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The migration of endothelial cells (ECs) is critical for various processes including vascular wound healing, tumor angiogenesis, and the development of viable endovascular implants. Recent observations (time-lapse imaging over 12hr periods) in our laboratory of ECs cultured on line patterns - surfaces where cellular adhesion is limited to 15 ?m wide lines - have demonstrated the presence of three distinct migration phenotypes: a) running - cells are polarized and migrate continuously and persistently on the adhesive lines with possible directional changes, b) undecided - cells are elongated and exhibit periodic changes in the direction of their polarization and minimal net migration, and c) tumbling-like - cells migrate persistently for a certain amount of time but then stop and round up for a few hours before spreading again and resuming migration. Because EC migration is regulated by intracellular ATP levels and cellular elongation induced ATP release, we hypothesize that the three migration phenotypes on line patterns, which translate into different cell length variations in time, are related to different intracellular ATP profiles. Thus, we have developed a mathematical model to provide a description of the complex interactions between cell length, cytoskeletal (F-actin) organization, and intracellular ATP concentration. To identify the parameters that reproduce the experimental observations, we have implemented an optimization procedure that yields the parameter values that best fit the experimental data on cell lengths. The results show that depending on the parameter values adopted for the simulations, the different ATP profiles can indeed be obtained. Future work will focus on providing experimental evidence for the involvement of intracellular ATP in determining the three types of migration behavior.

Purpose Assess the long term cardiovascular outcomes of heart rate reduction strategy (HRR) using ivabradine in children with chronic heart failure (HF). Background Chronic heart failure (HF) due to dilated cardiomyopathy (DCM) remains a significant medical challenge in pediatric population. There is paucity of evidence about pharmacological management of this population. Methods We conducted a retrospective cohort study including all children with end stage dilated cardiomyopathy (DCM) with LV function Results 72 children were included in the study and 23 treated with HRR strategy. After 1 year, HRR strategy was able to reduce heart rate [from 109.2 ± 26.4 bpm to 79.04 ± 18.8 bpm (p Conclusion Treatment with HRR strategy, in addition to standard HF therapy, seemed to be effective in reducing the incidence of acute adverse events and improving ventricular function in children with DCM and chronic HF.

We present a general mechanistic model of mass diffusion for a composite sphere placed in a large ambient medium. The multi-layer problem is described by a system of diffusion equations coupled via interlayer boundary conditions such as those imposing a finite mass resistance at the external surface of the sphere. While the work is applicable to the generic problem of heat or mass transfer in a multi-layer sphere, the analysis and results are presented in the context of drug kinetics for desorbing and absorbing spherical microcapsules. We derive an analytical solution for the concentration in the sphere and in the surrounding medium that avoids any artificial truncation at a finite distance. The closed-form solution in each concentric layer is expressed in terms of a suitably-defined inverse Laplace transform that can be evaluated numerically. Concentration profiles and drug mass curves in the spherical layers and in the external environment are presented and the dependency of the solution on the mass transfer coefficient at the surface of the sphere analyzed.

Drug releasing capsules and droplets are largely used in biomedical applications. Such vehicles consist of a drug-loaded core surrounded by a thin semi-permeable layer. Diffusion is by far the dominant mechanism in drug delivery, beside other physico-chemical factors, such as osmosis, drug dissolution, polymer swelling and degradation. We upgrade existing mechanistic models by extending their applications to the composite structures, and characterize the kinetics of the drug eluted from the vehicle into the external targeted medium. We develop a theoretical and computational study aimed at modelling the drug release from a composite spherical core-shell capsule or a double emulsion having either a protective coating or a surfactant, under the assumption of radial symmetry. The problem of release from such a layer-by-layer composite systems is described by a system of coupled partial differential equations, which we solve analytically in terms of Fourier series or using numerical solutions. In addition to the conventional partitioning and interlayer conditions, we consider a finite mass transfer coefficient, to model the resistance at the surface. Expressions for the concentration and the cumulative mass in all layers are given to show the dependence and sensitivity to parameters, such as diffusivity, permeability and partition coefficients. The release curve characterizes the drug transport mechanism and suggests how to guarantee a controlled release. The proposed model constitutes a simple tool to predict the release from composite materials that, measuring their performance or comparing different configurations, can help in designing novel drug delivery systems.

