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Find video protocols related to scientific articles indexed in Pubmed.
Parabiotic model for differentiating local and systemic effects of continuous and intermittent hypoxia.
J. Appl. Physiol.
PUBLISHED: 11-08-2014
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Hypoxia can be damaging either because cells are directly sensitive to low oxygen pressure in their local microenvironment and/or because they are exposed to circulating factors systemically secreted in response to hypoxia. The conventional hypoxia model -breathing hypoxic air- does not allow to distinguish between these local and systemic effects. Here we propose and validate a model for differentially applying local and systemic hypoxic challenges in an animal. We used parabiosis -two mice sharing circulation by surgical union through the skin- and tested the hypothesis that when one of the parabionts breathes room air and the other one is subjected to hypoxic air both mice share systemic circulation but remain normoxic and hypoxic, respectively. We tested two common hypoxic paradigms in 10 parabiotic pairs: continuous hypoxia (10% O2) mimicking chronic lung diseases and intermittent hypoxia (40 s 21% O2; 20 s 5%O2) simulating sleep apnea. Arterial oxygen saturation and oxygen partial pressure at muscle tissue were measured in both parabionts. Effective cross-circulation was assessed by intraperitoneally injecting a dye in one of the parabionts and measuring blood dye concentration in both animals after 2 h. The results confirmed the hypothesis that tissues of the parabiont under room air were perfused with normally oxygenated blood and, at the same time, were exposed to all the systemic mediators secreted by the other parabiont actually subjected to hypoxia. In conclusion, combination of parabiosis and hypoxic/normoxic air breathing is a novel approach to investigate the effects of local and systemic hypoxia in respiratory diseases.
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Male fertility is reduced by chronic intermittent hypoxia mimicking sleep apnea in mice.
Sleep
PUBLISHED: 11-04-2014
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Obstructive sleep apnea (OSA) is characterized by intermittent hypoxia and oxidative stress. However, it is unknown whether intermittent hypoxia mimicking OSA modifies male fertility. We tested the hypothesis that male fertility is reduced by chronic intermittent hypoxia mimicking OSA in a mouse model.
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Effect of ovariectomy on inflammation induced by intermittent hypoxia in a mouse model of sleep apnea.
Respir Physiol Neurobiol
PUBLISHED: 08-20-2014
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Patient data report marked gender and pre-vs-postmenopausal differences in obstructive sleep apnea (OSA). However, no experimental data are available on how sexual hormones modulate OSA consequences. Here we report novel results on estrogen-modulated heart and brain inflammation in female mice subjected to intermittent hypoxia, a major injurious challenge in OSA. C57BL/6J (14-week old) intact and ovariectomized mice (n=6 each) were subjected to intermittent hypoxia (20 s at 5% and 40s at 21%, 60 cycles/h; 6 h/day). Identical intact and ovariectomized groups breathing room air were controls. After 30 days, the gene expressions of interleukins 6 and 8 (IL-6, IL-8) in the brain and heart tissues were measured. Whereas, compared with normoxia, intermittent hypoxia considerably increased IL-6 and IL-8 gene expressions in intact females, no change was found in ovariectomized mice when comparing normoxia and intermittent hypoxia. These data suggest that estrogens modulate the inflammatory effects of intermittent hypoxia and point to further studies on the role played by sex hormones in OSA.
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Management of sleep apnea without high pretest probability or with comorbidities by three nights of portable sleep monitoring.
Sleep
PUBLISHED: 08-02-2014
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Obstructive sleep apnea (OSA) diagnosis using simplified methods such as portable sleep monitoring (PM) is only recommended in patients with a high pretest probability. The aim is to determine the diagnostic efficacy, consequent therapeutic decision-making, and costs of OSA diagnosis using polysomnography (PSG) versus three consecutive studies of PM in patients with mild to moderate suspicion of sleep apnea or with comorbidity that can mask OSA symptoms.
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Brain tissue hypoxia and oxidative stress induced by obstructive apneas is different in young and aged rats.
Sleep
PUBLISHED: 07-26-2014
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To test the hypotheses that brain oxygen partial pressure (PtO2) in response to obstructive apneas changes with age and that it might lead to different levels of cerebral tissue oxidative stress.
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Low oxygen tension enhances the generation of lung progenitor cells from mouse embryonic and induced pluripotent stem cells.
Physiol Rep
PUBLISHED: 07-16-2014
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Whole-organ decellularization technology has emerged as a new alternative for the fabrication of bioartificial lungs. Embryonic stem cells (ESC) and induced pluripotent stem cells (iPSC) are potentially useful for recellularization since they can be directed to express phenotypic marker genes of lung epithelial cells. Normal pulmonary development takes place in a low oxygen environment ranging from 1 to 5%. By contrast, in vitro ESC and iPSC differentiation protocols are usually carried out at room-air oxygen tension. Here, we sought to determine the role played by oxygen tension on the derivation of Nkx2.1+ lung/thyroid progenitor cells from mouse ESC and iPSC. A step-wise differentiation protocol was used to generate Nkx2.1+ lung/thyroid progenitors under 20% and 5% oxygen tension. On day 12, gene expression analysis revealed that Nkx2.1 and Foxa2 (endodermal and early lung epithelial cell marker) were significantly upregulated at 5% oxygen tension in ESC and iPSC differentiated cultures compared to 20% oxygen conditions. In addition, quantification of Foxa2+Nkx2.1+Pax8- cells corresponding to the lung field, with exclusion of the potential thyroid fate identified by Pax8 expression, confirmed that the low physiologic oxygen tension exerted a significant positive effect on early pulmonary differentiation of ESC and iPSC. In conclusion, we found that 5% oxygen tension enhanced the derivation of lung progenitors from mouse ESC and iPSC compared to 20% room-air oxygen tension.
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Mechanical properties of acellular mouse lungs after sterilization by gamma irradiation.
