Search

Małgorzata Farnik, Władysław PierzchałaDepartment of Pneumonology, Silesian University of Medicine, Katowice, PolandAbstract: Patient-related outcomes measures could provide important information for the current state of the art in medical care and even have an impact on macrodecisions in the health care system. Patient-related outcomes were initially defined as subjective health indicators that allow disability and illness to be assessed, based on patient, caregiver, or physician self-reports. As illness involves psychological and behavioral complex processes of care, a multidisciplinary approach in measuring patient-reported outcomes should be recommended, such as quality of life questionnaires. Patient-related outcomes measures should correspond to specific clinical situations and bring opportunities to improve quality of care. Objective measurements enable quantitative data to be collected and analyzed. Depending on the aim of the research, investigators can use existing methods or develop new tools. This publication presents a methodology for developing patient-related outcomes measures, based on a multistage procedure. The proper definition of specific study objectives and the methodology of instrument development are crucial for successfully transferring the study concept. The model of instrument development is the process of starting from the preliminary phase and includes questionnaire design and scaling, pilot testing (cognitive debriefing), revision of the preliminary version, evaluation of the new tool, and implementation. Validation of the new instrument includes reliability, reproducibility, internal consistency, and responsiveness. The process of designing the new tool should involve a panel of experts, including clinicians, psychologists (preliminary phase), and statisticians (scale development and scoring), and patients (cognitive debriefing). Implementation of a new tool should be followed by evaluation study – assessment of the tool's usefulness in clinical practice. An instrument must show not only the expected methodological properties and performance but also a positive contribution to care. The necessity of implementation of direct patient-reporting methods has been highlighted by both the Food and Drug Administration and the European Medicines Agency.Keywords: instrument development, patient-related outcomes, evaluation

Abstract Background Childhood chronic disease may affect patients' and their family's functioning. Particularly parents, who play an important role in cooperation between patient and health care professionals, report impaired health - related quality of life (HRQOL). The aim of this study was development, evaluation and validation of a new instrument: Quality of Life in a Child's Chronic Disease Questionnaire (QLCCDQ). The questionnaire is addressed to parents of children with a chronic disease. Methods Study design included semi structured interview and qualitative study, which allowed to identify most troublesome problems. Following the results the questionnaire was developed, which consists of 15 questions and covers domains - emotions, patients -perceived symptoms, roles limitations. An observational study involving parents of asthma and diabetes children was conducted to assess the psychometric characteristics of the measure. Psychometric testing was based on the reliability of defined subscales, construct validity, reproducibility assessment, as well as comparison between stable/unstable disease stages and parents of healthy children. Results Most troublesome concerns for parents of child with chronic disease included emotional distress and feeling depressed due to child's disease, avoiding social interactions due to child's disease or symptoms. 98 parents of children with asthma or insulin - depended diabetes participated in the psychometric testing of QLCCDQ. Internal consistency reliability for the defined subscales ranged between 0.77 and 0.93. Reproducibility based on the weighted kappa coefficients showed expected level of agreement and was almost perfect in case of 8 questions, substantial for 5 questions and moderate for 2 questions. QLCCDQ demonstrated very good construct validity - all subscales showed statistically significant correlations ranging from 0.4 to 0.9. QLCCDQ scores differed significantly by clinical status - parents of children qualified as stable presented higher scores in most subscales in comparison to parents of children with unstable disease. Conclusions The QLCCDQ shows good internal consistency, test-retest reliability, and construct validity. The questionnaire may be useful in helping to understand the impact of chronic child's disease on parental perception of health outcomes.

