of pregnant rats were extracted to define any changes to the proportions of collagens types I, III and V. The total concentration of extracted collagen was determined in tissue samples from implant and adjacent non-implant (NI) sites. Extracts were also subjected to polyacrylamide gel electrophoresis (PAGE), immunoblotting and gel densitometry to define the collagen types and to determine their relative proportions. By relating the proportions to the collagen concentrations in the extracts, type I was found to be the predominant collagen in both tissue regions although the concentration in the implant sites was lower than that in the NI sites. The concentration of Type I collagen decreased significantly over the period of observation in both implant and NI sites. Although the concentrations of collagen type III and type V also decreased in the implant sites, they did not alter in the NI sites. The results demonstrate that shortly after the initiation of implantation the uterus responds to the presence of the implanting embryo by decreasing the concentration of all three types of collagen. This indicates that their metabolism may, in part, be regulated by similar mechanisms. Furthermore, it was evident that a decrease in the concentration of collagen type I was initiated in uterine areas that, at the time of sampling, were not directly involved with implantation. During the study, it was found that the alpha 1 chain of collagen type V separated into two distinct bands when run on gels containing 3.8 M urea.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Is computed tomographic grading of splenic injury useful in the nonsurgical management of blunt trauma?

Seventy adult and pediatric patients with blunt splenic injury were managed nonsurgically using previously published clinical criteria without regard to the appearance of the spleen on computed tomographic (CT) scans. Seven patients (10%) who underwent delayed surgery were considered failures of nonsurgical therapy; all recovered after total splenectomy. Two radiologists, blinded to patient outcome, retrospectively reviewed the admission CT scans of all 70 patients and graded them according to three published scoring systems. Higher grades of splenic injury on CT were not associated with an increased risk of failure (Fisher's exact test, p > 0.05). Nine of ten patients with very high scores on each of the scales were successfully managed without surgery; conversely, three patients with very low scores required urgent surgery. An elevated Injury Severity Score significantly increased the risk of failure of nonsurgical management (Chi-square test of trend, p = 0.001). No failures occurred in patients under age 17 years. Our data support the hypothesis that properly selected patients can be safely observed regardless of the magnitude of splenic injury on CT scans. A decision to undergo early exploration should be based on clinical criteria, including the patient's age and associated injuries.

Abdominal Injuries↗
PubMed1994

Blunt traumatic thoracic aortic lacerations in the elderly: an analysis of outcome.

We found no previous work examining outcome after blunt traumatic aortic laceration (TAL) that has focused on elderly patients (age > 55 years) with this lesion. A 20-year retrospective review from two trauma centers of survival outcome for patients with TAL was performed to assess the effects of surgical therapy in the elderly cohort. Seventy-five cases were identified. Patients were assigned to one of two groups (Young < 55 or Old > or = 55) and data were analyzed for differences between them. There was a significantly higher mortality rate in the elderly patients (82.4% Old vs. 12.1% Young; p < 0.001). Moreover, surgical treatment in the Old group had up to a 163-fold increased likelihood of mortality compared with surgical treatment in the Young group (p < 0.001). We conclude that Old patients have higher mortality associated with surgical repair of TAL. Because of the increased risk of surgical intervention for TAL, elderly patients may be candidates for nonsurgical management as has been advocated for patients with asymptomatic peripheral traumatic pseudoaneurysms.

Adolescent↗
PubMed1994

Optimal location for a helicopter in a rural trauma system: prediction using discrete-event computer simulation.

