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PubMed2002

The power to act: two model state statutes.

Enabling statutes for state and local public health agencies set forth their powers and duties and provide the legal basis for their work. Obsolescence, inconsistency, and inadequacy may render some public health laws ineffective or even counterproductive. Reforming state public health law can improve the legal infrastructure that supports public health systems in responding to bioterrorism and other public health threats. Two legal tools available to assist the process of establishing a strong legal foundation for public health practice are the Model State Emergency Health Powers Act, developed in 2001 by the Center for Law and the Public's Health, and the Model State Public Health Act, currently under development by the Turning Point Public Health Statute Modernization National Collaborative. These model acts can serve as guides for assessing current state public health law, and they provide example statutory language for use by those working to update their laws. That strong state public health law and model public health acts serve as resources for law reform is recognized by local health officials and state legislators as well as by state public health officials. Lessons learned from recent experiences with crafting and introducing legislation based on the Model State Emergency Health Powers Act can prove useful in the future to those working on public health law reform efforts in their states.

Bioterrorism↗
PubMed1995

[Models of causal inference: critical analysis of the use of statistics in epidemiology].

The foundations on which the concept of risk has been constructed are discussed. A description of Rubin's model of causal inference, which was first developed in the domain of applied statistics, and later incorporated into a branch of epidemiology, is taken as the starting point. Analysis of the premisses of causal inference brings to light the logical stages in the construction of the concept of risk, allowing it to be understood "from the inside". The abovementioned branch of statistics and epidemiology seeks to demonstrate that statistics can infer causality instead of simply revealing statistical associations; the model gives the basis for estimating that which way be defined as the effect of a cause. Using this procedural distinction between causal inference and association, the model also seeks to differentiate between the epidemiologial dimension of concepts and the merely statistical dimension. This leads to greater complexity when handing the concepts of interation and coofounding. The redective aspects inherent in this methodological construction of risk are here high lighted. Thus, whether applied to individual or populational inferences, this methodological construction imposes limits that need to be taken into account in its theoretical and practical application to epidemiology.

Causality↗
PubMedDate not supplied

Pharmacokinetics of liposomes designed to carry glucocorticoids.

Over the past decade, particulate drug formulations have been successfully employed to reduce undesired side effects and improve drug biodistribution. Despite numerous experimental data, there are relatively few theoretical studies regarding the pharmacokinetics of such formulations. A quantitative pharmacokinetic description of particulate drug forms requires serious adjustments in existing theoretical approaches, due to formulation size. Thus, blood vessel permeabilization and the immunological system need to be accounted for. In this paper, we present a pharmacokinetic model intended to describe the distribution of glucocorticoid (prednisolone phosphate) encapsulated in long-circulated liposomes and its qualitative analysis. In order to achieve qualitative and quantitative agreement with experimental patterns of time-dependent liposome concentration changes in blood, liver and spleen, the existence of two hypothetical liposome populations was assumed. The two populations differ in their accumulation capacities, dosage and time constants. The first population is accumulated in the liver with a time constant of 50 s(-1) and a saturation level of 0.005 micromol/animal, whereas the second with 0.003 s(-1) and 50 micromol/animal, respectively. Such liposome parameterization results from the theoretical model used, however, it may have a physiological foundation. If the two opsonin and/or macrophage types that interact with the liposomes are assumed to have different characteristics, then the pharmacokinetic data obtained experimentally in an animal model can be described correctly.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1997

Immune-deficient SCID and NOD/SCID mice models as functional assays for studying normal and malignant human hematopoiesis.

Many events and requirements of the developmental program of human hematopoietic stem cells have not yet been discovered. A major impediment has been the lack of an appropriate experimental system. At present the conditions for maintaining human stem cells in vitro are not fully known. As a result within a short period the small stem cell pool is lost due to differentiation, making it difficult to examine the correlation between these cells and their function in vivo. Most of our knowledge of hematopoietic stem cells is from animal models in which purified stem cell canididates are assayed based on their functional ability to rescue lethally conditioned recipients. The permanent correction of many genetic disorders of the hematopoietic system requires efficient methods for introducing genes into stem cells in vitro. However, progress has been hindered by the absence of preclinical models that assay the repopulating capacity of primitive human cells. In addition, the development of therapy for malignant diseases also requires assays to identify the target leukemic stem cells based on their ability to initiate the disease. The recent development of methods to transplant or implant both normal and leukemic cells into immune-deficient mice provides the foundation for human stem cell assays. These models assay the repopulating capacity of primitive human cells and provide an important approach to identify and characterize human stem cells, both normal and leukemic. This review focuses on the development of functional assays for normal and leukemic human stem cells and on the new insights that these models are beginning to provide on the organization of the human stem cell hierarchy.

