Lung transplantation is a life-saving therapy for patients suffering from end-stage lung disease; however, the majority of donor lungs are injured and attempts to transplant them results in a high risk of primary graft dysfunction in the recipient, a type of severe acute lung injury. Previously, a novel method of lung preservation known as ex vivo lung perfusion (EVLP) has been developed in which donor lungs are continuously perfused and ventilated at normothermia using a protective strategy. Donor lungs have been shown to tolerate at least 12 h of preservation in this manner without the accrual of injury. Hence, EVLP could act as a platform on which injured donor lungs could potentially be evaluated and repaired. To explore this concept, we utilized interleukin-10 (IL-10), an anti-inflammatory cytokine, as a prototypical drug for ex vivo delivery. Because IL-10 protein has a prolonged half-life during EVLP, we delivered recombinant IL-10 by the intravascular and intratracheal routes to clinically-rejected injured human lungs. Intratracheal delivery resulted in elevated levels of IL-10 in both tissue and perfusate whereas intravascular delivery resulted in elevated levels of IL-10 only in the perfusate over 12 h of EVLP. There was, however, no beneficial effect to either lung function or lung inflammation. This was thought to be a result of intratracheally delivered IL-10 leaking out into the perfusate where it may not be biologically active. Constant IL-10 production within the lung tissue could be achieved using a gene therapy approach. Thus, we subsequently explored the delivery of IL-10 by adenoviral gene therapy during EVLP. Ex vivo administered intratracheal adenoviral gene therapy could increase transgene protein levels within the lung. More importantly, it did so with less vector-associated inflammation when compared to in vivo delivery of adenoviral gene therapy. Having explored drug delivery, we sought to develop a large animal injury model on which to test ex vivo therapies. Given that the majority of organ donors are brain dead and therefore exposed to the injurious sequelae resulting from brain death, we developed a brain-death injury model in pig. Use of EVLP as a platform for repair necessitates an accurate recognition of both lung injury and lung improvement during EVLP. Thus, we utilized this injury model to explore the profile of physiological parameters when an injured lung is perfused during EVLP. Because of the alteration of the PO2 to oxygen content relationship of an acellular perfusate, we found that PaO2 changes are less dramatic than in the in vivo situation. However, as injured lungs begin to become edematous, the mechanical effects on the lung by the increased water content can be measured by corresponding falls in compliance and increases in airway pressure. Overall, use of EVLP demonstrates promise for reducing the organ shortage currently prevalent in clinical lung transplantation. Improved evaluation will instill confidence in transplant clinicians to transplant previously questionable organs. Lungs which prove to be injured during evaluation can potentially be repaired using IL-10 therapy as explored herein or with other therapies using the delivery methods described.

No description available.

This thesis investigates variability in airway caliber and the distribution of ventilation within the human lung as thought to occur in asthma. Currently, the understanding of how an integrated network of airways can lead to temporal and spatial variation as found in the human lung is unclear. Throughout this thesis, a multibranch airway tree model was used in a forward modeling approach. In a variability study, the mean airway resistance (RL) was observed to be proportional to the standard deviation in airway resistance (SDRL) as reported in the literature under several conditions of airway diameter indicating the strong robustness of this behavior. The model predicted previously reported RL distributions and the reported proportionality of SDRL and RL, but only when we included coherency between airways. In a second study, patient specific ventilation was investigated using an image functional approach by closing specific airways (creating defects) identified by hyperpolarized 3He MRI from asthmatic subjects. Impedance predictions from the imposed heterogeneous ventilation were then calculated and correlated to 3He MRI ventilation defect percent (VDP), plethysmography, and spirometry data. These predictions suggest the forced oscillation technique (FOT) to be a superior metric toward the evaluation of the VDP. In a third study, we investigated how asymmetric branching could play a role in ventilation defect emergence and persistence. At high muscle activation levels simulating an asthmatic episode, airway trees with greater asymmetry reached steady state sooner, with defects that were more persistent in location, had lower RL values (~50%), and greater EL values (~25%) after bronchoconstriction. These results suggest the initial formation of ventilation defects was dependent on airway instability; however, the location and persistence of ventilation defects may be due to geometric airway structure. By modeling the contribution of ventilation defects to lung impedance, we were able to show that defects can play a role in governing the relationship between RL and its variation, and the effect of defects through VDP could be better assessed using FOT. Moreover, lung structure contributed to the emergence and persistence of ventilation defects, meaning that defects could be potentially ameliorated through structural intervention.

Changsha city in Hunan province, China. Place: Changsha Center Hospital, Hunan province. City Area: 11,819 square kilometers City population: 714.66 million   I watched the whole process of chest drainage surgery, introduced by Yang Jicheng, who is a thoracic surgeon attending doctor at this capital. During the field research in China, I also had research opportunity of chest drainage management, mostly performed by nurses, where I found out lots of design opportunities about the Chong canister, which was the most popular chest drainage canister used all over the  China Then I went back to Umea, Sweden, met Fredrik Homner who is a thoracic surgery doctor working in Norrlands University Hospital for almost 30 years. I told him what I saw in China and we exchanged lots of opinion about chest drainage. I realized that Chinese chest drainage patients were suffering unnecessary pain from outmoded equipment, which in Sweden they had already updated since 20 years ago. Whit help of Fredrik Holmner, I had opportunity to watch the whole process of pulmonary resection and endoscope technical, the focus of this process was the insertion of chest drainage tube at the end of this 5 hours surgery. After I had seen so many materials related to chest drainage, I found out my design focus, which was the Maquet Oasis Drain,  that had been recognized as the most advanced chest drainage equipment in the world and had been widely used in Europe and United States.

