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Campillo, N., Falcones, B., Montserrat, J. M., Gozal, D., Obeso, A., Gallego-Martin, T., Navajas, D., Almendros, I., Farré, R., (2017). Frequency and magnitude of intermittent hypoxia modulate endothelial wound healing in a cell culture model of sleep apnea Journal of Applied Physiology 123, (5), 1047-1054

Intermittent hypoxia (IH) has been implicated in the cardiovascular consequences of obstructive sleep apnea (OSA). However, the lack of suitable experimental systems has precluded assessment as to whether IH is detrimental, protective, or both for the endothelium. The aim of the work was to determine the effects of frequency and amplitude of IH oxygenation swings on aortic endothelial wound healing. Monolayers of human primary endothelial cells were wounded and subjected to constant oxygenation (1%, 4%, 13%, or 20% O2) or IH at different frequencies (0.6, 6, or 60 cycles/h) and magnitude ranges (13–4% O2 or 20–1% O2), using a novel well-controlled system, with wound healing being measured after 24 h. Cell monolayer repair was similar at 20% O2 and 13% O2, but was considerably increased (approximately twofold) in constant hypoxia at 4% O2. The magnitude and frequency of IH considerably modulated wound healing. Cycles ranging 13–4% O2 at the lowest frequency (0.6 cycles/h) accelerated endothelial wound healing by 102%. However, for IH exposures consisting of 20% to 1% O2 oscillations, wound closure was reduced compared with oscillation in the 13–4% range (by 74% and 44% at 6 cycles/h and 0.6 cycles/h, respectively). High-frequency IH patterns simulating severe OSA (60 cycles/h) did not significantly modify endothelial wound closure, regardless of the oxygenation cycle amplitude. In conclusion, the frequency and magnitude of hypoxia cycling in IH markedly alter wound healing responses and emerge as key factors determining how cells will respond in OSA. NEW & NOTEWORTHY Intermittent hypoxia (IH) induces cardiovascular consequences in obstructive sleep apnea (OSA) patients. However, the vast array of frequencies and severities of IH previously employed in OSA-related experimental studies has led to controversial results on the effects of IH. By employing an optimized IH experimental system here, we provide evidence that the frequency and magnitude of IH markedly alter human aortic endothelial wound healing, emerging as key factors determining how cells respond in OSA.

Keywords: Sleep apnea, Repair, Endothelium, Hypoxia, Reoxygenation

Jorba, I., Menal, M. J., Torres, M., Gozal, D., Piñol-Ripoll, G., Colell, A., Montserrat, J. M., Navajas, D., Farré, R., Almendros, I., (2017). Ageing and chronic intermittent hypoxia mimicking sleep apnea do not modify local brain tissue stiffness in healthy mice Journal of the Mechanical Behavior of Biomedical Materials 71, 106-113

Recent evidence suggests that obstructive sleep apnea (OSA) may increase the risk of Alzheimer´s disease (AD), with the latter promoting alterations in brain tissue stiffness, a feature of ageing. Here, we assessed the effects of age and intermittent hypoxia (IH) on brain tissue stiffness in a mouse model of OSA. Two-month-old and 18-month-old mice (N=10 each) were subjected to IH (20% O2 40 s – 6% O2 20 s) for 8 weeks (6 h/day). Corresponding control groups for each age were kept under normoxic conditions in room air (RA). After sacrifice, the brain was excised and 200-micron coronal slices were cut with a vibratome. Local stiffness of the cortex and hippocampus were assessed in brain slices placed in an Atomic Force Microscope. For both brain regions, the Young's modulus (E) in each animal was computed as the average values from 9 force-indentation curves. Cortex E mean (±SE) values were 442±122 Pa (RA) and 455±120 (IH) for young mice and 433±44 (RA) and 405±101 (IH) for old mice. Hippocampal E values were 376±62 (RA) and 474±94 (IH) for young mice and 486±93 (RA) and 521±210 (IH) for old mice. For both cortex and hippocampus, 2-way ANOVA indicated no statistically significant effects of age or challenge (IH vs. RA) on E values. Thus, neither chronic IH mimicking OSA nor ageing up to late middle age appear to modify local brain tissue stiffness in otherwise healthy mice.

Keywords: Atomic Force Microscopy, Brain mechanics, Cortex stiffness, Hippocampus stiffness, Obstructive sleep apnea, Young's modulus

Camara, M. A., Castillo, Y., Blanco-Almazan, D., Estrada, L., Jane, R., (2017). MHealth tools for monitoring Obstructive Sleep Apnea patients at home: Proof-of-concept Engineering in Medicine and Biology Society (EMBC) 39th Annual International Conference of the IEEE , IEEE (Seogwipo, South Korea) , 1555-1558

Obstructive Sleep Apnea (OSA) is a sleep disorder that affects mainly the adult and elderly population. Due to the high percentage of patients who remain undiagnosed and untreated because of limitations of current diagnosis methods, the management of OSA is an important social, scientific and economic problem that will be difficult to be assumed by health systems. On the other hand, smartphone platforms (mHealth systems) are being considered as an innovative solution, thanks to the integration of the essential sensors to obtain clinically relevant parameters in the same device or in combination with wireless wearable devices.

Keywords: Sleep apnea, Microphones, Monitoring, Sensors, Accelerometers, Biomedical monitoring, Band-pass filters

Sola-Soler, J., Giraldo, B. F., Fiz, J. A., Jane, R., (2017). Relationship between heart rate excursion and apnea duration in patients with Obstructive Sleep Apnea Engineering in Medicine and Biology Society (EMBC) 39th Annual International Conference of the IEEE , IEEE (Seogwipo, South Korea) , 1539-1542

Obstructive Sleep Apnea (OSA) is a sleep disorder with a high prevalence in the general population. It is a risk factor for many cardiovascular diseases, and an independent risk factor for cerebrovascular diseases such as stroke. After an apnea episode, both arterial blood pressure and cerebral blood flow velocity change in function of the apnea duration (AD). We hypothesized that the relative excursion in heart rate (AHR), defined as the percentage difference between the maximum and the minimum heart rate values associated to an obstructive apnea event, is also related to AD. In this work we studied the relationship between apnea-related AHR and AD in a population of eight patients with severe OSA. AHR and AD showed a moderate but statistically significant correlation (p <; 0.0001) in a total of 1454 obstructive apneas analyzed. The average heart rate excursion for apneas with AD ≥ 30s (ΔHR = 31.29 ± 6.64%) was significantly greater (p = 0.0002) than for apneas with AD ∈ [10,20)s (ΔHR = 18.14±3.08%). We also observed that patients with similar Apnea-Hypopnea Index (AHI) may exhibit remarkably different distributions of AHR and AD, and that patients with a high AHI need not have a higher average AHR than others with a lower severity index. We conclude that the overall apnea-induced heart rate excursion is partially explained by the duration of apnoeic episodes, and it may be a simple measure of the cardiovascular stress associated with OSA that is not directly reflected in the AHI.

