ORCID Profile
0000-0002-9531-8411
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Cellular Immunology | Allergy | Immunology | Bacteriology
Respiratory System and Diseases (incl. Asthma) | Immune System and Allergy |
Publisher: Springer Science and Business Media LLC
Date: 03-02-2010
Publisher: Wiley
Date: 28-06-2017
DOI: 10.1111/IMR.12549
Publisher: Springer Science and Business Media LLC
Date: 28-05-2012
Abstract: e-learning resources may be beneficial for complex or conceptually difficult topics. Leukaemia is one such topic, yet there are no reports on the efficacy of e-learning for leukaemia. This study compared the learning impact on senior medical students of a purpose-built e-learning module on leukaemia, compared with existing online resources. A randomised controlled trial was performed utilising volunteer senior medical students. Participants were randomly allocated to Study and Control groups. Following a pre-test on leukaemia administered to both groups, the Study group was provided with access to the new e-learning module, while the Control group was directed to existing online resources. A post-test and an evaluation questionnaire were administered to both groups at the end of the trial period. Study and Control groups were equivalent in gender distribution, mean academic ability, pre-test performance and time studying leukaemia during the trial. The Study group performed significantly better than the Control group in the post-test, in which the group to which the students had been allocated was the only significant predictor of performance. The Study group’s evaluation of the module was overwhelmingly positive. A targeted e-learning module on leukaemia had a significant effect on learning in this cohort, compared with existing online resources. We believe that the interactivity, dialogic feedback and integration with the curriculum offered by the e-learning module contributed to its impact. This has implications for e-learning design in medicine and other disciplines.
Publisher: American Society for Clinical Investigation
Date: 08-2006
DOI: 10.1172/JCI24767
Publisher: Wiley
Date: 19-08-2015
DOI: 10.1111/RESP.12606
Abstract: Exacerbations of allergic asthma are often triggered by respiratory viral infections. We have previously shown that in a T-helper type 2 (Th2)-biased cytokine environment, mouse and human airway epithelial cells (AEC) exhibit increased expression of pro-inflammatory and anti-viral genes in response to synthetic double-stranded ribonucleic acid (dsRNA), a virus-like stimulus. This implies coordinated regulation of gene expression, suggesting possible involvement of microRNA. To investigate this, we developed a novel approach to identifying candidate microRNA using online databases, then confirmed their expression by quantitative real-time polymerase chain reaction (qRT-PCR). Using a list of genes of interest, defined on the basis of the previous study as being up-regulated in a Th2 environment, we searched mouse and human microRNA databases for possible regulatory microRNA, and selected 10 candidates that were conserved across species or predicted by more than one human database. Expression of these microRNA was tested by qRT-PCR, in primary human AEC pre-treated with Th2 cytokines and exposed to dsRNA. Expression of hsa-miR-139-5p, miR-423-5p and miR-542-3p was significantly decreased in Th2 pre-treated AEC, and miR-135a-5p exhibited a trend towards decreased expression. Further database searches confirmed that these microRNA regulated additional pro-inflammatory and anti-viral response genes for which expression had previously been shown to be up-regulated, confirming the validity of this approach. Our study demonstrates the value of using multiple online databases to identify candidate regulatory microRNA and provides the first evidence that in an allergic environment, microRNA may be important in altering the pro-inflammatory and anti-viral responses of human AEC during exacerbations of asthma.
Publisher: Informa UK Limited
Date: 06-2013
Publisher: Elsevier BV
Date: 12-1992
DOI: 10.1016/0165-2478(92)90230-L
Abstract: A group of doctors concerned about the environment and health has applied for letters patent and charitable status registration for a new organization, the Canadian Association of Physicians for the Environment. The goal of the new group, says founder Dr. Tee Guidotti, is to create a network for physicians who are interested in the relationship between health and the environment, and to educate and support physicians who take an active interest in environmental issues in their communities.
Publisher: Informa UK Limited
Date: 2018
Publisher: Elsevier BV
Date: 10-2007
DOI: 10.1053/J.GASTRO.2007.06.062
Abstract: This study examined the possible role of endotoxinemia (from increased gut permeability) as an additional trigger factor for overt pancreatic disease and as a promoter of chronic pancreatic injury in alcoholics by using a rat model of chronic alcohol feeding and in vitro experiments with cultured pancreatic stellate cells (PSCs), the key mediators of pancreatic fibrosis. In the in vivo model, Sprague-Dawley rats fed isocaloric Lieber-DeCarli liquid diets +/- alcohol for 10 weeks were challenged with a single dose or 3 repeated doses of the endotoxin lipopolysaccharide (LPS) and the pancreas was examined. In the in vitro studies, rat PSCs were assessed for activation on exposure to LPS +/- ethanol. The expression of LPS receptors TLR4 and CD14 also was assessed in rat and human PSCs. In the in vivo model, single or repeated LPS challenge resulted in significantly greater pancreatic injury in alcohol-fed rats compared with rats fed the control diet without alcohol. Notably, repeated LPS injections caused pancreatic fibrosis in alcohol-fed rats, but not in rats fed the control diet. In the in vitro studies, PSCs were activated by LPS. Alcohol + LPS exerted a synergistic effect on PSC activation. Importantly, both rat and human PSCs expressed TLR4 and CD14. This study describes, for the first time, a clinically relevant animal model of alcohol-related pancreatic injury and provides strong in vivo and in vitro evidence that suggests that LPS is a trigger factor in the initiation and progression of alcoholic pancreatitis.
