Pathogenesis of chronic rhinosinusitis with nasal polyps: role of IL-6 in airway epithelial cell dysfunction.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by an alteration in airway epithelial cell functions including barrier function, wound repair mechanisms, mucociliary clearance. The mechanisms leading to epithelial cell dysfunction in nasal polyps (NPs) remain poorly understood. Our hypothesis was that among the inflammatory cytokines involved in NPs, IL-6 could alter epithelial repair mechanisms and mucociliary clearance. The aim of this study was to evaluate the in vitro effects of IL-6 on epithelial repair mechanisms in a wound repair model and on ciliary beating in primary cultures of Human Nasal Epithelial Cells (HNEC). METHODS: Primary cultures of HNEC taken from 38 patients during surgical procedures for CRSwNP were used in an in vitro model of wound healing. Effects of increasing concentrations of IL-6 (1 ng/mL, 10 ng/mL, and 100 ng/mL) and other ILs (IL-5, IL-9, IL-10) on wound closure kinetics were compared to cultures without IL-modulation. After wound closure, the differentiation process was characterized under basal conditions and after IL supplementation using cytokeratin-14, MUC5AC, and ßIV tubulin as immunomarkers of basal, mucus, and ciliated cells, respectively. The ciliated edges of primary cultures were analyzed on IL-6 modulation by digital high-speed video-microscopy to measure: ciliary beating frequency (CBF), ciliary length, relative ciliary density, metachronal wavelength and the ciliary beating efficiency index. RESULTS: Our results showed that: (i) IL-6 accelerated airway wound repair in vitro, with a dose-response effect whereas no effect was observed after other ILs-stimulation. After 24 h, 79% of wounded wells with IL6-100 were fully repaired, vs 46% in the IL6-10 group, 28% in the IL6-1 group and 15% in the control group; (ii) specific migration analyses of closed wound at late repair stage (Day 12) showed IL-6 had the highest migration compared with other ILs (iii) The study of the IL-6 effect on ciliary function showed that CBF and metachronal wave increased but without significant modifications of ciliary density, length of cilia and efficiency index. CONCLUSION: The up-regulated epithelial cell proliferation observed in polyps could be induced by IL-6 in the case of prior epithelial damage. IL-6 could be a major cytokine in NP physiopathology.

Surfactant delivery in rat lungs: Comparing 3D geometrical simulation model with experimental instillation.

Surfactant Replacement Therapy (SRT), which involves instillation of a liquid-surfactant mixture directly into the lung airway tree, is a major therapeutic treatment in neonatal patients with respiratory distress syndrome (RDS). This procedure has proved to be remarkably effective in premature newborns, inducing a five-fold decrease of mortality in the past 35 years. Disappointingly, its use in adults for treating acute respiratory distress syndrome (ARDS) experienced initial success followed by failures. Our recently developed numerical model has demonstrated that transition from success to failure of SRT in adults could, in fact, have a fluid mechanical origin that is potentially reversible. Here, we present the first numerical simulations of surfactant delivery into a realistic asymmetric conducting airway tree of the rat lung and compare them with experimental results. The roles of dose volume (VD), flow rate, and multiple aliquot delivery are investigated. We find that our simulations of surfactant delivery in rat lungs are in good agreement with our experimental data. In particular, we show that the monopodial architecture of the rat airway tree plays a major role in surfactant delivery, contributing to the poor homogeneity of the end distribution of surfactant. In addition, we observe that increasing VD increases the amount of surfactant delivered to the acini after losing a portion to coating the involved airways, the coating cost volume, VCC. Finally, we quantitatively assess the improvement resulting from a multiple aliquot delivery, a method sometimes employed clinically, and find that a much larger fraction of surfactant reaches the alveolar regions in this case. This is the first direct qualitative and quantitative comparison of our numerical model with experimental studies, which enhances our previous predictions in adults and neonates while providing a tool for predicting, engineering, and optimizing patient-specific surfactant delivery in complex situations.

FcRn-Dependent Transcytosis of Monoclonal Antibody in Human Nasal Epithelial Cells In Vitro: A Prerequisite for a New Delivery Route for Therapy?

