Choice of friction coefficient deeply affects tissue behaviour in stochastic epithelial vertex models.

To understand the mechanisms that coordinate the formation of biological tissues, the use of numerical implementations is necessary. The complexity of such models involves many assumptions and parameter choices that result in unpredictable consequences, obstructing the comparison with experimental data. Here, we focus on vertex models, a family of spatial models used extensively to simulate the dynamics of epithelial tissues. Usually, in the literature, the choice of the friction coefficient is not addressed using quasi-static deformation arguments that generally do not apply to realistic scenarios. In this manuscript, we discuss the role that the choice of friction coefficient has on the relaxation times and consequently in the conditions of cell cycle progression and division. We explore the effects that these changes have on the morphology, growth rate and topological transitions of the tissue dynamics. These results provide a deeper understanding of the role that an accurate mechanical description plays in the use of vertex models as inference tools. This article is part of a discussion meeting issue 'Causes and consequences of stochastic processes in development and disease'.

The ECM and tissue architecture are major determinants of early invasion mediated by E-cadherin dysfunction.

Germline mutations of E-cadherin cause Hereditary Diffuse Gastric Cancer (HDGC), a highly invasive cancer syndrome characterised by the occurrence of diffuse-type gastric carcinoma and lobular breast cancer. In this disease, E-cadherin-defective cells are detected invading the adjacent stroma since very early stages. Although E-cadherin loss is well established as a triggering event, other determinants of the invasive process persist largely unknown. Herein, we develop an experimental strategy that comprises in vitro extrusion assays using E-cadherin mutants associated to HDGC, as well as mathematical models epitomising epithelial dynamics and its interaction with the extracellular matrix (ECM). In vitro, we verify that E-cadherin dysfunctional cells detach from the epithelial monolayer and extrude basally into the ECM. Through phase-field modelling we demonstrate that, aside from loss of cell-cell adhesion, increased ECM attachment further raises basal extrusion efficiency. Importantly, by combining phase-field and vertex model simulations, we show that the cylindrical structure of gastric glands strongly promotes the cell's invasive ability. Moreover, we validate our findings using a dissipative particle dynamics simulation of epithelial extrusion. Overall, we provide the first evidence that cancer cell invasion is the outcome of defective cell-cell linkages, abnormal interplay with the ECM, and a favourable 3D tissue structure.

Efectividad de anticuerpos monoclonales anti-PRGC en el tratamiento preventivo de la migraña: estudio prospectivo de 63 pacientes / Effectiveness of anti-CGRP monoclonal antibodies in the preventive treatment of migraine: A prospective study of 63 patients

Introducción: El péptido relacionado con el gen de la calcitonina (PRGC) ha supuesto una revolución en el conocimiento de la fisiopatología de la migraña y ha llevado al desarrollo de nuevos fármacos específicos contra esta nueva diana.MétodosPresentamos un estudio prospectivo de 63 pacientes con migraña episódica (ME) y crónica (MC) tratados con anticuerpos monoclonales anti-PRGC y describimos su eficacia, seguridad y recaídas tras su suspensión. Se analizan predictores de respuesta que puedan ayudar a planificar mejor los tratamientos.ResultadosLa edad media fue de 48,3 ± 11,81 años, siendo 84,1% mujeres. La media de días de migraña al mes (DMM) fue de 15,59 días; 63,5% tenían MC. En todos se comenzó con erenumab 70 mg subcutáneo. Se aumentó la dosis a 140 mg en 47,6% de los pacientes. Se obtuvo una reducción entre 49,85 y 59,53% de DMM entre los tres primeros meses y el año de tratamiento; 17,5% presentó estreñimiento y 4,8% reacción en el lugar de la inyección. En cinco pacientes (17,9%) se cambió el tratamiento a galcanezumab. Tras suspender el tratamiento 23 pacientes sufrieron recaídas, con buena respuesta al reintroducirlo. No hemos podido establecer predictores de respuesta, pero sí observamos de forma estadísticamente significativa mayor número de días de mejora cuantos más DMM hubiera al inicio (p = 0,002).ConclusionesLos anticuerpos monoclonales anti-PRGC son fármacos eficaces, seguros y bien tolerados. Observamos que su interrupción, en algunos casos, puede conllevar recaídas frecuentes y precoces, por lo que recomendamos prolongar el tratamiento en aquellos pacientes con mayor DMM. (AU)