Publisher: Elsevier BV
Date: 03-2004
Publisher: Springer Science and Business Media LLC
Date: 08-01-2016
Publisher: The Company of Biologists
Date: 05-11-2009
DOI: 10.1242/DMM.001719
Publisher: Informa UK Limited
Date: 18-03-2012
Publisher: Springer Science and Business Media LLC
Date: 10-04-2014
Publisher: Wiley
Date: 04-2015
DOI: 10.1111/RESP.12381
Abstract: Exposure to airborne particulate matter (PM) may promote development of childhood asthma and trigger acute exacerbations of existing asthma via injury to airway epithelial cells (AEC). We compared the response of AEC to ambient particulates with median aerodynamic diameters of <10 μm or <2.5 μm from the Sydney metropolitan region (Sydney PM10 or PM2.5), to traffic-derived particulates from the exhaust stack of a motorway tunnel or to inert carbon black as a control. Sydney PM10 strongly stimulated messenger RNA expression and secretion of the pro-inflammatory cytokines interleukin 6 (IL-6) and chemokine (C-X-C motif) ligand 1 (CXCL1) by mouse tracheal AEC. In contrast, traffic-derived particulates did not. Similarly, PM10 stimulated expression of IL6, IL8 and IL1B by human AEC. Mass spectrometric analysis showed that PM10 contained much higher levels of elements associated with dusts of geological origin. In contrast, tunnel soot contained much higher levels of various organic compounds, notably including long straight-chain alkanes and diesel-derived polycyclic aromatic hydrocarbons. Sydney PM2.5, as well as PM10 collected during a period including a major dust storm, both of which contained relatively lower levels of iron but similar levels of other crustal elements, did not stimulate expression or secretion of CXCL1 by mouse AEC. Ambient PM10 is likely to be more important than traffic-derived PM in causing injury to AEC leading to production of pro-inflammatory cytokines. The injurious effects may be related to the presence of iron in the coarse fraction of airborne PM. These findings are likely to be relevant to the pathogenesis of asthma.
Publisher: Elsevier BV
Date: 10-2015
DOI: 10.1016/J.ACRA.2015.07.002
Abstract: Diagnostic imaging is under-represented in medical curricula globally. Adaptive tutorials, online intelligent tutoring systems that provide a personalized learning experience, have the potential to bridge this gap. However, there is limited evidence of their effectiveness for learning about diagnostic imaging. We performed a randomized mixed methods crossover trial to determine the impact of adaptive tutorials on perceived engagement and understanding of the appropriate use and interpretation of common diagnostic imaging investigations. Although concurrently engaged in disparate blocks of study, 99 volunteer medical students (from years 1-4 of the 6-year program) were randomly allocated to one of two groups. In the first arm of the trial on chest X-rays, one group received access to an adaptive tutorial, whereas the other received links to an existing peer-reviewed Web resource. These two groups crossed over in the second arm of the trial, which focused on computed tomography scans of the head, chest, and abdomen. At the conclusion of each arm of the trial, both groups completed an examination-style assessment, comprising questions both related and unrelated to the topics covered by the relevant adaptive tutorial. Online questionnaires were used to evaluate student perceptions of both learning resources. In both arms of the trial, the group using adaptive tutorials obtained significantly higher assessment scores than controls. This was because of higher assessment scores by senior students in the adaptive tutorial group when answering questions related to topics covered in those tutorials. Furthermore, students indicated significantly better engagement with adaptive tutorials than the Web resource and rated the tutorials as a significantly more valuable tool for learning. Medical students overwhelmingly accept adaptive tutorials for diagnostic imaging. The tutorials significantly improve the understanding of diagnostic imaging by senior students.
