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Chung L.P.,University of Western Australia | Chung L.P.,Lung Institute of Western Australia | Waterer G.W.,University of Western Australia | Waterer G.W.,Level 2 Industries
Critical Reviews in Clinical Laboratory Sciences | Year: 2011

Genetic variations, in part, determine individual susceptibility to sepsis and pneumonia. Advances in genetic sequence analysis as well as high throughput platform analysis of gene expression has allowed for a better understanding of immunopathogenesis during sepsis. Differences in genes can also modulate immune and inflammatory response during sepsis thereby translating to differences in clinical outcomes. An increasing number of candidate genes have been implicated to play a role in sepsis susceptibility, most of which are controversial with few exceptions. This does not refute the significance of genetic polymorphisms in sepsis, but rather highlights the difficulties and pitfalls related to genetic association studies. These difficulties include differences in study design such as heterogeneous patient cohorts and differences in pathogenic organisms, linkage disequilibrium, and lack of power for detailed haplotype analysis or examination of gene-gene interactions. There is extensive diversity in the pathways of inflammation and immune response during sepsis making it even harder to prove the functional and clinical significance of one single genetic polymorphism which could be easily masqueraded or compensated by other upstream or downstream events of the pathway involved. The majority of studies have analysed candidate genes in isolation from other possible polymorphisms. It is likely that susceptibility to sepsis is the result of polymorphisms from multiple genes rather than one single mutation. Future studies should aim for multi-centered collaborative approach looking at genome wide association or gene profiling to provide a more complete appraisal of the key genetic players in determining genetic susceptibility to sepsis. This review paper will summarise the prominent candidate gene polymorphisms with known functional changes or those with haplotype data. In addition, a summary of the expanding research in the field of epigenetics and post-sepsis immunosuppression will be discussed. © 2011 Informa Healthcare USA, Inc.

Davies H.E.,University of Cardiff | Rosenstengel A.,Prince Charles Hospital | Lee Y.C.G.,University of Western Australia | Lee Y.C.G.,Lung Institute of Western Australia
Current Opinion in Pulmonary Medicine | Year: 2011

PURPOSE OF REVIEW: Pleural disease is common. Traditionally, many patients were subjected to surgery for diagnosis and treatment. Most pleural surgical procedures have not been subjected to high-quality clinical appraisal and their use is based on anecdotal series with selection bias. The evidence (or the lack) of benefits of surgery in common pleural conditions is reviewed. RECENT FINDINGS: Recent studies do not support the routine therapeutic use of surgery in patients with malignant pleural effusions, empyema or mesothelioma. Four randomized studies have failed to show significant benefits of thoracoscopic poudrage over bedside pleurodesis. Surgery as first-line therapy for empyema was studied in four randomized studies with mixed results and no consistent benefits. Cumulative evidence suggests that radical surgery in mesothelioma, especially extrapleural pneumonectomy, is not justified. Advances in imaging modalities and histopathological tools have minimized the need for surgery in the workup of pleural effusions. Complications associated with surgery are increasingly recognized. SUMMARY: Surgery has associated perioperative risks and costs, and residual pain is not uncommon. Many conventional pleural surgeries have not been assessed in randomized studies. Pulmonologists should be aware of the evidence that supports surgical interventions, or the lack of it, in order to make informed clinical decisions and optimize patient care. © 2011 Lippincott Williams & Wilkins, Inc.

Fysh E.T.H.,University of Western Australia | Smith N.A.,Sir Charles Gairdner Hospital | Lee Y.C.G.,University of Western Australia | Lee Y.C.G.,Lung Institute of Western Australia
Seminars in Respiratory and Critical Care Medicine | Year: 2010

Drainage of the pleural space is not a modern concept, but the optimal size of chest drains to use remains debated. Conventional teaching advocates blunt dissection and large-bore tubes; but in recent years, small-bore catheters have gained popularity. In the absence of high-quality randomized data, this review summarizes the available literature on the choice of chest drains. The objective data supporting the use of large-bore tubes is scarce in most pleural diseases. Increasing evidence shows that small-bore catheters induce less pain and are of comparable efficacy to large-bore tubes, including in the management of pleural infection, malignant effusion, and pneumothoraces. The onus now is on those who favor large tubes to produce clinical data to justify the more invasive approach. Copyright © 2010 by Thieme Medical Publishers, Inc.