Animals↗
PubMed2005

Correlation between clinical and histological features in a pig model of choroidal neovascularization.

PURPOSE: To analyse the histological changes in the retina and the choroid in a pig model of choroidal neovascularization (CNV) and to correlate these findings with fundus photographic and fluorescein angiographic features. METHODS: CNV was induced by surgical removal of the retinal pigment epithelium (RPE) and perforation of Bruch's membrane in four pig eyes. In addition, two eyes had an amniotic membrane implanted in the subretinal space. Retinal landmarks such as arterioles, crossing of vessels and the optic nerve were used to obtain an exact mapping of histological findings on colour fundus photographs (FPs) and fluorescein angiograms (FAs). We analysed the appearance on the FPs and FAs of the following histological features: CNV, hypo/hyperpigmented RPE, and pathological changes to the retina and choroid. RESULTS: CNV was found in all eyes and correlated to areas with late staining but no leakage in the FAs. Areas of hypopigmented RPE were identified and corresponded to window defects in the FAs. Where fibrovascular tissue was covered with hyperpigmented RPE, blocked fluorescence was found on the FAs. The implanted amniotic membrane showed staining but no leakage in the FAs. CONCLUSION: In a pig model of surgically induced CNV, histological mapping was used to make clinicopathological correlations of the following lesion components: CNV, window defects, blocked fluorescence. Our findings give a more solid foundation for interpretation of fluorescein angiograms in pig models.

Amnion↗
PubMed2003

ADSA Foundation Scholar Award--An integrated science-based approach to dairy food safety: Listeria monocytogenes as a model system.

Transmission of food- and milkborne pathogens often involves complex interactions among the pathogen, the environment, and one or multiple host species. A complete understanding of these interactions is critical to allow the development of science-based, effective intervention strategies for foodborne infectious diseases. This article summarizes our studies on the transmission, ecology, pathogenesis and population genetics of Listeria monocytogenes, which we have used as model for a food- and milkborne pathogen that infects multiple hosts and also has considerable ability to survive and multiply in nonhost environments. Application of molecular subtyping tools in conjunction with phenotypic characterization of selected strains has allowed us to define distinct L. monocytogenes subtypes and clonal groups that appear to differ in relevant phenotypic characteristics that may affect their abilities to be transmitted through food systems. For example, a genetic group designated as lineage I has been shown to be not only more common among human listeriosis cases than among animal cases, but lineage I strains also appear to show an increased in vitro ability to spread intracellularly from host cell to host cell. These findings are consistent with the fact that while genetically diverse strains may be classified to one bacterial species, these strains often differ from one another in important genetic and phenotypic characteristics. I thus propose that evolutionary- and molecular subtyping-based definitions of bacterial subtypes and clonal groups will provide critical insight into the microbial ecology of dairy food systems, including not only foodborne pathogens, but also organisms important for dairy fermentation and spoilage.

Agriculture↗
PubMed2005

Measure dynamics on a one-dimensional continuous trait space: theoretical foundations for adaptive dynamics.

The measure dynamics approach to modelling single-species coevolution with a one-dimensional trait space is developed and compared to more traditional methods of adaptive dynamics and the Maximum Principle. It is assumed that individual fitness results from pairwise interactions together with a background fitness that depends only on total population size. When fitness functions are quadratic in the real variables parameterizing the one-dimensional traits of interacting individuals, the following results are derived. It is shown that among monomorphisms (i.e. measures supported on a single trait value), the continuously stable strategy (CSS) characterize those that are Lyapunov stable and attract all initial measures supported in an interval containing this trait value. In the cases where adaptive dynamics predicts evolutionary branching, convergence to a dimorphism is established. Extensions of these results to general fitness functions and/or multi-dimensional trait space are discussed.

