Pre- and post-natal exposure of children to organophosphate flame retardants: A nationwide survey in France.

The use of organophosphate flame retardants (OPFRs) has been on the rise ever since many brominated flame retardants were banned, back in the 2000 s. The objectives of this study are to describe the pre- and post-natal exposure of children to OPFRs, and to explore their possible determinants. A total of 259 children aged 3.5 years and 388 mothers from the French ELFE mother-child cohort were included. Both pre- and post-natal exposure to OPFRs were assessed, using OPFR concentrations in the hair of pregnant women (in 2011) and their 3.5-year-old children (in 2014-2015) for 15 OPFRs, of which 9 were detected in > 20 % hair samples. The highest geometric means for pre-natal exposure were 272 ng/g for tris(1-chloro-2-propyl) phosphate (TCPP), 69.7 ng/g for ng/g for triphenyl phosphate (TPP) and 54.4 ng/g for tris(1,3-dichloro-2-propyl) phosphate (TDCPP). The highest geometric means for post-natal exposure were 249.6 ng/g for TCPP, 85.3 ng/g for TDCPP and 83.8 ng/g for 2-ethylhexyl diphenyl phosphate (EHDPP). Correlations were found between both pre-natal exposures, and between pre-and post-natal exposures. No correlation was however found between pre-and post-natal exposures for any given OPFR. Pre-natal exposure to the 9 OPFRs was associated with pre-natal exposure to polybrominated diphenyl ethers 209 (BDE209), and 47 (BDE47). Maternal BMI was associated with pre-natal exposure to OPFRs other than TBEP. Home renovation work prior to birth was also associated with pre-natal exposure to OPFRs, with the exception of EHDPP, tris(2-butoxyethyl) phosphate (TBEP) and triethyl phosphate (TEP). Determinants of post-natal exposure appeared more disparate across OPFRs; although both the type of flooring in children's rooms and pre-natal exposure to polybrominated diphenyl ethers seem to be associated with post-natal exposure. Lastly, higher socioeconomic status appeared to be associated with lower exposure for several (though not all) OPFRs. The high prevalence of exposure to OPFRs suggests the need for studies to assess the health effects of OPFRs exposure, particularly on children.

Age-related changes in insulin receptor mRNA and protein expression in genetically obese Zucker rats.

AIM: The mechanisms underlying the age-related decrease in insulin-receptor (IR) binding in genetically obese Zucker rats are not well understood. For this reason, the present study analyzed the expression of IR mRNA and protein in selected tissues from 1- to 4-month-old obese (fa/fa) Zucker rats and lean (Fa/-) age-matched controls. METHODS: The following parameters were evaluated: (1) IR mRNA level, and proportion of isotypes A (exon 11-) and B (exon 11+) of IR mRNA in liver, brain and kidney; (2) level, molecular size and tyrosine phosphorylation of IR-beta subunit in liver subcellular fractions; and (3) stability of liver IR based on sensitivity in vivo of insulin-binding activity and IR-beta levels in response to tunicamycin, a glycosylation inhibitor. RESULTS: At one month, IR mRNA level was increased in liver and brain, but decreased in kidneys and, at four months, both mRNA level and isotype B proportion were decreased in liver. From age two months, the following changes in liver IR protein expression were observed: (1) decreased IR-beta level in whole homogenates, but increased IR-beta levels in endosomal fractions; (2) increased IR-beta tyrosine phosphorylation; and (3) at four months, increased levels of both intact IR-beta (95 kDa) and IR-beta fragments (72 and 52 kDa) in lysosomal fractions, along with decreased stability in vivo of the IR. CONCLUSION: These data show that obese Zucker rats display age-related alterations of IR gene expression at both pre- and post-translational stages and, in particular, increased endocytosis and degradation of IR protein.

Fatty acid recycling in adipocytes: a role for glyceroneogenesis and phosphoenolpyruvate carboxykinase.

FA (fatty acid) recycling in adipose tissue appears to be an important pathway for regulating FA release into the blood during fasting. Re-esterification requires G3P (glycerol 3-phosphate), which cannot be synthesized from glucose because glycolysis is much reduced under such circumstances. In addition, G3P can scarcely originate from glycerol since glycerol kinase has a very low activity in white adipose tissue. It was shown about 35 years ago that a metabolic pathway named glyceroneogenesis, which allows G3P synthesis from non-carbohydrate precursors like pyruvate, lactate or amino acids, is activated during fasting. The major enzyme in this pathway was shown to be PEPCK-C [cytosolic phosphoenolpyruvate carboxykinase (GTP); EC 4.1.1.32]. The present review analyses the mechanisms by which a series of hormones and nutrients affect PEPCK-C gene transcription and glyceroneogenesis and describes evidence for dysregulation of this pathway in type 2 diabetes.

