An Inhalation Chamber Model for Controlled Studies of Tobacco Smoke Toxicity in Rodents

Introduction: Smoking is a serious worldwide public health problem. Animal models act as a bridge between laboratory and human studies. The models applied are difficult to reproduce because of the use of different types of inhalation chambers and mainly because of the lack of continuous monitoring of smoke concentration. Objective: To develop an inhalation chamber for rats (with only the nose exposed) in which the amount of carbon monoxide (CO) can be maintained and monitored constantly. Material and methods: Male Wistar rats weighing 250 g were exposed to 50 ppm CO produced by the smoke from a filter-free cigarette. The animals were submitted to a single 2-h exposure and then sacrificed at 0, 4, 24 and 48 h. The control group was left restrained inside the small perpendicular chambers, receiving only 5 L/min of compressed air. Results: The model was able to increase HbCO levels immediately after the end of exposure (p < 0.001). with a decrease being observed from 2 h onwards when compared to the levels of the control group. Plasma cotinine increased immediately after exposure, and showed still detectable levels at 2 and 4 h (p < 0.05). Conclusion: We conclude that the presented inhalation chamber system is able to maintain a controlled CO concentration in a model in which small animals are exposed to the inhalation of cigarette smoke, permitting well-controlled studies, as well as investigations involving other toxic gases and air pollutants. (C) 2008 SEPAR. Published by Elsevier Espana, S.L. All rights reserved.

Continuous positive airway pressure increases inspiratory capacity of COPD patients

Background and objective: Hyperinflation with a decrease in inspiratory capacity (IC) is a common presentation for both unstable and stable COPD patients. As CPAP can reduce inspiratory load, possibly secondary to a reduction in hyperinflation, this study examined whether CPAP would increase IC in stable COPD patients. Methods: Twenty-one stable COPD patients (nine emphysema, 12 chronic bronchitis) received a trial of CPAP for 5 min at 4, 7 and 11 cmH(2)O. Fast and slow VC (SVC) were measured before and after each CPAP trial. In patients in whom all three CPAP levels resulted in a decreased IC, an additional trial of CPAP at 2 cmH(2)O was conducted. For each patient, a `best CPAP` level was defined as the one associated with the greatest IC. This pressure was then applied for an additional 10 min followed by spirometry. Results: Following application of the `best CPAP`, the IC and SVC increased in 15 patients (nine emphysema, six chronic bronchitis). The mean change in IC was 159 mL (95% CI: 80-237 mL) and the mean change in SVC was 240 mL (95% CI: 97-386 mL). Among these patients, those with emphysema demonstrated a mean increase in IC of 216 mL (95% CI: 94-337 mL). Six patients (all with chronic bronchitis) did not demonstrate any improvement in IC. Conclusions: The best individualized CPAP can increase inspiratory capacity in patients with stable COPD, especially in those with emphysema.

Furosemide impairs nasal mucociliary clearance in humans

Furosemide, a potent diuretic, affects ion and water movement across the respiratory epithelium. However, the effects of furosemide, as clinically used, on mucociliary clearance, a critical respiratory defense mechanism, are still lacking in humans. Fourteen young healthy subjects were assigned to three random interventions, spaced one-week apart: no intervention (control), oral furosemide (40 mg), and furosemide + oral volume replacement (F + R). Nasal mucociliary clearance was assessed by saccharine test (STT), and mucus properties were in vitro evaluated by means of contact angle and transportability by sneeze. Urine output and osmolality were also evaluated. Urine output increased and reduced urine osmolality in furosemide and F + R compared to the control condition. STT remained stable in the control group. In contrast, STT increased significantly (40%) after furosemide and F + R. There were no changes in vitro mucus properties in all groups. In conclusion, furosemide prolongs STT in healthy young subjects. This effect is not prevented by fluid replacement, suggesting a direct effect of furosemide on the respiratory epithelium. (C) 2010 Elsevier B.V. All rights reserved.