Publisher: Elsevier BV
Date: 12-2003
DOI: 10.1016/J.RESP.2003.09.003
Abstract: Our recently developed murine asthma model is capable of inducing airway-specific chronic inflammatory changes and remodeling, features of human asthma commonly missing in conventional animal models. To validate this model by site-specific physiological evaluation of hyperresponsiveness. Non-sensitized and sensitized mice received either short-term uncontrolled or long-term controlled low-level exposures to aerosolized ovalbumin (OVA). Respiratory impedance (Zrs) was measured in response to increasing doses of methacholine (Mch). The constant-phase model was fitted to Zrs spectra to determine the specific site of hyperresponsiveness. Sensitized acutely exposed mice had significantly increased tissue d ing (G), tissue elastance (H) and hysteresivity (eta) in response to Mch, but no significant increase in airway resistance (Raw), indicating tissue-specific hyperresponsiveness. In contrast, sensitized chronically exposed mice had significantly elevated Raw at all concentrations of Mch but no increases in G, H or eta indicating airway-specific hyperresponsiveness. Chronic inhalational exposure of sensitized mice to low-mass concentrations of OVA induces airway-specific hyperresponsiveness.
Publisher: BMJ
Date: 05-2003
DOI: 10.1136/GUT.52.5.677
Abstract: Pancreatic stellate cells (PSCs), implicated as key mediators of pancreatic fibrogenesis, are found in increased numbers in areas of pancreatic injury. This increase in PSC number may be due to increased local proliferation and/or migration of these cells from adjacent areas. The ability of PSCs to proliferate has been well established but their potential for migration has not been examined. Therefore, the aims of this study were to determine whether cultured rat PSCs have the capacity to migrate and, if so, to characterise this migratory capacity with respect to the influence of basement membrane components and the effect of platelet derived growth factor (PDGF, a known stimulant for migration of other cell types). Migration of freshly isolated (quiescent) and culture activated (passaged) rat PSCs was assessed across uncoated or Matrigel (a basement membrane-like substance) coated porous membranes (pore size 8 micro m) in the presence or absence of PDGF (10 and 20 ng/ml) in the culture medium. A checkerboard assay was performed to assess whether the effect of PDGF on PSC migration was chemotactic or chemokinetic. Cell migration was observed with both freshly isolated and passaged PSCs. However, compared with passaged (culture activated) cells, migration of freshly isolated cells was delayed, occurring only at or after 48 hours of incubation when the cells displayed an activated phenotype. PSC migration through Matrigel coated membranes was delayed but not prevented by basement membrane components. PSC migration was increased by PDGF and this effect was predominantly chemotactic (that is, in the direction of a positive concentration gradient). (i) PSCs have the capacity to migrate. (ii) Activation of PSCs appears to be a prerequisite for migration. (iii) PDGF stimulates PSC migration and this effect is predominantly chemotactic. Chemotactic factors released during pancreatic injury may stimulate the migration of PSCs through surrounding basement membrane towards affected areas of the gland.
Publisher: Elsevier BV
Date: 1998
DOI: 10.1080/00313029800169665
Abstract: The murine S-100 protein designated CP-10 is a potent chemotactic factor for phagocytic cells, exhibiting optimal activity in the picomolar range. We assessed the role of this cytokine in the inflammatory response to pulmonary injury following intratracheal administration of bleomycin to mice. In the lungs of normal animals, strong cytoplasmic immunostaining for CP-10 was demonstrable in all recognisable neutrophil leucocytes sequestered within alveolar capillaries. Following induction of pulmonary inflammation in susceptible C57BL/6 mice, numerous CP-10-positive neutrophils were observed, but many of the recruited neutrophils did not exhibit staining for CP-10. No other cells were immunoreactive. The concentration of CP-10 in bronchoalveolar lavage (BAL) fluids from normal mice and mice administered intratracheal saline was below the level of detection by enzyme immunoassay. In contrast, nanomolar levels of CP-10 were detected in unconcentrated BAL fluids from C57BL/6 mice after bleomycin-induced injury, and the presence of monomeric CP-10 was demonstrable by Western blotting. Elevation of CP-10 levels correlated with the influx of inflammatory cells in C57BL/6 mice, but was not demonstrable in BAL fluids from BALB/c mice, which are resistant to pulmonary injury by bleomycin. We conclude that CP-10 may contribute to the recruitment of inflammatory cells in bleomycin-induced lung damage.
Publisher: Wiley
Date: 09-06-2014
DOI: 10.1111/MEDU.12422
Abstract: Concept maps have been used to promote meaningful learning and critical thinking. Although these are crucially important in all disciplines, evidence for the benefits of concept mapping for learning in medicine is limited. We performed a randomised crossover study to assess the benefits of online testable concept maps for learning in pathology by volunteer junior medical students. Participants (n = 65) were randomly allocated to either of two groups with equivalent mean prior academic performance, in which they were given access to either online maps or existing online resources for a 2-week block on renal disease. Groups then crossed over for a 2-week block on hepatic disease. Outcomes were assessed using timed online quizzes, which included questions unrelated to topics in the pathogenesis maps as an internal control. Questionnaires were administered to evaluate students' acceptance of the maps. In both blocks, the group with access to pathogenesis maps achieved significantly higher average scores than the control group on quiz questions related to topics covered by the maps (Block 1: p < 0.001, Cohen's d = 0.9 Block 2: p = 0.008, Cohen's d = 0.7). However, mean scores on unrelated questions did not differ significantly between the groups. In a third block on pancreatic disease, both groups received pathogenesis maps and collectively performed significantly better on quiz topics related to the maps than on unrelated topics (p < 0.01, Cohen's d = 0.5). Regression analysis revealed that access to pathogenesis maps was the dominant contributor to variance in performance on map-related quiz questions. Responses to questionnaire items on pathogenesis maps were overwhelmingly positive in both groups. These results indicate that online testable pathogenesis maps are well accepted and can improve learning of concepts in pathology by medical students.
