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1.  Quality of asthma care under different primary care models in Canada: a population-based study 
BMC Family Practice  2015;16:19.
Background
Previous research has shown variations in quality of care and patient outcomes under different primary care models. The objective of this study was to use previously validated, evidence-based performance indicators to measure quality of asthma care over time and to compare quality of care between different primary care models.
Methods
Data were obtained for years 2006 to 2010 from the Ontario Asthma Surveillance Information System, which uses health administrative databases to track individuals with asthma living in the province of Ontario, Canada. Individuals with asthma (n=1,813,922) were divided into groups based on the practice model of their primary care provider (i.e., fee-for-service, blended fee-for-service, blended capitation). Quality of asthma care was measured using six validated, evidence-based asthma care performance indicators.
Results
All of the asthma performance indicators improved over time within each of the primary care models. Compared to the traditional fee-for-service model, the blended fee-for-service and blended capitation models had higher use of spirometry for asthma diagnosis and monitoring, higher rates of inhaled corticosteroid prescription, and lower outpatient claims. Emergency department visits were lowest in the blended fee-for-service group.
Conclusions
Quality of asthma care improved over time within each of the primary care models. However, the amount by which they improved differed between the models. The newer primary care models (i.e., blended fee-for-service, blended capitation) appear to provide better quality of asthma care compared to the traditional fee-for-service model.
Electronic supplementary material
The online version of this article (doi:10.1186/s12875-015-0232-y) contains supplementary material, which is available to authorized users.
doi:10.1186/s12875-015-0232-y
PMCID: PMC4336688
Asthma; Quality of care; Performance measures; Health indicators; Health services use
2.  Long-acting muscarinic antagonist use in adults with asthma: real-life prescribing and outcomes of add-on therapy with tiotropium bromide 
Background
Randomized controlled trials indicate that addition of a long-acting muscarinic antagonist (LAMA) such as tiotropium may improve asthma control and reduce exacerbation risk in patients with poorly controlled asthma, but broader clinical studies are needed to investigate the effectiveness of LAMA in real-life asthma care.
Methods
Medical records of adults with asthma (aged ≥18 years) prescribed tiotropium were obtained from the UK Optimum Patient Care Research Database for the period 2001–2013. Patients diagnosed with chronic obstructive pulmonary disease were excluded, but no other clinical exclusions were applied. Two primary outcomes were compared in the year before (baseline) and the year after (outcome) addition of tiotropium: exacerbations (asthma-related hospital emergency department attendance or inpatient admission, or acute oral corticosteroid course) and acute respiratory events (exacerbation or antibiotic prescription with lower respiratory consultation). Secondary outcomes included lung function test results and short-acting β2 agonist usage. The Wilcoxon signed-rank test was used for variables measured on the interval scale, the marginal homogeneity test for categorized variables, and the paired t-test for lung function indices.
Results
Of the 2,042 study patients, 83% were prescribed an inhaled corticosteroid and 68% a long-acting β2 agonist during the baseline year; 67% were prescribed both. Comparing baseline and outcome years, the percentage of patients having at least one exacerbation decreased from 37% to 27% (P<0.001) and the percentage having at least one acute respiratory event decreased from 58% to 47% (P<0.001). There were no significant changes in lung function, and usage of short-acting β2 agonists (in salbutamol/albuterol equivalents) increased from a median (interquartile range) of 274 (110, 548) to 329 (110, 603) μg/day (P=0.01).
Conclusion
In this real-life asthma population, addition of LAMA therapy was associated with significant decreases in the incidence of exacerbations and antibiotic prescriptions for lower respiratory tract infections in the following year.
doi:10.2147/JAA.S76639
PMCID: PMC4298307  PMID: 25609985
anticholinergic; bronchodilator; exacerbation; asthma control; oral corticosteroids
3.  Patterns of Care in Testicular Torsion: Influence of Hospital Transfer on Testicular Outcomes 
Journal of pediatric urology  2013;9(6 0 0):713-720.
Objective
To investigate patterns of care for testicular torsion and influence of hospital transfers on testicular outcomes. Hospital transfer may be a source of treatment delay in a condition where delays increase likelihood of orchiectomy.
Methods
We used a retrospective cohort of Californian males with ICD-9/CPT-defined torsion from inpatient, emergency department (ED), and ambulatory surgery center (ASC) data. Logistic regression assessed predictors of orchiectomy.
