A stochastic model of corneal epithelium maintenance and recovery following perturbation.

Various biological studies suggest that the corneal epithelium is maintained by active stem cells located in the limbus, the so-called limbal epithelial stem cell hypothesis. While numerous mathematical models have been developed to describe corneal epithelium wound healing, only a few have explored the process of corneal epithelium homeostasis. In this paper we present a purposefully simple stochastic mathematical model based on a chemical master equation approach, with the aim of clarifying the main factors involved in the maintenance process. Model analysis provides a set of constraints on the numbers of stem cells, division rates, and the number of division cycles required to maintain a healthy corneal epithelium. In addition, our stochastic analysis reveals noise reduction as the epithelium approaches its homeostatic state, indicating robustness to noise. Finally, recovery is analysed in the context of perturbation scenarios.

[Graft-versus-host disease, a rare complication of lung transplantation]. / La maladie du greffon contre l'hôte, graft-versus-host disease, une complication exceptionnelle de la transplantation pulmonaire.

Graft-versus-host disease (GVHD) is a classic and frequent multisystemic complication of bone marrow allografts. It has also been reported after the transplantation of solid organs such as the liver or gut. Recent cases of GVHD have been reported after lung and heart-lung transplant. Skin, liver, gastrointestinal tract and bone marrow are the organ preferentially affected by GVHD. Corticosteroid is the first line treatment of GVHD. The prognosis reported in solid organ transplants is poor with infectious complications favoured by immunosuppressive therapy. In this article, we report a case of a patient with cystic fibrosis who presented a probable GVHD 18 months after a lung transplant and a literature review of similar cases.

[Indications of lung transplantation: Patients selection, timing of listing, and choice of procedure]. / Indications de la transplantation pulmonaire : sélection des candidats, critères d'inscription en liste d'attente, choix du type d'intervention.

Lung transplantation (LT) is now considered as an excellent treatment option for selected patients with end-stage pulmonary diseases, such as COPD, cystic fibrosis, idiopathic pulmonary fibrosis, and pulmonary arterial hypertension. The 2 goals of LT are to provide a survival benefit and to improve quality of life. The 3-step decision process leading to LT is discussed in this review. The first step is the selection of candidates, which requires a careful examination in order to check absolute and relative contraindications. The second step is the timing of listing for LT; it requires the knowledge of disease-specific prognostic factors available in international guidelines, and discussed in this paper. The third step is the choice of procedure: indications of heart-lung, single-lung, and bilateral-lung transplantation are described. In conclusion, this document provides guidelines to help pulmonologists in the referral and selection processes of candidates for transplantation in order to optimize the outcome of LT.

[Does antifungal therapy influence postoperative morbidity or long-term survival after surgical resection for pulmonary aspergilloma?]. / Un traitement antifongique périopératoire influence-t-il la morbidité postopératoire et la survie à long terme après une résection pulmonaire pour aspergillome ?

BACKGROUND: Surgical resection of pulmonary aspergilloma is associated with symptoms control, complications prevention, and improved survival, given that the disease is localized and the patient fit enough to undergo surgery. In these operable forms, the impact of perioperative antifungal therapy remains controversial. The purpose of this study was to analyze the impact of antifungal therapy on postoperative morbidity and overall survival in patients with operable pulmonary aspergilloma. METHODS: The clinical records of 113 patients who underwent thoracic surgery for aspergilloma in our institution from January 1989 to December 2010 were retrospectively reviewed. Of these, 64 patients received antifungal therapy in the perioperative period and were included in group 1, and 49 patients did not receive antifungal therapy and were included in group 2. RESULTS: Postoperative complication rates were 31.2% in group 1 and 20.4% in group 2 (P = 0.30). Univariable analysis showed that immunocompromised status (P < 0.001), past history of cancer (P = 0.50), preoperative purulent sputum (P = 0.024), and pneumonectomy (P < 0.001) were significantly associated with postoperative complications, but that antifungal therapy was not. Five- and 10-year overall survival rates were respectively 78.3% and 57.8% in group 1 vs. 85.9% and 65.7% in group 2 (P = 0.23). Multivariate analysis revealed that age higher than 50, immunocompromised status and pneumonectomy were significantly associated with adverse long-term survival (χ(2) = 6.59, df = 5, P < 0.001), but that antifungal therapy was not. CONCLUSION: Antifungal therapy has no significant impact on postoperative morbidity or long-term survival following surgical resection of pulmonary aspergilloma. Such procedure is associated with acceptable postoperative morbidity and long-term survival.

