Twenty publications are submitted. All deal with the issues of control of two ends of the spectrum of immune-mediated respiratory disorders in children, namely atopic (asthma and allergic rhinitis) and HIV-related lung disease. This submission summarises the research by the author into this spectrum of lung diseases of children in South Africa, highlighting the diversity of conditions that are not only clinically important, but also common. Understanding of all conditions is required to improve the health of children in this region. Management of chronic conditions requires two major end points - adequate and timely diagnosis and - management to control the condition. The author has a passion for improving the quality of life of children and firmly believes that the research findings will, and have, led to transformation in management of both these common disorders. This document follows the progression of the authors research work and highlights how interesting and important is the scope of two disorders which could be thought to have a central origin, namely in the T-cell. T-cells form the basis of cellular immunity and an excess of T-helper 2 cell activity promotes atopy, whilst the human immunodeficiency (HI) virus infects T-helper cells and promotes cellular immune deficiency and its attendant clinical disorders. The author’s research work is not based on the immunological basis of these conditions but does deal with the clinical implications and especially aspects relating to control of these two extremes of a clinical spectrum of disorders. To take the clarity of two diseases at the end of a spectrum to its natural conclusion these extremes are defined in aetiology or pathophysiological differences (excess versus suppression of the immune system), occurring in the affluent and poor alike versus just the poor, control being required to improve quality of life versus to save lives and finally that management requires anti-inflammatory therapy versus antibiotic and anti-infective therapy. For the eight publications based on atopic respiratory disease in children the themes are firstly that children with asthma and chronic rhinitis are diagnosed late, that most individuals with these conditions are not well controlled and finally that the reasons for lack of control are becoming obvious. For the first time, the significant lack of asthma and allergic rhinitis control in South Africa is documented. These studies suggest that, like surveys from the rest of the world, asthma control is seriously under-estimated and neglected in all asthmatics in South Africa, in both the privileged and the under-privileged. The research also defines reasons for poor asthma and allergic rhinitis control in this region. As in many studies published from around the world it is now evident that poor asthma and allergic rhinitis control cannot be blamed on any one source. A multitude of reasons underlie this phenomenon and each of the subsequent papers in this section illustrates attempts at defining these principles. The three most important reasons for poor control are probably that most asthmatics are managed in the wrong hands (by doctors who don’t understand adequate control and who aren’t empowered to use the correct therapy), that control may actually be a pipe dream and practically difficult to do or even impossible to achieve and lastly that the allergic basis of asthma is over emphasised and may not in fact determine all asthma. The subsequent papers summarise research work in the field of HV infection in children and exposes the opposite end of a spectrum of Paediatric respiratory disease and highlight research into the conditions common in HIV-infected children. Eleven papers are presented. For the diseases associated with the HI virus the major complications of inadequate diagnosis and prevention in children are acute pneumonia (especially severe pneumonia) and bronchiectasis. Bronchiolitis is not common in HIV infected children, despite epidemics of this condition in non-infected children. Passive smoking does not aggrevate or worsen disease progression in children. The complications of HIV related diseases in children require the same principles of adequate diagnosis and control as would apply to the chronic atopic conditions. Once the author delved into the disorders at the other end of the clinical spectrum, namely those associated with immune deficiency secondary to HIVinfection he faced the question of a possible relationship between the conditions. One submission explores that relationship. This research has a unique perspective, conferred by the fact that these two conditions do not occur to the same extent anywhere else in the world. Atopic respiratory conditions and HIV-related lung diseases occur side by side in abundance in this region. This perspective has created a clarity for research to address the two most important aims in clinical medicine, namely to diagnose correctly and then to manage the condition so that control is achieved. These must be universal principles of the successful practice of medicine. / Thesis (DSc)--University of Pretoria, 2013. / gm2013 / Paediatrics and Child Health / unrestricted

