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Issuing the challenge: creating leadership for health information management.

Fundamental and profound changes are occurring within the health care industry that directly affect and change the roles and functions of health information managers. To meet and survive these changes, the health information management profession must exercise leadership and transform itself. A model of leadership consisting of systems thinking, personal mastery, mental models, shared vision, and team learning to accomplish this transformation is described.

Hospital Administrators↗

4-Anilino-7,8-dialkoxybenzo[g]quinoline-3-carbonitriles as potent Src kinase inhibitors.

It has been previously reported that appropriately substituted 4-anilinoquinoline-3-carbonitriles are potent inhibitors of Src kinase, with biological activity in vitro and in vivo. Structural modifications to these compounds have been explored, providing the 4-anilinobenzo[g]quinoline-3-carbonitriles as a series with enhanced Src inhibitory properties. The synthesis and structure-activity relationships of these 4-anilino-7,8-dialkoxybenzo[g]quinoline-3-carbonitriles are presented here. Analogues with cyclic basic amine groups attached via ethoxy linkages at the C-8 position were the most active in vitro, with subnanomolar IC50 values against Src kinase observed for a majority of the compounds synthesized. Compound 17d was more potent in vitro than the analogously substituted 4-anilinoquinoline-3-carbonitrile SKI-606, which is undergoing evaluation in clinical trials. The most potent analogue synthesized was 17a, with an IC50 of 0.15 nM against Src kinase and with an IC50 of 10 nM against Src-transformed fibroblasts. Molecular modeling studies provided a rationale for the exceptional activity observed for these compounds, with favorable van der Waals interactions playing the major role. Compound 17c was found to be highly selective for Src kinase when tested against a panel of other kinases, with modest selectivity versus the Src family kinases Lyn and Fyn. Following ip dosing at 50 mg/kg, analogues 17c and 17d were shown to have plasma levels that significantly exceeded the cellular IC50 values against Src-transformed fibroblasts. In an Src-transformed fibroblast xenograft model, both compounds exhibited a significant inhibition of tumor growth.

Aniline Compounds↗

Production of androgens by microbial transformation of progesterone in vitro: a model for androgen production in rivers.

We have previously documented the presence of progesterone and androstenedione in the water column and bottom sediments of the Fenholloway River, Taylor County, Florida. This river receives paper mill effluent and contains masculinized female mosquitofish. We hypothesized that plant sterols (e.g., ss-sitosterol) derived from the pulping of pine trees are transformed by bacteria into progesterone and subsequently into 17alpha-hydroxyprogesterone, androstenedione, and other androgens. In this study, we demonstrate that these same androgens can be produced in vitro from the bacterium Mycobacterium smegmatis. In a second part to this study, we reextracted and reanalyzed the sediment from the Fenholloway River and verified the presence of androstadienedione, a delta1 steroid with androgen activity.

Androgens↗

Stability of multivariable fractional polynomial models with selection of variables and transformations: a bootstrap investigation.

Sauerbrei and Royston have recently described an algorithm, based on fractional polynomials, for the simultaneous selection of variables and of suitable transformations for continuous predictors in a multivariable regression setting. They illustrated the approach by analyses of two breast cancer data sets. Here we extend their work by considering how to assess possible instability in such multivariable fractional polynomial models. We first apply the algorithm repeatedly in many bootstrap replicates. We then use log-linear models to investigate dependencies among the inclusion fractions for each predictor and among the simplified classes of fractional polynomial function chosen in the bootstrap samples. To further evaluate the results, we define measures of instability based on a decomposition of the variability of the bootstrap-selected functions in relation to a reference function from the original model. For each data set we are able to identify large, reasonably stable subsets of the bootstrap replications in which the functional forms of the predictors appear fairly stable. Despite the considerable flexibility of the family of fractional polynomials and the consequent risk of overfitting when several variables are considered, we conclude that the multivariable selection algorithm can find stable models.

Algorithms↗

SOIL-SOILN simulations of water drainage and nitrate nitrogen transport from soil core lysimeters.

Water resources protection from nitrate nitrogen (NO3-N) contamination is an important public concern and a major national environmental issue. The abilities of the SOIL-SOILN model to simulate water drainage and nitrate N fluxes from orchardgrass (Dactylis glomerata L.) were evaluated using data from a 3-yr field experiment. The soil is classified as a Hagerstown silt loam soil (fine, mixed, semiactive, mesic Typic Hapludalf). Nitrate losses below the 1-m depth from N-fertilized grazed orchardgrass were measured with intact soil core lysimeters. Five N-fertilizer treatments consisted of a control, urine application in the spring, urine application in the summer, urine application in the fall, and feces application in the summer. The SOIL-SOILN models were evaluated using water drainage and nitrate flux data for 1993-1994, 1994-1995, and 1995-1996. The N rate constants from a similar experiment with inorganic fertilizer and manure treatments under corn (Zea mays L.) were used to evaluate the SOILN model under orchardgrass sod. Results indicated that the SOIL model accurately simulated water drainage for all three years. The SOILN model adequately predicted nitrate losses for three urine treatments in each year and a control treatment in 1994-1995. However, it failed to produce accurate simulations for two control treatments in 1993-1994 and 1995-1996, and feces treatments in all three years. The inaccuracy in the simulation results for the control and feces treatments seems to be related to an inadequate modeling of N transformation processes. In general, the results demonstrate the potential of the SOILN model to predict NO3-N fluxes under pasture conditions using N transformation rate constants determined through the calibration process from corn fields on similar soils.