Effects of bursty protein production on the noisy oscillatory properties of downstream pathways.

Experiments show that proteins are translated in sharp bursts; similar bursty phenomena have been observed for protein import into compartments. Here we investigate the effect of burstiness in protein expression and import on the stochastic properties of downstream pathways. We consider two identical pathways with equal mean input rates, except in one pathway proteins are input one at a time and in the other proteins are input in bursts. Deterministically the dynamics of these two pathways are indistinguishable. However the stochastic behavior falls in three categories: (i) both pathways display or do not display noise-induced oscillations; (ii) the non-bursty input pathway displays noise-induced oscillations whereas the bursty one does not; (iii) the reverse of (ii). We derive necessary conditions for these three cases to classify systems involving autocatalysis, trimerization and genetic feedback loops. Our results suggest that single cell rhythms can be controlled by regulation of burstiness in protein production.

Estudio mediante densitometría y ergoespirometría de los efectos de un programa de ejercicio físico en pacientes con cirrosis hepática y sobrepeso / Study by densitometry and ergospirometry of the effects of an exercise programme in overweight patients with liver cirrhosis

Objetivo: Estudiar los efectos del programa de ejercicio físico moderado sobre la composición corporal y la capacidad de esfuerzo evaluadas mediante densitometría y ergoespirometría, respectivamente, en pacientes con cirrosis y sobrepeso. Pacientes y metodología: Se incluyeron 14 pacientes con cirrosis y sobrepeso compensados que realizaron un programa de ejercicio físico moderado durante tres meses de una hora, tres días/semana. Se midió la variación antropométrica, la composición corporal mediante densitometría, la capacidad de esfuerzo mediante ergoespirometría y la calidad de vida (SF-36). Resultados: Al final del estudio, respecto al inicio, no hubo diferencias en el índice de masa corporal. Encontramos aumento de la masa muscular total y disminución de la masa grasa total. Aumentó el tiempo de esfuerzo total y el tiempo de esfuerzo aerobio. La presión arterial media y la creatinina sérica disminuyeron. La calidad de vida mejoró en todos los dominios del SF-36 aunque alcanzó significación estadística en la función física. Conclusiones: Un programa de ejercicio físico moderado disminuye la masa grasa y aumenta la masa muscular y la capacidad de esfuerzo en pacientes con cirrosis y sobrepeso (AU)

Objective: To study the effects of a moderate exercise programme on body composition and effort capacity evaluated by means of densitometry and ergospirometry, respectively, in overweight patients with cirrhosis. Patients and methods: Fourteen compensated overweight patients with cirrhosis underwent a moderate exercise programme during 3 months one hour 3 days/week. We analyzed the changes in anthropometric measures, body composition by densitometry, effort capacity by ergospirometry and quality of life by SF-36 questionnaire. Results: At the end of the study there were not differences in body mass index with respect to basal values, but we observed an increase in total body muscle mass evaluated by densitometry and a decrease in total fat body mass. Ergospirometry showed an increase in effort time and in aerobic effort time. Mean arterial pressure and serum creatinine decreased at the end of the study. With respect to quality of life, there was an improvement in all SF-36 domains that reached statistical significance in physical functioning. Conclusions: A moderate exercise programme decreases total body fat and increases total body muscle mass and effort capacity in overweight patients with cirrhosis (AU)

Molecular noise induces concentration oscillations in chemical systems with stable node steady states.

It is well known that internal or molecular noise induces concentration oscillations in chemical systems whose deterministic models exhibit damped oscillations. In this article we show, using the linear-noise approximation of the chemical master equation, that noise can also induce oscillations in systems whose deterministic descriptions admit no damped oscillations, i.e., systems with a stable node. This non-intuitive phenomenon is remarkable since, unlike noise-induced oscillations in systems with damped deterministic oscillations, it cannot be explained by noise excitation of the deterministic resonant frequency of the system. We here prove the following general properties of stable-node noise-induced oscillations for systems with two species: (i) the upper bound of their frequency is given by the geometric mean of the real eigenvalues of the Jacobian of the system, (ii) the upper bound of the Q-factor of the oscillations is inversely proportional to the distance between the real eigenvalues of the Jacobian, and (iii) these oscillations are not necessarily exhibited by all interacting chemical species in the system. The existence and properties of stable-node oscillations are verified by stochastic simulations of the Brusselator, a cascade Brusselator reaction system, and two other simple chemical systems involving auto-catalysis and trimerization. It is also shown how external noise induces stable node oscillations with different properties than those stimulated by internal noise.

