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Objective: The aim of the present study was to measure the correlation between the level of exhaled Nitric Oxide (NO) and Obstructive Sleep Apnea (OSA) severity and to evaluate its modification after Continuous Positive Airway Pressure (CPAP) treatment in severe OSA patients. Methods: It was a descriptive and cross-sectional study. Subjects were classified by mild-moderate or severe OSA. CPAP was used for severe OSA patients and followed up for 3 months. Exhaled NO was measured in the morning after the previous night of Respiratory Polygraphy (RPG) recording. Results: This study recruited 123 subjects, including 40 mild-moderate and 83 severe OSA patients. The level of maximum bronchial NO production (J’awNO) in patients with severe OSA was significantly higher than mild-moderate OSA [36.2 (6.1–92.2) vs. 19.6 (1.6-73.0) ppb; p=0.001)]. The level of concentration of NO in the gas phase of the alveolar (CANO) in patients with severe OSA was lower than mild-moderate OSA [5.2 (1.2-12.7) vs. 6.9 (0.8-14.0) ppb; p=0.002). The total flux of NO in the conducting airway compartment (J’awNO) and CANO were correlated with an apnea-hypopnea index (AHI) (rho=0.25 and p=0.02; rho= 0.18 and p=0.04, respectively). There was a weak significant correlation between J’awNO and nadir SpO2 in patients with OSA (rho = -0.22 and p= 0.023). After 3-month treatment with CPAP, the level of J’awNO was significantly reduced in patients with severe OSA [23.4 (12.9-44.5) vs. 33.1 (21.2-55.0); p Conclusion: J’awNO is proportionally increased in patients with severe OSA and reduced after treatment with CPAP. Thus, J’awNO may be used as a relevant and surrogate biomarker of severe OSA.

International audience; Bruxism is a heterogeneous condition related to various underlying mechanisms, including the presence of OSA. This case report illustrates that sleep mandibular movement monitoring and analysis could provide a useful opportunity for detection of both sleep bruxism and respiratory effort. The current case suggests that tracking of respiratory effort could enable evaluation of bruxism and its potential interactions. Successful treatment of sleep-related respiratory effort may lead to improved or resolution of bruxism in cases where such a causal relationship does exist.

Khue Dang-Thi-Mai,1 Nhat-Nam Le-Dong,2 Vu Le-Thuong,1 Ngoc Tran-Van,1 Sy Duong-Quy3,4 1Department of Respiratory Diseases, Cho Ray Hospital, Ho Chi Minh City, Vietnam; 2Department of Technology, Sunrise, Namur, Belgium; 3Bio-Medical Research Centre, Lam Dong Medical College, Dalat, Vietnam; 4Penn State Medical College, Hershey Medical Center, Hershey, PA, USACorrespondence: Sy Duong-QuyBio-Medical Research Centre, Lam Dong Medical College, 16 Ngo Quyen, Dalat, VietnamTel +84 918413813Fax +84 2633815000Email sduongquy.jfvp@gmail.comPurpose: Our study aimed to evaluate the relationship between exhaled nitric oxide (eNO) markers and obstructive sleep apnea (OSA) severity and verify the changes in eNO profiles among mild, moderate, and severe OSA subgroups.Methods: This study was a cross-sectional and in-hospital population-based study. We investigated 123 OSA patients (17 mild, 23 moderate and, 83 severe OSA) in the department of respiratory diseases. Studied data included anthropometry, respiratory polygraphy, biological markers, spirometry, and multi-flow eNO measurements. Data analysis implied linear correlation, non-parametric ANOVA, and pair-wise comparison.Results: No significant difference could be found among 3 OSA severity subgroups for FENO at – four sampling flow rates (50– 350 mL/s). The bronchial production rate of NO (J’awNO) was proportionally increased, with median values of 11.2, 33.9, and 36.2 in mild, moderate, and severe OSA, respectively (p=0.010). The alveolar concentration of NO (CANO) changed with a non-linear pattern; it was increased in moderate (6.49) vs mild (7.79) OSA but decreased in severe OSA (5.20, p = 0.015). The only correction that could be established between OSA severity and exhaled nitric oxide markers is through J’AWNO (rho=0.25, p=0.02) and CANO (rho= 0.18, p=0.04). There was no significant correlation between FENO measured at three different flow rates and the OSA severity. We also found a weak but significant correlation between FENO 100 and averaged SpO2 (rho = 0.07, p= 0.03).Conclusion: The present study showed that J’AWNO, which represents eNO derived from the central airway, is proportionally increased in more severe OSA, while eNO from alveolar space, indicated by CANO, was also associated with OSA severity and relatively lower in the most severe OSA patients. In contrast, stand-alone FENO metrics did not show a clear difference among the three severity subgroups.Keywords: exhaled nitric oxide, FENO, J’AWNO, CANO, obstructive sleep apnea

