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Search Results: 1 - 10 of 501183 matches for " Paul M O'Byrne "
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Functional genomics of the peripheral blood response to allergen inhalation challenge
Kam Sarah HY,Ruan Jian,Gauvreau Gail M,O'Byrne Paul M
Allergy, Asthma & Clinical Immunology , 2010, DOI: 10.1186/1710-1492-6-s3-p3
Abstract:
Bone marrow contribution to eosinophilic inflammation
Denburg, Judah A;Wood, Lorna;Gauvreau, Gail;Sehmi, Roma;Inman, Mark D;O'Byrne, Paul M;
Memórias do Instituto Oswaldo Cruz , 1997, DOI: 10.1590/S0074-02761997000800006
Abstract: allergen-induced bone marrow responses are observable in human allergic asthmatics, involving specific increases in eosinophil-basophil progenitors (eo/b-cfu), measured either by hemopoietic assays or by flow cytometric analyses of cd34-positive, il-3ra-positive, and/or il-5-responsive cell populations. the results are consistent with the upregulation of an il-5-sensitive population of progenitors in allergen-induced late phase asthmatic responses. studies in vitro on the phenotype of developing eosinophils and basophils suggest that the early acquisition of il-5ra, as well as the capacity to produce cytokines such as gm-csf and il-5, are features of the differentiation process. these observations are consistent with findings in animal models, indicating that allergen-induced increases in bone marrow progenitor formation depend on hemopoietic factor(s) released post-allergen. the possibility that there is constitutive marrow upregulation of eosinophilopoiesis in allergic airways disease is also an area for future investigation.
Roflumilast attenuates allergen-induced inflammation in mild asthmatic subjects
Gail M Gauvreau, Louis-Philippe Boulet, Christine Schmid-Wirlitsch, Johanne C?té, MyLinh Duong, Kieran J Killian, Joanne Milot, Francine Deschesnes, Tara Strinich, Richard M Watson, Dirk Bredenbr?ker, Paul M O'Byrne
Respiratory Research , 2011, DOI: 10.1186/1465-9921-12-140
Abstract: 25 subjects with mild allergic asthma were randomized to oral roflumilast 500 mcg or placebo, once daily for 14 days in a double-blind, placebo-controlled, crossover study. Allergen challenge was performed on Day 14, and FEV1 was measured until 7 h post challenge. Methacholine challenge was performed on Days 1 (pre-dose), 13 (24 h pre-allergen), and 15 (24 h post-allergen), and sputum induction was performed on Days 1, 13, 14 (7 h post-allergen), and 15.Roflumilast inhibited the allergen-induced late phase response compared to placebo; maximum % fall in FEV1 (p = 0.02) and the area under the curve (p = 0.01). Roflumilast had a more impressive effect inhibiting allergen-induced sputum eosinophils, neutrophils, and eosinophil cationic protein (ECP) at 7 h post-allergen (all p = 0.02), and sputum neutrophils (p = 0.04), ECP (p = 0.02), neutrophil elastase (p = 0.0001) and AHR (p = 0.004) at 24 h post-allergen.This study demonstrates a protective effect of roflumilast on allergen-induced airway inflammation. The observed attenuation of sputum eosinophils and neutrophils demonstrates the anti-inflammatory properties of PDE4 inhibition and supports the roles of both cell types in the development of late phase bronchoconstriction and AHR.ClinicalTrials.gov: NCT01365533Asthma is characterized by the presence of cough, wheeze, dyspnea, reversible airway obstruction and airway hyperresponsiveness. Eosinophils are cells recognized to be a key feature of allergic asthma [1], however patients with severe asthma have increases in both eosinophils and neutrophils in their sputum [2]. Furthermore, severe asthma exacerbations are associated with bronchial mucosal eosinophilia and neutrophilia, as well as upregulation of CXC chemoattractants and their receptors [3]. Although current asthma therapies such as corticosteroids are effective in inhibiting eosinophilic inflammation through Th2 suppression, they may enhance neutrophil accumulation into the airways and until now therapies th
Gene-Metabolite Expression in Blood Can Discriminate Allergen-Induced Isolated Early from Dual Asthmatic Responses