J Mech Behav Biomed Mater
PUBLISHED: 06-09-2014
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Lung bioengineering using decellularized organ scaffolds is a potential alternative for lung transplantation. Clinical application will require donor scaffold sterilization. As gamma-irradiation is a conventional method for sterilizing tissue preparations for clinical application, the aim of this study was to evaluate the effects of lung scaffold sterilization by gamma irradiation on the mechanical properties of the acellular lung when subjected to the artificial ventilation maneuvers typical within bioreactors. Twenty-six mouse lungs were decellularized by a sodium dodecyl sulfate detergent protocol. Eight lungs were used as controls and 18 of them were submitted to a 31kGy gamma irradiation sterilization process (9 kept frozen in dry ice and 9 at room temperature). Mechanical properties of acellular lungs were measured before and after irradiation. Lung resistance (RL) and elastance (EL) were computed by linear regression fitting of recorded signals during mechanical ventilation (tracheal pressure, flow and volume). Static (Est) and dynamic (Edyn) elastances were obtained by the end-inspiratory occlusion method. After irradiation lungs presented higher values of resistance and elastance than before irradiation: RL increased by 41.1% (room temperature irradiation) and 32.8% (frozen irradiation) and EL increased by 41.8% (room temperature irradiation) and 31.8% (frozen irradiation). Similar increases were induced by irradiation in Est and Edyn. Scanning electron microscopy showed slight structural changes after irradiation, particularly those kept frozen. Sterilization by gamma irradiation at a conventional dose to ensure sterilization modifies acellular lung mechanics, with potential implications for lung bioengineering.
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Mechanical properties of mouse lungs along organ decellularization by sodium dodecyl sulfate.
Respir Physiol Neurobiol
PUBLISHED: 04-29-2014
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Lung decellularization is based on the use of physical, chemical, or enzymatic methods to break down the integrity of the cells followed by a treatment to extract the cellular material from the lung scaffold. The aim of this study was to characterize the mechanical changes throughout the different steps of lung decellularization process. Four lungs from mice (C57BL/6) were decellularized by using a conventional protocol based on sodium dodecyl sulfate. Lungs resistance (R(L)) and elastance (E(L)) were measured along decellularization steps and were computed by linear regression fitting of tracheal pressure, flow, and volume during mechanical ventilation. Transients differences found were more distinct in an intermediate step after the lungs were rinsed with deionized water and treated with 1% SDS, whereupon the percentage of variation reached approximately 80% for resistance values and 30% for elastance values. In conclusion, although a variation in extracellular matrix stiffness was observed during the decellularization process, this variation can be considered negligible overall because the resistance and elastance returned to basal values at the final decellularization step.
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Association between sleep disordered breathing and aggressiveness markers of malignant cutaneous melanoma.
Eur. Respir. J.
PUBLISHED: 03-23-2014
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Some recent studies have shown an association between sleep disordered breathing (SDB) and cancer mortality and incidence but no study has focused on a specific type of cancer. The objective of this study was to analyse the relationship between the severity of SDB and factors related to cutaneous malignant melanoma (CMM) aggressiveness. We performed a multicentre observational study in 82 consecutive patients diagnosed with CMM. 56 patients in whom melanoma measurements were available were finally included in the study. Melanoma measurements of aggressiveness included: tumour mitotic rate, Breslow index, presence of ulceration, stage of disease and growth rate of melanoma. A sleep study was performed in all the included patients. Multivariate analyses were used to examine the independent relationship between SDB severity (apnoea-hypopnea index (AHI) and nocturnal oxygen desaturation indexes (ODI3% and ODI4%)) and measures of CMM aggressiveness. 60.7% of patients had SDB (AHI ? 5) and 14.3% severe obstructive sleep apnoea (AHI ? 30). In fully adjusted multivariate analyses, AHI (OR 1.08, 95% CI 1.02-1.14), ODI3% (OR 1.08, 95% CI 1.02-1.11) and ODI4% (OR 1.1, 95% CI 1.02-1.2) were independently associated with an increased melanoma growth rate. Furthermore, AHI, ODI4% and ODI3% were significantly correlated with other aggressiveness factors of CMM, such as Breslow index, presence of ulceration and mitotic index. SDB severity markers are associated with some aggressiveness markers of CMM.
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Atrial fibrosis in a chronic murine model of obstructive sleep apnea: mechanisms and prevention by mesenchymal stem cells.
Respir. Res.
PUBLISHED: 03-18-2014
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OSA increases atrial fibrillation (AF) risk and is associated with poor AF treatment outcomes. However, a causal association is not firmly established and the mechanisms involved are poorly understood. The aims of this work were to determine whether chronic obstructive sleep apnea (OSA) induces an atrial pro-arrhythmogenic substrate and to explore whether mesenchymal stem cells (MSC) are able to prevent it in a rat model of OSA.
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Heterogeneous micromechanical properties of the extracellular matrix in healthy and infarcted hearts.
Acta Biomater
PUBLISHED: 03-07-2014
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Infarcted hearts are macroscopically stiffer than healthy organs. Nevertheless, although cell behavior is mediated by the physical features of the cell niche, the intrinsic micromechanical properties of healthy and infarcted heart extracellular matrix (ECM) remain poorly characterized. Using atomic force microscopy, we studied ECM micromechanics of different histological regions of the left ventricle wall of healthy and infarcted mice. Hearts excised from healthy (n=8) and infarcted mice (n=8) were decellularized with sodium dodecyl sulfate and cut into 12 ?m thick slices. Healthy ventricular ECM revealed marked mechanical heterogeneity across histological regions of the ventricular wall with the effective Young's modulus ranging from 30.2 ± 2.8 to 74.5 ± 8.7 kPa in collagen- and elastin-rich regions of the myocardium, respectively. Infarcted ECM showed a predominant collagen composition and was 3-fold stiffer than collagen-rich regions of the healthy myocardium. ECM of both healthy and infarcted hearts exhibited a solid-like viscoelastic behavior that conforms to two power-law rheology. Knowledge of intrinsic micromechanical properties of the ECM at the length scale at which cells sense their environment will provide further insight into the cell-scaffold interplay in healthy and infarcted hearts.
