Tolerance and microbiological efficacy of cefepime or piperacillin/tazobactam in combination with vancomycin as empirical antimicrobial therapy of prosthetic joint infection: a propensity-matched cohort study.

BACKGROUND: The use of piperacillin/tazobactam with vancomycin as empirical antimicrobial therapy (EAT) for prosthetic joint infection (PJI) has been associated with an increased risk of acute kidney injury (AKI), leading us to propose cefepime as an alternative since 2017 in our reference centre. OBJECTIVES: To compare microbiological efficacy and tolerance of these two EAT strategies. METHODS: All adult patients with PJI empirically treated with vancomycin+cefepime (n = 89) were enrolled in a prospective observational study and matched with vancomycin+piperacillin/tazobactam-treated historical controls (n = 89) according to a propensity score including age, baseline renal function and concomitant use of other nephrotoxic agents. The two groups were compared using Kaplan-Meier curve analysis, and non-parametric tests regarding the proportion of efficacious empirical regimen and the incidence of empirical therapy-related adverse events (AE). RESULTS: Among 146 (82.0%) documented infections, the EAT was considered efficacious in 77 (98.7%) and 65 (98.5%) of the piperacillin/tazobactam- and cefepime-treated patients, respectively (P = 1.000). The rate of AE, particularly AKI, was significantly higher in the vancomycin+piperacillin/tazobactam group [n = 27 (30.3%) for all AE and 23 (25.8%) for AKI] compared with the vancomycin+cefepime [n = 13 (14.6%) and 6 (6.7%)] group (P = 0.019 and <0.001, respectively), leading to premature EAT discontinuation in 20 (22.5%) and 5 (5.6%) patients (P = 0.002). The two groups were not significantly different regarding their comorbidities, and AKI incidence was not related to vancomycin plasma overexposure. CONCLUSIONS: Based on the susceptibility profile of bacterial isolates from included patients, microbiological efficacy of both strategies was expected to be similar, but vancomycin + cefepime was associated with a significantly lower incidence of AKI.

Combined ACL reconstruction and opening wedge high tibial osteotomy at 10-year follow-up: excellent laxity control but uncertain return to high level sport.

PURPOSE: The purpose of this study was to report the long-term outcomes of a continuous series of patients who underwent simultaneous anterior cruciate ligament (ACL) reconstruction and opening wedge high tibial osteotomy (HTO) for varus-related early medial tibio-femoral osteoarthritis. It was hypothesized that this combined surgery sustainably allowed return to sport with efficient clinical and radiological results. METHODS: From 1995 to 2015, all combined ACL reconstruction (bone-patellar tendon-bone graft) and opening wedge HTO for anterior laxity and early medial arthritis were included. Clinical evaluation at final follow-up used Tegner activity score, Lysholm score, subjective and objective IKDC scores. Radiologic evaluation consisted in full-length, standing, hip-to-ankle X-rays, monopodal weight-bearing X-rays and skyline views. AP laxity assessment used Telos™ at 150 N load. Student's t test was performed for matched parametric data, Wilcoxon for nonparametric variables and Friedman test was used to compare small cohorts, with p < 0.05. RESULTS: 35 Patients (36 knees) were reviewed with a mean follow-up of 10 ± 5.2 years. The mean age at surgery was 39 ± 9. At final follow-up 28 patients (80%) returned to sport (IKDC ≥ B): 11 patients (31%) returned to sport at the same level and 6 (17%) to competitive sports. Mean subjective IKDC and Lysholm scores were 71.8 ± 14.9 and 82 ± 14.1, respectively. The mean decrease of the Tegner activity level from preinjury state to follow-up was 0.8 (p < 0.01). Mean side-to-side difference in anterior tibial translation was 5.1 ± 3.8 mm. Three patients were considered as failures. The mean preoperative mechanical axis was 4.2° ± 2.6° varus and 0.8° ± 2.7° valgus at follow-up. Osteoarthritis progression for medial, lateral, and femoro-patellar compartments was recorded for 12 (33%, p < 0.05), 6 (17%, p < 0.001), and 8 (22%, p < 0.05) knees, respectively. No femoro-tibial osteoarthritis progression was observed in 22 knees (61%). CONCLUSIONS: Combined ACL reconstruction and opening wedge HTO allowed sustainable stabilization of the knee at 10-year follow-up. However, return to sport at the same level was possible just for one-third of patients, with femoro-tibial osteoarthritis progression in 39% of cases. LEVEL OF EVIDENCE: III.