Results
Predictors of orchiectomy were ages <1 year (OR 19.2, 95% CI 6.3–58.9), 1–9 years (OR 2.7, 95% CI 1.4–5.2), and ≥40 years (OR 6.6, 95% CI 3.1–13.9) (vs. masked age). Treatment at mid-volume (vs. high-volume) facilities was associated with lower odds of orchiectomy (OR 0.5, 95% CI 0.3–0.7). Rural location, non-private insurance, and hospital transfer were associated with orchiectomy on univariate but not multivariate analysis.
During 2008–2010, 2,794 subjects experienced torsion (average incidence 5.08 per 100,000 males yearly). Encounters occurred in ASCs (55%), inpatient facilities (36%), and EDs (9%). 60% of subjects were privately insured, 2% experienced hospital transfer, and 31% underwent orchiectomy.
Conclusion
Our census found that most cases of testicular torsion were treated in outpatient settings. Hospital transfer was not associated with orchiectomy.
doi:10.1016/j.jpurol.2013.06.003
PMCID: PMC3999916  PMID: 23896260
4.  Caspase-3 Mediates the Pathogenic Effect of Yersinia pestis YopM in Liver of C57BL/6 Mice and Contributes to YopM's Function in Spleen 
PLoS ONE  2014;9(11):e110956.
The virulence protein YopM of the plague bacterium Yersinia pestis has different dominant effects in liver and spleen. Previous studies focused on spleen, where YopM inhibits accumulation of inflammatory dendritic cells. In the present study we focused on liver, where PMN function may be directly undermined by YopM without changes in inflammatory cell numbers in the initial days of infection, and foci of inflammation are easily identified. Mice were infected with parent and ΔyopM-1 Y. pestis KIM5, and effects of YopM were assessed by immunohistochemistry and determinations of bacterial viable numbers in organs. The bacteria were found associated with myeloid cells in foci of inflammation and in liver sinusoids. A new in-vivo phenotype of YopM was revealed: death of inflammatory cells, evidenced by TUNEL staining beginning at d 1 of infection. Based on distributions of Ly6G+, F4/80+, and iNOS+ cells within foci, the cells that were killed could have included both PMNs and macrophages. By 2 d post-infection, YopM had no effect on distribution of these cells, but by 3 d cellular decomposition had outstripped acute inflammation in foci due to parent Y. pestis, while foci due to the ΔyopM-1 strain still contained many inflammatory cells. The destruction depended on the presence of both PMNs in the mice and YopM in the bacteria. In mice that lacked the apoptosis mediator caspase-3 the infection dynamics were novel: the parent Y. pestis was limited in growth comparably to the ΔyopM-1 strain in liver, and in spleen a partial growth limitation for parent Y. pestis was seen. This result identified caspase-3 as a co-factor or effector in YopM's action and supports the hypothesis that in liver YopM's main pathogenic effect is mediated by caspase-3 to cause apoptosis of PMNs.
doi:10.1371/journal.pone.0110956
PMCID: PMC4220956  PMID: 25372388
5.  Canadian guidelines for acute bacterial rhinosinusitis 
Canadian Family Physician  2014;60(3):227-234.
Objective
To provide a clinical summary of the Canadian clinical practice guidelines for acute bacterial rhinosinusitis (ABRS) that includes relevant considerations for family physicians.
Quality of evidence
Guideline authors performed a systematic literature search and drafted recommendations. Recommendations received both strength of evidence and strength of recommendation ratings. Input from external content experts was sought, as was endorsement from Canadian medical societies (Association of Medical Microbiology and Infectious Disease Canada, Canadian Society of Allergy and Clinical Immunology, Canadian Society of Otolaryngology—Head and Neck Surgery, Canadian Association of Emergency Physicians, and the Family Physicians Airways Group of Canada).
Main message
Diagnosis of ABRS is based on the presence of specific symptoms and their duration; imaging or culture are not needed in uncomplicated cases. Treatment is dependent on symptom severity, with intranasal corticosteroids (INCSs) recommended as monotherapy for mild and moderate cases, although the benefit might be modest. Use of INCSs plus antibiotics is reserved for patients who fail to respond to INCSs after 72 hours, and for initial treatment of patients with severe symptoms. Antibiotic selection must account for the suspected pathogen, the risk of resistance, comorbid conditions, and local antimicrobial resistance trends. Adjunct therapies such as nasal saline irrigation are recommended. Failure to respond to treatment, recurrent episodes, and signs of complications should prompt referral to an otolaryngologist. The guidelines address situations unique to the Canadian health care environment, including actions to take during prolonged wait periods for specialist referral or imaging.