In this paper, we consider a multi-layer diffusion model of drug release from a composite spherical microcapsule into an external surrounding medium. Based on this model, we present two approaches for estimating the release time, i.e. the time required for the drug-filled capsule to be depleted. Both approaches make use of temporal moments of the drug concentration at the centre of the capsule, which provide useful insight into the timescale of the process and can be computed exactly without explicit calculation of the full transient solution of the multi-layer diffusion model. The first approach, which uses the zeroth and first temporal moments only, provides a crude approximation of the release time taking the form of a simple algebraic expression involving the various parameters in the model (e.g. layer diffusivities, mass transfer coefficients, partition coefficients) while the second approach yields an asymptotic estimate of the release time that depends on consecutive higher moments. Through several test cases, we show that both approaches provide a computationally- cheap and useful tool to quantify the release time of composite microcapsule configurations.

Introduction To evaluate the knowledge of healthcare workers about first-aid measures to be performed during and after a tonic–clonic seizure. Methods One hundred and fifty-four healthcare workers (86 physicians) working at 8 tertiary hospitals in the Apulia region, Italy, responded to a questionnaire comprising of 28 questions based on available Italian and international recommendations about what to do during a tonic–clonic seizure. Results One hundred and fifty-four healthcare workers completed and returned surveys with a response rate of 96.25%. There were 55 nurses (35.7%), 86 physicians (55.8%), and 13 healthcare workers with different roles (Electroencephalograph technicians, psychologists, social workers). Among physicians, there were 7 cardiologists, 3 surgeons, 12 infectious-disease specialists, 11 internal medicine specialists, 2 psychiatrists, 2 gynecologists, 27 specialists working in the emergency department, and 22 physicians with different specializations. Nearly 90% of the respondents identified head protection as important first aid, while 100% responded to not keep the legs elevated. To avoid tongue bite, both physicians and other healthcare workers would put something in the mouth (54.0%), like a Guedel cannula (71.0%) fingers (29.5%). Grabbing arms and legs, trying to stop the seizure, would be potentially performed by 11.6% of our sample. Physicians would administer a benzodiazepine during the seizure (65.7%) and during the postictal phase (29.2%), even if the patient is known to have epilepsy (23.7%), and in this case, 11.3% of respondents would administer the usual antiepileptic medications. More than half of respondents would call the emergency telephone number, because of necessary hospitalization in case of tonic–clonic seizure, even if it is experienced by a patient known to have epilepsy. Conclusion Our survey suggests the need for epilepsy educational programs on first-aid management of seizures among healthcare workers.

The topic of controlled drug release has received much attention in recent years, for example in the design of tablets and in local drug delivery devices such as stents, transdermal patches and orthopaedic implants. In recent years, we have developed a series of models for such devices to describe drug release from a polymeric platform and transport in surrounding biological tissues. These works have culminated in the development of a mathematical model that demonstrates agreement with in-vivo drug release and tissue uptake data, for the case of a drug-eluting stent. If, on the one hand, these fully coupled models are indeed necessary to understand the spatio-temporal drug concentration in the surrounding environment, on the other hand it is clear that device manufacturers cannot intervene on the underlying biology. What they can control, however, are the properties of the polymeric platform to ensure the desired drug release profile is achieved. Indeed, the release profile is known to be a key predictor of device performance. Therefore, in the present work we focus instead primarily on the properties of the drug-containing coating. We consider two particular aspects of the drug coating design. Firstly, the delivery of two therapeutic agents, what we refer to as dual drug delivery. Depending on the particular application in question, it may be desirable for the drugs to be released at similar rates, or perhaps one of the drugs released rapidly with the other being eluted over a longer period of time. In the case of drug-eluting stents, for example, devices which release an anti-proliferative and a 'pro-healing' drug have been proposed, whilst a combination of the two has also been suggested. Secondly, motivated by today's advances in micro and nanotechnology, we propose variable porosity multi-layer coatings as an additional means of controlling the dual drug delivery. In this talk we present our mathematical model of dual drug delivery from a durable polymer coated device. We demonstrate how the release rate of each drug may in principle be controlled by varying the underlying microstructure of polymer coating or by changing the initial loading configuration of the two drugs . Our results show the role of the relevant material parameters used to tailor the release curves to a given application.