Agriculture↗

Effect of blood transfusion on gene expression of transforming growth factor beta-1 and the alpha subunit of interleukin-2 receptor in a model of colonic wound healing.

Blood transfusions have been shown in the past to compromise wound healing in experimental models of colonic anastomosis. Transforming growth factor beta (TGFbeta) has been proposed to play a major role in the process of colonic wound healing, and its expression is believed to be modulated by interleukin-2 (IL2). According to an earlier report, the postoperative administration of the histamine receptor-2 antagonist ranitidine increases the blood levels of soluble IL2 receptor in humans undergoing abdominal surgery and could thus affect molecular determinants of colonic anastomosis. In this study we examined the effect of blood transfusions, with and without ranitidine administration, on the gene expression of TGFbeta(1) and the specificity-conveying alpha subunit of the receptor for IL2, in rat perianastomotic tissue. Analysis of gene expression by semiquantitative RT-PCR revealed a tendency for downregulation of both genes, albeit in a statistically nonsignificant manner. This effect was not prevented by the postoperative administration of ranitidine. On the other hand, there appears to be a significant correlation between expression of TGFbeta(1) and that of IL2 receptor alpha subunit, irrespective of treatment.

Animals↗

An in vitro model of intra-epithelial expansion of transformed urothelial cells.

Replacement of normal urothelium by pre-cancerous epithelium may explain the high recurrence rate of human bladder cancer. An in vitro model was designed in order to study the mechanisms of expansion of transformed urothelial cells at the expense of normal urothelium. For this purpose, mouse bladder explants were allowed to expand on a transparent porous membrane. Subsequently, cell sheets of the non-tumorigenic mouse urothelial cell line NUC-5, the tumorigenic mouse urothelial cell line NUC-5 Py and the human bladder-carcinoma cell line T24 were inoculated adjacent to the primary explant. Daily measurements of the outgrowth of the bladder explant were performed, and all cultures were terminated on day 24. At this time the post-confluent primary urothelial cell outgrowths still showed proliferative activity, as demonstrated by bromodeoxyuridine incorporation. In due course the non-tumorigenic NUC-5 cells were replaced by the bladder outgrowth. T24 and NUC-5 Py cells were able to inhibit the bladder outgrowth, or even infiltrate or replace the explant. This was confirmed by immunohistochemistry with (species-specific) anti-cytokeratin antibodies and by microscopic evaluation of cross-sections of the porous membrane. This co-cultivation model appears to be suitable for the in vitro study of the mechanisms of intra-epithelial expansion of transformed urothelial cell lines.

Animals↗

Comparison of time-frequency distribution techniques for analysis of simulated Doppler ultrasound signals of the femoral artery.

The time-frequency distribution of the Doppler ultrasound blood flow signal is normally computed by using the short-time Fourier transform or autoregressive modeling. These two techniques require stationarity of the signal during a finite interval. This requirement imposes some limitations on the distribution estimate. In the present study, three new techniques for nonstationary signal analysis (the Choi-Williams distribution, a reduced interference distribution, and the Bessel distribution) were tested to determine their advantages and limitations for analysis of the Doppler blood flow signal of the femoral artery. For the purpose of comparison, a model stimulating the quadrature Doppler signal was developed, and the parameters of each technique were optimized based on the theoretical distribution. Distributions computed using these new techniques were assessed and compared with those computed using the short-time Fourier transform and autoregressive modeling. Three indexes, the correlation coefficient, the integrated squared error, and the normalized root-mean-squared error of the mean frequency waveform, were used to evaluate the performance of each technique. The results showed that the Bessel distribution performed the best, but the Choi-Williams distribution and autoregressive modeling are also techniques which can generate good time-frequency distributions of Doppler signals.

Bias↗

Models of esophageal carcinogenesis.