Introduction: Calcitonine Gen-Related Peptide (CGRP) established a revolution in migraine pathophysiology knowledge and has led to the development of new drugs specifically targeting this disease.MethodsWe present a prospective study in which 63 episodic and chronic migraine patients have been treated with anti-CGRP monoclonal antibodies describing their efficacy, security and relapses after their interruption. Response predictors have been analyzed such they can help us to create a better treatment plan.ResultsAverage age was 48.3 ± 11.81 years old, 84.1% of them being women. The average was of 15.59 migraine days per month (MDM). 63.5% of all patients suffered chronic migraine. The initial dose of Erenumab in all patient was 70 mg subcutaneous. This was increased to 140 mg in 47.6% of the patients. An MDM reduction between 49.85% and 59.53% was obtained within three to twelve months from the start of treatment. Constipation was present in 17.5% of the patients and 4.8% suffered injection site reaction. The treatment was changed to Galcanezumab in 17.9% of the patients. After interrupting the treatment, 23 patients relapsed with a good response on reintroduction of the treatment. It was not possible to establish a clear response predictor, however a statistically significant increase in the number of days of improvement was observed with more MDM at baseline level (p = 0.002).ConclusionsAnti-CGRP monoclonal antibodies are effective, safe, and well tolerated drugs. We have observed that their discontinuation, in some cases can lead to frequent and early relapses so we strongly recommend to extend the treatment in those patients with a higher MDM. (AU)

[Effectiveness of anti-CGRP monoclonal antibodies in the preventive treatment of migraine: A prospective study of 63 patients]. / Efectividad de anticuerpos monoclonales anti-PRGC en el tratamiento preventivo de la migraña: estudio prospectivo de 63 pacientes.

INTRODUCTION: Calcitonine Gen-Related Peptide (CGRP) established a revolution in migraine pathophysiology knowledge and has led to the development of new drugs specifically targeting this disease. METHODS: We present a prospective study in which 63 episodic and chronic migraine patients have been treated with anti-CGRP monoclonal antibodies describing their efficacy, security and relapses after their interruption. Response predictors have been analyzed such they can help us to create a better treatment plan. RESULTS: Average age was 48.3 ± 11.81 years old, 84.1% of them being women. The average was of 15.59 migraine days per month (MDM). 63.5% of all patients suffered chronic migraine. The initial dose of Erenumab in all patient was 70 mg subcutaneous. This was increased to 140 mg in 47.6% of the patients. An MDM reduction between 49.85% and 59.53% was obtained within three to twelve months from the start of treatment. Constipation was present in 17.5% of the patients and 4.8% suffered injection site reaction. The treatment was changed to Galcanezumab in 17.9% of the patients. After interrupting the treatment, 23 patients relapsed with a good response on reintroduction of the treatment. It was not possible to establish a clear response predictor, however a statistically significant increase in the number of days of improvement was observed with more MDM at baseline level (p = 0.002). CONCLUSIONS: Anti-CGRP monoclonal antibodies are effective, safe, and well tolerated drugs. We have observed that their discontinuation, in some cases can lead to frequent and early relapses so we strongly recommend to extend the treatment in those patients with a higher MDM.

Hospitalizaciones por cardiopatías congénitas en la Unidad de Cardiología Pediátrica del Centro Hospitalario Pereira Rossell / Hospitalization due to congenital heart disease at the Pereira Rossell Pediatric Hospital's Cardiology Unit / Internações por cardiopatia cardíaca congênita na Unidade de Cardiologia Pediátrica do Centro Hospitalar Pereira Rossell

Introducción: las cardiopatías congénitas (CC) son patologías frecuentes en pediatría. Son causa de importante morbimortalidad en la infancia. Son pacientes complejos, que requieren abordaje integral, en equipo interdisciplinario. Objetivos: describir las características epidemiológicas, clínicas y evolutivas de niños portadores de CC asistidos en la Unidad de Cardiología del HP-CHPR durante el año 2015, así como su estado nutricional y los factores que pudieran influir en este. Material y método: estudio descriptivo, retrospectivo, a través de la revisión de historias clínicas de pacientes portadores de CC, hospitalizados en la Unidad de Cardiología del HP-CHPR en 2015. Se describieron características epidemiológicas y clínicas de los pacientes. Resultados: en el período evaluado egresaron 63 pacientes, que representaron una tasa de 6,58/1.000 egresos hospitalarios. Tenían un promedio de edad de 23,8 meses. Un total de 8 pacientes fueron diagnosticados en el período prenatal, 54 presentaban CC no cianóticas. Habían sido sometidos a tratamiento quirúrgico 24 niños, 13 con cirugía correctiva. Se diagnosticó desnutrición en 43%. Esta fue más prevalente en portadores de CC cianótica, de defectos complejos, y de cromosomopatías u otras malformaciones. Conclusión: los niños con CC representaron un pequeño porcentaje de quienes requirieron hospitalización en el HP-CHPR. El porcentaje de desnutrición fue elevado. Este estudio confirma la importante morbimortalidad de los niños pequeños portadores de CC. Es importante reconocer el mayor riesgo de estos pacientes y actuar en forma individualizada y oportuna.