Mast cell-associated alveolar inflammation in patients with atopic uncontrolled asthma

Background: A significant proportion of patients with asthma have persistent symptoms despite treatment with inhaled glucocorticosteroids. Objective: We hypothesized that in these patients, the alveolar parenchyma is subjected to mast cell-associated alterations. Methods: Bronchial and transbronchial biopsies from healthy controls (n = 8), patients with allergic rhinitis (n = 8), and patients with atopic uncontrolled asthma (symptoms despite treatment with inhaled glucocorticosteroids; mean dose, 743 mu g/d; n = 14) were processed for immunohistochemical identification of mast cell subtypes and mast cell expression of Fc epsilon RI and surface-bound IgE. Results: Whereas no difference in density of total bronchial mast cells was observed between patients with asthma and healthy controls, the total alveolar mast cell density was increased in the patients with asthma (P < .01). Division into mast cell subtypes revealed that in bronchi of patients with asthma, tryptase positive mast cells (MC(T)) numbers decreased compared with controls (P <= .05), whereas tryptase and chymase positive mast cells (MC(TC)) increased (P <= .05). In the alveolar parenchyma from patients with asthma, an increased density was found for both MC(T) (P <= .05) and MC(TC) (P <= .05). The increased alveolar mast cell densities were paralleled by an increased mast cell expression of FceRI (P < .001) compared with the controls. The patients with asthma also had increased numbers (P < .001) and proportions (P < .001) of alveolar mast cells with surface-bound IgE. Similar increases in densities, FceRI expression, and surface-bound IgE were not seen in separate explorations of alveolar mast cells in patients with allergic rhinitis. Conclusion: Our data suggest that patients with atopic uncontrolled asthma have an increased parenchymal infiltration of MCT and MCTC populations with increased expression of FceRI and surface-bound IgE compared with atopic and nonatopic controls. (J Allergy Clin Immunol 2011;127:905-12.)

A practical approach to assess depression risk and to guide risk reduction strategies in later life

Background: Many factors have been associated with the onset and maintenance of depressive symptoms in later life, although this knowledge is yet to be translated into significant health gains for the population. This study gathered information about common modifiable and non-modifiable risk factors for depression with the aim of developing a practical probabilistic model of depression that can be used to guide risk reduction strategies. \Methods: A cross-sectional study was undertaken of 20,677 community-dwelling Australians aged 60 years or over in contact with their general practitioner during the preceding 12 months. Prevalent depression (minor or major) according to the Patient Health Questionnaire (PHQ-9) assessment was the main outcome of interest. Other measured exposures included self-reported age, gender, education, loss of mother or father before age 15 years, physical or sexual abuse before age 15 years, marital status, financial stress, social support, smoking and alcohol use, physical activity, obesity, diabetes, hypertension, and prevalent cardiovascular diseases, chronic respiratory diseases and cancer. Results: The mean age of participants was 71.7 +/- 7.6 years and 57.9% were women. Depression was present in 1665 (8.0%) of our subjects. Multivariate logistic regression showed depression was independently associated with age older than 75 years, childhood adverse experiences, adverse lifestyle practices (smoking, risk alcohol use, physical inactivity), intermediate health hazards (obesity, diabetes and hypertension), comorbid medical conditions (clinical history of coronary heart disease, stroke, asthma, chronic obstructive pulmonary disease, emphysema or cancers), and social or financial strain. We stratified the exposures to build a matrix that showed that the probability of depression increased progressively with the accumulation of risk factors, from less than 3% for those with no adverse factors to more than 80% for people reporting the maximum number of risk factors. Conclusions: Our probabilistic matrix can be used to estimate depression risk and to guide the introduction of risk reduction strategies. Future studies should now aim to clarify whether interventions designed to mitigate the impact of risk factors can change the prevalence and incidence of depression in later life.