Purpose Sleep bruxism (SBx) activity is classically identified by capturing masseter and/or temporalis masticatory muscles electromyographic activity (EMG-MMA) during in-laboratory polysomnography (PSG). We aimed to identify stereotypical mandibular jaw movements (MJM) in patients with SBx and to develop rhythmic masticatory muscles activities (RMMA) automatic detection using an artificial intelligence (AI) based approach. Patients and Methods This was a prospective, observational study of 67 suspected obstructive sleep apnea (OSA) patients in whom PSG with masseter EMG was performed with simultaneous MJM recordings. The system used to collect MJM consisted of a small hardware device attached on the chin that communicates to a cloud-based infrastructure. An extreme gradient boosting (XGB) multiclass classifier was trained on 79,650 10-second epochs of MJM data from the 39 subjects with a history of SBx targeting 3 labels: RMMA episodes (n=1072), micro-arousals (n=1311), and MJM occurring at the breathing frequency (n=77,267). Results Validated on unseen data from 28 patients, the model showed a very good epoch-by-epoch agreement (Kappa = 0.799) and balanced accuracy of 86.6% was found for the MJM events when using RMMA standards. The RMMA episodes were detected with a sensitivity of 84.3%. Class-wise receiver operating characteristic (ROC) curve analysis confirmed the well-balanced performance of the classifier for RMMA (ROC area under the curve: 0.98, 95% confidence interval [CI] 0.97–0.99). There was good agreement between the MJM analytic model and manual EMG signal scoring of RMMA (median bias −0.80 events/h, 95% CI −9.77 to 2.85). Conclusion SBx can be reliably identified, quantified, and characterized with MJM when subjected to automated analysis supported by AI technology., Video Abstract Point your SmartPhone at the code above. If you have a QR code reader the video abstract will appear. Or use: https://youtu.be/M7LqfF1ZCyk

IMPORTANCE: Given the high prevalence of obstructive sleep apnea (OSA), there is a need for simpler and automated diagnostic approaches. OBJECTIVE: To evaluate whether mandibular movement (MM) monitoring during sleep coupled with an automated analysis by machine learning is appropriate for OSA diagnosis. DESIGN, SETTING, AND PARTICIPANTS: Diagnostic study of adults undergoing overnight in-laboratory polysomnography (PSG) as the reference method compared with simultaneous MM monitoring at a sleep clinic in an academic institution (Sleep Laboratory, Centre Hospitalier Universitaire Université Catholique de Louvain Namur Site Sainte-Elisabeth, Namur, Belgium). Patients with suspected OSA were enrolled from July 5, 2017, to October 31, 2018. MAIN OUTCOMES AND MEASURES: Obstructive sleep apnea diagnosis required either evoking signs or symptoms or related medical or psychiatric comorbidities coupled with a PSG-derived respiratory disturbance index (PSG-RDI) of at least 5 events/h. A PSG-RDI of at least 15 events/h satisfied the diagnosis criteria even in the absence of associated symptoms or comorbidities. Patients who did not meet these criteria were classified as not having OSA. Agreement analysis and diagnostic performance were assessed by Bland-Altman plot comparing PSG-RDI and the Sunrise system RDI (Sr-RDI) with diagnosis threshold optimization via receiver operating characteristic curves, allowing for evaluation of the device sensitivity and specificity in detecting OSA at 5 events/h and 15 events/h. RESULTS: Among 376 consecutive adults with suspected OSA, the mean (SD) age was 49.7 (13.2) years, the mean (SD) body mass index was 31.0 (7.1), and 207 (55.1%) were men. Reliable agreement was found between PSG-RDI and Sr-RDI in patients without OSA (n = 46; mean difference, 1.31; 95% CI, -1.05 to 3.66 events/h) and in patients with OSA with a PSG-RDI of at least 5 events/h with symptoms (n = 107; mean difference, -0.69; 95% CI, -3.77 to 2.38 events/h). An Sr-RDI underestimation of -11.74 (95% CI, -20.83 to -2.67) events/h in patients with OSA with a PSG-RDI of at least 15 events/h was detected and corrected by optimization of the Sunrise system diagnostic threshold. The Sr-RDI showed diagnostic capability, with areas under the receiver operating characteristic curve of 0.95 (95% CI, 0.92-0.96) and 0.93 (95% CI, 0.90-0.93) for corresponding PSG-RDIs of 5 events/h and 15 events/h, respectively. At the 2 optimal cutoffs of 7.63 events/h and 12.65 events/h, Sr-RDI had accuracy of 0.92 (95% CI, 0.90-0.94) and 0.88 (95% CI, 0.86-0.90) as well as posttest probabilities of 0.99 (95% CI, 0.99-0.99) and 0.89 (95% CI, 0.88-0.91) at PSG-RDIs of at least 5 events/h and at least 15 events/h, respectively, corresponding to positive likelihood ratios of 14.86 (95% CI, 9.86-30.12) and 5.63 (95% CI, 4.92-7.27), respectively. CONCLUSIONS AND RELEVANCE: Automatic analysis of MM patterns provided reliable performance in RDI calculation. The use of this index in OSA diagnosis appears to be promising.

