Is diurnal variation in absorption of slow-release aminophylline an age-related phenomenon?

Summary To specifically assess the possible influence of ageing on the changes in theophylline absorption, the plasma concentration-time profiles of sustained-release aminophylline were studied in 8 young and 8 elderly subjects after 9 a.m. and 9 p.m. administration.After 9 p.m. administration, in elderly subjects, maximum plasma theophylline concentrations (C_max) were decreased, time to maximum concentration (t_max) was increased, and area under plasma concentration-time curve (AUC) was decreased compared to 9 a.m. dosing. This was true for single dose and at steady-state and suggests delayed and diminished absorption at night. No statistically significant changes were seen in the young subjects.This study therefore suggests that time related changes in absorption may be more significant in elderly subjects, possibly due to postural differences after 9 p.m. dosing, and this should be borne in mind when prescribing.     

Role of calcium in arachidonic acid-induced contractions of guinea pig airways

We have previously shown that arachidonic acid (AA)-induced contractions of indomethacin-pretreated guinea pig trachea and parenchyma are due to the synthesis of leukotrienes C4 and D4. The present experiments were designed to investigate the role of calcium (Ca2+) in the above. AA (66 microM)-induced contractions of trachea, but not parenchyma, were reduced in Ca2+-free Krebs-Henseleit solution ( KHS ). However the contractions of both trachea and parenchyma were abolished in Ca2+-free KHS with either lanthanum chloride (1 mM) or EDTA (300 microM). The Ca2+ antagonists, verapamil (100 microM), nitrendipine (100 microM), and TMB-8 (100 microM), reduced AA-induced contractions of both trachea and parenchyma. Re-addition of Ca2+ (2.2 mM) to trachea and parenchyma in Ca2+-free KHS in the presence of lanthanum restored the AA-induced contractions. This effect of Ca2+ was reduced by verapamil (100 microM) or nitrendipine (100 microM). LTC4-induced contractions of trachea and parenchyma were unaffected by nitrendipine (100 microM), whereas tracheal contractions were reduced in Ca2+-free KHS . Both tracheal and parenchymal contractions to LTC4 were reduced in Ca2+-free KHS in the presence of lanthanum chloride (1 mM). We conclude that superficially bound pools of Ca2+ are important in AA-induced contractions of the airways. Furthermore, nitrendipine reduces AA-induced contractions by inhibiting AA metabolism and not by inhibiting airway smooth muscle contraction induced by released leukotrienes.     

Morphologic findings in central bronchi correlated to lung function data in obstructive airways disease.

Quantitative analyses of morphologic findings are the condition of clinico-pathological correlation studies. These quantitative analyses are possible by morphometry. The present correlation study shows that morphometry may therefore contribute to understanding the pathogenesis of obstructive airways disease: decreasing bronchial lumen and increasing volume of grandular ducts are correlated to increasing airways resistances (clinical parameters: RAW, FEV1). Increasing volume of bronchial muscles is correlated with resistance of airways at quiet breathing (RAW) and less with increasing residual volume (RV). Increasing volume of bronchial glands and glandular ducts is correlated with increasing resistance at forced expiration which is clinically shown by decreasing FEV1. These findings can be interpreted as follows. Airway resistances are mainly influenced by airway narrowing.At quiet breathing, muscle constriction is an additional cause of increasing airflow resistance due to bronchial narrowing. At forced expiration, however, mucus plugs probably limit the airflow because thickening of bronchial glands points to increased secretory activity. Until now it is not possible to understand why bronchial muscle volume correlates with residual volume.     

