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PubMed1993

Ethanol-induced changes in astrocyte gene expression during rat central nervous system development.

Disruption of spatial and temporal patterns of gene expression in cells of the developing brain could result in abnormal development. We report that briefly exposing neonatal rats to a moderate dose of ethanol on postnatal days 5 through 7 caused a large, specific increase in glial fibrillary acidic protein (GFAP) mRNA and GFAP. Astrocytes of the cerebral cortex were apparently more sensitive to this effect of ethanol than astrocytes in several other brain regions. As a first step in the characterization of an vitro model of ethanol's effect on GFAP gene expression, ethanol was added to the media of primary cultures of cortical astrocytes in a pattern of exposure and at concentrations equal to pups' peak blood levels. This resulted in an increase in GFAP mRNA whose magnitude and specificity mirrored that observed in the animal model. Together, these results suggest that even brief exposure to ethanol can alter gene expression in astrocytes, and forms the foundation for further characterization of an in vitro model that may be used to determine the mechanism of this effect.

Animals↗
PubMed2004

Population pharmacokinetics II: estimation methods.

OBJECTIVE: To present, compare, and contrast the various approaches to estimating population pharmacokinetic (PPK) models with respect to the mathematical foundation, statistical aspects, software programs for implementation, and underlying assumptions. DATA SOURCES: Information on PPK was retrieved from a MEDLINE search (1977-August 2004) of literature and a bibliographic review of review articles and books. This information is used in conjunction with experience to explain the various methodologic approaches to PPK. STUDY SELECTION AND DATA EXTRACTION: All articles indentified from data sources were evaluated and relevant information was included in this review. DATA SYNTHESIS: Over 80 articles dealing with PPK estimation methods and/or their implementation were identified and reviewed. Sixty-four of these were chosen for their direct relevance to the subject of this article. Different estimation methods ranging from the naive averaging and naive pooled approaches through the standard two-stage approach to the nonlinear mixed-effects modeling approaches for estimating PPK are reviewed with their advantages and limitations. CONCLUSIONS: PPK estimation methods that rely on the characterizing of mixed (fixed and random) effects are known to produce PPK parameter estimates that are less biased than those obtained using the naive and standard two-stage approaches. The NONMEM software is the most widely used software for the characterization of PPK.

Bayes Theorem↗
PubMed1995

A supervisory model of professional competence: a joint service/education initiative.

This article is concerned with describing how a National Health Service (NHS) Hospital Trust teamed up with a College of Nursing and Midwifery to develop a model of clinical supervision. The article discusses definitions of clinical supervision, which were used as a basis for the development of the model; identifies the roles and responsibilities of clinical supervisors and describes the foundations of an integrated system of educational and professional development. The model aims to set standards for clinical competence which facilitate continuity in professional development throughout the practitioner's career. The collaboration between the two organisations has ensured that the model reflects the inter-relationship between theory and practice, thus enhancing both academic and professional development. The result is a comprehensive model for clinical supervision which encompasses key national initiatives in both professional and educational fields; in particular the United Kingdom Central Council (UKCC) requirements for continuing registration, maintenance of a portfolio of professional development, and continuing education (PREP) and the Ten Key Characteristics of the English National Board (ENB) Higher Award. It also encourages practitioners to demonstrate good practice through the requirement to articulate and enhance professional knowledge using a portfolio, along with a system of peer review and defined clinical competencies.

Clinical Competence↗
PubMed2001

Comparing personal trajectories and drawing causal inferences from longitudinal data.

This review considers statistical analysis of data from studies that obtain repeated measures on each of many participants. Such studies aim to describe the average change in populations and to illuminate individual differences in trajectories of change. A person-specific model for the trajectory of each participant is viewed as the foundation of any analysis having these aims. A second, between-person model describes how persons very in their trajectories. This two-stage modeling framework is common to a variety of popular analytic approaches variously labeled hierarchical models, multilevel models, latent growth models, and random coefficient models. Selected published examples reveal how the approach can be flexibly adapted to represent development in domains as diverse as vocabulary growth in early childhood, academic learning, and antisocial propensity during adolescence. The review then considers the problem of drawing causal inferences from repeated measures data.

Adolescent↗
PubMed1994

Motor behavior research: implications for therapeutic approaches to central nervous system dysfunction.