Monoclonal antibodies (mAbs) are promising therapies to treat airway chronic inflammatory disease (asthma or nasal polyps). To date, no study has specifically assessed, in vitro, the potential function of neonatal Fc receptor (FcRn) in IgG transcytosis through the human nasal airway epithelium. The objective of this study was to report the in vitro expression and function of FcRn in nasal human epithelium. FcRn expression was studied in an air⁻liquid interface (ALI) primary culture model of human nasal epithelial cells (HNEC) from polyps. FcRn expression was characterized by quantitative RT-PCR, western blot, and immunolabeling. The ability of HNECs to support mAb transcytosis via FcRn was assessed by transcytosis assay. This study demonstrates the expression of FcRn mRNA and protein in HNEC. We report a high expression of FcRn in the cytosol of ciliated, mucus, and basal cells by immunohistochemistry with a higher level of FcRn proteins in differentiated HNEC. We also proved in vitro transepithelial delivery of an IgG1 therapeutic mAb with a dose⁻response curve. This is the first time that FcRn expression and mAb transcytosis has been shown in a model of human nasal respiratory epithelium in vitro. This study is a prerequisite for FcRn-dependent nasal administration of mAbs.

A new index for characterizing micro-bead motion in a flow induced by ciliary beating: Part II, modeling.

Mucociliary clearance is one of the major lines of defense of the human respiratory system. The mucus layer coating the airways is constantly moved along and out of the lung by the activity of motile cilia, expelling at the same time particles trapped in it. The efficiency of the cilia motion can experimentally be assessed by measuring the velocity of micro-beads traveling through the fluid surrounding the cilia. Here we present a mathematical model of the fluid flow and of the micro-beads motion. The coordinated movement of the ciliated edge is represented as a continuous envelope imposing a periodic moving velocity boundary condition on the surrounding fluid. Vanishing velocity and vanishing shear stress boundary conditions are applied to the fluid at a finite distance above the ciliated edge. The flow field is expanded in powers of the amplitude of the individual cilium movement. It is found that the continuous component of the horizontal velocity at the ciliated edge generates a 2D fluid velocity field with a parabolic profile in the vertical direction, in agreement with the experimental measurements. Conversely, we show than this model can be used to extract microscopic properties of the cilia motion by extrapolating the micro-bead velocity measurement at the ciliated edge. Finally, we derive from these measurements a scalar index providing a direct assessment of the cilia beating efficiency. This index can easily be measured in patients without any modification of the current clinical procedures.

A new index for characterizing micro-bead motion in a flow induced by ciliary beating: Part I, experimental analysis.

Mucociliary clearance is one of the major lines of defense of the respiratory system. The mucus layer coating the pulmonary airways is moved along and out of the lung by the activity of motile cilia, thus expelling the particles trapped in it. Here we compare ex vivo measurements of a Newtonian flow induced by cilia beating (using micro-beads as tracers) and a mathematical model of this fluid flow, presented in greater detail in a second companion article. Samples of nasal epithelial cells placed in water are recorded by high-speed video-microscopy and ciliary beat pattern is inferred. Automatic tracking of micro-beads, used as markers of the flow generated by cilia motion, enables us also to assess the velocity profile as a function of the distance above the cilia. This profile is shown to be essentially parabolic. The obtained experimental data are used to feed a 2D mathematical and numerical model of the coupling between cilia, fluid, and micro-bead motion. From the model and the experimental measurements, the shear stress exerted by the cilia is deduced. Finally, this shear stress, which can easily be measured in the clinical setting, is proposed as a new index for characterizing the efficiency of ciliary beating.

Characterisation of cellular adhesion reinforcement by multiple bond force spectroscopy in alveolar epithelial cells.