Keywords: Heart rate, Sleep apnea, Correlation, Indexes, Sociology, Blood vessels

Campillo, N., Jorba, I., Schaedel, L., Casals, B., Gozal, D., Farré, R., Almendros, I., Navajas, D., (2016). A novel chip for cyclic stretch and intermittent hypoxia cell exposures mimicking obstructive sleep apnea Frontiers in Physiology 7, Article 319

Intermittent hypoxia (IH), a hallmark of obstructive sleep apnea (OSA), plays a critical role in the pathogenesis of OSA-associated morbidities, especially in the cardiovascular and respiratory systems. Oxidative stress and inflammation induced by IH are suggested as main contributors of end-organ dysfunction in OSA patients and animal models. Since the molecular mechanisms underlying these in vivo pathological responses remain poorly understood, implementation of experimental in vitro cell-based systems capable of inducing high-frequency IH would be highly desirable. Here, we describe the design, fabrication, and validation of a versatile chip for subjecting cultured cells to fast changes in gas partial pressure and to cyclic stretch. The chip is fabricated with polydimethylsiloxane (PDMS) and consists of a cylindrical well-covered by a thin membrane. Cells cultured on top of the membrane can be subjected to fast changes in oxygen concentration (equilibrium time ~6 s). Moreover, cells can be subjected to cyclic stretch at cardiac or respiratory frequencies independently or simultaneously. Rat bone marrow-derived mesenchymal stem cells (MSCs) exposed to IH mimicking OSA and cyclic stretch at cardiac frequencies revealed that hypoxia-inducible factor 1a (HIF-1a) expression was increased in response to both stimuli. Thus, the chip provides a versatile tool for the study of cellular responses to cyclical hypoxia and stretch.

Keywords: Cell stretch, Hypoxia-inducible factor, Intermittent hypoxia, Lab-on-a-chip, Obstructive sleep apnea

Solà-Soler, J., Giraldo, B. F., Fiz, J. A., Jané, R., (2016). Study of phase estimation methods to analyse cardiorespiratory synchronization in OSA patients Engineering in Medicine and Biology Society (EMBC) 38th Annual International Conference of the IEEE , IEEE (Orlando, USA) , 4280-4283

Obstructive Sleep Apnea (OSA) is a sleep disorder highly prevalent in the general population. Cardiorespiratory Phase Synchronization (CRPS) is a form of non-linear interaction between respiratory and cardiovascular systems that was found to be reduced in severe OSA patients. The Hilbert Transform (HT) method was the recommended choice for estimating the respiratory phase in CRPS studies. But we have noticed that HT provides a phase that is aligned to the transition between the exhalation and the inhalation parts of different breathing cycles, instead of being aligned to the breathing onsets. In this work we proposed a Realigned HT phase estimation method (RHT) and we compared it to the conventional HT and to the Linear Phase (LP) approximation for estimating CRPS in a database of 28 patients with different OSA severity levels. RHT provided similar synchronization percentages (%Sync) as HT, and it enhanced the significant differences in %Sync between mild and severe OSA patients. %Sync showed the highest negative correlation with the Apnea-Hypopnea Index (AHI) when using RHT (rAHI=-0.692, p<;0.001), which only had an 10% extra computational cost. On the other hand, LP method significantly overestimated %Sync especially in the more severe patients, because it was unable to track the phase non-linearities that can be observed during sleep disordered breathing. Therefore, the newly proposed RHT can be the preferred alternative over the conventional HT or the LP approximation for estimating CRPS in OSA patients.

Keywords: Correlation, Databases, Electrocardiography, Phase estimation, Sleep apnea, Synchronization, Transforms

da Palma, R. K., Farré, R., Montserrat, J. M., Gorbenko Del Blanco, D., Egea, G., de Oliveira, L. V. F., Navajas, D., Almendros, I., (2015). Increased upper airway collapsibility in a mouse model of Marfan syndrome Respiratory Physiology & Neurobiology 207, 58-60

Marfan syndrome (MFS) is a genetic disorder caused by mutations in the FBN1 gene that codifies for fibrilin-1. MFS affects elastic fiber formation and the resulting connective tissue shows abnormal tissue laxity and organization. Although an increased prevalence of obstructive sleep apnea among patients with MFS has been described, the potential effects of this genetic disease on the collapsible properties of the upper airway are unknown. The aim of this study was to assess the collapsible properties of the upper airway in a mouse model of MFS Fbn1(C1039G/+) that is representative of most of the clinical manifestations observed in human patients. The upper airway in wild-type and Marfan mice was cannulated and its critical pressure (Pcrit) was measured in vivo by increasing the negative pressure through a controlled pressure source. Pcrit values from MFS mice were higher (less negative) compared to wild-type mice (-3.1±0.9cmH2O vs. -7.8±2.0cm H2O) suggesting that MFS increases the upper airway collapsibility, which could in turn explain the higher prevalence of OSA in MFS patients.

Keywords: Marfan syndrome, Obstructive sleep apnea, Upper airway collapsibility

Sola-Soler, J., Giraldo, B. F., Fiz, J. A., Jané, R., (2015). Cardiorespiratory Phase Synchronization in OSA subjects during wake and sleep states Engineering in Medicine and Biology Society (EMBC) 37th Annual International Conference of the IEEE , IEEE (Milan, Italy) , 7708-7711

Cardiorespiratory Phase Synchronization (CRPS) is a manifestation of coupling between cardiac and respiratory systems complementary to Respiratory Sinus Arrhythmia. In this work, we investigated CRPS during wake and sleep stages in Polysomnographic (PSG) recordings of 30 subjects suspected from Obstructive Sleep Apnea (OSA). The population was classified into three severity groups according to the Apnea Hypopnea Index (AHI): G1 (AHI<;15), G2 (15<;=AHI<;30) and G3 (AHI>30). The synchrogram between single lead ECG and respiratory abdominal band signals from PSG was computed with the Hilbert transform technique. The different phase locking ratios (PLR) m:n were monitored throughout the night. Ratio 4:1 was the most frequent and it became more dominant as OSA severity increased. CRPS was characterized by the percentage of synchronized time (%Sync) and the average duration of synchronized epochs (AvDurSync) using three different thresholds. Globally, we observed that %Sync significantly decreased and AvDurSync slightly increased with OSA severity. A high synchronization threshold enhanced these population differences. %Sync was significantly higher in NREM than in REM sleep in G2 and G3 groups. Population differences observed during sleep did not translate to the initial wake state. Reduced CRPS could be an early marker of OSA severity during sleep, but further studies are needed to determine whether CRPS is also present during wakefulness.

Keywords: Band-pass filters, Electrocardiography, Heart beat, Sleep apnea, Sociology, Statistics, Synchronization

Isetta, V., León, C., Torres, M., Embid, C., Roca, J., Navajas, D., Farré, R., Montserrat, J. M., (2014). Telemedicine-based approach for obstructive sleep apnea management: Building evidence Interactive Journal of Medical Research 3, (1), e6

Background: 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. Objective: The objective of our study was to evaluate the application of a telemedicine-based approach in the CPAP therapy management, focusing on patients' CPAP follow-up and training. Methods: We performed two studies. First, (study 1) we enrolled 50 consecutive OSA patients who came to our sleep center for the CPAP follow-up visit. Patients performed a teleconsultation with a physician, and once finalized, they were asked to answer anonymously to a questionnaire regarding their opinion about the teleconsultation. In a second randomized controlled trial (RCT) (study 2). we included 40 OSA patients scheduled for CPAP training. There were 20 that received the usual face-to-face training and 20 that received the training via videoconference. After the session, they were blindly evaluated on what they learned about OSA and mask placement. Results: More than 95% (49/50) of the interviewed patients were satisfied with the teleconsultation, and 66% (33/50) of them answered that the teleconsultation could replace 50%-100% of their CPAP follow-up visits. Regarding the RCT patients who received the CPAP training via videoconference demonstrated the same knowledge about OSA and CPAP therapy as the face-to-face group (mean 93.6% of correct answers vs mean 92.1%; P=.935). Performance on practical skills (mask and headgear placement, leaks avoidance) was also similar between the two groups. Conclusions: OSA patients gave a positive feedback about the use of teleconsultation for CPAP follow-up, and the CPAP training based on a telemedicine approach proved to be as effective as face-to-face training. These results support the use of this telemedicine-based approach as a valuable strategy for patients' CPAP training and clinical follow-up.

