Efficient Magnon Injection and Detection via the Orbital Rashba-Edelstein Effect.

Orbital currents and accumulation provide a new avenue to boost spintronic effects in nanodevices. Here, we use interconversion effects between charge current and orbital angular momentum to demonstrate a dramatic increase in the magnon spin injection and detection efficiencies in nanodevices consisting of a magnetic insulator contacted by Pt/CuO_{x} electrodes. Moreover, we note distinct variations in efficiency for magnon spin injection and detection, indicating a disparity in the direct and inverse orbital Rashba-Edelstein effect efficiencies.

Altered thoracic gas compression contributes to improvement in spirometry with lung volume reduction surgery.

BACKGROUND: Thoracic gas compression (TGC) exerts a negative effect on forced expiratory flow. Lung resistance, effort during a forced expiratory manoeuvre, and absolute lung volume influence TGC. Lung volume reduction surgery (LVRS) reduces lung resistance and absolute lung volume. LVRS may therefore reduce TGC, and such a reduction might explain in part the improvement in forced expiratory flow with the surgery. A study was conducted to determine the effect of LVRS on TGC and the extent to which reduced TGC contributed to an improvement in forced expiratory volume in 1 second (FEV1) following LVRS. METHODS: The effect of LVRS on TGC was studied using prospectively collected lung mechanics data from 27 subjects with severe emphysema. Several parameters including FEV1, expiratory and inspiratory lung resistance (Rle and Rli), and lung volumes were measured at baseline and 6 months after surgery. Effort during the forced manoeuvre was measured using transpulmonary pressure. A novel method was used to estimate FEV1 corrected for the effect of TGC. RESULTS: At baseline the FEV1 corrected for gas compression (NFEV1) was significantly higher than FEV1 (p<0.0001). FEV1 increased significantly from baseline (p<0.005) while NFEV1 did not change following surgery (p>0.15). TGC decreased significantly with LVRS (p<0.05). Rle and maximum transpulmonary pressure (TP(peak)) during the forced manoeuvre significantly predicted the reduction in TGC following the surgery (Rle: p<0.01; TP(peak): p<0.0001; adjusted R2 = 0.68). The improvement in FEV1 was associated with the reduction in TGC after surgery (p<0.0001, adjusted R2 = 0.58). CONCLUSIONS: LVRS decreased TGC by improving expiratory flow limitation. In turn, the reduction in TGC decreased its negative effect on expiratory flow and therefore explained, in part, the improvement in FEV1 with LVRS in this cohort.

Regional expiratory flow limitation studied with Technegas in asthma.

Regional expiratory flow limitation (EFL) may occur during tidal breathing without being detected by measurements of flow at the mouth. We tested this hypothesis by using Technegas to reveal sites of EFL. A first study (study 1) was undertaken to determine whether deposition of Technegas during tidal breathing reveals the occurrence of regional EFL in induced bronchoconstriction. Time-activity curves of Technegas inhaled during 12 tidal breaths were measured in four asthmatic subjects at control conditions and after exposure to inhaled methacholine at a dose sufficient to abolish expiratory flow reserve near functional residual capacity. A second study (study 2) was conducted in seven asthmatic subjects at control and after three increasing doses of methacholine to compare the pattern of Technegas deposition in the lung with the occurrence of EFL. The latter was assessed at the mouth by comparing tidal with forced expiratory flow or with the flow generated on application of a negative pressure. Study 1 documented enhanced and spotty deposition of Technegas in the central lung regions with increasing radioactivity during tidal expiration. This is consistent with increased impaction of Technegas on the airway wall downstream from the flow-limiting segment. Study 2 showed that both methods based on analysis of flow at the mouth failed to detect EFL at the time spotty deposition of Technegas occurred. We conclude that regional EFL occurs asynchronously across the lung and that methods based on mouth flow measurements are insensitive to it.

Respiratory control during independent lung ventilation.

We describe the case of a lung transplant patient with primary graft failure and an emphysematous native lung, who displayed different respiratory rates between the transplanted lung and the native lung. Inflation of the native lung delayed the next inspiratory effort relative to inflation of the denervated transplanted lung. Synchronous inflation of both lungs required more pressure in each lung than when that lung was inflated with the contralateral lung near functional residual capacity, suggesting the two lungs compete for space within the thoracic cavity.

Effects of smooth muscle activation on axial mechanical properties of excised canine bronchi.