Introduction: congenital heart disease (CHD) is a frequent pathology among children. It may cause significant morbidity and mortality during childhood. These are complex patients, who require a comprehensive approach and an interdisciplinary team. Objective: to describe the epidemiological, clinical and evolutionary characteristics of children with CHD assisted in the Cardiology Department of the Children Hospital-CHPR in 2015. Material and Methods: descriptive, retrospective study, review of clinical records of patients with CHD, hospitalized in the Cardiology Department of the Children's Hospital PRHC in 2015. Epidemiological and clinical characteristics of patients were described. Results: 63 patients were hospitalized during the evaluated period, a total rate of 6.58/1.000 discharges. They had an average age of 23.8 months. Eight patients were diagnosed in the prenatal period, 54 presented non-cyanotic CHD. Twenty-four children had undergone surgical treatment, 13 had had corrective surgery. Malnutrition was diagnosed in 43% and it was more prevalent in cyanotic CHD carriers, complex defects, and chromosomopathies or other malformations. Conclusion: CHD represented a small percentage of the children who required hospitalization at the PH-PRHC. The percentage of malnutrition was high. The study confirmed the significant morbidity and mortality of these patients. It is important to recognize the highest risk of these patients and act in a customized and timely fashion.

Introdução: as cardiopatias congênitas (CC) são patologias comuns em pediatria. Elas são uma causa significativa de morbidade e mortalidade na infância. Os pacientes são complexos e requerem uma abordagem integral e uma equipe interdisciplinar. Objetivos: descrever as características epidemiológicas, clínicas e evolutivas de crianças com CC atendidas na Unidade de Cardiologia do Hospital Pediátrico PHPR durante o ano de 2015, descrever seu estado nutricional e os fatores que poderiam influenciá-lo. Material e métodos: estudo descritivo, retrospectivo, feito por meio da revisão de prontuários de pacientes com CC, internados na Unidade de Cardiologia do HP-CHPR em 2015. Foram descritas as características epidemiológicas e clínicas dos pacientes. Resultados: no período avaliado, 63 pacientes receberam alta hospitalar, representando uma taxa de 6,5/1.000 altas hospitalares. Eles tinham uma idade média de 23,8 meses. Oito pacientes foram diagnosticados no período pré-natal, 54 apresentavam CC não cianótica. 24 crianças tinham sido submetidas a tratamento cirúrgico, 13 tinham recebido cirurgia corretiva. 43% foram diagnosticadas com desnutrição, a qual foi mais prevalente em portadores de CC cianótica, defeitos complexos e malformações cromossômicas ou outras. Conclusão: os CCs representaram um pequeno percentual de crianças que necessitaram de internação no HP-CHPR. O percentual de desnutrição foi alto. Este estudo confirma a morbidade e mortalidade significativas de crianças pequenas com CC. É importante reconhecer o risco aumentado desses pacientes e agir de forma individualizada e oportuna.

Canine Distemper Outbreak by Natural Infection in a Group of Vaccinated Maned Wolves in Captivity.

Canine distemper virus (CDV) is one of the most significantinfectious disease threats to the health and conservation of free-ranging and captive wild carnivores. CDV vaccination using recombinant canarypox-based vaccines has been recommended for maned wolf (Chrysocyon brachyurus) after the failure of modified live vaccines that induced disease in vaccinated animals. Here, we report a CDV outbreak in a captive population of maned wolves that were previously vaccinated. Five juveniles and one adult from a group of seven maned wolves housed in an outdoor exhibit died in April-May 2013 in a zoo in the Metropolitan Region, Chile. Clinical signs ranged from lethargy to digestive and respiratory signs. Diagnosis of CDV was confirmed by histopathology, antibody assays, and viral molecular detection and characterization. The phylogenetic analyses of the nucleotide sequence of the H gene of the CDV genome identified in the two positive samples suggest a close relation with the lineage Europe 1, commonly found in South America and Chile. CDV infections in maned wolves have not been previously characterized. To the authors' best knowledge, this is the first report of the clinical presentation of CDV in a canine species previously immunized with a recombinant vaccine.

