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PubMed1991

A compartmental model to analyze ruminal digestion.

In contrast to digestion models that include a discrete lag phase, a compartmental digestion model was proposed. It assumed the existence of a lag compartment and a digestion compartment. Substrate present in the digestion compartment was subject to first-order kinetics digestion. Flow of substrate from the lag compartment to the digestion compartment was proposed to be a first-order process and likely was affected by hydration of substrate, bacterial attachment, and colonization. The proposed model was compared with models that assumed the existence of a discrete lag phase. Parameter estimates for these models were obtained either through logarithmic transformation of data or nonlinear regression. Statistically, there was no difference between the compartmental model and the nonlinear model with a discrete lag phase. Differences in parameter estimates between these two models were small. Residual mean squares were higher for the logarithmically transformed models. Differences in parameter estimates between these models and the compartmental model depended on the structure of the experimental data. In a number of cases, the nonlinear parameters of the compartmental model converged to the same value, resulting in a different interpretation of the model. Residual mean squares for predicting rate of disappearance were lowest for the compartmental model.

Animals↗

PubMed2000

Problems due to small samples and sparse data in conditional logistic regression analysis.

Conditional logistic regression was developed to avoid "sparse-data" biases that can arise in ordinary logistic regression analysis. Nonetheless, it is a large-sample method that can exhibit considerable bias when certain types of matched sets are infrequent or when the model contains too many parameters. Sparse-data bias can cause misleading inferences about confounding, effect modification, dose response, and induction periods, and can interact with other biases. In this paper, the authors describe these problems in the context of matched case-control analysis and provide examples from a study of electrical wiring and childhood leukemia and a study of diet and glioma. The same problems can arise in any likelihood-based analysis, including ordinary logistic regression. The problems can be detected by careful inspection of data and by examining the sensitivity of estimates to category boundaries, variables in the model, and transformations of those variables. One can also apply various bias corrections or turn to methods less sensitive to sparse data than conditional likelihood, such as Bayesian and empirical-Bayes (hierarchical regression) methods.

Bias↗

PubMed2000

Effects of mutant c-kit in early myeloid cells.

Activating mutations in c-Kit, the receptor for Stem Cell Factor (SCF), have been identified in dysplasias and leukaemias of the mast cell lineage and have been shown to contribute to transformation in model systems. Early myeloid cells also normally express c-Kit and their survival, proliferation and differentiation is promoted by SCF. It might therefore be expected that c-Kit mutations could also be involved in some acute and/or chronic myeloid leukaemias. We have found that mutant c-Kit (and normal c-Kit in the presence of SCF) provides a strong differentiation stimulus in normal and immortalised murine early myeloid cells. Since maturation of haemopoietic cells, with the exception of mast cells, results in down-regulation of c-Kit expression, the transforming effects of mutant receptor may be self-limiting in most lineages. This is consistent with the observation that multipotential progenitor cells from some patients with systemic mastocytosis express mutant c-Kit. However, c-Kit mutations have been observed in a few cases of myelodysplastic syndromes or AML without mast cell features. Oncogenesis involves multiple genetic changes and the phenotype of malignant haemopoietic cells expressing mutant c-Kit may be influenced by co-oncogenic events. For example mutations blocking the differentiative effect of mutant c-Kit might result in AML rather than mastocytosis. Thus the extent to which c-Kit mutations contribute to malignancies of early myeloid phenotype remains unknown, and resolution of this issue is complicated by the heterogeneity of this family of diseases.

Animals↗

PubMed1999

Effects of mutant c-Kit in early myeloid cells.

Activating mutations in c-Kit, the receptor for Stem Cell Factor (SCF), have been identified in dysplasias and leukaemias of the mast cell lineage and have been shown to contribute to transformation in model systems. Early myeloid cells also normally express c-Kit and their survival, proliferation and differentiation is promoted by SCE It might therefore be expected that c-Kit mutations could also be involved in some acute and/or chronic myeloid leukaemias. We have found that mutant c-Kit (and normal c-Kit in the presence of SCF) provides a strong differentiation stimulus in normal and immortalised murine early myeloid cells. Since maturation of haemopoietic cells, with the exception of mast cells, results in down-regulation of c-Kit expression, the transforming effects of mutant receptor may be self-limiting in most lineages. This is consistent with the observation that multipotential progenitor cells from some patients with systemic mastocytosis express mutant c-Kit. However, c-Kit mutations have been observed in a few cases of myelodysplastic syndromes or AML without mast cell features. Oncogenesis involves multiple genetic changes and the phenotype of malignant haemopoietic cells expressing mutant c-Kit may be influenced by co-oncogenic events. For example mutations blocking the differentiative effect of mutant c-Kit might result in AML rather than mastocytosis. Thus the extent to which c-Kit mutations contribute to malignancies of early myeloid phenotype remains unknown, and resolution of this issue is complicated by the heterogeneity of this family of diseases.