Conclusion
The Canadian guidelines provide up-to-date recommendations for diagnosis and treatment of ABRS that reflect an evolving understanding of the disease. In addition, the guidelines offer useful tools to help clinicians discern viral from bacterial episodes, as well as optimally manage their patients with ABRS.
PMCID: PMC3952756  PMID: 24627376
6.  Lignes directrices canadiennes sur la rhinosinusite bactérienne aiguë 
Canadian Family Physician  2014;60(3):e149-e156.
Résumé
Objectif
Faire un résumé clinique des lignes directrices canadiennes sur la rhinosinusite bactérienne aiguë (RSBA) qui présente des éléments d’intérêt pour les médecins de famille.
Source des données
Les auteurs des lignes directrices ont effectué une recherche documentaire systématique et ont rédigé des recommandations. Une cote a été donnée à la fois en fonction de la fiabilité des données probantes et de la solidité des recommandations. On a sollicité les commentaires d’experts en la matière venant de l’extérieur, ainsi que l’aval de sociétés médicales canadiennes (Association pour la microbiologie médicale et l’infectiologie Canada, Société canadienne d’allergie et d’immunologie clinique, Société canadienne d’otorhinolaryngologie et de chirurgie cervicofaciale, Association canadienne des médecins d’urgence et Regroupement canadien des médecins de famille en santé respiratoire).
Message principal
Le diagnostic de la RSBA repose sur la présence de symptômes particuliers et leur durée; l’imagerie ou une culture n’est pas nécessaire dans les cas peu compliqués. Le traitement dépend de la gravité des symptômes, notamment avec des corticostéroïdes intranasaux (CSIN) recommandés comme monothérapie pour les cas de légers à modérés, quoique leurs bienfaits soient modestes. Le recours à des CSIN accompagnés d’antibiotiques est réservé aux patients qui ne répondent pas aux CSIN après 72 heures et comme traitement initial des patients dont les symptômes sont graves. Le choix de l’antibiotique doit tenir compte du pathogène soupçonné, du risque de résistance, des problèmes concomitants et des tendances locales de la résistance aux antimicrobiens. Des thérapies d’appoint comme l’irrigation nasale avec une solution saline sont recommandées. En présence de cas réfractaires au traitement, d’épisodes récurrents et de signes de complications, on devrait demander une consultation en otorhinolaryngologie. Les lignes directrices portent sur les situations particulières à l’environnement canadien des soins de santé, y compris les actions à prendre durant les périodes d’attente prolongées pour avoir une consultation avec un spécialiste ou une imagerie.
Conclusion
Les lignes directrices canadiennes offrent des recommandations à jour pour le diagnostic et le traitement de la RSBA qui tiennent compte de la compréhension en évolution de la maladie. De plus, les lignes directrices présentent des outils utiles pour aider les cliniciens à cerner les épisodes viraux par opposition à ceux d’origine bactérienne, ainsi qu’à prendre en charge de manière optimale leurs patients atteints de RSBA.
PMCID: PMC3952776
7.  Canadian guidelines for chronic rhinosinusitis 
Canadian Family Physician  2013;59(12):1275-1281.
Abstract
Objective
To provide a clinical summary of the Canadian clinical practice guidelines for chronic rhinosinusitis (CRS) that includes recommendations relevant for family physicians.
Quality of evidence
Guideline authors performed a systematic literature search and drafted recommendations. Recommendations received both strength of evidence and strength of recommendation ratings. Input from external content experts was sought, as was endorsement from Canadian medical societies (Association of Medical Microbiology and Infectious Disease Canada, Canadian Society of Allergy and Clinical Immunology, Canadian Society of Otolaryngology—Head and Neck Surgery, Canadian Association of Emergency Physicians, and Family Physicians Airways Group of Canada).
Main message
Diagnosis of CRS is based on type and duration of symptoms and an objective finding of inflammation of the nasal mucosa or paranasal sinuses. Chronic rhinosinusitis is categorized based on presence or absence of nasal polyps, and this distinction leads to differences in treatment. Chronic rhinosinusitis with nasal polyps is treated with intranasal corticosteroids. Antibiotics are recommended when symptoms indicate infection (pain or purulence). For CRS without nasal polyps, intranasal corticosteroids and second-line antibiotics (ie, amoxicillin– clavulanic acid combinations or fluoroquinolones with enhanced Gram-positive activity) are recommended. Saline irrigation, oral steroids, and allergy testing might be appropriate. Failure of response should prompt consideration of alternative diagnoses and referral to an otolaryngologist. Patients undergoing endoscopic sinus surgery require postoperative treatment and follow-up.
