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PubMed2003

Web services-based access to local clinical trial databases: a standards initiative of the Association of American Cancer Institutes.

Electronic discovery of the clinical trials being performed at a specific research center is a challenging task, which presently requires manual review of the center's locally maintained databases or web pages of protocol listings. Near real-time automated discovery of available trials would increase the efficiency and effectiveness of clinical trial searching, and would facilitate the development of new services for information providers and consumers. Automated discovery efforts to date have been hindered by issues such as disparate database schemas, vocabularies, and insufficient standards for easy intersystem exchange of high-level data, but adequate infrastructure now exists that make possible the development of applications for near real-time automated discovery of trials. This paper describes the current state (design and implementation) of the Web Services Specification for Publication and Discovery of Clinical Trials as developed by the Technology Task Force of the Association of American Cancer Institutes. The paper then briefly discusses a prototype web service-based application that implements the specification. Directions for evolution of this specification are also discussed.

Cancer Care Facilities↗
PubMed2004

Genetic basis of the trade-off between offspring number and quality in the bank vole.

One of the main tenets of modern life-history theory is the negative relationship (trade-off) between the number and quality of offspring produced. Theory predicts a negative genetic correlation between these traits since both are closely related to fitness of individuals. However, the genetic basis of the trade-off has only been tested to a limited extent in natural populations. We examined whether size and quality of offspring are negatively related to litter size in the bank vole Clethrionomys glareolus. First, we found a significant negative phenotypic correlation between the number and size of offspring at birth in both laboratory and field populations of the bank vole. Second, a larger size at birth decreased the maturation age of female offspring in the laboratory, and increased the probability of breeding and the size of the first litter in the field. Furthermore, manipulation of offspring size at weaning indicated that structural effects of birth size in mammals have a more profound effect on the expression of life-history traits than weaning size. Finally, in addition to the phenotypic negative correlation between the number and size of offspring, we found evidence for a negative genetic correlation between these two traits, which confirms the genetic basis of the trade-off. This negative genetic covariation may have considerable effects on the rate and direction of evolution of the two related life-historical traits.

Analysis of Variance↗
PubMedDate not supplied

Long-term evolution of a case of direct pulp capping by adhesion to dentin.

This article presents the long-term follow-up of a female patient who suffered pulp exposure during removal of a large caries lesion from the mandibular right first molar. The clinical decision to perform direct pulp capping was made. The tooth was treated with 5% chlorhexidine, etched with 37% phosphoric acid, and then restored with Heliomolar composite after application of Gluma dentin adhesive. The patient was followed for more than 8 years.

Acrylic Resins↗
PubMed1990

Converting catabolic ornithine carbamoyltransferase to an anabolic enzyme.

Pseudomonas aeruginosa has an anabolic and a catabolic ornithine carbamoyltransferase (OTCase). In vitro, these homologous enzymes catalyze the same reaction (ornithine + carbamoyl phosphate (CP) in equilibrium citrulline + Pi), yet in vivo they function unidirectionally owing to specific kinetic properties. The catabolic OTC-ase cannot promote the anabolic reaction (citrulline formation) in vivo because of a sigmoidal CP saturation curve and a high CP concentration for half-maximal velocity. The structural basis for this kinetic specialization was examined. The catabolic OTCase lost most of its homotropic cooperativity and gained anabolic activity when an amino acid residue near the CP binding site, Glu-106, was replaced by alanine or glycine. In the anabolic OTCase of Escherichia coli the glutamine residue corresponding to Glu-106 was exchanged for glutamate; however, in this case no CP cooperativity was acquired. Thus, in catabolic OTCase, sequence features in addition to Glu-106 are important for sigmoidal CP saturation, and such a sequence was identified in the C-terminal part. By an in vivo gene fusion technique the 9 C-terminal amino acids of catabolic OTCase were replaced by the homologous 8 amino acids from anabolic OTCase of E. coli; the hybrid enzyme had a markedly reduced homotropic cooperativity. This gene fusion method should be generally useful for directed enzyme evolution.