Acute Disease↗

PubMed1998

An analysis of the Milwaukee cryptosporidiosis outbreak based on a dynamic model of the infection process.

We combined information on the temporal pattern of disease incidence for the 1993 cryptosporidiosis outbreak in Milwaukee with information on oocyst levels to obtain insight into the epidemic process. We constructed a dynamic process model of the epidemic with continuous population compartments using reasonable ranges for the possible distribution of the model parameters. We then explored which combinations of parameters were consistent with the observations. A poor fit of the March 1-22 portion of the time series suggested that a smaller outbreak occurred before the March 23 treatment failure, beginning sometime on or before March 1. This finding suggests that had surveillance systems detected the earlier outbreak, up to 85% of the cases might have been prevented. The same conclusion was obtained independent of the model by transforming the incidence time series data of Mac Kenzie et al. This transformation is based on a background monthly incidence rate for watery diarrhea in the Milwaukee area of 0.5%. Further analysis using the incidence data from the onset of the major outbreak, March 23, through the end of April, resulted in three inferred properties of the infection process: (1) the mean incubation period was likely to have been between 3 and 7 days; (2) there was a necessary concurrent increase in Cryptospordium oocyst influent concentration and a decrease in treatment efficiency of the water; and (3) the variability of the dose-response function in the model did not appreciably affect the simulated outbreaks.

Animals↗

PubMed1976

[Analysis of muscle electrical activity during indirect rhythmic stimulation].

A mathematical model of transformation of the electrical signals in the peripheral neuromuscular junction, and a method of analysing the experimental data obtained in experiments on the muscle and muscle fibers of rat diaphragm in indirect rhythmic stimulation is described. The parameters characterizing the muscle by frequency potentiation and depression properties were determined as a result of the EMG analysis.

Animals↗

PubMed2006

The pituitary tumor-transforming gene promotes angiogenesis in a mouse model of follicular thyroid cancer.

Overexpression of the pituitary tumor-transforming gene (PTTG) has been associated with tumorigenesis. In a mouse model that spontaneously develops follicular thyroid cancer (FTC) with distant metastasis (TRbetaPV mouse), PTTG is overexpressed, similar to human thyroid cancer. To evaluate the role of PTTG in thyroid carcinogenesis, we studied the offspring of TRbetaPV mice with mice lacking PTTG (PTTG(-/-) mice). The thyroids of TRbeta(PV/PV) PTTG(-/-) mice were significantly smaller than TRbeta(PV/PV) mice. Ki-67 staining showed a decrease in thyroid proliferation in TRbeta(PV/PV) PTTG(-/-) mice. Our evaluation of the Rb-E2F pathway, a central mediator of cell growth, found that TRbeta(PV/PV) PTTG(-/-) mice exhibited a decrease in protein levels of phosphorylated Rb along with an elevation of the cdk inhibitor p21. Histological examination documented no difference in FTC occurrence between TRbeta(PV/PV) and TRbeta(PV/PV) PTTG(-/-) mice, which indicates that PTTG removal does not prevent the initiation of FTC. However, TRbeta(PV/PV) PTTG(-/-) mice had a significant decrease in vascular invasion and less development of lung metastasis as they progressively aged. CD31 staining also showed a decrease in vessel density in TRbeta(PV/PV) PTTG(-/-) versus TRbeta(PV/PV) thyroids. Given the decreased vascular invasion in the PTTG knockout mice, we studied genes involved in angiogenesis. Real-time reverse transcription-polymerase chain reaction showed a consistent decrease in pro-angiogenic factors, fibroblast growth factor (FGF2), its receptor FGFR1 and vascular endothelial growth factor. Our results highlight the dual roles of PTTG as a regulator of thyroid growth and contributor to tumor progression. The separation of the pathways regulating cell proliferation, tumor initiation and tumor progression should direct future therapeutic options.

