ALBERT

Notes: Abstract In the theory of organismic sets (Bull. Math. Biophysics,31, 159–198, 1969) we considered organisms as sets endowed with certain “activities,” the latter’s resulting in a set of “products.” Those products may be of a material nature, like a hormone secreted by a cell, or of a non-material nature, like a feeling or an attitude. In the present paper aggressiveness and submissiveness are considered as such non-material products of the activities of the brain cells. A general description of aggressiveness and submissiveness is given in terms of organismic sets. Cycles in “peck order” are thus naturally explained.

Notes: Abstract In line with previous studies on organismic sets, the division of all organismic sets intogeneral autotrophic and heterotrophic is introduced. The first produce their food themselves from some external source of energy, which in general may be an energy of any kind. The others use other organismic sets as the source of their food and energy. On earth we know only one kind of generalgeneral autotrophic organismic sets, namely, the autotrophic plants which use solar radiation as their source of energy and for production of their own food. It is shown why autotrophic animals do not exist on earth except as microorganisms like, e.g.,Euglena. A rigorous proof of the previously derived theorem that in an organismic set of ordern〉1 no element can be completely specialized is given. It requires the introduction of new postulates. Finally, in considering the organic world as a whole, the notion of organismic sets ofmixed order is introduced.

Notes: Abstract It appears to be axiomatic that termolecular and higher order reactions occur relatively rarely. The basis for this judgment seems to lie in the supposition that successful 3-Body collisions of 3 interactive species of molecules cannot occur frequently enought to account for chemical or biochemical transformation. In order to provide a more complete mathematical framework than now exists for examining this hypothesis the probability of effective termolecular “δ-collisions” as a function of time is derived. This amounts to adding to the class of reactions for which stochastic models are now available the termolecular reaction. In common with the unimolecular and bimolecular cases this process is seen to satisfy the criterion of consistency-in-the-mean with respect to deterministic formulations. It is planned next to use the termolecular process and the lower order processes in computer-assistedin numero experimental studies aimed at comparing alternative mechanisms of reaction.

Notes: Abstract Small sample properties of the maximum likelihood estimator for the rate constant of a stochastic first order reaction are investigated. The approximate bias and variance of the maximum likelihood estimator are derived and tabulated. If observations of the system are made at timesiτ,i=1, 2, ...,N; τ〉0, the observational spacing τ which minimizes the approximate variance of the maximum likelihood estimator is found. The non-applicability of large sample theory to confidence interval derivation is demonstrated by examination of the relative likelihood. Bartlett’s method is employed to derive approximate confidence limits, and is illustrated by using simulated kinetic runs.

Notes: Abstract The representation of biological systems by means of organismic supercategories, developed in previous papers (Bull. Math. Biophysics,30, 625–636;31, 59–71;32, 539–561), is further discussed. The different approaches to relational biology, developed by Rashevsky, Rosen and by Băianu and Marinescu, are compared with Qualitative Dynamics of Systems which was initiated by Henri Poincaré (1881). On the basis of this comparison some concrete result concerning dynamics of genetic system, development, fertilization, regeneration, analogies, and oncogenesis are derived.

Notes: Abstract Some years ago (Rosen 1958a, b; 1959) we described a class of metaphorical, relational paradigms for cellular activity which we termed (M, R)-systems. A sizable amount of subsequent work, to be itemized below, has been devoted to an exploration of some of the properties of these systems. The main purpose of the present paper is to put this class of paradigms into a general system-theoretic perspective, with a particular view to appraising the relation between the type of system description embodied in the (M, R)-system and other kinds of physical and mathematical descriptions of cellular systems. Thus, the principal aim is to establish the relationships and connections between the global relational formalism embodied in the (M, R)-systems and the empirical descriptions which still represent the bulk of our biological knowledge.

Notes: Abstract After giving a brief review of the theory of organismic sets (Bull. Math. Biophysics,29, 139–152, 1967;31, 159–198, 1969), in which the concept of relational forces, introduced earlier (Bull. Math. Biophysics,28, 283–308, 1966a) plays a fundamental role, the author discusses examples of possible different structures produced by relational forces. For biological organisms the different structures found theoretically are in general agreement with observation. For societies, which are also organismic sets as discussed in the above references, the structures can be described only in an abstract space, the nature of which is discussed. Different isomorphisms between anatomical structures, as described in ordinary Euclidean space, and the sociological structures described in an abstract space are noted, as should be expected from the theory of organismic sets.

Notes: Abstract Current psychological research into the inference (diagnostic) process is briefly reviewed, using as a vehicle an investigation of the prediction of the probability of success of hypothetical applicants to a graduate program in biology. Brunswik’s lens model and multiple regression analysis are used, as is a Bayesian approach. Four judges’ (biologists’) predictions are analyzed. Some general conclusions about inference, drawn from the current data in psychology, are presented.

Notes: Abstract A mathematical model has been developed to simulate the glucose-insulin interaction following a glucose load such as occurs in an IVGTT. This model differs from earlier models in that the insulin response to glucose loading is a recurring all or none threshold response. The model has been simulated on a digital computer using the digital analog simulation language CSMP.

Notes: Abstract The composite nature of bone dictates the use of a model for bone which is transversely isotropic. We solve the associated sets of partial differential equations governing the dynamic elastic behavoor of a two-layered cylindrical-shaped bone. The solution is analyzed for long, short, and intermediate length waves. The special case of compact bone is treated for long and short wave lengths and a numerical example is worked out to determine the wave speeds (for short wave lengths) given a set of elastic constants, determined by ultrasonic methods, and the bone density, wave frequency, and radius.

Notes: Abstract A stochastic model is developed for a compartment with a single time-dependent input, and generalized to include inputs from several sources. With the number of particles of a given molecular species in the compartment as the random variable, the mean, variance and third central moment of this variable are calculated from its generating function, and compared with previous results. The behavior of the calculated moments is discussed, and the possibility of applying the model to chemical and biological systems is considered.

Notes: Abstract It is shown that from the definition of organismic sets (Rashevsky,Organismic Sets. Some Reflections on the Nature of Life and Society, Holland, Michigan, Mathematical Biology, Inc. and Grosse Pointe, Michigan, J. M. Richards Laboratory) a complete sensory deprivation of an organismic set of ordern=2 should result in malfunctioning of the set. A generalization to higher order sets is suggested.

Notes: Abstract Optimality in branching structure of the vascular tree was studied. Analysis on its physiological roles as the duct system for blood supply to the capillaries predicted that the vascular tree should be constructed with minimum volume under restriction of determinant pressure, flow and location at the origin and the terminals. Mathematical derivations of this conditional extremum problem yielded some equations expressing the relations between the radii of the branches and their branching angles, which provided numerical solutions for branching points of bi- and poli-terminal minimum volume trees. Comparison of the peritoneal vascular tree in a dog with the minimum volume one computed under the same restrictive conditions showed good agreement in their branching structure.