Physical and Chemical Restraints (an Update).

Violent, combative and intoxicated patients are a common problem in the emergency department, and the emergency physician must be prepared to control the situation safely and effectively when a patient begins to exhibit dangerous behavior. This article reviews initial de-escalation techniques to reduce the need for patient restraint. It then details the 2 types of restraints (physical and chemical) and the clear indications for each type. The high-risk nature of utilization of restraints is reviewed, as well as the means by which to ensure patient and staff safety and decrease adverse outcomes.

Neuronal differentiation influences progenitor arrangement in the vertebrate neuroepithelium.

Cell division, movement and differentiation contribute to pattern formation in developing tissues. This is the case in the vertebrate neural tube, in which neurons differentiate in a characteristic pattern from a highly dynamic proliferating pseudostratified epithelium. To investigate how progenitor proliferation and differentiation affect cell arrangement and growth of the neural tube, we used experimental measurements to develop a mechanical model of the apical surface of the neuroepithelium that incorporates the effect of interkinetic nuclear movement and spatially varying rates of neuronal differentiation. Simulations predict that tissue growth and the shape of lineage-related clones of cells differ with the rate of differentiation. Growth is isotropic in regions of high differentiation, but dorsoventrally biased in regions of low differentiation. This is consistent with experimental observations. The absence of directional signalling in the simulations indicates that global mechanical constraints are sufficient to explain the observed differences in anisotropy. This provides insight into how the tissue growth rate affects cell dynamics and growth anisotropy and opens up possibilities to study the coupling between mechanics, pattern formation and growth in the neural tube.

SAFETY AND SEROLOGICAL RESPONSE TO MULTIVALENT CANINE DISTEMPER VIRUS VACCINE IN RED FOXES (VULPES VULPES).

Canine distemper virus (CDV) vaccination using commercial vaccines has been recommended as a useful preventive tool in zoological collections worldwide for the past 30 yr. Zoological facilities have not conducted studies to assess the effectiveness and safety of the multivalent Recombitek C6 and C8 in nondomestic carnivores. They are the only CDV recombinant vaccines available in Latin America. Seventeen clinically healthy red foxes born in Buin Zoo were divided into three groups and administered 1 ml of Recombitek C6 vaccine. Group A consisted of three animals of 9 mo of age without previous vaccination (WPV) that received a single dose. Group B consisted of four animals of 10 mo of age WPV; they received a series of three doses with a 21-day interval between doses. Group C consisted of eight animals > 1 yr of age that had received a previous vaccination > 1 yr ago; they received a single-dose booster vaccination. Titers for antibodies against CDV were measured by a serum neutralization test. All animals remained clinically healthy throughout the study period and without clinical signs of disease. Only two foxes (group C) did not show any increase in the antibody titer to the vaccine. All animals of groups A and B seroconverted at 21 days after the first vaccination. Only two animals (both from group B) showed an adequate antibody protective response (titers >100) after 180 days. Absence of adverse reactions in red foxes included in this study supports the safety and apparently nondeleterious effect of CDV recombinant vaccine reported in other nondomestic carnivores. Low antibody response and lack of persistence in the serological response 6 mo after vaccination with a single dose suggested limited protective benefits in this species. Additional research is needed to confirm the antibody titer response to multiple vaccinations in this species.

Arteriovenous malformation masking associated anaplastic ganglioglioma in an adolescent / Malformación arteriovenosa asociada enmascara un ganglioglioma anaplásico multifocal en un adolescente

Abstract Grade III anaplastic ganglioglioma is an aggressive, rare, and radiosensitive central nervous system (CNS) tumour. It is more common in males, with a ratio of 1.3 to 1. Its peak incidence is in the third decade of life. Only 10 cases were recorded in children in Colombia from 2000 to 2014, with a fatal outcome in spite of radiation therapy. This is a case of an adolescent, who began having headaches, with warning signs related to an arteriovenous malformation hindering the diagnosis of this rare tumour. This presented in its aggressive, multi-focus form. Knowledge of clinical manifestations of space-occupying intracranial lesions facilitates the assessment and treatment of affected children.