Conclusion
The Canadian guidelines provide diagnosis and treatment approaches based on the current understanding of the disease and available evidence. Additionally, the guidelines provide the expert opinion of a diverse group of practice and academic experts to help guide clinicians where evidence is sparse.
PMCID: PMC3860922  PMID: 24336538
8.  Lignes directrices canadiennes sur la rhinosinusite chronique 
Canadian Family Physician  2013;59(12):e528-e534.
Résumé
Objectif
Présenter un résumé clinique des lignes directrices canadiennes sur la rhinosinusite chronique (RSC) qui comporte des recommandations pertinentes aux médecins de famille.
Qualité des données
Les auteurs des lignes directrices ont effectué une recherche documentaire systématique dans la littérature médicale et ont rédigé une ébauche de recommandations. Une cote a été donnée à la fois en fonction de la fiabilité des données probantes et de la solidité des recommandations. On a sollicité les commentaires d’experts en contenu de l’extérieur, ainsi que l’aval des sociétés médicales (Association pour la microbiologie médicale et l’infectiologie Canada, Société canadienne d’allergie et d’immunologie clinique, Canadian Society of Otolaryngology—Head and Neck Surgery, Association canadienne des médecins d’urgence et Regroupement canadien des médecins de famille en santé respiratoire).
Message principal
Le diagnostic d’une RSC se fonde sur le type et la durée des symptômes et une constatation objective d’une inflammation de la muqueuse nasale ou des sinus paranasaux. La rhinosinusite chronique est catégorisée en fonction de la présence ou de l’absence de polypes nasaux et cette distinction entraîne des différences dans le traitement. On traite la rhinosinusite chronique avec polypes nasaux au moyen de corticostéroïdes par voie intranasale. Des antibiotiques sont recommandés quand les symptômes indiquent une infection (douleur ou purulence). Pour une RSC sans polypes nasaux, on recommande des corticostéroïdes par voie intranasale et des antibiotiques de deuxième ligne (par ex. combinaisons amoxicilline–acide clavulanique ou fluoroquinolones à activité accrue contre Gram positif). Une irrigation avec une solution saline, des stéroïdes par voie orale et des tests d’allergies pourraient être appropriées. Si le patient ne répond pas au traitement, il faudrait envisager d’autres diagnostics et une demande de consultation en otorhinolaryngologie. Les patients qui subissent une chirurgie endoscopique des sinus ont besoin d’un traitement postopératoire et d’un suivi.
Conclusion
Les lignes directrices canadiennes présentent des approches au diagnostic et au traitement en se fondant sur ce qu’on comprend actuellement de la maladie et les données probantes disponibles. De plus, les lignes directrices fournissent les opinions d’experts de divers groupes de pratique et de spécialistes scientifiques pour aider à orienter les cliniciens lorsque les données probantes sont rares.
PMCID: PMC3860941
9.  Chronic obstructive pulmonary disease and exacerbations: Patient insights from the global Hidden Depths of COPD survey 
Background
Although chronic obstructive pulmonary disease (COPD) is a major global health burden there is a lack of patient awareness of disease severity, particularly in relation to exacerbations.
Methods
We conducted a global patient survey using an innovative, internet-based methodology to gain insight into patient perceptions of COPD and exacerbations in a real-world sample typical of today’s working-age COPD population.
Results
Two thousand patients with COPD (53%), chronic bronchitis (52%) and/or emphysema (22%) from 14 countries completed an online questionnaire developed by the authors. The Medical Research Council (MRC) breathlessness scale was used to delineate symptom severity. Over three quarters of patients (77%) had experienced an exacerbation, with 27% of MRC 1 and 2 patients and 52% of MRC 3, 4 and 5 patients requiring hospitalization as a result of an exacerbation. While a majority of MRC 1 and 2 patients (51%) reported being back to normal within a few days of an exacerbation, 23% of MRC 3, 4 and 5 patients took several weeks to return to normal and 6% never fully recovered. A high proportion of patients (39%) took a ‘wait and see’ approach to exacerbations.
Despite the high prevalence of exacerbations and their negative impact on quality of life, 73% of MRC 1 and 2 patients and 64% of MRC 3, 4 and 5 patients felt that they had control of their COPD. However, 77% of all patients were worried about their long-term health, and 38% of MRC 1 and 2 patients and 59% of MRC 3, 4 and 5 patients feared premature death due to COPD.