Notes: Abstract In order to determine the kinetics of passage of a substance through an organ containing a tangle of vessels, we study the response of a tube to various inflows (perfusion, brief injection, ...). The introduction of the catabolic terms and of the spatial dependence between bulk concentration and surface concentration allows one to account for the difference of arteriovenous concentrations observed experimentally for many metabolites. The relationships between the physico-chemical parameters of the organ and the operational parameters of the model demonstrate the importance of the transit time through the considered vessels. If one considers the different pathways as independent, the introduction of the transit time distribution for an inert substance enables one to compute the response of the organ analytically or by recurrence, using convolution. The parameters of the model can be obtained by the moments method.

Notes: Abstract The solution of the diffusion equation in the gas phase of the human lung is very difficult because of the structure of the bronchial tree. It is shown by means of physical arguments, how one can reduce the diffusion equation to a simple one-dimensional form. The solution is then obtained by a stochastic simulation, which is easily realized on a digital computer.

Notes: Abstract A new mathematical model of the oscillatory behavior of the respiratory center has been developed based upon published records of neuronal activity during respiration in the pons and medulla. In contrast with a previous model, four, rather than two, networks are assumed to interact in the respiratory center so as to produce the respiratory oscillation. A mathematical description of this interaction, in the form of a set of four first-order, nonlinear, coupled differential equations, is derived; the behavior of the solutions of this system is studied qualitatively, and expressions for the durations of the inspiratory and expiratory phases are obtained in terms of some parameters. It is found that central and chemical influences drive the medullar neurons to a position somewhere between saturation and full cutoff, and the pontine neurons deeply into cutoff. The control of the duration of the different phases by these chemical and central means is discussed. In order to effect a decrease in the magnitude of the various times, the neurons have to be driven towards operating points of higher central facilitation.

Notes: Abstract In vivo control of calcium is analysed under the assumption that hormonal influences via plasma levels of parathormone and calcitonin are of prime (but not absolutely dominating) importance. A brief review concerning the physiological significance of body calcium and the mode of action of these two hormones is presented as an introduction to the basic philosophy of the study. A theoretical quasi-linear lumped-parameter model is developed to describe variations in ionic calcium, parathormone and calcitonin plasma concentrations to specific input stimuli. Formal evaluation of the system response requires the determination of ten constants, together with quantitation of ingested calcium entry into the plasma compartment which isindependent of hormonal influences. Values for various parameters are deduced from published data and experimental procedures are outlined to facilitate determination of the remaining unknowns. It is suggested that the proposed model should prove useful for investigations concerning general hormonal actions on calcium homeostatic mechanisms in both normal and diseased states, with particular reference to calcitonin.

Notes: Abstract Ann species predator-prey chain is analyzed to determine what oscillations occur in population sizes. It is found that only the populations of the first and second species in the chain must necessarily oscillate around the point of equilibrium if they do not come to equilibrium. The other species may or may not oscillate.

Notes: Abstract Sangren and Sheppard developed a mathematical model for first-order processes taking place in the regional circulation, applicable—for example—to tracer studies of potassium transport. It permits calculation of specific activity at any point along a “tube of flow” or in the cuff of tissue surrounding it as a function of time following a spike injection of tracer. In efforts to relate to the exchange a rate curves obtained within vivo counters pointed at the region of interest, we developed a compartment-system model of the process. In investigating the properties of the Sangren and Sheppard model integrated over an entire circulatory bed, as thein vivo counter would see it, we found that when the distribution of transit times of the “tubes of flow” can be approximated by an exponential sum, the solution reduces to that of the compartment system model. This results in an important simplification in the calculation, and insight into the assumptions underlying the two different models. A curve-fitting computer program for the compartment model has been written and applied to double-isotope studies of potassium transport in the hind leg of the dog.

Notes: Abstract Two chemicals,A andB, are allowed to diffuse together and a reaction described by $$A + B\mathop \rightleftharpoons \limits_{K_{ - 1} }^{K_1 } C$$ is allowed to proceed. This system is described mathematically by a system of partial differential equations. A numerical procedure is presented to find the rate constants ofK 1 andK −1. A systematic analysis of the effects of errors is also presented.

Notes: Abstract Equations are developed to describe the energy expenditure of the human heart. As well as the external potential and kinetic energy terms, general consideration is given to other possible avenues of energy consumption. Emphasis is placed upon using mathematical variables which are readily available for experimental verification. The errors involved in assuming that mean values for the physiological parameters give reasonable estimations for the external mechanical performance are examined, and a theoretical estimation for the discrepancy in the kinetic component is presented. Logical extension of the mathematical derivation leads to a determination of cardiac external mechanical efficiency and clearly demonstrates the significance of the ventricular pressure-volume loop in this context. Finally, experimental procedures are suggested to clarify further some of the conclusions reached through the theoretical analysis.

Notes: Abstract The question is discussed as to the reason why some animal societies, such as bees or ants, are sexually differentiated, that is, onlysome of its members are exhibiting reproducing activities. It is indicated that human society may be on its way to such a sexual differentiation which may eventually come.

Notes: Abstract X-ray diffraction patterns obtained experimentally for fibers, together with their chemical structures, can be analyzed theoretically in terms of an integral equation. The partially unknown electron density function can be solved by iteration. This mathematical technique has been applied with success to study the secondary structures of DNA fibers.

Notes: Abstract For an environmental system described by a system of nonlinear first-order differential equations, the problem of achieving specified terminal conditions in a given time with a minimum expenditure of resources is considered. The initial conditions and the minimum value are found numerically in a particular example.

Notes: Abstract A kinetic model of neural systems is introduced and discussed with statistical mechanics techniques. It is assumed that, for a macroscopic description of the model, it suffices to consider only the distribution for the velocity and position of the impulses, and the distribution for the excitation and position of the neurons, at any timet. Making use of Boltzmann's method for the study of a dilute gas, coupled differential equations for the rate of change with time of the distributions have been constructed.

Notes: Abstract Creeping flow of a Newtonian fluid through a rigid permeable tube is considered and the transmural seepage is assumed to obey Darcy's law. Closed-form solutions for the pressure and velocity fields are presented and equations describing the axial variation of the mean cross-sectional pressure, the axial volumetric flow and the transmural fluid flux are derived. Approximate solutions for small seepage rates are given and are applied to the flow in the proximal renal tubule. Probable values for the epithelium permeability and the intraluminal hydrostatic pressure drop are obtained.

Notes: Abstract The paper demonstrates that it is possible to construct memory models where the information inserted is stored in disseminated form, using sequential coding, the changes in the units forming the models being determined by their geometrical connections and by the incoming stream of information. The models are shown to have large storage capacity and their efficiency can be made insensitive to loss of or damage to a large fraction of their units. The satisfactory verification by computer simulation of the analysis and results described in the present paper will be the subject of a future paper.