A discrete-event computer simulation was developed using the C programming language to determine the optimal base location for a trauma system helicopter in Maine, a rural area with unevenly distributed population. Ambulance run reports from a one-year period provided input data on the times and places where major injuries occurred. Data from a statewide trauma registry were used to estimate the percentage of cases which would require trauma center care and the locations of functional trauma centers. Climatic data for this region were used to estimate the likelihood that a helicopter could not fly due to bad weather. The incidence of trauma events was modeled as a nonstationary Poisson process, and location of the events by an empirical distribution. For each simulated event, if the injuries were sufficiently severe, if weather permitted flying, if the occurrence were not within 20 miles of a center or outside the range of the helicopter, and if the helicopter were not already in service, then it was used for transportation. 35 simulated years were run for each of 4 proposed locations for the helicopter base. One of the geographically intermediate locations was shown to produce the most frequent utilization of the helicopter. Discrete-event simulation is a potentially useful tool in planning for emergency medical services systems. Further refinements and validation of predictions may lead to wider utilization.

Air Ambulances↗
PubMed1994

Management of major hepatic trauma involving interhospital transfer.

A recent 10-year experience with major liver trauma at the Maine Medical Center was reviewed in order to examine treatment options involving interhospital transfer in the management of major liver trauma in rural areas. Liver injuries of at least Grade III by the systems of Moore or Mirvis were included, except for patients admitted without vital signs. We found 98 cases of major hepatic trauma, of which 54 had been referred by 21 smaller hospitals. Of 15 patients received after laparotomy elsewhere, nine underwent reoperation for control of bleeding or removal of packs, and three died of associated injury or multiple organ failure (MOF). Of the other 39 transferred patients, 23 diagnosed by computed tomography (CT) were selected for nonoperative management with success, 11 survived after operation, one died of hemorrhage, and four died of associated injuries or MOF. For the entire group of 98 cases, adjuncts perceived as useful included perihepatic gauze packing (11 cases) and angiographic embolization (6 cases). Mortality increased with increasing magnitude of injury. Even with major hepatic trauma on CT, stable patients are unlikely to require surgery. Active hemorrhage in unstable patients may be controlled temporarily by expeditious operative techniques including gauze packing. These findings usually allow cooperation between rural hospital and referral center in the management of these potentially serious cases.

Adolescent↗
PubMed1993

Immunolocalization of collagen type I and laminin in the uterus on days 5 to 8 of embryo implantation in the rat.

This study investigated the immunohistochemical distribution of collagen type I and laminin during remodeling of the uterine extracellular matrix in response to embryo implantation in the rat. Collagen type I was found to be virtually absent around the embryo on the evening of day 5 of pregnancy. On days 6 to 8 of pregnancy the areas of primary and secondary decidualized tissue contained very little collagen in contrast to the outer nondecidualized stroma and myometrial tissues in which the staining patterns did not appear to alter. Day 8 of pregnancy was also notable for the appearance of collagen type I at the site of the developing placenta. Localization of laminin corresponded to areas of basement membrane and was associated with the redistribution of blood vasculature during implantation. By day 7 laminin staining was diminished in the basal areas of the lumenal epithelium around the implanting embryo. Laminin was also located in a punctate fashion at the margins of the primary decidual cells on day 6 of pregnancy, but by days 7 and 8 this staining pattern was no longer evident. This study has provided further evidence for a decline in a major fibrillar collagen during natural decidualization and also revealed a localized and transient expression of laminin in association with the differentiation of cells during primary decidual formation.

Animals↗
PubMed1993

Pharmacophoric pattern matching in files of three-dimensional chemical structures: implementation of flexible searching.

The conformational space of a flexible three-dimensional (3D) molecule can be represented for searching purposes by a smoothed bounded distance matrix. Such matrices provide an effective way of carrying out flexible searching, but search times can be very long when compared with rigid searches that take no account of conformational flexibility. This paper considers two techniques for minimizing the computational requirements of flexible searching. In the first part, we compare four different indices that have been suggested for the quantification of molecular flexibility, and demonstrate that they produce comparable rankings of sets of molecules in order of decreasing flexibility. We then demonstrate that the prioritization of a set of structures in order of increasing flexibility can result in substantial reductions in the time requirements of flexible searching if some fixed number of hit structures is desired. In the second part, we report an analysis of the 3D crystal structures in the Cambridge Structural Database to generate distance ranges that are tighter than those produced by distance geometry. Experiments with a set of six query pharmacophores demonstrate that use of these tightened ranges results in substantial reductions in search times, but that this may also lead to a reduction in the number of hit molecules obtained from the final conformational search.

