In vivo biocompatibility evaluation of composite polymeric materials for use in a novel artificial heart valve

A novel trileaflet polymer valve is a composite design of a biostable polymer poly(styrene-isobutylene-styrene) (SIBS) with a reinforcement polyethylene terephthalate (PET) fabric. Surface roughness and hydrophilicity vary with fabrication methods and influence leaflet biocompatibility. The purpose of this study was to investigate the biocompatibility of this composite material using both small animal (nonfunctional mode) and large animal (functional mode) models. Composite samples were manufactured using dip coating and solvent casting with different coating thickness (251μm and 50μm). Sample's surface was characterized through qualitative SEM observation and quantitative surface roughness analysis. A novel rat abdominal aorta model was developed to test the composite samples in a similar pulsatile flow condition as its intended use. The sample's tissue response was characterized by histological examination. Among the samples tested, the 25μm solvent-cast sample exhibited the smoothest surface and best biocompatibility in terms of tissue capsulation thickness, and was chosen as the method for fabrication of the SIBS valve. Phosphocholine was used to create a hydrophilic surface on selected composite samples, which resulted in improved blood compatibility. Four SIBS valves (two with phosphocholine modification) were implanted into sheep. Echocardiography, blood chemistry, and system pathology were conducted to evaluate the valve's performance and biocompatibility. No adverse response was identified following implantation. The average survival time was 76 days, and one sheep with the phosphocholine modified valve passed the FDA minimum requirement of 140 days with approximately 20 million cycles of valve activity. The explanted valves were observed under the aid of a dissection microscope, and evaluated via histology, SEM and X-ray. Surface cracks and calcified tissue deposition were found on the leaflets. In conclusion, we demonstrated the applicability of using a new rat abdominal aorta model for biocompatibility assessment of polymeric materials. A smooth and complete coating surface is essential for the biocompatibility of PET/SIBS composite, and surface modification using phosphocholine improves blood compatibility. Extrinsic calcification was identified on the leaflets and was associated with regions of surface cracks.

Design and performance assessment of aortic heart valve for tissue engineering

Current artificial heart valves are classified as mechanical and bioprosthetic. An appealing pathway that promises to overcome the shortcomings of commercially available heart valves is offered by the interdisciplinary approach of cardiovascular tissue engineering. However, the mechanical properties of the Tissue Engineering Heart Valves (TEHV) are limited and generally fail in the long-term use. To meet this performance challenge novel biodegradable triblock copolymer poly(ethylene oxide)-polypropylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO or F108) crosslinked to Silk Fibroin (F108-SilkC) to be used as tri-leaflet heart valve material was investigated. ^ Synthesis of ten polymers with varying concentration and thickness (55 µm, 75 µm and 100 µm) was achieved via a covalent crosslinking scheme using bifunctional polyethylene glycol diglycidyl ether (PEGDE). Static and fatigue testing were used to assess mechanical properties of films, and hydrodynamic testing was performed to determine performance under a simulated left ventricular flow regime. The crosslinked copolymer (F108-Silk C) showed greater flexibility and resilience, but inferior ultimate tensile strength, by increasing concentration of PEGDE. Concentration molar ratio of 80:1 (F108: Silk) and thickness of 75 µm showed longer fatigue life for both tension-tension and bending fatigue tests. Four valves out of twelve designed satisfactorily complied with minimum performance requirement ISO 5840, 2005. ^ In conclusion, it was demonstrated that the applicability of a degradable polymer in conjugation with silk fibroin for tissue engineering cardiovascular use, specifically for aortic valve leaflet design, met the performance demands. Thinner thicknesses (t<75 µm) in conjunction with stiffness lower than 320 MPa (80:1, F108: Silk) are essential for the correct functionality of proposed heart valve biomaterial F108-SilkC. Fatigue tests were demonstrated to be a useful tool to characterize biomaterials that undergo cyclic loading. ^