Publisher: BMJ
Date: 21-10-2010
Abstract: Infections with some bacteria, including Streptococcus pneumoniae, have been associated with a reduced incidence of asthma. Components of S pneumoniae may have the potential to modulate allergic inflammatory responses and suppress the development of asthma. To determine if human S pneumoniae vaccines have the potential to suppress asthma by elucidating their effect on allergic airways disease (AAD) in mouse models. AAD was induced in BALB/c mice by intraperitoneal sensitisation and intranasal challenge with ovalbumin. Pneumococcal conjugate or polysaccharide vaccines were administered at the time of sensitisation or during established AAD. Hallmark features of AAD were assessed. Levels of regulatory T cells (Tregs) were quantified by fluorescence-activated cell sorting, and their immunoregulatory capacity was assessed using proliferation assays and anti-CD25 antibody treatment. Intranasal administration of the conjugate vaccine, but not the polysaccharide vaccine, suppressed the hallmark features of AAD, including: eosinophilic and T helper 2-mediated inflammation airway hyper-responsiveness circulating immunoglobulin E (IgE) levels and mucus hypersecretion. Intramuscular administration of the conjugate vaccine had limited protective effects. The conjugate vaccine increased Tregs in the lung-draining lymph nodes, lung and spleen. Furthermore, conjugate vaccine-induced Tregs had an enhanced capacity to suppress T effector responses. Anti-CD25 administration reversed the suppressive effects of the conjugate vaccine. A currently available human conjugate vaccine suppresses the hallmark features of AAD through the induction of Tregs. Thus targeted administration may provide a novel immunoregulatory treatment for asthma.
Publisher: Informa UK Limited
Date: 2002
DOI: 10.1080/01421590220145806
Abstract: An interactive computer-assisted learning (CAL) module on glomerulonephritis, previously identified by fourth-year medical students as a difficult topic, was developed. The module comprised background material, case studies, graphics, animation, video and supporting quizzes with feedback. The impact of the module on student learning was evaluated by comparing the performance of two matched groups of students, only one of which accessed the CAL module, in an online assessment. The analysis examined the effect of having completed a clinical term in renal medicine. A significant improvement in the performance of those students who used the CAL module was demonstrated. Unexpectedly, completing a renal medicine term had no beneficial influence on students' performance. Students who used the CAL module perceived a significant decrease in the difficulty of the topic. It is concluded that the module is an effective learning tool, but important caveats are noted associated with using CAL modules in redesigned medical curricula.
Publisher: The American Association of Immunologists
Date: 10-2010
Abstract: Inflammation and airway hyperresponsiveness (AHR) are hallmark features of asthma and often correlate with the severity of clinical disease. Although these features of asthma can be effectively managed with glucocorticoid therapy, a subgroup of patients, typically with severe asthma, remains refractory to therapy. The mechanisms leading to steroid resistance in severe asthmatics are poorly understood but may be related to the activation of innate host defense pathways. Previously, we have shown that IFN-γ–producing cells and LPS, two factors that are associated with severe asthma, induce steroid-resistant AHR in a mouse model. We now demonstrate that cooperative signaling induced by IFN-γ and LPS results in the production of IL-27 by mouse pulmonary macrophages. IL-27 and IFN-γ uniquely cooperate to induce glucocorticoid-resistant AHR through a previously unknown MyD88-dependent mechanism in pulmonary macrophages. Importantly, integrated signaling by IL-27/IFN-γ inhibits glucocorticoid-induced translocation of the glucocorticoid receptor to the nucleus of macrophages. Furthermore, expression of both IL-27 and IFN-γ was increased in the induced sputum of steroid-refractory asthmatics. These results suggest that a potential mechanism for steroid resistance in asthma is the activation of MyD88-dependent pathways in macrophages that are triggered by IL-27 and IFN-γ, and that manipulation of these pathways may be a therapeutic target.