Chronic inflation of ferret lungs with CPAP reduces airway smooth muscle contractility in vivo and in vitro.

The mechanical stress imposed on the lungs during breathing is an important modulator of airway responsiveness in vivo. Our recent study demonstrated that continuous positive airway pressure applied to the lungs of nonanesthetized, tracheotomized rabbits for 4 days decreased lower respiratory system responsiveness to challenge with ACh (Xue Z, Zhang L, Ramchandani R, Liu Y, Antony VB, Gunst SJ, Tepper RS. J. Appl Physiol 99: 677-682, 2005). In addition, airway segments excised from the lungs of these animals and studied in vitro exhibited reduced contractility. However, the mechanism for this reduction in contractility was not determined. The stress-induced decrease in airway responsiveness could have resulted from alterations in the excitation-contraction coupling mechanisms of the smooth muscle cells, or it might reflect changes in the structure and/or composition of the airway wall tissues. In the present study, we assessed the effect of prolonged chronic stress of the lungs in vivo on airway smooth muscle force generation, myosin light chain phosphorylation, and airway wall structure. To enhance the potential development of stress-induced structural changes, we applied mechanical stress for a prolonged period of time of 2-3 wk. Our results demonstrate a direct connection between the decreased airway responsiveness caused by chronic mechanical stress of the lungs in vivo and a persistent decrease in contractile protein activation in the airway smooth muscle isolated from those lungs. The chronic stress also caused an increase in airway size but no detectable changes in the composition of the airway wall.

Percutaneous fixation of valgus displaced fracture of the proximal humerus using a single screw.

Valgus-impacted proximal humerus fracture is a classic but rare entity in shoulder traumatology. Surgical treatment is controversial, with increasing use of minimally invasive techniques. Our technique uses a minimally invasive approach under fluoroscopic control. Raising the humeral head to reduce the valgus enables spontaneous and well-positioned reduction of the tuberosities and screw fixation between the greater tuberosity and the humeral shaft. Indications comprise valgus-impacted fracture without comminution of the medial epiphyseal-metaphyseal hinge or greater tuberosity; the rotator cuff contributes to reduction and must be intact. This type of fixation restores proximal humerus anatomy and achieves consolidation with low risk of secondary necrosis. Minimally invasive single-screw fixation is an alternative of choice for surgical treatment of valgus-impacted proximal humerus fracture.

Central tarsal bone fractures in horses not used for racing: Computed tomographic configuration and long-term outcome of lag screw fixation.

REASONS FOR PERFORMING STUDY: There are no reports on the configuration of equine central tarsal bone fractures based on cross-sectional imaging and clinical and radiographic long-term outcome after internal fixation. OBJECTIVES: To report clinical, radiographic and computed tomographic findings of equine central tarsal bone fractures and to evaluate the long-term outcome of internal fixation. STUDY DESIGN: Retrospective case series. METHODS: All horses diagnosed with a central tarsal bone fracture at our institution in 2009-2013 were included. Computed tomography and internal fixation using lag screw technique was performed in all patients. Medical records and diagnostic images were reviewed retrospectively. A clinical and radiographic follow-up examination was performed at least 1 year post operatively. RESULTS: A central tarsal bone fracture was diagnosed in 6 horses. Five were Warmbloods used for showjumping and one was a Quarter Horse used for reining. All horses had sagittal slab fractures that began dorsally, ran in a plantar or plantaromedial direction and exited the plantar cortex at the plantar or plantaromedial indentation of the central tarsal bone. Marked sclerosis of the central tarsal bone was diagnosed in all patients. At long-term follow-up, 5/6 horses were sound and used as intended although mild osteophyte formation at the distal intertarsal joint was commonly observed. CONCLUSIONS: Central tarsal bone fractures in nonracehorses had a distinct configuration but radiographically subtle additional fracture lines can occur. A chronic stress related aetiology seems likely. Internal fixation of these fractures based on an accurate diagnosis of the individual fracture configuration resulted in a very good prognosis.

Chronic strain alters the passive and contractile properties of rabbit airways.