This article reviews the models and theories of motor behavior that are the foundation for the traditional approaches to central nervous system (CNS) dysfunction and presents a new theoretical model and approach that are beginning to influence practice. Reflex, hierarchical, and systems models of motor control and developmental and motor learning theories are discussed. The relationships of these models and theories to past, present, and future treatment approaches to CNS dysfunction are explored. The assumptions and limitations of the muscle reeducation, neurodevelopmental, and motor relearning approaches are discussed. A contemporary task-oriented approach based on the systems model is proposed and contrasted with traditional neurodevelopmental approaches.

Central Nervous System Diseases↗
PubMedDate not supplied

Student upward mobility: utilization of an educational support model.

Hampton University School of Nursing was funded by the Teagle Foundation in 1990 for four years and later expanded for an additional year to develop, implement and evaluate an innovative Individualized Educational Support Model for licensed practical nurses (LPNs) residing in Southeastern Virginia. Project staff assigned the Teagle Initiative developed a model program for LPNs seeking the Bachelor of Science degree in nursing. The Teagle model offers opportunities for advanced placement through National League for Nursing Mobility Examinations, CLEP, ACT-PEP, and challenge examinations; tutoring by faculty and peers; counseling by project staff for academic and financial aid, and other concerns as needed; socialization with other project students and generic students; monthly stipends to assist with additional expenses incurred when the adult student returns to school and an alternative admissions criteria for the LPN who may not meet all aspects of the Hampton University admissions criteria.

Career Mobility↗
PubMed2005

From oppression towards empowerment in clinical practice--offering doctors a model for reflection1.

OBJECTIVES: This article aims to present an Oppression Model describing how and explaining why doctors sometimes take up the role of oppressor in clinical practice, and to furthermore create change by proposing alternatives. The model is intended to increase awareness of power issues in medical practitioners, thus creating an urge for empowering practices. DESIGN: The Oppression Model is constructed by theoretical reasoning, inspired by empirical findings of doctor-as-oppressor from a Norwegian research project with users of psychiatric services. The model is composed of the chosen theoretical elements, assembled as a staircase model. The model is intended to give descriptions and explanations and foster change relevant to oppressive processes in clinical practice, and is mainly relevant when meeting patients from vulnerable or stigmatized groups. An Empowerment Track is conceptualized in a similar way by theoretical reasoning. RESULTS: The Oppression Model describes a staircase built on a foundation of objectifying, proceeding by steps of stereotypes, prejudice, and discrimination up to the final step of institutionalized oppression. An Empowerment Track is proposed, built on a foundation of acknowledgement, proceeding by steps of diversity, positive regard, and solidarity towards empowerment. It represents, however, only one of several possible ways of proceeding in developing empowering practices. CONCLUSION: Keeping the Oppression Model in mind during patient encounters may help the busy clinician to counteract oppressive attitudes and actions.

Attitude of Health Personnel↗
PubMed2006

Local extinction of a foundation species in a hypoxic estuary: integrating individuals to ecosystem.

We integrated across individual, population, community, and ecosystem levels to understand the impact of environmental stress by tracking the foundation species Mytilus edulis in the hypoxic estuary Narragansett Bay, Rhode Island, USA. Our initial surveys revealed that the mussels occurred in nine extensive (2-28 ha) dense (814-9943 individuals/m2) subtidal reefs that attracted a diverse suite of predators (sea stars, crabs, gastropods). Hypoxia occurred in the summer of 2001, and a mussel transplant experiment revealed overall reduced growth rates of individuals, and higher mortality rates among larger mussels. At the population level, large decreases in densities and cover of mussels were correlated with dissolved oxygen concentrations, leading to extinction at one site and reductions of over an order of magnitude at others. Within one year, seven of the eight remaining populations were edged to extinction, and the previously extinct population was recolonized. At the community level, a predator exclusion experiment indicated that predation was an unimportant source of mussel mortality during the hypoxic period, in part due to the emigration of sea stars, as predicted by the Consumer Stress Model. However, mussels were too intolerant to hypoxia to have a net benefit from the predation refuge. The seasonal (summer) occurrence of hypoxia allowed sea stars to return following a lag, as predicted by a stress return time model, and the resumption of predation contributed to the subsequent extinction of mussel populations. At the ecosystem level, the initial filtration rate of the mussel reefs was estimated at 134.6 x 10(6) m3/d, equivalent to filtering the volume of the bay 1.3 times during the 26-d average residence time. That function was reduced by >75% following hypoxia. The effect of hypoxia on each level of organization had consequences at others. For example, size-specific mortality and decreased growth of individuals, and reduced filtration capacity of reefs, indicated a loss of the ability of mussels to entrain planktonic productivity and potential to control future eutrophication and hypoxia. Our study quantified patterns of loss and identified pathways within an integrative framework of feedbacks, summarized in a conceptual model that is applicable to similar foundation species subjected to environmental stress.