Amino Acid Sequence↗
PubMedDate not supplied

[The direction and motivation for an evolution in methods of antiulcer surgery].

A 23-year retroactive analysis of a heterogeneous series of observations with unfavourable tardy results after antiulcer surgeries showed that the most failures requiring a second surgery appear after large resections with gastrojejunal or gastroduodenal anastomosis and after vagotomies associated with gastric drainage. The most favourable tardy results followed the vagotomy associated with limited gastric resection (hemigastrectomy). This kind of intervention prevents the appearance of the ulcerous relapses and lowers significantly the incidence of the other type of post-surgical iatrogenic complications. The optimal protection against the ulcerous relapse given by vagotomy associated with hemigastrectomy permits a tactical adaptation of the intervention to the lesional and physiopathological characteristics of each case.

Anastomosis, Surgical↗
PubMed1984

Effects of 2,4-dinitrophenol and other metabolic inhibitors on the thermograms of Ehrlich ascites carcinoma cells registered with a microcalorimeter.

The heat produced by Ehrlich ascites carcinoma cells was measured microcalorimetrically to investigate the characteristics of the energetics of these cells. 2,4-Dinitrophenol and other inhibitors were used to obtain the standard thermograms. The heat level of starved Ehrlich ascites carcinoma cells (endogenous) was almost constant and linear and depended on the cell number used in the experiments (about 1 cal/1 X 10(8) cells/hr). The endogenous heat generation was suppressed strongly by potassium cyanide but not by iodoacetic acid or 2,4-dinitrophenol. On the other hand, heat evolution was directly related to the amount of glucose added to the medium but not to the number of cells (19 cal/mmol of glucose). The addition of iodoacetic acid markedly suppressed heat generation, but potassium cyanide did not. In contrast, glucose with dinitrophenol increased heat production markedly to about 10% higher than that of the control, possibly due to the uncoupled energy from oxidative phosphorylation. Malonic acid (1 mM) suppressed slightly the endogenous heat but caused a 15% reduction in exogenous heat. The amount of heat produced by the addition of glucose (19 cal/mmol) was equivalent to 40% of the theoretical value of energy released through glycolysis (47 cal/mmol). Thus, the heat produced by exogenous glucose appears to be mainly dependent on glycolysis.

2,4-Dinitrophenol↗
PubMed1980

Ureteric hemorrhage in hemophilia with rapid healing.

A rapidly regressing ureteric hemorrhage, probably intramural, in a 14-year-old hemophiliac, is demonstrated by two closely sequential intravenous urograms. In the presence of hematuria, the intravenous urogrom outlines both the complications of hemophilia and their evolution, often directing therapy, and identifies concurrent disease.

Adolescent↗
PubMed1997

Repeated elicitation of contact hypersensitivity induces a shift in cutaneous cytokine milieu from a T helper cell type 1 to a T helper cell type 2 profile.

We previously demonstrated that repeated application of 2,4,6-trinitro-1-chlorobenzene resulted in a site-restricted shift in the time course of Ag-specific hypersensitivity responses from a typical delayed-type to an early-type response. Here we demonstrated that the cutaneous microenvironment at the time of Ag presentation to T cells in the elicitation, but not the induction, phase of contact hypersensitivity is responsible for the shift. To investigate the differences in the cutaneous cytokine milieu between the acute and chronic phases of contact hypersensitivity, sequential cytokine dynamics after 2,4,6-trinitro-1-chlorobenzene application were assessed in the acute vs chronic lesions. In the acute lesions, increased mRNA levels for IFN-gamma and IL-2 were rapidly detected at 1 h and remained elevated at 12 h, while mRNA expression for IL-4 and IL-10 was minimally up-regulated between approximately 12 and 24 h. In chronic lesions, high levels of constitutive expression of IL-4 mRNA were observed and IL-10 mRNA was dramatically up-regulated at 1 approximately 3 h in an Ag-specific fashion, whereas the expression of Th1-type cytokines was markedly reduced. Increased mRNA levels for Th2-type cytokines in the chronic lesions was also reflected at the protein level. These results indicate that repeated elicitation with Ag alters the balance of cytokines released locally, with a shift toward Th2-dominated responses, which would represent the natural evolution processes directed toward reducing a more deleterious Th1 response.