Steady-state fluctuations of a genetic feedback loop: an exact solution.

Genetic feedback loops in cells break detailed balance and involve bimolecular reactions; hence, exact solutions revealing the nature of the stochastic fluctuations in these loops are lacking. We here consider the master equation for a gene regulatory feedback loop: a gene produces protein which then binds to the promoter of the same gene and regulates its expression. The protein degrades in its free and bound forms. This network breaks detailed balance and involves a single bimolecular reaction step. We provide an exact solution of the steady-state master equation for arbitrary values of the parameters, and present simplified solutions for a number of special cases. The full parametric dependence of the analytical non-equilibrium steady-state probability distribution is verified by direct numerical solution of the master equations. For the case where the degradation rate of bound and free protein is the same, our solution is at variance with a previous claim of an exact solution [J. E. M. Hornos, D. Schultz, G. C. P. Innocentini, J. Wang, A. M. Walczak, J. N. Onuchic, and P. G. Wolynes, Phys. Rev. E 72, 051907 (2005), and subsequent studies]. We show explicitly that this is due to an unphysical formulation of the underlying master equation in those studies.

[Lung volume reduction surgery for emphysema and bullous pulmonary emphysema]. / Chirurgie de réduction volumique et des bulles géantes dans l'emphysème pulmonaire.

The improvement of respiratory symptoms for emphysematous patients by surgery is a concept that has evolved over time. Initially used for giant bullae, this surgery was then applied to patients with diffuse microbullous emphysema. The physiological and pathological concepts underlying these surgical procedures are the same in both cases: improve respiratory performance by reducing the high intrapleural pressure. The functional benefit of lung volume reduction surgery (LVRS) in the severe diffuse emphysema has been validated by the National Emphysema Treatment Trial (NETT) and the later studies which allowed to identify prognostic factors. The quality of the clinical, morphological and functional data made it possible to develop recommendations now widely used in current practice. Surgery for giant bullae occurring on little or moderately emphysematous lung is often a simpler approach but also requires specialised support to optimize its results.

An effective rate equation approach to reaction kinetics in small volumes: theory and application to biochemical reactions in nonequilibrium steady-state conditions.

Chemical master equations provide a mathematical description of stochastic reaction kinetics in well-mixed conditions. They are a valid description over length scales that are larger than the reactive mean free path and thus describe kinetics in compartments of mesoscopic and macroscopic dimensions. The trajectories of the stochastic chemical processes described by the master equation can be ensemble-averaged to obtain the average number density of chemical species, i.e., the true concentration, at any spatial scale of interest. For macroscopic volumes, the true concentration is very well approximated by the solution of the corresponding deterministic and macroscopic rate equations, i.e., the macroscopic concentration. However, this equivalence breaks down for mesoscopic volumes. These deviations are particularly significant for open systems and cannot be calculated via the Fokker-Planck or linear-noise approximations of the master equation. We utilize the system-size expansion including terms of the order of Omega(-1/2) to derive a set of differential equations whose solution approximates the true concentration as given by the master equation. These equations are valid in any open or closed chemical reaction network and at both the mesoscopic and macroscopic scales. In the limit of large volumes, the effective mesoscopic rate equations become precisely equal to the conventional macroscopic rate equations. We compare the three formalisms of effective mesoscopic rate equations, conventional rate equations, and chemical master equations by applying them to several biochemical reaction systems (homodimeric and heterodimeric protein-protein interactions, series of sequential enzyme reactions, and positive feedback loops) in nonequilibrium steady-state conditions. In all cases, we find that the effective mesoscopic rate equations can predict very well the true concentration of a chemical species. This provides a useful method by which one can quickly determine the regions of parameter space in which there are maximum differences between the solutions of the master equation and the corresponding rate equations. We show that these differences depend sensitively on the Fano factors and on the inherent structure and topology of the chemical network. The theory of effective mesoscopic rate equations generalizes the conventional rate equations of physical chemistry to describe kinetics in systems of mesoscopic size such as biological cells.