Animals↗
PubMed2001

Aquaria fish models of human disease: reports and recommendations from the working groups.

On September 21-24, 2000, the National Cancer Institute, Southwest Texas State University, and the Roy and Joan Mitte Foundation sponsored an international conference entitled "Aquaria Fish Models of Human Disease" at Southwest Texas State University (SWT), San Marcos, Texas, USA. Over 100 scientists, representing various fish model systems, participated in four roundtable working groups. We considered the first step in promoting the exciting research with fish models was to unify the efforts within this scientific community towards accomplishing specific goals. With this objective in mind, the following four working groups were convened: (1) fish cancer models: sustenance and enhancement; (2) fish genomics and transgenics: resources and technology; (3) fish pathology: standards for tumor pathology classification; and, (4) resources underpinning aquaria fish research. Each working group was charged with preparing a report of their discussions with recommendations on how researchers and funding agencies might best direct and strengthen research support to ensure a healthy future for such work. Included are the final reports from these working groups, together with a brief summary of the discussions held during the sessions and the consensus recommendations from each group.

Journal Article↗
PubMed2005

A microscale in vitro physiological model of the liver: predictive screens for drug metabolism and enzyme induction.

In vitro models of the liver using isolated primary hepatocytes have been used as screens for measuring the metabolism, toxicity and efficacy of xenobiotics, for studying hepatocyte proliferation, and as bioartificial liver support systems. Yet, primary isolated hepatocytes rapidly lose liver specific functions when maintained under standard in vitro cell culture conditions. Many modifications to conventional culture methods have been developed to foster retention of hepatocyte function. Still, not all of the important functions -- especially the biotransformation functions of the liver -- can as yet be replicated at desired levels, prompting continued development of new culture systems. In the first part of this article, we review primary hepatocyte in vitro systems used in metabolism and enzyme induction studies. We then describe a scalable microreactor system that fosters development of 3D-perfused micro-tissue units and show that primary rat cells cultured in this system are substantially closer to native liver compared to cells cultured by other in vitro methods, as assessed by a broad spectrum of gene expression, protein expression and biochemical activity metrics. These results provide a foundation for extension of this culture model to other applications in drug discovery -- as a model to study drug-drug interactions, as a model for the assessment of acute and chronic liver toxicity arising from exposure to drugs or environmental agents; and as a disease model for the study of viral hepatitis infection and cancer metastasis.

Animals↗
PubMed2006

Occupancy modeling of coverage distribution for whole genome shotgun DNA sequencing.

Expected-value models have long provided a rudimentary theoretical foundation for random DNA sequencing. Here, we are interested in improving characterization of genome coverage in terms of its underlying probability distributions. We find that the mathematical notion of occupancy serves as a good model for evolution of the coverage distribution function and reveals new insights related to sequence redundancy. Established concepts, such as "full shotgun depth," have been assumed invariant, but actually depend on project size and decrease over time. For most microbial projects, the full shotgun milestone should be revised downward by about 30%. Accordingly, many already-completed genomes appear to have been over-sequenced. Results also suggest that read lengths for emerging high-throughput sequencing methods must be increased substantially before they can be considered as possible successors to the standard Sanger method. In particular, gains in throughput and sequence depth cannot be made to compensate for diminished read length. Limits are well approximated by a simple logarithmic equation, which should be useful in estimating maximum coverage-based redundancy for future projects.

Algorithms↗
PubMed2005

The conceptual basis of function learning and extrapolation: comparison of rule-based and associative-based models.