A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in partial fulfillment of the requirements for the degree of Master of Medicine in the branch of Internal Medicine / Medical Oncology. Johannesburg 1st September 2014 / Introduction: Tyrosine kinase inhibitors and EGFR mutations has changed the treatment approach to lung cancer globally. This retrospective study will look at factors associated with EGFR mutations and define the EGFR mutation rate in South Africa. Methods: Retrospective record review from NSCLC patients in South Africa who were tested for EGFR mutations at Lancet Laboratories during 1st September 2009 to 30th June 2012. Chi-squared test was used to determine association with categorical variables. Kaplan- Meier survival analysis was done for OS and PFS between EGFR mutation positive and negative patients. Cox proportional hazards were used for subgroup analysis. Treatment practices and response were described. Results: 170 lung cancer samples were evaluable for EGFR mutation and 37 were EGFR mutation positive (21.8%). There were 22 (59.5%) exon 19 deletions, 11 (29.7%) L858R mutations, two G719X mutations, one S768I mutation and one exon 20 insertion. The median age was 63 (range 27-85). There were more females (55.6%) than males (44.4%) sent for mutation testing. Most patients were whites (71%), followed by blacks (18.3%), and other race (10.7%). 85% of all NSCLC samples tested were adenocarcinoma. None of the squamous cell carcinoma tested was positive for EGFR mutation. Smoking status was inversely proportional to EGFR mutation status (p<0.001). Over 60% patients received chemotherapy first and second line and responses decreased with each line of chemotherapy. Median PFS and OS were not different between the EGFR mutation positive and negative groups (6.85 versus 6.8 months; HR 1.6; 95% CI 0.70-3.65; p=0.2543 and 11.5 versus 12.9 months; HR 0.70; 95% CI 0.28-1.75; p=0.44, respectively). On multivariate analysis, only non-white race was associated with decrease in OS (HR 6.66; 95% CI 2.31-19.19; p=0.0004). Conclusion: EGFR mutation rate in South African lung cancer patients was 21.8%. 89% of all EGFR mutations were either exon 19 deletions or L858R point mutations. Most EGFR mutations were associated with adenocarcinoma of the lung in non-smokers. These findings were consistent with current literature in western countries. Treatment practice remained chemotherapy based, with few patients receiving EGFR TKIs. Efforts should be made to prioritized targeted treatment approach in lung cancer in South Africa.

A Thesis submitted to The University of Arizona College of Medicine - Phoenix in partial fulfillment of the requirements for the Degree of Doctor of Medicine.

To fully understand the mechanisms of lower airway inflammation associated with many equine diseases such as heaves or Rhodococcus equi infection, which are age specific, we must first identify baseline “normal” structural characteristics of the horse lung. To develop a detailed understanding of the morphology of the horse lung, stereological methods were adapted and applied to the lungs from healthy adult horses (n=4) and one day (n=5) and 30 day (n=5) old foals. The left lung from each animal was fixed in situ and was then removed from the body cavity and remained in fixative overnight before beginning an unbiased sampling procedure. The tissue samples were fixed in plastic and paraffin blocks for stereological evaluation and immunohistochemistry, respectively. The lung was characterised into parenchyma and non-parenchyma, where median parenchymal density (alveolar airspace, ductal airspace and tissue) was 81.0% in one day old foals, 84.4% in 30 day old foals and 93.7% in adult lungs. The median volume density of alveolar airspace per lung was 45.9% in one day old, 55.5% in 30 day and 66.9% in adult horse lungs. Ductal airspace and alveolar tissue volume density was unchanged between the age groups. The median alveolar surface area (m^2) seemed to increase with age, from about 205.3m^2, 258.2m^2 and 629.9m^2 in one day old foals, 30 day old foals, and adults, respectively. While the median alveolar surface density decreased with age, the mean linear intercept increased with age. Alveolar surface area was consistently greater than endothelial surface area (m^2) within each lung, however the ratio between alveolar and endothelial surface density remains unchanged with age. The median endothelium surface area was 106.2m^2 in one day, 147.5m^2 in 30 day and 430m^2 in adult lungs. The data show that the foal is born with a functionally developed lung and its basic architecture changes with age. Foal lung development and remodelling postnatally is a result of alveolar expansion paralleled with angiogenesis.

Thesis (Ph. D.)--University of Hong Kong, 2007. / Also available online.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2006. / Härtill 4 uppsatser.

Thesis (Ph. D.)--University of Hong Kong, 2007. / Title proper from title frame. Also available in printed format.