Pathophysiological conditions of the lung may shift the balance of forces so as to chronically alter the amount of strain imposed on the airways. This chronic strain could result in changes in the structure and/or function of the airways that affect its physiological properties. We evaluated the effects of imposing physiological levels of chronic mechanical strain on the passive and active physiological properties of intraparenchymal rabbit airways. Isolated bronchial segments were cultured for 48 h at transmural pressures of 0 cmH(2)O (No Strain) or 7 cmH(2)O (Strain). Effects of strain on small parenchymal airways were evaluated in lung tissue slices cultured under conditions of No Strain or approximately 50% increased in diameter (Strain). Chronic strain resulted in a higher passive compliance of the bronchial segments and larger airway lumen size. In addition, bronchi not subjected to chronic Strain were more responsive to ACh than bronchi subjected to chronic Strain, and airways in lung slices subjected to No Strain narrowed more in response to ACh than airways in lung slices subjected to Strain. The greatest effects of chronic strain occurred in the smallest sized airways. Our results suggest that chronic distension of the airways has physiologically important effects on their passive and active properties, which are most prominent in the smaller, more peripheral airways.

Respiratory system responsiveness in rabbits in vivo is reduced by prolonged continuous positive airway pressure.

Active, nonanesthetized, tracheotomized rabbits were subjected to continuous positive airway pressure (CPAP) for 4 days to determine the effects of chronic mechanical strain on lung and airway function. Rabbits were maintained for 4 days at a CPAP of 6 cmH(2)O (high CPAP), at a CPAP of 0 cmH(2)O (low CPAP), or without tracheostomy (no CPAP). After treatment with CPAP, changes in respiratory resistance in response to increasing concentrations of inhaled ACh were measured during mechanical ventilation to evaluate respiratory system responsiveness in vivo. Intraparenchymal bronchial segments were isolated from the lungs of all animals to evaluate airway smooth muscle responsiveness and bronchial compliance in vitro. Rabbits maintained for 4 days at high CPAP demonstrated significantly lower responsiveness to ACh compared with rabbits that were maintained at low CPAP or with no CPAP. Airways isolated from the lungs of animals subjected to the chronic application of high CPAP were also less responsive to ACh in vitro than the airways isolated from animals subjected to low CPAP or no CPAP. The persistence of the decreased responsiveness in the excised airway tissues suggests that the decreased respiratory system responsiveness observed in vivo results primarily from direct effects on the airways. The results demonstrate that the application of prolonged mechanical strain in vivo can reduce airway reactivity.

Effects of extracellular calcium on canine tracheal smooth muscle.

Strips of canine tracheal smooth muscle were studied in vitro to determine the effects of changes in the extracellular calcium (Cao) concentration on tonic contractions induced by acetylcholine and 5-hydroxytryptamine. Strips were contracted with graded concentrations of the above agents in 2.4 mM Ca, after which CaCl2 was administered to achieve final concentrations of 5.0, 10.0, and 20.0 mM. Increases in Cao to 5 mM or above caused significant relaxation of muscles contracted with 5-hydroxytryptamine but did not significantly relax muscles contracted with acetylcholine. Increases in Cao also caused significant relaxation of muscles contracted with low concentrations of K+ (20 or 30 mM). However, in 60 or 120 mM K+, increases in Cao resulted predominantly in muscle contraction. Inhibition of the Na+-K+-ATPase by ouabain (10(-5) M) or K+ depletion reversed the effects of Cao from relaxation to contraction in tissues contracted with 5-hydroxytryptamine. Increases in Cao also caused contraction rather than relaxation in the presence of verapamil (10(-6) M). We conclude that calcium has both excitatory and inhibitory effects on the contractile responses of canine tracheal smooth muscle. The inhibitory effects of Ca2+ appear to be linked to the activity of the membrane Na+-K+-ATPase.

Selected contribution: roles of focal adhesion kinase and paxillin in the mechanosensitive regulation of myosin phosphorylation in smooth muscle.