This study tested the hypothesis that airway smooth muscle (ASM) activation produces an airway active axial force (AAAF). Bronchi (n = 10) immersed in a tissue bath containing 95% O2-5% CO2-equilibrated Krebs solution were subjected to passive axial lengthening and shortening at 0-20 cmH2O of transmural pressure. ASM was relaxed with isoproterenol and activated with methacholine. Axial tensile (epsilonx), transverse compressive (epsilony), and shear strains (epsilonxy) were computed from the displacements of four markers placed onto the specimen's surface. The AAAF was estimated by subtracting the control axial force (AF) values at a given epsilonx from those obtained after methacholine. epsilonx-AF relationships were curvilinear, with maximum epsilonx being approached at approximately 15 g of AF. The epsilony decreased during bronchial lengthening. Cholinergic stimulation produced 1) a decrease of both epsilonx and epsilony at a given AF relative to control, indicating ASM shortening, and 2) an AAAF that increased with increasing epsilonx and transmural pressure. A portion of the work of expanding the lungs is required to lengthen the airways; therefore, an AAAF would increase lung elastance and recoil.

Respiratory dynamics during laughter.

Lung and chest wall mechanics were studied during fits of laughter in 11 normal subjects. Laughing was naturally induced by showing clips of the funniest scenes from a movie by Roberto Benigni. Chest wall volume was measured by using a three-dimensional optoelectronic plethysmography and was partitioned into upper thorax, lower thorax, and abdominal compartments. Esophageal (Pes) and gastric (Pga) pressures were measured in seven subjects. All fits of laughter were characterized by a sudden occurrence of repetitive expiratory efforts at an average frequency of 4.6 +/- 1.1 Hz, which led to a final drop in functional residual capacity (FRC) by 1.55 +/- 0.40 liter (P < 0.001). All compartments similarly contributed to the decrease of lung volumes. The average duration of the fits of laughter was 3.7 +/- 2.2 s. Most of the events were associated with sudden increase in Pes well beyond the critical pressure necessary to generate maximum expiratory flow at a given lung volume. Pga increased more than Pes at the end of the expiratory efforts by an average of 27 +/- 7 cmH2O. Transdiaphragmatic pressure (Pdi) at FRC and at 10% and 20% control forced vital capacity below FRC was significantly higher than Pdi at the same absolute lung volumes during a relaxed maneuver at rest (P < 0.001). We conclude that fits of laughter consistently lead to sudden and substantial decrease in lung volume in all respiratory compartments and remarkable dynamic compression of the airways. Further mechanical stress would have applied to all the organs located in the thoracic cavity if the diaphragm had not actively prevented part of the increase in abdominal pressure from being transmitted to the chest wall cavity.

Modeling the kinematics of the canine midcostal diaphragm.

The hypotheses that the chest wall insertion (CW) is displaced laterally during inspiration and that this displacement is essential in maintaining muscle curvature of the costal diaphragmatic muscle fibers were tested. With the use of data from three dogs, caudal, lateral, and ventral displacements of CW during both quiet, spontaneous inspiration and during inspiratory efforts against an occluded airway were observed and recorded. We have developed a kinematic model of the diaphragm that incorporates these displacements. This model describes the motions of the muscle fibers and central tendon; the displacements of the midplane, muscle-tendon junction (MTJ), CW, and center of the muscle fiber-central tendon arcs are modeled as functions of muscle fiber length. In the model, the center of the fiber arcs and MTJ both move caudally parallel to the midplane during inspiration, whereas CW moves both caudally and laterally. The observed lateral displacement of CW and the observed caudal displacement of MTJ, as functions of muscle fiber length, both approximate well the theoretical displacements that would be necessary to maintain curvature of the fiber arcs. In confirming our hypotheses, we have found that lateral displacement of CW is a mechanism by which changes in the shape of the costal diaphragm, as described by its curvature, are limited.

Desmin integrates the three-dimensional mechanical properties of muscles.

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.

Shape and tension distribution of the passive rat diaphragm.

We developed an in vitro preparation to investigate shape and stress distribution in the intact rat diaphragm. Our hypothesis was that the diaphragm is anisotropic with smaller compliance in transverse fiber direction than along fibers, and therefore shape change may be small. After the animals were killed (8 rats), the entire diaphragm was excised and fixed into a mold at the insertions. Oxygenated Krebs-Ringer solution was circulated under the diaphragm and perfused over its surface. A total of 20-23 small markers were sutured on the diaphragm surface. At transdiaphragmatic pressure (P(di)) of 3-15 cmH(2)O, curvature was smaller in transverse direction than along fibers. Using finite element analysis we computed membrane tension. At P(di) of 15 cmH(2)O, tension in central tendon was larger than muscle. In costal region maximum principal tension (sigma(1)) is essentially along the fibers and ranged from 6-10 g/cm. Minimum principal tension (sigma(2)) was 0. 3-4 g/cm. In central tendon, sigma(1) was 10-15 g/cm, compared with 4-10 g/cm for sigma(2). The diaphragm was considerably stiffer in transverse fiber direction than along the fibers.