Objectives Adenotonsillectomy (AT) markedly improves but does not necessarily normalize polysomnographic findings in children with adenotonsillar hypertrophy and related sleep-disordered breathing (SDB). Adenotonsillectomy efficacy should be evaluated by follow-up polysomnography (PSG), but this method may underestimate persistent respiratory effort (RE). Mandibular movement (MMas) monitoring is an innovative measurement that readily identifies RE during upper airway obstruction. We hypothesized that MMas indices would decrease in parallel of PSG indices and that children with persistent RE more reliably could be identified with MMas. Methods Twenty-five children (3–12 years of age) with SDB were enrolled in this individual prospective-cohort study. Polysomnography was supplemented with a midsagittal movement magnetic sensor that measured MMas during each respiratory cycle before and > 3 months after AT. Results Adenotonsillectomy significantly improved PSG indices, except for RE-related arousals (RERA). Mandibular movement index changes after AT significantly were correlated with corresponding decreases in sleep apnea–hypopnea index (AHI) and O2 desaturation index (ODI) (Spearman's rho = 0.978 and 0.922, respectively), whereas changes in MMas duration significantly were associated with both RERA duration (rho = 0.475, P = 0.017) and index (rho = 0.564, P = 0.003). Conditional multivariate analysis showed that both AHI and RERA significantly contributed to the variance of MMas index after AT (P = 0.0003 and 0.0005, respectively), whereas MMas duration consistently was related to the duration of RERA regardless of AT. Conclusion Adenotonsillectomy significantly reduced AHI. However, persistent RERA were apparent in a significant proportion of children, and this was reflected by the remaining abnormal MMas pattern. Follow-up of children after AT can be recommended and readily achieved by monitoring MMas to identify persistent RE. Level of Evidence 4. Laryngoscope, 2017

Context: Accurate discrimination between obstructive and central hypopneas requires quantitative assessments of respiratory effort by esophageal pressure (OeP) measurements, which preclude widespread implementation in sleep medicine practice. Mandibular Movement (MM) signals are closely associated with diaphragmatic effort during sleep.Objective: We aimed at reliably detecting obstructive off central hypopneas events using MM statistical characteristics.Methods: A bio-signal learning approach was implemented whereby raw MM fragments corresponding to normal breathing (NPB; n = 501), central (n = 263), and obstructive hypopneas (n = 1861) were collected from 28 consecutive patients (mean age = 54 years, mean AHI = 34.7 n/h) undergoing in-lab polysomnography (PSG) coupled with a MM magnetometer, and OeP recordings. Twenty three input features were extracted from raw data fragments to explore distinctive changes in MM signals. A Random Forest model was built upon those input features to classify the central and obstructive hypopnea events. External validation and interpretive analysis were performed to evaluate the model's performance and the contribution of each feature to the model's output.Results: Obstructive hypopneas were characterized by a longer duration (21.9 vs. 17.8 s, p < 10−6), more extreme low values (p < 10−6), a more negative trend reflecting mouth opening amplitude, wider variation, and the asymmetrical distribution of MM amplitude. External validation showed a reliable performance of the MM features-based classification rule (Kappa coefficient = 0.879 and a balanced accuracy of 0.872). The interpretive analysis revealed that event duration, lower percentiles, central tendency, and the trend of MM amplitude were the most important determinants of events.Conclusions: MM signals can be used as surrogate markers of OeP to differentiate obstructive from central hypopneas during sleep.

