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Mathematical modeling of adhesion of bacteria to host cell lines.

A mathematical model which describes adhesion of bacteria to host cell lines is presented. The model is flexible enough to account for the following situations: extracellular bacteria are either in exponential or in stationary phase. Adhesion is described as a reversible binding process in which the bacteria attach to or detach from specific receptors uniformly distributed on the cell surface. In turn, attached bacteria can either replicate or, conversely, they are restrained to remain in stationary phase. In the first case, however, we must consider the problem of whether the decrease of unoccupied receptors as adhesion progresses imposes a limit to the replicating capacity of the attached bacteria. The effect exerted by the multiplicity of infection (MOI), i.e. the ratio of the number of bacteria to the number of host cells, on the process of adhesion is also contemplated by the model. This has revealed that experiments performed at the same values of MOI can show completely different levels of adhered bacteria, depending on the number of host cells in the assays. This finding demonstrates that the report of the MOI values is insufficient to characterize comparative studies of bacterial adhesion since it could lead to a misunderstanding of the corresponding data. Simplified models based on the steady-state approximation and in equilibrium analysis by means of a Lagmuir absorption isotherm for the attached bacteria are also discussed. This allows us to define the adhesion coefficient ( beta) in a given bacterium-cell system so that, with the exception of those systems where these coefficients cannot be defined, larger values of beta are related to a greater adhesion capacity. An overview of the procedures to perform quantitative adhesion data analysis is outlined. Finally, theoretical predictions are compared with experimental results from the literature.

Animals↗

Role of erythrocytes in leukocyte-endothelial interactions: mathematical model and experimental validation.

The binding of circulating cells to the vascular wall is a central process in inflammation, metastasis, and therapeutic cell delivery. Previous in vitro studies have identified the adhesion molecules on various circulating cells and the endothelium that govern the process under static conditions. Other studies have attempted to simulate in vivo conditions by subjecting adherent cells to shear stress as they interact with the endothelial cells in vitro. These experiments are generally performed with the cells suspended in Newtonian solutions. However, in vivo conditions are more complex because of the non-Newtonian flow of blood, which is a suspension consisting of 20-40% erythrocytes by volume. The forces imparted by the erythrocytes in the flow can contribute to the process of cell adhesion. A number of experimental and theoretical studies have suggested that the rheology of blood can influence the binding of circulating leukocytes by increasing the normal and axial forces on leukocytes or the frequency of their collision with the vessel wall, but there have been no systematic investigations of these phenomena to date. The present study quantifies the contribution of red blood cells (RBCs) in cell capture and adhesion to endothelial monolayers using a combination of mathematical modeling and in vitro studies. Mathematical modeling of the flow experiments suggested a physical mechanism involving RBC-induced leukocyte dispersion and/or increased normal adhesive contact. Flow chamber studies performed with and without RBCs in the suspending medium showed increases in wall collision and binding frequencies, and a decrease in rolling velocity in the presence of erythrocytes. Increased fluid viscosity alone did not influence the binding frequency, and the differences could not be attributed to large near-wall excesses of the lymphocytes. The results indicate that RBCs aid in the transport and initial engagement of lymphocytes to the vascular wall, modifying the existing paradigm for immune cell surveillance of the vascular endothelium by adding the erythrocyte as an essential contributor to this process.

Biophysical Phenomena↗

Mathematical modelling and simulation of a tennis racket.

By constructing a mathematical model, we consider the dynamics of a tennis racket hit by a ball. Using this model, known experimental results can be simulated on the computer, and it becomes possible to make a parametric study of a racket. Such a simulation is essential in the study of two important problems related to tennis: computation of the resulting forces and moments transferred to the hand should assist understanding of the medical problem 'tennis elbow'; secondly, simulation will enable a study to be made of the relationships between the impact time, tension in the strings, forces transmitted to the rim and return velocity of the ball, all of which can lead to the optimal design of rackets.

Biomechanical Phenomena↗

A mathematical model of proliferation and aging of cells in culture.

