Static and dynamic stress heterogeneity in a multiscale model of the asthmatic airway wall

Airway hyperresponsiveness (AHR) is a key characteristic of asthma that remains poorly understood. Tidal breathing and deep inspiration ordinarily cause rapid relaxation of airway smooth muscle (ASM) (as demonstrated via application of length fluctuations to tissue strips) and are therefore implicated in modulation of AHR, but in some cases (such as application of transmural pressure oscillations to isolated intact airways) this mechanism fails. Here we use a multiscale biomechanical model for intact airways that incorporates strain stiffening due to collagen recruitment and dynamic force generation by ASM cells to show that the geometry of the airway, together with interplay between dynamic active and passive forces, gives rise to large stress and compliance heterogeneities across the airway wall that are absent in tissue strips. We show further that these stress heterogeneities result in auxotonic loading conditions that are currently not replicated in tissue-strip experiments; stresses in the strip are similar to hoop stress only at the outer airway wall and are under- or overestimates of stresses at the lumen. Taken together these results suggest that a previously underappreciated factor, stress heterogeneities within the airway wall and consequent ASM cellular response to this micromechanical environment, could contribute to AHR and should be explored further both theoretically and experimentally

LITTLE FRIENDS OF ALL THE WORLD?’ THE EXPERIENCES OF BRITISH DIPLOMATIC SERVICE CHILDREN 1945 – 1990

PhDThis thesis is a historical reconstruction of the experiences of children born in to the British Diplomatic Service between 1945 and 1990. The first academic investigation of its kind, in a greatly under-documented area, it uses oral history testimony as its primary method of investigation. Source material was gathered by the author through interviews and correspondence with a sample of 23 former Diplomatic Service children born between 1942 and 1992. This evidence was compared with existing material which referred to Diplomatic Service children. This included the contents of Newsletters produced by the Foreign Service Wives Association, later the Diplomatic Service Wives’ Association, and twentieth-century memoirs by diplomats. The dominant themes suggested by interviewees and respondents formed the basis of the thesis’ four thematic chapters. These take as their subjects Separation, Transience, Identity and Home. A preceding Chapter which outlines internal Foreign Office policy towards children and families during the period under consideration provides background. The main questions considered were whether the findings shed light on existing stereotyped understandings of Foreign Office children, whether the participants’ experiences challenged historical narratives of childhood during the period and examined whether experiences differed according to gender. The richness and diversity of experiences recorded have made a multi-disciplinary approach necessary in order to provide a sufficiently structured framework for their interpretation.Arts and Humanities Research Council as part of its Extended Collaborative Doctoral Award Programme (grant reference number AH/L003201/1, this studentship advertised in 2013 as ‘The diplomatic family at home and abroad.’

Mathematical modelling and imaging of asthmatic airways

The hyper-responsiveness of airway smooth muscle to certain external stimuli, and the associated remodelling of the airway wall, is central to the development of asthma, making it of widespread clinical significance. In this thesis, mathematical models for the asthmatic airway embedded in parenchymal tissue are presented. The stiffening due to recruitment of collagen fibres and force generation by smooth muscle is taken into account, to develop a nonlinear elastic model for the airway wall. The contractile force of the muscle is governed by the dynamically changing subcellular crossbridge populations. A nonlinear elastic and, to take into account the viscoelasticity of the lung, a linear viscoelastic model for the parenchyma are developed. Consistent with experimental findings, deforming the airway passively, the model predicts strain-stiffening on inflation and deflation. The displacements predicted within the parenchyma are much smaller when the airway is inflated internally than externally, due to the airway wall shielding the parenchyma. Stress heterogeneities are predicted within the thickened airway wall when active contractile forcing is applied, which may contribute to further remodelling of the wall. If tidal stretching is applied to a contracted airway, the model predicts that the contractile force reduces, resulting in a reversal of bronchoconstriction. This is more exaggerated when the parenchyma is viscoelastic. Image analysis techniques are also developed to investigate data from lung-slice experiments, whereby pharmacological stimuli can be added to segments of lung tissue to stimulate smooth muscle contraction. By tracking the lumen area and fitting to exponential functions, two timescales of contraction are found to exist, consistent with the mathematical model predictions, and that the ratio of the timescales is robust. Methods are also developed and tested to find the displacement field of the tissue surrounding the airway lumen and it is shown that there are important heterogeneities within the tissue

Transport mechanisms in 8-tris-hydroxyquinoline aluminium (Alq3) electronic layers: a study by photodipolar absorption

