SEARCH · Search PubMed
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
Using a combination of computational and combinatorial chemistry methodologies, a phenothiazine compound was discovered that is a selective inhibitor of cyclooxygenase-2 and serves as a lead compound for a potentially novel series of anti-inflammatory compounds.
Medicinal chemistry principles are being increasingly applied to the design of smaller, high purity, information-rich libraries. Recent computational advances in statistical methodology, the design of libraries to reduce ADMET problems, targeting protein families and revisiting natural products as sources of inspiration for scaffolds and reagents are all areas of progressive research.
In recent years, molecular dynamics simulations of biomolecular free energy differences have benefited from significant methodological advances and increased computer power. Applications to molecular recognition provide an understanding of the interactions involved that goes beyond, and is an important complement to, experimental studies. Poisson-Boltzmann electrostatic models provide a faster and simpler free energy method in cases where electrostatic interactions are important. We illustrate both molecular dynamics and Poisson-Boltzmann methods with a detailed study of amino acid recognition by aspartyl-tRNA synthetase, whose specificity is important for maintaining the integrity of the genetic code.
The conformational dynamics of enzymes is a computational resource that fuses milieu signals in a nonlinear fashion. Response surface methodology can be used to elicit computational functionality from enzyme dynamics. We constructed a tabletop prototype to implement enzymatic signal processing in a device context and employed it in conjunction with malate dehydrogenase to perform the linearly inseparable exclusive-or operation. This shows that proteins can execute signal processing operations that are more complex than those performed by individual threshold elements. We view the experiments reported, though restricted to the two-variable case, as a stepping stone to computational networks that utilize the precise reproducibility of proteins, and the concomitant reproducibility of their nonlinear dynamics, to implement complex pattern transformations.
The continuous symmetry measures approach, designed to assess quantitatively the degree of any symmetry within any structure, is extended to the important class of the polyhedra. For this purpose, we developed a general methodology and a general computational tool, which identify the minimal distance of a given structure to a desired general shape with the same number of vertexes. Specifically, we employ this tool to evaluate quantitatively the degree of polyhedricity within distorted polyhedra, taking as examples the most central and abundant polyhedral structures in chemistry in general and in coordination chemistry in particular, namely the tetrahedron, the bipyramid, the octahedron, the cube, the icosahedron, and the dodecahedron. After describing the properties of the symmetry measurement tool, we show its application and versatility in a number of cases where the deviation from exact symmetry has been an issue, including z-axis Jahn-Teller type polyhedral distortions, tantalum hydride complexes, pentacoordinated zinc complexes, tetrahedral/octahedral Sn complexes, and icosahedrally distorted C(60)-fullerene anions.
We have developed a novel and simple mathematical model of a slow excitatory postsynaptic potential (EPSP) based on an abstraction of the processes of activation, inactivation, and summation of a cAMP, protein kinase A (PKA)-dependent second-messenger cascade. The model describes the activation of receptors, G-proteins, and production of cAMP as the first stage and uses first-order, non-rate-limited kinetics. The second stage corresponds to the release of active, PKA catalytic subunit and can use first- or higher-order kinetics. The third stage represents simple phosphorylation of ion channels and is limited by the number of channels available. The decay of each stage is based on first-order, mass-action kinetics. These equations and some variations were solved numerically and values of the parameters were determined by fitting to a variety of experimental data from myenteric neurons of the guinea-pig ileum. The model produced a slow EPSP with a nonlinear stimulus-response relationship that resulted from the underlying kinetics of the signaling cascade. This system of equations is suitable for incorporation into a large-scale computer simulation, and the methodology should be generalizable to other pathways.
BACKGROUND: This study investigated social and psychological determinants of preventive behaviour in HIV-relevant situations. METHODS: Using computer-assisted telephone survey methodology, 2275 male and female were interviewed about their sexual habits. RESULTS: For the first time in Switzerland, data concerning HIV-relevant protection as well as their determinants were systematically collected also from persons older than 45. This age group (n=834) showed an increased risk with regard to HIV-relevant sexual contacts. CONCLUSIONS: The present findings call for more adequate monitoring of sexual behaviour of people older than 40 and suggest the development and implementation of respective age-specific prevention measures.