BACKGROUND INFORMATION: Integrin-mediated adhesion is a key process by which cells physically connect with their environment, and express sensitivity and adaptation through mechanotransduction. A critical step of cell adhesion is the formation of the first bonds which individually generate weak contacts (∼tens pN) but can sustain thousand times higher forces (∼tens nN) when associated. RESULTS: We propose an experimental validation by multiple bond force spectroscopy (MFS) of a stochastic model predicting adhesion reinforcement permitted by non-cooperative, multiple bonds on which force is homogeneously distributed (called parallel bond configuration). To do so, spherical probes (diameter: 6.6 µm), specifically coated by RGD-peptide to bind integrins, are used to statically indent and homogenously stretch the multiple bonds created for short contact times (2 s) between the bead and the surface of epithelial cells (A549). Using different separation speeds (v = 2, 5, 10 µm/s) and measuring cellular Young's modulus as well as the local stiffness preceding local rupture events, we obtain cell-by-cell the effective loading rates both at the global cell level and at the local level of individual constitutive bonds. Local rupture forces are in the range: f*=60-115 pN , whereas global rupture (detachment) forces reach F*=0.8-1.7 nN . Global and local rupture forces both exhibit linear dependencies with the effective loading rate, the slopes of these two linear relationships providing an estimate of the number of independent integrin bonds constituting the tested multiple bond structure (∼12). CONCLUSIONS: The MFS method enables to validate the reinforcement of integrin-mediated adhesion induced by the multiple bond configuration in which force is homogeneously distributed amongst parallel bonds. Local rupture events observed in the course of a spectroscopy manoeuver (MFS) lead to rupture force values considered in the literature as single-integrin bonds. SIGNIFICANCE: Adhesion reinforcement permitted by the parallel multiple bond association is particularly challenging to verify for two reasons: first, it is difficult to control precisely the direction of forces experimentally, and second, because both global and local bond rupture forces depend on the effective loading rate applied to the bond. Here, we propose an integrin-specific MFS method capable of detecting bond number and characterising bond configuration and its impact on adhesion strength.

Exposure to Bordetella pertussis adenylate cyclase toxin affects integrin-mediated adhesion and mechanics in alveolar epithelial cells.

BACKGROUND INFORMATION: The adenylate cyclase (CyaA) toxin is a major virulent factor of Bordetella pertussis, the causative agent of whooping cough. CyaA toxin is able to invade eukaryotic cells where it produces high levels of cyclic adenosine monophosphate (cAMP) affecting cellular physiology. Whether CyaA toxin can modulate cell matrix adhesion and mechanics of infected cells remains largely unknown. RESULTS: In this study, we use a recently proposed multiple bond force spectroscopy (MFS) with an atomic force microscope to assess the early phase of cell adhesion (maximal detachment and local rupture forces) and cell rigidity (Young's modulus) in alveolar epithelial cells (A549) for toxin exposure <1 h. At 30 min of exposure, CyaA toxin has a minimal effect on cell viability (>95%) at CyaA concentration of 0.5 nM, but a significant effect (≈81%) at 10 nM. MFS performed on A549 for three different concentrations (0.5, 5 and 10 nM) demonstrates that CyaA toxin significantly affects both cell adhesion (detachment forces are decreased) and cell mechanics (Young's modulus is increased). CyaA toxin (at 0.5 nM) assessed at three indentation/retraction speeds (2, 5 and 10 µm/s) significantly affects global detachment forces, local rupture events and Young modulus compared with control conditions, while an enzymatically inactive variant CyaAE5 has no effect. These results reveal the loading rate dependence of the multiple bonds newly formed between the cell and integrin-specific coated probe as well as the individual bond kinetics which are only slightly affected by the patho-physiological dose of CyaA toxin. Finally, theory of multiple bond force rupture enables us to deduce the bond number N which is reduced by a factor of 2 upon CyaA exposure (N ≈ 6 versus N ≈ 12 in control conditions). CONCLUSIONS: MFS measurements demonstrate that adhesion and mechanical properties of A549 are deeply affected by exposure to the CyaA toxin but not to an enzymatically inactive variant. This indicates that the alteration of cell mechanics triggered by CyaA is a consequence of the increase in intracellular cAMP in these target cells. SIGNIFICANCE: These results suggest that mechanical and adhesion properties of the cells appear as pertinent markers of cytotoxicity of CyaA toxin.

A Macroscopic Model for Simulating the Mucociliary Clearance in a Bronchial Bifurcation: The Role of Surface Tension.

The mucociliary clearance in the bronchial tree is the main mechanism by which the lungs clear themselves of deposited particulate matter. In this work, a macroscopic model of the clearance mechanism is proposed. Lubrication theory is applied for thin films with both surface tension effects and a moving wall boundary. The flow field is computed by the use of a finite-volume scheme on an unstructured grid that replicates a bronchial bifurcation. The carina in bronchial bifurcations is of special interest because it is a location of increased deposition of inhaled particles. In this study, the mucus flow is computed for different values of the surface tension. It is found that a minimal surface tension is necessary for efficiently removing the mucus while maintaining the mucus film thickness at physiological levels.