Background and Objective. The concentration of exhaled nitric oxide (eNO), reflecting the activity of inducible NO synthase in airway epithelium, has been found to increase in patients with obstructive sleep apnea (OSA). This study aimed to measure eNO concentration in patients with suspected OSA and to correlate different eNO parameters with clinical and sleep apnea characteristics.Methods. In this cross-sectional study, all patients underwent in-lab overnight polysomnography (PSG) and eNO measurement using a method of multiple flow rates before and after PSG (pre- and post-PSG).Results. According to the result of PSG, 82 persons were divided into two groups: control subjects (n=30;54±14years) and patients with OSA defined as apnea-hypopnea index (AHI) ≥ 5/hour (n=52;53±12years). Body mass index (BMI) and neck and abdomen circumferences of OSA patients were significantly higher than those from control subjects. In OSA group, post-PSG alveolar NO concentration (CANO) (5.3±1.9 ppb) was significantly higher than pre-PSG CANO (4.0±1.7 ppb;P<0.001). Significant correlations have been found between CANO and AHI (P<0.001) and between CANO and nadir SpO2(P<0.05). The daytime CANO value of more than 4.1 ppb can be used to screen symptomatic subjects for the presence of OSA with a high specificity of 93.3%.Conclusion. Our findings indicate CANO as a surrogate marker for OSA in persons with suggestive symptoms.

Objective: Our study aims to apply a Machine learning (ML) approach to detect the presence of Interstitial Lung disease (ILD) in patients with systemic sclerosis (SSc), using combined data from multiple pulmonary function tests (PFT). Methods: PFT data (Spirometry, Plethysmography and DLNO-CO measurements, all converted into Z-score scale) were obtained in 273 patients with confirmed diagnosis of SSc and 50 healthy non-smokers. The main outcome is ILD, as determined by HRCT. An exhaustive feature selection was performed in R statistical programming language. This process consists of building many classification models (based on support vector machine algorithm) from every possible combination between the PFT indices, then voting for the one that shows the best performance (highest accuracy and lowest error) through a repeated cross-validation (10x10 iterations). Results: The best decision rule implies 7 parameters: DLNO, DLCO, VA, Vc, KCO, TLC and FVC (Figure) This model showed steady and good classification performance through 100 resampled iterations: AUC=0.85, balanced-accuracy=0.76, true positive rate=0.62, true negative rate=0.89, mean misclassification error=0.2, false negative rate=0.38 and false positive rate=0.11. Conclusion: Our results suggest that applying ML technique and multiple PFT data could improve the likelihood to detect early SSc patients with higher risk of ILD.

Chest surface EMG at diaphragmatic insertions (IC-EMG) is an alternative way for capturing respiratory effort (RE) during SAHOS.IC-EMG wasn9t investigated with regards to oesophageal crural diaphragmatic EMG (DI-EMG). Our study aimed to assess the similarity between IC and DI-EMG and the ability of IC-EMG to classify RE episodes. Methods 14 adults SAHOS underwent a lab-based PSG study with IC-EMG and DI-EMG. 70 periods of normal breathing (NB),309 RE events (including 135 RERA,70 OH and104 OA) were randomly selected for analysis in R-studio. After noise reduction, AUC and peak-to-peak distance (d) were calculated for both signals. Similarity between 2 signals was evaluated by cross-correlation as a function of the lag of one relative to the other. Correlation and d-value were compared among 4 groups of RE levels. Ability of each signal to detect RE was evaluated by multiclass CART algorithm. Results Patients have a mean age of 42.8±10.7 yrs and BMI of 31.1±8.6 kg/m2.Their averaged TST and AHI were 347±51.9 min and 35.3±25.1 n/h respectively. IC and DI-EMG signals are cross-correlated in either NB or RE events (r=0.6 to 0.86) by a lag of 0.5-0.9 second. AUC was also correlated (r=0.96). IC showed a significant difference in d-value among 4 groups (NB:14.6 vs RERA:21.9, OH:19.8 and OA:44.2). Using cut-offs at 17.8 and 31.5, IC distance allows classifying RERA, OAH and NB with accuracy, inter-class agreement and specificity of 0.8, 0.63 and 0.91, respectively. Conclusions IC-EMG is a useful method to assess RE and the obstructive nature of AH .