Whole lung lavage (WLL) under general anesthesia with a double-lumen endobronchial intubation has remained standard treatment option for pulmonary alveolar proteinosis (PAP) for over fifty years now. To the best of our knowledge, this is the first description of noninvasive ventilation (NIV) as an innovative alternative, which enables safe and effective treatment. NIV support enabled cost-effective lavage of the most affected segments and resulted in restoration and long-term maintenance of exercise capacity and diffusion, without WLL related hypoxaemia, volume overload, intubation, or mechanical ventilation related complications. The study presents all details of performed procedure, including anesthesia, NIV technique and bronchoscopy, therefore this may be easily implemented into clinical practice at other centers conducting PAP treatment. We assume that presented technique of therapeutic lung lavage (TLL) with NIV support may be considered a novel PAP treatment method, however, target population who will benefit the most from such therapy modification must be assessed in large scale prospective trials., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Background: Asthma is a chronic inflammatory disorder of the airways with the proven role of Th2 cells in its pathogenesis. The role and characteristic of different subsets of CD4(+) cells is much less known., Aim: The aim of the study was to analyze the incidence of different subsets of CD4(+) T cells, in particular different subsets of CD4(+) cells with the co-expression of different cytokines., Methods: Twenty five stable asthmatic and twelve age-matched control subjects were recruited to the study. Bronchoscopy and bronchoalveolar lavage (BAL) were performed in all study subjects. CD4(+) T cells were isolated from BAL fluid by positive magnetic selection. After stimulation simultaneous expression of TGF-β, FoxP3, CD25, IFN-γ, IL-4, TNF-α (set 1); IL-10, FoxP3, CD25, IFN-γ, IL-4, MIP-1β (set 2); IL-17A, IL-8, IFN-γ, IL-4, MIP-1β (set 3) were measured by flow cytometry., Results: The percentage of CD4(+) cells co-expressing Foxp3 and TGF-β (CD4(+)Foxp3(+)TGF-β(+) cells) was significantly lower (P = 0.03), whereas the percentage of CD4(+)IL-17(+) cells (P = 0.008), CD4(+)IL-17(+) IFN-γ(+) cells (P = 0.047) and CD4(+)IL-4(+) cells (P = 0.01) were significantly increased in asthmatics compared with that seen in healthy subjects. A significantly higher percentage of CD4(+)Foxp3(+) cells from asthma patients expressed IFN-γ (P = 0.01), IL-4 (P = 0.004) and CD25 (P = 0.04), whereas the percentage of CD4(+)IL-10(+) cells expressing Foxp3 was significantly decreased in asthmatics (P = 0.03). FEV1% predicted correlated negatively with the percentage of CD4(+)IL-17(+) cells (r = -0.33; P = 0.046) and positively with CD4(+)Foxp3(+)TGF-β(+) cells (r = 0.43; P = 0.01)., Conclusions: Our results suggest that in the airways of chronic asthma patients there is an imbalance between increased numbers of CD4(+)IL-17(+) cells and Th2 cells and decreased number of CD4(+)Foxp3(+)TGF-β(+).

Background: Interleukin 17 (IL-17) is produced by T(H)17 cells and was recently implicated in the development of the T(H)2 cell response. RANTES (regulated on activation of normal T cells expressed and secreted), among other chemokines, plays a crucial role in chemotaxis of eosinophils into airway mucosa. According to the "united airway" hypothesis, markers of inflammation in allergic diseases are elevated in the upper and lower airways., Objective: To assess the impact of a single nasal allergen challenge on IL-17 and RANTES levels in induced sputum of patients with allergic rhinitis (AR)., Methods: Eighteen patients with a history of AR due to grass pollen confirmed by positive skin prick test results and 10 control subjects entered the study. Initially, all the patients underwent sputum induction. A single nasal placebo challenge was performed 24 hours later, with repeated sputum induction 24 hours after challenge. After 4 weeks of washout, these procedures were repeated with allergen challenge. Differential cell counts in sputum were determined, and concentrations of IL-17 and RANTES were measured by means of enzyme-linked immunosorbent assay., Results: Levels of IL-17 and RANTES significantly increased in sputum of patients with AR after allergen (but not placebo) challenge (P = .03 and P = .007, respectively). Postallergen levels of both cytokines in sputum were positively correlated (r = 0.570, P = .02). Allergen challenge led to increased total inflammatory cell (P = .005) and eosinophil (P = .03) counts in induced sputum of patients with AR., Conclusions: Nasal allergen challenge induces the enhanced secretion of IL-17 and RANTES in the lower airways of nonasthmatic patients with AR.

Our aim was to analyze rheological properties of blood and plasma in patients (n=31) with obstructive sleep apnea (OSA) before and after five nights of continuous positive airway pressure (CPAP) therapy as compared with a well-matched control group (n=19). Rheology measurements included blood viscosity, plasma viscosity, erythrocyte elongation and erythrocyte deformability variables specific to the aggregation process. The mean whole blood viscosity of the OSA groups was 18.6% higher than that of the control group (P<0.001), plasma viscosity was 7.2% higher (P<0.001), and the blood count was 6% higher (P<0.001). The corrected viscosity of the OSA group was elevated 6.6% (P<0.05) and the aggregation index was 9.3% higher (P<0.05) relative to the control group. Aggregation half-time of the OSA group was 23.5% shorter than that of the control group (P<0.05). Following CPAP therapy, the rheological variables of the OSA group were significantly reduced: whole blood viscosity was 10.5% lower (P<0.001), plasma viscosity was 4.1% lower (P<0.05), corrected blood viscosity was 4.8% lower (P<0.05), and the aggregation index was 7% lower (P<0.05), while the aggregation half-time was increased 25.4% (P<0.05). There were significant correlations between rheologic and polysomnographic variables for the OSA group. Therefore, five consecutive nights of CPAP therapy improved blood rheological properties in patients with OSA. These findings may help to determine cardiovascular prognoses in these patients.