Hierarchical model of the population dynamics of hippocampal dentate granule cells.

A hierarchical modeling approach is used as the basis for a mathematical representation of the population activity of hippocampal dentate granule cells. Using neural field equations, the variation in time and space of dentate granule cell activity is derived from the summed synaptic potential and summed action potential responses of a population of granule cells evoked by monosynaptic excitatory input from entorhinal cortical afferents. In this formulation of the problem, we have considered a two-level hierarchy: the synapses of entorhinal cortical axons define the first level of organization, and dentate granule cells, which include these synapses, define the second, higher level of organization. The model is specified by two state field variables, for membrane potential and for synaptic efficacy, respectively, with both evolving according to different time scales. The two state field variables introduce new parameters, physiological and anatomical, which characterize the dentate from the point of view of neuronal and synaptic populations: (1) a set of geometrical constraints corresponding to the morphological properties of granule cells and anatomical characteristics of entorhinal-dentate connections; and (2) a set of neuronal parameters corresponding to physiological mechanisms. Assuming no interaction between granule cells, i.e., neither ephaptic nor synaptic coupling, the model is shown to be mathematically tractable and allows solution of the field equations leading to the determination of activity. This treatment leads to the definition of two state variables, volume of stimulated synapses and firing time, which describe observed activity. Numerical simulations are used to investigate the populational characterization of the dentate by individual parameters: (1) the relationship between the conditions of stimulation of active perforant path fibers, e.g., stimulating intensity, and activity in the granule cell layer; and (2) the influence of geometry on the generation of activity, i.e., the influence of neuron density and synaptic density-connectivity. As an example application of the model, the granule cell population spike is reconstructed and compared with experimental data.

Processing of the insulin-like growth factor-II-mannose 6-phosphate receptor in isolated liver subcellular fractions.

A truncated, soluble form of the insulin-like growth factor-II-mannose 6-phosphate (IGF-II-M6P) receptor has been identified in serum and shown to be released from cultured tissues and cells, liver being the main contributor to serum receptor in adult rats. In the present study, the processing of the IGF-II-M6P receptor has been characterized in isolated liver subcellular fractions using ligand binding, affinity crosslinking, and Western immunoblotting techniques. The receptor in plasma membrane fractions differed from that in Golgi-endosomal fractions by: (i) a lower molecular size upon reducing polyacrylamide gel electrophoresis (245 vs. 255 kDa); (ii) a less tight membrane association as judged upon extractibility by NaCI; and (iii) the inability to recognize antibody anti-22C, directed against the cytoplasmic domain of the receptor. Incubation of cell fractions at 30 degrees C led to a pH- and time-dependent release of the receptor into the medium. The pH optimum for release was 5.5 in the Golgi-endosomal fraction and 7.5 in plasma membrane fractions; at this pH, approximately 2% and 20%-30% of total receptors were released per hour, respectively. Receptor release was inhibited in a dose-dependent manner by aprotinin, benzamidine, and leupeptin in the Golgi-endosomal fraction, and by 1,10 phenanthroline in plasma membrane fractions, although high concentrations were required for inhibition. The receptor released from Golgi-endosomes showed a 5-10 kDa reduction in size and a loss of ability to recognize antibody anti-22C, but that released from plasma membranes showed little or no changes in size. We conclude that soluble, carboxy-terminally truncated forms of the IGF-II-M6P receptor are generated from the intact receptor in isolated Golgi-endosomal and plasma membrane fractions. However, receptor processing in these fractions exhibits different properties, suggesting the involvement of different proteases.

Identification of insulin domains important for binding to and degradation by endosomal acidic insulinase.