Feeling cold at work increases the risk of symptoms from muscles, skin, and airways in seafood industry workers

BACKGROUND: Norwegian workers in seafood industry plants are exposed to a cold and often wet environment. METHODS: 1,767 seafood industry workers participated in a questionnaire study. Seventeen plants were visited for thermal measurements. RESULTS: 15.9% of industrial workers and 1.7% of administrative workers reported that they often felt cold at work. Mean finger temperatures after 1 hr work varied between 16 and 22 degrees C. Foot temperature dropped from morning measurement until lunch time in 85% of the measurements. Industrial workers who reported that they often felt cold, had significantly increased prevalence of symptoms from muscles, skin, and airways while working, compared to workers who reported that they never felt cold at work. CONCLUSIONS: Moderate cooling, caused by a cold indoor working environment, may increase muscle-, airway-, and skin symptoms. The prevalence of feeling cold may be a useful exposure estimate in moderate cold exposure situations.     

Relevance of a portable spirometer for detection of small airways obstruction

While portable spirometers are increasingly used, little attention has been paid to test their validity for measurement of flows in small airways. The aim of this study was to compare the Spirotel portable spirometer to a laboratory spirometer (Jeager PFT), with regard to accuracy in measuring forced expiratory flows, and more specifically those influenced by small airways (FEF(25-75)). Fifty-nine children (mean age, 12 years; range, 7-17), were studied at baseline and after a bronchodilator inhalation. Spirometers were tested separately in a randomly designed order. A total of 117 sessions of flow-volume curves was performed with each spirometer. We obtained at least two acceptable and reproducible curves in 88% and 76% of the sessions, with the laboratory and the portable spirometers, respectively. Unacceptable curves were easily detected by visual inspection of flow-time and flow-volume waveforms. Agreement was excellent between spirometers for the measurement of all expiratory flows, both at baseline and postbronchodilator. More specifically, agreement between spirometers was as high for measurements of FEF(25-75) (intraclass correlation coefficients 0.97) as for proximal flows. High correlations were found between baseline expiratory flows measured by each spirometer (and expressed as percent of predicted values), both in large and small airways (P < 0.001). The portable spirometer was highly sensitive for detecting small airways obstruction, as compared to the laboratory spirometer. Finally, the magnitudes of bronchodilator-related flow changes were also highly correlated, both in large and small airways (P < 0.001 and P = 0.004, respectively). We conclude that the Spirotel portable spirometer is reliable for measurement of forced expiratory flows, in large and small airways, provided that all curve waveforms can be stored and available for visual inspection.     

Mitogenic signaling pathways in airway smooth muscle

Increased airway smooth muscle mass has been demonstrated in patients with asthma, bronchopulmonary dysplasia and most recently, cystic fibrosis. These observations emphasize the need for further knowledge of the events involved in airway smooth muscle mitogenesis and hypertrophy. Workers in the field have developed cell culture systems involving tracheal and bronchial myocytes from different species. An emergent body of literature indicates that mutual signal transduction pathways control airway smooth muscle cell cycle entry across species lines. This article reviews what is known about mitogen-activated signal transduction in airway myocytes. The extracellular signal regulated kinase (ERK) and phosphatidylinositol 3-kinase (PI 3-kinase) pathways appear to be key positive regulators of airway smooth muscle mitogenesis; recent studies have also demonstrated specific roles for reactive oxygen and the JAK/STAT pathway. It is also possible that growth factor stimulation of airway smooth muscle concurrently elicits signaling through negative regulatory intermediates such as p38 mitogen-activated protein (MAP) kinase and protein kinase C (PKC) delta, conceivably as a defense against extreme growth.     

Occupational asthma (OA) with sensitization to diphenylmethane diisocyanate (MDI) presenting at the onset like a reactive airways dysfunction syndrome (RADS)

BACKGROUND: Two types of OA are distinguished: immunological (OA with sensitization) and non-immunological, i.e., irritant induced asthma or reactive airways dysfunction syndrome (RADS). METHODS: We describe the case of a worker who developed respiratory symptoms after a spill of diphenylmethane diisocyanate (MDI) at the workplace. RADS was initially diagnosed and the worker resumed working. The progressive worsening of symptoms and the appearance of symptoms-work relationship one year later, when concentrations of isocyanates were no longer "irritant," suggested immunological OA. RESULTS: The diagnosis was confirmed by specific inhalation challenge test, followed by removal from exposure and complete recovery. CONCLUSIONS: In the case of RADS due to an agent with both irritant and sensitizing properties, history should be repeatedly assessed for a possible symptom-work relationship. If this is found, further investigations should be carried out, including specific inhalation challenges, to confirm the possibility of immunological OA.     