Notes: Abstract We examine in detail Edward Kerner’s method for linearizing the equations of enzyme kinetics. Our main result is the determination of canonical forms for systems which can be linearized by the method. This is done both in general and in the special cases of two and three dimensions where complete results are obtained. The practical problem of identifying linearizable systems is also considered and computable necessary criteria are presented.

Notes: Abstract A general method for determination of the volume of a space in a non steady state condition, in case diffusion might be significant, is developed. Instantaneous mixing of indicators with native fluid is assumed in this first stage of investigation. Theoretical expressions are obtained for the volume of the space and the diffusion coefficient as a function of time. An analysis of feasibility of the method is also included.

Notes: Abstract The theory of transfer of low-molecular nonelectrolytes across deformable semipermeable membranes of large curvature developed in Part I (Rubinstein, 1974) is used to describe the dynamics of swelling and shrinking of a muscle fiber at the influx and efflux of low-molecular nonelectrolytes. A large set of computations showed that the theory explains the experiments described in the literature.

Notes: Abstract Green's function for heat and matter transport is calculated for an infinite medium in which a convection field v(r,t) makes a contribution to the total heat and matter current. It is given by a uniformly and absolutely convergent series in which every term is calculated from the preceding one merely by integration. The solution procedure is interpreted physically and illustrated by a simple problem in which v(r,t)=const. in space and time. Since the solution contains no intrinsic spatial symmetry, it can serve as a starting point for a theory of heat and mass transport in perfused biological tissue.

Notes: Abstract The hydrodynamics of a microorganism swimming in a channel is investigated. The microorganism is modeled as a two-dimensional sheet swimming at low Reynolds numbers between two rigid walls. The wavelengths of the propulsive waves passing down the sheet are assummed to be very large compared to the channel spacing, but the amplitude of the propulsive waves is arbitrary. Explicit analytical solutions for the propulsive velocity and the rate of energy dissipated in terms of the wave amplitude, channel spacing, wave number, and wave speeds are given.

Notes: Abstract It is shown from the statistical-mechanical overview of Volterra's ecological model how to reckon the fluctuations of collective variables such as the total population of a genus: and that these fluctuations are much decreased (or that the collective populationsteadiness is enhanced) as the speciation is increased. (A niching of species in time, or phase-niching, is entailed here.) Secondly, it is shown how Preston's log-normal distribution describing the species-abundance relationship, as well as a generalization of such distributions, come forth simply and naturally from the statistical-Volterra-dynamics.

Notes: Abstract In the framework of the neural network theory effects similar to hypnotic displays are constructed. They are based on the associative paradigm involving non-linear interaction of excitatory and inhibitory channels with synaptic memory. The non-linearity of long-term memorizing processes may cause effects exhibited by blind spots, which are interpreted as the first stage of hypnosis. More complicated phenomena are discussed in terms of a two-layer network.

Notes: Abstract Mutation is introduced into autocatalytic reaction networks. The differential equations obtained are neither of repliator-type nor can they be transformed straightway into a linear equation. Examples of low dimensional dynamical systems —n=2, 3 and 4 — are discussed and complete qualitative analysis is presented. Error thresholds known from simple replication-mutation kinetics with frequency independent replication rates occur here as well. Instead of cooperative transitions or higher order phase transitions the thresholds appear here as supercritical or subcritical bifurcations being analogous to first-order phase transitions.

Notes: Abstract The non-linear behavior of a differential equations-based predator-prey model, incorporating a spatial refuge protecting a consant proportion of prey and with temperature-dependent parameters chosen appropriately for a mite interaction on fruit trees, is examined using the numerical bifurcation code AUTO 86. The most significant result of this analysis is the existence of a temperature interval in which increasing the amount of refuge dynamically destabilizes the system; and on part of this interval the interaction is less likely to persist in that predator and prey minimum population densities are lower than when no refuge is available. It is also shown that increasing the amount of refuge can lead to population outbreaks due to the presence of multiple stable states. The ecological implications of a refuge are discussed with respect to the biological control of mite pests.

Notes: Abstract In many applications of control theory on plant growth models biomass maximization is postulated to avoid analytically unsolvable problems while fruit maximization is commonly considered to be a more realistic criterion. In a special case, we are able to compare these criteria. Iwasa and Roughgarden (1984,Theor. Pop. Biol. 25, 78–105) have investigated a certain class of plant growth models using a fruit maximization criterion. They proved that, in the vegetative growth period, the organs follow a certain path of balanced growth. We show that this path remains optimal when biomass maximization is postulated. This underlines the importance of the balanced growth path found by Iwasa and Roughgarden. Furthermore, our result suggests that in the vegetative growth period the biomass maximization criterion is a good approximation of fruit maximization. In another theoretical control investigation, Schultzeet al. (1983,Oecologia 58, 169–177) derived a different type of balanced growth path. We apply the theory of Iwasa and Roughgarden to an improved version of the model of Schulzeet al. This leads to a new description of balanced growth between root and shoot that reflects non-linearities in the water uptake process and constitutes an interesting hypothesis for further experimental testing.

Notes: Abstract In this paper the effects of changing the ion concentration in and around a sample of soft tissue are investigated. The triphasic theory developed by Laiet al. (1990,Biomechanics of Diarthrodial Joints, Vol. 1, Berlin, Springer-Verlag) is reduced to two coupled partial differential equations involving fluid ion concentration and tissue solid deformation. These equations are given in general form for Cartesian, cylindrical and spherical geometries. After solving the two equations quantities such as fluid velocity, fluid pressure, chemical potentials and chemical expansion stress may be easily calculated. In the Cartesian geometry comparison is made with the experimental and theoretical work of Myerset al. (1984,ASME J. biomech. Engng,106, 151–158). This dealt with changing the ion concentration of a salt shower on a strip of bovine articular cartilage. Results were obtained in both free swelling and isometric tension states, using an empirical formula to acount for ion induced deformation. The present theory predicts lower ion concentrations inside the tissue than this earlier work. A spherical sample of tissue subjected to a change in salt bath ion concentration is also considered. Numerical results are obtained for both hypertonic and hypotonic bathing solutions. Of particular interest is the finding that tissue may contract internally before reaching a final swollen equilibrium state or swell internally before finally contracting. By considering the relative magnitude, and also variation throughout the time course of terms in the governing equations, an even simpler system is deduced. As well as being linear the concentration equation in the new system is uncoupled. Results obtained from the linear system compare well with those from the spherical section. Thus, biological swelling situations may be modelled by a simple system of equations with the possibility, of approximate analytic solutions in certain cases.