The endosomal compartment of hepatic parenchymal cells contains an acidic endopeptidase, endosomal acidic insulinase (EAI), which hydrolyzes internalized insulin at a limited number of sites. Although the positions of these cleavages are partially known, the residues of insulin important in its binding to and proteolysis by EAI have not been defined. To this end, we have studied the degradation over time of native human insulin and three insulin-analog peptides using a soluble endosomal extract from rat liver parenchyma followed by purification of the products by HPLC and determination of their structure by mass spectrometry. We found variable rates of ligand processing, i.e. high ([Asp(B10)]- and [Glu(A13),Glu(B10)]-insulin), moderate (insulin) and low (the H2-analog). On the basis of IC(50) values, competition studies revealed that human and mutant insulins display nearly equivalent affinity for the EAI. Proteolysis of human and mutant insulins by EAI resulted in eight cleavages in the B-chain which occurred in the central region (Glu(B13)-Leu(B17)) and at the C-terminus (Arg(B22)-Thr(B27)), the latter region comprising the initial cleavages at Phe(B24)-Phe(B25) (major pathway) and Phe(B25)-Tyr(B26) (minor pathway) bonds. Except for the [Glu(A13),Glu(B10)]-insulin mutant, only one cleavage on the A-chain was observed at residues Gln(A15)-Leu(A16). Analysis of the nine cleavage sites showed a preference for hydrophobic and aromatic amino acid residues on both the carboxyl and amino sides of a cleaved peptide bond. Using the B-chain alone as a substrate resulted in a 30-fold increase in affinity for EAI and a 6-fold increase in the rate of hydrolysis compared with native insulin. A similar role for the C-terminal region of the B-chain of insulin in the high-affinity recognition of EAI was supported by the use of the corresponding B(22)-B(30) peptide, which displayed an increase in EAI affinity similar to the entire B-chain vs. wild-type insulin. Thus, we have identified a highly specific molecular interaction of insulin with EAI at the aromatic locus Phe(B24)-Phe(B25)-Tyr(B26). Analytical subfractionation of a postmitochondrial supernatant fraction showed that a pulse of internalized [(125)I]Tyr(A14)-H2-analog, a protease-resistant insulin analog, undergoes a greater lysosomal transfer and lesser degradation than [(125)I]Tyr(A14)-insulin, confirming that endosomal sorting is regulated directly or indirectly by endosomal proteolysis.

Insulin-induced redistribution of the insulin-like growth factor II/mannose 6-phosphate receptor in intact rat liver.

The ability of acute insulin treatment to elicit a redistribution of the liver insulin-like growth factor-II/ mannose 6-phosphate (IGF-II/M6P) receptor has been studied in rats, using cell fractionation. Injection of insulin (0.4-50 microg) led to a time- and dose-dependent decrease in IGF-II binding activity in Golgi-endosomal (GE) fractions, along with an increase in activity in the plasma membrane (PM) fraction; only receptor number was affected. Quantitative subfractionation of the microsomal fraction on sucrose density gradients showed that IGF-II binding activity distributed similarly to galactosyltransferase (a Golgi marker), at slightly higher densities than in vivo internalized (125)I-insulin, and at lower densities than 5' nucleotidase and alkaline phosphodiesterase (two plasma membrane markers). Insulin treatment led to a slight time-dependent and reversible shift of IGF-II binding activity toward higher densities. Subfractionation of the GE fraction on Percoll gradients showed that IGF-II binding activity was broadly distributed, with about 60% at low densities coinciding with galactosyltransferase and early internalized (125)I-insulin and with 40% at high densities in the region of late internalized (125)I-insulin. Insulin treatment caused a time-dependent and reversible shift of the distribution of IGF-II binding activity toward low densities. On SDS-PAGE, the size of the affinity-labeled IGF-II/M6P receptor was comparable in GE and PM fractions (about 255 kDa), but on Western blots receptor size was slightly lower in the latter (245 kDa) than in the former (255 kDa). Insulin treatment did not affect the size, but modified the abundance of the IGF-II/M6P receptor in a manner similar to that of IGF-II binding. In vivo chloroquine treatment fully suppressed the changes in IGF-II binding activity in liver GE and PM fractions observed in insulin-treated rats. We conclude that insulin elicits a time-dependent and reversible redistribution of liver IGF-II receptors from Golgi elements and endosomes to the plasma membrane, presumably via early endosomes.

In vitro endosome-lysosome transfer of dephosphorylated EGF receptor and Shc in rat liver.