Durability Assessment of Polymer Trileaflet Heart Valves

The durability of a polymer trileaflet valve is dependent on leaflet stress concentrations, so valve designs that reduce stress can, hypothetically, increase durability. Design aspects that are believed to contribute to reduced leaflet stress include stent flexibility, parabolic coaptation curvature, and leaflet anisotropy. With this in mind, the purpose of this investigation was to elucidate what specific combinations of these parameters promote optimal acute and long-term valve function. A combination of four stent designs, seven leaflet reinforcement materials, and three coaptation geometries were evaluated through a combination of experimentation and modeling. Static tensile and Poisson’s ratio tests and dynamic tensile fatigue testing were used to evaluate the individual leaflet components; and hydrodynamic testing and accelerated valve fatigue was used to assess complete valve prototypes. The two most successful designs included a 0.40 mm thick knit-reinforced valve with a fatigue life of 10.35 years, and a 0.20 mm thick knit-reinforced valve with a 28.9 mmHg decrease in pressure drop over the former. A finite element model was incorporated to verify the impact of the above-mentioned parameters on leaflet stress concentrations. Leaflet anisotropy had a large impact on stress concentrations, and matching the circumferential modulus to that of the natural valve showed the greatest benefit. Varying the radial modulus had minimal impact. Varying coaptation geometry had no impact, but stent flexibility did have a marked effect on the stress at the top of the commissure, where a completely rigid stent resulted in a higher peak stress than a flexible stent (E = 385 MPa). In conclusion, stent flexibility and leaflet anisotropy do effect stress concentrations in the SIBS trileaflet valve, but coaptation geometry does not. Regions of high stress concentrations were linked to failure locations in vitro, so a fatigue prediction model was developed from the S/N curves generated during dynamic tensile testing of the 0.20 mm knit-reinforced leaflets. Failure was predicted at approximately 400 million cycles (10 years) at the top of the commissure. In vitro fatigue of this valve showed failure initiation after approximately 167 million cycles (4.18 years), but it was related to a design defect that is subsequently being changed.

Static and dynamic mechanical testing of a polymer with potential use as heart valve material

Synthetic tri-leaflet heart valves generally fail in the long-term use (more than 10 years). Tearing and calcification of the leaflets usually cause failure of these valves as a consequence of high tensile and bending stresses borne on the material. The primary purpose of this study was to explore the possibilities of a new polymer composite to be used as synthetic tri-leaflet heart valve material. This composite was comprised of polystyrene-polyisobutylene-polystyrene (Quatromer), a proprietary polymer, embedded with continuous polypropylene (PP) fibers. Quatromer had been found to be less likely to degrade in vivo than polyurethane. Moreover, it was postulated that a decrease in tears and perforations might result from fiber-reinforced leaflets reducing high stresses on the leaflets. The static and dynamic mechanical properties of the Quatromer/PP composite were compared with those of an implant-approved polyurethane (PU) for cardiovascular applications. Results show that the reinforcement of Quatromer with PP fibers improves both its static and dynamic properties as compared to the PU. Hence, this composite has the potential to be a more suitable material for synthetic tri-leaflet heart valves.

EspZ of enteropathogenic and enterohemorrhagic Escherichia coli regulates type III secretion system protein translocation

UNLABELLED: Translocation of effector proteins via a type III secretion system (T3SS) is a widespread infection strategy among Gram-negative bacterial pathogens. Each pathogen translocates a particular set of effectors that subvert cell signaling in a way that suits its particular infection cycle. However, as effector unbalance might lead to cytotoxicity, the pathogens must employ mechanisms that regulate the intracellular effector concentration. We present evidence that the effector EspZ controls T3SS effector translocation from enteropathogenic (EPEC) and enterohemorrhagic (EHEC) Escherichia coli. Consistently, an EPEC espZ mutant is highly cytotoxic. Following ectopic expression, we found that EspZ inhibited the formation of actin pedestals as it blocked the translocation of Tir, as well as other effectors, including Map and EspF. Moreover, during infection EspZ inhibited effector translocation following superinfection. Importantly, while EspZ of EHEC O157:H7 had a universal "translocation stop" activity, EspZ of EPEC inhibited effector translocation from typical EPEC strains but not from EHEC O157:H7 or its progenitor, atypical EPEC O55:H7. We found that the N and C termini of EspZ, which contains two transmembrane domains, face the cytosolic leaflet of the plasma membrane at the site of bacterial attachment, while the extracellular loop of EspZ is responsible for its strain-specific activity. These results show that EPEC and EHEC acquired a sophisticated mechanism to regulate the effector translocation.

IMPORTANCE: Enteropathogenic Escherichia coli (EPEC) and enterohemorrhagic E. coli (EHEC) are important diarrheal pathogens responsible for significant morbidity and mortality in developing countries and the developed world, respectively. The virulence strategy of EPEC and EHEC revolves around a conserved type III secretion system (T3SS), which translocates bacterial proteins known as effectors directly into host cells. Previous studies have shown that when cells are infected in two waves with EPEC, the first wave inhibits effector translocation by the second wave in a T3SS-dependent manner, although the factor involved was not known. Importantly, we identified EspZ as the effector responsible for blocking protein translocation following a secondary EPEC infection. Interestingly, we found that while EspZ of EHEC can block protein translocation from both EPEC and EHEC strains, EPEC EspZ cannot block translocation from EHEC. These studies show that EPEC and EHEC employ a novel infection strategy to regulate T3SS translocation.