A mathematical model is presented which describes the proliferative senescence of cells in culture. The model is based on the DNA damage hypothesis of cellular aging and is able to account for both the limited and unlimited in vitro proliferative potential of normal and transformed cells. It is predicted that the destiny of a cell population is determined by two counteracting factors: the proliferation rate of the dividable cells and the gene damage accumulation rate. The formation of an immortal cell line requires high rate of proliferation and/or low rate of gene damage accumulation. The related computer simulations on a number of proliferative properties of cell culture produces results in agreement, in the general properties, with experimental observations.

Animals↗

Mathematical modelling of immobilized animal cell growth.

A two-dimensional mathematical model for animal cell growth was employed to study the suspension, as well as stationary, culture of micro-encapsulated and gel immobilized animal cells. For stationary microcapsules with low-viscosity intracapsular liquid, it was found that capsule radius, capsule loading and medium-change time have the most significant effects on the intracapsular cell density. The model was also adapted to simulate other scenarios of cell growth such as in gel beads and suspended microcapsules. The simulated time course of oxygen concentration and specific growth rate revealed a complicated interaction between material transport and cell growth kinetics. With the mass transfer coefficient for oxygen transfer (KLa') into the medium equal to 4.0 hr-1, for instance, it was found that the specific growth rate of the microencapsulated cells was controlled by the supply of glucose and oxygen. When the value of KLa' was reduced to 0.6 hr-1, however, oxygen supply appeared to be the sole factor affecting the specific growth rate. In the case of suspended gel beads, a simulation revealed a higher cell density towards the gel bead surface. The transport of nutrients and oxygen to the central region of the gel bead was apparently blocked by the surrounding cells.

Animals↗

Experimental evaluation of a mathematical model for predicting transfer efficiency of a high volume-low pressure air spray gun.

The transfer efficiency of a spray-painting gun is defined as the amount of coating applied to the workpiece divided by the amount sprayed. Characterizing this transfer process allows for accurate estimation of the overspray generation rate, which is important for determining a spray painter's exposure to airborne contaminants. This study presents an experimental evaluation of a mathematical model for predicting the transfer efficiency of a high volume-low pressure spray gun. The effects of gun-to-surface distance and nozzle pressure on the agreement between the transfer efficiency measurement and prediction were examined. Wind tunnel studies and non-volatile vacuum pump oil in place of commercial paint were used to determine transfer efficiency at nine gun-to-surface distances and four nozzle pressure levels. The mathematical model successfully predicts transfer efficiency within the uncertainty limits. The least squares regression between measured and predicted transfer efficiency has a slope of 0.83 and an intercept of 0.12 (R2 = 0.98). Two correction factors were determined to improve the mathematical model. At higher nozzle pressure settings, 6.5 psig and 5.5 psig, the correction factor is a function of both gun-to-surface distance and nozzle pressure level. At lower nozzle pressures, 4 psig and 2.75 psig, gun-to-surface distance slightly influences the correction factor, while nozzle pressure has no discernible effect.

Air Pollutants, Occupational↗

Mathematical modelling of metabolic pathways affected by an enzyme deficiency.

The regulation of metabolic pathways of the red cell affected by an enzyme deficiency is studied on the basis of comprehensive mathematical models. The main steps of such a theoretical approach are outlined considering individual alterations in the kinetic properties of two regulatory enzymes: pyruvate kinase and glucose-6-phosphate dehydrogenase. It is demonstrated that mathematical modelling helps to relate the observed changes of cellular quantities as shortened life-span, or as resistance against oxidative stress to alterations in the metabolic regulation.

Animals↗

[Discrete and continuous mathematical models of intraspecific behavior in the pharmacoethology of the mouse].

An algorithm and software library were compiled in order to interpret the intraspecies agonistic animal behaviour in terms of discrete or continuous mathematical model. Applied aspects of the use of mathematical models in pharmacoethology were shown on concrete examples. The ways of construction of standard prototypes, and the integrative criteria of psychotropic drugs action were developed. The possibility was shown of identification of unknown substances by comparing with standard drugs by calculating the norm of standardized matrices.

Aggression↗

Reproduction of MIGET retention and excretion data using a simple mathematical model of gas exchange in lung damage caused by oleic acid infusion.