We have studied the endosome-lysosome transfer of internalized epidermal growth factor receptor (EGFR) complexes in a cell-free system from rat liver. Analytical subfractionation of a postmitochondrial supernatant fraction showed that a pulse of internalized [(125)I]EGF was largely associated with a light endosomal fraction devoid of lysosomal markers. After an additional 30 min incubation in vitro in the presence of an ATP-regenerating system, the amount of [(125)I]EGF in this compartment decreased by 39%, with an increase in [(125)I]EGF in lysosomes. No transfer of [(125)I]EGF to the cytosol was detected. To assess the fate of the internalized EGFR protein over the time course of the endo-lysosomal transfer of the ligand, the effect of a saturating dose of native EGF on subsequent lysosomal targeting of the EGFR was evaluated by immunoblotting. A massive translocation of the EGFR to the endosomal compartment was observed in response to ligand injection coincident with its tyrosine phosphorylation and receptor recruitment of the tyrosine-phosphorylated adaptor protein Shc. During cell-free endosome-lysosome fusion, a time-dependent increase in the content of the EGFR and the two 55- and 46-kDa Shc isoforms was observed in lysosomal fractions with a time course superimposable with the lysosomal transfer of the ligand; no transfer of the 66-kDa Shc isoform was detected. The relationship between EGFR tyrosine kinase activity and EGFR sorting in endosomes investigated by immunoblot studies with anti-phosphotyrosine antibodies revealed that endosomal dephosphorylation of EGFR and Shc preceded lysosomal transfer. These results support the view that a lysosomal targeting machinery distinct from the endosomal receptor kinase activity, such as the recruitment of the signaling molecule Shc, may regulate this sorting event in the endosome.

On the role of anatomy in learning by the cerebellar cortex.

The properties due to the location of neurons, synapses, and possibly even synaptic channels, in neuron networks are still unknown. Our preliminary results suggest that not only the interconnections but also the relative positions of the different elements in the network are of importance in the learning process in the cerebellar cortex. We have used neural field equations to investigate the mechanisms of learning in the hierarchical neural network. The numerical resolution of these equations reveals two important properties: (i) The hierarchical structure of this network has the expected effect on learning because the flow of information at the neuronal level is controlled by the heterosynaptic effect through the synaptic density-connectivity function, i.e. the action potential field variable is controlled by the synaptic efficacy field variable at different points of the neuron. (ii) The geometry of the system involves different velocities of propagation along different fibers, i.e. different delays between cells, and thus has a stabilizing effect on the dynamics, allowing the Purkinje output to reach a given value. The field model proposed should be useful in the study of the spatial properties of hierarchical biological systems.

Purkinje local circuits with delays: mathematical conditions of stability for learning and retrieval.

Mathematical conditions of stability of learning and retrieval by a Purkinje local circuit, the Purkinje unit, are investigated in the case of delay between any two neurons. The model used takes into account anatomical and physiological constraints: (i) real connectivity; (ii) specific activatory and inhibitory synaptic properties; and (iii) anatomical hierarchical structure. The Purkinje unit is defined in terms of the topology and the geometry of the network, i.e. the anatomical connectivity and the distance between given granule cells and a Purkinje cell. The neurons are assumed to be linear. The network of Purkinje units is general with regard to the number of elements, cells and synapses. For this linear model of a Purkinje unit with delay, we have obtained the conditions of stability for learning and retrieval in two cases: (i) for a single Purkinje unit, the condition is an inequality between the synaptic efficacies which occur in the granule cells-Golgi cell loop; and (ii) for a two-unit system, i.e. two coupled Purkinje units, a strong condition independent of the delay is obtained. This condition includes the granule cell-Golgi cell loop of the two units. We show that the condition of stability for the two-unit system implies the stability of each of the units. This work allows us to define the Purkinje unit in terms of the stability of its function: the physiological process of learning and retrieving must be stable within the anatomical structure that supports this physiological process. It is thus shown that a parameter of a biological nature, the ratio r between the delays of propagation from one unit to another and inside the granule cell-Golgi cell loop, governs the behaviour of the two-unit system. Another result, obtained in the framework of our theory of the functional organization [Chauvet, G. A. (1993). Phil. Trans. R. Soc. Lond. B, 339, 425-444], shows that the association of two unstable units provides a stable unit for certain values of the delay. These results constitute a basis for an eventual interpretation of the coordination of movement by means of a network of non-linear Purkinje units.

On the viability of a physiological system. Regulation of potassium by aldosterone.

Physiological systems maintain their variables within limits through regulatory processes. We have studied potassium regulation on the basis of the viability theory. The viability kernel is determined by taking into account the constraints of the variables of the dynamical system, i.e. the set of initial states for which there exists at least one viable trajectory. The set of regulations which maintain the viability of the physiological system is also determined. Finally, we investigate the influence of various strategies that allow the choice of one control among the viable regulations.