Notes: Abstract Many models of immune networks have been proposed since the original work of Jerne [1974,Ann. Immun. (Inst. Pasteur) 125C, 373–389]. Recently, a limited class of models (Weisbuchet al., 1990,J. theor. Biol. 146, 483–499) have been shown to maintain immunological memory by idiotypic network interactions. We examine generalizations of these models when the networks are both large and highly connected to study their memory capacity, i.e. their ability to account for immunization to a large number of random antigens. Our calculations show that in these minimal models, random connectivities with continuously distributed affinities reduce the memory capacity to essentially nil.

Notes: Abstract A kinetic model is proposed to delineate the factors that determine the coronary reactive hyperemic response (RHR) to transient ischemia. The model comprises of myocardial-interstitial (M) and vascular (V) compartments. Vasodilator metabolites (VM) are produced in the M compartment during the interval of coronary occlusion. The rate of VM production is dependent on the flow rate during the ischemic period, the ratio of excess flow above the control level (R) to the loss of flow during occlusion period (D), the amount of oxygen stored and the degree of vasodilation in the V compartment prior to occlusion. Following a complete release of occlusion, VM are transported from the M to V compartment and are washed out or degraded with time. The time course of RHR is determined by the coronary patency which is proportional to VM concentration in the V compartment. Based on a set of numerical constants, the model is tested by simulating RHR to the various occlusion manoeuvres: a pair of 10 sec occlusions separated by brief release, a 15 sec release followed by a second brief occlusion, a brief release of an occlusion followed by restriced inflow and a period of restricted inflow after occlusion. The simulated results fit the experimental R/D and RH durations data of canine hearts. Factors that determine the impairment of RH capacity in coronary stenosis are suggested in terms of the model scheme.

Notes: Abstract In the present paper a kinetic study is made of the behaviour of a Michaelis-Menten enzyme-catalysed reaction in the presence of irreversible inhibitors rendered unstable in the medium by their reaction with the product of enzymatic catalysis. A general mechanism involving competitive, non-competitive, uncompetitive and mixed irreversible inhibition with one or two steps has been analysed. The differential equation that describes the kinetics of the reaction is non-linear and computer simulations of its dynamic behaviour are presented. The results obtained show that the systems studied here present kinetic co-operativity for a target enzyme that follows the simple Michaelis-Menten mechanism in its action on the substrate, except in the case of an uncompetitive-type inhibitor.

Notes: Abstract The relative contributions of mitochondrial β-oxidation and peroxisomal β-oxidation and peroxisomal ω-oxidation to the oxidation of a given fatty acidin vivo can be quantitated by an isotopic method. The approach requires infusion of a fatty acid labelled on two specific carbon atoms (e.g. [1-14C] and [11-14C] palmitate) to an isotopic steady state, with subsequent isolation and degradation of an acetylated conjugate as a product of the liver cytosolic acetyl CoA pool and of ketone bodies as a product of the liver mitochondrial acetyl CoA pool.

Notes: Abstract Pancreatic β-cells in intact islets of Langerhans perfused with various glucose concentrations exhibit periodic bursting electrical activity (BEA) consisting of active and silent phases. The fraction of the time spent in the active phase is called the plateau fraction and appears to be strongly correlated with the rate of release of insulin from islets as glucose concentration is varied. Here this correlation is quantified and a theoretical development is presented in detail. Experimental rates of insulin release are correlated with “effective” plateau fractions over a range of glucose concentrations. There are a number of different models for BEA in pancreatic β-cells and a method is developed here to quantify the dependence of a glucose dependent parameter on glucose concentration. As an example, the plateau fractions computed from the Sherman-Rinzel-Keizer model are matched with experimental plateau fractions to obtain a relationship between the model's glucose-dependent parameter, β, and glucose concentration. Knowledge of the relationships between β and glucose concentration and between experimental measurements of rates of insulin release and plateau fractions permits the determination of theoretical rates of insulin release from the model.

Notes: Abstract When a suspension of bacterial cells of the speciesBacillus subtilis is placed in a chamber with its upper surface open to the atmosphere complex bioconvection patterns are observed. These arise because the cells: (1) are denser than water; and (2) usually swim upwards, so that the density of an initially uniform suspension becomes greater at the top than the bottom. When the vertical density gradient becomes large enough, an overturning instability occurs which ultimately evolves into the observed patterns. The reason that the cells swim upwards is that they are aerotactic, i.e. they swim up gradients of oxygen, and they consume oxygen. These properties are incorporated in conservation equations for the cell (N) and oxygen (C) concentrations, and these are solved in the pre-instability phase of development whenN andC depend only on the vertical coordinate and time. Numerical results are obtained for both shallow- and deep-layer chambers, which are intrinsically different and require different mathematical and numerical treatments. It is found that, for both shallow and deep chambers, a thin boundary layer, densely packed with cells, forms near the surface. Beneath this layer the suspension becomes severely depleted of cells. Furthermore, in the deep chamber cases, a discontinuity in the cell concentration arises between this cell-depleted region and a cell-rich region further below, where no significant oxygen concentration gradients develop before the oxygen is fully consumed. The results obtained from the model are in good qualitative agreement with the experimental observations.

Notes: Abstract We describe a classification scheme for bursting oscillations which encompasses many of those found in the literature on bursting in excitable media. This is an extension of the scheme of Rinzel (inMathematical Topics in Population Biology, Springer, Berlin, 1987), put in the context of a sequence of horizontal cuts through a two-parameter bifurcation diagram. We use this to describe the phenomenological character of different types of bursting, addressing the issue of how well the bursting can be characterized given the limited amount of information often available in experimental settings.

Notes: Abstract To ensure its sustained growth, a tumour may secrete chemical compounds which cause neighbouring capillaries to form sprouts which then migrate towards it, furnishing the tumour with an increased supply of nutrients. In this paper a mathematical model is presented which describes the migration of capillary sprouts in response to a chemoattractant field set up by a tumour-released angiogenic factor, sometimes termed a tumour angiogenesis factor (TAF). The resulting model admits travelling wave solutions which correspond either to successful neovascularization of the tumour or failure of the tumour to secure a vascular network, and which exhibit many of the characteristic features of angiogenesis. For example, the increasing speed of the vascular front, and the evolution of an increasingly developed vascular network behind the leading capillary tip front (the brush-border effect) are both discernible from the numerical simulations. Through the development and analysis of a simplified caricature model, valuable insight is gained into how the balance between chemotaxis, tip proliferation and tip death affects the tumour's ability to induce a vascular response from neighbouring blood vessels. In particular, it is possible to define the success of angiogenesis in terms of known parameters, thereby providing a potential framework for assessing the viability of tumour neovascularization in terms of measurable quantities.

Notes: Abstract The parameter domain for which the quasi-steady state assumption is valid can be considerably extended merely by a simple change of variable. This is demonstrated for a variety of biologically significant examples taken from enzyme kinetics, immunology and ecology.