Over the past several decades, the rate of pulmonary nontuberculous my- cobacterial (PNTM) disease has been increasing. PNTM patients gener- ally consist of lean and tall women presenting with symptoms in the sixth decade of life. They have a de nitive morphophenotype, but no consistent immunological abnormalities despite extensive investigation. I hypothesized that respiratory epithelial dysfunction might play a critical role in PNTM disease predisposition because diseases with defects of mucociliary transport have high rates of PNTM disease that increase with age, suggesting a direct connection between airway epithelial function and PNTM disease. I found that PNTM patients have a distinct respiratory epithelial phenotype ex vivo and decreased nasal nitric oxide levels in vivo. The PNTM ex vivo phenotype consists of an abnormally low resting ciliary beat frequency (CBF) and abnormal CBF response to toll-like receptor (TLR) agonists. The depressed baseline CBF response in PNTM patient cells can be normalized ex vivo by augmenting the nitric oxide-cyclic guanosine monophosphate pathway without appreciable e ect on CBF in healthy controls. In healthy controls, bacterial TLR agonists increase CBF and viral TLR agonists decrease CBF. In PNTM patients these responses are impaired and are not normalized with the normalization of the resting CBF rate. Inhibitor-induced disruption of signalling pathways associated with CBF regulation demonstrated that the majority of the CBF response to TLR agonists involves the PI-3K pathway and PKC. Inhibition of the PI-3K pathway (PI-3K , Akt1, and PDK1) closely mimicked the ex vivo phenotype seen in PNTM patient respiratory epithelia. These data identify a novel aspect of PNTM disease with in vivo and ex vivo correlates that suggest that PNTM infection is associated with abnormal function at both the CBF and TLR response levels. This phenotype is novel, reproducible, and provide a foundation with which to determine the genetic basis of PNTM infection.

No description available.

Radon gas may be a major air quality hazard issue inside the home. Radon (222Rn) comes from the natural breakdown of radioactive uranium (238U) via radium (226Ra) in soil, rocks, and water. Radon and its progeny contribute more than 50% of the total radiation dose to the human population due to inhalation; it can result in severe and fatal lung disease. This investigation has determined the radon concentrations in seventy-seven domestic houses in a mountainous area of Hamadan in Iran which were monitored using track-etch detectors of type CR-39 exposed for three month periods. The arithmetic mean radon concentration in Hamadan buildings was determined to be 80 Bqm-3 and also an average indoor annual effective dose equivalent for the Hamadan city population was calculated as 1.5 mSv. Maximum radon concentrations were noted during the winter and spring season. In addition to this, 28 water wells were monitored by utilizing a Sarad Doseman detector at hourly intervals over extended periods. Radon measurements were also carried out in the nearby Alisadr show cave, using Solid State Nuclear Track etch Detectors (SSNTDs) during the winter and the spring periods. In the cave, the average annual effective geometric and arithmetic mean dose for guides was 28.1 and 34.2 mSv respectively. The dose received by visitors was very low. Hamadan city is built on alluvial fan deposits which are the source of the local water supply. The data from the wells shows that the groundwater in these alluvial deposits influences the flux of radon. The atmospheric radon concentration measurement in wells above the water surface ranged from 1,000 Bqm-3 to 36,600 Bqm-3. There is evidence that radon-rich ground waters play a significant role in the transport of radon through the alluvial fan system. There is evidence that the radon concentrations in homes in Hamadan are greatly influenced by the porous nature of the underlying geology and the movement of groundwater within the alluvial fan. / The Ministry of Health and Education; the University of Hamadan in Iran: University of Bradford: University of Kingston