Keywords: CPAP therapy, Sleep apnea, Teleconsultation, Telemedicine

Dalmases, M., Torres, M., Márquez-Kisinousky, L., Almendros, I., Planas, A. M., Embid, C., Martínez-Garcia, M. A., Navajas, D., Farré, R., Montserrat, J. M., (2014). Brain tissue hypoxia and oxidative stress induced by obstructive apneas is different in young and aged rats Sleep 37, (7), 1249-1256

Study Objectives: 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. Design: Prospective controlled animal study. Setting: University laboratory. Participants: Sixty-four male Wistar rats: 32 young (3 mo old) and 32 aged (18 mo). Interventions: Protocol 1: Twenty-four animals were subjected to obstructive apneas (50 apneas/h, lasting 15 sec each) or to sham procedure for 50 min. Protocol 2: Forty rats were subjected to obstructive apneas or sham procedure for 4 h. Measurements and Results: Protocol 1: Real-time PtO2 measurements were performed using a fast-response oxygen microelectrode. During successive apneas cerebral cortex PtO2 presented a different pattern in the two age groups; there was a fast increase in young rats, whereas it remained without significant changes between the beginning and the end of the protocol in the aged group. Protocol 2: Brain oxidative stress assessed by lipid peroxidation increased after apneas in young rats (1.34 ± 0.17 nmol/mg of protein) compared to old ones (0.63 ± 0.03 nmol/mg), where a higher expression of antioxidant enzymes was observed. Conclusions: The results suggest that brain oxidative stress in aged rats is lower than in young rats in response to recurrent apneas, mimicking obstructive sleep apnea. This could be due to the different PtO2 response observed between age groups and the increased antioxidant expression in aged rats.

Keywords: Aging, Animal model, Obstructive apnea, Oxidative stress, Tissue oxygenation, antioxidant, glutathione disulfide, aged, animal experiment, animal model, animal tissue, apnea, arterial oxygen saturation, article, brain cortex, brain oxygen tension, brain tissue, controlled study, groups by age, hypoxia, lipid peroxidation, male, nonhuman, oxidative stress, pressure, priority journal, rat

Jané, R., (2014). Engineering Sleep Disorders: From classical CPAP devices toward new intelligent adaptive ventilatory therapy IEEE Pulse 5, (5), 29-32

Among the most common sleep disorders are those related to disruptions in airflow (apnea) or reductions in the breath amplitude (hypopnea) with or without obstruction of the upper airway (UA). One of the most important sleep disorders is obstructive sleep apnea (OSA). This sleep-disordered breathing, quantified by the apnea-hypopnea index (AHI), can produce a significant reduction of oxygen saturation and an abnormal elevation of carbon dioxide levels in the blood. Apnea and hypopnea episodes are associated with arousals and sleep fragmentation during the night and compensatory response of the autonomic nervous system.

Keywords: Biomedical engineering, Biomedical measurements, Biomedical monitoring, Breathing disorders, Medical conditions, Medical treatment, Sleep, Sleep apnea

Solà, J., Fiz, J. A., Torres, A., Jané, R., (2014). Identification of Obstructive Sleep Apnea patients from tracheal breath sound analysis during wakefulness in polysomnographic studies Engineering in Medicine and Biology Society (EMBC) 36th Annual International Conference of the IEEE , IEEE (Chicago, USA) , 4232-4235

Obstructive Sleep Apnea (OSA) is currently diagnosed by a full nocturnal polysomnography (PSG), a very expensive and time-consuming method. In previous studies we were able to distinguish patients with OSA through formant frequencies of breath sound during sleep. In this study we aimed at identifying OSA patients from breath sound analysis during wakefulness. The respiratory sound was acquired by a tracheal microphone simultaneously to PSG recordings. We selected several cycles of consecutive inspiration and exhalation episodes in 10 mild-moderate (AHI<;30) and 13 severe (AHI>=30) OSA patients during their wake state before getting asleep. Each episode's formant frequencies were estimated by linear predictive coding. We studied several formant features, as well as their variability, in consecutive inspiration and exhalation episodes. In most subjects formant frequencies were similar during inspiration and exhalation. Formant features in some specific frequency band were significantly different in mild OSA as compared to severe OSA patients, and showed a decreasing correlation with OSA severity. These formant characteristics, in combination with some anthropometric measures, allowed the classification of OSA subjects between mild-moderate and severe groups with sensitivity (specificity) up to 88.9% (84.6%) and accuracy up to 86.4%. In conclusion, the information provided by formant frequencies of tracheal breath sound recorded during wakefulness may allow identifying subjects with severe OSA.

Keywords: Correlation, Databases, Sensitivity, Sleep apnea, Speech, Synchronization

Jané, R., Lazaro, J., Ruiz, P., Gil, E., Navajas, D., Farre, R., Laguna, P., (2013). Obstructive Sleep Apnea in a rat model: Effects of anesthesia on autonomic evaluation from heart rate variability measures CinC 2013 Computing in Cardiology Conference (CinC) , IEEE (Zaragoza, Spain) , 1011-1014

Rat model of Obstructive Sleep Apnea (OSA) is a realistic approach for studying physiological mechanisms involved in sleep. Rats are usually anesthetized and autonomic nervous system (ANS) could be blocked. This study aimed to assess the effect of anesthesia on ANS activity during OSA episodes. Seven male Sprague-Dawley rats were anesthetized intraperitoneally with urethane (1g/kg). The experiments were conducted applying airway obstructions, simulating 15s-apnea episodes for 15 minutes. Five signals were acquired: respiratory pressure and flow, SaO2, ECG and photoplethysmography (PPG). In total, 210 apnea episodes were studied. Normalized power spectrum of Pulse Rate Variability (PRV) was analyzed in the Low Frequency (LF) and High Frequency (HF) bands, for each episode in consecutive 15s intervals (before, during and after the apnea). All episodes showed changes in respiratory flow and SaO2 signal. Conversely, decreases in the amplitude fluctuations of PPG (DAP) were not observed. Normalized LF presented extremely low values during breathing (median=7,67%), suggesting inhibition of sympathetic system due to anesthetic effect. Subtle increases of LF were observed during apnea. HRV and PPG analysis during apnea could be an indirect tool to assess the effect and deep of anesthesia.