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Intermittent hypoxia-induced changes in tumor-associated macrophages and tumor malignancy in a mouse model of sleep apnea.
Am. J. Respir. Crit. Care Med.
PUBLISHED: 01-30-2014
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An increased cancer aggressiveness and mortality have been recently reported among patients with obstructive sleep apnea (OSA). Intermittent hypoxia (IH), a hallmark of OSA, enhances melanoma growth and metastasis in mice.
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Telemedicine-based approach for obstructive sleep apnea management: building evidence.
Interact J Med Res
PUBLISHED: 01-19-2014
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Telemedicine seems to offer reliable solutions to health care challenges, but significant contradictory results were recently found. Therefore, it is crucial to carefully select outcomes and target patients who may take advantage of this technology. Continuous positive airway pressure (CPAP) therapy compliance is essential to treat patients with obstructive sleep apnea (OSA). We believe that OSA patients could benefit greatly from a telemedicine approach for CPAP therapy management.
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Obstructive sleep apnea is associated with cancer mortality in younger patients.
Sleep Med.
PUBLISHED: 01-15-2014
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The association between obstructive sleep apnea (OSA) and cancer mortality has scarcely been studied. The objective of this study was to investigate whether OSA is associated with increased cancer mortality in a large cohort of patients with OSA suspicion.
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Inhomogeneity of local stiffness in the extracellular matrix scaffold of fibrotic mouse lungs.
J Mech Behav Biomed Mater
PUBLISHED: 01-14-2014
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Lung disease models are useful to study how cell engraftment, proliferation and differentiation are modulated in lung bioengineering. The aim of this work was to characterize the local stiffness of decellularized lungs in aged and fibrotic mice. Mice (2- and 24-month old; 14 of each) with lung fibrosis (N=20) and healthy controls (N=8) were euthanized after 11 days of intratracheal bleomycin (fibrosis) or saline (controls) infusion. The lungs were excised, decellularized by a conventional detergent-based (sodium-dodecyl sulfate) procedure and slices of the acellular lungs were prepared to measure the local stiffness by means of atomic force microscopy. The local stiffness of the different sites in acellular fibrotic lungs was very inhomogeneous within the lung and increased according to the degree of the structural fibrotic lesion. Local stiffness of the acellular lungs did not show statistically significant differences caused by age. The group of mice most affected by fibrosis exhibited local stiffness that were ~2-fold higher than in the control mice: from 27.2±1.64 to 64.8±7.1kPa in the alveolar septa, from 56.6±4.6 to 99.9±11.7kPa in the visceral pleura, from 41.1±8.0 to 105.2±13.6kPa in the tunica adventitia, and from 79.3±7.2 to 146.6±28.8kPa in the tunica intima. Since acellular lungs from mice with bleomycin-induced fibrosis present considerable micromechanical inhomogeneity, this model can be a useful tool to better investigate how different degrees of extracellular matrix lesion modulate cell fate in the process of organ bioengineering from decellularized lungs.
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Effects of the Decellularization Method on the Local Stiffness of Acellular Lungs.
Tissue Eng Part C Methods
PUBLISHED: 11-06-2013
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Lung bioengineering, a novel approach to obtain organs potentially available for transplantation, is based on decellularizing donor lungs and seeding natural scaffolds with stem cells. Various physicochemical protocols have been used to decellularize lungs, and their performance has been evaluated in terms of efficient decellularization and matrix preservation. No data are available, however, on the effect of different decellularization procedures on the local stiffness of the acellular lung. This information is important since stem cells directly sense the rigidity of the local site they are engrafting to during recellularization, and it has been shown that substrate stiffness modulates cell fate into different phenotypes. The aim of this study was to assess the effects of the decellularization procedure on the inhomogeneous local stiffness of the acellular lung on five different sites: alveolar septa, alveolar junctions, pleura, and vessels tunica intima and tunica adventitia. Local matrix stiffness was measured by computing Youngs modulus with atomic force microscopy after decellularizing the lungs of 36 healthy rats (Sprague-Dawley, male, 250-300?g) with four different protocols with/without perfusion through the lung circulatory system and using two different detergents (sodium dodecyl sulfate [SDS] and 3-[(3-cholamidopropyl) dimethylammonio]-1-propanesulfonate [CHAPS]). The local stiffness of the acellular lung matrix significantly depended on the site within the matrix (p<0.001), ranging from ?15?kPa at the alveolar septum to ?60?kPa at the tunica intima. Acellular lung stiffness (p=0.003) depended significantly, albeit modestly, on the decellularization process. Whereas perfusion did not induce any significant differences in stiffness, the use of CHAPS resulted in a ?35% reduction compared with SDS, the influence of the detergent being more important in the tunica intima. In conclusion, lung matrix stiffness is considerably inhomogeneous, and conventional decellularization procedures do not result in substantially different local stiffness in the acellular lung.
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Chronic intermittent hypoxia preserves bone density in a mouse model of sleep apnea.
Respir Physiol Neurobiol
PUBLISHED: 08-12-2013
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Very recent clinical research has investigated whether obstructive sleep apnea (OSA) may modulate bone homeostasis but the few data available are conflicting. Here we report novel data obtained in a mouse study specifically designed to determine whether chronic intermittent hypoxia realistically mimicking OSA modifies bone mineral density (BMD). Normal male and female mice and orchidectomized mice (N=10 each group) were subjected to a pattern of high-frequency intermittent hypoxia (20s at 5% and 40s at 21%, 60 cycles/h) for 6h/day. Identical groups breathing room air (normoxia) were the controls. After 32 days of intermittent hypoxia/normoxia the trabecular bone mineral density (BMD) in the peripheral femora were measured by micro-CT scanning. When compared with normoxia (two-way ANOVA), intermittent hypoxia did not significantly modify BMD in the three animal groups tested. Data in this study suggest that the type of intermittent hypoxia characterizing OSA, applied as a single challenge, preserves bone homeostasis.