Resumen El ganglioglioma anaplásico grado III es un tumor del sistema nervioso central (SNC) agresivo, infrecuente y radiosensible. Afecta más a hombres en una relación 1,3 a 1. Su pico de incidencia se encuentra en la tercera década de la vida. Existen solo 10 casos registrados en niños en Colombia desde el 2000 al 2014, con desenlace fatal a pesar de la radioterapia. Se presenta un caso de un adolescente que debutó con cefalea con signos de alarma asociado a una malformación arteriovenosa que dificultó el diagnóstico de este raro tumor, cuya presentación fue la más agresiva: la forma multicéntrica. El conocer las manifestaciones clínicas de lesiones intracraneales ocupantes de espacio facilita la evaluación y tratamiento a los niños afectados.

Minimum Action Path Theory Reveals the Details of Stochastic Transitions Out of Oscillatory States.

Cell state determination is the outcome of intrinsically stochastic biochemical reactions. Transitions between such states are studied as noise-driven escape problems in the chemical species space. Escape can occur via multiple possible multidimensional paths, with probabilities depending nonlocally on the noise. Here we characterize the escape from an oscillatory biochemical state by minimizing the Freidlin-Wentzell action, deriving from it the stochastic spiral exit path from the limit cycle. We also use the minimized action to infer the escape time probability density function.

Coarse-graining and hybrid methods for efficient simulation of stochastic multi-scale models of tumour growth.

The development of hybrid methodologies is of current interest in both multi-scale modelling and stochastic reaction-diffusion systems regarding their applications to biology. We formulate a hybrid method for stochastic multi-scale models of cells populations that extends the remit of existing hybrid methods for reaction-diffusion systems. Such method is developed for a stochastic multi-scale model of tumour growth, i.e. population-dynamical models which account for the effects of intrinsic noise affecting both the number of cells and the intracellular dynamics. In order to formulate this method, we develop a coarse-grained approximation for both the full stochastic model and its mean-field limit. Such approximation involves averaging out the age-structure (which accounts for the multi-scale nature of the model) by assuming that the age distribution of the population settles onto equilibrium very fast. We then couple the coarse-grained mean-field model to the full stochastic multi-scale model. By doing so, within the mean-field region, we are neglecting noise in both cell numbers (population) and their birth rates (structure). This implies that, in addition to the issues that arise in stochastic-reaction diffusion systems, we need to account for the age-structure of the population when attempting to couple both descriptions. We exploit our coarse-graining model so that, within the mean-field region, the age-distribution is in equilibrium and we know its explicit form. This allows us to couple both domains consistently, as upon transference of cells from the mean-field to the stochastic region, we sample the equilibrium age distribution. Furthermore, our method allows us to investigate the effects of intracellular noise, i.e. fluctuations of the birth rate, on collective properties such as travelling wave velocity. We show that the combination of population and birth-rate noise gives rise to large fluctuations of the birth rate in the region at the leading edge of front, which cannot be accounted for by the coarse-grained model. Such fluctuations have non-trivial effects on the wave velocity. Beyond the development of a new hybrid method, we thus conclude that birth-rate fluctuations are central to a quantitatively accurate description of invasive phenomena such as tumour growth.

Intrinsic Noise Profoundly Alters the Dynamics and Steady State of Morphogen-Controlled Bistable Genetic Switches.

During tissue development, patterns of gene expression determine the spatial arrangement of cell types. In many cases, gradients of secreted signalling molecules-morphogens-guide this process by controlling downstream transcriptional networks. A mechanism commonly used in these networks to convert the continuous information provided by the gradient into discrete transitions between adjacent cell types is the genetic toggle switch, composed of cross-repressing transcriptional determinants. Previous analyses have emphasised the steady state output of these mechanisms. Here, we explore the dynamics of the toggle switch and use exact numerical simulations of the kinetic reactions, the corresponding Chemical Langevin Equation, and Minimum Action Path theory to establish a framework for studying the effect of gene expression noise on patterning time and boundary position. This provides insight into the time scale, gene expression trajectories and directionality of stochastic switching events between cell states. Taking gene expression noise into account predicts that the final boundary position of a morphogen-induced toggle switch, although robust to changes in the details of the noise, is distinct from that of the deterministic system. Moreover, the dramatic increase in patterning time close to the boundary predicted from the deterministic case is substantially reduced. The resulting stochastic switching introduces differences in patterning time along the morphogen gradient that result in a patterning wave propagating away from the morphogen source with a velocity determined by the intrinsic noise. The wave sharpens and slows as it advances and may never reach steady state in a biologically relevant time. This could explain experimentally observed dynamics of pattern formation. Together the analysis reveals the importance of dynamical transients for understanding morphogen-driven transcriptional networks and indicates that gene expression noise can qualitatively alter developmental patterning.