Keywords: electrocardiography, fluctuations, medical disorders, medical signal detection, medical signal processing, neurophysiology, photoplethysmography, pneumodynamics, sleep, ECG, SaO2 flow, SaO2 signal, airway obstructions, amplitude fluctuations, anesthesia effects, anesthetized nervous system, autonomic evaluation, autonomic nervous system, breathing, heart rate variability, high-frequency bands, low-frequency bands, male Sprague-Dawley rats, normalized power spectrum, obstructive sleep apnea, photoplethysmography, physiological mechanisms, pulse rate variability, rat model, respiratory flow, respiratory pressure, signal acquisition, sympathetic system inhibition, time 15 min, time 15 s, Abstracts, Atmospheric modeling, Computational modeling, Electrocardiography, Rats, Resonant frequency

Giraldo, B. F., Tellez, J. P., Herrera, S., Benito, S., (2013). Study of the oscillatory breathing pattern in elderly patients Engineering in Medicine and Biology Society (EMBC) 35th Annual International Conference of the IEEE , IEEE (Osaka, Japan) , 5228-5231

Some of the most common clinical problems in elderly patients are related to diseases of the cardiac and respiratory systems. Elderly patients often have altered breathing patterns, such as periodic breathing (PB) and Cheyne-Stokes respiration (CSR), which may coincide with chronic heart failure. In this study, we used the envelope of the respiratory flow signal to characterize respiratory patterns in elderly patients. To study different breathing patterns in the same patient, the signals were segmented into windows of 5 min. In oscillatory breathing patterns, frequency and time-frequency parameters that characterize the discriminant band were evaluated to identify periodic and non-periodic breathing (PB and nPB). In order to evaluate the accuracy of this characterization, we used a feature selection process, followed by linear discriminant analysis. 22 elderly patients (7 patients with PB and 15 with nPB pattern) were studied. The following classification problems were analyzed: patients with either PB (with and without apnea) or nPB patterns, and patients with CSR versus PB, CSR versus nPB and PB versus nPB patterns. The results showed 81.8% accuracy in the comparisons of nPB and PB patients, using the power of the modulation peak. For the segmented signal, the power of the modulation peak, the frequency variability and the interquartile ranges provided the best results with 84.8% accuracy, for classifying nPB and PB patients.

Keywords: cardiovascular system, diseases, feature extraction, geriatrics, medical signal processing, oscillations, pneumodynamics, signal classification, time-frequency analysis, Cheyne-Stokes respiration, apnea, cardiac systems, chronic heart failure, classification problems, discriminant band, diseases, elderly patients, feature selection process, frequency variability, interquartile ranges, linear discriminant analysis, nonperiodic breathing, oscillatory breathing pattern, periodic breathing, respiratory How signal, respiratory systems, signal segmentation, time 5 min, time-frequency parameters, Accuracy, Aging, Frequency modulation, Heart, Senior citizens, Time-frequency analysis

Almendros, Isaac, Carreras, Alba, Montserrat, Josep M., Gozal, David, Navajas, Daniel, Farre, Ramon, (2012). Potential role of adult stem cells in obstructive sleep apnea Frontiers in Neurology 3, 1-6

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.

Keywords: Mesenchymal Stem Cells, Sleep Apnea, Endothelial progenitor cells, Very Small-like Embryonic Stem Cells, Adult bone-marrow derived stem cells

Fiz, J. A., Jané, R., (2012). Snoring Analysis. A Complex Question Journal of Sleep Disorders: Treatment & Care 1, (1), 1-3

The snore is a breathing sound that originates during sleep, either nocturnal or diurnal. Many procedures have been used for its analysis, from simple interrogation, going through acoustic methods that have been developed thanks to the advance of biomedical techniques in recent years. So far a procedure homologated by different laboratories for its study doesn’t exist. The present editorial describes the current state of the art in the snoring analysis procedures.

Keywords: Snoring, Sleep apnea, OSAS

Almendros, I., Montserrat, J. M., Torres, M., Bonsignore, M. R., Chimenti, L., Navajas, D., Farre, R., (2012). Obesity and intermittent hypoxia increase tumor growth in a mouse model of sleep apnea Sleep Medicine 13, (10), 1254-1260

Background: Intermittent hypoxia and obesity which are two pathological conditions commonly found in patients with obstructive sleep apnea (OSA), potentially enhance cancer progression. Objective: To investigate whether obesity and/or intermittent hypoxia (IH) mimicking OSA affect tumor growth. Methods: A subcutaneous melanoma was induced in 40 mice [22 obese (40-45 g) and 18 lean (20-25 g)] by injecting 10(6) B16F10 cells in the flank. Nineteen mice (10 obese/9 lean) were subjected to IH (6 h/day for 17 days). A group of 21 mice (12 obese/9 lean) were kept under normoxia. At day 17, tumors were excised, weighed and processed to quantify necrosis and endothelial expression of vascular endothelial growth factor (VEGF) and CD-31. VEGF in plasma was also assessed. Results: In lean animals, IH enhanced tumor growth from 0.81 +/- 0.17 to 1.95 +/- 0.32 g. In obese animals, a similar increase in tumor growth (1.94 +/- 0.18 g) was observed under normoxia, while adding IH had no further effect (1.69 +/- 0.23 g). IH only promoted an increase in tumoral necrosis in lean animals. However, obesity under normoxic conditions increased necrosis, VEGF and CD-31 expression in tumoral tissue. Plasma VEGF strongly correlated with tumor weight (rho = 0.76, p < 0.001) in the whole sample; it increased in lean IH-treated animals from 66.40 +/- 3.47 to 108.37 +/- 9.48 pg/mL, p < 0.001), while the high baseline value in obese mice (106.90 +/- 4.32 pg/mL) was unaffected by IH. Conclusions: Obesity and IH increased tumor growth, but did not appear to exert any synergistic effects. Circulating VEGF appeared as a crucial mediator of tumor growth in both situations.

Keywords: Intermittent hypoxia, Obesity, Cancer, Sleep apnea, Animal model

Tsapikouni, T., Garreta, E., Melo, E., Navajas, D., Farré, R., (2012). A bioreactor for subjecting cultured cells to fast-rate intermittent hypoxia Respiratory Physiology & Neurobiology 182, (1), 47-52

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 bioreactor's 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.

Keywords: Hypoxia-reoxygenation, Obstructive sleep apnea, Oxygen partial pressure

Mesquita, J., Solà, J., Fiz, J. A., Morera, J., Jané, R., (2012). All night analysis of time interval between snores in subjects with sleep apnea hypopnea syndrome Medical and Biological Engineering and Computing 50, (4), 373-381

Sleep apnea-hypopnea syndrome (SAHS) is a serious sleep disorder, and snoring is one of its earliest and most consistent symptoms. We propose a new methodology for identifying two distinct types of snores: the so-called non-regular and regular snores. Respiratory sound signals from 34 subjects with different ranges of Apnea-Hypopnea Index (AHI = 3.7-109.9 h -1) were acquired. A total number of 74,439 snores were examined. The time interval between regular snores in short segments of the all night recordings was analyzed. Severe SAHS subjects show a shorter time interval between regular snores (p = 0.0036, AHI cp: 30 h -1) and less dispersion on the time interval features during all sleep. Conversely, lower intra-segment variability (p = 0.006, AHI cp: 30 h -1) is seen for less severe SAHS subjects. Features derived from the analysis of time interval between regular snores achieved classification accuracies of 88.2 % (with 90 % sensitivity, 75 % specificity) and 94.1 % (with 94.4 % sensitivity, 93.8 % specificity) for AHI cut-points of severity of 5 and 30 h -1, respectively. The features proved to be reliable predictors of the subjects' SAHS severity. Our proposed method, the analysis of time interval between snores, provides promising results and puts forward a valuable aid for the early screening of subjects suspected of having SAHS.