Crowding-induced anisotropic transport modulates reaction kinetics in nanoscale porous media.

We quantify the emergence of persistent anisotropy in the diffusion of spherical tracer particles through a nanoscale porous medium composed of a uniform distribution of purely symmetric crowding particles. We focus on the interior of a biological cell as an example of such a medium and find that diffusion is highly directional for distances comparable to the size of some organelles. We use a geometrical procedure that avoids the standard orientational averaging to quantify the anisotropy of diffusive paths and show that the point source distributions are predominantly of prolate ellipsoidal shape as a result of local volume exclusion. This geometrical symmetry breaking strongly skews the distribution of kinetic rates of diffusion-limited reactions toward small values, leading to the result that, for short to intermediate times, almost 80% of the rates measured in an ensemble of heterogeneous media are smaller than the expected rate in an ideal homogeneous medium of similar excluded volume fraction. This crowding-induced modulation may have implications for our understanding and measurement of diffusion-controlled intracellular reaction kinetics and for experimental nanotechnology applications, such as nanoparticle-based bioimaging and drug delivery, where diffusion plays an important role.

Noise-induced breakdown of the Michaelis-Menten equation in steady-state conditions.

The Michaelis-Menten (MM) equation is the basic equation of enzyme kinetics; it is also a basic building block of many models of biological systems. We build a stochastic and microscopic model of enzyme kinetics inside a small subcellular compartment. Using both theory and simulations, we show that intrinsic noise induces a breakdown of the MM equation even if steady-state metabolic conditions are enforced. In particular, we show that (i) given a reaction velocity, deterministic rate equations can severely underestimate steady-state intracellular substrate concentrations and (ii) different reaction schemes which on a macroscopic level are indistinguishable because they are described by the same MM equation obey distinctly different equations in subcellular compartments.

Long-term follow-up of bradycardia in elite athletes.

The aim of the study was to examine the hypothesis that when former high-level athletes retired from competition, bradycardia would vanish. ECG changes and factors possibly related to the persistence of bradycardia were investigated. We performed a longitudinal follow-up study in 157 former elite athletes who had records of bradycardia < 50 bpm when they were active in high-level competition. All had retired from competitive sport for a minimum of five years prior to participation in the follow-up examination. Data on sport modality, hours of weekly training during competition periods, years participating in high-level competition, and years since retirement from competition were abstracted from medical records at two sports medicine centers. ECGs from this time were studied. At the post-retirement follow-up examination, participants underwent a clinical examination that included blood pressure and ECG recordings, and answered a structured questionnaire about their physical exercise since retirement from their sporting career. In the post-retirement period, a total of 65 % of participants had persistent bradycardia, 18 % with bradycardia < 50 bpm. Multivariate analysis showed that persistence of resting bradycardia was associated with regular exercise and number of years in high-level competition, but not with symptoms such as palpitations, dizziness or syncope, or major ECG alterations.

[Pleural diffusion of amoxicillin 1 and vancomycin in patients treated for post-surgical empyema]. / Empyème après chirurgie d'exérèse pulmonaire: étude de la diffusion pleurale de l'amoxicilline et de la vancomycine.

INTRODUCTION: Treatment of post surgical thoracic empyema consists of chest tube drainage, antibiotic administration, and in some cases surgical lavage of infected spaces. Data in human on the diffusion of antibiotics in pleural cavity after post surgical empyema are lacking. METHODS: We studied on 9 patients with post surgical thoracic empyema (including 6 pneumonectomy) the diffusion of 2 antibiotics commonly used in this situation: amoxicillin (for 7 patients) and vancomycin (for 2 patients). Antibiotics concentrations were measured after at least 3 days of treatment (3-12 days), in order to reach a plateau concentration in the pleural space. RESULTS: The ratio pleural/plasma antibiotic concentration was 1.96 (range: 0.6-4.9). The pleural infection was cured for 8 on 9 patients. The last patients required thoracostomy, and the outcome was favorable after this procedure. CONCLUSION: That the penetration of amoxicillin and vancomycin in pleural space after post surgical empyema is good. Pleural antibiotics concentrations are in the majority of cases higher than plasmatic concentrations.