Phase-contrast helium-3 MRI of aerosol deposition in human airways.

One of the key challenges in the study of health-related aerosols is predicting and monitoring sites of particle deposition in the respiratory tract. The potential health risks of ambient exposure to environmental or workplace aerosols and the beneficial effects of medical aerosols are strongly influenced by the site of aerosol deposition along the respiratory tract. Nuclear medicine is the only current modality that combines quantification and regional localization of aerosol deposition, and this technique remains limited by its spatial and temporal resolutions and by patient exposure to radiation. Recent work in MRI has shed light on techniques to quantify micro-sized magnetic particles in living bodies by the measurement of associated static magnetic field variations. With regard to lung MRI, hyperpolarized helium-3 may be used as a tracer gas to compensate for the lack of MR signal in the airways, so as to allow assessment of pulmonary function and morphology. The extrathoracic region of the human respiratory system plays a critical role in determining aerosol deposition patterns, as it acts as a filter upstream from the lungs. In the present work, aerosol deposition in a mouth-throat phantom was measured using helium-3 MRI and compared with single-photon emission computed tomography. By providing high sensitivity with high spatial and temporal resolutions, phase-contrast helium-3 MRI offers new insights for the study of particle transport and deposition.

Plastinated nasal model: a new concept of anatomically realistic cast.

BACKGROUND: For many years, researchers have been interested in investigating airflow and aerosol deposition in the nasal cavities. The nasal airways appear to be a complex geometrical system. Thus, in vitro experimental studies are frequently conducted with a more or less biomimetic nasal replica. AIM: This study is devoted to the development of an anatomically realistic nose model with bilateral nasal cavities, i.e. nasal anatomy, airway geometry and aerodynamic properties as close as possible to in vivo behaviour. METHODS: A specific plastination technique of cephalic extremities was developed by the Anatomy Laboratory at the Saint-Etienne University in the last 10 years. The plastinated models obtained were anatomically, geometrically and aerodynamically validated using several techniques (endoscopy, CT scans, acoustic rhinometry and rhinomanometry). RESULTS: Our plastination model exhibited a high level of anatomic quality, including a very good mucosa preservation. Aerodynamical and geometrical investigations highlighted a global behaviour of plastinated models perfectly in accordance with a nasal decongested healthy subject. CONCLUSIONS: The present plastination model provides a realistic cast of nasal airways, and may be a useful tool for nasal flow, drug delivery and aerosol deposition studies.

Functional and structural consequences of epithelial cell invasion by Bordetella pertussis adenylate cyclase toxin.

Bordetella pertussis, the causative agent of whopping cough, produces an adenylate cyclase toxin (CyaA) that plays a key role in the host colonization by targeting innate immune cells which express CD11b/CD18, the cellular receptor of CyaA. CyaA is also able to invade non-phagocytic cells, via a unique entry pathway consisting in a direct translocation of its catalytic domain across the cytoplasmic membrane of the cells. Within the cells, CyaA is activated by calmodulin to produce high levels of cyclic adenosine monophosphate (cAMP) and alter cellular physiology. In this study, we explored the effects of CyaA toxin on the cellular and molecular structure remodeling of A549 alveolar epithelial cells. Using classical imaging techniques, biochemical and functional tests, as well as advanced cell mechanics method, we quantify the structural and functional consequences of the massive increase of intracellular cyclic AMP induced by the toxin: cell shape rounding associated to adhesion weakening process, actin structure remodeling for the cortical and dense components, increase in cytoskeleton stiffness, and inhibition of migration and repair. We also show that, at low concentrations (0.5 nM), CyaA could significantly impair the migration and wound healing capacities of the intoxicated alveolar epithelial cells. As such concentrations might be reached locally during B. pertussis infection, our results suggest that the CyaA, beyond its major role in disabling innate immune cells, might also contribute to the local alteration of the epithelial barrier of the respiratory tract, a hallmark of pertussis.

Inductive plethysmography to control volume-targeted ventilation for leak compensation.