Keywords: Sleep apnea, Snore sounds, Snore time interval

Garde, A., Giraldo, B.F., Jané, R., Latshang, T.D., Turk, A.J., Hess, T., Bosch, M-.M., Barthelmes, D., Hefti, J.P., Maggiorini, M., Hefti, U., Merz, T.M., Schoch, O.D., Bloch, K.E., (2012). Periodic breathing during ascent to extreme altitude quantified by spectral analysis of the respiratory volume signal Engineering in Medicine and Biology Society (EMBC) 34th Annual International Conference of the IEEE , IEEE (San Diego, USA) , 707-710

High altitude periodic breathing (PB) shares some common pathophysiologic aspects with sleep apnea, Cheyne-Stokes respiration and PB in heart failure patients. Methods that allow quantifying instabilities of respiratory control provide valuable insights in physiologic mechanisms and help to identify therapeutic targets. Under the hypothesis that high altitude PB appears even during physical activity and can be identified in comparison to visual analysis in conditions of low SNR, this study aims to identify PB by characterizing the respiratory pattern through the respiratory volume signal. A number of spectral parameters are extracted from the power spectral density (PSD) of the volume signal, derived from respiratory inductive plethysmography and evaluated through a linear discriminant analysis. A dataset of 34 healthy mountaineers ascending to Mt. Muztagh Ata, China (7,546 m) visually labeled as PB and non periodic breathing (nPB) is analyzed. All climbing periods within all the ascents are considered (total climbing periods: 371 nPB and 40 PB). The best crossvalidated result classifying PB and nPB is obtained with Pm (power of the modulation frequency band) and R (ratio between modulation and respiration power) with an accuracy of 80.3% and area under the receiver operating characteristic curve of 84.5%. Comparing the subjects from 1st and 2nd ascents (at the same altitudes but the latter more acclimatized) the effect of acclimatization is evaluated. SaO2 and periodic breathing cycles significantly increased with acclimatization (p-value <; 0.05). Higher Pm and higher respiratory frequencies are observed at lower SaO2, through a significant negative correlation (p-value <; 0.01). Higher Pm is observed at climbing periods visually labeled as PB with >; 5 periodic breathing cycles through a significant positive correlation (p-value <; 0.01). Our data demonstrate that quantification of the respiratory volum- signal using spectral analysis is suitable to identify effects of hypobaric hypoxia on control of breathing.

Keywords: Frequency domain analysis, Frequency modulation, Heart, Sleep apnea, Ventilation, Visualization, Cardiology, Medical disorders, Medical signal processing, Plethysmography, Pneumodynamics, Sensitivity analysis, Sleep, Spectral analysis, Cheyne-Stokes respiration, Climbing periods, Dataset, Heart failure patients, High altitude PB, High altitude periodic breathing, Hypobaric hypoxia, Linear discriminant analysis, Pathophysiologic aspects, Physical activity, Physiologic mechanisms, Power spectral density, Receiver operating characteristic curve, Respiratory control, Respiratory frequency, Respiratory inductive plethysmography, Respiratory pattern, Respiratory volume signal, Sleep apnea, Spectral analysis, Spectral parameters

Mesquita, J., Poree, F., Carrault, G., Fiz, J. A., Abad, J., Jané, R., (2012). Respiratory and spontaneous arousals in patients with Sleep Apnea Hypopnea Syndrome Engineering in Medicine and Biology Society (EMBC) 34th Annual International Conference of the IEEE , IEEE (San Diego, USA) , 6337-6340

Sleep in patients with Sleep Apnea-Hypopnea Syndrome (SAHS) is frequently interrupted with arousals. Increased amounts of arousals result in shortening total sleep time and repeated sleep-arousal change can result in sleep fragmentation. According to the American Sleep Disorders Association (ASDA) an arousal is a marker of sleep disruption representing a detrimental and harmful feature for sleep. The nature of arousals and its role on the regulation of the sleep process raises controversy and has sparked the debate in the last years. In this work, we analyzed and compared the EEG spectral content of respiratory and spontaneous arousals on a database of 45 SAHS subjects. A total of 3980 arousals (1996 respiratory and 1984 spontaneous) were analyzed. The results showed no differences between the spectral content of the two kinds of arousals. Our findings raise doubt as to whether these two kinds of arousals are truly triggered by different organic mechanisms. Furthermore, they may also challenge the current beliefs regarding the underestimation of the importance of spontaneous arousals and their contribution to sleep fragmentation in patients suffering from SAHS.

Keywords: Adaptive filters, Correlation, Databases, Electroencephalography, Hospitals, Sleep apnea, Electroencephalography, Medical signal processing, Pneumodynamics, Sleep, EEG spectral content, Organic mechanism, Respiratory, Sleep apnea hypopnea syndrome, Sleep fragmentation, Spectral content, Spontaneous arousal

Almendros, Isaac, Farre, Ramon, Planas, Anna M., Torres, Marta, Bonsignore, Maria R., Navajas, Daniel, Montserrat, Josep M., (2011). Tissue oxygenation in brain, muscle, and fat in a rat model of sleep apnea: Differential effect of obstructive apneas and intermittent hypoxia Sleep 34, (8), 1127-1133

Study Objectives: 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. Design: Prospective controlled animal study. Setting: University laboratory. Participants: 98 Sprague-Dawley rats. Interventions: Cerebral cortex, skeletal muscle, or visceral fat tissues were exposed in anesthetized animals subjected to either obstructive apneas or intermittent hypoxia (apneic and hypoxic events of 15 s each and 60 events/h) for 1 h. Measurements and Results: Arterial oxygen saturation (spO(2)) presented a stable pattern, with similar desaturations during both stimuli. The PtO(2) was measured by a microelectrode. During obstructive apneas, a fast increase in cerebral PtO(2) was observed (38.2 +/- 3.4 vs. 54.8 +/- 5.9 mm Hg) but not in the rest of tissues. This particular cerebral response was not found during intermittent hypoxia. The cerebral content of reduced glutathione was decreased after obstructive apneas (46.2% +/- 15.2%) compared to controls (100.0% +/- 14.7%), but not after intermittent hypoxia. This antioxidant consumption after obstructive apneas was accompanied by increased cerebral lipid peroxidation under this condition. No changes were observed for these markers in the other tissues. Conclusions: These results suggest the cerebral cortex could be protected in some way from hypoxic periods caused by obstructive apneas. The increased cerebral PtO(2) during obstructive apneas may, however, cause harmful effects (oxidative stress). The obstructive apnea model appears to be more adequate than the intermittent hypoxia model for studying brain changes associated with OSA.