Adjuncts to Physical Training of Patients With Severe COPD: Oxygen or Noninvasive Ventilation?

BACKGROUND: Previous studies have shown positive effects from noninvasive ventilation (NIV) or supplemental oxygen on exercise capacity in patients with COPD. However, the best adjunct for promoting physiologic adaptations to physical training in patients with severe COPD remains to be investigated. METHODS: Twenty-eight patients (mean +/- SD age 68 +/- 7 y) with stable COPD (FEV(1) 34 +/- 9% of predicted) undergoing an exercise training program were randomized to either NIV (n = 14) or supplemental oxygen (n = 14) during group training to maintain peripheral oxygen saturation (S(pO2)) >= 90%. Physical training consisted of treadmill walking (at 70% of maximal speed) 3 times a week, for 6 weeks. Patients were assessed at baseline and after 6 weeks. Assessments included physiological adaptations during incremental exercise testing (ratio of lactate concentration to walk speed, oxygen uptake [(V) over dot(O2)], and dyspnea), exercise tolerance during 6-min walk test, leg fatigue, maximum inspiratory pressure, and health-related quality of life. RESULTS: Two patients in each group dropped out due to COPD exacerbations and lack of exercise program adherence, and 24 completed the training program. Both groups improved 6-min walk distance, symptoms, and health-related quality of life. However, there were significant differences between the NIV and supplemental-oxygen groups in lactate/speed ratio (33% vs -4%), maximum inspiratory pressure (80% vs 23%), 6-min walk distance (122 m vs 47 m), and leg fatigue (25% vs 11%). In addition, changes in S(pO2)/speed, (V) over dot(O2), and dyspnea were greater with NIV than with supplemental-oxygen. CONCLUSIONS: NIV alone is better than supplemental oxygen alone in promoting beneficial physiologic adaptations to physical exercise in patients with severe COPD.

Drug use evaluation of ipratropium bromide at two tertiary referral hospitals in Brisbane.

Objective: To assess the appropriateness of ipratropium bromide prescribing in two tertiary referral hospitals. Method: Criteria for optimal use were developed based on current literature and modified after consultation with respiratory physicians and clinical pharmacists. A prospective review of prescribing was performed over a 2-month period to assess conformity to these criteria. Results: Information was collected from 84 patients; 5% were receiving inhalers and 96% nebuliser therapy (one patient used both). 77% of patients (n = 65) had a principal diagnosis of chronic obstructive pulmonary disease, 14% (n = 12) asthma and 8% (n = 7) had neither diagnosis. 75% of patients were using ipratropium outside the guidelines. The major areas where the guidelines were not met were a lack of therapeutic justification, use of inappropriate doses, and use of an inappropriate delivery device. Feedback and educational interventions were designed and delivered based on the data obtained. Conclusions: There was widespread use of ipratropium outside the developed guidelines. Interventions in specific areas could lead to significant improvements in the use of this high cost drug

Coal dust exposures in the longwall mines of New South Wales, Australia: a respiratory risk assessment

This paper presents an analysis of personal respirable coal dust measurements recorded by the Joint Coal Board in the underground longwall mines of New South Wales from 1985 to 1999. A description of the longwall mining process is given. In the study, 11 829 measurements from 33 mines were analysed and the results given for each occupation, for seven occupational groups, for individual de-identified mines and for each year of study. The mean respirable coal dust concentration for all jobs was 1.51 mg/m(3) (SD 1.08 mg/m(3)). Only 6.9% of the measurements exceeded the Australian exposure standard of 3 mg/m(3). Published exposure-response relationships were used to predict the prevalence of progressive massive fibrosis and the mean loss of FEV1, after a working lifetime (40 years) of exposure to the mean observed concentration of 1.5 mg/m(3). Prevalences of 1.3 and 2.9% were predicted, based on data from the UK and the USA, respectively. The mean loss of FEV1 was estimated to be 73.7 ml.