Adaptation, Physiological↗
PubMed2000

Foundations of dissipative particle dynamics

We derive a mesoscopic modeling and simulation technique that is very close to the technique known as dissipative particle dynamics. The model is derived from molecular dynamics by means of a systematic coarse-graining procedure. This procedure links the forces between the dissipative particles to a hydrodynamic description of the underlying molecular dynamics (MD) particles. In particular, the dissipative particle forces are given directly in terms of the viscosity emergent from MD, while the interparticle energy transfer is similarly given by the heat conductivity derived from MD. In linking the microscopic and mesoscopic descriptions we thus rely on the macroscopic or phenomenological description emergent from MD. Thus the rules governing this form of dissipative particle dynamics reflect the underlying molecular dynamics; in particular, all the underlying conservation laws carry over from the microscopic to the mesoscopic description. We obtain the forces experienced by the dissipative particles together with an approximate form of the associated equilibrium distribution. Whereas previously the dissipative particles were spheres of fixed size and mass, now they are defined as cells on a Voronoi lattice with variable masses and sizes. This Voronoi lattice arises naturally from the coarse-graining procedure, which may be applied iteratively and thus represents a form of renormalization-group mapping. It enables us to select any desired local scale for the mesoscopic description of a given problem. Indeed, the method may be used to deal with situations in which several different length scales are simultaneously present. We compare and contrast this particulate model with existing continuum fluid dynamics techniques, which rely on a purely macroscopic and phenomenological approach. Simulations carried out with the present scheme show good agreement with theoretical predictions for the equilibrium behavior.

Journal Article↗
PubMed2006

Mice expressing constitutively active Gsalpha exhibit stimulus encoding deficits similar to those observed in schizophrenia patients.

People with schizophrenia display sensory encoding deficits across a broad range of electrophysiological and behavioral measures, suggesting fundamental impairments in the ability to transduce the external environment into coherent neural representations. This inability to create basic components of complex stimuli interferes with a high fidelity representation of the world and likely contributes to cognitive deficits. The current study evaluates the effects of constitutive forebrain activation of the G(s)alpha G-protein subunit on auditory threshold and gain using acoustic brainstem responses and cortically generated N40 event-related potentials to assess the role of cyclic AMP signaling in sensory encoding. Additionally, we examine the ability of pharmacological treatments that mimic (amphetamine) or ameliorate (haloperidol) positive symptoms of schizophrenia to test the hypothesis that the encoding deficits observed in G(s)alpha transgenic mice can be normalized with treatment. We find that G(s)alpha transgenic mice have decreased amplitude of cortically generated N40 but normal acoustic brainstem response amplitude, consistent with forebrain transgene expression and a schizophrenia endophenotype. Transgenic mice also display decreased stimulus intensity response (gain) in both acoustic brainstem response and N40, indicating corticofugal influence on regions that lack transgene expression. N40 deficits in transgenic animals were ameliorated with low dose haloperidol and reversed with higher dose, suggesting dopamine D2 receptor-linked Gi activity contributes to the impairment. Consistent with this hypothesis, we recreated the G(s)alpha transgenic deficit in wild type animals using the indirect dopamine agonist amphetamine. This transgenic model of sensory encoding deficits provides a foundation for identifying biochemical contributions to sensory processing impairments associated with schizophrenia.

Acoustic Stimulation↗
PubMedDate not supplied

A community-based alternative: the comprehensive community health models initiative.

Health care is undergoing a quiet revolution in communities across America as purchasers, providers and consumers explore new options for controlling health care costs, expanding access and improving health status. A major Michigan effort in this regard is the Comprehensive Community Health Models (CCHMs) Initiative funded by the W.K. Kellogg Foundation.

Community Health Planning↗
PubMed1978

On the rationing of health services and resource availability.

Government controls on availability of physicians and hospital resources can counteract some undesired aggregate consequences of reimbursement insurance. Given aggregate controls, many important questions arise concerning nonprice rationing of services by physicians. A theoretical model of rationing should be consistent with existing items of evidence on delays, disequilibrium, and "availability effects." The model discussed in this paper has a foundation in the mutual advantages of a long-term association between an individual client and physician; these advantages motivate an implicit contract for rationing with a variety of testable implications.

Economics, Medical↗
PubMedDate not supplied

Global theory and the nature of risk, Part I. How orthodox managed care stifles innovation.

The growing awareness that managed care is rapidly unraveling has not only produced a good deal of alarm, but also a call for prognostications regarding the future. Unfortunately, old habits die hard, and wedded ideologies die even harder. Instead of paving the way for innovation, most managed care pundits refuse to read the tea leaves properly and acknowledge that the orthodox regime is irretrievably comatose. Not understanding the fundamental flaws inherent in the old model, many persevere with rehashed predictions that only echo the very non-starters that got us in the present jam in the first place. Managed care has so far focused its energies on integrating the wrong objects, insurance and care, with all the predictably bad effects. Part 2 of this article will explore what this means and introduce the global theory of managed care as an alternative vision. Global theory lays a new foundation based on a more sound microeconomic model of risk, bifurcated markets, global fees for integrated episodes of care, and most important of all, patient/physician sovereignty.