Amrit Singh, Masatsugu Yamamoto, Sarah H. Y. Kam, Jian Ruan, Gail M. Gauvreau, Paul M. O'Byrne, J. Mark FitzGerald, Robert Schellenberg, Louis-Philippe Boulet, Gabriella Wojewodka, Cynthia Kanagaratham, Juan B. De Sanctis, Danuta Radzioch, Scott J. Tebbutt
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0067907
Abstract: Some asthmatic individuals undergoing allergen inhalation challenge develop an isolated early response whereas others develop a dual response (early plus late response). In the present study we have used transcriptomics (microarrays) and metabolomics (mass spectrometry) of peripheral blood to identify molecular patterns that can discriminate allergen-induced isolated early from dual asthmatic responses. Peripheral blood was obtained prior to (pre-) and 2 hours post allergen inhalation challenge from 33 study participants. In an initial cohort of 14 participants, complete blood counts indicated significant differences in neutrophil and lymphocyte counts at pre-challenge between early and dual responders. At post-challenge, significant genes (ALOX15, FADS2 and LPCAT2) and metabolites (lysolipids) were enriched in lipid metabolism pathways. Enzymes encoding for these genes are involved in membrane biogenesis and metabolism of fatty acids into pro-inflammatory and anti-inflammatory mediators. Correlation analysis indicated a strong negative correlation between ALOX15, FADS2, and IL5RA expression with 2-arachidonoylglycerophosphocholine levels in dual responders. However, measuring arachidonic acid and docosahexaenoic acid levels in a validation cohort of 19 participants indicated that the free form of DHA (nmoles/μg of protein) was significantly (p = 0.03) different between early and dual responders after allergen challenge. Collectively these results may suggest an imbalance in lipid metabolism which dictates pro- (anti-) inflammatory and pro-resolving mechanisms. Future studies with larger sample sizes may reveal novel mechanisms and therapeutic targets of the late phase asthmatic response.
In Vivo-to-In Silico Iterations to Investigate Aeroallergen-Host Interactions
Alba Llop-Guevara, Marc Colangelo, Derek K. Chu, Cheryl Lynn Moore, Nicole A. Stieber, Tina D. Walker, Susanna Goncharova, Anthony J. Coyle, Lennart K. A. Lundblad, Paul M. O'Byrne, Miroslav Lovric, Manel Jordana
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0002426
Abstract: Background Allergic asthma is a complex process arising out of the interaction between the immune system and aeroallergens. Yet, the relationship between aeroallergen exposure, allergic sensitization and disease remains unclear. This knowledge is essential to gain further insight into the origin and evolution of allergic diseases. The objective of this research is to develop a computational view of the interaction between aeroallergens and the host by investigating the impact of dose and length of aeroallergen exposure on allergic sensitization and allergic disease outcomes, mainly airway inflammation and to a lesser extent lung dysfunction and airway remodeling. Methods and Principal Findings BALB/C mice were exposed intranasally to a range of concentrations of the most pervasive aeroallergen worldwide, house dust mite (HDM), for up to a quarter of their lifespan (20 weeks). Actual biological data delineating the kinetics, nature and extent of responses for local (airway inflammation) and systemic (HDM-specific immunoglobulins) events were obtained. Mathematical equations for each outcome were developed, evaluated, refined through several iterations involving in vivo experimentation, and validated. The models accurately predicted the original biological data and simulated an extensive array of previously unknown responses, eliciting two- and three-dimensional models. Our data demonstrate the non-linearity of the relationship between aeroallergen exposure and either allergic sensitization or airway inflammation, identify thresholds, behaviours and maximal responsiveness for each outcome, and examine inter-variable relationships. Conclusions This research provides a novel way to visualize allergic responses in vivo and establishes a basic experimental platform upon which additional variables and perturbations can be incorporated into the system.