Conclusions
To reduce the adverse effects of COPD on patients’ quality of life and address their fears for the future, we need better patient education and improved prevention and treatment of exacerbations.
doi:10.1186/1471-2466-13-54
PMCID: PMC3765923  PMID: 23971625
COPD; Exacerbation; Patient-reported; Survey
10.  Assessment of COPD wellness tools for use in primary care: an IPCRG initiative 
COPD is considered a complex disease and global problem that is predicted to be the third most common cause of death by 2030. While managing this chronic condition, primary health care practitioners are faced with the ongoing challenge of achieving good quality of life and overall “wellness” for those affected. As such, a practical tool for monitoring quality of life in a clinical setting is required. However, due to the wide variety of general and disease-specific tools from which to choose, primary health care practitioners are given minimal guidance as to which tool may be most appropriate. To address these challenges, the International Primary Care Respiratory Group (IPCRG) proposed the creation of a user’s guide for primary health care practitioners to assess “wellness” in COPD patients in an everyday clinical setting. This short report outlines the process by which the IPCRG Users’ Guide to COPD “Wellness” Tools was developed. It also describes why this guide has the potential to be of great value in guiding primary health care practitioners to improve patient wellness.
doi:10.2147/COPD.S29868
PMCID: PMC3422123  PMID: 22927752
wellness; quality of life; primary care; instrument
11.  Effectiveness of Same Versus Mixed Asthma Inhaler Devices: A Retrospective Observational Study in Primary Care 
Purpose
Correct use of inhaler devices is fundamental to effective asthma management but represents an important challenge for patients. The correct inhalation manoeuvre differs markedly for different inhaler types. The objective of this study was to compare outcomes for patients prescribed the same inhaler device versus mixed device types for asthma controller and reliever therapy.
Methods
This retrospective observational study identified patients with asthma (ages 4-80 years) in a large primary care database who were prescribed an inhaled corticosteroid (ICS) for the first time. We compared outcomes for patients prescribed the same breath-actuated inhaler (BAI) for ICS controller and salbutamol reliever versus mixed devices (BAI for controller and pressurised metered-dose inhaler [pMDI] for reliever). The 2-year study included 1 baseline year before the ICS prescription (to identify and correct for confounding factors) and 1 outcome year. Endpoints were asthma control (defined as no hospital attendance for asthma, oral corticosteroids, or antibiotics for lower respiratory tract infection) and severe exacerbations (hospitalisation or oral corticosteroids for asthma).
Results
Patients prescribed the same device (n=3,428) were significantly more likely to achieve asthma control (adjusted odds ratio, 1.15; 95% confidence interval [CI], 1.02-1.28) and recorded significantly lower severe exacerbation rates (adjusted rate ratio, 0.79; 95% CI, 0.68-0.93) than those prescribed mixed devices (n=5,452).
Conclusions
These findings suggest that, when possible, the same device should be prescribed for both ICS and reliever therapy when patients are initiating ICS.
doi:10.4168/aair.2012.4.4.184
PMCID: PMC3378924  PMID: 22754711
Asthma; breath-actuated inhaler; inhaled corticosteroids; inhaler device; pressurised metered-dose inhaler; short-acting β2-agonist
12.  A gut feeling about murine syngeneic GVHD 
Chimerism  2011;2(2):58-60.
Murine syngeneic graft-versus-host disease (SGVHD) results in chronic colon and liver inflammation following syngeneic bone marrow transplantation (BMT) and treatment with the calcineurin inhibitor, cyclosporine A (CsA). SGVHD was initially thought to arise as a result of an autoreactive immune response, but more recently it has been shown that enhanced antimicrobial responses develop in SGVHD mice. Consequently, we performed studies to analyze the role of the microbiota in the development of murine SGVHD. Treatment with broad-spectrum antibiotics eliminated disease-associated inflammatory immune responses and pathology, linking the role of the microbiota and microbial-specific immunity to the development of murine SGVHD. In a broader context, these results bring into question the role that anti-microbial immune responses play in post-transplant immune pathologies that develop following allogeneic stem cell transplantation and use of calcineurin inhibitors.