OBJECTIVE: Volume-targeted ventilation is associated with poor compensation for leaks yet is frequently used in neuromuscular patients, many of whom experience mouth leaks. Our objective was to test the feasibility and efficacy of a prototype ventilator designed to achieve leak compensation by feed-back control of the actual tidal volume based on either the volume blown to the expiratory circuit (VTEVC-compensation) or the tidal volume measured by inductive plethysmography (VTplet-compensation). DESIGN AND SETTING: Randomized, cross-over, physiological study in a physiological ward of a university teaching hospital. PARTICIPANTS: Nine normal individuals. INTERVENTION: Subjects tested volume-targeted assist-control ventilation without compensation, with VTEVC-compensation, and with VTplet-compensation. Tests were done with the mouth closed, with mouth leaks during inspiration, and with mouth leaks during expiration. MEASUREMENTS AND RESULTS: With inspiratory mouth leaks compared to mouth closed, the delivered volume remained unchanged without leak compensation, increased to 143 +/- 30% with VTEVC-compensation, and increased to 132 +/- 17% with VTplet-compensation; the expired tidal volume decreased to 46 +/- 24% without compensation, 66 +/- 20% with VTEVC-compensation, and 68 +/- 23% with VTplet-compensation. With expiratory mouth leaks, the ventilator-delivered volume and expired tidal volume were unchanged with no compensation and with VTplet-compensation; they increased with VTEVC-compensation. CONCLUSION: Leak compensation can be achieved during volume-targeted ventilation. VTEVC-compensation and VTplet-compensation were equally effective in compensating for inspiratory leaks, and VTplet-compensation also performed well when expiratory leaks occurred.

Cell mechanics of alveolar epithelial cells (AECs) and macrophages (AMs).

Cell mechanics provides an integrated view of many biological phenomena which are intimately related to cell structure and function. Because breathing constitutes a sustained motion synonymous with life, pulmonary cells are normally designed to support permanent cyclic stretch without breaking, while receiving mechanical cues from their environment. The authors study the mechanical responses of alveolar cells, namely epithelial cells and macrophages, exposed to well-controlled mechanical stress in order to understand pulmonary cell response and function. They discuss the principle, advantages and limits of a cytoskeleton-specific micromanipulation technique, magnetic bead twisting cytometry, potentially applicable in vivo. They also compare the pertinence of various models (e.g., rheological; power law) used to extract cell mechanical properties and discuss cell stress/strain hardening properties and cell dynamic response in relation to the structural tensegrity model. Overall, alveolar cells provide a pertinent model to study the biological processes governing cellular response to controlled stress or strain.

Perfluorocarbon induces alveolar epithelial cell response through structural and mechanical remodeling.

During total liquid ventilation, lung cells are exposed to perfluorocarbon (PFC) whose chemophysical properties highly differ from standard aqueous cell feeding medium (DMEM). We herein perform a systematic study of structural and mechanical properties of A549 alveolar epithelial cells in order to characterize their response to PFC exposure, using DMEM as control condition. Changes in F-actin structure, focal adhesion density and glycocalyx distribution are evaluated by confocal fluorescent microscopy. Changes in cell mechanics and adhesion are measured by multiscale magnetic twisting cytometry (MTC). Two different microrheological models (single Voigt and power law) are used to analyze the cell mechanics characterized by cytoskeleton (CSK) stiffness and characteristic relaxation times. Cell-matrix adhesion is analyzed using a stochastic multibond deadhesion model taking into account the non-reversible character of the cell response, allowing us to quantify the adhesion weakness and the number of associated bonds. The roles of F-actin structure and glycocalyx layer are evaluated by depolymerizing F-actin and degrading glycocalyx, respectively. Results show that PFC exposure consistently induces F-actin remodeling, CSK softening and adhesion weakening. These results demonstrate that PFC triggers an alveolar epithelial cell response herein evidenced by a decay in intracellular CSK tension, an adhesion weakening and a glycocalyx layer redistribution. These PFC-induced cell adjustments are consistent with the hypothesis that cells respond to a decrease in adhesion energy at cell surface. This adhesion energy can be even further reduced in the presence of surfactant adsorbed at the cell surface.

Inflammatory Cellular Response to Mechanical Ventilation in Elastase-Induced Experimental Emphysema: Role of Preexisting Alveolar Macrophages Infiltration.