Arterial physiopathological behavior involves multiphysics mechanisms, as the result of the complex interplay between microscale transport phenomena and mechanical equilibrium. This chapter draws a modeling strategy for coupling macroscopic mechanics and molecular diffusive/reactive mechanisms via biochemically-motivated tissue remodeling laws. Results have been obtained by addressing the effects of extracellular matrix remodeling driven by matrix metalloproteinases, transforming growth factor-beta and interleukines on the compliance of an axisymmetric arterial segment. Remarkably, obtained results show that the present approach is able to capture arterial dilation as a consequence of alterations in the cellular activity, as well as to incorporate the protective role of pharmacological treatments.

In this paper we describe a theoretical mathematical model of dual drug delivery from a durable polymer coated medical device. We demonstrate how the release rate of each drug may in principle be controlled by altering the initial loading configuration of the two drugs. By varying the underlying microstructure of polymer coating, further control may be obtained, providing the opportunity to tailor the release profile of each drug for the given application.

We consider the mathematical modeling of the coupled mechanical-transport problem found in arterial physiopathology. The chapter provides an extensive description of the physiology and the microstructure of the arterial wall and explains how these are coupled to the molecular transport problem. The details of the most recent developments of the mechanistic descriptions of the multi-scale multi-physics are presented.

Background Children with HIV will be on antiretroviral therapy (ART) longer than adults, and therefore the durability of first-line ART and timing of switch to second-line are key questions. We assess the long-term outcome of protease inhibitor and non-nucleoside reverse transcriptase inhibitor (NNRTI) first-line ART and viral load switch criteria in children. Methods In a randomised open-label factorial trial, we compared effectiveness of two nucleoside reverse transcriptase inhibitors (NRTIs) plus a protease inhibitor versus two NRTIs plus an NNRTI and of switch to second-line ART at a viral load of 1000 copies per mL versus 30,000 copies per mL in previously untreated children infected with HIV from Europe and North and South America. Random assignment was by computer-generated sequentially numbered lists stratified by age, region, and by exposure to perinatal ART. Primary outcome was change in viral load between baseline and 4 years. Analysis was by intention to treat, which we defined as all patients that started treatment. This study is registered with ISRCTN, number ISRCTN73318385. Findings Between Sept 25, 2002, and Sept 7, 2005, 266 children (median age 6.5 years; IQR 2.8-12.9) were randomly assigned treatment regimens: 66 to receive protease inhibitor and switch to second-line at 1000 copies per mL (PI-low), 65 protease inhibitor and switch at 30,000 copies per mL (PI-higher), 68 NNRTI and switch at 1000 copies per mL (NNRTI-low), and 67 NNRTI and switch at 30,000 copies per mL (NNRTI-higher). Median follow-up was 5.0 years (IQR 4.2-6.0) and 188 (71%) children were on first-line ART at trial end. At 4 years, mean reductions in viral load were -3.16 log(10) copies per mL for protease inhibitors versus -3.31 log(10) copies per mL for NNRTIs (difference -0.15 log(10) copies per mL, 95% CI -0.41 to 0.11; p=0.26), and -3.26 log(10) copies per mL for switching at the low versus -3.20 log(10) copies per mL for switching at the higher threshold (difference 0.06 log(10) copies per mL, 95% CI -0.20 to 0.32; p=0.56). Protease inhibitor resistance was uncommon and there was no increase in NRTI resistance in the PI-higher compared with the PI-low group. NNRTI resistance was selected early, and about 10% more children accumulated NRTI mutations in the NNRTI-higher than the NNRTI-low group. Nine children had new CDC stage-C events and 60 had grade 3/4 adverse events; both were balanced across randomised groups. Interpretation Good long-term outcomes were achieved with all treatments strategies. Delayed switching of protease-inhibitor-based ART might be reasonable where future drug options are limited, because the risk of selecting for NRTI and protease-inhibitor resistance is low. Funding Paediatric European Network for Treatment of AIDS (PENTA) and Pediatric AIDS Clinical Trials Group (PACTG/IMPAACT).