Background: Indacaterol is a new once-daily inhaled beta(2)-agonist in clinical development for asthma as a component of a fixed-dose combination with an inhaled corticosteroid., Objectives: To investigate the efficacy and safety of indacaterol in patients with chronic persistent asthma., Methods: A total of 115 patients were randomized in a double-blind, incomplete-block cross-over design to sequences of four 7-day treatment periods (separated by 7-day washouts) with indacaterol 100, 200, 300, 400, or 600 micro g or placebo, once daily, via single-dose dry-powder inhaler. After the fourth washout, patients received 1 day of open-label formoterol 12 mu g twice daily. Forced expiratory volume in 1 second (FEV(1)) was measured for 24 hours post-dose on days 1 and 7., Results: For standardized (with respect to time) FEV(1) area under the curve at 22 to 24 hours (AUC(22-24h)) on day 1, indacaterol doses >or=200 micro g were superior to placebo (p < 0.05) and similar or greater than formoterol 12 micro g twice daily. By day 7, mean differences from placebo in FEV(1) standardized AUC(22-24h) were 0.08, 0.16, 0.15, 0.11, and 0.16 L for indacaterol 100, 200, 300, 400, and 600 micro g, respectively (all p < 0.05 vs. placebo). Mean FEV(1) for indacaterol doses >or= 200 micro g on day 7 was higher than placebo (p < 0.05) pre-dose and at all post-dose time points. AEs were generally mild in severity; no serious AEs occurred. No clinically meaningful differences were observed between treatments in any safety assessments., Conclusions: Once-daily indacaterol demonstrated sustained 24-hour bronchodilator efficacy, with similar efficacy on days 1 and 7, and was generally well tolerated.

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide. Smoking is considered the major cause of the disease. All smokers develop airway inflammation through oxidative stress with macrophages, neutrophiles, lymphocytes, eosinophils, NK-cells and mediators involved. Macrophages through the activation of Nuclear Factor kappa B (NF.-kappaB) release proinflammatory mediators, lymphocyte chemotactic agents and elastolytic enzymes, activate neutrophil driven serine proteases and GM-CSF. Neutrophiles release IL-8 which in turn recruits neutrophils to the airways. In response to cigarette smoke lung epithelium may release TNF-alpha, TGF-beta, IL-1beta, GM-CSF, IL-8 reactive oxygen species (ROS). Increased number of lymphocyte T CD8+ and CD4+ subpopulations may lead to lung epithelium cells apoptosis and necrosis through perphorines and granzyme-B and TNF-alpha activation. Moreover, increased expression of IL-6, IL-10, IL-12, IL-13, and INF-gamma is observed. Authors indicate the possibility of new treatment strategies such as: agents directed against adhesion molecules, chemokines, phosphodiesterase 4, p38 MAPK, NF.-kappaB phosphoinositide-3-kinase gamma, TGF-beta, NOS synthase, serine proteinases and matrix metalloproteinases.

Background: Inhaled glucocorticoids may decrease exacerbations in some patients with COPD, and oral glucocorticoids may improve FEV(1) and shorten hospital stay during exacerbations. The mechanism of these improvements is unknown. This study examines the effect of oral glucocorticoids on markers of neutrophilic airway inflammation., Methods: Eighteen patients with COPD received oral prednisone, 0.5 mg/kg/d for 2 weeks. Clinical status, lung function measurements, and sputum induction were performed before and after treatment with oral prednisone. Levels of the neutrophil chemoattractant (interleukin-8 [IL-8]) and neutrophil activation marker (myeloperoxidase [MPO]) were measured in the supernatant of induced sputum by enzyme-linked immunosorbent assay., Results: Levels of MPO decreased significantly after treatment with prednisone (p = 0.0004): before treatment median, 2.54 microg/mL (range, 1.49 to 12.58 microg/mL); after treatment median, 1.79 microg/mL (range, 1.32 to 3.57 microg/mL). Treatment with prednisone did not influence the levels of IL-8., Conclusions: The treatment of patients with COPD with oral glucocorticoids decreases the activation of neutrophils, which may be partially responsible for clinical improvement in these patients.

The formation of N-linked oligosaccharides of eukaryotic glycoproteins starts with the attachment of a common precursor at the recognition site Asn-X-Ser/Thr. Subsequent processing, by yet unknown controlling factors, leads to the formation of three different glycans: the high mannose type, the complex type and the hybrid type. In order to gain insight into the processing mechanisms, we studied the glycan pattern of a panel of related molecules constructed by insertion, duplication or deletion of the domains encoded by the cDNA of a fibrinolytic glycoprotein, tissue-type plasminogen activator (t-PA). These variant molecules are identical in regard to the glycosylation sites originally situated in particular domains, but differ with respect to the sequential alignment of the domains. The variant and native t-PA genes were transfected into mouse C127 cells and their carbohydrate structures analyzed by the susceptibility to specific endoglycosidases and by reaction with sugar-specific lectins. We found that with one exception, all mutant activators lack the high mannose glycan found at asn 117 of native t-PA. The exception was a molecule that retains the original domain arrangement up to and through the glycosylation site at asn 117. These results demonstrate for the first time that structural alterations in the primary sequence distal to the actual glycosylation site can result in altered processing of N-linked oligosacharides.