Estimates of global and regional potential health gains from reducing multiple major risk factors

Background Estimates of the disease burden due to multiple risk factors can show the potential gain from combined preventive measures. But few such investigations have been attempted, and none on a global scale. Our aim was to estimate the potential health benefits from removal of multiple major risk factors. Methods We assessed the burden of disease and injury attributable to the joint effects of 20 selected leading risk factors in 14 epidemiological subregions of the world. We estimated population attributable fractions, defined as the proportional reduction in disease or mortality that would occur if exposure to a risk factor were reduced to an alternative level, from data for risk factor prevalence and hazard size. For every disease, we estimated joint population attributable fractions, for multiple risk factors, by age and sex, from the direct contributions of individual risk factors. To obtain the direct hazards, we reviewed publications and re-analysed cohort data to account for that part of hazard that is mediated through other risks. Results Globally, an estimated 47% of premature deaths and 39% of total disease burden in 2000 resulted from the joint effects of the risk factors considered. These risks caused a substantial proportion of important diseases, including diarrhoea (92%-94%), lower respiratory infections (55-62%), lung cancer (72%), chronic obstructive pulmonary disease (60%), ischaemic heart disease (83-89%), and stroke (70-76%). Removal of these risks would have increased global healthy life expectancy by 9.3 years (17%) ranging from 4.4 years (6%) in the developed countries of the western Pacific to 16.1 years (43%) in parts of sub-Saharan Africa. Interpretation Removal of major risk factors would not only increase healthy life expectancy in every region, but also reduce some of the differences between regions, The potential for disease prevention and health gain from tackling major known risks simultaneously would be substantial.

Estimates of global mortality attributable to smoking in 2000

Background Smoking is a risk factor for several diseases and has been increasing in many developing countries. Our aim was to estimate global and regional mortality in 2000 caused by smoking, including an analysis of uncertainty. Methods Following the methods of Peto and colleagues, we used lung-cancer mortality as an indirect marker for accumulated smoking risk. Never-smoker lung-cancer mortality was estimated based on the household use of coal with poor ventilation. Relative risks were taken from the American Cancer Society Cancer Prevention Study, phase II, and the retrospective proportional mortality analysis of Liu and colleagues in China. Relative risks were corrected for confounding and extrapolation to other regions. Results We estimated that in 2000, 4.83 (uncertainty range 3.94-5.93) million premature deaths in the world were attributable to smoking; 2.41 (1.80-3.15) million in developing countries and 2.43 (2.13-2.78) million in industrialised countries. 3.84 million of these deaths were in men. The leading causes of death from smoking were cardiovascular diseases (1.69 million deaths), chronic obstructive pulmonary disease (0.97 million deaths), and lung cancer (0.85 million deaths). Interpretation Smoking was an important cause of global mortality in 2000. In view of the expected demographic and epidemiological transitions and current smoking patterns in the developing world, the health loss due to smoking will grow even larger unless effective interventions and policies that reduce smoking among men and prevent increases among women in developing countries are implemented.

Ventilação não invasiva durante o exercício em pacientes com DPOC: revisão sistemática com meta-análise

Mestrado em Fisioterapia

Analysis of the respiratory dynamics during normal breathing by means of pseudo phase plots and pressure-volume loops

This paper reports on the analysis of tidal breathing patterns measured during noninvasive forced oscillation lung function tests in six individual groups. The three adult groups were healthy, with prediagnosed chronic obstructive pulmonary disease, and with prediagnosed kyphoscoliosis, respectively. The three children groups were healthy, with prediagnosed asthma, and with prediagnosed cystic fibrosis, respectively. The analysis is applied to the pressure–volume curves and the pseudophaseplane loop by means of the box-counting method, which gives a measure of the area within each loop. The objective was to verify if there exists a link between the area of the loops, power-law patterns, and alterations in the respiratory structure with disease. We obtained statistically significant variations between the data sets corresponding to the six groups of patients, showing also the existence of power-law patterns. Our findings support the idea that the respiratory system changes with disease in terms of airway geometry and tissue parameters, leading, in turn, to variations in the fractal dimension of the respiratory tree and its dynamics.