Bel E.H.,University of Amsterdam | Wenzel S.E.,University of Pittsburgh | Thompson P.J.,Lung Institute of Western Australia | Thompson P.J.,University of Western Australia | And 5 more authors.
New England Journal of Medicine | Year: 2014

Background: Many patients with severe asthma require regular treatment with oral glucocorticoids despite the use of high-dose inhaled therapy. However, the regular use of systemic glucocorticoids can result in serious and often irreversible adverse effects. Mepolizumab, a humanized monoclonal antibody that binds to and inactivates interleukin-5, has been shown to reduce asthma exacerbations in patients with severe eosinophilic asthma. Methods: In a randomized, double-blind trial involving 135 patients with severe eosinophilic asthma, we compared the glucocorticoid-sparing effect of mepolizumab (at a dose of 100 mg) with that of placebo administered subcutaneously every 4 weeks for 20 weeks. The primary outcome was the degree of reduction in the glucocorticoid dose (90 to 100% reduction, 75 to less than 90% reduction, 50 to less than 75% reduction, more than 0 to less than 50% reduction, or no decrease in oral glucocorticoid dose, a lack of asthma control during weeks 20 to 24, or withdrawal from treatment). Other outcomes included the rate of asthma exacerbations, asthma control, and safety. Results: The likelihood of a reduction in the glucocorticoid-dose stratum was 2.39 times greater in the mepolizumab group than in the placebo group (95% confidence interval, 1.25 to 4.56; P = 0.008). The median percentage reduction from baseline in the glucocorticoid dose was 50% in the mepolizumab group, as compared with no reduction in the placebo group (P = 0.007). Despite receiving a reduced glucocorticoid dose, patients in the mepolizumab group, as compared with those in the placebo group, had a relative reduction of 32% in the annualized rate of exacerbations (1.44 vs. 2.12, P = 0.04) and a reduction of 0.52 points with respect to asthma symptoms (P = 0.004), as measured on the Asthma Control Questionnaire 5 (in which the minimal clinically important difference is 0.5 points). The safety profile of mepolizumab was similar to that of placebo. Conclusions: In patients requiring daily oral glucocorticoid therapy to maintain asthma control, mepolizumab had a significant glucocorticoid-sparing effect, reduced exacerbations, and improved control of asthma symptoms. Copyright © 2014 Massachusetts Medical Society.

Kolios G.,Democritus University of Thrace | Moodley Y.,University of Western Australia | Moodley Y.,Lung Institute of Western Australia
Respiration | Year: 2013

Stem cells are a population of undifferentiated cells characterized by the ability to extensively proliferate (self-renewal), usually arise from a single cell (clonal), and differentiate into different types of cells and tissue (potent). There are several sources of stem cells with varying potencies. Pluripotent cells are embryonic stem cells derived from the inner cell mass of the embryo and induced pluripotent cells are formed following reprogramming of somatic cells. Pluripotent cells can differentiate into tissue from all 3 germ layers (endoderm, mesoderm, and ectoderm). Multipotent stem cells may differentiate into tissue derived from a single germ layer such as mesenchymal stem cells which form adipose tissue, bone, and cartilage. Tissue-resident stem cells are oligopotent since they can form terminally differentiated cells of a specific tissue. Stem cells can be used in cellular therapy to replace damaged cells or to regenerate organs. In addition, stem cells have expanded our understanding of development as well as the pathogenesis of disease. Disease-specific cell lines can also be propagated and used in drug development. Despite the significant advances in stem cell biology, issues such as ethical controversies with embryonic stem cells, tumor formation, and rejection limit their utility. However, many of these limitations are being bypassed and this could lead to major advances in the management of disease. This review is an introduction to the world of stem cells and discusses their definition, origin, and classification, as well as applications of these cells in regenerative medicine. Copyright © 2012 S. Karger AG, Basel.

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