Animals↗

PubMed2004

Oncogenic transformation of human cells: shortcomings of rodent model systems.

Long-standing difficulties in the in vitro transformation of human cells have been overcome. Using telomerase, several successful oncogene-mediated transformations of human cells have been reported and the following cellular requirements for human cell transformation have been proposed: the maintenance of telomere sequences, the inactivation of Rb and p53 pathways, the perturbation of protein phosphatase 2A (PP2A) and the expression of activated Ras. Even when all of these requirements are fulfilled, however, the transformed phenotypes of human cells seem to be much less malignant than those of rodent cells meeting the same requirements. This suggests the existence of undefined cell-autonomous mechanisms that render human cells resistant to malignant transformation.

Animals↗

PubMed2003

Ghosts of paradigms past: the once and future evolution of psychoanalytic thought.

An example of the psychoanalytic mode of thought is put forward concerning how psychoanalytic theories have historically been constituted and transformed. The model of world hypotheses, characterized by multiple irresolvable truth claims, captures the nature of most psychoanalytic theorizing until about 1970. Each of two world hypotheses--one grounded in intrapsychic conflict (seen when the analyst observes from outside the transference) and the other in interpersonal internalization (seen when the analyst observes from inside the bidirectional interactive processes)--is an autonomous and self-sufficient aggregate. The stance taken by the analyst-observer with respect to the analytic interaction is key to seeing how the two world hypotheses are made manifest in clinical work and in theory. By contrast, the model of competing programs captures the essential nature of most psychoanalytic theorizing since about 1970, and is characterized by the necessity of each progressively evolving through a particular kind of commerce with its neighbors. Such commerce is necessary when a program is in danger of degenerating. In this way of thinking, there is a fundamental tension between classical psychoanalysis adapting to the demands and exigencies of its particular and ever evolving historical niche and simultaneously retaining the core commitments that guarantee continuity. Honoring the forces of progression displaces the quest for truth as a paramount goal of psychoanalysis. A developmental lag in recognizing this transformation has hindered progress toward a comparative, process-centered psychoanalysis.

Conflict, Psychological↗

PubMed1996

Qualitative analysis of biochemical reaction systems.

The qualitative analysis of biochemical reaction systems is presented. A discrete event systems approach is used to represent and analyze bioreaction pathways. The approach is based on Petri nets, which are particularly suited to modeling stoichiometric transformations, i.e. the inter-conversion of metabolites in fixed proportions. The properties and methods for the analysis of Petri nets, along with their interpretation for biochemical systems, are presented. As an example, the combined glycolytic and pentose phosphate pathway of the erythrocyte cell is presented to illustrate the concepts of the methodology.

Animals↗

PubMed1998

The Role of Weak Interactions in Biological Systems: the Dual Dynamics Model.

The dual dynamics model is a random autonomous network of nodes whose dynamical behavior is determined by both strong and weak interactions. The model combines discrete decision-making features reflective of logical operations with arithmetic features that represent graded influences. Dual dynamics abstracts the ubiquitous fact that biological systems at all levels of organization consist of components that respond both to specific (strong) signals and to the cumulative effect of numerous weak interactions. We have thoroughly studied the dynamical characteristics of three-valued dual dynamics networks in the range from four to 14 nodes and have compared these characteristics to those of non-boolean three-valued networks (without weak interaction) and to Kauffman boolean networks. Properties studied include: attractor length, number of attractors, basin sizes, orbital stability, and evolutionary transformability in response both to individual and cumulative mutations (where mutations are implemented as random changes in the response of a node to the pattern of strong influences impinging on it). The introduction of weak interactions and their manner of coupling to strong interactions has major altering effects on these properties. With suitable coupling it is possible to significantly enhance equifinality and evolutionary transformability. The model demonstrates that self-organizing dynamics are compatible with evolutionary plasticity when weak interactions are taken into account.Copyright 1998 Academic Press

Journal Article↗

PubMed2000

Microbial models of mammalian metabolism: microbial transformation of naproxen.