Stochastic multi-scale models of competition within heterogeneous cellular populations: Simulation methods and mean-field analysis.

We propose a modelling framework to analyse the stochastic behaviour of heterogeneous, multi-scale cellular populations. We illustrate our methodology with a particular example in which we study a population with an oxygen-regulated proliferation rate. Our formulation is based on an age-dependent stochastic process. Cells within the population are characterised by their age (i.e. time elapsed since they were born). The age-dependent (oxygen-regulated) birth rate is given by a stochastic model of oxygen-dependent cell cycle progression. Once the birth rate is determined, we formulate an age-dependent birth-and-death process, which dictates the time evolution of the cell population. The population is under a feedback loop which controls its steady state size (carrying capacity): cells consume oxygen which in turn fuels cell proliferation. We show that our stochastic model of cell cycle progression allows for heterogeneity within the cell population induced by stochastic effects. Such heterogeneous behaviour is reflected in variations in the proliferation rate. Within this set-up, we have established three main results. First, we have shown that the age to the G1/S transition, which essentially determines the birth rate, exhibits a remarkably simple scaling behaviour. Besides the fact that this simple behaviour emerges from a rather complex model, this allows for a huge simplification of our numerical methodology. A further result is the observation that heterogeneous populations undergo an internal process of quasi-neutral competition. Finally, we investigated the effects of cell-cycle-phase dependent therapies (such as radiation therapy) on heterogeneous populations. In particular, we have studied the case in which the population contains a quiescent sub-population. Our mean-field analysis and numerical simulations confirm that, if the survival fraction of the therapy is too high, rescue of the quiescent population occurs. This gives rise to emergence of resistance to therapy since the rescued population is less sensitive to therapy.

Deterministic and Stochastic Study for a Microscopic Angiogenesis Model: Applications to the Lewis Lung Carcinoma.

Angiogenesis modelling is an important tool to understand the underlying mechanisms yielding tumour growth. Nevertheless, there is usually a gap between models and experimental data. We propose a model based on the intrinsic microscopic reactions defining the angiogenesis process to link experimental data with previous macroscopic models. The microscopic characterisation can describe the macroscopic behaviour of the tumour, which stability analysis reveals a set of predicted tumour states involving different morphologies. Additionally, the microscopic description also gives a framework to study the intrinsic stochasticity of the reactive system through the resulting Langevin equation. To follow the goal of the paper, we use available experimental information on the Lewis lung carcinoma to infer meaningful parameters for the model that are able to describe the different stages of the tumour growth. Finally we explore the predictive capabilities of the fitted model by showing that fluctuations are determinant for the survival of the tumour during the first week and that available treatments can give raise to new stable tumour dormant states with a reduced vascular network.

From invasion to latency: intracellular noise and cell motility as key controls of the competition between resource-limited cellular populations.

In this paper we analyse stochastic models of the competition between two resource-limited cell populations which differ in their response to nutrient availability: the resident population exhibits a switch-like response behaviour while the invading population exhibits a bistable response. We investigate how noise in the intracellular regulatory pathways and cell motility influence the fate of the incumbent and invading populations. We focus initially on a spatially homogeneous system and study in detail the role of intracellular noise. We show that in such well-mixed systems, two distinct regimes exist: In the low (intracellular) noise limit, the invader has the ability to invade the resident population, whereas in the high noise regime competition between the two populations is found to be neutral and, in accordance with neutral evolution theory, invasion is a random event. Careful examination of the system dynamics leads us to conclude that (i) even if the invader is unable to invade, the distribution of survival times, PS(t), has a fat-tail behaviour (PS(t) ∼ t(-1)) which implies that small colonies of mutants can coexist with the resident population for arbitrarily long times, and (ii) the bistable structure of the invading population increases the stability of the latent population, thus increasing their long-term likelihood of survival, by decreasing the intensity of the noise at the population level. We also examine the effects of spatial inhomogeneity. In the low noise limit we find that cell motility is positively correlated with the aggressiveness of the invader as defined by the time the invader takes to invade the resident population: the faster the invasion, the more aggressive the invader.