Characterization of the interstitial lung diseases via density-based and texture-based analysis of computed tomography images of lung structure and function

RATIONALE AND OBJECTIVES: Efforts to establish a quantitative approach to the computed tomography (CT)-based character ization of the lung parenchyma in interstitial lung disease (including emphysema) has been sought. The accuracy of these tools must be site independent. Multi-detector row CT has remained the gold standard for imaging the lung, and it provides the ability to image both lung structure as well as lung function. MATERIAL AND METHODS: Imaging is via multi-detector row CT and protocols include careful control of lung volume during scanning. Characterization includes not only anatomic-based measures but also functional measures including regional parameters derived from measures of pulmonary blood flow and ventilation. Image processing includes the automated detection of the lungs, lobes, and airways. The airways provide the road map to the lung parenchyma. Software automatically detects the airways, the airway centerlines, and the branch points, and then automatically labels the airway tree segments with a standardized set of labels, allowing for intersubject as well intrasubject comparisons across time. By warping all lungs to a common atlas, the atlas provides the range of normality for the various parameters provided by CT imaging. RESULTS: Imaged density and textural changes mark underlying structural changes at the most peripheral regions of the lung. Additionally, texture-based alterations in the parameters of blood flow may provide early evidence of pathologic processes. Imaging of stable xenon gas provides a regional measure of ventilation which, when coupled with measures of flow, provide for a textural analysis regional of ventilation-perfusion matching. CONCLUSION: With the improved resolution and speed of CT imaging, the patchy nature of regional parenchymal pathology can be imaged as texture of structure and function. With careful control of imaging protocols and the use of objective image analysis methods it is possible to provide site-independent tools for the assessment of interstitial lung disease. There remains a need to validate these methods, which requires interdisciplinary and cross-institutional efforts to gather appropriate data bases of images along with a consensus on appropriate ground truths associated with the images. Furthermore, there is the growing need for scanner manufacturers to focus on not just visually pleasing images, but on quantitatifiably accurate images.     

Proliferation during early phases of bronchiolar repair in neonatal rabbits following lung injury by 4-ipomeanol

Nonciliated bronchiolar (Clara cells) are progenitor cells during development. During differentiation, they are more susceptible to injury by environmental toxicants metabolized by the cytochrome P450 monooxygenase system, and injury results in altered bronchiolar repair and development. Squamous cells and abnormal cuboidal epithelium persist into early adulthood. The hypothesis tested in this study was that the failure of bronchiolar epithelium to repair normally in neonates following injury is due to an inhibition of proliferation. A model of differential repair in rabbit kits was used. Proliferation was followed for 1 week post injury in rabbit kits treated with a single dose of the P450-mediated cytotoxicant 4-ipomeanol (IPO) at 7 days old (repair abnormal) and compared to rabbits treated with a single dose of IPO at 21 days old (repair normal). Proliferation was measured by the nuclear incorporation of 5-chloro-2'-deoxyuridine (CldU) within epithelium at the target site (terminal bronchiole). The repair pattern between the two age groups was histologically defined. There was no difference in the CldU labeling index during the week of repair between the two age groups, even though the bronchiolar epithelium did not return to normal in the animals treated at 7 days old. In summary, proliferation (through S-phase) is not inhibited during repair in neonatal rabbits treated with IPO at 7 days old compared to animals treated at 21 days old, and we conclude that other factors may be responsible for the altered repair in the young neonates injured by a P450-mediated cytotoxicant.