Administration, Cutaneous↗
PubMed1998

Benign prostatic hyperplasia.

Insight into the dysfunctional physiology of benign prostatic hyperplasia has expanded appropriate therapies. As the proportion of the population to whom BPH will be a problem increases our attention is directed to evolution in clinical management.

Adrenergic alpha-Antagonists↗
PubMed1998

Senior executive behaviors for the Army Dental Care System of the 21st century.

Challenges will most likely confront the Army Dental Care System as it moves into the next century. Like any other learning organization, the Army dental care system must develop a continuous stream of dynamic leaders to direct its evolution if it wants to survive. Using the Delphi method, the investigators surveyed senior dental leaders to determine the attitudes and behaviors believed to be required to perform successfully as commanders, residency directors, and senior staff officers. The essential executive behaviors appear to be consistent: be honest, act with integrity, be accountable for your actions, be dedicated to mission accomplishment, and perform your duty with care and compassion. Relying solely on ratings assigned to the behaviors, discriminant function analyses could predict proper group membership with an accuracy of 79.4%. When demographic information was included, prediction accuracy improved to 96.7%.

Adult↗
PubMed1998

Short- and long-term projections about the use of drug metabolism in drug discovery and development.

The science of drug metabolism, like any other science, has advanced from simple beginnings (by today's standards) to its present state. One can examine the path that has been taken to understand the forces driving the direction of evolution of this science. The trends discovered can then be used to make reasonable extrapolations about the changes that might be expected in the future. That exercise is the subject of this article. The main focus will be on drug metabolism as practiced in the industrial environment, representing the author's main experience as well as the principal arena of practical applications of the science. The discussion will draw mainly on broad phenomena occurring in this application of drug metabolism to drug discovery and development.

Animals↗
PubMed2003

An enantioselective synthesis of FR182877 provides a chemical rationalization of its structure and affords multigram quantities of its direct precursor.

The evolution of a strategy culminating in an efficient, enantioselective synthesis of the potent microtubule-stabilizing agent FR182877 is described. Guided by a proposed biogenesis of this complex natural product, a solution emerged that involved the first reported example of a double transannular Diels-Alder reaction to fashion the key elements of its hexacyclic structure. This pivotal transformation creates a complex pentacycle from a 19-membered macrocyclic pentaene, forming seven new stereogenic centers in a fully diastereocontrolled fashion. The efficiency of the approach ultimately enabled the preparation of multigram quantities of the direct precursor of FR182877 for conversion to the relatively unstable natural product when required. The reactivity of the strained, bridgehead olefin of this secondary metabolite with biologically relevant nucleophiles is also described.

Cyclization↗
PubMed1993

Directional mutation pressure, mutator mutations, and dynamics of molecular evolution.

Using a general form of the directional mutation theory, this paper analyzes the effect of mutations in mutator genes on the G+C content of DNA, the frequency of substitution mutations, and evolutionary changes (cumulative mutations) under various degrees of selective constraints. Directional mutation theory predicts that when the mutational bias between A/T and G/C nucleotide pairs is equilibrated with the base composition of a neutral set of DNA nucleotides, the mutation frequency per gene will be much lower than the frequency immediately after the mutator mutation takes place. This prediction explains the wide variation of the DNA G+C content among unicellular organisms and possibly also the wide intragenomic heterogeneity of third codon positions for the genes of multicellular eukaryotes. The present analyses lead to several predictions that are not consistent with a number of the frequently held assumptions in the field of molecular evolution, including belief in a constant rate of evolution, symmetric branching of phylogenetic trees, the generality of higher mutation frequency for neutral sets of nucleotides, the notion that mutator mutations are generally deleterious because of their high mutation rates, and teleological explanations of DNA base composition.

Animals↗
PubMed2003

Application of phylogeny reconstruction and character-evolution analysis to inferring patterns of directional microbial transmission.