Hybrid approaches for multiple-species stochastic reaction-diffusion models.

Reaction-diffusion models are used to describe systems in fields as diverse as physics, chemistry, ecology and biology. The fundamental quantities in such models are individual entities such as atoms and molecules, bacteria, cells or animals, which move and/or react in a stochastic manner. If the number of entities is large, accounting for each individual is inefficient, and often partial differential equation (PDE) models are used in which the stochastic behaviour of individuals is replaced by a description of the averaged, or mean behaviour of the system. In some situations the number of individuals is large in certain regions and small in others. In such cases, a stochastic model may be inefficient in one region, and a PDE model inaccurate in another. To overcome this problem, we develop a scheme which couples a stochastic reaction-diffusion system in one part of the domain with its mean field analogue, i.e. a discretised PDE model, in the other part of the domain. The interface in between the two domains occupies exactly one lattice site and is chosen such that the mean field description is still accurate there. In this way errors due to the flux between the domains are small. Our scheme can account for multiple dynamic interfaces separating multiple stochastic and deterministic domains, and the coupling between the domains conserves the total number of particles. The method preserves stochastic features such as extinction not observable in the mean field description, and is significantly faster to simulate on a computer than the pure stochastic model.

The effects of intrinsic noise on the behaviour of bistable cell regulatory systems under quasi-steady state conditions.

We analyse the effect of intrinsic fluctuations on the properties of bistable stochastic systems with time scale separation operating under quasi-steady state conditions. We first formulate a stochastic generalisation of the quasi-steady state approximation based on the semi-classical approximation of the partial differential equation for the generating function associated with the chemical master equation. Such approximation proceeds by optimising an action functional whose associated set of Euler-Lagrange (Hamilton) equations provides the most likely fluctuation path. We show that, under appropriate conditions granting time scale separation, the Hamiltonian can be re-scaled so that the set of Hamilton equations splits up into slow and fast variables, whereby the quasi-steady state approximation can be applied. We analyse two particular examples of systems whose mean-field limit has been shown to exhibit bi-stability: an enzyme-catalysed system of two mutually inhibitory proteins and a gene regulatory circuit with self-activation. Our theory establishes that the number of molecules of the conserved species is order parameters whose variation regulates bistable behaviour in the associated systems beyond the predictions of the mean-field theory. This prediction is fully confirmed by direct numerical simulations using the stochastic simulation algorithm. This result allows us to propose strategies whereby, by varying the number of molecules of the three conserved chemical species, cell properties associated to bistable behaviour (phenotype, cell-cycle status, etc.) can be controlled.

Postdural puncture headache: impact of needle type, a randomized trial.

BACKGROUND CONTEXT: The most common adverse event after a lumbar puncture (LP) is a headache: In anaesthesiology, well studied is the protective effect of atraumatic spinal needles, and they are routinely used. However, this is less well known in diagnostic LP, and neurologists use atraumatic needles in less than 2% of times. PURPOSE: The purpose of this study was to define the impact of needle type, atraumatic (Sprotte [S]) versus traumatic (Quincke [Q]) on postdural puncture headache (PDPH) incidence. STUDY DESIGN: The study is based on a prospective, randomized, and simple-blinded clinical trial. PATIENT SAMPLE: Patients older than 14 years were scheduled for a diagnostic or therapeutic LP. OUTCOME MEASURES: The outcome measure included the development of PDPH according to the International Headache Association criteria. METHODS: Patients fulfilling eligibility criteria were randomly allocated to one of two kinds of spinal needle: atraumatic or S-type or traumatic or Q-type. They were interviewed on days 2 and 7 about the development of PDPH. RESULTS: The incidence of PDPH was 22.43% with Q-type needle and 8.51% with S-type needle, p=.04. The duration of PDPH in patients in the S-type was 1 day or less, compared with a median of 4.14 days in the Q-type (p=.00). In the logistic regression model, the S-type needle together with the age of the patient were the only two statistically significant factors in the development of postlumbar puncture headache (PLPH), both of them being protective. CONCLUSIONS: We found a lower incidence of PDPH with atraumatic needles, and it was statistically significant compared with the traumatic needles. Our study confirms the effectiveness of the atraumatic needles to prevent PDPH.