The purpose of this article is to provide a foundation for a more formal, systematic, and integrative approach to function learning that parallels the existing progress in category learning. First, we note limitations of existing formal theories. Next, we develop several potential formal models of function learning, which include expansion of classic rule-based approaches and associative-based models. We specify for the first time psychologically based learning mechanisms for the rule models. We then present new, rigorous tests of these competing models that take into account order of difficulty for learning different function forms and extrapolation performance. Critically, detailed learning performance was also used to conduct the model evaluations. The results favor a hybrid model that combines associative learning of trained input-prediction pairs with a rule-based output response for extrapolation (EXAM).

Animals↗
PubMed1997

The rotation of maxillary first molars, mandibular first molars, and maxillary first premolars in acceptable occlusions.

The rotation of the maxillary molars is considered important in the orthodontic treatment of malocclusions. In this study, a computer analysis program was developed to examine the rotations of maxillary molars, mandibular molars, and maxillary first premolars in casts of permanent dentitions with acceptable occlusions. Ninety-three sets of untreated 'acceptable occlusion' models from the collection of the Foundation for Orthodontic Research (FOR) were scanned on a flat bed scanner. The images were analysed using custom software. Measurements were made by relating maxillary first permanent molars to the midline, archform, opposite canine, and mandibular first permanent molars. The mandibular first molars and maxillary first premolars were also analysed and their rotations measured. The mean rotations of the maxillary first molars, measured as the angle between a line joining the tips of the buccal cusps and a line tangent to the appropriate archwire form (from Ricketts' Pentamorphic Arches) at the first molars, were 0.59 and -0.72 degree (positive values represent mesio-lingual rotations) for the right and left, respectively. For the mandibular molars, these means were 6.34 and 8.40 degrees, respectively. The mean differences in rotation between buccal cusp tips of maxillary and mandibular first molars in occlusion were 5.75 and 9.12 degrees for the right and left, respectively, with the mandibular being more mesio-lingually rotated. The differences between left and right were significant for all measurements. The present study brings into question the suitability of our present "straight wire" prescriptions in producing similar occlusions. It also suggests that scanning models for computer analysis may be a practical and precise way to measure similar rotations in untreated normal and treated occlusions.

Analysis of Variance↗
PubMed1997

Local rules for protein folding on a triangular lattice and generalized hydrophobicity in the HP model.

We consider the problem of determining the three-dimensional folding of a protein given its one-dimensional amino acid sequence. We use the HP model for protein folding proposed by Dill (1985), which models protein as a chain of amino acid residues that are either hydrophobic or polar, and hydrophobic interactions are the dominant initial driving force for the protein folding. Hart and Istrail (1996a) gave approximation algorithms for folding proteins on the cubic lattice under the HP model. In this paper, we examine the choice of a lattice by considering its algorithmic and geometric implications and argue that the triangular lattice is a more reasonable choice. We present a set of folding rules for a triangular lattice and analyze the approximation ratio they achieve. In addition, we introduce a generalization of the HP model to account for residues having different levels of hydrophobicity. After describing the biological foundation for this generalization, we show that in the new model we are able to achieve similar constant factor approximation guarantees on the triangular lattice as were achieved in the standard HP model. While the structures derived from our folding rules are probably still far from biological reality, we hope that having a set of folding rules with different properties will yield more interesting folds when combined.

Algorithms↗
PubMed1997

An Internet service for manipulating 3D models of human organs reconstructed from computer tomography and magnetic resonance imaging.

Our paper describes an integrated methodology addressing the development of an Internet service for medical professionals, medical students and generally, people interested in medicine. The service (currently developed in the framework of IAEVA, a Telematics Application Programme project of the European Union), incorporates a mechanism for retrieving from a relational database (reference library) 3D volumetric models of human organs reconstructed from computer tomography (CT) and/or magnetic resonance imaging (MRI). Retrieval is implemented in a way transparent to the actual physical location of the database. Prospective users are provided with a Solid Object Viewer that offers them manipulation (rotation, zooming, dissection etc.) of 3D volumetric models. The service constitutes an excellent foundation of understanding for medical professionals/students and a mechanism for broad and rapid dissemination of information related to particular pathological conditions; although pathological conditions of the knee and skin are supported currently, our methodology allows easy service extension into other human organs ultimately covering the entire human body. The service accepts most Internet browsers and supports MS-Windows 32 platforms; no graphics accelerators or any specialised hardware are necessary, thereby allowing service availability to the widest possible audience. Nevertheless, the service operates in near real-time not only over high speed expensive network lines but also over low/medium network connections.