Publisher: Informa UK Limited
Date: 11-04-2011
DOI: 10.1080/10401334.2011.561700
Abstract: Concept maps can assist learning by integrating new information with existing cognitive structure to facilitate meaningful understanding. The benefits of testable concept maps to illustrate cause-and-effect sequences in the pathogenesis of disease have not yet been determined. A controlled trial was employed to evaluate the learning benefits of testable pathogenesis maps. Consecutive cohorts of junior medical students allocated to control and study groups participated in case-based pathology practical classes. Online testable pathogenesis maps were integrated into classes for the study group. An online quiz and questionnaire were used to evaluate outcomes. The study group scored significantly higher on the quiz (p= .014), including significantly better performance in topics covered by pathogenesis maps (p= .049). The study group's questionnaire responses regarding pathogenesis maps were overwhelmingly positive. Testable pathogenesis maps significantly improved medical students' understanding of the pathogenesis of disease. Wider use of such maps should be explored.
Publisher: Springer Science and Business Media LLC
Date: 25-11-2008
Publisher: Informa UK Limited
Date: 1994
DOI: 10.3109/08977199409000234
Abstract: We investigated whether development of pulmonary fibrosis following inhalational exposure of mice to silica (quartz) dust was accompanied by enhanced secretion of activity resembling epidermal growth factor (EGF). Mitogenic activity for pulmonary fibroblasts was assessed in bronchoalveolar lavage fluid (BALF) using a serum-free bioassay. Activity in BALF from mice exposed to nonfibrogenic titanium dioxide dust was comparable to that in BALF from normal animals. In contrast, mitogenic activity was significantly increased at 6 and 12 weeks after inhalation of silica particles, coinciding with the appearance of collagenised lesions in the lung. BALF from mice exposed to silica 6 weeks previously had significantly higher concentrations of growth factor(s) able to bind to EGF receptors on pulmonary fibroblasts. In parallel, macrophages within inflammatory lesions in the airspaces acquired immunoreactivity for EGF. The presence of an increased concentration of EGF-like growth factor(s) in BALF might constitute a marker of particle-induced pulmonary fibrosis.
Publisher: American Physiological Society
Date: 08-2018
DOI: 10.1152/AJPLUNG.00063.2018
Abstract: Chronic obstructive pulmonary disease (COPD), one of the leading causes of death in the world, is a chronic inflammatory disease of the airways usually caused by long-term exposure to inhaled irritants. Airway epithelial cells (AECs) play a key role in initializing COPD and driving the exacerbation of this disease through the release of various cytokines. This AEC-derived cytokine response is tightly regulated possibly through the regulatory effects of noncoding RNAs (ncRNAs). Although the importance of ncRNAs in pulmonary diseases has been increasingly realized, little is known about the role of ncRNA in the regulation of inflammatory responses in COPD. This review outlines the features of AEC-derived cytokine responses in COPD and how ncRNAs regulate these inflammatory responses.
Publisher: Wiley
Date: 2006
DOI: 10.1002/AR.B.20105
Abstract: The new medicine program at the University of New South Wales employs scenario-based learning with vertically integrated classes of year 1 and year 2 students, as well as horizontally integrated teaching with no discipline-specific courses. Coinciding with its introduction, we undertook comprehensive revision of the approach to teaching microscopic anatomy and pathology. We designed practical classes around virtual slides, which are high-magnification digital images of tissue sections stored in a multiresolution file format, viewable in a Web browser in a manner closely simulating conventional microscopy. In these classes, we integrated the teaching of histology and histopathology, introducing students to the microscopic features of tissues and organs, and giving them the opportunity to compare and contrast the normal with the abnormal in various disease states. Members of academic staff from both anatomy and pathology were present to promote discussion and respond to questions. Worksheets defined learning objectives and provided clinical cases as contexts for learning in each class. Evaluation revealed that students strongly supported the integrated approach. The efficiency of the teaching method meant that it was possible to work through 5-8 virtual slides per 2-hr class without difficulty. Students displayed considerable initiative in exploring the histological features of tissues, identifying the changes in various pathological states, and recognizing their relationship to clinical manifestations. We believe that the approach we have developed should help to minimize the potential adverse impact of curriculum reform on the teaching of morphology, while ensuring that learning remains both meaningful and interesting.
Publisher: Wiley
Date: 02-04-2013
DOI: 10.1111/IMR.12058
Abstract: Chronic inflammatory diseases of the lung are leading causes of morbidity and mortality worldwide. Many of these disorders can be attributed to abnormal immune responses to environmental stimuli and infections. As such, understanding the innate host defense pathways and their regulatory systems will be critical to developing new approaches to treatment. In this regard, there is increasing interest in the role of microRNAs (miRNAs) in the regulation of pulmonary innate host defense responses and the inflammatory sequelae in respiratory disease. In this review, we discuss recent findings that indicate an important role for miRNAs in the regulation in mouse models of various respiratory diseases and in host defense against bacterial and viral infection. We also discuss the potential utility and limitations of targeting these molecules as anti-inflammatory strategies and also as a means to improve pathogen clearance from the lung.