Databases, Factual↗
PubMed1993

Development of a statewide trauma registry using multiple linked sources of data.

In order to develop a cost-effective method of injury surveillance and trauma system evaluation in a rural state, computer programs were written linking records from two major hospital trauma registries, a statewide trauma tracking study, hospital discharge abstracts, death certificates, and ambulance run reports. A general-purpose database management system, programming language, and operating system were used. Data from 1991 appeared to be successfully linked using only indirect identifying information. Familiarity with local geography and the idiosyncracies of each data source were helpful in programming for effective matching of records. For each individual case identified in this way, data from all available sources were then merged and imported into a standard database format. This inexpensive, population-based approach, maintaining flexibility for end-users with some database training, may be adaptable for other regions. There is a need for further improvement and simplification of the record-linkage process for this and similar purposes.

Computer Communication Networks↗
PubMed1993

The neurovascular outcome of scapulothoracic dissociation.

PURPOSE: The purpose of this study was to define the role of acute revascularization in the management of scapulothoracic dissociation (SD), a rare injury of the upper extremity in which severe traction to the shoulder girdle results in combined arterial, brachial plexus, and musculoskeletal injury. METHODS: The results of a retrospective study of 11 patients with SD who were compared with 41 patients from the literature are presented. RESULTS: All 11 patients were involved in high-speed accidents. All patients had chest wall hematoma, absent radial pulse, and complete brachial plexus palsy. All patients had subclavian or axillary occlusion shown by angiography; one patient with simultaneous brachial artery injury had limb-threatening ischemia. No patient had active bleeding from the injured artery. Six limbs were revascularized, five were not. All five non-revascularized limbs remained viable. No patient had delayed hemorrhage. No patient had significant neurologic recovery; all limbs remained insensate and functionless. Two viable arms underwent late amputation because of neurologic dysfunction. CONCLUSION: The infrequent occurrence of delayed hemorrhage and limb-threatening ischemia and the dismal functional outcome of the brachial plexus injury suggest a conservative policy toward revascularization for the arterial injury in SD.

Arm↗
PubMed1992

Radiographic demonstration of oronasal fistulas in patients with cleft palate with the use of barium sulfate contrast.

The purpose of this investigation was to determine the overlapping and unique contributions that radiographic techniques might provide for accurate characterization of hard palate fistulas associated with cleft palate. Five subjects with oronasal fistulas were selected for radiographic imaging, and their informed consent was obtained. Results indicated that radiographs with contrast can provide important supplemental and unique information. Qualitative descriptions of the inferior-superior course and location, and the size of the narrowest aperture could be obtained from the combination of maxillary occlusal, posteroanterior tomographic, and lateral tomographic projections. This information could not be obtained from the common clinical methods in use to describe fistulas. This technique can provide valuable information to all members of a multidisciplinary cleft palate team to document palatal fistulas for both clinical and research purposes.

Barium Sulfate↗
PubMed1992

Pharmacophoric pattern matching in files of three-dimensional chemical structures: use of bounded distance matrices for the representation and searching of conformationally flexible molecules.

This paper discusses the use of bounded distance matrices for the representation of conformationally flexible three-dimensional (3D) molecules. It is shown that pharmacophoric pattern searches of databases of flexible 3D molecules represented in this way can be carried out using screen and geometric searching algorithms that are analogous to those used for searching databases of rigid 3D structures. Molecules matching a query pattern after the geometric search must then undergo a final conformational search to determine whether they can, in fact, adopt a conformation that matches the query. An analysis of this three-stage searching procedure shows that searching databases of flexible 3D molecules is extremely demanding of computational resources.

Algorithms↗