Brownian motion of an asymmetrical particle in a potential field.

It is well known that a free ellipsoidal Brownian particle exhibits anisotropic diffusion for short times which changes to isotropic at long times, and, that the long-time diffusion coefficient is an average of the translational diffusion coefficients along the different semiaxes of the particle. We show analytically that in the presence of external forces, the long-time diffusion coefficient is different from that of a free particle. The magnitude of the difference in the two diffusion coefficients is found to increase proportionately with the particle's asymmetry, being zero only for a perfectly spherical Brownian particle. It is also found that, for asymmetrical particles, the application of external forces can amplify the non-Gaussian character of the spatial probability distributions which consequently delays the transition to the classical behavior. We illustrate these phenomena by considering the quasi-two-dimensional Brownian motion of an ellipsoidal rigid particle in linear and harmonic potential fields. These two examples provide insight into the role played by particle asymmetry in electrophoresis and microconfinement due to a laser trap or due to intracellular macromolecular crowding.

Phase transitions and superuniversality in the dynamics of a self-driven particle.

We study an active random walker model in which a particle's motion is determined by a self-generated field. The field encodes information about the particle's path history. This leads to either self-attractive or self-repelling behavior. For self-repelling behavior, we find a phase transition in the dynamics: when the coupling between the field and the walker exceeds a critical value, the particle's behavior changes from renormalized diffusion to one characterized by a diverging diffusion coefficient. The dynamical behavior for all cases is surprisingly independent of dimension and of the noise amplitude.

A systematic investigation of the rate laws valid in intracellular environments.

Recently there has been significant interest in deducing the form of the rate laws for chemical reactions occurring in the intracellular environment. This environment is typically characterized by low-dimensionality and a high macromolecular content; this leads to a spatial heterogeneity not typical of the well stirred in vitro environments. For this reason, the classical law of mass action has been presumed to be invalid for modeling intracellular reactions. Using lattice-gas automata models, it has recently been postulated [H. Berry, Monte Carlo simulations of enzyme reactions in two dimensions: Fractal kinetics and spatial segregation, Biophys. J. 83 (2002) 1891-1901; S. Schnell, T.E. Turner, Reaction kinetics in intracellular environments with macromolecular crowding: simulations and rate laws, Prog. Biophys. Mol. Biol. 85 (2004) 235-260] that the reaction kinetics is fractal-like. In this article we systematically investigate for the first time how the rate laws describing intracellular reactions vary as a function of: the geometry and size of the intracellular surface on which the reactions occur, the mobility of the macromolecules responsible for the crowding effects, the initial reactant concentrations and the probability of reaction between two reactant molecules. We also compare the rate laws valid in heterogeneous environments in which there is an underlying spatial lattice, for example crystalline alloys, with the rate laws valid in heterogeneous environments where there is no such natural lattice, for example in intracellular environments. Our simulations indicate that: (i) in intracellular environments both fractal kinetics and mass action can be valid, the major determinant being the probability of reaction, (ii) the geometry and size of the intracellular surface on which reactions are occurring does not significantly affect the rate law, (iii) there are considerable differences between the rate laws valid in heterogeneous non-living structures such as crystals and those valid in intracellular environments. Deviations from mass action are less pronounced in intracellular environments than in a crystalline material of similar heterogeneity.

Strong-coupling dynamics of a multicellular chemotactic system.

Chemical signaling is one of the ubiquitous mechanisms by which intercellular communication takes place at the microscopic level, particularly via chemotaxis. Such multicellular systems are popularly studied using continuum, mean-field equations. In this Letter we study a stochastic model of chemotactic signaling. The Langevin formalism of the model makes it amenable to calculation via nonperturbative analysis, which enables a quantification of the effect of fluctuations on both the weak and the strongly coupled biological dynamics. In particular, we show that the (i) self-localization due to autochemotaxis is impossible. (ii) When aggregation occurs, the aggregate performs a random walk with a renormalized diffusion coefficient D(R) proportiuonal to epsilon-2N-3. (iii) The stochastic model exhibits sharp transitions in cell motile behavior for negative chemotaxis, behavior that has no parallel in the mean-field Keller-Segel equations.