I used phylogenetic analyses to reconstruct patterns of directional interspecific transmission during a pseudorabies virus outbreak in Illinois, USA, in 1989. Isolates were recovered from five species: cattle, sheep, goats, pigs, and raccoons (Procyon lotor). I generated DNA sequences for 16 isolates of pseudorabies virus at the glycoprotein C gene, from which I constructed phylogenetic trees. I then used these trees, in combination with parsimony-based analyses of character evolution, to infer the frequency and direction of interspecific transmission events. Comparing inferred frequencies and directions of transmission to null expectations based on 10,000 random trees indicated a significant excess of transmission events from pigs to pigs and a corresponding lack of transmission events from non-porcine species. These results are concordant with the know biology and natural history of pseudorabies virus, and they demonstrate that retrospective phylogeny reconstruction and analyses of character evolution can be used to investigate the transmission ecology of pathogens.

Animals↗
PubMed2006

Evolution of branched regulatory genetic pathways: directional selection on pleiotropic loci accelerates developmental system drift.

Developmental systems are regulated by a web of interacting loci. One common and useful approach in studying the evolution of development is to focus on classes of interacting elements within these systems. Here, we use individual-based simulations to study the evolution of traits controlled by branched developmental pathways involving three loci, where one locus regulates two different traits. We examined the system under a variety of selective regimes. In the case where one branch was under stabilizing selection and the other under directional selection, we observed "developmental system drift": the trait under stabilizing selection showed little phenotypic change even though the loci underlying that trait showed considerable evolutionary divergence. This occurs because the pleiotropic locus responds to directional selection and compensatory mutants are then favored in the pathway under stabilizing selection. Though developmental system drift may be caused by other mechanisms, it seems likely that it is accelerated by the same underlying genetic mechanism as that producing the Dobzhansky-Muller incompatibilities that lead to speciation in both linear and branched pathways. We also discuss predictions of our model for developmental system drift and how different selective regimes affect probabilities of speciation in the branched pathway system.

Animals↗
PubMed2003

Major life-history transitions by deterministic directional natural selection.

For large-scale evolution on Earth there has been a directional change where simple self-replicators evolved into large organisms with high metabolic rates and long pre-reproductive periods. Associated with this increase there have been major life-history transitions from asomatic, non-senescing, haploid, and asexually reproducing organisms to somatic, senescing, diploid, and sexually reproducing organisms with male and female individuals. Using a game theoretical model, it is shown that this trajectory can be explained by deterministic natural selection as it arises from first principles of the self-replication process in mobile organisms. It is shown (i) that selection for an increase in the energetic state of the organism puts a direction to evolution, (ii) that selection by density-dependent competitive interactions can explain the major life-history transitions as a function of the energetic state of the organism, and (iii) that the two selection processes combined can explain an exponentially increasing body mass. It is also shown (iv) why, for the case with an increasing body mass, we may expect many life histories to evolve in accordance with the exponents of the body mass allometries, (v) that an upper constraint on the body mass and metabolic rate can induce an additional transition into eusocial communities, and (vi) that the evolutionary trajectory is likely reversible with backward evolution during periods of environmental crises.

Animals↗
PubMed2002

Direct conversion of EPR dipolar time evolution data to distance distributions.

Shallow electron spin echo envelope modulations due to dipole-dipole couplings between electron spins provide information on the radial distribution function of the spins in disordered systems while angular correlations between spin pairs are negligible. Under these conditions and in the absence of orientational selection, the dipolar time evolution data can be quantitatively simulated for arbitrary radial distribution functions by shell factorization, i.e., by performing the orientational average separately for thin spherical shells and multiplying the signals of all the shells. For distances below 5 nm, a linear superposition of the signals of the shells is sufficient. The dipolar time evolution data can be separated into this linear contribution and a nonlinear background. The linear contribution can then be converted directly to a radial distribution function. For a series of shape-persistent and flexible biradicals with end-to-end distances between 2 and 5 nm, shell factorization and direct conversion of the data are in good agreement with each other and with force-field computations of the end-to-end distances. The neglect of orientation selection does not cause significant distortions of the determined distance distributions.

Journal Article↗