Capitation Fee↗
PubMed2004

Genetically engineered mouse models for lung cancer.

The lung is a complex organ consisting of numerous cell types that function to ensure sufficient gas exchange to oxygenate the blood. In order to accomplish this function, the lung must be exposed to the external environment and at the same time maintain a homeostatic balance between its function in gas exchange and the maintenance of inflammatory balance. During the past two decades, as molecular methodologies have evolved with the sequencing of entire genomes, the use of in vivo models to elucidate the molecular mechanisms involved in pulmonary physiology and disease have increased. The mouse has emerged as a potent model to investigate pulmonary physiology due to the explosion in molecular methods that now allow for the developmental and tissue-specific regulation of gene transcription. Initial efforts to manipulate gene expression in the mouse genome resulted in the generation of transgenic mice characterized by the constitutive expression of a specific gene and knockout mice characterized by the ablation of a specific gene. The utility of these original mouse models was limited, in many cases, by phenotypes resulting in embryonic or neonatal lethality that prevented analysis of the impact of the genetic manipulation on pulmonary biology. Second-generation transgenic mouse models employ multiple strategies that can either activate or silence gene expression thereby providing extensive temporal and spatial control of the experimental parameters of gene expression. These highly regulated mouse models are intended to serve as a foundation for further investigation of the molecular basis of human disease such as tumorigenesis. This review describes the principles, progress, and application of systems that are currently employed in the conditional regulation of gene expression in the investigation of lung cancer.

Animals↗
PubMed1982

Hospitals reorganize to survive the '80s.

Corporate restructuring and development of multi-institutional arrangements can enable hospitals to implement strategies for ensuring quality of care, developing access to capital, developing new sources of revenue, and more. Several models of these two approaches to reorganization are described.

Foundations↗
PubMed1983

The mechanical properties of porcine aortic valve tissues.

In uniaxial tensile experiments in vitro mechanical properties of the different parts of porcine aortic valves, i.e. the leaflets, the sinus wall and the aortic wall, have been dealt with. Tissue strips cut in different directions were investigated. The collagen bundles in the leaflets show a stiffening effect and cause a marked anisotropy: within the physiological range of strains the largest slopes of the stress-strain curves of leaflet specimens in the bundle direction are a factor of about 20 larger than those of specimens taken along the perpendicular direction. For the sinus and aortic tissues, these values are 50-200 times smaller than those obtained from the leaflet specimens in the bundle direction. Two aspects of viscoelastic behaviour were examined: the strain rate sensitivity of the stress-strain curves and the relaxation behaviour. The stress-strain curves of the different valve parts appeared to be rather insensitive to the strain rate: the most pronounced sensitivity observed in our experiments, was a doubling of the stress at the same strain caused by a hundredfold increase of the strain rate. In analyzing the relaxation behaviour, use was made of the relaxation model proposed by Fung (1972, in Biomechanics, its Foundations and Objectives; Fung, Perrone and Anliker. Prentice Hall). In the leaflets, about 45% stress relaxation was found whereas this amounted to 30% in the sinus and aortic walls. Predictions based upon the model indicate that on cyclic loading the larger viscous losses have to be expected in the leaflets.

Animals↗
PubMed2005

Interval duration effects on blocking in appetitive conditioning.

Three experiments examined absolute (Experiment 1) and relative (Experiments 2a and 2b) duration effects on blocking. In Experiment 1, rats were pretrained with a short or long conditioned stimulus (CS1) followed by food, after which they were given reinforced short-short or long-long CS1-CS2 simultaneous compounds. Compared to overshadowing control groups, both pretrained groups displayed blocking, and there was no clear effect of absolute stimulus duration on the magnitude of blocking. In Experiments 2a and 2b, the rats received partially overlapping short-long CS1-CS2 compounds. In both experiments, a long CS1 blocked a short CS2, but not vice versa. This was the case when the long CS1 was nine times (Experiment 2a) or only 1.5 times (Experiment 2b) the duration of the short CS2. The pattern of results is most consistent with a real-time model of conditioning, such as the Sutton and Barto [Sutton, R.S., Barto, A.G., 1990. Time derivative models of Pavlovian reinforcement. In: Gabriel, M.R., Moore, J.W. (Eds.), Learning and Computational Neuroscience: Foundations of Adaptive Networks. MIT Press, Cambridge, MA, 497-537] temporal difference model.

Animals↗