The multiple inert-gas elimination technique (MIGET) is a complex mathematical model and experimental technique for understanding pulmonary gas exchange. Simpler mathematical models have been proposed that have a limited view compared with MIGET but may be applicable for use in clinical practice. This study examined the use of a simple model of gas exchange to describe MIGET retention and excretion data in seven pigs before and following lung damage caused by oleic acid infusion and subsequently at different levels of positive end-expiratory pressure. The simple model was found to give, on average, a good description of MIGET data, as evaluated by a chi(2) test on the weighted residual sum of squares resulting from the model fit (P > 0.2). Values of the simple model's parameters (dead-space volume, shunt, and the fraction of alveolar ventilation going to compartment 2) compared well with the similar MIGET parameters (dead-space volume, shunt, log of the standard deviation of the perfusion, log of the standard deveation of the ventilation), giving values of bias and standard deviation on the differences between dead-space volume and shunt of 0.002 +/- 0.002 liter and 7.3 +/- 2.1% (% of shunt value), respectively. Values of the fraction of alveolar ventilation going to compartment 2 correlated well with log of the standard deviation of the perfusion (r(2) = 0.86) and log of the standard deviation of the ventilation (r(2) = 0.92). These results indicate that this simple model provides a good description of lung pathology following oleic acid infusion. It remains to be seen whether physiologically valid values of the simple model parameters can be obtained from clinical experiments varying inspired oxygen fraction. If so, this may indicate a role for simple models in the clinical interpretation of gas exchange.

Animals↗

To verify four 5-year-old mathematical models to predict the outcome of ICU patients.

AIM: The aim of this study is to verify calibration and discrimination after 5 years in the case mix of patients admitted to the Intensive Care Unit (ICU) during the year 2000. In this way we want to perform a quality control of our ICU in order to justify the increased amount of money spent for intensive care. METHODS: A prospective study has been made on the 357 patients admitted to the ICU during the year 2000. The Apache II score was calculated within the first 24 hours and, depending on the length of stay in the ICU, on the 5(th), 10(th) and 15(th) day after ICU admission. On the basis of the 4 mathematical models death risk has been calculated for each of the 4 times. The Hosmer-Lemeshow test was performed for calibration and ROC curves for discrimination, always for each of the 4 mathematical models. RESULTS: The 1(st) model, at 24 hours from ICU admission, showed a bad calibration (p=0.000088), while the ROC curve was 0.744+/-0.32. Also the 2(nd) model, at the 5(th) day from admission, showed a bad calibration (p=0.000588), with ROC curve of 0.827+/-0.04. The 3(rd) model (10(th) day), was well calibrated (p=0.112247) and discriminating (ROC=0.888 +/-0.04). Finally the models at 15 days showed again a bad calibration (p=0.001422) but a very good discrimination (area=0.906+/-0.06). CONCLUSION: Developing mathematical models to predict mortality within ICUs can be useful to assess quality of care, even if these models should not be the only ICU quality controls, but must be accompanied by other indicators, looking at quality of life of the patients after ICU discharge.

Critical Care↗

Mathematical modeling of ligaments and tendons.

Ligaments and tendons serve a variety of important functions in maintaining the structure of the human body. Although abundant literature exists describing experimental investigations of these tissues, mathematical modeling of ligaments and tendons also contributes significantly to understanding their behavior. This paper presents a survey of developments in mathematical modeling of ligaments and tendons over the past 20 years. Mathematical descriptions of ligaments and tendons are identified as either elastic or viscoelastic, and are discussed in chronological order. Elastic models assume that ligaments and tendons do not display time dependent behavior and thus, they focus on describing the nonlinear aspects of their mechanical response. On the other hand, viscoelastic models incorporate time dependent effects into their mathematical description. In particular, two viscoelastic models are discussed in detail; quasi-linear viscoelasticity (QLV), which has been widely used in the past 20 years, and the recently proposed single integral finite strain (SIFS) model.

Animals↗

A mathematical model of cerebrospinal fluid dynamics.

