Pathophysiological correlations in maedi: a chronic lymphoid interstitial pneumonia of sheep

Maedi is a chronic lymphoid interstitial pneumonia (LIP) of sheep caused by the lentivirus, maedi-visna virus (MW). Following a long prepatent phase maedi progresses to clinical disease characterised by exercise intolerance and dyspnoea. Although maedi is well characterised at a pathological level, physiological studies of the disease have not been undertaken. As a consequence, the nature of the functional abnormality that underlies the clinical disease is unknown, whether there exists measurable functional deficit in the preclinical phase of the disease is unknown and the relationship between lung pathology and functional deficit is unknown. These questions are fundamental to understanding the way in which pathological events ultimately conspire to bring about organ dysfunction and clinical disease. Further, knowledge of the way in which pathology relates to measurable lung dysfunction offers a potential means of assessing the progress and prognosis of this disease. This thesis describes an investigation into the pathophysiological mechanisms responsible for inducing lung functional deficits in maedi.As a prelude to establishing the nature of the functional deficit in maedi, repeated measurements of static lung compliance (Cst), lung distensibility (K), effective alveolar volume (VA,eff) and transfer factor for carbon monoxide (TL,CO,'sb') were made in anaesthetized control sheep, seronegative for MW, over a period of 5 months. This study furnished regression equations and prediction intervals for lung function indices in normal sheep using bodyweight as the independent variable. By comparison with predicted normal values sheep naturally infected with MW had reduced lung volumes and gas diffusing capabilities and increased lung elastic recoil.A pathophysiological study was instigated to identify structural correlates of lung functional deficits. Preliminary investigation involved the quantitative morphometric characterisation of the normal sheep lung. Data from this study indicated that the ratio of fixed to physiological lung volume ranged from 0.49 to 0.59 and that this ratio was positively correlated with the time between euthanasia and inflation fixation of the lungs. Values for tissue volume fraction within the lung parenchyma (Fvt) ranged from 0.18 to 0.25 and values for alveolar surface density (Svt) ranged from 592 to 716 cm2/cm3. Pathophysiological correlations in MW-infected sheep indicated that lung volume and transfer factor measurements were more sensitive indices of pathology than measurements of Cst or K. Transfer factor was reduced even in sheep with minimal histopathology suggesting this index as a sensitive means of assessing this condition. The density of surface forces could not account for variation in K seen in vivo, however tissue factors such as the quantity and functional tone of contractile tissue in the parenchyma, airways or blood vessels may contribute. Given that parenchymal smooth muscle hyperplasia is a pathological feature of maedi, it was hypothesized that this tissue element is responsible for the observed reduction in K.In order to further investigate this relationship, the distribution and morphometric quantitation of a-smooth muscle actin (ASMA) in lung parenchyma from normal and MW-infected 4 sheep was determined and related to in vivo functional measurements. The volume density of ASMA (IVASMA1) was negatively correlated with K and Cst, however partial correlation coefficients indicated that IVASMA' and Fvt were strongly interdependent thus complicating interpretation of the link between Fv'ASMA' and K. In order to separate the influence of dynamic and passive tissue elements, histamine and clenbuterol were administered to normal and MWinfected sheep in an attempt to cause relaxation and contraction of parenchymal contractile tissue. The functional response of the cardiopulmonary system to intravenous infusion of these agents was measured and correlated with Fv'ASMA'. K and Cst were significantly increased following clenbuterol injection, however only the increase in K was correlated with the quantity of Fv'ASMA', and this correlation was negative. These results could be explained if the site of action of clenbuterol was not the contractile tissue at the level of the alveolar ducts, but rather that which surrounds conducting airways.The dose of histamine required to lower dynamic compliance to 65% of baseline values was negatively correlated with Fv'ASMA' and the attendant percentage change in K was positively correlated with Fv'ASMA'. These findings support the contention that parenchymal contractile tissue is of functional relevance and capable of regulating overall lung elastic properties.Maedi is a naturally occurring disease in sheep in which the aetiologic agent and target cell is known and in which the pathology is well characterised. As such it has potential as a model for LIP associated with human immunodeficiency virus infection in children and adults. The present study has both served to establish the functional characteristics of this disease and indicate structural correlates of observed functional deficits. Moreover, evidence is presented to suggest that the observed reduction in lung distensibility in maedi is a consequence of increased tissue forces associated with the parenchymal smooth muscle hyperplasia that is a feature of this disease

BrdU Pulse Labelling In Vivo to Characterise Cell Proliferation during Regeneration and Repair following Injury to the Airway Wall in Sheep

The response of S-phase cells labelled with bromodeoxyuridine (BrdU) in sheep airways undergoing repair in response to endobronchial brush biopsy was investigated in this study. Separate sites within the airway tree of anaesthetised sheep were biopsied at intervals prior to pulse labelling with BrdU, which was administered one hour prior to euthanasia. Both brushed and spatially disparate unbrushed (control) sites were carefully mapped, dissected, and processed to facilitate histological analysis of BrdU labelling. Our study indicated that the number and location of BrdU-labelled cells varied according to the age of the repairing injury. There was little evidence of cell proliferation in either control airway tissues or airway tissues examined six hours after injury. However, by days 1 and 3, BrdU-labelled cells were increased in number in the airway wall, both at the damaged site and in the regions flanking either side of the injury. Thereafter, cell proliferative activity largely declined by day 7 after injury, when consistent evidence of remodelling in the airway wall could be appreciated. This study successfully demonstrated the effectiveness of in vivo pulse labelling in tracking cell proliferation during repair which has a potential value in exploring the therapeutic utility of stem cell approaches in relevant lung disease models