Molecular models of six anthracycline antibiotics and their complexes with 32 distinct DNA octamer sequences were created and analyzed using HINT (Hydropathic INTeractions) to describe binding. The averaged binding scores were then used to calculate the free energies of binding for comparison with experimentally determined values. In parsing our results based on specific functional groups of doxorubicin, our calculations predict a free energy contribution of -3.6 +/- 1.1 kcal x mol(-1) (experimental -2.5 +/- 0.5 kcal x mol(-1)) from the groove binding daunosamine sugar. The net energetic contribution of removing the hydroxyl at position C9 is -0.7 +/- 0.7 kcal x mol(-1) (-1.1 +/- 0.5 kcal x mol(-1)). The energetic contribution of the 3' amino group in the daunosamine sugar (when replaced with a hydroxyl group) is -3.7 +/- 1.1 kcal x mol(-1) (-0.7 +/- 0.5 kcal x mol(-1)). We propose that this large discrepancy may be due to uncertainty in the exact protonation state of the amine. The energetic contribution of the hydroxyl group at C14 is +0.4 +/- 0.6 kcal x mol(-1) (-0.9 +/- 0.5 kcal x mol(-1)), largely due to unfavorable hydrophobic interactions between the hydroxyl oxygen and the methylene groups of the phosphate backbone of the DNA. Also, there appears to be considerable conformational uncertainty in this region. This computational procedure calibrates our methodology for future analyses where experimental data are unavailable.
People make decisions all the time using intuition. But what happens when you are asked: "Are you sure your predictions are accurate? How much will a mistake cost? What are the risks associated with this change?" Once a new process is engineered, it is difficult to analyze what would have been different if other options had been chosen. Simulating a process can help senior clinical officers solve complex patient flow problems and avoid wasted efforts. Simulation software can give you the data you need to make decisions. The author introduces concepts, methodologies, and applications of computer aided simulation to illustrate their use in making decisions to improve workflow design.
Tacit knowledge of health-care experts is an important source of experiential know-how, yet due to various operational and technical reasons, such health-care knowledge is not entirely harnessed and put into professional practice. Emerging knowledge-management (KM) solutions suggest strategies to acquire the seemingly intractable and nonarticulated tacit knowledge of health-care experts. This paper presents a KM methodology, together with its computational implementation, to 1) acquire the tacit knowledge possessed by health-care experts; 2) represent the acquired tacit health-care knowledge in a computational formalism--i.e., clinical scenarios--that allows the reuse of stored knowledge to acquire tacit knowledge; and 3) crystallize the acquired tacit knowledge so that it is validated for health-care decision-support and medical education systems.
To investigate the prevalence of food insufficiency and factors associated with it, two questions assessing household and individual food insufficiency were included in 13 regional health surveys conducted in Queensland in 1993. The surveys used computer-assisted telephone interviewing methodology. Of the 10,451 people interviewed, 9.7 per cent and 6.4 per cent reported household and individual food insufficiency, respectively, and 11.3 per cent reported at least one type. Prevalence was significantly higher in women than men and in urban than rural residents, and decreased monotonically with increasing age from 16.6 per cent in 18- to 30-year-olds to 1.7 per cent in over-70-year-olds. Higher prevalence also was associated with lower income, unemployment, single or separated, divorced or widowed status versus married (or de facto), one-adult households, and shared accommodation. Lower prevalence was associated with more education in those aged 50 and under but not in those over 50 years. Using logistic regression to control simultaneously for important sociodemographic factors, we found that risk of food insufficiency was most highly associated with age and income (threefold risk), unemployment and shared accommodation (twofold risk) and one-adult households, and being single versus separated, widowed or divorced (one-and-a-half-fold risk). Some differences in risks existed between men and women and between rural and urban residents, although none excluded the role of chance. Association of the items with lower reported fruit, vegetable and meat intake, poorer health status, and greater underweight supports their validity.