doi:10.4161/chim.2.2.16783
PMCID: PMC3166486  PMID: 21912721
bone marrow transplantation; cyclosporine A; syngeneic graft-versus-host disease; microbiota; broad-spectrum antibiotic therapy
13.  Toward a molecular pathogenic pathway for Yersinia pestis YopM 
YopM is one of the six “effector Yops” of the human-pathogenic Yersinia, but its mechanism has not been defined. After delivery to J774A.1 monocyte-like cells, YopM can rapidly bind and activate the serine/threonine kinases RSK1 and PRK2. However, in infected mice, effects of Y. pestis YopM have been seen only after 24–48 h post-infection (p.i.). To identify potential direct effects of YopM in-vivo we tested for effects of YopM at 1 h and 16–18 h p.i. in mice infected systemically with 106 bacteria. At 16 h p.i., there was a robust host response to both parent and ΔyopM-1 Y. pestis KIM5. Compared to cells from non-infected mice, CD11b+ cells from spleens of infected mice produced more than 100-fold greater IFNγ. In the corresponding sera there were more than 100-fold greater amounts of IFNγ, G-CSF, and CXCL9, as well as more than 10-fold greater amounts of IL-6, CXCL10, and CXCL1. The only YopM-related differences were slightly lower CXCL10 and IL-6 in sera from mice infected 16 h with parent compared to ΔyopM-1 Y. pestis. Microarray analysis of the CD11b+ cells did not identify consistent transcriptional differences of ≥4-fold at 18 h p.i. However, at 1 h p.i. mRNA for early growth response transcription factor 1 (Egr1) was decreased when YopM was present. Bone marrow-derived macrophages infected for 1 h also expressed lower Egr1 message when YopM was present. Infected J774A.1 cells showed greater expression of Egr1 at 1 h p.i. when YopM was present, but this pattern reversed at 3 h. At 6 h p.i., Cxcl10 mRNA was lower in parent-strain infected cells. We conclude that decreased Egr1 expression is a very early transcriptional effect of YopM and speculate that a pathway may exist from RSK1 through Egr1. These studies revealed novel early transcriptional effects of YopM but point to a time after 18 h of infection when critical transitional events lead to later major effects on cytokine gene transcription.
doi:10.3389/fcimb.2012.00155
PMCID: PMC3518861  PMID: 23248776
YopM; plague; Yersinia; chemokine; microarray
14.  Development of a TH17 immune response during the induction of murine syngeneic graft-versus-host disease 
Cytokine  2010;52(3):265-273.
Syngeneic graft-versus-host disease (SGVHD) develops following lethal irradiation, reconstitution with syngeneic bone marrow (BM) and treatment with a 21 day course of the immunosuppressive agent cyclosporine A (CsA). Clinical symptoms of SGVHD appear 2-3 weeks post CsA with inflammation occurring in the colon and liver. Previously we have demonstrated that CD4+ T cells and a T helper cell type 1 cytokine response (TH1) are involved in the development of SGVHD associated intestinal inflammation. Studies have recently discovered an additional T cell lineage that produces IL-17 and is termed TH17. It has been suggested that inflammatory bowel disease is a result of a TH17 response rather than a TH1 response. This study was designed to investigate TH17 involvement in SGVHD-associated colitis. Following induction of SGVHD, the levels of TH17 and TH1 cytokine mRNA and protein were measured in control and SGVHD animals. In vivo cytokine neutralization was performed to determine the role of the prototypic TH17 cytokine, IL-17, in the disease process. We found that during CsA-induced murine SGVHD there was an increase in both TH17 and TH1 mRNA and cytokines within the colons of diseased mice. The administration of an anti-mouse IL-17A mAb did not alter the course of disease. However, neutralization of IL-17A resulted in an increased production of IL-17F, a related family member, with an overlapping range of effector activities. These results demonstrate that in the pathophysiology of SGVHD, there is a redundancy in the TH17 effector molecules that mediate the development of SGVHD.
doi:10.1016/j.cyto.2010.08.006
PMCID: PMC2975790  PMID: 20833063
IL-17; CD4+ T cells; transplantation; cyclosporine A; mucosal inflammation
15.  Evidence of Mobilization of Pluripotent Stem Cells into Peripheral Blood of Patients with Myocardial Ischemia 
Experimental hematology  2010;38(12):1131-1142.e1.
Objective
The ischemic myocardium releases multiple chemotactic factors responsible for the mobilization and recruitment of bone marrow-derived cells to injured myocardium. However, the mobilization of primitive pluripotent stem cells (PSCs) enriched in Very Small Embryonic-Like stem cells (VSELs) in various cardiac ischemic scenarios is not well understood.