Agrandissement des feuillets mitraux en insuffisance aortique : un mécanisme actif pouvant prévenir l’insuffisance mitrale dans le ventricule dilaté

L’insuffisance mitrale (IM) fonctionnelle est une complication fréquente des cardiopathies, causée par la dilatation du ventricule gauche (VG) qui empêche la valve de se fermer. L’insuffisance aortique (IA) est une condition associée à des valves mitrales (VM) inhabituellement grandes, et relativement peu d’IM malgré des VG très dilatés. Cet élargissement de la VM a le potentiel de prévenir l’IM dans les VG dilatés. Les mécanismes sont cependant peu compris : il n’est pas clair s’il s’agit d’une croissance active ou d’un étirement passif des feuillets. Également, le timing de l’adaptation valvulaire n’est pas connu. Notre hypothèse est que l’agrandissement de la valve mitrale en IA est un phénomène actif avec réactivation des mécanismes de croissance embryonnaire. Cent-onze rats ont été divisés en deux groupes : IA (perforation aortique) et contrôle. Les animaux ont été sacrifiés à 48 h, 1 semaine et 3 mois après la création du modèle. Des échocardiographies ont évalué la sévérité de l’IA, la présence d’IM et les dimensions du VG. Les valves ont été prélevées pour analyses microscopiques et moléculaires. La création de l’insuffisance aortique a entrainé une dilatation et une hypertrophie du VG. Malgré cette dilatation rapide du VG, aucun animal n’a développé de l’IM fonctionnelle. À l’échographie, le feuillet antérieur mitral était significativement plus long dans les groupes IA. Par microscopie, les feuillets étaient plus épais dés la première semaine. L’IA était associée à une surexpression de collagène α-SMA (un marqueur de myofibroblastes), TGF-β1 et MMP-2 dans le tissu valvulaire dès la première semaine. Les valves exposées à l’IA étaient également positives pour ces différents facteurs dés les premiers jours. L’agrandissement de la VM est un phénomène actif qui survient rapidement après la création de l’IA, en parallèle de la dilatation du VG. La stimulation de cette croissance dans d’autres pathologies pourrait contribuer à prévenir l’IM fonctionnelle.

Indoor environment and the impact on the health of pre-exisiting asthmatics at work: the development of a risk management framework

This thesis examines the spatial and temporal variation in nitrogen dioxide (NO2) levels in Guernsey and the impacts on pre-existing asthmatics. Whilst air quality in Guernsey is generally good, the levels of NO2 exceed UK standards in several locations. The evidence indicates that people suffering from asthma have exacerbation of their symptoms if exposed to elevated levels of air pollutants including NO2, although this research has never been carried out in Guernsey before. In addition, exposure assessment of individuals is rarely carried out and research in this area is limited due to the complexity of undertaking such a study, which will include a combination of exposures in the home, the workplace and ambient exposures, which vary depending on the individual daily experience. For the first time in Guernsey, this research has examined NO2 levels in correlation with asthma patient admissions to hospital, assessment of NO2 exposures in typical homes and typical workplaces in Guernsey. The data showed a temporal correlation between NO2 levels and the number of hospital admissions and the trend from 2008-2012 was upwards. Statistical analysis of the data did not show a significant linear correlation due to the small size of the data sets. Exposure assessment of individuals showed a spatial variation in exposures in Guernsey and assessment in indoor environments showed that real-time analysis of NO2 levels needs to be undertaken if indoor micro environments for NO2 are the be assessed adequately. There was temporal and spatial variation in NO2 concentrations measured using diffusion tubes, which provide a monthly mean value, and analysers measuring NO2 concentrations in real time. The research shows that building layout and design are important factors for good air flow and ventilation and the dispersion of NO2 indoors. Environmental Health Officers have statutory responsibilities for ambient air quality, hygiene of buildings and workplace environments and this role needs to be co-ordinated with healthcare professionals to improve health outcomes for asthmatics. The outcome of the thesis was the development of a risk management framework for pre-existing asthmatics at work for use by regulators of workplaces and an information leaflet to assist in improving health outcomes for asthmatics in Guernsey.

The Missionary outlook.

"Representing the General Missionary Society and the Woman's Missionary Society of the Methodist Church, Canada" (<1903-1904> also the Young People's Forward Movement for Missions).

XML-Intensive software development

168 p.