Fractional-order impulse response of the respiratory system

This paper presents the measurement, frequency-response modeling and identification, and the corresponding impulse time response of the human respiratory impedance and admittance. The investigated adult patient groups were healthy, diagnosed with chronic obstructive pulmonary disease and kyphoscoliosis, respectively. The investigated children patient groups were healthy, diagnosed with asthma and cystic fibrosis, respectively. Fractional order (FO) models are identified on the measured impedance to quantify the respiratory mechanical properties. Two methods are presented for obtaining and simulating the time-domain impulse response from FO models of the respiratory admittance: (i) the classical pole-zero interpolation proposed by Oustaloup in the early 90s, and (ii) the inverse discrete Fourier Transform (DFT). The results of the identified FO models for the respiratory admittance are presented by means of their average values for each group of patients. Consequently, the impulse time response calculated from the frequency response of the averaged FO models is given by means of the two methods mentioned above. Our results indicate that both methods provide similar impulse response data. However, we suggest that the inverse DFT is a more suitable alternative to the high order transfer functions obtained using the classical Oustaloup filter. Additionally, a power law model is fitted on the impulse response data, emphasizing the intrinsic fractal dynamics of the respiratory system.

Is multidimensional scaling suitable for mapping the input respiratory impedance in subjects and patients?

This paper presents the application of multidimensional scaling (MDS) analysis to data emerging from noninvasive lung function tests, namely the input respiratory impedance. The aim is to obtain a geometrical mapping of the diseases in a 3D space representation, allowing analysis of (dis)similarities between subjects within the same pathology groups, as well as between the various groups. The adult patient groups investigated were healthy, diagnosed chronic obstructive pulmonary disease (COPD) and diagnosed kyphoscoliosis, respectively. The children patient groups were healthy, asthma and cystic fibrosis. The results suggest that MDS can be successfully employed for mapping purposes of restrictive (kyphoscoliosis) and obstructive (COPD) pathologies. Hence, MDS tools can be further examined to define clear limits between pools of patients for clinical classification, and used as a training aid for medical traineeship.

Prevalência de obstrução numa população exposta ao fumo do tabaco – Projecto PNEUMOBIL

A espirometria não atingiu ainda a divulgação que se justificaria em patologia respiratória, ou indivíduos que se encontram em risco relativamente a esta patologia, cujo diagnóstico é insuficiente, havendo um escasso conhecimento, e consequente controlo, dos custos atribuíveis a estas doenças, com destaque para a doença pulmonar obstrutiva crónica (DPOC). O PNEUMOBIL, iniciativa que visa esta divulgação entre fumadores e ex-fumadores, foi reactivado, após 10 anos de aplicação em Portugal, revelando agora, numa amostra de 5324 indivíduos, em que cerca de 50% ainda mantêm os hábitos tabágicos, sejam do sexo masculino ou feminino, que houve uma elevada prevalência de obstrução detectada por espirometria (30% e 25%, respectivamente) nas pessoas rastreadas perto de centros de saúde (grupo público) e em empresas (grupo privado). Este risco não se explica em regra por exposição ocupacional, nem se relaciona com a maioria dos sintomas respiratórios, muito frequentes nos rastreados. Apenas a dispneia (OR = 1,28; p = 0,02) e os episódios frequentes de expectoração (OR = 1,21; p = 0,008) ou de bronquite aguda (OR = 1,31; p = 0,05) revelam alguma relação com a obstrução. O reconhecimento prévio da DPOC é muito reduzi-do e a presença de obstrução não se correlaciona (p = 0,204) com o assumir da condição de portador.