Notes: Abstract The ability of random fluctuations in selection to maintain genetic diversity is greatly increased when generations overlap. This result has been derived previously using genetic models with very special assumptions about the population age structure. Here we explore its robustness in more realistic population models, with very general age structure or physiological structure. For a range of genetic models (haploid, diploid, single and multilocus) we find that the condition for maintaining genetic diversity generalizes almost without change. Genetic diversity is maintained by selection if a product of the form (generation overlap)×(selection intensity)×(variability in the selection regime) is sufficiently large, where the generation overlap is measured in units of Fisher's reproductive value. This conclusion is based on a local evolutionary stability analysis, which differs from the standard “protected polymorphism” criterion for the maintenance of genetic diversity. Simulation results match the predictions from the local stability analysis, but not those from the protected polymorphism criterion. The condition obtained here for maintaining genetic diversity requires fitness fluctuations that are substantial but well within the range observed in many studies of natural populations.

Notes: Abstract Premised on relatively simple assumptions, mathematical models like those of Monod, Pirt or Droop inadequately explain the complex transient behavior of microbial populations. In particular, these models fail to explain many aspects of the dynamics of aTetrahymena pyriformis-Escherichia coli community. In this study an alternative approach, an individual-based model, is employed to investigate the growth and interactions ofTetrahymena pyriformis andE. coli in a batch culture. Due to improved representation of physiological processes, the model provides a better agreement with experimental data of bacterial density and ciliate biomass than previous modeling studies. It predicts a much larger coexistence domain than rudimentary models, dependence of biomass dynamics on initial conditions (bacteria to ciliate biomasses ratio) and appropriate timing of minimal bacteria density. Moreover, it is found that accumulation ofE. coli sized particles andE. coli toxic metabolites has a stabilizing effect on the system.

Notes: Abstract At the core of contemporarymorphometrics—the quantitative study of biological shape variation—is a synthesis of two originally divergent methodological styles. One contributory tradition is the multivariate analysis of covariance matrices originally developed as biometrics and now dominant across a broad expanse of applied statistics. This approach, couched solely in the linear geometry of covariance structures, ignores biomathematical aspects of the original measurements. The other tributary emphasizes the direct visualization of changes in biological form. However, making objective the biological meaning of the features seen in those diagrams was always problematical; also, the representation of variation, as distinct from pairwise difference, proved infeasible. To combine these two variants of biomathematical modeling into a valid praxis for quantitative studies of biological shape was a goal earnestly sought though most of this century. That goal was finally achieved in the 1980s when techniques from mathematical statistics, multivariate biometrics, non-Euclidean geometry and computer graphics were combined in a coherent new system of tools for the complete regionalized quantitative analysis oflandmark points together with the biomedical images in which they are seen. In this morphometric synthesis, correspondence of landmarks (biologically labeled geometric points, like “bridge of the nose”) across specimens is taken as a biomathematical primitive. The shapes of configurations of landmarks are defined as equivalence classes with respect to the Euclidean similarity group and then represented as single points in David Kendall'sshape space, a Riemannian manifold with Procrustes distance as metric. All conventional multivariate strategies carry over to the study of shape variation and covariation when shapes are interpreted in the tangent space to the shape manifold at an average shape. For biomathematical interpretation of such analyses, one needs a basis for the tangent space compatible with the reality of local biotheoretical processes and explanations at many different geometric scales, and one needs graphics for visualizing average shape differences and other statistical contrasts there. Both of these needs are managed by thethin-plate spline, a deformation function that has an unusually helpful linear algebra. The spline also links the biometrics of landmarks to deformation analysis of the images from which the landmarks originally arose. This article reviews the history and principal tools of this synthesis in their biomathematical and biometrical context and demonstrates their usefulness in a study of focal neuroanatomical anomalies in schizophrenia.

Notes: Abstract A competition model describing tumor-normal cell interaction with the added effects of periodically pulsed chemotherapy is discussed. The model describes parameter conditions needed to prevent relapse following attempts to remove the tumor or tumor metastasis. The effects of resistant tumor subpopulations are also investigated and recurrence prevention strategies are explored.

Notes: Abstract Increasing attention is being paid to the configuration and development of vascular structures and their possible correlations with physiological events. The study of angiogenesis in normal and pathological states as well as in the embryo and adult has provided new insights into the mechanism of vessel growth and organization of the vasculature. Various mathematical branching models have been developed. These constructions are mainly geometrical and only involve a branching phenomenon. We propose the use of a deterministic non-linear model based on physiological laws and hydrodynamics. Growth, branching and anastomosis, the three actual main events occurring in vascular growth, are included in this model. Space growth, including cells and vessels, is defined by a decreasing transformation. Space density and the length of new sprouts are controlled by a set of parameters. The conditions on these parameters are well established, which allows the production of realistic patterns.

Notes: Abstract The quasi-stationary distribution of a population within a system of interacting populations is approximated by a stochastic logistic process. The parameters of this process can be expressed in the parameters of the full system. Using the diffusion approximation, an expression for the expected extinction time is derived from this logistic process. Since the expected extinction time is expressed in the parameters of the full system, the effect of these parameters on the extinction risk can be easily evaluated, which may be of use for studies in ecology, conservation biology and epidemiology. The outcome is compared with simulation results for the case of a prey-predator system.

Notes: Abstract The cytokines are the information superhighway of the immune system. They are an important component of the integrated behavior of the system. In order to be able to have a good understanding of the immune system, we must be able to model the effect of cytokines and their combined effect. This work is a step in that direction. We study the combined effect of two cytokines: interleukin-2 (IL-2) and interleukin-4 (IL-4) on some cells of the immune system. Interleukin-2 and interleukin-4 are important growth and differentiation factors for B and T cells. Interleukin-4 antagonizes the effect of interleukin-2 on B cells and some T cells while it synergizes with interleukin-2 on other T cells. We build a mathematical model of the interaction of both cytokines on T and B cells as a building block toward a model of the Th1/Th2 cross-regulation. The response of a given cell to the combination of interleukin-2 and interleukin-4 is shown to involve competing dynamical effects which can lead to either antagnostic or synergistic combined effect.

Notes: Abstract We propose a mathematical approach to the modelling of self-organizing hierarchies in animal societies. This approach relies on a basic positive feedback mechanism that reinforces the ability of a given individual to win or to lose in a hierarchical interaction, depending on how many times it won or lost in previous interactions. Motivated by experiments carried out on primitively eusocial waspsPolistes, the model, is based on coupled differential equations supplemented with a small stochastic term. Numerical integrations allow many different hierarchical profiles to be obtained depending on the model parameters: (1) the particular form of the probability for an individual to win or lose a fight given its history, (2) the probability of interaction between two individuals, (3) the forgetting strength, which determines the rate at which events in the past are forgotten and no longer influence the force of an individual and (4) two individual recognition parameters, which set the contribution of individual recognition in the process of hierarchical genesis. We compare the results, expressed in terms of a hierarchical index or of the Landau number that describes the degree of linearity of the hierarchy, with various experimental results.