<p> Lung disease is the leading threat to human health worldwide. In particular, two threats are responsible for the majority of the pulmonary disease burden: infection and tobacco smoke exposure. Efforts to combat these diseases have been hampered by gaps in our understanding of the complex interactions between environmental threats and the host's own immune defences. Indeed, much of the pulmonary disease burden should be ascribed not to direct smoke-, virus-or bacteria-induced damage, but to maladaptive host defence responses against these threats. This is an understudied topic. Efforts to redress this deficiency have been hampered by the lack of available animal models. Thus, the present studies developed and examined models of Heterologous pulmonary infection, in which hosts must defend against two different infections, and of tobacco smoke exposure. In the first study, a critical role for MIP-2 driven pulmonary neutrophilia was elucidated in the pathology associated with bacterial superinfection of influenza virus infection. This study further demonstrated that the timing and sequence in which pathogens were encountered played important roles in determining the outcome of disease, and that viral and bacterial infections have different but long-lived impacts on alveolar macrophages. In the second study, it was determined that cigarette smoke exposure impacts host defence without exhausting T-or B-cells. Collectively, these studies have advanced our understanding of complex lung pathologies, and suggest an important role for the innate immune system in mediating such diseases. </p> / Thesis / Doctor of Philosophy (PhD)

Fibroproliferative disorders are the leading cause of morbidity and mortality worldwide, with one specific group of fibroproliferative disorders being interstitial lung diseases (ILD). Idiopathic pulmonary fibrosis is the most common ILD; however its pathogenesis is not entirely understood. What is known is that there is repetitive cellular injury preceding the fibrotic remodeling in the lungs that contributes to the irreversible deposition of extracellular matrix (ECM) proteins. Myofibroblasts that accumulate at the site of injury are thought to be the key drivers of ECM deposition and are often associated in the disease. Although it is poorly understood how these immune cells differentiate in the lung, one hypothesis suggests the role of alternatively activated profibrotic macrophages in this process. The data presented in this thesis suggest that there are a presence of UPR and macrophage proteins in the lungs of IPF patients and the UPR may be necessary in the polarization of alternatively activated macrophages. / Thesis / Master of Science (MSc)

Background – Feeding horses round bale hay (RBH) has been associated with airway inflammation. The purpose of this study was to determine if horses fed RBH for a 6-week period demonstrated more evidence of airway inflammation than horses fed square bale hay (SBH) of comparable quality. Hypothesis - The respiratory health of horses fed RBH will not differ from horses fed SBH of comparable quality. Animals – Two feeding groups of 15 healthy horses (mixed ages, breeds) from the University riding program. Methods – This was a prospective study performed during fall of 2009. At the beginning and end of a 6- week feeding trial, horses were examined (physical, upper airway endoscopic) and samples (tracheal aspirate (TA), bronchoalveolar lavage (BAL)) collected for cytology and/or bacterial/fungal culture. Hay was analyzed for nutritional value and bacterial/fungal content. Results – Horses fed RBH demonstrated an increase in pharyngeal lymphoid hyperplasia (p=0.0143) and percentage neutrophils (p=0.0078) in the TA samples post-feeding as compared to pre-feeding values. Nutritional analysis of hay and measurements of bacterial/fungal load did not differ over time and/or between hay types. Conclusions and clinical importance – The identification of airway inflammation in the horses fed RBH indicates that factors associated with the manner in which the hay is fed and consumed contribute to the development of subclinical airway inflammation. RBH affords horses continuous daily exposure to hay and as horses bury their muzzles in the bale, exposure to particulate matter is likely increased. These factors may partially explain the response in horses fed RBH. Further studies are required to confirm these predictions. / Master of Science