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Mesenchymal Stem Cells in Solid Organ Transplantation (MiSOT) Fourth Meeting: lessons learned from first clinical trials.
Transplantation
PUBLISHED: 06-14-2013
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The Fourth Expert Meeting of the Mesenchymal Stem Cells in Solid Organ Transplantation (MiSOT) Consortium took place in Barcelona on October 19 and 20, 2012. This meeting focused on the translation of preclinical data into early clinical settings. This position paper highlights the main topics explored on the safety and efficacy of mesenchymal stem cells as a therapeutic agent in solid organ transplantation and emphasizes the issues (proper timing, concomitant immunossupression, source and immunogenicity of mesenchymal stem cells, and oncogenicity) that have been addressed and will be followed up by the MiSOT Consortium in future studies.
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Oxygen diffusion and consumption in extracellular matrix gels: Implications for designing three-dimensional cultures.
J Biomed Mater Res A
PUBLISHED: 06-06-2013
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Three-dimensional (3D) cultures are increasingly used as tissue surrogates to study many physiopathological processes. However, to what extent current 3D culture protocols provide physiologic oxygen tension conditions remains ill defined. To address this limitation, oxygen tension was measured in a panel of acellular or cellularized extracellular matrix (ECM) gels with A549 cells, and analyzed in terms of oxygen diffusion and consumption. Gels included reconstituted basement membrane, fibrin and collagen. Oxygen diffusivity in acellular gels was up to 40% smaller than that of water, and the lower values were observed in the denser gels. In 3D cultures, physiologic oxygen tension was achieved after 2 days in dense (?3 mg/mL) but not sparse gels, revealing that the latter gels are not suitable tissue surrogates in terms of oxygen distribution. In dense gels, we observed a dominant effect of ECM composition over density in oxygen consumption. All diffusion and consumption data were used in a simple model to estimate ranges for gel thickness, seeding density and time-window that may support physiologic oxygen tension. Thus, we identified critical variables for oxygen tension in ECM gels, and introduced a model to assess initial values of these variables, which may short-cut the optimization step of 3D culture studies. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2013.
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An in vitro study to assess determinant features associated with fluid sealing in the design of endotracheal tube cuffs and exerted tracheal pressures.
Crit. Care Med.
PUBLISHED: 04-09-2013
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To assess the structural characteristics involved in the design of high-volume low-pressure endotracheal tube cuffs that are associated with fluid sealing effectiveness and to determine the extent of transmitted tracheal pressures upon cuff inflation.
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Antioxidant effect of human adult adipose-derived stromal stem cells in alveolar epithelial cells undergoing stretch.
Respir Physiol Neurobiol
PUBLISHED: 04-07-2013
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Alveolar epithelial cells undergo stretching during mechanical ventilation. Stretch can modify the oxidative balance in the alveolar epithelium. The aim of the present study was to evaluate the antioxidant role of human adult adipose tissue-derived stromal cells (hADSCs) when human alveolar epithelial cells were subjected to injurious cyclic overstretching.
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The effects of intermittent hypoxia on redox status, NF-?B activation, and plasma lipid levels are dependent on the lowest oxygen saturation.
Free Radic. Biol. Med.
PUBLISHED: 03-17-2013
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Obstructive sleep apnea syndrome (OSAS) is described as repetitive obstructions of the upper airways during sleep, causing concomitant episodes of systemic hypoxia and associated cardiovascular and metabolic pathologies. The mechanisms generating these pathologies are controversial. Because recurrent hypoxia is the element of inadequate respiration that leads to the pathology, experimental models of OSAS consist in the exposure of the animals to intermittent hypoxia (IH) by cycling O2 percentages in their habitats. A proposed mechanism linking the IH of OSAS to pathologies is the increased production of reactive oxygen species (ROS). However, it has been argued that many patients seem to lack oxidative stress and that, to augment ROS in IH animals, intense hypoxia, seldom encountered in patients, has to be applied. To solve the controversy, we have exposed rats to two intensities of IH (cycles of 10 or 5% O2, 40s, and then 21% O2, 80s; 8h/day, 15 days). We then measured reduced and oxidized glutathione and lipid peroxide levels, aconitase and fumarase activities, and ROS-disposal enzyme activity in liver, brain, and lung. Liver levels of nuclear NF-?B-p65 and plasma C-reactive protein (CRP), as well as lipid levels, were also assessed. Lowest hemoglobin saturations were 91.7±0.8 and 73.5±1.4%. IH caused tissue-specific oxidative stress related to hypoxic intensity. Nuclear NF-?B-p65 and lipid content in the liver and CRP in the plasma all increased with IH intensity, as did both plasma triglycerides and cholesterol. We conclude that IH, even of moderate intensity, causes oxidative stress probably related to the pathologies encountered in OSAS patients.
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Intermittent hypoxia increases melanoma metastasis to the lung in a mouse model of sleep apnea.
Respir Physiol Neurobiol
PUBLISHED: 02-22-2013
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Obstructive sleep apnea (OSA) has recently been associated with an increased risk of cancer incidence and mortality in humans. Experimental data in mice have also shown that intermittent hypoxia similar to that observed in OSA patients enhances tumor growth. The aim of this study was to test the hypothesis that intermittent hypoxia mimicking OSA enhances lung metastasis. A total of 75 C57BL/6J male mice (10-week-old) were subjected to either spontaneous or induced melanoma lung metastasis. Normoxic animals breathed room air and intermittent hypoxic animals were subjected to cycles of 20s of 5% O2 followed by 40s of room air for 6h/day. Spontaneous and induced lung metastases were studied after subcutaneous and intravenous injection of B16F10 melanoma cells, respectively. Compared with normoxia, intermittent hypoxia induced a significant increase in melanoma lung metastasis. These animal model results suggest that intermittent hypoxia could contribute to cancer metastasis in patients with OSA.