The increase in intracellular Ca(2+) and myosin light chain (MLC) phosphorylation in response to the contractile activation of tracheal smooth muscle is greater at longer muscle lengths (21). However, MLC phosphorylation can also be stimulated by Ca(2+)-insensitive signaling pathways (19). The cytoskeletal proteins paxillin and focal adhesion kinase (FAK) mediate a Ca(2+)-independent length-sensitive signaling pathway in tracheal smooth muscle (30). We used alpha-toxin-permeabilized tracheal smooth muscle strips to determine whether the length sensitivity of MLC phosphorylation can be regulated by a Ca(2+)-insensitive signaling pathway and whether the length sensitivity of active tension depends on the length sensitivity of myosin activation. Although active tension remained length sensitive, ACh-induced MLC phosphorylation was the same at optimal muscle length (L(o)) and 0.5 L(o) when intracellular Ca(2+) was maintained at pCa 7. MLC phosphorylation was also the same at L(o) and 0.5 L(o) in strips stimulated with 10 microM Ca(2+). In contrast, the Ca(2+)-insensitive tyrosine phosphorylation of FAK and paxillin stimulated by ACh was higher at L(o) than at 0.5 L(o). We conclude that the length-sensitivity of MLC phosphorylation depends on length-dependent changes in intracellular Ca(2+) but that length-dependent changes in MLC phosphorylation are not the primary mechanism for the length sensitivity of active tension.

Invited review: focal adhesion and small heat shock proteins in the regulation of actin remodeling and contractility in smooth muscle.

Smooth muscle cells are able to adapt rapidly to chemical and mechanical signals impinging on the cell surface. It has been suggested that dynamic changes in the actin cytoskeleton contribute to the processes of contractile activation and mechanical adaptation in smooth muscle. In this review, evidence for functionally important changes in actin polymerization during smooth muscle contraction is summarized. The functions and regulation of proteins associated with "focal adhesion complexes" (membrane-associated dense plaques) in differentiated smooth muscle, including integrins, focal adhesion kinase (FAK), c-Src, paxillin, and the 27-kDa small heat shock protein (HSP27) are described. Integrins in smooth muscles are key elements of mechanotransduction pathways that communicate with and are regulated by focal adhesion proteins that include FAK, c-Src, and paxillin as well as proteins known to mediate cytoskeletal remodeling. Evidence that functions of FAK and c-Src protein kinases are closely intertwined is discussed as well as evidence that focal adhesion proteins mediate key signal transduction events that regulate actin remodeling and contraction. HSP27 is reviewed as a potentially significant effector protein that may regulate actin dynamics and cross-bridge function in response to activation of p21-activated kinase and the p38 mitogen-activated protein kinase signaling pathway by signaling pathways linked to integrin proteins. These signaling pathways are only part of a large number of yet to be defined pathways that mediate acute adaptive responses of the cytoskeleton in smooth muscle to environmental stimuli.

Selected contribution: plasticity of airway smooth muscle stiffness and extensibility: role of length-adaptive mechanisms.

Airway smooth muscle exhibits the property of length adaptation, which enables it to optimize its contractility to the mechanical conditions under which it is activated. Length adaptation has been proposed to result from a dynamic modulation of contractile and cytoskeletal filament organization, in which the cell structure adapts to changes in cell shape at different muscle lengths. Changes in filament organization would be predicted to alter muscle stiffness and extensibility. We analyzed the effects of tracheal muscle length at the time of contractile activation on the stiffness and extensibility of the muscle during subsequent stretch over a constant range of muscle lengths. Muscle strips were significantly stiffer and less extensible after contractile activation at a short length than after activation at a long length, consistent with the prediction of a shorter, thicker array of the cytoskeletal filaments at a short muscle length. Stretch beyond the length of contractile activation resulted in a persistent reduction in stiffness, suggesting a stretch-induced structural rearrangement. Our results support a model in which the filament organization of airway smooth muscle cells is plastic and can be acutely remodeled to adapt to the changes in the external physical environment.

Effect of Na-K adenosinetriphosphatase activity on relaxation of canine tracheal smooth muscle.

The effect of Na-K adenosinetriphosphatase (ATPase) on relaxation induced by isoproterenol, prostaglandin E2, sodium nitroprusside, and forskolin, a specific stimulant of adenylate cyclase, was investigated in canine tracheal smooth muscle strips. Relaxation in response to isoproterenol, prostaglandin E2, and forskolin was significantly decreased after inhibition of the Na-K ATPase by ouabain or a potassium-free medium, but relaxation to sodium nitroprusside was not affected. Relaxation to isoproterenol was greater in muscles contracted by 5-hydroxytryptamine than in those contracted by acetylcholine. The stimulation of Na-K ATPase activity with potassium also caused differences in relaxation between tissues contracted with 5-hydroxytryptamine or acetylcholine. Relaxation caused by isoproterenol by activation of the Na-K-ATPase was also decreased by the Ca2+-channel antagonists, verapamil and diltiazem. The results suggest 1) Na-K ATPase activity modulates relaxation caused by isoproterenol, prostaglandin E2, and forskolin in canine tracheal smooth muscle, 2) isoproterenol or activation of the Na-K ATPase may cause relaxation partly by reducing Ca2+ influx through potential-dependent Ca2+ channels, and 3) the differences in the inhibitory effects of isoproterenol and Na-K ATPase activity on muscles contracted by acetylcholine and 5-hydroxytryptamine could be due to differences between these contractile agents in their dependence on extracellular Ca2+ for activation.

