Relationship between maximal expiratory flows and lung volumes in growing humans

We examined airway vs. lung parenchymal growth, as inferred from maximal expiratory flows (MEF) and lung volumes (V), respectively, to determine whether the interindividual variability of airway size (inferred from MEF) changes during lung growth and whether a young child with large (or small) airways for his parenchymal size (inferred from V) maintains relatively large (or small) airways for his lung size as he grows to adulthood. Serial measurements of MEF and V were obtained from a cohort of healthy 6- to 27-yr-old males (n = 26) and females (n = 21) over a period of 18 yr. Data were analyzed using logarithmic transformation of the power law equation, MEF = aVb, to fit a regression line to each subject's data points. These growth trajectories were satisfactorily modeled as parallel lines with 20-30% variability of their y-intercepts, indicating that substantial intersubject variability of MEF relative to V is present in early childhood and remains constant during growth. The results further indicate that MEF does track V during lung growth. We conclude that dysanapsis originates in early childhood.     

Positive effort dependence of maximal expiratory flow

The maximal expiratory-flow volume (MEFV) curve in normal subjects is thought to be relatively effort independent over most of the vital capacity (VC). We studied seven normal males and found positive effort dependence of maximal expiratory flow between 50 and 80% VC in five of them, as demonstrated by standard isovolume pressure-flow (IVPF) curves. We then attempted to distinguish the effects of chest wall conformational changes from possible mechanisms intrinsic to the lungs as an explanation for positive effort dependence. IVPF curves were repeated in four of the subjects who had demonstrated positive effort dependence. Transpulmonary pressure was varied by introducing varied resistances at the mouth but effort, as defined by pleural pressure, was maintained constant. By this method, chest wall conformation at a given volume would be expected to remain the same despite changing transpulmonary pressures. When these four subjects were retested in this way, no increases in flow with increasing transpulmonary pressure were found. In further studies, voluntarily altering the chest wall pattern of emptying (as defined by respiratory inductive plethysmography) did however alter maximal expiratory flows, with transpulmonary pressure maintained constant. We conclude that maximal expiratory flow can increase with effort over a larger portion of the vital capacity than is commonly recognized, and this effort dependence may be the result of changes in central airway mechanical properties that occur in relation to changes in chest wall shape during forced expiration.     

Mechanistic Role of Structurally Dynamic Regions in Dicistroviridae IGR IRESs

Dicistroviridae intergenic region (IGR) internal ribosome entry site(s) (IRES) RNAs drive a cap-independent pathway of translation initiation, recruiting both small and large ribosomal subunits to viral RNA without the use of any canonical translation initiation factors. This ability is conferred by the folded three-dimensional structure of the IRES RNA, which has been solved by X-ray crystallography. Here, we report the chemical probing of Plautia stali intestine virus IGR IRES in the unbound form, in the 40S-subunit-bound form, and in the 80S-ribosome-bound form. The results, when combined with an analysis of crystal structures, suggest that parts of the IRES RNA change structure as the preinitiation complex forms. Using mutagenesis coupled with native gel electrophoresis, preinitiation complex assembly assays, and translation initiation assays, we show that these potentially structurally dynamic elements of the IRES are involved in different steps in the pathway of ribosome recruitment and translation initiation. Like tRNAs, it appears that the IGR IRES undergoes local structural changes that are coordinated with structural changes in the ribosome, and these are critical for the IRES mechanism of action.     

Density dependence of maximal expiratory flow before and during tracheal constriction in dogs

The effect of carbachol-induced central bronchoconstriction on density dependence of maximal expiratory flow (MEF) was assessed in five dogs. MEFs were measured on air and an 80% He-20% O2 mixture before and after local application of carbachol to the trachea. Airway pressures were measured using a pitot-static probe, from which central airway areas were estimated. At lower concentrations of carbachol the flow-limiting site remained in the trachea over most of the vital capacity (VC), and tracheal area and compliance decreased in all five dogs. In four dogs, decreases in choke point area predominated and produced decreases in flows. In one dog the increase in airway "stiffness" apparently offset the fall in area to account for an increase in MEF. Density dependence measured as the ratio of MEF on HeO2 to MEF on air at 50% of VC increased in all five dogs. Increases in density dependence appeared to be related to increases in airway stiffness at the choke point rather than decreases in gas-related airway pressure differences. Lower concentrations produced a localized decrease in tracheal area and extended the plateau of the flow-volume curve to lower lung volumes. Higher concentrations caused further reductions in tracheal area and greater longitudinal extension of bronchoconstriction, resulting in upstream movement of the site of flow limitation at higher lung volumes. Density dependence increased if the flow-limiting sites remained in the trachea at mid-VC but fell if the flow-limiting site had moved upstream by that volume.     