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Barrier-protective effects of activated protein C in human alveolar epithelial cells.
PLoS ONE
PUBLISHED: 01-17-2013
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Acute lung injury (ALI) is a clinical manifestation of respiratory failure, caused by lung inflammation and the disruption of the alveolar-capillary barrier. Preservation of the physical integrity of the alveolar epithelial monolayer is of critical importance to prevent alveolar edema. Barrier integrity depends largely on the balance between physical forces on cell-cell and cell-matrix contacts, and this balance might be affected by alterations in the coagulation cascade in patients with ALI. We aimed to study the effects of activated protein C (APC) on mechanical tension and barrier integrity in human alveolar epithelial cells (A549) exposed to thrombin. Cells were pretreated for 3 h with APC (50 µg/ml) or vehicle (control). Subsequently, thrombin (50 nM) or medium was added to the cell culture. APC significantly reduced thrombin-induced cell monolayer permeability, cell stiffening, and cell contraction, measured by electrical impedance, optical magnetic twisting cytometry, and traction microscopy, respectively, suggesting a barrier-protective response. The dynamics of the barrier integrity was also assessed by western blotting and immunofluorescence analysis of the tight junction ZO-1. Thrombin resulted in more elongated ZO-1 aggregates at cell-cell interface areas and induced an increase in ZO-1 membrane protein content. APC attenuated the length of these ZO-1 aggregates and reduced the ZO-1 membrane protein levels induced by thrombin. In conclusion, pretreatment with APC reduced the disruption of barrier integrity induced by thrombin, thus contributing to alveolar epithelial barrier protection.
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Cost-effectiveness of a new internet-based monitoring tool for neonatal post-discharge home care.
J. Med. Internet Res.
PUBLISHED: 01-13-2013
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The application of information and communication technologies in nursing care is becoming more widespread, but few applications have been reported in neonatal care. A close monitoring of newborns within the first weeks of life is crucial to evaluating correct feeding, growth, and health status. Conventional hospital-based postdischarge monitoring could be improved in terms of costs and clinical effectiveness by using a telemedicine approach.
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Effects of freezing/thawing on the mechanical properties of decellularized lungs.
J Biomed Mater Res A
PUBLISHED: 01-08-2013
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Lung bioengineering based on decellularized organ scaffolds is a potential alternative for transplantation. Freezing/thawing, a usual procedure in organ decellularization and storage could modify the mechanical properties of the lung scaffold and reduce the performance of the bioengineered lung when subjected to the physiological inflation-deflation breathing cycles. The aim of this study was to determine the effects of repeated freezing/thawing on the mechanical properties of decellularized lungs in the physiological pressure-volume regime associated with normal ventilation. Fifteen mice lungs (C57BL/6) were decellularized using a conventional protocol not involving organ freezing and based on sodium dodecyl sulfate detergent. Subsequently, the mechanical properties of the acellular lungs were measured before and after subjecting them to three consecutive cycles of freezing/thawing. The resistance (RL ) and elastance (EL ) of the decellularized lungs were computed by linear regression fitting of the recorded signals (tracheal pressure, flow, and volume) during mechanical ventilation. RL was not significantly modified by freezing-thawing: from 0.88 ± 0.37 to 0.90 ± 0.38 cmH2 O·s·mL(-1) (mean ± SE). EL slightly increased from 64.4 ± 11.1 to 73.0 ± 16.3 cmH2 O·mL(-1) after the three freeze-thaw cycles (p = 0.0013). In conclusion, the freezing/thawing process that is commonly used for both organ decellularization and storage induces only minor changes in the ventilation mechanical properties of the organ scaffold. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 102A: 413-419, 2014.
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Rapid detection of sepsis in rats through volatile organic compounds in breath.
J. Chromatogr. B Analyt. Technol. Biomed. Life Sci.
PUBLISHED: 10-06-2011
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Sepsis is one of the main causes of death in adult intensive care units. The major drawbacks of the different methods used for its diagnosis and monitoring are their inability to provide fast responses and unsuitability for bedside use. In this study, performed using a rat sepsis model, we evaluate breath analysis with Ion Mobility Spectrometry (IMS) as a fast, portable and non-invasive strategy.
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Tissue oxygenation in brain, muscle, and fat in a rat model of sleep apnea: differential effect of obstructive apneas and intermittent hypoxia.
Sleep
PUBLISHED: 08-02-2011
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To test the hypotheses that the dynamic changes in brain oxygen partial pressure (PtO(2)) in response to obstructive apneas or to intermittent hypoxia differ from those in other organs and that the changes in brain PtO(2) in response to obstructive apneas is a source of oxidative stress.
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Oscillation mechanics of the respiratory system.
Compr Physiol
PUBLISHED: 07-01-2011
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The mechanical impedance of the respiratory system defines the pressure profile required to drive a unit of oscillatory flow into the lungs. Impedance is a function of oscillation frequency, and is measured using the forced oscillation technique. Digital signal processing methods, most notably the Fourier transform, are used to calculate impedance from measured oscillatory pressures and flows. Impedance is a complex function of frequency, having both real and imaginary parts that vary with frequency in ways that can be used empirically to distinguish normal lung function from a variety of different pathologies. The most useful diagnostic information is gained when anatomically based mathematical models are fit to measurements of impedance. The simplest such model consists of a single flow-resistive conduit connecting to a single elastic compartment. Models of greater complexity may have two or more compartments, and provide more accurate fits to impedance measurements over a variety of different frequency ranges. The model that currently enjoys the widest application in studies of animal models of lung disease consists of a single airway serving an alveolar compartment comprising tissue with a constant-phase impedance. This model has been shown to fit very accurately to a wide range of impedance data, yet contains only four free parameters, and as such is highly parsimonious. The measurement of impedance in human patients is also now rapidly gaining acceptance, and promises to provide a more comprehensible assessment of lung function than parameters derived from conventional spirometry.
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Potential Role of Bone Marrow Mesenchymal Stem Cells in Obstructive Sleep Apnea.