Publisher: Wiley
Date: 07-10-2004
DOI: 10.1002/PATH.1658
Abstract: Virtual slides are high-magnification digital images of tissue sections, stored in a multi-resolution file format. Using appropriate software, these slides can be viewed in a web browser in a manner that closely simulates examination of glass slides with a real microscope. We describe the successful implementation of teaching microscopic pathology with virtual slides and, for the first time, their use in summative assessment. Both students and teaching staff readily adapted to the use of virtual microscopy. Questionnaire feedback from students strongly indicated that virtual slides solved a number of problems in their learning, while providing good to excellent image quality. A deliberate policy of allocating two students per workstation promoted collaboration and helped to maintain interest in microscopic pathology. The use of a secure browser facilitated assessment using virtual slides, with no technical or security issues arising despite high peak demand. The new Medicine programme at the University of New South Wales will exclusively utilize virtual microscopy for the study of both histology and histopathology. We believe that the use of high-quality learning resources such as virtual slides can ensure that microscopic examination of tissues remains both meaningful and interesting.
Publisher: Oxford University Press (OUP)
Date: 04-2012
DOI: 10.1189/JLB.0711357
Abstract: Asthma is recognized as a heterogeneous disorder, although in most patients, the clinical manifestations are effectively managed with established combination therapies. However, 5–10% of asthmatics have severe asthma, which does not respond to treatment, and these patients account for & % of asthma-related healthcare costs. New investigations into the pathogenesis of glucocorticoid resistance in severe asthma indicate that pulmonary macrophages may play central roles in promoting airway inflammation, particularly in asthma that is resistant to steroid therapy. Importantly, factors that are linked to the activation of pulmonary macrophages may contribute to glucocorticoid resistance and severe asthma. Here, we review recent advances in understanding the roles of pulmonary macrophages in the mechanisms of glucocorticoid resistance and the pathogenesis of severe asthma. We discuss the role of macrophage phenotype, infection, IFN-γ, LPS, associated signaling pathways, TNF-α, MIF, and other macrophage-associated factors. Understanding the pathogenesis of steroid-resistant severe asthma will contribute to the identification of optimal therapeutic strategies for the effective management of the disease.
Publisher: The Company of Biologists
Date: 2013
DOI: 10.1242/DMM.011247
Publisher: Springer Science and Business Media LLC
Date: 08-05-2019
Publisher: Bentham Science Publishers Ltd.
Date: 09-2008
Publisher: Hindawi Limited
Date: 25-08-2019
DOI: 10.1155/2019/7281462
Abstract: Chronic obstructive pulmonary disease (COPD) is characterized by airway inflammation associated with a Th1/17-biased cytokine environment. Acute exacerbations of COPD (AECOPD) are most often triggered by respiratory infections, which elicit an exaggerated inflammatory response in these patients, via poorly defined mechanisms. We investigated the responses of airway epithelial cells (AECs) to infective stimuli in COPD and the effects of the Th1/17-biased environment on these responses. Cytokine expression was assessed following exposure to virus-like stimuli (poly I:C or imiquimod) or bacterial LPS. The effects of pretreatment with Th1/17 cytokines were evaluated in both primary AECs and the Calu-3 AEC cell line. We found that poly I:C induced increased expression of the proinflammatory cytokines IL1 β , IL6, CXCL8, and TNF and IFN- β 1 in AECs from both control subjects and COPD patients. Expression of IL1 β in response to all 3 stimuli was significantly enhanced in COPD AECs. Primary AECs pretreated with Th1/17 cytokines exhibited enhanced expression of mRNA for proinflammatory cytokines in response to poly I:C. Similarly, Calu-3 cells responded to virus-like/bacterial stimuli with increased expression of proinflammatory cytokines, and a Th1/17 environment significantly enhanced their expression. Furthermore, increased expression of pattern recognition receptors for viruses (TLR3, TLR7, IFIH1, and DDX58) was induced by Th1/17 cytokines, in both primary AECs and Calu-3 cells. These findings suggest that the Th1/17-biased environment associated with COPD may enhance the proinflammatory cytokine response of AECs to viral and bacterial infections and that increased signaling via upregulated receptors may contribute to exaggerated inflammation in virus-induced AECOPD.