Keywords: Tissue oxygenation, Obstructive apnea, Intermittent hypoxia, Animal model, Oxidative stress

Almendros, I., Farré, R., Torres, M., Bonsignore, M. R., Dalmases, M., Ramírez, J., Navajas, D., Montserrat, J. M., (2011). Early and mid-term effects of obstructive apneas in myocardial injury and inflammation Sleep Medicine 12, (10), 1037-1040

Background: 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. Methods: Thirty-six male Sprague-Dawley rats (300-350. g) were either acutely (3. h) or sustainably (5. h/day, for 10. days) subjected to obstructive apneas with a pattern of 15. s each, 60. apneas/h. Corresponding control groups were formed for the acute and sustained models. To assess the induction of systemic inflammation, IL1-β was measured in plasma. Ventricular tissue injury was evaluated by histological techniques (presence of inflammatory cell infiltration, eosin autofluorescence, and detection of apoptosis). Results: After 3. h of obstructive apneas, a significant increase in IL1-β (64.9. ±. 29.6. ng/μl) were observed with respect to the controls (7.3. ±. 1.0. ng/μl), but no myocardial injury was present. Conversely to the acute model, the systemic inflammation triggered by obstructive apneas for 10. days was reduced. However, the percentage of area with enhanced eosin autofluorescence and of apoptotic cells (1.83. ±. 0.35% and 24.4. ±. 1.5%, respectively) was increased when compared to the control group (0.72. ±. 0.20% and 5.0. ±. 2.8%, respectively). Conclusions: This study suggests that obstructive apneas are a potential source of early systemic and ventricular inflammation and myocardial cell injury after sustained apneas application, which could represent an initial phase in the progression of heart disease associated with OSA.

Keywords: Animal models, Inflammation, Myocardial injury, Obstructive sleep apnea

Dellaca, Raffaele, Montserrat, Josep M., Govoni, Leonardo, Pedotti, Antonio, Navajas, Daniel, Farre, Ramon, (2011). Telemetric CPAP titration at home in patients with sleep apnea-hypopnea syndrome Sleep Medicine 12, (2), 153-157

Background: 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). Objectives: To test the feasibility of a novel telemetric system for home CPAP titration. Methods: One-night home CPAP titration was carried out on 20 SAHS patients (56 +/- 3 years; BMI = 35 +/- 2 kg/m(2)). A telemetric unit, based on the conventional GPRS mobile phone network and connected to a commercial CPAP device, allowed the hospital technician to monitor flow, pressure and air leaks by remote control and titrate CPAP (elimination of apneas, hypopneas, flow limitation and snoring) in real time. After 1 week, a full hospital polysomnography was performed while the patient was subjected to the value of CPAP that was previously titrated at home via telemetry. Results: The home-titrated CPAP systematically improved patients' breathing: the apnea-hypopnea index and percentage of sleep time with arterial oxygen saturation below 90% were reduced from 58.1 +/- 5.1 to 3.8 +/- 0.6 events/h and from 19.8 +/- 1.1% to 4.4 +/- 0.7%, respectively. This CPAP value (9.15 +/- 0.47 cmH(2)O) was virtually the same as the pressure that optimized breathing during hospital polysomnography (9.20 +/- 0.41 cmH(2)O; mean difference: 0.02 cmH(2)O, limits of agreement: +/- 1.00 cmH(2)O). Conclusions: This pilot study shows that a simple telemetric system, requiring neither a special telemedicine network nor any infrastructure in the patient's home, made it possible to perform effective remote CPAP titration on SAHS patients.

Keywords: Home CPAP titration by telemetry, Telecare, Telemedicine, E-health, Obstructive sleep apnea, Point of care

Carreras, Alba, Wang, Yang, Gozal, David, Montserrat, Josep M., Navajas, Daniel, Farre, Ramon, (2011). Non-invasive system for applying airway obstructions to model obstructive sleep apnea in mice Respiratory Physiology & Neurobiology 175, (1), 164-168

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 mouse's 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(2)). Application of recurrent obstructive apneas (6s each, 120/h) for 6h resulted in SaO(2) 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.

Keywords: Animal model, Upper airway Obstruction, Mouse model, Non-invasive system, Model sleep apnea, Respiratory disease

Fiz, José Antonio, Solà, J., Jané, Raimon, (2011). Métodos de análisis del ronquido Medicina Clínica 137, (1), 36-42

El ronquido es un sonido respiratorio que se produce durante el sueño, ya sea nocturno o diurno. El ronquido puede ser inspiratorio, espiratorio o puede ocupar todo el ciclo respiratorio. Tiene su origen en la vibración de los diferentes tejidos de la vía aérea superior. Se han descrito numerosos métodos para analizarlo, desde el simple interrogatorio, pasando por cuestionarios estándares, hasta llegar a los métodos acústicos más sofisticados, que se han desarrollado gracias al gran avance de las técnicas biomédicas en los últimos años. El presente trabajo describe el estado del arte actual en los procedimientos de análisis del ronquido.

Keywords: Ronquido, Apnea del sueño, Síndrome de apnea-hipoapnea del sueño, Snoring, Sleep apnea, Sleep Apnea and Hipoapnea Syndrome

Almendros, I., Montserrat, J. M., Torres, M., Gonzalez, C., Navajas, D., Farre, R., (2010). Changes in oxygen partial pressure of brain tissue in an animal model of obstructive apnea Respiratory Research 11, (3), 1-6

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 (SpO(2)) 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 O-2 supply during recurrent swings in arterial SpO(2) in an animal model of OSA. Methods: Twenty-four male Sprague-Dawley rats (300-350 g) were used. Sixteen rats were anesthetized and noninvasively subjected to recurrent obstructive apneas: 60 apneas/h, 15 s each, for 1 h. A control group of 8 rats was instrumented but not subjected to obstructive apneas. PtO2 in the cerebral cortex was measured using a fast-response oxygen microelectrode. SpO(2) was measured by pulse oximetry. The time dependence of arterial SpO(2) and brain tissue PtO2 was carried out by Friedman repeated measures ANOVA. Results: Arterial SpO(2) showed a stable periodic pattern (no significant changes in maximum [95.5 +/- 0.5%; m +/- SE] and minimum values [83.9 +/- 1.3%]). By contrast, brain tissue PtO2 exhibited a different pattern from that of arterial SpO(2). The minimum cerebral cortex PtO2 computed during the first apnea (29.6 +/- 2.4 mmHg) was significantly lower than baseline PtO2 (39.7 +/- 2.9 mmHg; p = 0.011). In contrast to SpO(2), the minimum and maximum values of PtO2 gradually increased (p < 0.001) over the course of the 60 min studied. After 60 min, the maximum (51.9 +/- 3.9 mmHg) and minimum (43.7 +/- 3.8 mmHg) values of PtO2 were significantly greater relative to baseline and the first apnea dip, respectively. Conclusions: These data suggest that the cerebral cortex is partially protected from intermittently occurring interruption of O-2 supply induced by obstructive apneas mimicking OSA.