Delay equation analysis of human respiratory stability.

A mathematical analysis of the stability in human respiration, based on the tau-decomposition method, is conducted on a simple, but realistic CO2 model of the respiratory system. This model incorporates a two-compartment representation (lungs and tissues) for the plant and a very general class of controller. By deriving an explicit stability criterion, the stability domain of the respiratory system can be characterized. We quantify the influence of four major parameters of respiratory instability, i.e. transport delay, lung volume, and equilibrium values of lung CO2 partial pressure and controller gain. We demonstrate the existence of a bifurcation point and periodic solutions, giving some characteristics of solutions near the bifurcation point.

Endosome-lysosome transfer of insulin and glucagon in a liver cell-free system.

The endosome-lysosome transfer of in vivo internalized insulin and glucagon has been studied in a rat liver cell-free system and compared to that of galactosylated bovine serum albumin (GalBSA), a ligand of the asialoglycoprotein receptor. Density-gradient analysis of a postmitochondrial supernatant isolated 8 min after injection of [125I]iodoinsulin showed that the membrane-associated radioactivity (55% of the total) migrated as a single peak at the position of galactosyltransferase, a Golgi marker (1.08-1.10 g/ml). After incubation at 37 degrees C in the presence of ATP, an additional peak of radioactivity (12%) was detected at the position of acid phosphatase, a lysosomal marker (1.12-1.14 g/ml). No such peak was observed in a lysosome-depleted fraction. An ATP-dependent conversion of [125I]iodoinsulin to trichloroacetic-acid-soluble products occurred during incubation (20%) but this was unaffected by lysosome depletion. Gel-filtration and HPLC analysis of acid extracts of gradient fractions isolated after injection of [125I]iodoinsulins selectively labeled at tyrosine residues A14 or B26 revealed the presence of components which differed from intact iodoinsulins by size and/or hydrophobicity. Low molecular-mass components were less abundant and, conversely, intact iodoinsulin and/or high molecular-mass components more abundant in lysosomal fractions than in endosomal fractions. In vivo internalized [125I]iodoglucagon and [125I]iodogalBSA underwent a greater lysosomal transfer (17-21%) and lesser degradation (8-11%) than [125I]iodoinsulin. Glycyl-L-phenylalanine 2-naphtylamide and methionine O-methyl ester, two lysosome-disrupting enzyme substrates, partially released the radioactivity associated with lysosomal fractions (GalBSA > insulin = glucagon) but caused little or no release of that associated with endosomal fractions. Analysis of the alpha and beta subunits of the insulin receptor by cross-linking to [125I]iodoinsulin and Western immunoblotting, respectively, revealed a partial lysosomal transfer of these subunits during endosome-lysosome interaction. We conclude that an endosome-lysosome transfer of insulin and glucagon occurs in a liver cell-free system and suggest that the low recovery of these peptides in lysosomal fractions in vivo results from their rapid degradation within endosomes.

An algorithmic method for determining the kinetic system of receptor-channel complexes.

The mathematical study of receptor-channel kinetics involving numerous sites and conformations of the channel calls for specific analytic methods generally based on stochastic formulation in terms of Markov processes. These methods allow the determination of the number of states from the experimental data. When the number of states is known, it is necessary to try numerous kinetic diagrams to find the best one. The construction of the kinetic diagram and the corresponding kinetic system are based on physiological hypotheses. When the number of states is large, the kinetic schema becomes difficult to establish. We present a method that uses an algorithmic scheme to deduce a kinetic system directly from physiological hypotheses. This method takes into account any number of ligands and sites. The set of all the states given by the combination of site occupation and channel conformations is reduced by using two types of hypothesis: (1) molecular constraints that specify the transitions physically possible between states and (2) kinetic considerations related to the assumed physiology of the system, which gives the conditions necessary for a transition between two states. These hypotheses are expressed in terms of rules operating on the initial states of transitions. The expression of rules does not ensure their coherence (i.e., the fact that each kinetic transition is defined by one and only one rule). A mathematical condition has been found that ensures the coherence of rules. When coherence has been established, the corresponding dynamic system can be automatically generated. Because the rules are established in a systematic way and their coherence can be mathematically established, the computer implementation of this method makes it easy to test various kinetic hypotheses for problems where the number of states is large.

