Striated muscle is a linear motor whose properties have been defined in terms of uniaxial structures. The question addressed here is what contribution is made to the properties of this motor by extramyofilament cytoskeletal structures that are not aligned in parallel with the myofilaments. This question arose from observations that transverse loads increase muscle force production in diaphragm but not in the hindlimb muscle, thereby indicating the presence of structures that couple longitudinal and transverse properties of diaphragmatic muscle. Furthermore, we find that the diaphragms of null mutants for the cytoskeletal protein desmin show 1) significant reductions in coupling between the longitudinal and transverse properties, indicating for the first time a role for a specific protein in integrating the three-dimensional mechanical properties of muscle, 2) significant reductions in the stiffness and viscoelasticity of muscle, and 3) significant increases in tetanic force production. Thus desmin serves a complex mechanical function in diaphragm muscle by contributing both to passive stiffness and viscoelasticity and to modulation of active force production in a three-dimensional structural network. Our finding changes the paradigm of force transmission among cells by placing our understanding of the function of the cytoskeleton in the context of the structural and mechanical complexity of muscles.

We compared four algorithms by using least squares regression for determination of pulmonary resistance and dynamic elastance in subjects with emphysema, normal subjects, and subjects with asthma before and after bronchoconstriction. The four methods evaluated include 1) a single resistance and elastance, 2) separate resistances and elastances for each half breath, 3) separate inspiratory and expiratory resistances with a single elastance, and 4) separate inspiratory and expiratory resistances, an expiratory volume interaction term, and a single elastance. All methods gave comparable results in normal and asthmatic subjects. We found expiratory resistance was larger than inspiratory resistance in normal and asthmatic subjects during control conditions, but inspiratory resistance was higher than expiratory resistance in subjects who experienced severe bronchoconstriction in response to methacholine. In subjects who are flow limited, method 2 gives a higher inspiratory resistance than would be computed by assuming that the elastic pressure-volume curve passes through the zero-flow points. Methods 1 and 3 overestimate dynamic elastance and inspiratory resistance. Method 4 appears to identify flow limitation and dynamic hyperinflation and gives a good measure of inspiratory resistance and dynamic elastance.

A total of 48 patients presenting to the emergency department as acute asthma exacerbation were prospectively studied. Rhinolaryngoscopy was conducted with simultaneous flow measurements and spirometry performed before and after the procedure. Measurements of the vocal cord opening during various phases of respiration were analyzed. Only 4 of 48 patients had anterior two-thirds closure of the vocal cords with a diamond-shaped opening posteriorly during expiration. One additional patient had inspiratory and expiratory closure of the vocal cords. The previously unreported high incidence of anterior two-thirds closure (10.4%) of the vocal cords suggests that the upper airway has a role to play in a significant number of patients presenting with symptoms of asthma exacerbation.

Rationale: Improvement in FEV 1 is a main endpoint in clinical trials assessing the efficacy of bronchodilators. However, the effect of bronchodilators on maximal expiratory flow may be confounded by thoracic gas compression (TGC). Objective: To determine whether TGC confounds effect of albuterol on FEV 1 . Methods: We evaluated the response to albuterol inhalation in 10 healthy subjects, 9 subjects with asthma, and 15 subjects with chronic obstructive pulmonary disease (COPD) with mean (SD) age in years of 38 (SD, 11), 45 (SD, 11), and 64 (SD, 8), respectively. Lung mechanics were measured at baseline and 20 minutes after inhalation of 180 g of albuterol. We then applied a novel method to calculate FEV 1 corrected for the effect of TGC (NFEV 1 ). Results: Prior to albuterol administration, NFEV 1 was significantly higher than FEV 1 . However, post-albuterol inhalation, FEV 1 increased more than NFEV 1 because of reduced TGC. In multiple regression analysis, the changes in TGC, inspiratory lung resistance, and ratio of residual volume to total lung capacity postalbuterol predicted more than 75% of FEV 1 improvement in patients with COPD. Conclusion: Improvements in FEV 1 after albuterol in patients with COPD are due to reduction of lung resistance, hyperinflation, and TGC. The latter is negligible during tidal breathing. Thus, although reduction of lung resistance and hyperinflation may result in improved dyspnea with a bronchodilator, the contribution of TGC reduction to improvement of FEV 1 may not exert any meaningful clinical effect during tidal breathing. This fact has to be taken into consideration when assessing the efficacy of new bronchodilators. Keywords: FEV 1 ; chronic obstructive pulmonary disease; asthma; lung mechanics; albuterol Expiratory airflow limitation is the hallmark of physiologic abnormality in asthma and chronic obstructive pulmonary disease (COPD) (1-3). Bronchodilators improve expiratory airflow, thus improving exercise capacity and relieving symptoms in patients suffering from these diseases. Clinical trials assessing the effect of bronchodilators use the improvement in FEV 1 as the main efficacy endpoint. However, FEV 1 improvement does not correlate very well with improvement in symptoms and exercise capacity (4).

During forced vital capacity maneuvers in subjects with expiratory flow limitation, lung volume decreases during expiration both by air flowing out of the lung (i.e., exhaled volume) and by compression of gas within the thorax. As a result, a flow-volume loop generated by using exhaled volume is not representative of the actual flow-volume relationship. We present a novel method to take into account the effects of gas compression on flow and volume in the first second of a forced expiratory maneuver (FEV(1)). In addition to oral and esophageal pressures, we measured flow and volume simultaneously using a volume-displacement plethysmograph and a pneumotachograph in normal subjects and patients with expiratory flow limitation. Expiratory flow vs. plethysmograph volume signals was used to generate a flow-volume loop. Specialized software was developed to estimate FEV(1) corrected for gas compression (NFEV(1)). We measured reproducibility of NFEV(1) in repeated maneuvers within the same session and over a 6-mo interval in patients with chronic obstructive pulmonary disease. Our results demonstrate that NFEV(1) significantly correlated with FEV(1), peak expiratory flow, lung expiratory resistance, and total lung capacity. During intrasession, maneuvers with the highest and lowest FEV(1) showed significant statistical difference in mean FEV(1) (P < 0.005), whereas NFEV(1) from the same maneuvers were not significantly different from each other (P > 0.05). Furthermore, variability of NFEV(1) measurements over 6 mo was <5%. We concluded that our method reliably measures the effect of gas compression on expiratory flow.