Attempting to formulate a model for the development of esophageal cancer, we have undertaken three interrelated projects: (1) identification and characterization of stem cells as a basis to understand lineage specification in the normal esophageal squamous epithelium and possibly transdifferentiation into an intestinal metaplastic phenotype that defines Barrett's esophagus; (2) elucidation of the role of epidermal growth factor receptor and signaling mechanisms in proliferation and transformation in squamous cell carcinoma; and (3) modeling transformation in organotypic culture, a 3-dimensional culture system, as a platform for investigating epithelial-stromal interactions. It is hoped that development of these models for carcinogenesis will permit formulation of effective chemoprevention, diagnostic, and therapeutic strategies.

Animals↗

Conservation of connectivity of model-space effective interactions under a class of similarity transformation.

Effective interaction operators usually act on a restricted model space and give the same energies (for Hamiltonian) and matrix elements (for transition operators, etc.) as those of the original operators between the corresponding true eigenstates. Various types of effective operators are possible. Those well defined effective operators have been shown to be related to each other by similarity transformation. Some of the effective operators have been shown to have connected-diagram expansions. It is shown in this paper that under a class of very general similarity transformations, the connectivity is conserved. The similarity transformation between Hermitian and non-Hermitian Rayleigh-Schrodinger perturbative effective operators is one of such transformations and hence the connectivity can be deducted from each other.

Journal Article↗

In vitro CD4+ lymphocyte transformation and infection in a rabbit model with a molecular clone of human T-cell lymphotrophic virus type 1.

We transfected human and rabbit peripheral blood mononuclear cells (PBMC) with the ACH molecular clone of human T-cell lymphotropic virus type 1 (HTLV-1) to study its in vitro and in vivo properties. PBMC transfected with ACH were shown to transfer infection to naive PBMC. ACH transformed rabbit PBMC, as indicated by interleukin-2-independent proliferation of a transfectant culture. This transformant culture was shown by flow cytometric analysis to be a CD4+ CD25+ T-lymphocyte population containing, as determined by Southern blot analysis, at least three integrated HTLV-1 proviral copies. HTLV-1 infection was produced in rabbits inoculated with ACH-transfected, irradiated PBMC. Inoculated rabbits seroconverted to positivity for antibodies against HTLV-1 and had steady or rising HTLV-1 enzyme-linked immunosorbent assay antibody titers. Western blot (immunoblot) analysis revealed sustained seroconversion of rabbits to positivity for antibodies against all major viral antigenic determinants. Infection of rabbits was further demonstrated by antigen capture assay of p24 in PBMC and lymph node cultures and PCR amplification of proviral sequences from PBMC. These data suggest that ACH, like wild-type HTLV-1, infects and transforms primary CD4+ T lymphocytes and is infectious in vivo. This clone will facilitate investigations into the role of viral genes on biological properties of HTLV-1 in vitro and in vivo.

Animals↗

Evolution of bacterial transformation: is sex with dead cells ever better than no sex at all?

Computer simulations of bacterial transformation are used to show that, under a wide range of biologically reasonable assumptions, transforming populations undergoing deleterious mutation and selection have a higher mean fitness at equilibrium than asexual populations. The source of transforming DNA, the amount of DNA taken up by each transforming cell, and the relationship between number of mutations and cell viability (the fitness function) are important factors. When the DNA source is living cells, transformation resembles meiotic sex. When the DNA source is cells killed by selection against mutations, transformation increases the average number of mutations per genome but can nevertheless increase the mean fitness of the population at equilibrium. In a model of regulated transformation, in which the most fit cells of a transforming population do not transform, transforming populations are always fitter at equilibrium than asexual populations. These results show that transformation can reduce mutation load.

Models, Biological↗

The Attending Nurse Caring Model: integrating theory, evidence and advanced caring-healing therapeutics for transforming professional practice.

This paper presents a proposed model: The Attending Nursing Caring Model (ANCM) as an exemplar for advancing and transforming nursing practice within a reflective, theoretical and evidence-based context. Watson's theory of human caring is used as a guide for integrating theory, evidence and advanced therapeutics in the area of children's pain. The ANCM is offered as a programme for renewing the profession and its professional practices of caring-healing arts and science, during an era of decline, shortages, and crises in care, safety, and hospital and health reform. The ANCM elevates contemporary nursing's caring values, relationships, therapeutics and responsibilities to a higher/deeper order of caring science and professionalism, intersecting with other professions, while sustaining the finest of its heritage and traditions of healing.

Child↗

The organotypic culture of HPV-transformed keratinocytes: an effective in vitro model for the development of new immunotherapeutic approaches for mucosal (pre)neoplastic lesions.

The purpose of this study is to develop a reliable in vitro human model to test new immunotherapeutic approaches for squamous cell carcinoma that develop on mucosal surfaces. The organotypic (raft) culture permits cells to proliferate and differentiate at an air-liquid interface on a dermal equivalent support. Normal keratinocytes stratify and fully differentiate in a manner similar to the normal squamous epithelial tissues, while human papillomavirus-immortalized and established squamous carcinoma cell lines exhibit dysplastic morphologies similar to (pre)neoplastic lesions seen in vivo. We have demonstrated the ability of these organotypic cultures to be manipulated by altering the epithelial stratification with cytokines (interferon-gamma and tumor necrosis factor-alpha) and by integrating activated lymphocytes or dendritic cells into the in vitro formed epithelial sheet. This model may provide a useful tool to investigate the factors contributing to the presence and function of immunocompetent cells within a neoplastic epithelium that develops on a mucosal surface.