Preparative-scale fermentation of S-naproxen, the known antiinflammatory, analgesic and antipyretic drug, with Cunninghamella elegans ATCC 9245 afforded S-demethylnaproxen, the known human active metabolite of naproxen, in a 90% yield. Demethylnaproxen was also detected as the major metabolite of naproxen using Cunninghamella blakesleeana ATCC 8688a. A review of the previous microbial metabolism studies using the fungi Cunninghamella species suggested that it could be a plausible in vitro predictor for mammalian metabolism.

Animals↗

PubMed1987

Transformation of macrophages into foam cells in vitro induced by cholesteryl oleate liquid crystals.

Transformation of macrophages into foam cells after the uptake of cholesteryl oleate anisotropic liquid crystals was studied. A new technique to enhance the uptake of the liquid crystals by macrophages using an inverted petri dish was developed. Uptake of lipid droplets was found to increase in parallel with the amount of liquid crystals in the medium. A lysosomal enzyme was shown (by using lysosomotropic chloroquine) to be involved in the hydrolysis of the liquid crystals. About 47 and 72% of the [3H]cholesterol in liquid crystal-laden cells had disappeared after chase for 24 and 48 h, respectively. Thus the 50% clearance time of the liquid crystals by the macrophages was about 24 h, which was longer than that of denatured lipoprotein. A possible model of transformation of macrophages to foam cells is discussed.

Animals↗

PubMed2001

Use of longitudinal data analysis in the determination of a global score for total hip replacement indication in osteoarthritis patients.

BACKGROUND: A composite index would help in medical practice for considering total hip replacement (THR) in hip osteoarthritis. In association with other parameters, such as age or general status, this index could serve to objectively determine the time to THR surgery, and might be used as an outcome measure in therapeutic trials. The objective of this study was to propose such an index, taking into account symptomatic, structural and therapeutic variables, and impact on lifestyle. METHODS: A curve-fitting procedure and a marginal model were used to highlight the average change in the variables over time. A discrete Cox model, with time-dependent covariates. was then performed to study the association between the variables and hip surgery, leading to the construction of a composite index. RESULTS: The smoothing and fitting analysis suggested takes into account not only the variables, but also the changes in their values during the preceding year, when studying the association between variables and hip surgery. Five covariates were retained in the Cox model, among them only one concerns the changes during the preceding year, showing that the values of the covariates are more important that their changes during the preceding year for THR indication. The coefficients of the model were transformed into new coefficients, so that their sum provided a severity score with individual values 0-100. DISCUSSION: Based on the values of reliable variables recorded during the four last visits, this score can be regarded as a valid index able to objectively help with THR indications. This score might also be used as an outcome measure in therapeutic trials.

Aged↗

PubMed2006

Primary care physician perspective on management of patients with depression.

OBJECTIVE: To discuss the relationship between the primary care physician and other health care professionals and best practice strategies in the management of depression. SUMMARY: Useful chronic clinical models can transform a visit between a patient with depression and the primary care provider from an unfocused encounter to one that is anticipated, planned, and productive. With the proper decision and organizational support to manage their patients with depression, primary care providers will have the increased confidence to treat these patients and have more knowledge about the treatment plan, whether that is a referral or continuation of treatment in the provider.s office. CONCLUSION: The primary care provider must recognize that he or she cannot work alone. In addition to decision support and clinical information systems, there needs to be a delivery system that supports a depression care manager and identifies the patient as the key player in the system. Participation and cooperation by the entire health care system will determine the success of such depression care models.

Delivery of Health Care↗

PubMed1994

Key questions--a strategy for modifying clinical communication. Transforming tacit skills into a clinical method.

BACKGROUND: A clinical communicative method designed to promote the doctor's understanding of women's "undefined" disorders is presented and discussed. The method is composed of key questions, which are problem-oriented speech acts, inviting the patient to share with the doctor her conception of illness. The questions are directed towards specific clinical problems, and are not meant as global devices for better doctor-patient communication in general. PROCEDURE: The clinical method is the outcome of a procedure where key questions are systematically developed. The procedure starts with individual successful communicative experiences and moves towards questions that are applicable towards various patients presenting the actual clinical problem. The procedure is described qualitatively, and delivers cues from which the modes of asking can be adjusted and employed by other doctors. OUTCOMES: The procedure consists of these steps: 1) declaring the clinical problem for investigation, 2) specifying a relevant communicative intention, 3) assigning fertile themes of knowledge, 4) identifying an efficacious utterance for further refinement, and 5) expanding the validity of the utterance. CONCLUSION: By making visible, systematizing and refining the doctor's tacit conversational skills, the clinical method represents a model for transforming individual clinical experiences into medical knowledge. Premises for generalization of the method towards clinical problems beyond women's "undefined" disorders are discussed.