Computer Communication Networks↗
PubMed1999

A statewide system to track medical students' careers: the Pennsylvania model.

In 1994 the Commonwealth of Pennsylvania announced a statewide Generalist Physician Initiative (GPI) modeled after The Robert Wood Johnson Foundation's GPI. Three-year grants totaling more than $9 million were awarded to seven of Pennsylvania's medical schools, including two that had already received GPI grants from the foundation. Stimulated by these initiatives, the state's six allopathic and two osteopathic medical schools decided to work together to develop a collaborative longitudinal tracking system to follow the careers of all their students from matriculation into their professional careers. This statewide data system, which includes information for more than 18,000 students and graduates beginning with the entering class of 1982, can be used to evaluate the impact of the Pennsylvania GPI, and it also yielded a local longitudinal tracking system for each medical school. This paper outlines the concept of the system, its technical implementation, and the corresponding implications for other medical schools considering the development of similar outcomes assessment systems.

Career Choice↗
PubMed2003

Optknock: a bilevel programming framework for identifying gene knockout strategies for microbial strain optimization.

The advent of genome-scale models of metabolism has laid the foundation for the development of computational procedures for suggesting genetic manipulations that lead to overproduction. In this work, the computational OptKnock framework is introduced for suggesting gene deletion strategies leading to the overproduction of chemicals or biochemicals in E. coli. This is accomplished by ensuring that a drain towards growth resources (i.e., carbon, redox potential, and energy) must be accompanied, due to stoichiometry, by the production of a desired product. Computational results for gene deletions for succinate, lactate, and 1,3-propanediol (PDO) production are in good agreement with mutant strains published in the literature. While some of the suggested deletion strategies are straightforward and involve eliminating competing reaction pathways, many others suggest complex and nonintuitive mechanisms of compensating for the removed functionalities. Finally, the OptKnock procedure, by coupling biomass formation with chemical production, hints at a growth selection/adaptation system for indirectly evolving overproducing mutants.

Algorithms↗
PubMed2004

Use of artificial intelligence to identify cardiovascular compromise in a model of hemorrhagic shock.

OBJECTIVE: To determine whether a prototype artificial intelligence system can identify volume of hemorrhage in a porcine model of controlled hemorrhagic shock. DESIGN: Prospective in vivo animal model of hemorrhagic shock. SETTING: Research foundation animal surgical suite; computer laboratories of collaborating industry partner. SUBJECTS: Nineteen, juvenile, 25- to 35-kg, male and female swine. INTERVENTIONS: Anesthetized animals were instrumented for arterial and systemic venous pressure monitoring and blood sampling, and a splenectomy was performed. Following a 1-hr stabilization period, animals were hemorrhaged in aliquots to 10, 20, 30, 35, 40, 45, and 50% of total blood volume with a 10-min recovery between each aliquot. Data were downloaded directly from a commercial monitoring system into a proprietary PC-based software package for analysis. MEASUREMENTS AND MAIN RESULTS: Arterial and venous blood gas values, glucose, and cardiac output were collected at specified intervals. Electrocardiogram, electroencephalogram, mixed venous oxygen saturation, temperature (core and blood), mean arterial pressure, pulmonary artery pressure, central venous pressure, pulse oximetry, and end-tidal CO(2) were continuously monitored and downloaded. Seventeen of 19 animals (89%) died as a direct result of hemorrhage. Stored data streams were analyzed by the prototype artificial intelligence system. For this project, the artificial intelligence system identified and compared three electrocardiographic features (R-R interval, QRS amplitude, and R-S interval) from each of nine unknown samples of the QRS complex. We found that the artificial intelligence system, trained on only three electrocardiographic features, identified hemorrhage volume with an average accuracy of 91% (95% confidence interval, 84-96%). CONCLUSIONS: These experiments demonstrate that an artificial intelligence system, based solely on the analysis of QRS amplitude, R-R interval, and R-S interval of an electrocardiogram, is able to accurately identify hemorrhage volume in a porcine model of lethal hemorrhagic shock. We suggest that this technology may represent a noninvasive means of assessing the physiologic state during and immediately following hemorrhage. Point of care application of this technology may improve outcomes with earlier diagnosis and better titration of therapy of shock.

Animals↗