Int J Stem Cells
PUBLISHED: 03-11-2011
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Obstructive sleep apnea syndrome (OSA) is a prevalent disease caused by increased collapsibility of the upper airway. OSA induces oxidative stress, inflammation and endothelial dysfunction, with important clinical consequences such as neurocognitive alterations and cardiovascular diseases. Although it has been shown that bone marrow-derived stem cells play a protective and reparative function in several diseases involving inflammatory processes and endothelial dysfunction, the data currently available on the potential role of adult stem cells in OSA are scarce. The present review presents recent data on the potential role of bone marrow-derived mesenchymal stem cells (MSC) in OSA. The results obtained in animal models that realistically mimic the events characterizing this sleep breathing disorder strongly support the notion that MSC are mobilized in circulating blood and then activated to play an anti-inflammatory role in OSA.
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Telemetric CPAP titration at home in patients with sleep apnea-hypopnea syndrome.
Sleep Med.
PUBLISHED: 01-17-2011
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Home continuous positive airway pressure (CPAP) titration with automatic devices is not possible in a non-negligible percentage of patients with sleep apnea-hypopnea syndrome (SAHS).
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Early and mid-term effects of obstructive apneas in myocardial injury and inflammation.
Sleep Med.
PUBLISHED: 01-14-2011
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Obstructive sleep apnea (OSA) is associated with cardiovascular disorders, but the different comorbidities in OSA patients make it difficult to know their specific effects on the development of cardiovascular injury. The aim of the present study was to investigate whether recurrent obstructive apneas could lead to myocardial injury.
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Non-invasive system for applying airway obstructions to model obstructive sleep apnea in mice.
Respir Physiol Neurobiol
PUBLISHED: 09-22-2010
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Obstructive sleep apnea (OSA) is characterized by recurrent upper airway obstructions during sleep. The most common animal model of OSA is based on subjecting rodents to intermittent hypoxic exposures and does not mimic important OSA features, such as recurrent hypercapnia and increased inspiratory efforts. To circumvent some of these issues, a novel murine model involving non-invasive application of recurrent airway obstructions was developed. An electronically controlled airbag system is placed in front of the mouses snout, whereby inflating the airbag leads to obstructed breathing and spontaneous breathing occurs with the airbag deflated. The device was tested on 29 anesthetized mice by measuring inspiratory effort and arterial oxygen saturation (SaO?). Application of recurrent obstructive apneas (6 s each, 120/h) for 6h resulted in SaO? oscillations to values reaching 84.4 ± 2.5% nadir, with swings mimicking OSA patients. This novel system, capable of applying controlled recurrent airway obstructions in mice, is an easy-to-use tool for investigating pertinent aspects of OSA.
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Alternating ventilation in a rat model of increased abdominal pressure.
Respir Physiol Neurobiol
PUBLISHED: 06-15-2010
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During alternating ventilation (AV) one lung is inflating while the other is deflating. Considering the possible respiratory and hemodynamic advantages of AV, we investigated its effects during increased intra-abdominal pressure (IAP=10 mmHg). In Sprague-Dawley rats (n=6, 270-375g) the main bronchi were independently cannulated, and respiratory mechanics determined while animals underwent different ventilatory patterns: synchronic ventilation without increased IAP (SV-0), elevated IAP during SV (SV-10), and AV with elevated IAP (AV-10). Thirty-three other animals (SV-0, n=10; SV-10, n=11 and AV-10, n=12) were ventilated during 3h. Mean arterial pressure (MAP), and lung histology were assessed. Increased IAP resulted in significantly higher elastances (p<0.001), being AV-10 lower than SV-10 (p<0.020). SV-10 showed higher central venous pressure (p<0.003) than S-0; no change was observed in AV-10. Wet/dry lung weight ratio was lower in AV-10 than SV-10 (p=0.009). Application of AV reduced hemodynamic and lung impairments induced by increased IAP during SV.
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Mesenchymal stem cells reduce inflammation in a rat model of obstructive sleep apnea.
Respir Physiol Neurobiol
PUBLISHED: 05-14-2010
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The aim was to test the hypothesis that mesenchymal stem cells (MSC) could reduce the inflammation induced by recurrent airway occlusions in an animal model of obstructive sleep apnea (OSA). A nasal mask was applied to 30 anesthetized rats. Twenty rats were subjected to a pattern of recurrent obstructive apneas mimicking OSA (60/h, lasting 15 s each) for 5h. MSC (5x10(6) cells) were intravenously injected into 10 of these rats. Ten rats not subjected to apneas or MSC injection were used as controls. The rat blood serum concentrations of pro-inflammatory cytokine IL-1beta were measured by ELISA. IL-1beta was significantly greater in the rats subjected to recurrent apneas (66.7+/-41.2 pg/mL; m+/-SEM) than in controls (1.9+/-1.0 pg/mL; p<0.05). In the group of apneic rats subjected to MSC injection, IL-1beta was significantly reduced (6.1+/-3.8 pg/mL; p<0.05). In conclusion, MSC triggered an early anti-inflammatory response in rats subjected to recurrent obstructive apneas, suggesting that these stem cells could play a role in the physiological response to counterbalance inflammation in OSA.
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Obstructive apneas induce early activation of mesenchymal stem cells and enhancement of endothelial wound healing.
Respir. Res.
PUBLISHED: 03-29-2010
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The aim was to test the hypothesis that the blood serum of rats subjected to recurrent airway obstructions mimicking obstructive sleep apnea (OSA) induces early activation of bone marrow-derived mesenchymal stem cells (MSC) and enhancement of endothelial wound healing.
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Effects of heated humidification on nasal inflammation in a CPAP rat model.
Sleep Med.
PUBLISHED: 03-09-2010
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Rhinitis is a potential side effect of nasal continuous positive airway pressure (nCPAP). Heated Humidification (HH) is applied to treat rhinitic symptoms, but its usefulness is controversial. Confounding factors such as previous rhinitis or nasal obstruction make it difficult to draw definitive conclusions. Animal models could therefore be useful.