Cancer Vaccines↗

In vivo evaluation of epidermal growth factor and transforming growth factor beta 1 in mouse tumor models.

The influence of modulating circulating levels of epidermal growth factor (EGF) and transforming growth factor beta 1 (TGF-beta 1) on tumor growth was examined in a variety of mouse models. Removal of the EGF-rich submandibular gland from host mice failed to alter the growth of a variety of human tumor xenografts or a C3H mouse tumor. Infusion of EGF from Alzet minipumps raised circulating EGF levels. However, only the A549 human tumor xenograft showed any significant increase in growth in the presence of EGF infusion and this response was marginal. The growth of Wehi 3BD+ and A549 tumor lines in culture was inhibited by TGF-beta 1. The growth of these lines in vivo, however, was not significantly altered by the administration of TGF-beta 1 via a variety of routes.

Animals↗

Logistic patterning of brain activity.

Brain activity is a set of electrochemical events in the neural tissue during a specified period of time. Neural networks are the functionally connected and dynamically organized population of neurons and neuroglial cells, serving as a unified interface between environmental input and behavioral output at a specified time. They are patterned dynamically in neural space, time and intensity. It is proposed that 1. the electrophysiological patterning of brain activity follows the laws of logistic growth, decay and impulse response function and 2. that this process of logistic transform (LOGIT) of electrochemical processes is itself the general code of information transfer in the brain. A mathematical model of logistic transformation and new electrophysiological data based on the topographic mapping of event-related potentials (ERP) during selective auditory attentional tasks from nine healthy adults is presented. The N100-P200 and the N200-P300 segments of ERP's were analyzed at 20 ms intervals. Logarithmic latencies and voltages were highly correlated. Significant correlation was found between the mathematically estimated and actual values. The interpeak latencies also followed the logistic growth pattern and could be predicted by the model. A general equation of logistic transformation of brain activity, including variables of cortical voltage and frequency is proposed.

Adult↗

Predicting methyl tert-butyl ether, tert-butyl formate, and tert-butyl alcohol levels in the environment using the fugacity approach.

Through its extensive use as a fuel oxygenate, methyl tert-butyl ether (MTBE) is found nearly ubiquitouslythroughout the environment. To better understand the environmental fate of MTBE, fugacity models are commonly used. However, models developed by the scientific community and by governmental bodies differ in their predictions of relative MTBE concentrations for relevant environmental compartments and of seasonal concentration variations; further, to date they have not considered the formation of transformation products. In this study, the sensitivity of predicted environmental concentrations of MTBE and its two major degradation products, tert-butyl formate (TBF) and tert-butyl alcohol (TBA), to all types of model input parameters is analyzed in a probabilistic sensitivity analysis. This analysis allowed for an assessment of the most influential parameters for predicting soil, water, and air concentrations and thereby provided insight into why previous modeling studies on MTBE differed. Further, the information from the sensitivity analysis was used to parametrize a multispecies transformation model for predicting European concentration levels of MTBE and, for the first time, TBF and TBA. Water and air concentrations of MTBE predicted with the transformation model were in good agreement with measurements of environmental samples. No studies are available on environmental TBF and TBA levels to compare with model predictions; however, the modeling results indicate that, in the water phase, TBA concentrations may reach appreciable levels. One major uncertainty identified regarding the prediction of TBA levels was the fraction of TBA formed from atmospheric MTBE and TBF.

Air Pollutants↗

Similarity transformation approach to identifiability analysis of nonlinear compartmental models.

Through use of the local state isomorphism theorem instead of the algebraic equivalence theorem of linear systems theory, the similarity transformation approach is extended to nonlinear models, resulting in finitely verifiable sufficient and necessary conditions for global and local identifiability. The approach requires testing of certain controllability and observability conditions, but in many practical examples these conditions prove very easy to verify. In principle the method also involves nonlinear state variable transformations, but in all of the examples presented in the paper the transformations turn out to be linear. The method is applied to an unidentifiable nonlinear model and a locally identifiable nonlinear model, and these are the first nonlinear models other than bilinear models where the reason for lack of global identifiability is nontrivial. The method is also applied to two models with Michaelis-Menten elimination kinetics, both of considerable importance in pharmacokinetics, and for both of which the complicated nature of the algebraic equations arising from the Taylor series approach has hitherto defeated attempts to establish identifiability results for specific input functions.

Kinetics↗