Balloon angioplasty of the coarctation of the aorta can result in intimal or medial or even adventitial dissections as demonstrated by in vitro studies and animal experiments. As a typical sign of stretching of the aortic wall, patients complain of pain during the angioplasty procedure. In the literature, aortic wall rupture and ventricular fibrillation during the procedure are reported. Additional sudden deaths can occur within 40 hours after the procedure. Mortality ranges from 0.1% to 2.5%. By transesophageal echocardiography, monitoring of balloon angioplasty, control of the positioning of the balloon, and control of the results and detection of complications are possible. Intimal as well as medial dissections can be detected with observed healing for intimal but also medial dissections. In order to avoid the patient's discomfort, intraaortic ultrasound will be used in the future, when major methodological improvements are done. Computed tomography demonstrates medial dissections but is not able to visualize intimal dissections. Using computed tomography and magnetic resonance after angioplasty of the coarctation of the aorta, irregularities are described in up to 17% of the patients. For angiography, a low detection rate of medial dissections has to be expected, when not biplane angiographies of the whole thoracic aorta are performed. Medial dissections can be seen, but intimal dissections are missed. In conclusion, a review of the literature demonstrates a high incidence of intimal and medial dissections after angioplasty of the coarctation of the aorta with spontaneous healing in most patients. As is the way with coronary angioplasty, aortic wall ruptures are rare, but stand-by surgery is necessary.
BACKGROUND: The use of clinical decision support systems to facilitate the practice of evidence-based medicine promises to substantially improve health care quality. OBJECTIVE: To describe, on the basis of the proceedings of the Evidence and Decision Support track at the 2000 AMIA Spring Symposium, the research and policy challenges for capturing research and practice-based evidence in machine-interpretable repositories, and to present recommendations for accelerating the development and adoption of clinical decision support systems for evidence-based medicine. RESULTS: The recommendations fall into five broad areas--capture literature-based and practice-based evidence in machine--interpretable knowledge bases; develop maintainable technical and methodological foundations for computer-based decision support; evaluate the clinical effects and costs of clinical decision support systems and the ways clinical decision support systems affect and are affected by professional and organizational practices; identify and disseminate best practices for work flow-sensitive implementations of clinical decision support systems; and establish public policies that provide incentives for implementing clinical decision support systems to improve health care quality. CONCLUSIONS: Although the promise of clinical decision support system-facilitated evidence-based medicine is strong, substantial work remains to be done to realize the potential benefits.
PURPOSE: We have identified a subset of patients exhibiting extended survival with metastases from androgenindependent prostate cancer of which the principal site of progression was the tumor primary. The purpose of this study was to evaluate the expression of selected biomarkers to characterize this subset of prostate cancer patients. EXPERIMENTAL DESIGN: A 105 core tissue microarray was constructed from primary tumor samples from 16 patients, with matched lymph node metastases in 5 cases. Immunohistochemistry was used to evaluate selected biomarkers associated with prostate cancer progression. Standard statistical methodologies were used to compute the distribution of time to progression and overall survival associations between pairs of biomarkers. Hierarchical clustering was done between groups of biomarkers, and we devised new methods to assess homogeneity of biomarker expression. RESULTS: The median interval from diagnosis to salvage surgery was 65 months. The profile of biomarker expression was notable for virtual absence of neuroendocrine features, high CD10, low matrix metalloproteinase (MMP)-9, high E-cadherin expression, and high membranous beta-catenin. The mean proliferative index was 12.1 +/- 10.1%, and the mean apoptotic index was 3.48 +/- 2.22%, and there was a significant correlation between these indices. Expression of the epidermal growth factor receptor was associated with phospho-AKT and proliferative index but inversely associated with phospho-STAT3. CONCLUSIONS: The cohort of prostate cancer patients, characterized by locally aggressive disease rather than lethal metastatic progression, was associated with a distinctive biomarker signature. The biomarker profile was, in general, more consistent with low-grade prostate cancer exhibiting local growth rather than metastatic progression. Ongoing studies will establish whether this unique subset of patients can be identified prospectively.