On the functional organization in a biological structure: the example of enzyme organization.

In this paper, we have considered how the spatial localization of enzymatic reactions, ranging from the elementary type (one step) to that of a metabolic pathway in 2 different phases, may affect the stability of metabolite concentrations. The spatial localization of molecules in the reactions involves: (1) the confinement of some enzymes to cellular substructures (organelles, membranes, cytoskeleton, multienzyme complexes); (2) exchanges of metabolites between cellular substructures (local phase) and cytosol. This organization may be called as structural. Under these conditions, we have studied the dynamical behaviour of the metabolic pathway investigating the velocity of convergence towards the reference steady-state after perturbation of metabolite concentrations. This type of stability may be called as functional stability. We show that an increase in exchanges by diffusion of metabolites between the local phase and cytosol from one hand, or a decrease in the local phase volume on the other hand, result in an increase of the functional stability around the steady-state. This is verified for one step of the pathway as well as for the entire pathway or when the pathway is present in the local phase and in the cytosol.

A mathematical analysis of intestinal peristaltic waves.

Gut motility is usually investigated by introducing probes in the intestinal lumen. Image analysis could be used instead of intraluminal pressure measurements to avoid the inconvenience of this invasive procedure. The present study exposes the theoretical principles of intestinal peristalsis in terms of indirect intraluminal pressure and content velocity measurements. A geometrical model of intestinal contractions is mathematically described by using Stokes' equations in order to evaluate velocities and pressures in the equations established by quantitative analysis of cinematography pictures. The couple velocity-pressure is calculated at each point of the geometrical model for a viscous and non-compressible fluid. This fluid flows in a geometrical structure, the boundaries of which vary with time and behave in a periodic and regular way by simulating the movements of intestinal contractions. A comparison is made between experimental pressure recordings in isolated rat intestines and pressure values calculated by utilizing the geometrical model. Velocity values calculated at every grid node show positive and negative zones in the geometrical model output. The position of these zones vary from one geometrical model to another. Moreover, the calculated pressure and velocity values change according to the applied vector efforts. The similarity of the results obtained shows the efficiency of the finite element technique in the case of Stokes' equations.

On associative motor learning by the cerebellar cortex: from Purkinje unit to network with variational learning rules.

This paper is an attempt to describe the ability of the cerebellar cortical network to coordinate movement on the basis of the continuous behavior of individual neural networks, the so-called "Purkinje units." The problem is considered from the point of view of a hierarchical network with two levels of organization: the level of Purkinje units including Purkinje, star and basket cells, and the level of granule cells and Golgi cells which is a network with a specific architecture. We suggest that the coordination of movements is based on a new class of learning rules between Purkinje units, called variational learning rules (VLR), which are mathematically deduced from the dynamics of a Purkinje unit. This network is driven by two functions H0 and H, defined for each Purkinje unit, which depend on external signals for this unit. Specifically, the proposed interpretation of the coordination of movement depends on three main features: (i) The definition of a unit of function, the Purkinje unit, made up of a Purkinje cell and closely associated cells and connections; (ii) a new learning rule called the "Variational Learning Rule" (VLR), operating at the level of the Purkinje units; (iii) the interpretation of the coordination of movements in terms of excitatory and inhibitory interactions between Purkinje units. An emergent property of the model is that Purkinje units occur in groups which act in opposition in the sense that when the output of one group increases, that of the other decreases.

An ACSL simulation of the respiratory system.

A simulation program for the respiratory system using ACSL (Advanced Continuous Simulation Language) is presented. The underlying model is based on the representation of ventilation as a phasic air movement in lungs during the respiratory cycle. The translation of the model with ACSL instructions is described in particular for continuous processes, such as respiratory gas exchanges, and discrete events, such as changes of respiratory phase. The advantages of using ACSL are discussed, and the utility of such a simulation program in both research and education is demonstrated.

Cyclic model of respiration applied to asymmetrical ventilation and periodic breathing.

A model taking into account the cyclic character of respiration in humans is developed using two classical simplifications: CO2 is the only respiratory gas involved; and respiration is regulated only by a CO2 linear controller. The model is used to investigate two important clinical aspects of respiratory disease: asymmetrical ventilation and periodic breathing. We show that asymmetry in ventilation significantly influences the time course of the CO2 partial pressure in the expired alveolar air at the mouth and the elimination of CO2 through the lungs. Furthermore, the CO2 controller delay plays a major role in periodic breathing.