Bailouts in a common market: a strategic approach

Governments in the EU grant Rescue and Restructure Subsidies to bail out ailing firms. In an international asymmetric Cournot duopoly we study effects of such subsidies on market structure and welfare. We adopt a common market setting, where consumers from the two countries form one market. We show that the subsidy is positive also when it fails to prevent the exit. The reason is a strategic effect, which forces the more efficient firm to make additional cost-reducing effort. When the exit is prevented, allocative and productive efficiencies are lower and the only gaining player is the rescued firm

Local lung responses following endobronchial elastase and lipopolysaccharide instillation in sheep

Chronic lipopolysaccharide (LPS) exposure may contribute to the pathogenesis of a number of lung diseases including COPD and emphysema. We sought to develop a large- animal model of emphysema using repeated LPS administration into sheep lung segments. An experimental protocol was designed to facilitate comparisons with elastase-treated and control segments within the same lung of individual sheep. Histopathologic evaluation of segments treated with LPS demonstrated low-grade inflammation characterized by an increase in the number of intra-alveolar macrophages and lymphocytes. Treated segments demonstrated a significant reduction in airspace surface area (ASA), an increase in percent disrupted alveolar attachments and the distance between normal alveolar attachments, and a reduction in the number of normal alveolar attachments surrounding nonrespiratory bronchioles. Coefficient of variation of individual ASA measurements in elastase-treated segments was indicative of a heterogeneous parenchymal response, in contrast to that associated with chronic LPS treatment. Our results demonstrate that chronic LPS treatment of individual lung segments in sheep induces microscopic emphysema qualitatively and quantitatively consistent with both accepted pathologic definitions of this condition and with that produced by airway instillation of elastolytic enzymes. Development of this phenotype is associated with evidence of downregulated activation of transforming growth factor beta

The Partonic Nature of Instantons

In both Yang-Mills theories and sigma models, instantons are endowed with degrees of freedom associated to their scale size and orientation. It has long been conjectured that these degrees of freedom have a dual interpretation as the positions of partonic constituents of the instanton. These conjectures are usually framed in d=3+1 and d=1+1 dimensions respectively where the partons are supposed to be responsible for confinement and other strong coupling phenomena. We revisit this partonic interpretation of instantons in the context of d=4+1 and d=2+1 dimensions. Here the instantons are particle-like solitons and the theories are non-renormalizable. We present an explicit and calculable model in d=2+1 dimensions where the single soliton in the CP^N sigma-model can be shown to be a multi-particle state whose partons are identified with the ultra-violet degrees of freedom which render the theory well-defined at high energies. We introduce a number of methods which reveal the partons inside the soliton, including deforming the sigma model and a dual version of the Bogomolnyi equations. We conjecture that partons inside Yang-Mills instantons hold the key to understanding the ultra-violet completion of five-dimensional gauge theories.Comment: 28 pages. v3: extra references and comments. Mathematica notebooks for the figures can be downloaded from http://www.damtp.cam.ac.uk/user/dt281/parton.htm

Adaptability and Social Support: Examining Links with Psychological Wellbeing Among UK Students and Non-students

The purpose of this multi-study article was to investigate the roles of adaptability and social support in predicting a variety of psychological outcomes. Data were collected from Year 12 college students (N = 73; Study 1), university students (N = 102; Study 2), and non-studying members of the general public (N = 141; Study 3). Findings showed that, beyond variance attributable to social support, adaptability made a significant independent contribution to psychological wellbeing (life satisfaction, psychological wellbeing, flourishing, and general affect) and psychological distress across all studies. Beyond the effects of adaptability, social support was found to make a significant independent contribution to most wellbeing outcomes (but not psychological distress in university students). In a multi-group analysis comparing predictors of psychological wellbeing in university students and non-studying adults, where the same outcome measures were used (Study 4; N = 243), it was found that adaptability played a stronger role (relative to social support) for university students, whereas social support played a stronger role for non-studying adults. Finally, (contrary to expectations) there was no evidence of an interaction between adaptability and social support predicting psychological outcomes—adaptability and social support operated as independent main effects. These findings demonstrate the importance of adaptability and social support in uniquely predicting psychological wellbeing in different sample groups. It is argued here that these two factors, should be given greater consideration in discussions of psychological wellbeing, and are relevant to psychological wellbeing at different major developmental life stages

Experimental implications of mirror matter-type dark matter

Mirror matter-type dark matter is one dark matter candidate which is particularly well motivated from high energy physics. The theoretical motivation and experimental evidence are pedagogically reviewed, with emphasis on the implications of recent orthopositronium experiments, the DAMA/NaI dark matter search, anomalous meteorite events etc.Comment: about 12 pages lon

A 5d/3d duality from relativistic integrable system

We propose and prove a new exact duality between the F-terms of supersymmetric gauge theories in five and three dimensions with adjoint matter fields. The theories are compactified on a circle and are subject to the Omega deformation. In the limit proposed by Nekrasov and Shatashvili, the supersymmetric vacua become isolated and are identified with the eigenstates of a quantum integrable system. The effective twisted superpotentials are the Yang-Yang functional of the relativistic elliptic Calogero-Moser model. We show that they match on-shell by deriving the Bethe ansatz equation from the saddle point of the five-dimensional partition function. We also show that the Chern-Simons terms match and extend our proposal to the elliptic quiver generalizations.Comment: 30 pages, 4 figures. v2: typo corrected, references adde