Algorithms↗

PubMed1985

X-ray diffraction studies of 14-filament models of deoxygenated sickle cell hemoglobin fibers. Models based on electron micrograph reconstructions.

The transforms of a large number of models of deoxygenated sickle hemoglobin fibers, related to that derived from image reconstruction of electron micrographs, have been calculated and compared with X-ray diffraction data of 15 A resolution. The model of the fiber, determined from the reconstructed image, is a helix consisting of 14 filaments that associate in a specific mode to form seven pairs, or protofilaments. Pairs were identified through the pattern of filament loss in partially disassembled fibers and by the separation between molecules, in adjacent filaments, of half a molecular diameter, along the fiber axis. An alternative mode of filament association can be derived also from the surface lattice of the reconstruction, which meets these criteria for the pairing of molecular filaments. Both pairing modes have been used in the search for structures whose transforms show the best agreement with the diffraction data. Models were generated by the systematic translation of six protofilaments, taken in symmetry related pairs, in steps of 3.5 A along the fiber axis relative to a fixed central protofilament. Each translation of a protofilament corresponds to a different fiber model, whose transform was compared with observed data. In all, over 11,000 transforms were calculated. Of all the models considered, three have been found whose residuals are minimal. At 30 A resolution, similar to that of electron micrographs, the model derived from image reconstruction and the three found through our search procedure are indistinguishable. At 15 A, however, the transforms of these models show better agreement with the observed data than the transform of the reconstructed image. Comparison of residuals shows that the model derived from the reconstructed image can be rejected with 99.5% probability relative to the model, with the same pairing scheme, found by our search procedures. The two other models, derived from the alternative pairing scheme, are also more credible than the reconstructed image, but at a lower confidence level. Each of our three models is equally acceptable. Their existence may reflect structural polymorphism of the fiber.

Hemoglobin, Sickle↗

PubMed1983

Cultured cells transformed by Rous sarcoma virus: a genetically defined model and its phenotype.

The mechanism by which Rous sarcoma virus transforms cells is better understood at the molecular level than that of any other oncogenic agent. The gene (src) responsible for transformation has been identified and its nucleotide sequence has been determined. The transforming protein (pp60src) has been identified and an enzymatic activity assigned to it. The unusual enzymatic activity of pp60src (phosphorylation of proteins on tyrosine) has allowed us to identify a large number of putative targets of this protein. And genetic evidence indicates that the phosphorylation of various targets is responsible for generating the various manifestations of the transformed phenotype. What can this model system contribute to understanding of hereditary large bowel cancer? First of all, it provides an intellectual paradigm for analyzing the mechanism by which a single autosomal dominant gene can alter the metabolism and regulatory behavior of a cell. A cellular homolog of src or of some other onc gene could be responsible for hereditary colon cancer. Second, it provides a model for understanding why some "markers" of malignancy are not invariably associated with cancer: since the oncogenic protein can interact with a variety of primary targets giving rise to the various parameters of transformation, not every sort of biological effect need be necessary for malignancy. Third, it points out that the various syndromes which constitute hereditary colon cancer may well be due to a single gene: since mutations in the src gene are capable of generating a variety of distinct phenotypic alterations in infected cells, different from that generated by the wild-type virus, it certainly is conceivable that different alleles of a single transforming gene could give rise to the different types of hereditary colon cancer. Whether this is the explanation for the various forms of hereditary colon cancer, or whether they result from the activities of several different onc genes can only be determined by identification of the gene(s) at the molecular level. Finally, this model system has provided information which may prove useful in improving the specificity of cancer chemotherapy. Since production of plasminogen activator seems to correlate well with growth in soft agar and tumorigenicity, an anti-cancer prodrug which is activated specifically by cells producing plasminogen activator might be selectively toxic to malignant cells. We have in fact synthesized such drugs and shown them to be selectively toxic in vitro to malignant cells (Carl et al 1980). In vivo tests of these agents are in progress.

Avian Sarcoma Viruses↗