Inferences on force transmission from muscle fiber architecture of the canine diaphragm.

Functional properties of the diaphragm are mediated by muscle structure. Modeling of force transmission necessitates a precise knowledge of muscle fiber architecture. Because the diaphragm experiences loads both along and transverse to the long axes of its muscle fibers in vivo, the mechanism of force transmission may be more complex than in other skeletal muscles that are loaded uniaxially along the muscle fibers. Using a combination of fiber microdissections and histological and morphological methods, we determined regional muscle fiber architecture and measured the shape of the cell membrane of single fibers isolated from diaphragm muscles from 11 mongrel dogs. We found that muscle fibers were either spanning fibers (SPF), running uninterrupted between central tendon (CT) and chest wall (CW), or were non-spanning fibers (NSF) that ended within the muscle fascicle. NSF accounted for the majority of fibers in the midcostal, dorsal costal, and lateral crural regions but were only 25-41% of fibers in the sternal region. In the midcostal and dorsal costal regions, only approximately 1% of the NSF terminated within the fascicle at both ends; the lateral crural region contained no such fibers. We measured fiber length, tapered length, fiber diameters along fiber length, and the taper angle for 271 fibers. The lateral crural region had the longest mean length of SPF, which is equivalent to the mean muscle length, followed by the costal and sternal regions. For the midcostal and crural regions, the percentage of tapered length of NSF was 45.9 +/- 5.3 and 40.6 +/- 7.5, respectively. The taper angle was approximately 0.15 degrees for both, and, therefore, the shear component of force was approximately 380 times greater than the tensile component. When the diaphragm is submaximally activated, as during normal breathing and maximal inspiratory efforts, muscle forces could be transmitted to the cell membrane and to the extracellular intramuscular connective tissue by shear linkage, presumably via structural transmembrane proteins.

2,4,5-Trisubstituted imidazoles: novel nontoxic modulators of P-glycoprotein mediated multidrug resistance. Part 1.

N-4,5-Di-(4-dialkylamino)phenyl imidazoles (A) are potent modulators of P-glycoprotein mediated multidrug resistance. This manuscript describes the discovery and lead optimization of this novel class of inhibitors.

2,4,5-Trisubstituted imidazoles: novel nontoxic modulators of P-glycoprotein mediated multidrug resistance. Part 2.

Solution-phase combinatorial chemistry was applied to the optimization and development of clinical candidate OC144-093 (22), a novel and nontoxic modulator of P-glycoprotein mediated multidrug resistance.

Biaxial constitutive relations for the passive canine diaphragm.

Samples of the muscular sheet excised from the midcostal region of dog diaphragms were subjected to biaxial loading. That is, stresses in the direction of the muscle fibers and in the direction perpendicular to the fibers in the plane of the sheet were measured at different combinations of strains in the two directions. Stress-strain relations were obtained by fitting equations to these data. In the direction of the muscle fibers, for strains up to 0.7, stress is a modestly nonlinear function of strain and ranges up to approximately 60 g/cm. In the direction perpendicular to the fibers, the sheet is stiffer and more strongly nonlinear. At a strain in the perpendicular direction of approximately 0.35, stress increases abruptly. The stress-strain relation in the muscle direction is consistent with observations of passive muscle shortening in vivo. However, the stiffness in the perpendicular direction is not high enough to explain the observation that strains in the perpendicular direction in vivo are nearly zero. We conclude that, in the passive diaphragm in vivo, stress in the direction perpendicular to the muscle fibers is small.

Mechanism of reduced maximal expiratory flow with aging.