Coronary restenosis consists of the partial/total re-occlusion of the artery lumen following percutaneous transluminal angioplasty (PTCA). In order to match this pathology, PTCA is followed by the implantation of rigid scaffolds (stent or coated stent) aimed to contrast the most important mechanical (coronary wall elastic recoil and late remodelling) and biological (smooth muscle cells iper-proliferation) factors leading to restenosis. In the light of the clinical problems recently arisen about the use of traditional coated stents, this paper proposes a theoretical study to comprehend the release kinetics of novel anti-proliferative drugs, i.e. nucleic acid based drugs (NABD), complexed with the proper delivery agent (DA). The release of NABD-DA is supposed to occur from a double gel layer adhering to coronary wall and embedding the stent. The proposed mathematical model assumes that diffusion, convection and cellular internalisation/metabolism are the leading mechanisms ruling drug spreading in the coronary wall. In addition, stent void fraction, positioning (totally embedded or totally out of the coronary wall) and continuous or discontinuous character of the gel layer are other three important model parameters. In order to generalise the results, stent geometry is idealised as a series of not connected, equally spaced, rings positioned in the stented zone. In correspondence of stent strut, drug transport cannot occur. The most important outcomes of this study are that, in the usual void fraction range (0.7-0.9), stent presence does not sensibly affect NABD-DA release kinetics. In addition, whereas stent positioning in the continuous gel configuration (totally embedded or totally out of coronary wall) is not very important, in the discontinuous case, it becomes relevant. Finally, this study evidences that a proper mixture of NABD complexed with different (in dimensions and kind) DA can ensure an almost constant NABD coronary concentration for several months, as requested by clinical observations.

AIM To evaluate the effect of gender, gestational age, birthweight, mode of delivery, 5'-Apgar score and maternal conditions on calprotectin concentrations in meconium. METHODS Calprotectin was measured in 131 neonates, in the first passed meconium. RESULTS Calprotectin levels (mean +/- SD) resulted in 145.2 +/- 78.5 mg kg(-1) meconium, significantly correlated with birthweight (r = -0.333; p < 0.001), gestational age (r = -0.206; p = 0.018) and 5'-Apgar score (r = -0.243, p = 0.035). The estimated regression model was: calprotectin levels (mg kg(-1)) = 269.58-41.54 weight (kg): r = 0.383, p < 0.001. No differences were found in relation to gender, mode of delivery and maternal conditions. CONCLUSION Calprotectin is already present in the first passed meconium, with higher levels in preterm and low birthweight neonates, as well as in neonates with some degree of perinatal asphyxia, as indicated by the negative correlation with 5'-Apgar score. These findings are probably secondary to both the immaturity of the intestinal mucosa and its hypoxic-ischaemic damage.