OBJECTIVE: The hemodynamic environment is a determinant of susceptibility to atherosclerosis in the vasculature. Although mouse models are commonly used in atherosclerosis studies, little is known about local variations in wall shear stress (WSS) in the mouse and whether the levels of WSS are comparable to those in humans. The objective of this study was to determine WSS values in the mouse aorta and to relate these to expression of gene products associated with atherosclerosis. METHODS AND RESULTS: Using micro-CT and ultrasound methodologies we developed a computational fluid dynamics model of the mouse aorta and found values of WSS to be much larger than those for humans. We also used a quantum dot-based approach to study vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 expression on the aortic intima and demonstrated that increased expression for these molecules occurs where WSS was relatively low for the mouse. CONCLUSIONS: Despite large differences in WSS in the two species, the spatial distributions of atherogenic molecules in the mouse aorta are similar to atherosclerotic plaque localization found in human aortas. These results suggest that relative differences in WSS or in the direction of WSS, as opposed to the absolute magnitude, may be relevant determinants of flow-mediated inflammatory responses.
This article provides the first comprehensive review of value of information (VOI) analyses related to health risk management published in English in peer-reviewed journals by the end of 2001. VOI analysis represents a decision analytic technique that explicitly evaluates the benefit of collecting additional information to reduce or eliminate uncertainty. Through a content analysis of VOI applications, this article characterizes various attributes of VOI applications, shows the evolution of the methodology and advances in computing tools that allow analysis of increasingly complex problems, and suggests the need for some standardization of reporting methods and results. The authors' analysis shows a lack of cross-fertilization across topic areas and the tendency of articles to focus on demonstrating the usefulness of the VOI approach rather than applications to actual management decisions. This article provides important insights for VOI applications in medical decision making.
BACKGROUND: Malignant transformation requires the accumulation of multiple genetic alterations such as chromosomal abnormalities, oncogene activation, loss of tumor suppressor genes, or abnormalities in genes that control DNA repair and genomic instability. Sarcomas are a heterogeneous group of malignant mesenchymal tumors of difficult histologic classification and strong genetic predisposition. This article provides a comprehensive review of the cytogenetic abnormalities observed in bone and soft-tissue tumors, emphasizing known downstream molecular changes that may play a role in oncogenesis. METHODS: The database of the National Library of Medicine was searched for literature relating to genetic and molecular mechanisms in sarcomas in general and in each of the main tumor entities. RESULTS: Recent techniques in chromosome analysis and molecular cytogenetics have improved our ability to characterize genetic changes in mesenchymal tumors. Some changes are so characteristic as to be virtually pathognomonic of particular histologic types, while others are complex, difficult to characterize, and of unknown relevance to pathogenesis. The implications to the cell of some of these abnormalities are now being recognized. CONCLUSIONS: The study of sarcomas will benefit from the information derived from genetic studies and translational research. The human genome project and new methodologies, such as computer-based DNA microarray, may help in the histogenetic classification of sarcomas and in the identification of molecular targets for therapy.
In this article we contrast static and dynamic theories of the effects of increasing the costs and benefits of cooperation in a repeated play prisoners' dilemma (PD). Using computer simulation as the methodology, we show that different decision heuristics respond differently to changes in the cost-benefit structure of a PD game, an effect not expected by static theories of cooperation. In addition, one of the heuristics, "win-stay, lose-change,"" displays the pattern of cooperation predicted by static theories, but the underlying mechanisms are qualitatively different from those assumed in the static theory. This demonstration raises questions about the external validity of the different types of social psychological theory.