Das Sjögren-Syndrom (SjS) stellt eine mögliche autoimmune Ursache einer interstitiellen Lungenerkrankung dar. Die Abklärung in Richtung SjS ist aber im Vergleich zu anderen systemischen Autoimmunerkrankungen bisher kaum standardisiert. Die subjektive Sicca-Symptomatik, die Anti-SS-A/Ro-Antikörper und selbst die ANA-Diagnostik als Suchtest haben alle relevante Einschränkungen in ihrer Sensitivität und/oder Spezifität. Vor diesem Hintergrund haben wir in einer interdisziplinären Diskussion einen Konsens für die SjS-Abklärung entwickelt, den wir hier für die breitere Diskussion vorstellen. Neben ANA sollten sowohl Anti-SS-A/Ro-Antikörper als auch Antikörper gegen α‑Fodrin bestimmt werden. Wichtig ist die Objektivierung der Trockenheit mittels Schirmer- und Saxon-Test und bei fehlenden typischen Autoantikörpern die Speicheldrüsenbiopsie. / Sjögren’s syndrome (SjS) is a possible autoimmune cause of interstitial lung disease. The diagnostic pathway for SjS, however, is largely undefined in comparison to other systemic autoimmune diseases. Subjective sicca symptoms, anti-SS-A/Ro antibodies and even ANA as screening tests all have relevant limitations in sensitivity and/or specificity. Against this background, in an interdisciplinary discussion we have developed a consensus for the clarification of SjS, which is presented here for broader discussion. In addition to ANA and anti-SS-A/Ro antibodies, antibodies against alpha-fodrin should be included. Objective measures of dryness, such a Schirmer and Saxon tests are important, as is a salivary gland biopsy in the absence of typical autoantibodies.

No / We report patients, family members and health professionals' experiences of Chronic Obstructive Pulmonary Disease (COPD) in Barnsley, northern England. A widespread belief that having "bad lungs" is part of normal ageing shapes everyday experience in this former mining town. People with COPD, and their families, link its cause to the areas industrial past and are sceptical of a medical orthodoxy that attributes cause to smoking. They doubt doctors' objectivity. Encouraging uptake of care, promoting smoking cessation, and developing care planning would be enhanced by engaging with the significance of place in the social narrative of health evident in this town.

Bakgrund: Rökning står för mer än vart tionde dödsfall i Sverige och hälften av alla långsiktiga rökare avlider av rökrelaterade sjukdomar. Lungcancer är den femte vanligaste cancersjukdomen i Sverige och orsakas i första hand av rökning. Kronisk obstruktiv lungsjukdom (KOL) orsakas också i första hand av rökning och är den tredje vanligaste dödsorsaken i världen. Fler kvinnor än män dör av KOL i Sverige men förklaringen till detta är oklar. Den komplexa kemiska blandningen som inhaleras vid förbränning av tobak orsakar negativa hälsoresultat, särskilt cancer och lungsjukdomar. Risken för och svårighetsgraden av många negativa hälsoeffekter orsakade av rökning kan variera beroende på om man själv är rökare eller bara exponeras för tobaksrök. Rökavvänjningen är potentiellt den mest effektiva av alla förbyggande åtgärder. Rökning påverkar också metabolisering av olika läkemedel. Nikotin är den beroendeframkallande substansen i tobak som orsakar abstinensbesvär. Rökfri tobak t.ex. snustobak orsakar också sjukdomar men i mycket mindre utsträckning än cigaretter. Syfte: Syftet med detta examensarbete var att ytterligare belysa kända hälsoproblem med rökning samt att beskriva eventuella ytterligare, tidigare okända, hälsoproblem. Metod: Detta arbete är en litteraturstudie baserat på 6 vetenskapliga artiklar. Resultat: Rökning ökar mortalitet och förkortar därmed livslängd. En stor del av dessa dödsfall orsakas av hjärt-kärl sjukdomar, kronisk obstruktiv lungsjukdom och många olika cancersjukdomar. Det finns ingen riskfri nivå av exponering för tobaksrök. Slutsats: Rökning ökar risken för alla typer av hjärt-kärl sjukdomar, låg födelsevikt för barn och många olika typer av cancer. Risken för pankreascancer i samband med rökning är relaterat till mängden av tobak som rökts dagligen. Minskning av antal rökta cigaretter per dag eller förpackningar per år har annars ingen större effekt på att minska risken för sjukdomar eller minska mortaliteten.