Overall asthma control achieved with budesonide/formoterol maintenance and reliever therapy for patients on different treatment steps
Eric D Bateman, Tim W Harrison, Santiago Quirce, Helen K Reddel, Roland Buhl, Marc Humbert, Christine R Jenkins, Stefan Peterson, Ollie ?stlund, Paul M O'Byrne, Malcolm R Sears, G?ran S Eriksson
Respiratory Research , 2011, DOI: 10.1186/1465-9921-12-38
Abstract: This is a post hoc analysis of the results of five large clinical trials (>12000 patients) comparing BUD/FORM maintenance and reliever therapy with other treatments categorised by treatment step at study entry. Both current clinical asthma control during the last week of treatment and exacerbations during the study were examined.At each GINA treatment step, the proportion of patients achieving target levels of current clinical control were similar or higher with BUD/FORM maintenance and reliever therapy compared with the same or a higher fixed maintenance dose of inhaled corticosteroid/long-acting β2-agonist (ICS/LABA) (plus short-acting β2-agonist [SABA] as reliever), and rates of exacerbations were lower at all treatment steps in BUD/FORM maintenance and reliever therapy versus same maintenance dose ICS/LABA (P < 0.01) and at treatment Step 4 versus higher maintenance dose ICS/LABA (P < 0.001). BUD/FORM maintenance and reliever therapy also achieved significantly higher rates of current clinical control and significantly lower exacerbation rates at most treatment steps compared with a higher maintenance dose ICS + SABA (Steps 2-4 for control and Steps 3 and 4 for exacerbations). With all treatments, the proportion of patients achieving current clinical control was lower with increasing treatment steps.BUD/FORM maintenance and reliever therapy may be a preferable option for patients on Steps 2 to 4 of asthma guidelines requiring a more effective treatment and, compared with other fixed dose alternatives, is most effective in the higher treatment steps.A major objective of the 2006 revision of the Global Initiative for Asthma (GINA) guidelines [1] was to simplify the process of assessing patients' treatment needs at both initial and follow-up visits. Instead of assessing "asthma severity" using severity classification tables, a simplified assessment of current asthma control is recommended and treatment is either initiated or altered according to the assessed contro
The MyD88+ Phenotype Is an Adverse Prognostic Factor in Epithelial Ovarian Cancer
Charles J. d'Adhemar, Cathy D. Spillane, Michael F. Gallagher, Mark Bates, Katie M. Costello, Jacqui Barry-O'Crowley, Kathryn Haley, Niamh Kernan, Ciara Murphy, Paul C. Smyth, Ken O'Byrne, Stephen Pennington, Aoife A. Cooke, Brendan Ffrench, Cara M. Martin, Dearbhaile O'Donnell, Bryan Hennessy, Britta Stordal, Stephen Finn, Amanda McCann, Noreen Gleeson, Tom D'Arcy, Brian Flood, Luke A. J. O'Neill, Orla Sheils, Sharon O'Toole, John J. O'Leary
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0100816
Abstract: The prognosis of epithelial ovarian cancer is poor in part due to the high frequency of chemoresistance. Recent evidence points to the Toll-like receptor-4 (TLR4), and particularly its adaptor protein MyD88, as one potential mediator of this resistance. This study aims to provide further evidence that MyD88 positive cancer cells are clinically significant, stem-like and reproducibly detectable for the purposes of prognostic stratification. Expression of TLR4 and MyD88 was assessed immunohistochemically in 198 paraffin-embedded ovarian tissues and in an embryonal carcinoma model of cancer stemness. In parallel, expression of TLR4 and MyD88 mRNA and regulatory microRNAs (miR-21 and miR-146a) was assessed, as well as in a series of chemosensitive and resistant cancer cells lines. Functional analysis of the pathway was assessed in chemoresistant SKOV-3 ovarian cancer cells. TLR4 and MyD88 expression can be reproducibly assessed via immunohistochemistry using a semi-quantitative scoring system. TLR4 expression was present in all ovarian epithelium (normal and neoplastic), whereas MyD88 was restricted to neoplastic cells, independent of tumour grade and associated with reduced progression-free and overall survival, in an immunohistological specific subset of serous carcinomas, p<0.05. MiR-21 and miR-146a expression was significantly increased in MyD88 negative cancers (p<0.05), indicating their participation in regulation. Significant alterations in MyD88 mRNA expression were observed between chemosensitive and chemoresistant cells and tissue. Knockdown of TLR4 in SKOV-3 ovarian cells recovered chemosensitivity. Knockdown of MyD88 alone did not. MyD88 expression was down-regulated in differentiated embryonal carcinoma (NTera2) cells, supporting the MyD88+ cancer stem cell hypothesis. Our findings demonstrate that expression of MyD88 is associated with significantly reduced patient survival and altered microRNA levels and suggest an intact/functioning TLR4/MyD88 pathway is required for acquisition of the chemoresistant phenotype. Ex vivo manipulation of ovarian cancer stem cell (CSC) differentiation can decrease MyD88 expression, providing a potentially valuable CSC model for ovarian cancer.