To investigate the determinants of maximal expiratory flow (MEF) with aging, 17 younger (7 men and 10 women, 39 +/- 4 yr, mean +/- SD) and 19 older (11 men and 8 women, 69 +/- 3 yr) subjects with normal pulmonary function were studied. For further comparison, we also studied 10 middle-aged men with normal lung function (54 +/- 6 yr) and 15 middle-aged men (54 +/- 7 yr) with mild chronic airflow limitation (CAL; i.e., forced expiratory volume in 1 s/forced vital capacity = 63 +/- 8%). MEF, static lung elastic recoil pressure (Pst), and the minimal pressure for maximal flow (Pcrit) were determined in a pressure-compensated, volume-displacement body plethysmograph. Values were compared at 60, 70, and 80% of total lung capacity. In the older subjects, decreases in MEF (P < 0.01) and Pcrit (P < 0.05), compared with the younger subjects, were explained mainly by loss of Pst (P < 0.05). In the CAL subjects, MEF and Pcrit were lower (P < 0.05) than in the older subjects, but Pst was similar. Thus decreases in MEF and Pcrit were greater than could be explained by the loss of Pst and appeared to be related to increased upstream resistance. These data indicate that the loss of lung recoil explains the decrease in MEF with aging subjects, but not in the mild CAL patients that we studied.

Shape of the canine diaphragm.

In an earlier study (Angelillo M, Boriek AM, Rodarte JR, and Wilson TA. J Appl Physiol 83: 1486-1491, 1997), we proposed a mathematical theory for the structure and shape of the diaphragm. Muscle bundles were assumed to lie on lines that are simultaneously geodesics and lines of principal curvature of the diaphragm surface, and the class of surfaces that are formed by line elements that are both geodesics and lines of principal curvature was described. Here we present data on the shape of the canine diaphragm that were obtained by the radiopaque marker technique, and we describe a surface that fits the data and satisfies the requirements of the theory. The costal and crural diaphragms are fit by cyclides with radii of 3.7 and 2.3 cm, respectively. In addition, the theory is extended to include the description of a joint between cyclides, and the observed properties of the joint between the costal and crural diaphragms at the dorsal end of the costal diaphragm match those required by the theory.

Discovery and characterization of OC144-093, a novel inhibitor of P-glycoprotein-mediated multidrug resistance.

OC144-093 is a novel substituted diarylimidazole (Mr 495) generated using the OntoBLOCK system, a solid-phase combinatorial chemistry technology, in combination with high-throughput cell-based screening. OC144-093 reversed multidrug resistance (MDR) to doxorubicin, paclitaxel, and vinblastine in human lymphoma, breast, ovarian, uterine, and colorectal carcinoma cell lines expressing P-glycoprotein (P-gp) with an average EC50 of 0.032 microM. Inhibition of MDR by OC144-093 was reversible, but the effect persisted for at least 12 h after removal of compound from the culture medium. OC144-093 had no effect on the response to cytotoxic agents by cells in vitro lacking P-gp expression or expressing a multidrug resistance-associated protein (MRP-1). OC144-093 was not cytotoxic by itself against 15 normal, nontransformed, or tumor cell lines, regardless of P-gp status, with an average cytostatic IC50 of >60 microM. OC144-093 blocked the binding of [3H]azidopine to P-gp and inhibited P-gp ATPase activity. The compound was >50% p.o. bioavailable in rodents and dogs and did not alter the plasma pharmacokinetics of i.v.-administered paclitaxel. OC144-093 increased the life span of doxorubicin-treated mice engrafted with MDR P388 leukemia cells by >100% and significantly enhanced the in vivo antitumor activity of paclitaxel in MDR human breast and colon carcinoma xenograft models, without a significant increase in doxorubicin or paclitaxel toxicity. The results demonstrate that OC144-093 is an orally active, potent, and nontoxic inhibitor of P-gp-mediated multidrug resistance that exhibits all of the desired properties for treatment of P-gp-mediated MDR, as well as for prevention of MDR prior to selection and/or induction of refractory disease.

Breathing during exercise in subjects with mild-to-moderate airflow obstruction: effects of physical training.

In this study we explored the effects of physical training on the response of the respiratory system to exercise. Eight subjects with irreversible mild-to-moderate airflow obstruction [forced expiratory volume in 1 s of 85 +/- 14 (SD) % of predicted and ratio of forced expiratory volume in 1 s to forced vital capacity of 68 +/- 5%] and six normal subjects with similar anthropometric characteristics underwent a 2-mo physical training period on a cycle ergometer three times a week for 31 min at an intensity of approximately 80% of maximum heart rate. At this work intensity, tidal expiratory flow exceeded maximal flow at control functional residual capacity [FRC; expiratory flow limitation (EFL)] in the obstructed but not in the normal subjects. An incremental maximum exercise test was performed on a cycle ergometer before and after training. Training improved exercise capacity in all subjects, as documented by a significant increase in maximum work rate in both groups (P < 0.001). In the obstructed subjects at the same level of ventilation at high workloads, FRC was greater after than before training, and this was associated with an increase in breathing frequency and a tendency to decrease tidal volume. In contrast, in the normal subjects at the same level of ventilation at high workloads, FRC was lower after than before training, so that tidal volume increased and breathing frequency decreased. These findings suggest that adaptation to breathing under EFL conditions does not occur during exercise in humans, in that obstructed subjects tend to increase FRC during exercise after experiencing EFL during a 2-mo strenuous physical training period.

