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.
wellness; quality of life; primary care; instrument
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.
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).
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).
These findings suggest that, when possible, the same device should be prescribed for both ICS and reliever therapy when patients are initiating ICS.
Asthma; breath-actuated inhaler; inhaled corticosteroids; inhaler device; pressurised metered-dose inhaler; short-acting β2-agonist
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.
bone marrow transplantation; cyclosporine A; syngeneic graft-versus-host disease; microbiota; broad-spectrum antibiotic therapy
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.
YopM; plague; Yersinia; chemokine; microarray
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.
IL-17; CD4+ T cells; transplantation; cyclosporine A; mucosal inflammation
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.
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.
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.
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.
myocardial infarction; pluripotent stem cells; Very Small Embryonic-Like stem cells; mobilization; Oct-4; CXCR4
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.
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.
To evaluate the effectiveness of montelukast as monotherapy for patients with mild asthma who remain uncontrolled or unsatisfied while on inhaled corticosteroid (ICS) monotherapy.
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.
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.
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.
Adherence; Allergic rhinitis; Asthma; Inhaled corticosteroids (ICS); Montelukast
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.
To provide a review of α1-antitrypsin deficiency (AATD),
α1-antitrypsin (AAT) augmentation, and the
recommendations for timely recognition and treatment.
SOURCES OF INFORMATION
Published guidelines and the medical literature about AATD and AAT
augmentation were reviewed. The information presented is based on available
published literature obtained by searching PubMed, the Cochrane Library
databases, and the reference lists of relevant articles. Searches were
limited to English-language articles published between 1990 and 2009.
α1-Antitrypsin deficiency, a genetic disorder
characterized by low serum levels of AAT, predisposes affected patients to
development of early-onset pulmonary disease (most commonly emphysema and
chronic obstructive pulmonary disease) and occasionally even
life-threatening liver disease. Despite being one of the most common
inherited conditions (affecting about 1 in 2000 to 5000 people), AATD is
underrecognized. This is unfortunate; although there is no cure for AATD,
prompt diagnosis can help impede loss of lung function. Specific treatment
of this deficiency with augmentation therapy is effective.
α1-Antitrypsin deficiency is a common genetic condition
that can be involved in premature lung and liver disease. Consider the
diagnosis to allow earlier institution of AAT augmentation therapy to slow
the progression of premature lung disease in affected patients.
Most asthma patients prescribed maintenance asthma therapies still experience periods of asthma worsenings characterized by daytime or nighttime symptoms, or an increased need for rescue medication. In fact, these episodes are highly prevalent even in patients with well-controlled disease. Published literature suggests that asthma worsenings likely represent a window of opportunity during which patients could intervene early to prevent exacerbations or further deterioration of asthma symptoms. However, current evidence suggests that most patients fail to respond or to self-manage appropriately during these periods.
To address the issue of asthma worsenings, an interdisciplinary committee of respirologists, allergists, family physicians, pharmacists and certified asthma educators from across Canada developed a practical definition of asthma worsenings and provided approaches to the prevention and management of these episodes based on current literature. To date, combination inhaled corticosteroid/long-acting beta-agonist therapy, particularly single inhaler maintenance and reliever therapy, appears to be an effective strategy for preventing asthma worsenings and exacerbations. Addressing the potential barriers to appropriate patient self-management of asthma worsenings, such as failure to adequately identify and respond to worsenings, low expectations for controlling asthma, low health literacy and poor patient-health care professional communication, are also critical to the successful prevention and management of these episodes. Finally, an interdisciplinary team approach involving patients and their families, certified asthma educators, primary care physicians, pharmacists and specialists is likely to have the greatest impact on the identification, prevention and management of asthma worsenings.
Asthma worsenings; Education; Exacerbations; Inhaled corticosteroids; Long-acting beta-agonists
The information on usual care for patients with chronic obstructive pulmonary disease (COPD) in primary care is limited in Canada.
To evaluate primary care practice in patients with COPD in Quebec and Ontario compared with recommended care.