Notes: Abstract The normal process of dermal wound healing fails in some cases, due to fibro-proliferative disorders such as keloid and hypertrophic scars. These types of abnormal healing may be regarded as pathologically excessive responses to wounding in terms of fibroblastic cell profiles and their inflammatory growth-factor mediators. Biologically, these conditions are poorly understood and current medical treatments are thus unreliable. In this paper, the authors apply an existing deterministic mathematical model for fibroplasia and wound contraction in adult mammalian dermis (Olsenet al., J. theor. Biol. 177, 113–128, 1995) to investigate key clinical problems concerning these healing disorders. A caricature model is proposed which retains the fundamental cellular and chemical components of the full model, in order to analyse the spatiotemporal dynamics of the initiation, progression, cessation and regression of fibro-contractive diseases in relation to normal healing. This model accounts for fibroblastic cell migration, proliferation and death and growth-factor diffusion, production by cells and tissue removal/decay. Explicit results are obtained in terms of the model processes and parameters. The rate of cellular production of the chemical is shown to be critical to the development of a stable pathological state. Further, cessation and/or regression of the disease depend on appropriate spatiotemporally varying forms for this production rate, which can be understood in terms of the bistability of the normal dermal and pathological steady states—a central property of the model, which is evident from stability and bifurcation analyses. The work predicts novel, biologically realistic and testable pathogenic and control mechanisms, the understanding of which will lead toward more effective strategies for clinical therapy of fibro-proliferative disorders.

Notes: Abstract Populations often exhibit abrupt changes in abundance associated with a smooth, continuous change in some component of their environment, with the abruptness usually attributed to inter-specific interactions or physical extremes. This paper presents a spatially explicit single-species population model in which intra-specific interactions alone are responsible for such an abrupt change. The essential mechanism involves cooperation in both colonization (through enhanced recruitment near other individuals) and mortality (protection through a “safety-in-numbers” interaction). Large fluctuations in population density would likely be observable near the transition region.

Notes: Abstract A mathematical model of the nitrogen transformation cycle in an aquatic environment is studied. Using Pontryagin's maximum principle, a preferential utilization of ammonium to nitrate by phytoplankton is explained and verified by experimental data. A multiparameter bifurcation is given. The model was found to have four types of equilibrium sets. It is shown that a Hopf bifurcation may occur.

Notes: Abstract Parallel computation employing a domain decomposition method was used to calculate precisely without approximations the spatio-temporal distribution of Ca2+ in nerve terminals. The results showed, contrary to expectations, that for equal admitted Ca2+ currents at low (one channel open) and high (four channels open) depolarization, the average Ca2+ concentration at the release area is higher at the low depolarization. These calculations provide additional support for the Ca2+-voltage hypothesis for neurotransmitter release.

Notes: Abstract Type I hypersensitivity, which functions to protect the organism from parasites, is caused by binding of antigen to IgE antibodies pre-attached to the cell surface of tissue mast cells and their circulating counterparts, the basophils. In “allergy,” type I hypersensitivity is inappropriately induced by protein-based foreign substances (such as pollen) or protein components of insect stings, which in the normal course of events would be cleared from the organism without causing any damage. Paradoxically, a successful clinical treatment of allergy involves repeated immunization of allergic persons with low doses of the allergen—immunotherapy. Investigation of the available experimental evidence leads to the conclusion that the phenomena of immunotherapy are best addressed in terms of the interplay among the mechanism(s) of immune memory—Th1/Th2 cross-regulation—and the physical compart-mentalization of the immune system. These conclusions are illustrated with a numerical simulation.

Notes: Abstract We consider a host-solitary parasitoid system with three categories of individuals: parasitoids, healthy hosts and parasitized hosts. Parasitoids are assumed to discriminate perfectly between the two kinds of hosts and they can reject those which are already parasitized. If parasitoids systematically accept or reject superparasitism or behave randomly, the system is always unstable. Using an optimal foraging model, we determine the behavior of parasitoids which leads to maximization of the instantaneous reproductive rate. When following this adaptive decision rule, parasitoids accept or refuse superparasitism according to the densities of both healthy and parasitized hosts. We study the dynamics of the system when parasitoids follow the optimal rule and show that under certain conditions it possesses a locally stable equilibrium point. In addition, our model predicts that at equilibrium parasitoids show partial preferences for superparasitism.

Notes: Abstract A system of differential equations for the control of tumor growth cells in a cycle nonspecific chemotherapy is analyzed. Spontaneously acquired drug resistance is taken into account, and a criterion for the selection of chemotherapeutic treatment is used. This criterion purports to describe the possibility of improvement of the patient's health when treatment is discontinued. Contrary to our early results which also take drug resistance into account, in this context strategies of continuous chemotherapy in which rest periods take part may be better than maximum drug concentration throughout the treatment (which appears to be in accordance with clinical practice). This bears out our previous conjecture that when drug resistance is accounted for, the imperfections in the usual modelling of treatment criteria, which in general do not allow for patient recuperation, ruled out the possibility of rest periods in optimal continuous chemotherapy.

Notes: Abstract A logistic density-dependent matrix model is developed in which the matrices contain only parameters and recruitment is a function of adult population density. The model was applied to simulate introductions of white-tailed deer into an area; the fitted model predicted a carrying capacity of 215 deer, which was close to the observed carrying capacity of 220 deer. The rate of population increase depends on the dominant eigenvalue of the Leslie matrix, and the age structure of the simulated population approaches a stable age distribution at the carrying capacity, which was similar to that generated by the Leslie matrix. The logistic equation has been applied to study many phenomena, and the matrix model can be applied to these same processes. For example, random variation can be added to life history parameters, and population abundances generated with random effects on fecundity show both the affect of annual variation in fecundity and a longer-term pattern resulting from the age structure.

Notes: Abstract In the presence of seasonal forcing, predator-prey models with quadratic interaction terms and weak dissipation can exhibit infinite numbers of coexisting periodic attractors corresponding to cycles of different magnitude and frequency. These motions are best understood with reference to the conservative case, for which the degree of dissipation is, by definition, zero. Here one observes the familiar mix of “regular” (neutrally stable orbits and tori) and chaotic motion typical of non-integrable Hamiltonian systems. Perturbing away from the conservative limit, the chaos becomes transitory. In addition, the invariant tori are destroyed and the neutrally stable periodic orbits becomes stable limit cycles, the basins of attraction of which are intertwined in a complicated fashion. As a result, stochastic perturbations can bounce the system from one basin to another with consequent changes in system behavior. Biologically, weak dissipation corresponds to the case in which predators are able to regulate the density of their prey well below carrying capacity.