An excessive pulmonary inflammatory response could explain the poor prognosis of chronic obstructive pulmonary disease (COPD) patients submitted to invasive mechanical ventilation. The aim of this study was to evaluate the response to normal tidal volume mechanical ventilation in an elastase-induced murine model of pulmonary emphysema. In this model, two time points, associated with different levels of lung inflammation but similar lung destruction, were analyzed. C57BL/6 mice received a tracheal instillation of 5 IU of porcine pancreatic elastase (Elastase mice) or the same volume of saline (Saline mice). Fourteen (D14) and 21 (D21) days after instillation, mice were anesthetized, intubated, and either mechanically ventilated (MV) or maintained on spontaneous ventilation (SV) during two hours. As compared with Saline mice, Elastase mice showed a similarly increased mean chord length and pulmonary compliance at D14 and D21, while bronchoalveolar lavage cellularity was comparable between groups. Lung mechanics was similarly altered during mechanical ventilation in Elastase and Saline mice. Activated alveolar macrophages CD11bmid were present in lung parenchyma in both Elastase SV mice and Elastase MV mice at D14 but were absent at D21 and in Saline mice, indicating an inflammatory state with elastase at D14 only. At D14, Elastase MV mice showed a significant increase in percentage of neutrophils in total lung, as compared with Elastase SV mice. Furthermore, alveolar macrophages of Elastase MV mice at D14 overexpressed Gr1, and monocytes showed a trend to overexpression of CD62L, compared with Elastase SV mice. In an elastase-induced model of pulmonary emphysema, normal tidal volume mechanical ventilation may produce an increase in the proportion of pulmonary neutrophils, and an activation of alveolar macrophages and pulmonary monocytes. This response seems to be observed only when the emphysema model shows an underlying inflammation (D14), reflected by the presence of activated alveolar macrophages CD11bmid.

In vitro validation of computational fluid dynamic simulation in human proximal airways with hyperpolarized 3He magnetic resonance phase-contrast velocimetry.

Computational fluid dynamics (CFD) and magnetic resonance (MR) gas velocimetry were concurrently performed to study airflow in the same model of human proximal airways. Realistic in vivo-based human airway geometry was segmented from thoracic computed tomography. The three-dimensional numerical description of the airways was used for both generation of a physical airway model using rapid prototyping and mesh generation for CFD simulations. Steady laminar inspiratory experiments (Reynolds number Re = 770) were performed and velocity maps down to the fourth airway generation were extracted from a new velocity mapping technique based on MR velocimetry using hyperpolarized (3)He gas. Full two-dimensional maps of the velocity vector were measured within a few seconds. Numerical simulations were carried out with the experimental flow conditions, and the two sets of data were compared between the two modalities. Flow distributions agreed within 3%. Main and secondary flow velocity intensities were similar, as were velocity convective patterns. This work demonstrates that experimental and numerical gas velocity data can be obtained and compared in the same complex airway geometry. Experiments validated the simulation platform that integrates patient-specific airway reconstruction process from in vivo thoracic scans and velocity field calculation with CFD, hence allowing the results of this numerical tool to be used with confidence in potential clinical applications for lung characterization. Finally, this combined numerical and experimental approach of flow assessment in realistic in vivo-based human airway geometries confirmed the strong dependence of airway flow patterns on local and global geometrical factors, which could contribute to gas mixing.

Investigating hyperventilation syndrome in patients suffering from empty nose syndrome.

OBJECTIVES/HYPOTHESIS: Patients with empty nose syndrome (ENS) following turbinate surgery often complain about breathing difficulties. We set out to determine if dyspnea in patients with ENS was associated with hyperventilation syndrome (HVS). We hypothesized that lower airway symptoms in ENS could be explained by HVS. STUDY DESIGN: Observational prospective study. METHODS: All consecutive patients referred to our center for ENS over 1 year were invited to participate. Patients completed the Nijmegen score and underwent a hyperventilation provocation test (HVPT) and arterial blood gas and cardiopulmonary tests. HVS was defined by a delayed return of the end-tidal partial pressure of carbon dioxide in the expired gas to baseline during HVPT. Patients with HVS were asked to complete the Sinonasal Outcome Test (SNOT)-16 questionnaire before and after a specific eight-session respiratory rehabilitation program. RESULTS: Twenty-two of the 29 patients referred for ENS during the study period were eligible for inclusion and underwent a complete workup. HVS was diagnosed in 17 of these patients (77.3%). In the five patients who completed the SNOT-16, the score was significantly lower after rehabilitation. CONCLUSIONS: This study suggests that HVS is frequent in patients with ENS, and that symptoms can be improved by respiratory rehabilitation. Pathophysiological links between ENS and HVS deserve to be further explored. LEVEL OF EVIDENCE: 2b Laryngoscope, 127:1983-1988, 2017.