The COPD Care Gap Evaluation (CAGE) was a prospective, cross-sectional study. Physicians’ self-reported data of enrolled COPD patients were compared with the recommended care for the level of disease severity (using the Canadian Thoracic Society classification by symptoms) and stability, derived from Canadian Thoracic Society COPD guidelines. Pharmacological treatment, spirometric confirmation of diagnosis and nonpharmacological management, including smoking cessation counselling, influenza immunization and referral for pulmonary rehabilitation, were assessed.
Participating physicians (n=161; 44 in Quebec, 117 in Ontario) recruited 1090 patients (320 in Quebec, 770 in Ontario). The mean (± SD) age of the patients was 69.9±10.4 years; 60% were male and 40% were currently smoking. Pharmacological treatment that matched guideline recommendations was identified in 34% of patients. Discrepancies between reported and recommended treatment stemmed from nonprescription of long-acting bronchodilators (LABDs) for patients with moderate (27%) and severe (21%) COPD, nonprescription of two long-acting beta agonists (a beta2-agonist and an anticholinergic) for patients with severe COPD (51%), and prescription of inhaled corticosteroids (63%) and LABDs (47%) for patients with mild COPD for which the treatment is not recommended. Spirometric confirmation of diagnosis, as recommended by the guidelines, was reported in 56% of patients. For non-pharmacological management, smoking cessation counselling (95%) and influenza immunization (80%) were near optimal. Referral for pulmonary rehabilitation (9%) was not common. Differences between provinces were seen mainly in the prescription of short-acting bronchodilators (89% in Quebec, 76% in Ontario) and LABDs (60% in Quebec, 80% in Ontario).
Substantial gaps between recommended and current care exist in the management of COPD patients in primary care practice. Undertreatment of patients with severe COPD has potential clinical implications, including loss of autonomy and hospitalization.
Care gap; COPD; Practice patterns; Primary care; Treatment guidelines
Chronic obstructive pulmonary disease (COPD) is a major respiratory illness in Canada that is preventable and treatable but unfortunately remains underdiagnosed. The purpose of the present article from the Canadian Thoracic Society is to provide up-to-date information so that patients with this condition receive optimal care that is firmly based on scientific evidence. Important summary messages for clinicians are derived from the more detailed Update publication and are highlighted throughout the document. Three key messages contained in the update are: use targeted screening spirometry to establish a diagnosis and initiate prompt management (including smoking cessation) of mild COPD; improve dyspnea and activity limitation in stable COPD using new evidence-based treatment algorithms; and understand the importance of preventing and managing acute exacerbations, particularly in moderate to severe disease.
Chronic obstructive pulmonary disease; Management; National guidelines
To increase the likelihood of finding genetic variation conferring liability to eating disorders, we measured over 100 attributes thought to be related to liability to eating disorders on affected individuals from multiplex families and two cohorts: one recruited through a proband with anorexia nervosa (AN; AN cohort); the other recruited through a proband with bulimia nervosa (BN; BN cohort). By a multilayer decision process based on expert evaluation and statistical analysis, six traits were selected for linkage analysis (1): obsessionality (OBS), age at menarche (MENAR) and anxiety (ANX) for quantitative trait locus (QTL) linkage analysis; and lifetime minimum Body Mass Index (BMI), concern over mistakes (CM) and food-related obsessions (OBF) for covariate-based linkage analysis. The BN cohort produced the largest linkage signals: for QTL linkage analysis, four suggestive signals: (for MENAR, at 10p13; for ANX, at 1q31.1, 4q35.2, and 8q13.1); for covariate-based linkage analyses, both significant and suggestive linkages (for BMI, one significant [4q21.1] and three suggestive [3p23, 10p13, 5p15.3]; for CM, two significant [16p13.3, 14q21.1] and three suggestive [4p15.33, 8q11.23, 10p11.21]; and for OBF, one significant [14q21.1] and five suggestive [4p16.1, 10p13.1, 8q11.23, 16p13.3, 18p11.31]). Results from the AN cohort were far less compelling: for QTL linkage analysis, two suggestive signals (for OBS at 6q21 and for ANX at 9p21.3); for covariate-based linkage analysis, five suggestive signals (for BMI at 4q13.1, for CM at 11p11.2 and 17q25.1, and for OBF at 17q25.1 and 15q26.2). Overlap between the two cohorts was minimal for substantial linkage signals.
Complex disease; endophenotype; liability; mixture model; regression