Lung elastic recoil during breathing at increased lung volume.

During dynamic hyperinflation with induced bronchoconstriction, there is a reduction in lung elastic recoil at constant lung volume (R. Pellegrino, O. Wilson, G. Jenouri, and J. R. Rodarte. J. Appl. Physiol. 81: 964-975, 1996). In the present study, lung elastic recoil at control end inspiration was measured in normal subjects in a volume displacement plethysmograph before and after voluntary increases in mean lung volume, which were achieved by one tidal volume increase in functional residual capacity (FRC) with constant tidal volume and by doubling tidal volume with constant FRC. Lung elastic recoil at control end inspiration was significantly decreased by approximately 10% within four breaths of increasing FRC. When tidal volume was doubled, the decrease in computed lung recoil at control end inspiration was not significant. Because voluntary increases of lung volume should not produce airway closure, we conclude that stress relaxation was responsible for the decrease in lung recoil.

Ratio of active to passive muscle shortening in the canine diaphragm.

Active and passive shortening of muscle bundles in the canine diaphragm were measured with the objective of testing a consequence of the minimal-work hypothesis: namely, that the ratio of active to passive shortening is the same for all active muscles. Lengths of six muscle bundles in the costal diaphragm and two muscle bundles in the crural diaphragm of each of four bred-for-research beagle dogs were measured by the radiopaque marker technique during the following maneuvers: a passive deflation maneuver from total lung capacity to functional residual capacity, quiet breathing, and forceful inspiratory efforts against an occluded airway at different lung volumes. Shortening per liter increase in lung volume was, on average, 70% greater during quiet breathing than during passive inflation in the prone posture and 40% greater in the supine posture. For the prone posture, the ratio of active to passive shortening was larger in the ventral and midcostal diaphragm than at the dorsal end of the costal diaphragm. For both postures, active shortening during quiet breathing was poorly correlated with passive shortening. However, shortening during forceful inspiratory efforts was highly correlated with passive shortening. The average ratios of active to passive shortening were 1.23 +/- 0.02 and 1.32 +/- 0.03 for the prone and supine postures, respectively. These data, taken together with the data reported in the companion paper (T. A. Wilson, M. Angelillo, A. Legrand, and A. De Troyer, J. Appl. Physiol. 87: 554-560, 1999), support the hypothesis that, during forceful inspiratory efforts, the inspiratory muscles drive the chest wall along the minimal-work trajectory.

Airway responsiveness to methacholine: effects of deep inhalations and airway inflammation.

We determined the dose-response curves to inhaled methacholine (MCh) in 16 asthmatic and 8 healthy subjects with prohibition of deep inhalations (DIs) and with 5 DIs taken after each MCh dose. Flow was measured on partial expiratory flow-volume curves at an absolute lung volume (plethysmographically determined) equal to 25% of control forced vital capacity (FVC). Airway inflammation was assessed in asthmatic subjects by analysis of induced sputum. Even when DIs were prohibited, the dose of MCh causing a 50% decrease in forced partial flow at 25% of control FVC (PD(50)MCh) was lower in asthmatic than in healthy subjects (P < 0.0001). In healthy but not in asthmatic subjects, repeated DIs significantly decreased the maximum response to MCh [from 90 +/- 4 to 62 +/- 8 (SD) % of control, P < 0.001], increased PD(50)MCh (P < 0.005), without affecting the dose causing 50% of maximal response. In asthmatic subjects, neither PD(50)MCh when DIs were prohibited nor changes in PD(50)MCh induced by DIs were significantly correlated with inflammatory cell numbers or percentages in sputum. We conclude that 1) even when DIs are prohibited, the responsiveness to MCh is greater in asthmatic than in healthy subjects; 2) repeated DIs reduce airway responsiveness in healthy but not in asthmatic subjects; and 3) neither airway hyperresponsiveness nor the inability of DIs to relax constricted airways in asthmatic subjects is related to the presence of inflammatory cells in the airways.