Bench evaluation of flow limitation detection by automated continuous positive airway pressure devices.

STUDY OBJECTIVE: Automatic continuous positive airway pressure (CPAP) devices that adjust the pressure delivered to the patient are now available to treat sleep-disordered breathing. Sophisticated auto-CPAP devices can detect and correct flattened inspiratory flow contours (FIFCs) associated with subtle upper airway obstruction. However, evaluations of their performance are made difficult by differences across patients and devices. We performed a bench study of five commercially available auto-CPAP devices using a breath waveform simulator to evaluate sensitivity for detecting flattened inspiratory flow. DESIGN: Five degrees of FIFC were simulated. In addition, normal and abnormal flow contours from patients published in the literature were evaluated. MEASUREMENTS AND RESULTS: One device showed autotriggering leading to CPAP increases, and another device varied the CPAP level independently from the presence of an FIFC. The three remaining devices differed regarding the detection of FIFCs and the means used to increase CPAP. CONCLUSION: Based on the characteristics of each patient, physicians must choose among devices with different thresholds of FIFC detection and different pressure responses to detection. Therefore, physicians need details on the algorithms used in auto-CPAP devices. Manufacturers should supply detailed algorithms.

Nasal wall compliance in vasomotor rhinitis.

Nasal compliance is a measure related to the blood volume in the nasal mucosa. The objective of this study was to better understand the vascular response in vasomotor rhinitis by measuring nasal cross-sectional area and nasal compliance before and after mucosal decongestion in 10 patients with vasomotor rhinitis compared with 10 healthy subjects. Nasal compliance was inferred by measuring nasal area by acoustic rhinometry at pressures ranging from atmospheric pressure to a negative pressure of -10 cmH2O. Mucosal decongestion was obtained with one puff per nostril of 0.05% oxymetazoline. At atmospheric pressure, nasal cross-sectional areas were similar in the vasomotor rhinitis group and the healthy subject group. Mucosal decongestion did not induce any decrease of nasal compliance in patients with vasomotor rhinitis in contrast with healthy subjects. Our results support the hypothesis, already proposed, of an autonomic dysfunction based on a paradoxical response of the nasal mucosa in vasomotor rhinitis. Moreover, the clearly different behavior between healthy subjects and vasomotor rhinitis subjects suggests that nasal compliance measurement may therefore represent a potential line of research to develop a diagnostic tool for vasomotor rhinitis, which remains a diagnosis of exclusion.

Multiscale evaluation of cellular adhesion alteration and cytoskeleton remodeling by magnetic bead twisting.

Cellular adhesion forces depend on local biological conditions meaning that adhesion characterization must be performed while preserving cellular integrity. We presently postulate that magnetic bead twisting provides an appropriate stress, i.e., basically a clamp, for assessment in living cells of both cellular adhesion and mechanical properties of the cytoskeleton. A global dissociation rate obeying a Bell-type model was used to determine the natural dissociation rate ([Formula: see text]) and a reference stress ([Formula: see text]). These adhesion parameters were determined in parallel to the mechanical properties for a variety of biological conditions in which either adhesion or cytoskeleton was selectively weakened or strengthened by changing successively ligand concentration, actin polymerization level (by treating with cytochalasin D), level of exerted stress (by increasing magnetic torque), and cell environment (by using rigid and soft 3D matrices). On the whole, this multiscale evaluation of the cellular and molecular responses to a controlled stress reveals an evolution which is consistent with stochastic multiple bond theories and with literature results obtained with other molecular techniques. Present results confirm the validity of the proposed bead-twisting approach for its capability to probe cellular and molecular responses in a variety of biological conditions.