The ability to solve systems of simultaneous non-linear differential equations by a combination of analytical and computational techniques has encouraged the development of valid mathematical models of biological phenomena. The dynamics of the cerebrospinal fluid (CSF) system has been the subject of closer scrutiny in recent years since the recognition of symptomatic low-pressure hydrocephalic states in man. A mathematical model has been derived from 7 assumptions: (1) That the brain is a spherical shell. (2) That CSF is secreted at a constant rate. (3) That CSF absorption is linearly dependent on pressure. (4) That flow between the CSF compartments is proportional to the pressure difference. (5) That Laplace's Law holds for the visco-elastic properties of the brain. (6) That there is compliance in the spinal compartment of the CSF system. (7) That vascular pulsations in the cranial and spinal compartments are capacitatively coupled. Using known data (and estimates of as yet unknown values) for the several parameters, the validity of the model has been successfully tested against 3 clinical conditions. This model extends our understanding of derangements of CSF dynamics and suggest where further research may yield data at present lacking.

Cerebrospinal Fluid↗

Mathematical modelling of radiotherapy strategies for early breast cancer.

Targeted intraoperative radiotherapy (Targit) is a new concept of partial breast irradiation where single fraction radiotherapy is delivered directly to the tumour bed. Apart from logistic advantages, this strategy minimizes the risk of missing the tumour bed and avoids delay between surgery and radiotherapy. It is presently being compared with the standard fractionated external beam radiotherapy (EBRT) in randomized trials. In this paper we present a mathematical model for the growth and invasion of a solid tumour into a domain of tissue (in this case breast tissue), and then a model for surgery and radiation treatment of this tumour. We use the established linear-quadratic (LQ) model to compute the survival probabilities for both tumour cells and irradiated breast tissue and then simulate the effects of conventional EBRT and Targit. True local recurrence of the tumour could arise either from stray tumour cells, or the tumour bed that harbours morphologically normal cells having a predisposition to genetic changes, such as a loss of heterozygosity (LOH) in genes that are crucial for tumourigenesis, e.g. tumour suppressor genes (TSGs). Our mathematical model predicts that the single high dose of radiotherapy delivered by Targit would result in eliminating all these sources of recurrence, whereas the fractionated EBRT would eliminate stray tumour cells, but allow (by virtue of its very schedule) the cells with LOH in TSGs or cell-cycle checkpoint genes to pass on low-dose radiation-induced DNA damage and consequently mutations that may favour the development of a new tumour. The mathematical model presented here is an initial attempt to model a biologically complex phenomenon that has until now received little attention in the literature and provides a 'proof of principle' that it is possible to produce clinically testable hypotheses on the effects of different approaches of radiotherapy for breast cancer.

Brachytherapy↗

Mathematical modeling of cancer: the future of prognosis and treatment.

BACKGROUND: Cancer research has undergone radical changes in the past few years. Producing information both at the basic and clinical levels is no longer the issue. Rather, how to handle this information has become the major obstacle to progress. Intuitive approaches are no longer feasible. The next big step will be to implement mathematical modeling approaches to interrogate the enormous amount of data being produced and extract useful answers (a "top-down" approach to biology and medicine). METHODS: Quantitative simulation of clinically relevant cancer situations-based on experimentally validated mathematical modeling-provides an opportunity for the researcher, and eventually the clinician, to address data and information in the context of well-formulated questions and "what if" scenarios. RESULTS AND CONCLUSIONS: At the Vanderbilt Integrative Cancer Biology Center (VICBC), we are integrating cancer researchers, oncologists, chemical and biological engineers, computational biologists, computer modelers, theoretical and applied mathematicians, and imaging scientists, in order to implement a vision for a combined web site and computational server that will be a home for our mathematical modeling of cancer invasion. The web site (www.vanderbilt.edu/VICBC/) will serve as a portal to our code, which simulates tumor growth by calculating the dynamics of individual cancer cells (an experimental "bottom-up" approach to complement the top-down model). Eventually, cancer researchers outside of Vanderbilt will be able to initiate a simulation based on providing individual cell data through a web page. We envision placing the web site and computer cluster directly in the hands of biological researchers involved in data mining and mathematical modeling. Furthermore, the web site will also contain teaching props for a new generation of biomedical researchers fluent in both mathematics and biology. This is unconventional bioinformatics: We will be incorporating biological data and functional information into a unified community-based mathematical framework. The result will be a tool for cancer modeling that will ultimately have basic research, therapeutic and educational value.

Animals↗

[Changes in the levels of paramagnetic centers in the mouse liver and a mathematical model of synchronized auto-oscillations].