Macromolecular conformation of chitosan in dilute solution: A new global hydrodynamic approach

Chitosans of different molar masses were prepared by storing freshly prepared samples for up to 6 months at either 4, 25 or 40 °C. The weight-average molar masses, M_w and intrinsic viscosities, [η] were then measured using size exclusion chromatography coupled to multi-angle laser light scattering (SEC-MALLS) and a “rolling ball” viscometer, respectively.The solution conformation of chitosan was then estimated from:

(a) the Mark–Houwink–Kuhn–Sakurada (MHKS) power law relationship [η] = kM_w^a and

(b) the persistence length, L_p calculated from a new approach based on equivalent radii [Ortega, A., & Garcia de la Torre, J. (2007). Equivalent radii and ratios of radii from solution properties as indicators of macromolecular conformation, shape, and flexibility. Biomacromolecules, 8, 2464–2475].

Both the MHKS power law exponent (a = 0.95 ± 0.01) and the persistence length (L_p = 16 ± 2 nm) are consistent with a semi-flexible rod type (or stiff coil) conformation for all 33 chitosans studied. A semi-flexible rod conformation was further supported by the Wales–van Holde ratio, the translational frictional ratio and sedimentation conformation zoning.     

Density dependence of forced expiratory flows in healthy infants and toddlers.

In older children and adults, density dependence (DD) of forced expiratory flow is present over the majority of the full flow-volume curve. In healthy subjects, DD occurs because the pressure drop from peripheral to central airways is primarily dependent on turbulence and convective acceleration rather than laminar resistance; however, an increase in peripheral resistance reduces DD. We measured DD of forced expiratory flow in 22 healthy infants to evaluate whether infants have low DD. Full forced expiratory maneuvers were obtained while the subjects breathed room air and then a mixture of 80% helium-20% oxygen. Flows at 50 and 75% of expired forced vital capacity (FVC) were measured, and the ratio of helium-oxygen to air flow was calculated (DD at 50 and 75% FVC). The mean (range) of DD at 50 and 75% FVC was 1.37 (1.22-1.54) and 1.23 (1.02-1.65), respectively, values similar to those reported in older children and adults. There were no significant relationships between DD and age. Our results suggest that infants, compared with older children and adults, have similar DD, a finding that suggests that infants do not have a greater ratio of peripheral-to-central airway resistance.     

Model of forced expiratory flows and airway geometry in infants.

Early measurements of autopsied lungs from infants, children, and adults suggested that the ratio of peripheral to central airway resistance was higher in infants than older children and adults. Recent measurements of forced expiration suggest that infants have high flows relative to lung volume. We employed a computational model of forced expiratory flow along with physiological and anatomic data to evaluate whether the infant lung is a uniformly scaled-down version of the adult lung. First, we uniformly scaled an existing computational model of adult forced expiration to estimate forced expiratory flows (FEF) and density dependence for an 18-mo-old infant. The values obtained for FEF and density dependence were significantly lower than those reported for healthy 18-mo-old infants. Next, we modified the model for the infant lung to reproduce standard indexes of expiratory flow [forced expiratory volume in 0.5 s (FEV(0.5)), FEFs after exhalation of 50 and 75% forced vital capacity, FEF between 25 and 75% expired volume] for this age group. The airway sizes obtained for the infant lung model that produced accurate physiological measurements were similar to anatomic data available for this age and larger than those in the scaled model. Our findings indicate that the airways in the infant lung model differ from those in the scaled model, i.e., middle and peripheral airway sizes are larger than result from uniform downscaling of the adult lung model. We show that the infant lung model can be made to reproduce individual flow-volume curves by adjusting lumen area generation by generation.