Notes: Abstract The standard method for measuringin vitro antibiotic efficacy is based on a point observation of bacterial activity 18 hours after inoculation. The method, while simple, forgoes significant information by ignoring the dynamics of the interations between antibiotic and bacteria. This paper proposes a simple dynamic model describing these interactions. The model consists of two non-linear differential equations of the S-system type. Its parameter values are estimated, through the minimization of residual errors, from data on the effect of the carbapenem antibiotic imipenem onPseudomonas aeruginosa. The model adequately describes the dynamic behavior of the bacterial populations in the presence of the antibiotic: beginning with drug administration, then through the decline of the bacterial population and possibly ending with bacterial resurgence.

Notes: Abstract We have studied an ecological system of two species, which we denotestrong andweak, respectively, that compete for a single food resource. This system is modelled as a three component reaction-diffusion process. In the presence of a solitary pulse of increased resources, the weaker competitor can diffuse toward this surplus, gaining a competitive advantage and hence persisting in contraposition with the classical Lotka-Volterra result. An exact analytical solution has been found through a quantum mechanical analogy. A stability analysis of this solution against changes in different parameters has been carried out.

Notes: Abstract Collapsible-tube flow with self-excited oscillations has been extensively investigated. Though physiologically relevant, forced oscillation coupled with self-excited oscillation has received little attention in this context. Based on an ODE model of collapsible-tube flow, the present study applies modern dynamics methods to investigate numerically the responses of forced oscillation to a limit-cycle oscillation which has topological characteristics discovered in previous unforced experiments. A devil's staircase and period-doubling cascades are presented with forcing frequency and amplitude as control parameters. In both cases, details are provided in a bifurcation diagram. Poincaré sections, a frequency spectrum and the largest Lyapunov exponents verify the existence of chaos in some circumstances. The thin fractal structure found in the strange attractors is believed to be a result of high damping and low stiffness in such systems.

Notes: Abstract In this work, we show that a one-dimensional model of the blood flow across the lungs can reproduce the evolution of a bolus versus the time. Solving the differential equation governing the bolus concentration in the framework of this model, we determine the solution which fulfills Gaussian initial boundary conditions. An effective parameter related to the ratio of a diffusion coefficient to the square of the mean speed of the flow is defined. The determination of its numerical values following a semi-empirical approach enables us to know accurately the mean transit time and the cardiac output. The results have been compared to other methods, and were found in good agreement. Such an approach could be of interest in all studies where the knowledge of flow—including micro-circulation—is needed.

Notes: Abstract How two species interact during and after colonization influences which of them will be present in each stage of succession. In the tolerance model of ecological succession in a patchy environment, empty patches can be colonized by any species, but the ability to tolerate reduced resource levels determines which species will exclude the other. Here, we analyze a meta-population model of the possible roles of competition in colonization and succession, using non-linear Markov chains as a mathematical framework. Different kinds of competition affect the final equilibrial, abundances of the species involved in qualitatively different ways. An explicit criterion is given to determine which interactions have stronger effects on the final equilibrial levels of the weaker, species. Precise conditions are stated for the co-existence of both species. Both species are more likely to co-exist in the presence of an intermediate disturbance frequency.

Notes: Abstract A system of differential equations for the control of tumor cells growth in a cycle nonspecific chemotherapy is presented. Spontaneously acquired drug resistance is accounted for, as well as the evolution in time of normal cells. In addition, optimization of conflicting objectives forms the aim of the chemotherapeutic treatment. For general cell growth, some results are given, whereas for the special case of Malthusian (exponential) growth of tumor cells and rather general growth rate for normal cells, the optimal strategy is worked out. The latter, from the clinical standpoint, corresponds to maximum drug concentration throughout the treatment.

Notes: Abstract This study examines the influence of various host-feeding patterns on host-parasitoid population dynamics. The following types of host-feeding patterns are considered: concurrent and non-destructive, non-concurrent and non-destructive, and non-concurrent and destructive. The host-parasitoid population dynamics is described by the Lotka-Volterra continuous-time model. This study shows that when parasitoids behave optimally, i.e. they maximize their fitness measured by the instantaneous per capita growth rate, the non-destructive type of host feeding stabilizes host-parasitoid dynamics. Other types of host feeding, i.e. destructive, concurrent, or non-concurrent, do not qualitatively change the neutral stability of the Lotka-Volterra model. Moreover, it is shown that the pattern of host feeding which maximizes parasitoid fitness is either non-concurrent and destructive, or concurrent and non-destructive host feeding, depending on the host abundance and parameters of the model. The effects of the adaptive choice of host-feeding patterns on host-parasitoid population dynamics are discussed.

Notes: Abstract Game theory has had remarkable success as a framework for the discussion of animal behaviour and evolution. It suggested new interpretations and prompted new observational studies. Most of this work has been done with 2-player games. That is the individuals of a population compete in pairwise interactions. While this is often the case in nature, it is not exclusively so. Here we introduce a class of models for situations in which more than two (possibly very many) individuals compete simultaneously. It is shown that the solutions (i.e. the behaviour which may be expected to be observable for long periods) are more complex than for 2-player games. The concluding section lists some of the new phenomena which can occur.

Notes: Abstract A method allowing to measure the inhomogeneous distribution of purines/pyrimidines in nucleotide sequences is developed. We show that this measure relates to the coding or non-coding character of the considered sequence. Coding sequences present a near to the random Pu or Py distribution. This property is shared by both protein-coding DNA and functional RNA-coding DNA. Non-coding sequences present a highly clustered inhomogeneity. We propose the hypothesis, corroborated with appropriate computer simulations, that this is due to the action of various transposition events accumulated for long time periods.

Notes: Abstract The potential generated in the smooth muscle of the vas deferens on release of a quantum of transmitter from a varicosity was analyzed using a three-dimensional bidomain continuum model. Current was injected at the origin of the bidomain; this current had the temporal characteristics of the junctional current. The membrane potential, intracellular potential, and extracellular potential, as well as the extracellular current, were then calculated throughout the bidomain at different times. Calculations were performed to show the effect of changing the anisotropy ratios of the intracellular and extracellular conductivities on the spread of current and potential in each of the three dimensions. These results provide a theoretical framework for ascertaining the time course of transmitter interaction at a varicosity following the secretion of a quantum of transmitter.

Notes: Abstract Parabolic growth invariably results in the survival of all competing types. Under the constraint of constant total concentration, there is a unique equilibrium in the simplex interior, which is asymptotically stable inside the whole simplex. The appropriate Lyapunov function is obtained in terms of the excess productivity which is shown to be maximized for the competitive system with fractional order kinetics. Claims to the contrary are refuted.