Investigations of circadian rhythms in paramagnetic particles (free radicals and metal complexes) (PP) concentration variations in tissues are under continuation. A mathematical model advanced considers PP biorhythms as self-induced oscillations subjected to weak synchronization by an external source, by geomagnetic field intensity daily variations for example. By computation parameters of the model were obtained giving good agreement between the theory and experimental data. Due to the mathematical model the amplitude of external synchronizer influence is ten times less than the self-amplitude of PP biorhythm. The experiment was performed on the normal mouse liver. ESR signals g = 1.94, 2.00 and 2.25 were studied.

Animals↗

A mathematical model predicting anti-hepatitis B virus surface antigen (HBs) decay after vaccination against hepatitis B.

The determination of serum levels of antibodies against hepatitis B virus surface antigen (anti-HBs) after hepatitis B vaccination is currently the only simple test available to predict the decay of protection and to plan the administration of booster doses. A total of 3085 vaccine recipients of plasma-derived and recombinant vaccine have been followed for 10 years to determine the kinetics of anti-HBs production and to construct a mathematical model which could efficiently predict the anti-HBs level decline. The anti-HBs peak level was reached 68 days after the last dose of recombinant vaccine and 138 days after the last dose of plasma-derived vaccines. The age of vaccinees negatively influenced the anti-HBs levels and also the time necessary to reach the anti-HBs peak. A bilogarithmic mathematical model (log10 level, log10 time) of anti-HBs decay has been constructed on a sample of recombinant vaccine recipients and subsequently validated on different samples of recombinant or plasma-derived vaccine recipients. Age, gender, type of vaccine (recombinant or plasma-derived), number of vaccine doses (three or four) did not influence the mathematical model of antibody decay. The program can be downloaded at the site: http:@www2.stat.unibo.it/palareti/vaccine.htm . Introducing an anti-HBs determination obtained after the peak, the program calculates a prediction of individual anti-HBs decline and allows planning of an efficient booster policy.

Algorithms↗

Fashioning of aortic isthmoplasty patch. A mathematical model.

BACKGROUND: Patch enlargement of the aortic isthmus in congenital coarctation of the aorta (aortic isthmoplasty) has been extensively performed since its introduction in 1957. Even after forty years, the size and shape of the prosthetic patch used as an on a graft is still determined, most of the time, empirically through eyeballing. Not infrequently, it has resulted in an ugly looking repaired aortic segment or with a significant residual systolic gradient across it. These twin problems have called for a mathematical model for designing the patch more precisely. METHODS: The model envisages a patch of the shape of an asymmetric octagon whose cranio-caudal length equals the distance from a point 8 mm on the proximal aorta to a point 8 mm on the distal dilated aorta on either side of the coarcted segment. The side to side length of the patch is determined by first subtracting the circumference of the narrowest part of the coarcted segment from the circumference of the distal dilated portion of the aorta and then adding 4 mm more. The larger slant sides of the octagon are obtained by joining the four smaller sides, of 8 mm in length each. Since July 1993 this mathematical model has been employed in 7 patients to prepare the exact size and the shape of the tightly woven low porosity Dacron patch. RESULTS: In each instance a neat cylindrical aorta was obtained without any measurable post-repair systolic pressure gradient across the repaired site. CONCLUSIONS: In view of these very satisfying results, we believe that this mathematical model of tailoring the patch has succeeded in converting the patch-aortoplasty procedure for coarctation of the aorta into a precise and hemodynamically fully corrective operation.

Adolescent↗

Pest control through viral disease: mathematical modeling and analysis.

This paper deals with the mathematical modeling of pest management under viral infection (i.e. using viral pesticide) and analysis of its essential mathematical features. As the viral infection induces host lysis which releases more virus into the environment, on the average 'kappa' viruses per host, kappain(1,infinity), the 'virus replication parameter' is chosen as the main parameter on which the dynamics of the infection depends. We prove that there exists a threshold value kappa(0) beyond which the endemic equilibrium bifurcates from the free disease one. Still for increasing kappa values, the endemic equilibrium bifurcates towards a periodic solution. We further analyse the orbital stability of the periodic orbits arising from bifurcation by applying Poor's condition. A concluding discussion with numerical simulation of the model is then presented.

Agriculture↗