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Electroencephalographic slowing heralds mild cognitive impairment in idiopathic REM sleep behavior disorder.
Sleep Med.
PUBLISHED: 01-28-2010
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Patients with idiopathic rapid eye movement (REM) sleep behavior disorder (IRBD) may show electroencephalographic (EEG) slowing reflecting cortical dysfunction and are at risk for developing neurological conditions characterized by cognitive dysfunction including mild cognitive impairment (MCI), dementia with Lewy bodies and Parkinsons disease with associated dementia. We hypothesized that those IRBD patients who later developed MCI had pronounced cortical EEG slowing at presentation.
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Changes in oxygen partial pressure of brain tissue in an animal model of obstructive apnea.
Respir. Res.
PUBLISHED: 01-15-2010
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Cognitive impairment is one of the main consequences of obstructive sleep apnea (OSA) and is usually attributed in part to the oxidative stress caused by intermittent hypoxia in cerebral tissues. The presence of oxygen-reactive species in the brain tissue should be produced by the deoxygenation-reoxygenation cycles which occur at tissue level during recurrent apneic events. However, how changes in arterial blood oxygen saturation (SpO2) during repetitive apneas translate into oxygen partial pressure (PtO2) in brain tissue has not been studied. The objective of this study was to assess whether brain tissue is partially protected from intermittently occurring interruption of O2 supply during recurrent swings in arterial SpO2 in an animal model of OSA.
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Biological consequences of oxygen desaturation and respiratory effort in an acute animal model of obstructive sleep apnea (OSA).
Sleep Med.
PUBLISHED: 04-01-2009
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An animal model mimicking all the factors involved in obstructive sleep apnea (OSA) is useful for investigating mechanisms because the associated comorbidity usually present in such patients is an important limitation.
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Sleep breathing flow characteristics as a sign for the detection of wakefulness in patients with sleep apnea.
Respiration
PUBLISHED: 02-18-2009
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To improve the performance of simplified sleep studies, it is essential to properly estimate the sleep time.
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Obstructive apneas induce early release of mesenchymal stem cells into circulating blood.
Sleep
PUBLISHED: 02-05-2009
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To investigate whether noninvasive application of recurrent airway obstructions induces early release of mesenchymal stem cells into the circulating blood in a rat model of obstructive sleep apnea.
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Actual performance of mechanical ventilators in ICU: a multicentric quality control study.
Med Devices (Auckl)
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Even if the performance of a given ventilator has been evaluated in the laboratory under very well controlled conditions, inappropriate maintenance and lack of long-term stability and accuracy of the ventilator sensors may lead to ventilation errors in actual clinical practice. The aim of this study was to evaluate the actual performances of ventilators during clinical routines. A resistance (7.69 cmH(2)O/L/s) - elastance (100 mL/cmH(2)O) test lung equipped with pressure, flow, and oxygen concentration sensors was connected to the Y-piece of all the mechanical ventilators available for patients in four intensive care units (ICUs; n = 66). Ventilators were set to volume-controlled ventilation with tidal volume = 600 mL, respiratory rate = 20 breaths/minute, positive end-expiratory pressure (PEEP) = 8 cmH(2)O, and oxygen fraction = 0.5. The signals from the sensors were recorded to compute the ventilation parameters. The average ± standard deviation and range (min-max) of the ventilatory parameters were the following: inspired tidal volume = 607 ± 36 (530-723) mL, expired tidal volume = 608 ± 36 (530-728) mL, peak pressure = 20.8 ± 2.3 (17.2-25.9) cmH(2)O, respiratory rate = 20.09 ± 0.35 (19.5-21.6) breaths/minute, PEEP = 8.43 ± 0.57 (7.26-10.8) cmH(2)O, oxygen fraction = 0.49 ± 0.014 (0.41-0.53). The more error-prone parameters were the ones related to the measure of flow. In several cases, the actual delivered mechanical ventilation was considerably different from the set one, suggesting the need for improving quality control procedures for these machines.
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Association between obstructive sleep apnea and cancer incidence in a large multicenter Spanish cohort.
Am. J. Respir. Crit. Care Med.
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Obstructive sleep apnea (OSA) has been associated with increased cancer mortality, but whether it is also associated with cancer incidence is unknown.
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Obesity and intermittent hypoxia increase tumor growth in a mouse model of sleep apnea.
Sleep Med.
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Intermittent hypoxia and obesity which are two pathological conditions commonly found in patients with obstructive sleep apnea (OSA), potentially enhance cancer progression.
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Potential role of adult stem cells in obstructive sleep apnea.
Front Neurol
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Adult stem cells are undifferentiated cells that can be mobilized from the bone marrow or other organs, home into injured tissues, and differentiate into different cell phenotypes to serve in a repairing capacity. Furthermore, these cells can respond to inflammation and oxidative stress by exhibiting immunomodulatory properties. The protective and reparative roles of mesenchymal stem cells (MSCs), very small embryonic-like stem cells (VSELs), and endothelial progenitor cells (EPCs) have primarily been examined and characterized in auto-immune and cardiovascular diseases. Obstructive sleep apnea (OSA) is a very prevalent disease (4-5% of adult population and 2-3% of children) characterized by an abnormal increase in upper airway collapsibility. Recurrent airway obstructions elicit arterial oxygen desaturations, increased inspiratory efforts, and sleep fragmentation, which have been associated with important long-term neurocognitive, metabolic, and cardiovascular consequences. Since inflammation, oxidative stress and endothelial dysfunction are key factors in the development of the morbid consequences of OSA, bone marrow-derived stem cells could be important modulators of the morbid phenotype by affording a protective role. This mini-review is focused on the recent data available on EPCs, VSELs, and MSCs in both animal models and patients with OSA.
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Sleep-disordered breathing and cancer mortality: results from the Wisconsin Sleep Cohort Study.