Notes: Abstract Due to the increasing importance of the extracellular matrix in many biological problems, in this paper we develop a model for fibroblast and collagen orientation with the ultimate objective of understanding how fibroblasts form and remodel the extracellular matrix, in particular its collagen component. The model uses integrodifferential equations to describe the interaction between the cells and fibers at a point in space with various orientations. The equations are studied both analytically and numerically to discover different types of solutions and their behavior. In particular we examine solutions where all the fibroblasts and collagen have discrete orientations, a localized continuum of orientations and a continuous distribution of orientations with several maxima. The effect of altering the parameters in the system is explored, including the angular diffusion coefficient for the fibroblasts, as well as the strength and range of the interaction between fibroblasts and collagen. We find the initial conditions and the range of influence between the collagen and the fibroblasts are the two factors which determine the behavior of the solutions. The implications of this for wound healing and cancer are discussed including the conclusion that the major factor in determining the degree of scarring is the initial deposition of collagen.

Notes: Abstract This paper considers the time to extinction for a stochastic epidemic model of SEIR form without replacement of susceptibles. It first shows how previous rigorous results can be heuristically explained in terms of the more transparent dynamics of an approximating deterministic system. The model is then extended to include a host population structured into patches, with weak nearest-neighbour mixing of infection. It is shown, by considering the approximating deterministic system, that the expected time to extinction in a population of n + 1 patches each of size N is of the form a log N + bn, provided that N 〉 N c where N c is a critical patch size below which transits are unlikely to occur. This corresponds to the simple decomposition of the time of an epidemic into the time it takes to spread through one patch plus the time it takes to transit to each of n successive patches. Expressions for this threshold and the coefficients of the time to extinction are given in terms of the transmission parameters of infection and the coupling strength between patches. These expressions are compared with numerical results using parameters relevant to a study of phocine distemper virus in North Sea seals, and the agreement is found to be good for large and small N. In the region when N ≈ N c , where transits may or may not occur, interesting transitional behaviour is seen, leading to a non-monotonicity of the extinction time as a function of N.

Notes: Abstract When directly transmitted infectious diseases are modeled assuming an everlasting induced immunity (and constant contact rate), there are well-established formulas to deal with, which is not true if we include the loss of induced immunity. In general, the immunity induced by the disease is everlasting. We propose a model considering the loss of immunity and present methods for the estimation of two epidemiological parameters: the force of infection and the basic reproduction ratio. We also analyze the effects of the loss of immunity on these parameters. Based on these results, we conclude that reinfection can play an important role in highly vaccinated populations.

Notes: Abstract We studied mathematical models for the length distributions of actin filaments under the effects of polymerization/depolymerization, and fragmentation. In this paper, we emphasize the effects of these two processes acting alone. In this case, simple discrete and continuous models can be derived and solved explicitly (in several special cases), making the problem interesting from a modeling and pedagogical point of view. In a companion paper (Ermentrout and Edelstein-Keshet, 1998, Bull. Math. Biol. 60, 477–503) we investigate what happens when the processes act together, with particular attention to fragmentation by gelsolin, and with a greater level of biological detail.

Notes: Abstract A possible experimental design for combination experiments is to compare the doseresponse curve of a single agent with the corresponding curve of the same agent using either a fixed amount of a second one or a fixed dose ratio. No interaction is then often defined by a parallel shift of these curves. We have performed a systematic study for various types of doseresponse relations both for the dose-additivity (Loewe additivity) and for the independence (Bliss independence) criteria for defining zero interaction. Parallelism between doseresponse curves of a single agent and those of the same agent in the presence of a fixed amount of another one is found for the Loewe-additivity criterion for linear doseresponse relations. For nonlinear relations, one has to differentiate between effect parallelism (parallel shift on the effect scale) and dose parallelism (parallel shift on the dose scale). In the case of Loewe additivity, zero-interaction dose parallelism is found for power, Weibull, median-effect and logistic doseresponse relations, given that special parameter relationships are fulfilled. The mechanistic model of competitive interaction exhibits dose parallelism but not effect parallelism for Loewe additivity. Bliss independence and Loewe additivity lead to identical results for exponential doseresponse curves. This is the only case for which dose parallelism was found for Bliss independence. Parallelism between single-agent doseresponse relations and Loewe additivity mixture relations is found for examples with a fixed doseratio design. However, this is again not a general property of the design adopted but holds only if special conditions are fulfilled. The comparison of combination doseresponse curves with single-agent relations has to be performed taking into account both potency and shape parameters. The results of this analysis lead to the conclusion that parallelism between zero interaction combination and single-agent doseresponse relations is found only for special cases and cannot be used as a general criterion for defining zero-interaction in combined-action assessment even if the correct potency shift is taken into account.

Notes: Abstract The purpose of this study was to investigate strategies in the monotherapy treatment of HIV infection in the presence of drug-resistant (mutant) strains. A mathematical system is developed to model resistance in HIV chemotherapy. It includes the key players in the immune response to HIV infection: virus and both uninfected CD4+ and infected CD4+ T-cell populations. We model the latent and progressive stages of the disease, and then introduce monotherapy treatment. The model is a system of differential equations describing the interaction of two distinct classes of HIV—drug-sensitive (wild type) and drug-resistant (mutant)—with lymphocytes in the peripheral blood. We then introduce chemotherapy effects. In the absence of treatment, the model produces the three types of qualitative clinical behavior—anuninfected steady state, andinfected steady state (latency), andprogression to AIDS. Simulation of treatment is provided for monotherapy, during theprogression to AIDS state, in the consideration of resistance effects. Treatment benefit is based on an increase or retention in CD4+ T-cell counts together with a low viral titer. We explore the following treatment approaches: an antiviral drug which reduces viral infectivity that is administered early—when the CD4+ T-cell count is ≥300/mm3, and late—when the CD4+ T-cell count is less than 300/mm3. We compare all results with data. When treatment is initiated during the progression to AIDS state, treatment prevents T-cell collapse, but gradually loses effectiveness due to drug resistance. We hypothesize that it is the careful balance of mutant and wild-type HIV strains which provides the greatest prolonged benefit from treatment. This is best achieved when treatment is initiated when the CD4+ T-cell counts are greater than 250/mm3, but less than 400/mm3 in this model (i.e. not too early, not too late). These results are supported by clinical data. The work is novel in that it is the first model to accurately simultate data before, during and after monotherapy treatment. Our model also provides insight into recent clinical results, as well as suggests plausible guidelines for clinical testing in the monotherapy of HIV infection.

Notes: Abstract 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 adsorption isotherm for the attached bacteria are also discussed. This allows us to define the adhesion coefficient (β) in a given bacterium-cell system so that, with the exception of those systems where these coefficients cannot be defined, larger values of β 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.

Notes: Abstract A new measure of toxicity based on stochastic modelling of single photon-counting processes, representing time-resolved phagocyte luminescence of xenobiotic-perturbed human neutrophils, has been constructed. The stochastic measure of toxicity has been verified by the QSAR method, and then compared and contrasted with the traditional toxicity measure used in bio- and chemiluminescent research. Phenol and benzene homologues were chosen as perturbers due to their importance from the viewpoint of ecotoxicology and occupational medicine.