Methods
Fifty four ischemic heart disease patients, including subjects with stable angina, non-ST elevation (NSTME) myocardial infarction (MI) and ST elevation myocardial infarction (STEMI), and twelve matched controls were enrolled. The absolute numbers of circulating stem/primitive cells in samples of peripheral blood (PB) were quantitated by Image Stream Analysis and conventional flow cytometry. Gene expression of PSC (Oct-4 and Nanog), early cardiomyocyte (Nkx-2.5 and GATA-4), and endothelial (vWF) markers was analyzed by real-time PCR.
Results
The absolute numbers of PSCs, stem cell populations enriched in VSELs and hematopoietic stem cells (HSCs) present in PB were significantly higher in STEMI patients at presentation and declined over time. There was a corresponding increase in pluripotent, cardiac and endothelial gene expression in unfractionated PB cells and sorted PB-derived primitive CD34+ cells. The absolute numbers of circulating VSELs and HSCs in STEMI correlated negatively with patients' age.
Conclusions
Myocardial ischemia mobilizes primitive PSCs including pluripotent VSELs into the circulation. The peak of mobilization occurs within 12 hours in patients presenting with STEMI, which may represent a therapeutic window for future clinical applications. Reduced stem cell mobilization with advancing age could explain, in part, the observation that age is associated with poor prognosis in patients with MI.
doi:10.1016/j.exphem.2010.08.003
PMCID: PMC2992878  PMID: 20800644
myocardial infarction; pluripotent stem cells; Very Small Embryonic-Like stem cells; mobilization; Oct-4; CXCR4
16.  Distinct CCR2+ Gr1+ Cells Control Growth of the Yersinia pestis ΔyopM Mutant in Liver and Spleen during Systemic Plague▿ †  
Infection and Immunity  2010;79(2):674-687.
We are using a systemic plague model to identify the cells and pathways that are undermined by the virulence protein YopM of the plague bacterium Yersinia pestis. In this study, we pursued previous findings that Gr1+ cells are required to selectively limit growth of ΔyopM Y. pestis and that CD11b+ cells other than polymorphonuclear leukocytes (PMNs) are selectively lost in spleens infected with parent Y. pestis. When PMNs were ablated from mice, ΔyopM Y. pestis grew as well as the parent strain in liver but not in spleen, showing that these cells are critical for controlling growth of the mutant in liver but not spleen. In mice lacking expression of the chemokine receptor CCR2, wild-type growth was restored to ΔyopM Y. pestis in both organs. In spleen, the Gr1+ cells differentially recruited by parent and ΔyopM Y. pestis infections were CCR2+ Gr1+ CD11b+ CD11cLo-Int MAC3+ iNOS+ (inducible nitric oxide synthase-positive) inflammatory dendritic cells (iDCs), and their recruitment to spleen from blood was blocked when YopM was present in the infecting strain. Consistent with influx of iDCs being affected by YopM in spleen, the growth defect of the ΔyopM mutant was relieved by the parent Y. pestis strain in a coinfection assay in which the parent strain could affect the fate of the mutant in trans. In a mouse model of bubonic plague, CCR2 also was shown to be required for ΔyopM Y. pestis to show wild-type growth in skin. The data imply that YopM's pathogenic effect indirectly undermines signaling through CCR2. We propose a model for how YopM exerts its different effects in liver and spleen.
doi:10.1128/IAI.00808-10
PMCID: PMC3028864  PMID: 21149593
18.  Canadian clinical practice guidelines for acute and chronic rhinosinusitis 
This document provides healthcare practitioners with information regarding the management of acute rhinosinusitis (ARS) and chronic rhinosinusitis (CRS) to enable them to better meet the needs of this patient population. These guidelines describe controversies in the management of acute bacterial rhinosinusitis (ABRS) and include recommendations that take into account changes in the bacteriologic landscape. Recent guidelines in ABRS have been released by American and European groups as recently as 2007, but these are either limited in their coverage of the subject of CRS, do not follow an evidence-based strategy, or omit relevant stakeholders in guidelines development, and do not address the particulars of the Canadian healthcare environment.
Advances in understanding the pathophysiology of CRS, along with the development of appropriate therapeutic strategies, have improved outcomes for patients with CRS. CRS now affects large numbers of patients globally and primary care practitioners are confronted by this disease on a daily basis. Although initially considered a chronic bacterial infection, CRS is now recognized as having multiple distinct components (eg, infection, inflammation), which have led to changes in therapeutic approaches (eg, increased use of corticosteroids). The role of bacteria in the persistence of chronic infections, and the roles of surgical and medical management are evolving. Although evidence is limited, guidance for managing patients with CRS would help practitioners less experienced in this area offer rational care. It is no longer reasonable to manage CRS as a prolonged version of ARS, but rather, specific therapeutic strategies adapted to pathogenesis must be developed and diffused.