Anatomical, histochemical and immunohistochemical characterization of the outflow tract of ray hearts (Rajiformes; Chondrichthyes)

Recent work has shown that the cardiac outflow tract of sharks and chimaeras does not consist of a single myocardial component, the conus arteriosus, as classically accepted, but two, namely, the myocardial conus arteriosus and the non-myocardial bulbus arteriosus. However, the anatomical composition of the outflow tract of the batoid hearts remains unknown. The present study was designed to fill this gap. The material examined consisted of hearts of two species of rays, namely, the Mediterranean starry ray (Raja asterias) and sandy ray (Leucoraja circularis). They were studied using scanning electron microscopy, and histochemical and inmunohistochemical techniques. In both species, the outflow tract consists of two components, proximal and distal with regard to the ventricle. The proximal component is the conus arteriosus; it is characterized by the presence of compact myocardium in its wall and several transverse rows of pocket-shaped valves at its luminal side. Each valve consists of a leaflet and its supporting sinus. Histologically, the leaflet has two fibrosas, inner and outer, and a middle coat, the spongiosa. The distal component lacks myocardium. Its wall consists of smooth muscle cells, elastic fibers and collagen. Thus, it shows an arterial-like structure. However, it differs from the aorta because it is covered by the epicardium and crossed by coronary arteries. These findings indicate that the distal component is morphologically equivalent to the bulbus arteriosus of sharks and chimaeras. In contrast to foregoing descriptions, the valves of the first transverse row are distally anchored to the bulbus arteriosus and not to the ventral aorta. Our findings give added support to the notion that presence of a bulbus arteriosus at the arterial pole of the heart is common to all chondrichtyans, and not an apomorphy of actinopterygians as classically thought.

Evaluación de los contenidos de información de medicamentos en un grupo de agencias reguladoras de medicamentos

OBJETIVO: Evaluar las diferencias de información publicada por el Invima y otras Autoridades Reguladoras de Medicamentos en relación a un grupo de variables seleccionadas y analizar las diferencias aplicando estrategias de visualización de datos. METODOLOGÍA: Estudio descriptivo de corte transversal, en el cual se comparan las diferencias en la información de medicamentos publicada en las agencias reguladoras de medicamentos. Para la definición de los criterios de comparación, más relevantes se utilizó la técnica Delphi como metodología de consenso. Las visualizaciones fueron desarrolladas en Roassal, en el entorno de programación de Grafoscopio/Pharo. RESULTADOS Y CONCLUSIONES: De 24 variables en las que hubo acuerdo de considerarlas importantes y claves por el panel de expertos; el 96% se identificaron en la Aemps, MHRA e Infarmed; el 92% en Anmat, TGA, Anvisa, Health Canada y FDA; el 80% en Anamed. El grupo de agencias en las que se identificó una menor cantidad de información publicada fueron Cofepris, Invima, Dirección Nacional de Farmacias y Drogas de Panamá, Digemid, Arcsa y el Ministerio de Salud pública de Uruguay en las que se identificó el 67%, 58%, 46%, 46%, 38% y 4%, respectivamente. Las ausencias comunes de información en el grupo de agencias con menor cantidad de información se presentó en las variables relacionadas con usos fuera de indicación (off-label), gestión del riesgo, efectos adversos, restricciones especiales, precauciones y advertencias, prospecto, almacenamiento y resumen de las características del producto, es decir que mayor la limitación se presenta en la información relacionada con prescripción y uso.

Typing your mind away. Comparing keylogged tasks with the Task Segment Framework

One of the main process features under study in Cognitive Translation & Interpreting Studies (CTIS) is the chronological unfolding of the tasks. The analyses of time spans in translation have been conceived in two ways: (1) studying those falling between text units of different sizes: words, phrases, sentences, and paragraphs; (2) setting arbitrary time span thresholds to explore where do they fall in the text, whether between text units or not. Writing disfluencies may lead to comprehensive insights into the cognitive activities involved in typing while translating. Indeed, long time spans are often taken as hints that cognitive resources have been subtracted from typing and devoted to other activities, such as planning, evaluating, etc. This exploratory, pilot study combined both approaches to seek potential general tendencies and contrasts in informants’ inferred mental processes when performing different writing tasks, through the analysis of their behaviors, as keylogged. The study tasks were retyping, monolingual free writing, translation, revision and a multimodal task—namely, monolingual text production based on an infographic leaflet. Task logs were chunked, and shorter time spans, including those within words, were analyzed following the Task Segment Framework (Muñoz & Apfelthaler, in press). Finally, time span analysis was combined with the analysis of the texts as to their lexical density, type-token ratio and word frequency. Several previous results were confirmed, and some others were surprising. Time spans in free writing were longer between paragraphs and sentences, possibly hinting at planning and, in translation, between clauses and words, suggesting more cognitive activities at these levels. On the other hand, the infographic was expected to facilitate the writing process, but most time spans were longer than in both free writing and translation. Results of the multimodal task and some other results suggest venues for further research.