Objectives: To estimate the prevalence of and identify risk factors for lipodystrophy syndrome (LS) and body fat abnormality in a population of HIV-infected children and adolescents. Design: Cross-sectional observational study. Methods: HIV-infected subjects aged 2-18 years were recruited from 15 HIV centers in Belgium Italy, and Poland between January 2007 and December 2008. Standardized assessments by the patient's long-term clinician were performed to establish the presence of abnormality. Risk factors were explored in logistic regression models for fat abnormality outcomes and LS (abnormality plus dyslipidemia). Results: Among 426 subjects (70% white), median age was 12.2 years (interquartile range: 9.0-15.0 years) and median duration of antiretroviral therapy was 5.2 years (interquartile range: 2.2-8.8 years). Prevalence was 57% (n = 235) for LS and 42% (n =176) for fat abnormality; 90 subjects with abnormality were affected in ≥3 locations. Lipoatrophy occurred in 28% (n =117) of subjects and lipohypertrophy in 27% (n = 115), most commonly in the face and trunk, respectively. In multivariable analysis, white ethnicity, body mass index, ritonavir/lopinavir, and nonnucleoside reverse transcriptase inhibitors were each associated with an increased risk of LS (P

We present a general model of drug release from a drug delivery device and the subsequent transport in biological tissue. The model incorporates drug diffusion, dissolution and solubility in the polymer coating, coupled with diffusion, convection and reaction in the biological tissue. Each layer contains bound and free drug phases so that the resulting model is a coupled two-phase two-layer system of partial differential equations. One of the novelties is the generality of the model in each layer. Within the drug coating, our model includes diffusion as well as three different models of dissolution. We show that the model may also be used in cases where dissolution is rapid or not relevant, and additionally when drug release is not limited by its solubility. Within the biological tissue, the model can account for nonlinear saturable reversible binding, with lin- ear reversible binding and linear irreversible binding being recovered as special cases.

Implantation of drug eluting stents following percutaneous transluminal angioplasty has revealed a well established technique for treating occlusions caused by the atherosclerotic plaque. However, due to the risk of vascular re-occlusion, other alternative therapeutic strategies of drug delivery are currently being investigated. Polymeric endoluminal pave stenting is an emerging technology for preventing blood erosion and for optimizing drug release. The classical and novel methodologies are compared through a mathematical model able to predict the evolution of the drug concentration in a cross-section of the wall. Though limited to an idealized configuration, the present model is shown to catch most of the relevant aspects of the drug dynamics in a delivery system. Results of numerical simulations shows that a bi-layer gel paved stenting guarantees a uniform drug elution and a prolonged perfusion of the tissues, and remains a promising and effective technique in drug delivery.

A two-phasemathematical model describing the dynamics of a substance between two coupled media of different properties and dimensions is presented. A system of partial differential equations describes the diffusion and the binding/unbinding processes in both layers. Additional flux continuity at the interface and clearance conditions into systemic circulation are imposed. An eigenvalue problem with discontinuous coefficients is solved and an analytical solution is given in the form of an infinite series expansion. The model points out the role of the diffusion and reaction parameters, which control the complex transfer mechanism and the drug kinetics across the two layers.

A model of drug release from an eluting stent to the arterial wall is presented. The coating layer is described as a porous reservoir where the drug is initially loaded in a polymer-encapsulated solid phase, and is then released both to the coating and to the tissue of the arterial wall in a free phase. The wall is treated as a heterogeneous porous medium and the drug transfer through it is modeled by a non-homogeneous set of coupled partial differential equations that describe a convection-diffusion-reaction process. Change of phases due to drug dissolution in the coating and binding-unbinding reactions in the arterial wall are addressed. Numerical results show a strong coupling of the release kinetics in the polymer and the drug dynamics in the wall, and this coupling depends on the physico-chemical drug properties, the microstructure of the polymeric stent coating and the properties of the arterial wall.

The steady flow of an Oldroyd-B fluid between two porous concentric circular cylinders is studied. The equation of motion and the constitutive equations form a system of non-linear ODEs that is solved numerically, and in a few cases the numerical results are compared with a known analytical solution. We consider the effect of the non-Newtonian nature of the fluid on the drag and on the boundary layer structure near the walls. Numerical computations show the effect of the non-Newtonian quantities on the velocity and on the shear stress as the dimensionless parameters are varied. © by 1997 John Wiley & Sons, Ltd.