Guidelines must take into account all available evidence and incorporate these in an unbiased fashion into management recommendations based on the quality of evidence, therapeutic benefit, and risks incurred. This document is focused on readability rather than completeness, yet covers relevant information, offers summaries of areas where considerable evidence exists, and provides recommendations with an assessment of strength of the evidence base and degree of endorsement by the multidisciplinary expert group preparing the document.
These guidelines have been copublished in both Allergy, Asthma & Clinical Immunology and the Journal of Otolaryngology-Head and Neck Surgery.
doi:10.1186/1710-1492-7-2
PMCID: PMC3055847  PMID: 21310056
20.  Montelukast as an alternative to low-dose inhaled corticosteroids in the management of mild asthma (the SIMPLE trial): An open-label effectiveness trial 
OBJECTIVE:
To evaluate the effectiveness of montelukast as monotherapy for patients with mild asthma who remain uncontrolled or unsatisfied while on inhaled corticosteroid (ICS) monotherapy.
DESIGN:
A multicentre, open-label study. Patients (six years of age or older) had ICS therapy discontinued and were treated with orally administered montelukast once daily for six weeks.
MAIN OUTCOME MEASURES:
The primary outcome measure was the rate at which asthma symptom control was achieved or maintained after six weeks of treatment. The secondary outcome measures were to compare compliance and physician satisfaction, and to further assess the safety and tolerability of montelukast.
RESULTS:
Of the 534 patients enrolled, 481 (90.1%) completed the study. Mean (± SD) age was 27.8±19.0 years. The number of patients with uncontrolled symptoms decreased from 455 (85.2%) at baseline to 143 (26.8%) at week 6 (P<0.001), and mean Asthma Control Questionnaire score decreased from 1.4±0.8 to 0.6±0.6 (P<0.001), representing a clinically significant improvement. Of the 79 patients with controlled asthma symptoms at baseline, 73.4% maintained asthma control at week 6. Compliance to asthma therapy increased from 41% at baseline for ICS to 88% at week 6 for montelukast (P<0.001). Physician satisfaction with treatment increased from 43% to 85% (P<0.001) and patient satisfaction increased from 45% at baseline to 94% at week 6. No serious adverse events were reported over the course of the study.
CONCLUSION:
Montelukast is an effective and well-tolerated alternative to ICS treatment in patients with mild asthma who are uncontrolled or unsatisfied with low-dose ICS therapy.
PMCID: PMC3486709  PMID: 19557207
Adherence; Allergic rhinitis; Asthma; Inhaled corticosteroids (ICS); Montelukast
21.  Gr1+ Cells Control Growth of YopM-Negative Yersinia pestis during Systemic Plague▿  
Infection and Immunity  2009;77(9):3791-3806.
YopM, a protein toxin of Yersinia pestis, is necessary for virulence in a mouse model of systemic plague. We previously reported YopM-dependent natural killer (NK) cell depletion from blood and spleen samples of infected mice. However, in this study we found that infection with Y. pestis KIM5 (YopM+) caused depletion of NK cells in the spleen, but not in the liver, and antibody-mediated ablation of NK cells had no effect on bacterial growth. There was no YopM-associated effect on the percentage of dendritic cells (DCs) or polymorphonuclear leukocytes (PMNs) in the early stage of infection; however, there was a YopM-associated effect on PMN integrity and on the influx of monocytes into the spleen. Ablation of Gr1+ cells caused loss of the growth defect of YopM− Y. pestis in both the liver and spleen. In contrast, ablation of macrophages/DCs inhibited growth of both parent and mutant bacteria, accompanied by significantly fewer lesion sites in the liver. These results point toward PMNs and inflammatory monocytes as major cell types that control growth of YopM− Y. pestis. Infection with fully virulent Y. pestis CO92 and a YopM− derivative by intradermal and intranasal routes showed that the absence of YopM significantly increased the 50% lethal dose only in the intradermal model, suggesting a role for YopM in bubonic plague, in which acute inflammation occurs soon after infection.
doi:10.1128/IAI.00284-09
PMCID: PMC2738001  PMID: 19581396

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