Keywords: Near-infrared spectroscopy, Sleep-apnea, Iintermittent hypoxia, Cerebral oxygenation, Oxidative stress, Blood-flow, Rat, Apoptosis, Inflammation, Hypercapnia

Carreras, A., Rojas, M., Tsapikouni, T., Montserrat, J. M., Navajas, D., Farre, R., (2010). Obstructive apneas induce early activation of mesenchymal stem cells and enhancement of endothelial wound healing Respiratory Research 11, (91), 1-7

Background: 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. Methods: We studied 30 control rats and 30 rats subjected to recurrent obstructive apneas (60 per hour, lasting 15 s each, for 5 h). The migration induced in MSC by apneic serum was measured by transwell assays. MSC-endothelial adhesion induced by apneic serum was assessed by incubating fluorescent-labelled MSC on monolayers of cultured endothelial cells from rat aorta. A wound healing assay was used to investigate the effect of apneic serum on endothelial repair. Results: Apneic serum showed significant increase in chemotaxis in MSC when compared with control serum: the normalized chemotaxis indices were 2.20 +/- 0.58 (m +/- SE) and 1.00 +/- 0.26, respectively (p < 0.05). MSC adhesion to endothelial cells was greater (1.75 +/- 0.14 -fold; p < 0.01) in apneic serum than in control serum. When compared with control serum, apneic serum significantly increased endothelial wound healing (2.01 +/- 0.24 -fold; p < 0.05). Conclusions: The early increases induced by recurrent obstructive apneas in MSC migration, adhesion and endothelial repair suggest that these mechanisms play a role in the physiological response to the challenges associated to OSA.

Keywords: Induced acute lung, Sleep-apnea, Intermitent hypoxia, Cardiovascular-disease, Progenito Cells, Rat model, Inflammation, Mechanisms, Repair, Blood

Carreras, Alba, Almendros, Isaac, Montserrat, Josep M., Navajas, Daniel, Farre, Ramon, (2010). Mesenchymal stem cells reduce inflammation in a rat model of obstructive sleep apnea Respiratory Physiology & Neurobiology 172, (3), 210-212

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.

Keywords: Obstructive sleep apnea, Animal model, Airway obstruction, Inflammation

Fiz, J. A., Jané, R., Solà, J., Abad, J., Garcia, M. A., Morera, J., (2010). Continuous analysis and monitoring of snores and their relationship to the apnea-hypopnea index Laryngoscope 120, (4), 854-862

Objectives/Hypothesis: We used a new automatic snoring detection and analysis system to monitor snoring during full-night polysomnography to assess whether the acoustic characteristics of snores differ in relation to the apnea-hypopnea index (AHI) and to classify subjects according to their AHI Study Design: Individual Case-Control Study. Methods: Thirty-seven snorers (12 females and 25 males, ages 40-65 years; body mass index (BMI), 29.65 +/- 4.7 kg/m(2)) participated Subjects were divided into three groups: G1 (AHI <5), G2 (AHI >= 5, <15) and G3 (AHI >= 15) Snore and breathing sounds were : recorded with a tracheal microphone throughout 6 hours of nighttime polysomnography The snoring episodes identified were automatically and continuously analyzed with a previously trained 2-layer feed-forward neural network. Snore number, average intensity, and power spectral density parameters were computed for every subject and compared among AHI groups. Subjects were classified using different AHI thresholds by means of a logistic regression model. Results: There were significant differences in supine position between G1 and G3 in sound intensity, number of snores; standard deviation of the spectrum, power ratio in bands 0-500, 100-500, and 0-800 Hz, and the symmetry coefficient (P < .03); Patients were classified with thresholds AHI = 5 and AHI = 15 with a sensitivity (specificity) of 87% (71%) and 80% (90%), respectively. Conclusions: A new system for automatic monitoring and analysis of snores during the night is presented. Sound intensity and several snore frequency parameters allow differentiation of snorers according to obstructive sleep apnea syndrome severity (OSAS). Automatic snore intensity and frequency monitoring and analysis could be a promising tool for screening OSAS patients, significantly improving the managing of this pathology.

Keywords: Breathing sounds, Signal interpretation, Sleep apnea syndromes, Snoring

Mesquita, J., Fiz, J. A., Solà, J., Morera, J., Jané, R., (2010). Regular and non regular snore features as markers of SAHS Engineering in Medicine and Biology Society (EMBC) 32nd Annual International Conference of the IEEE , IEEE (Buenos Aires, Argentina) , 6138-6141

Sleep Apnea-Hypopnea Syndrome (SAHS) diagnosis is still done with an overnight multi-channel polysomnography. Several efforts are being made to study profoundly the snore mechanism and discover how it can provide an opportunity to diagnose the disease. This work introduces the concept of regular snores, defined as the ones produced in consecutive respiratory cycles, since they are produced in a regular way, without interruptions. We applied 2 thresholds (TH/sub adaptive/ and TH/sub median/) to the time interval between successive snores of 34 subjects in order to select regular snores from the whole all-night snore sequence. Afterwards, we studied the effectiveness that parameters, such as time interval between successive snores and the mean intensity of snores, have on distinguishing between different levels of SAHS severity (AHI (Apnea-Hypopnea Index)<5h/sup -1/, AHI<10 h/sup -1/, AHI<15h/sup -1/, AHI<30h/sup -1/). Results showed that TH/sub adaptive/ outperformed TH/sub median/ on selecting regular snores. Moreover, the outcome achieved with non-regular snores intensity features suggests that these carry key information on SAHS severity.

Keywords: Practical, Experimental/ acoustic signal processing, Bioacoustics, Biomedical measurement, Diseases, Feature extraction, Medical signal processing, Patient diagnosis, Pneumodynamics, Sleep/ nonregular snore features, SAHS markers, Sleep apnea hypopnea syndrome, Overnight multichannel polysomnography, Snore mechanism

Carreras, A., Almendros, I., Acerbi, I., Montserrat, J. M., Navajas, D., Farre, R., (2009). Obstructive apneas induce early release of mesenchymal stem cells into circulating blood Sleep 32, (1), 117-119

STUDY OBJECTIVES: 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. DESIGN: Prospective controlled animal study. SETTING: University laboratory. PATIENTS OR PARTICIPANTS: Twenty male Sprague-Dawley rats (250-300 g). INTERVENTIONS: A specially designed nasal mask was applied to the anesthetized rats. Ten rats were subjected to a pattern of recurrent obstructive apneas (60 per hour, lasting 15 seconds each) for 5 hours. Ten anesthetized rats were used as controls. MEASUREMENTS AND RESULTS: Mesenchymal stem cells from the blood and bone marrow samples were isolated and cultured to count the total number of colony-forming unit fibroblasts (CFU-F) of adherent cells after 9 days in culture. The number of CFU-F from circulating blood was significantly (P = 0.02) higher in the rats subjected to recurrent obstructive apneas (5.00 +/- 1.16; mean +/- SEM) than in controls (1.70 +/- 0.72). No significant (P = 0.54) differences were observed in CFU-F from bone marrow. CONCLUSIONS: Application of a pattern of airway obstructions similar to those experienced by patients with sleep apnea induced an early mobilization of mesenchymal stem cells into circulating blood.