A GM-CSF/IL-33 Pathway Facilitates Allergic Airway Responses to Sub-Threshold House Dust Mite Exposure
Alba Llop-Guevara, Derek K. Chu, Tina D. Walker, Susanna Goncharova, Ramzi Fattouh, Jonathan S. Silver, Cheryl Lynn Moore, Juliana L. Xie, Paul M. OByrne, Anthony J. Coyle, Roland Kolbeck, Alison A. Humbles, Martin R. St?mpfli, Manel Jordana
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0088714
Abstract: Allergic asthma is a chronic immune-inflammatory disease of the airways. Despite aeroallergen exposure being universal, allergic asthma affects only a fraction of individuals. This is likely related, at least in part, to the extent of allergen exposure. Regarding house dust mite (HDM), we previously identified the threshold required to elicit allergic responses in BALB/c mice. Here, we investigated the impact of an initial immune perturbation on the response to sub-threshold HDM exposure. We show that transient GM-CSF expression in the lung facilitated robust eosinophilic inflammation, long-lasting antigen-specific Th2 responses, mucus production and airway hyperresponsiveness. This was associated with increased IL-33 levels and activated CD11b+ DCs expressing OX40L. GM-CSF-driven allergic responses were significantly blunted in IL-33-deficient mice. IL-33 was localized on alveolar type II cells and in vitro stimulation of human epithelial cells with GM-CSF enhanced intracellular IL-33 independently of IL-1α. Likewise, GM-CSF administration in vivo resulted in increased levels of IL-33 but not IL-1α. These findings suggest that exposures to environmental agents associated with GM-CSF production, including airway infections and pollutants, may decrease the threshold of allergen responsiveness and, hence, increase the susceptibility to develop allergic asthma through a GM-CSF/IL-33/OX40L pathway.
The Need for Guidelines in Asplenic Patients Undergoing Total Joint Arthroplasty: A Case Report
S. R. Shaarani,D. Collins,J. M. O'Byrne
Case Reports in Orthopedics , 2012, DOI: 10.1155/2012/147042
Abstract: There are currently no guidelines for splenectomy patient undergoing total joint arthroplasty. We present a case history of a 63-year-old man with a history of splenectomy that underwent a total knee arthroplasty with standard intravenous antibiotic prophylaxis. Two weeks postoperatively, he developed a prosthetic joint infection and followed the standard antimicrobial management with intravenous and oral antibiotics prior to having revision surgery. We propose that there are guidelines to properly manage these patients in the pre- and perioperative setting following an orthopaedic procedure.
The Need for Guidelines in Asplenic Patients Undergoing Total Joint Arthroplasty: A Case Report
S. R. Shaarani,D. Collins,J. M. O'Byrne
Case Reports in Orthopedics , 2012, DOI: 10.1155/2012/147042
Abstract: There are currently no guidelines for splenectomy patient undergoing total joint arthroplasty. We present a case history of a 63-year-old man with a history of splenectomy that underwent a total knee arthroplasty with standard intravenous antibiotic prophylaxis. Two weeks postoperatively, he developed a prosthetic joint infection and followed the standard antimicrobial management with intravenous and oral antibiotics prior to having revision surgery. We propose that there are guidelines to properly manage these patients in the pre- and perioperative setting following an orthopaedic procedure. 1. Introduction Total joint arthroplasty is currently a procedure on the rise in Europe. The rate of the number of surgeries performed on the continent from 1998 until 2008 per 100,000 population has increased from 127 to 168 in total hip arthroplasties (THA) and from 57 to 157 in total knee arthroplasties (TKA). This is a rise by approximately 16% in THA and 50% in TKA over the ten-year period [1]. The presence of medical comorbidities such as coronary artery disease, pulmonary disease, obesity, and diabetes has increased the risk of perioperative and late complications [2]. This is further confounded with additional risks of immunocompromised patients and those susceptible to systemic infection [3]. The British Association for Haematology has updated their guidelines in 2011 for the prevention and management of infection in asplenic and hyposplenic patients [4]. Patients with anatomical or functional asplenia have a significantly increased lifelong risk for infections involving encapsulated bacteria such as Streptococcus pneumonia and Haemophilus influenzae type [5]. The current evidence supports patient education, up-to-date vaccinations, and the continued use of penicillin prophylaxis up to the age of 16 years old and those over 50 years old. However, the consensus for prophylactic antibiotics and preventive measures remains a void in most surgical settings including dental procedures. In the orthopaedic surgical setting, there is a greater need for guidelines in the pre- and perioperative management of asplenic patients. We present a case of a 63-year-old male with a history of splenectomy secondary to trauma and type 2 diabetes mellitus who developed a prosthetic joint infection (PJI) two weeks after the primary TKA. To our knowledge, this is the first reported case of periprosthetic joint infection in a patient with both a history of splenectomy and type II diabetes. 2. Case History A 63-year-old male presented to the outpatient with ongoing persistent pain
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