International audienceThis paper describes the role of traps in the electronic conductivity of 8-tris-hydroxyquinoline aluminium in a conventional sandwich structure with indium tin oxide and aluminium electrodes. New results obtained by photodipolar absorption techniques and impedance spectroscopy are presented. The former method acts as a probe to highlight the role of traps. It is shown that optical pumping of electrons to trap levels gives a clear increase in dielectric absorption due to the reorientation of dipoles associated with trapped charges. The trap depth is estimated to be around Et= 0.19 eV, a value in good agreement with theoretical calculations and thermoluminescence measurements. The latter method permits a representation of the sample in terms of a circuit composed of a parallel capacitor (Cp) and resistor (Rp) both in series with a resistor Rs≈ 50 Ωlocated on the anode side. A logarithmic plot of Rp as a function of the dc bias voltage gives a linear law that is recognized, for the first time, to be a consequence of a trapped charge limited (TCL) current. The linearity can be improved by the introduction of a field-dependent mobility

Mathematical modelling and imaging of asthmatic airways

The hyper-responsiveness of airway smooth muscle to certain external stimuli, and the associated remodelling of the airway wall, is central to the development of asthma, making it of widespread clinical significance. In this thesis, mathematical models for the asthmatic airway embedded in parenchymal tissue are presented. The stiffening due to recruitment of collagen fibres and force generation by smooth muscle is taken into account, to develop a nonlinear elastic model for the airway wall. The contractile force of the muscle is governed by the dynamically changing subcellular crossbridge populations. A nonlinear elastic and, to take into account the viscoelasticity of the lung, a linear viscoelastic model for the parenchyma are developed. Consistent with experimental findings, deforming the airway passively, the model predicts strain-stiffening on inflation and deflation. The displacements predicted within the parenchyma are much smaller when the airway is inflated internally than externally, due to the airway wall shielding the parenchyma. Stress heterogeneities are predicted within the thickened airway wall when active contractile forcing is applied, which may contribute to further remodelling of the wall. If tidal stretching is applied to a contracted airway, the model predicts that the contractile force reduces, resulting in a reversal of bronchoconstriction. This is more exaggerated when the parenchyma is viscoelastic. Image analysis techniques are also developed to investigate data from lung-slice experiments, whereby pharmacological stimuli can be added to segments of lung tissue to stimulate smooth muscle contraction. By tracking the lumen area and fitting to exponential functions, two timescales of contraction are found to exist, consistent with the mathematical model predictions, and that the ratio of the timescales is robust. Methods are also developed and tested to find the displacement field of the tissue surrounding the airway lumen and it is shown that there are important heterogeneities within the tissue

Airway and parenchymal strains during bronchoconstriction in the precision cut lung slice

The precision-cut lung slice (PCLS) is a powerful tool for studying airway reactivity, but biomechanical measurements to date have largely focused on changes in airway caliber. Here we describe an image processing tool that reveals the associated spatio-temporal changes in airway and parenchymal strains. Displacements of sub-regions within the PCLS are tracked in phase-contrast movies acquired after addition of contractile and relaxing drugs. From displacement maps, strains are determined across the entire PCLS or along user-specified directions. In a representative mouse PCLS challenged with 10−4M methacholine, as lumen area decreased, compressive circumferential strains were highest in the 50 μm closest to the airway lumen while expansive radial strains were highest in the region 50–100 μm from the lumen. However, at any given distance from the airway the strain distribution varied substantially in the vicinity of neighboring small airways and blood vessels. Upon challenge with the relaxant agonist chloroquine, although most strains disappeared, residual positive strains remained a long time after addition of chloroquine, predominantly in the radial direction. Taken together, these findings establish strain mapping as a new tool to elucidate local dynamic mechanical events within the constricting airway and its supporting parenchyma

A Rare Case of Microgranular Acute Promyelocytic Leukemia Associated with ider(17)(q10)t(15;17) in an Old-age Patient

We present a rare case of microgranular variant acute promyelocytic leukemia (APL) associated with ider(17)(q10)t(15;17)(q22;q12) of an old-age patient. The initial chromosome study showed a 46,XX,del(6)(?q21q25),der(15)t(15;17)(q22;q12),ider(17)(q10)t(15;17)[10]/47,sl,+ider(17)(q10)t(15;17)[3]/46,XX[16]. FISH signals from a dual color dual fusion translocation PML-RARA probe were consistent with the results of conventional cytogenetics. Because of the rarity of ider(17)(q10)t(15;17) in microgranular APL, further studies on both gene dosage effect of this chromosomal abnormality and the influence of ider(17)(q10)t(15;17) on clinical features such as prognosis, survival, and treatment response of APL cases are recommended

Serial optical coherence microscopy for label-free volumetric histopathology

The observation of histopathology using optical microscope is an essential procedure for examination of tissue biopsies or surgically excised specimens in biological and clinical laboratories. However, slide-based microscopic pathology is not suitable for visualizing the large-scale tissue and native 3D organ structure due to its sampling limitation and shallow imaging depth. Here, we demonstrate serial optical coherence microscopy (SOCM) technique that offers label-free, high-throughput, and large-volume imaging of ex vivo mouse organs. A 3D histopathology of whole mouse brain and kidney including blood vessel structure is reconstructed by deep tissue optical imaging in serial sectioning techniques. Our results demonstrate that SOCM has unique advantages as it can visualize both native 3D structures and quantitative regional volume without introduction of any contrast agents