Keywords: Adipocytes/cytology, Animals, Blood Cell Count, Bone Marrow Cells/ cytology, Cell Adhesion/physiology, Cell Count, Cell Differentiation/physiology, Cell Division/physiology, Disease Models, Animal, Fibroblasts/cytology, Male, Mesenchymal Stem Cells/ cytology, Osteocytes/cytology, Rats, Rats, Sprague-Dawley, Sleep Apnea, Obstructive/ blood, Stem Cells/cytology

Almendros, I., Acerbi, I., Vilaseca, I., Montserrat, J. M., Navajas, D., Farre, R., (2008). Continuous positive airway pressure (CPAP) induces early nasal inflammation Sleep 31, (1), 127-131

STUDY OBJECTIVES: To assess whether noninvasive application of nCPAP is a mechanical stimulus inducing early nasal inflammation. DESIGN: Prospective controlled animal study. SETTING: University laboratory. PATIENTS OR PARTICIPANTS: 32 male Sprague-Dawley rats (250-300 g). INTERVENTIONS: The rats were anesthetized and subjected to nCPAP=10 cm H2O and sham-CPAP through a mask for 3 h and 5 h (n=8 each). MEASUREMENTS AND RESULTS: After nCPAP or sham, nasal scraping was carried out to detect neutrophils, and septum and dorsal nasal concha were excised to assess gene expression of inflammatory markers by real time PCR. Percentage of neutrophils in nucleated cells in the nasal scrapings was significantly (P = 0.006) higher after 5 h of nCPAP (3.51% +/- 0.73%; m +/- SEM) than in the sham group (1.12% +/- 0.39%). When compared with sham, the mRNA of macrophage inflammatory protein-2 (MIP-2) in nasal tissue was significantly overexpressed after both 3 h (2.28-fold +/- 0.43-fold; P = 0.034) and 5 h (5.56-fold +/-1.88-fold; P = 0.002) of nCPAP=10 cm H2O. No significant changes were found in the gene expressions of tumor necrosis factor-alpha, nerve growth factor and tachykinin-1 receptor. CONCLUSIONS: The compression applied by nCPAP (10 cm H2O, 5 h) on the nasal wall of healthy rats is a mechanical stimulus that triggers an early inflammatory process mediated by MIP-2, resulting in neutrophil extravasation.

Keywords: Sleep apnea, CPAP, Rhinitis, Mechanical stimulus, Neutrophil, Extravasation

Farre, R., Montserrat, J. M., Navajas, D., (2008). Morbidity due to obstructive sleep apnea: insights from animal models Current Opinion in Pulmonary Medicine 14, (6), 530-536

PURPOSE OF REVIEW: Obstructive sleep apnea (OSA) is a prevalent disorder with clinically well known mid-term and long-term consequences. It is difficult, however, to investigate the mechanisms causing morbidity in OSA from human studies, owing to confounding factors in patients. Animal research is useful to analyze the various injurious stimuli--intermittent hypoxia/hypercapnia, mechanical stress and sleep disruption--that potentially cause OSA morbidity. This review is focused on the most recent advances in our understanding of the consequences of OSA, achieved as a result of animal models. RECENT FINDINGS: Animal research has improved our knowledge of various aspects of the cardiovascular consequences of OSA: myocardial damage, left ventricular dysfunction, vasoconstriction, hypertension and atherosclerosis. The systemic and metabolic consequences of OSA--inflammation, insulin resistance, alterations in lipid metabolism and hepatic morbidity--have also been investigated with animal models. Our understanding of the mechanisms involved in the neurocognitive consequences of OSA--neuronal and brain alterations and cognitive dysfunctions--has also been improved through animal research. Moreover, animal models have recently been used to investigate the mechanisms of upper airway inflammation and dysfunction. SUMMARY: The simple experimental models used to investigate OSA morbidity are useful for investigating isolated mechanisms. However, more complex and realistic models incorporating the various injurious challenges characterizing OSA are required to more precisely translate the results of animal research to patients and to design potentially preventive and therapeutic strategies.

Keywords: Animal model, Morbidity, Sleep apnea, Translational research

Farre, R., Montserrat, J. M., Navajas, D., (2008). Assessment of upper airway mechanics during sleep Respiratory Physiology & Neurobiology 163, (1-3), 74-81

Obstructive sleep apnea, which is the most prevalent sleep breathing disorder, is characterized by recurrent episodes of upper airway collapse and reopening. However, the mechanical properties of the upper airway are not directly measured in routine polysomnography because only qualitative sensors (thermistors for flow and thoraco-abdominal bands for pressure) are used. This review focuses on two techniques that quantify upper airway obstruction during sleep. A Starling model of collapsible conduit allows us to interpret the mechanics of the upper airway by means of two parameters: the critical pressure (Pcrit) and the upstream resistance (Rup). A simple technique to measure Pcrit and Rup involves the application of different levels of continuous positive airway pressure (CPAP) during sleep. The forced oscillation technique is another non-invasive procedure for quantifying upper airway impedance during the breathing cycle in sleep studies. The latest developments in these two methods allow them to be easily applied on a routine basis in order to more fully characterize upper airway mechanics in patients with sleep breathing disorders.

Keywords: Obstructive sleep apnea, Upper airway, Airway resistance, Critical pressure, Respiratory impedance

Correa, L. S., Laciar, E., Torres, A., Jané, R., (2008). Performance evaluation of three methods for respiratory signal estimation from the electrocardiogram IEEE Engineering in Medicine and Biology Society Conference Proceedings 30th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (ed. IEEE), IEEE (Vancouver, Canada) 1-8, 4760-4763

A comparative study of three methods for estimating respiratory signal through electrocardiogram (ECG) was carried out. The three methods analyzed were based on R wave area, R peak amplitude and heart rate variability (HRV). For each method, cross-correlation coefficient and spectral coherence in a range of frequencies up to 0.5 Hz were computed between the ECG derived respiratory signals (EDR) and the three real respiratory signals: oronasal, and two inductance plethysmographies recordings (chest and abdominal). Results indicate that EDR methods based on R wave area and HRV are better correlated and show a wider spectral coherence with real respiratory signals than the other EDR method based on R peak amplitude.

Keywords: Obstructive sleep-apnea

Farre, R., Nacher, M., Serrano-Mollar, A., Galdiz, J. B., Alvarez, F. J., Navajas, D., Montserrat, J. M., (2007). Rat model of chronic recurrent airway obstructions to study the sleep apnea syndrome Sleep 30, (7), 930-933

Study Objectives: To implement a chronic rat model of recurrent airway obstructions to study the obstructive sleep apnea (OSA) syndrome. Design: Prospective controlled animal study. Setting: University laboratory. Patients or Participants: 24 male Sprague-Dawley rats (250-300 g). Interventions: The rats were placed in a setup consisting of a body chamber and a head chamber separated by a neck collar specially designed to apply recurrent airway obstructions with OSA patterns. Rats in the Obstruction group (n=8) were subjected to 5-s obstructions at a rate of 60 per hour, 6 h/day during 4 weeks. Sham rats (n=8) were placed in the setup but no obstructions were applied. Naive rats (n=8) were subjected to no intervention. Measurements and Results: Breathing flow, pressure, CO2 air concentration, and SpO(2) showed that the model mimicked OSA respiratory events (obstructive apneas, increased respiratory efforts, and oxygen saturation dips). Animal stress, assessed by body weight and plasma corticosterone, was not significantly different across Obstruction and Sham groups. This supports the concept that this novel model does not introduce a significant burden of stress in the rat after acclimatization to the chamber. Thromboxane-B2/6-keto-Prostaglandin-F1a ratio in plasma, which is an index of vasoconstriction, was significantly increased in the rats subjected to obstructions. Conclusions: The designed animal model of chronic recurrent airway obstructions is feasible and potentially useful to study the mechanisms involved in the cardiovascular consequences of OSA.

Keywords: Obstructive sleep apnea, Animal model, Airway obstruction