Publisher: Springer Science and Business Media LLC
Date: 19-09-2005
Abstract: Exhaled nitric oxide (eNO) is decreased by cigarette smoking. The hypothesis that oxides of nitrogen (NO X ) in cigarette smoke solution (CSS) may exert a negative feedback mechanism upon NO release from epithelial (AEC, A549, and NHTBE) and basophilic cells (RBL-2H3) was tested in vitro. CSS inhibited both NO production and degranulation (measured as release of beta-hexosaminidase) in a dose-dependent manner from RBL-2H3 cells. Inhibition of NO production by CSS in AEC, A549, and NHTBE cells was also dose-dependent. In addition, CSS decreased expression of NOS mRNA and protein expression. The addition of NO inhibitors and scavengers did not, however, reverse the effects of CSS, nor did a NO donor (SNP) or nicotine mimic CSS. N-acetyl-cysteine, partially reversed the inhibition of beta-hexosaminidase release suggesting CSS may act via oxidative free radicals. Thus, some of the inhibitory effects of CSS appear to be via oxidative free radicals rather than a NO X -related negative feedback.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2004
DOI: 10.1097/00006676-200410000-00002
Abstract: Pancreatic cancer has a very poor prognosis, largely due to its propensity for early local and distant spread. Histopathologically, most pancreatic cancers are characterized by a prominent stromal/fibrous reaction in and around tumor tissue. The aims of this study were to determine whether (1) the cells responsible for the formation of the stromal reaction in human pancreatic cancers are activated pancreatic stellate cells (PSCs) and (2) an interaction exists between pancreatic cancer cells and PSCs that may facilitate local and distant invasion of tumor. Serial sections of human pancreatic cancer tissue were stained for desmin and glial fibrillary acidic protein (stellate cell selective markers) and alpha-smooth muscle actin (alphaSMA), a marker of activated PSC activation, by immunohistochemistry, and for collagen using Sirius Red. Correlation between the extent of positive staining for collagen and alphaSMA was assessed by morphometry. The cellular source of collagen in stromal areas was identified using dual staining methodology, ie, immunostaining for alphaSMA and in situ hybridization for procollagen alpha1I mRNA. The possible interaction between pancreatic cancer cells and PSCs was assessed in vitro by exposing cultured rat PSCs to control medium or conditioned medium from 2 pancreatic cancer cell lines (PANC-1 and MiaPaCa-2) for 24 hours. PSC activation was assessed by cell proliferation and alphaSMA expression. Stromal areas of human pancreatic cancer stained strongly positive for the stellate cell selective markers desmin and GFAP (indicating the presence of PSCs), for alphaSMA (suggesting that the PSCs were in their activated state) and for collagen. Morphometric analysis demonstrated a close correlation (r = 0.77 P < 0.04 8 paired sections) between the extent of PSC activation and collagen deposition. Procollagen mRNA expression was localized to alphaSMA-positive cells in stromal areas indicating that activated PSCs were the predominant source of collagen in stromal areas. Exposure of PSCs to pancreatic cancer cell secretions in vitro resulted in PSC activation as indicated by significantly increased cell proliferation and alphaSMA expression. Activated PSCs are present in the stromal reaction in pancreatic cancers and are responsible for the production of stromal collagen. PSC function is influenced by pancreatic cancer cells. Interactions between tumor cells and stromal cells (PSCs) may play an important role in the pathobiology of pancreatic cancer.
Publisher: Elsevier BV
Date: 2002
DOI: 10.1080/00313020220131372
Abstract: Formative assessment with appropriate feedback is an effective method of promoting learning. Software tools are now available to facilitate the delivery of formative self-assessments via the World Wide Web. For the past 5 years, we have offered on-line formative self-assessments in pathology to undergraduate medical students. These assessments, which have been authored using Questionmark Perception, have proved particularly popular and have received high ratings in course evaluation surveys. Furthermore, they appear to have been effective in promoting student learning, with evidence that students made a genuine attempt to answer the questions in the assessment and that they learnt from doing so. The potential of on-line formative self-assessments for postgraduate training and continuing education in pathology so far remains untapped.
Publisher: Elsevier BV
Date: 09-2015
Publisher: Elsevier BV
Date: 2001
DOI: 10.1080/00313020120083197
Abstract: Human infection by Cryptococcus neoformans var. neoformans is well characterised and usually occurs in immunocompromised patients. Less is known about infection by Cryptococcus neoformans var. gattii, which usually produces disease in previously normal in iduals. In two cases of human pulmonary infection by Cryptococcus neoformans var. gattii, we observed a mixed inflammatory pattern, including granulomas associated with numerous T lymphocytes and a lymphocytic interstitial pneumonitis with B lymphocytes and formation of follicles. We also established a murine model of pulmonary infection by Cryptococcus neoformans var. gattii, which reproduced most of these features. This model is likely to prove useful in studies of the pathogenesis of this infection.