Pressure-volume and length-stress relationships in canine bronchi in vitro.

Intraparenchymal canine airway segments with branches tied off were mounted between two fluid-filled cannulas in an organ chamber. Airways were inflated to successive volumes ranging from 4 to 100% of the segment volume at 25 cmH2O. At each volume, pressure was monitored during isovolumetric contractions elicited by 10(-3) M acetylcholine. Small bronchi developed pressures greater than 30 cmH2O in response to acetylcholine at all volumes and were able to constrict to closure. Large bronchi developed pressures greater than 30 cmH2O only near maximal volumes and were able to constrict to only 30% of maximal volume. Maximal active pressures occurred at low volumes in small bronchi and at high volumes in large bronchi. However, maximal active circumferential tension and stress occurred at near-maximal volumes in both large and small bronchi. Circumferential length active-stress curves and maximal active-stress development for bronchi and trachealis muscle strips were similar. Similar length active-stress properties in different bronchi may produce significant differences in volume-pressure characteristics.

Mechanical modulation of pressure-volume characteristics of contracted canine airways in vitro.

In normal humans and dogs, the airways do not constrict to closure even when maximally stimulated. However, airway closure can be produced in isolated canine lobes and bronchial segments that are stimulated with maximal concentrations of bronchoconstrictors. These observations suggest that under normal conditions, physiological mechanisms to limit bronchoconstriction exist in vivo. In this investigation, we evaluated how mechanical factors that influence airway smooth muscle contractility contribute to the modulation of the pressure-volume characteristics of contracted canine intraparenchymal airways in vitro. Our results demonstrated that maximal and even submaximal contractile stimuli can produce airway closure in bronchi that are allowed to contract under isobaric conditions. However, the effectiveness of bronchoconstrictors is significantly reduced when the airways are subjected to tidal volume oscillations during contraction. In addition, airways contracted isovolumetrically at low volumes exhibit a markedly reduced sensitivity to submaximal concentrations of acetylcholine. This may limit bronchoconstriction at low lung volumes and transpulmonary pressures where the effectiveness of parenchymal stress in keeping the airways open is reduced. Together these factors could provide a mechanism by which bronchoconstriction is limited to low levels of airway resistance under normal conditions in vivo.

Effect of tidal volume and frequency on airway responsiveness in mechanically ventilated rabbits.

We evaluated the effects of the rate and volume of tidal ventilation on airway resistance (Raw) during intravenous methacholine (MCh) challenge in mechanically ventilated rabbits. Five rabbits were challenged at tidal volumes of 5, 10, and 20 ml/kg at a frequency of 15 breaths/min and also under static conditions (0 ml/kg tidal volume). Four rabbits were subjected to MCh challenge at frequencies of 6 and 30 breaths/min with a tidal volume of 10 ml/kg and also under static conditions. In both groups, the increase in Raw with MCh challenge was significantly greater under static conditions than during tidal ventilation at any frequency or volume. Increases in the volume or frequency of tidal ventilation resulted in significant decreases in Raw in response to MCh. We conclude that tidal breathing suppresses airway responsiveness in rabbits in vivo. The suppression of narrowing in response to MCh increases as the magnitude of the volume or the frequency of the tidal oscillations is increased. Our findings suggest that the effect of lung volume changes on airway responsiveness in vivo is primarily related to the stretch of airway smooth muscle.

Maximal airway response in mature and immature rabbits during tidal ventilation.