Am. J. Respir. Crit. Care Med.
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Sleep-disordered breathing (SDB) has been associated with total and cardiovascular mortality, but an association with cancer mortality has not been studied. Results from in vitro and animal studies suggest that intermittent hypoxia promotes cancer tumor growth.
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Evaluation of upper airway patency during Cheyne-Stokes breathing in heart failure patients.
Eur. Respir. J.
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Little is known about the changes in upper airway calibre in Cheyne-Stokes respiration (CSR) during sleep in patients with congestive heart failure. This study aimed to test the hypothesis that upper airway closure occurs during central CSR events, by assessing upper airway calibre during sleep using the forced oscillation technique (FOT). Nine males with compensated heart failure (left ventricular ejection fraction mean ± sem 27.9 ± 5.1%) and predominant central CSR (apnoea/hypopnoea index 43.9 ± 4.2 events · h(-1)) were studied during overnight polysomnography, which included pneumotachography, inductance plethysmography or oesophageal pressure and FOT-derived impedance signal (|Z|). Baseline |Z| values during stable breathing in stage 2 sleep were 11.0 ± 1.3 cmH(2)O · s · L(-1). Mean |Z| increased to 31.9 ± 6.7 cmH(2)O · s · L(-1) during obstructive apnoeas (7% of events, n = 46). Increases in |Z| consistent with upper airway narrowing (more than two-fold baseline) were common during central apnoeas (50 ± 12% of events) occurring in the middle or end of apnoeas and occurred during some central hypopnoeas (16 ± 10% of events), typically in the expiratory phase. These findings indicate that in heart failure patients, reductions in upper airway calibre are common during CSR apnoeas, and may also occur during central hypopnoeas.
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Automatic CPAP performance in patients with sleep apnea plus COPD.
COPD
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Automatic CPAP devices have demonstrated good results in obtaining optimal fixed CPAP pressure to eliminate respiratory events in patients with sleep apnea-hypopnea syndrome (SAHS). However, automatic CPAP has not been fully studied in patients with COPD plus SAHS.
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Pre-treatment with mesenchymal stem cells reduces ventilator-induced lung injury.
Eur. Respir. J.
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Bone marrow-derived mesenchymal stem cells (MSCs) reduce acute lung injury in animals challenged by bleomycin or bacterial lipopolysaccaride. It is not known, however, whether MSCs protect from ventilator-induced lung injury (VILI). This study investigated whether MSCs have a potential role in preventing or modulating VILI in healthy rats subjected to high-volume ventilation. 24 Sprague-Dawley rats (250-300 g) were subjected to high-volume mechanical ventilation (25 mL·kg(-1)). MSCs (5 × 10(6)) were intravenously or intratracheally administered (n=8 each) 30 min before starting over-ventilation and eight rats were MSC-untreated. Spontaneously breathing anesthetised rats (n=8) served as controls. After 3 h of over-ventilation or control the animals were sacrificed and lung tissue and bronchoalveolar lavage fluid (BALF) were sampled for further analysis. When compared with controls, MSC-untreated over-ventilated rats exhibited typical VILI features. Lung oedema, histological lung injury index, concentrations of total protein, interleukin-1?, macrophage inflammatory protein-2 and number of neutrophils in BALF and vascular cell adhesion protein-1 in lung tissue significantly increased in over-ventilated rats. All these indices of VILI moved significantly towards normalisation in the rats treated with MSCs, whether intravenously or intratracheally. Both local and systemic pre-treatment with MSCs reduced VILI in a rat model.
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Integrin-specific mechanoresponses to compression and extension probed by cylindrical flat-ended AFM tips in lung cells.
PLoS ONE
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Cells from lung and other tissues are subjected to forces of opposing directions that are largely transmitted through integrin-mediated adhesions. How cells respond to force bidirectionality remains ill defined. To address this question, we nanofabricated flat-ended cylindrical Atomic Force Microscopy (AFM) tips with ~1 µm(2) cross-section area. Tips were uncoated or coated with either integrin-specific (RGD) or non-specific (RGE/BSA) molecules, brought into contact with lung epithelial cells or fibroblasts for 30 s to form focal adhesion precursors, and used to probe cell resistance to deformation in compression and extension. We found that cell resistance to compression was globally higher than to extension regardless of the tip coating. In contrast, both tip-cell adhesion strength and resistance to compression and extension were the highest when probed at integrin-specific adhesions. These integrin-specific mechanoresponses required an intact actin cytoskeleton, and were dependent on tyrosine phosphatases and Ca(2+) signaling. Cell asymmetric mechanoresponse to compression and extension remained after 5 minutes of tip-cell adhesion, revealing that asymmetric resistance to force directionality is an intrinsic property of lung cells, as in most soft tissues. Our findings provide new insights on how lung cells probe the mechanochemical properties of the microenvironment, an important process for migration, repair and tissue homeostasis.
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A bioreactor for subjecting cultured cells to fast-rate intermittent hypoxia.
Respir Physiol Neurobiol
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High frequency intermittent hypoxia is one of the most relevant injurious stimuli experienced by patients with obstructive sleep apnea (OSA). Given that the conventional setting for culturing cells under intermittent hypoxia conditions is limited by long equilibration times, we designed a simple bioreactor capable of effectively subjecting cultured cells to controlled high-frequency hypoxic/normoxic stimuli. The bioreactors operation is based on exposing cells to a medium that is bubbled with the appropriate mixture of gases into two separate containers, and from there it is directed to the cell culture dish with the aid of two bidirectional peristaltic pumps. The device was tested on human alveolar epithelial cells (A549) and mouse melanoma cells (B16-F10), subjecting them to patterns of intermittent hypoxia (20s at 5% O(2) and 50s at 20% O(2)), which realistically mimic OSA of up to severe intensity as defined by the apnea hypopnea index. The proposed bioreactor can be easily and inexpensively assembled and is of practical use for investigating the effects of high-rate changes in oxygen concentration in the cell culture medium.
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