Publisher: Elsevier BV
Date: 09-2015
DOI: 10.1016/J.HUMPATH.2015.05.009
Abstract: To determine whether cytopathology whole slide images and virtual microscopy adaptive tutorials aid learning by postgraduate trainees, we designed a randomized crossover trial to evaluate the quantitative and qualitative impact of whole slide images and virtual microscopy adaptive tutorials compared with traditional glass slide and textbook methods of learning cytopathology. Forty-three anatomical pathology registrars were recruited from Australia, New Zealand, and Malaysia. Online assessments were used to determine efficacy, whereas user experience and perceptions of efficiency were evaluated using online Likert scales and open-ended questions. Outcomes of online assessments indicated that, with respect to performance, learning with whole slide images and virtual microscopy adaptive tutorials was equivalent to using traditional methods. High-impact learning, efficiency, and equity of learning from virtual microscopy adaptive tutorials were strong themes identified in open-ended responses. Participants raised concern about the lack of z-axis capability in the cytopathology whole slide images, suggesting that delivery of z-stacked whole slide images online may be important for future educational development. In this trial, learning cytopathology with whole slide images and virtual microscopy adaptive tutorials was found to be as effective as and perceived as more efficient than learning from glass slides and textbooks. The use of whole slide images and virtual microscopy adaptive tutorials has the potential to provide equitable access to effective learning from teaching material of consistently high quality. It also has broader implications for continuing professional development and maintenance of competence and quality assurance in specialist practice.
Publisher: Wiley
Date: 10-2000
DOI: 10.1046/J.1365-2222.2000.00911.X
Abstract: Asthma is an acute-on-chronic inflammatory disease of the airways characterized by recruitment of eosinophils into the epithelial layer, chronic inflammation in the lamina propria, as well as variable accumulation of mast cells in the airway wall. The role of local production of allergen-specific immunoglobulins in triggering mast cell-mediated asthmatic inflammation is unknown. We used a chronic inhalational exposure model of asthma in ovalbumin-sensitized BALB/c mice to examine the phenotype of immunoglobulin-secreting cells and mast cells in the airway wall. In parallel, we assayed ovalbumin-specific IgG and total IgE in the plasma of these animals. In sensitized mice exposed to aerosolized ovalbumin for 6 weeks, aggregates of chronic inflammatory cells consisted of a majority of plasmacytoid cells, including numerous IgG-synthesizing cells, which were significantly increased in sensitized animals compared to controls. IgA-synthesizing cells were also present, but were not increased in the sensitized exposed mice. Immunoglobulins in the cytoplasm of the plasma cells were demonstrated to be antigen-specific. No IgM-or IgE-synthesizing cells were observed, although levels of total IgE in the plasma were significantly increased. There was no recruitment of mast cells of either the mucosal or the connective tissue phenotype into the lamina propria or the epithelium. In this experimental model of chronic asthma, the pattern of inflammation in the airway wall is consistent with development of a local IgG-mediated humoral immune response. However, there is no evidence of local production of IgE or recruitment of mast cells.
Publisher: Portland Press Ltd.
Date: 04-0003
DOI: 10.1042/CS20160939
Abstract: Airway epithelial cells (AEC) exhibit a pro-inflammatory phenotype in patients with allergic asthma. We examined the effect of an allergic cytokine environment on the response of AEC to rhinovirus (RV), the most common trigger of acute exacerbations of asthma. Calu-3 cells, a well-differentiated human AEC line, were cultured with or without the T-helper type 2 cytokines interleukin (IL)-4 and IL-13, then stimulated with a toll-like receptor (TLR) 3 agonist (poly I:C, dsRNA) or a TLR7 agonist (imiquimod), or infected with RV 16. Expression of pro-inflammatory and antiviral mediators, and of viral pattern-recognition molecules, was assessed using nCounter assays, quantitative real-time PCR (qRT-PCR) and protein immunoassays. Both dsRNA and imiquimod stimulated expression of mRNA for IL6 and IL8 whereas expression of several chemokines and antiviral response genes was induced only by dsRNA. Conversely, expression of other cytokines and growth factors was induced only by imiquimod. RV infection not only stimulated expression of the inflammation-related genes induced by dsRNA, but also of complement factor B and the novel pro-inflammatory cytokine IL-32. In the T helper type 2 (Th2) cytokine environment, several mediators exhibited significantly enhanced expression, whereas expression of interferons was either unchanged or enhanced. The allergic environment also increased expression of pattern-recognition receptors and of intercellular adhesion molecule 1, the cell surface receptor for RV. We conclude that Th2 cytokines promote increased production of pro-inflammatory mediators by AEC following infection with RV. Increased viral entry or enhanced signalling via pattern-recognition receptors could also contribute to the exaggerated inflammatory response to RV observed in allergic asthmatics.
No related organisations have been discovered for Rakesh Kumar.
Start Date: 07-2011
End Date: 12-2014
Amount: $285,000.00
Funder: Australian Research Council
View Funded ActivityStart Date: 07-2011
End Date: 12-2014
Amount: $148,000.00
Funder: Australian Research Council
View Funded Activity