Airway closure during maximal methacholine (MCh) challenge was evaluated using alveolar capsules in eight immature and eight mature anesthetized rabbits in vivo during imposed tidal ventilation. Changes in airway opening and alveolar pressures (delta PA) and pulmonary resistance (RL) were measured during MCh challenge at a positive end-expiratory pressure of 5 cmH2O. In immature rabbits, delta PA remained > 3 cmH2O in all animals, indicating no detectable airway closure. This contrasts to our previous study of isolated immature rabbit lungs under static conditions in which delta PA was < 0.1 cmH2O during maximal MCh challenge, findings consistent with airway closure. Airway closure also did not occur in mature animals during tidal ventilation in vivo; however, the frequency of closure in isolated lungs under static conditions was very low. With increasing MCh, end-expiratory PA increased in immature but not in mature rabbits. RL did not reach a plateau in immature rabbits during MCh, whereas a plateau was reached in mature rabbits. Immature rabbits also had greater increases in RL. These results suggest that tidal ventilation can limit bronchoconstriction in immature rabbits and prevent airway closure during maximal MCh challenge. Tidal ventilation may limit bronchoconstriction by inhibitory effects of stretch on airway smooth muscle contraction and also by causing hyperinflation and thereby increasing transpulmonary pressure.

Comparison of the shear modulus of mature and immature rabbit lungs.

Maximal airway narrowing during bronchoconstriction is greater in immature than in mature rabbits. At a given transpulmonary pressure (PL), the lung parenchyma surrounding the airway resists local deformation and provides a load that opposes airway smooth muscle shortening. We hypothesized that the force required to produce lung parenchymal deformation, quantified by the shear modulus, is lower in immature rabbit lungs. The shear modulus and the bulk modulus were measured in isolated mature (n = 8; 6 mo) and immature (n = 9; 3 wk) rabbit lungs at PL of 2, 4, 6, 8, and 10 cmH(2)O. The bulk modulus increased with increasing PL for mature and immature lungs; however, there was no significant difference between the groups. The shear modulus was lower for the immature than the mature lungs (P < 0.025), progressively increasing with increasing PL (P < 0.001) for both groups, and there was no difference between the slopes for shear modulus vs. PL for the mature and the immature lungs. The mean value of the shear modulus for mature and immature rabbit lungs at PL = 6 cmH(2)O was 4.5 vs. 3.8 cmH(2)O. We conclude that the shear modulus is less in immature than mature rabbit lungs. This small maturational difference in the shear modulus probably does not account for the greater airway narrowing in the immature lung, unless its effect is coupled with a relatively thicker and more compliant airway wall in the immature animal.

Bronchoprotective and bronchodilatory effects of deep inspiration in rabbits subjected to bronchial challenge.

The effect of deep inspiration (DI) on airway responsiveness differs in asthmatic and normal human subjects. The mechanism for the effects of DI on airway responsiveness in vivo has not been identified. To elucidate potential mechanisms, we compared the effects of DI imposed before or during induced bronchoconstriction on the airway response to methacholine (MCh) in rabbits. The changes in airway resistance in response to intravenous MCh were continuously monitored. DI depressed the maximum response to MCh when imposed before or during the MCh challenge; however, the inhibitory effect of DI was greater when imposed during bronchoconstriction. Because immature rabbits have greater airway reactivity than mature rabbits, we compared the effects of DI on their airway responses. No differences were observed. Our results suggest that the mechanisms by which DI inhibits airway responsiveness do not depend on prior activation of airway smooth muscle (ASM). These results are consistent with the possibility that reorganization of the contractile apparatus caused by stretch of ASM during DI contributes to depression of the airway response.

Comparison of elastic properties and contractile responses of isolated airway segments from mature and immature rabbits.

Immature rabbits have greater maximal airway narrowing with bronchoconstriction in vivo compared with mature animals. As isolated immature lungs have a lower shear modulus, it is unclear whether the greater airway narrowing in the immature lung is secondary to less tethering between the airways and the lung parenchyma or to differences in the mechanical properties of the mature and immature airways. In the present study, we compared the mechanical properties of fluid-filled, isolated, intraparenchymal airway segments of the same generation from mature and immature rabbits. Stimulation with ACh resulted in greater airway narrowing in immature than mature bronchi. The immature bronchi were more compliant, had a lower resting airway volume, and were more collapsible compared with the mature bronchi. When the airways were contracted with ACh under isovolume conditions, the immature bronchi generated greater active pressure, and they were more sensitive to ACh than were mature bronchi. Our results suggest that maturational differences in the structure and function of the airways in the absence of the lung parenchyma can account for the greater maximal narrowing of immature than mature airways in vivo.