Sy Duong-Quy,1–3 Thuc Vu-Minh,4 Thong Hua-Huy,1 Tram Tang-Thi-Thao,3 Khiet Le-Quang,3 Dinh Tran-Thanh,3 Nhu Doan-Thi-Quynh,3 Nhat-Nam Le-Dong,5 Timothy J Craig,2 Anh-Tuan Dinh-Xuan1 1Department of Respiratory Physiology, Cochin Hospital, Paris Descartes University, Sorbonne Paris Cité, Paris, France; 2Department of Medicine, Penn State University, Hershey, PA, USA; 3Bio-Medical Research Center, Lam Dong Medical College, Dalat, 4Department of Immuno-Allergology, ENT National Institute, Hanoi, Vietnam; 5Department of Pulmonology, St Elisabeth Hospital, Namur, Belgium Background: The measure of fractional exhaled nitric oxide (FENO) in the airways is a useful tool to guide the diagnosis and titration of inhaled corticosteroids in patients with asthma. However, its role in diagnosis of allergic rhinitis (AR), especially in subjects with asthma, is not well established. Objective: To study the cutoff of nasal FENO in the diagnosis of subjects with AR and AR-asthma compared to age-matched subjects without AR or asthma and its correlations with the clinical and functional characteristics. Methods: The study was cross sectional and descriptive. Subjects were grouped into control subjects, AR, and AR-asthma, based on the inclusion criteria. Exhaled NO (nasal FENO, bronchial FENO, and alveolar concentration of NO) was measured by multiple flow electroluminescence device. Results: Six hundred twenty-eight subjects were included: 217 control subjects (children: n=98, 10±4 years; adults: n=119, 50±16 years), 168 subjects with AR (children: n=54, 10±3 years; adults: n=114, 49±15 years), and 243 subjects with AR-asthma (children: n=115, 10±3 years; adults: n=128, 51±14 years). Nasal peak inspiratory flow and peak expiratory flow were lower in subjects with AR and AR-asthma than in control subjects (P

Context: Mandibular movements (MM) are considered as reliable reporters of respiratory effort (RE) during sleep and sleep disordered breathing (SDB) but MM accuracy has never been validated against the gold standard diaphragmatic EMG activity (EMG-d). Objectives: To assess the degree of agreement between MM and EMG-d signals during different sleep stages and abnormal respiratory events. Methods: Twenty-five consecutive adult patients with SDB were studied by polysomnography (PSG) that also included multipair oesophageal diaphragm electromyography and a magnetometer to record MM. EMG-d activity (µV) and MM (mm) amplitudes were extracted by envelope processing. Agreement between signals amplitudes was evaluated by mixed linear regression and cross-correlation function (CCF) and in segments of PSG including event-free and SDB periods. Results: The average total sleep time (TST) was 370±18 minutes and the apnea hypopnea index (AHI) was 24.8 ± 5.2 events/hour. MM and EMG-d amplitudes were significantly cross-correlated: median r (95%CI): 0.67 (0.23 to 0.96). A mixed linear model showed that for each 10 µV of increase in EMG-d activity, MM amplitude increased by 0.28 mm. The variations in MM amplitudes (median range: 0.11 to 0.84 mm) between normal breathing, respiratory effort related arousal, obstructive, mixed and central apnea periods closely corresponded to those observed with EMG-d activity (median range: 2.11 to 8.23 µV). Conclusion: MM amplitudes change proportionally to diaphragmatic EMG activity, and accurately identify variations of respiratory effort during normal sleep and SDB.

Systemic sclerosis (SSc) is a connective-tissue disease characterized by vascular injury, immune-system disorders, and excessive fibrosis of the skin and multiple internal organs. Recent reports found that RhoA/Rho-kinase (ROCK) pathway is implicated in various fibrogenic diseases. Intradermal injection of hypochlorous acid (HOCl)-generating solution induced inflammation, autoimmune activation, and fibrosis, mimicking the cutaneous diffuse form of SSc in humans. Our study aimed firstly to describe pulmonary inflammation and fibrosis induced by HOCl in mice, and secondly to determine whether fasudil, a selective inhibitor of ROCK, could prevent lung and skin fibroses in HOCl-injected mice.Female C57BL/6 mice received daily intradermal injection of hypochlorous acid (HOCl) for 6 weeks to induce SSc, with and without daily treatment with fasudil (30 mg·kg(-1)·day(-1)) by oral gavage.HOCl intoxication induced significant lung inflammation (macrophages and neutrophils infiltration), and fibrosis. These modifications were prevented by fasudil treatment. Simultaneously, HOCl enhanced ROCK activity in lung and skin tissues. Inhibition of ROCK reduced skin fibrosis, expression of α-smooth-muscle actin and 3-nitrotyrosine, as well as the activity of ROCK in the fibrotic skin of HOCl-treated mice, through inhibition of phosphorylation of Smad2/3 and ERK1/2. Fasudil significantly decreased the serum levels of anti-DNA-topoisomerase-1 antibodies in mice with HOCl-induced SSc.Our findings confirm HOCl-induced pulmonary inflammation and fibrosis in mice, and provide further evidence for a key role of RhoA/ROCK pathway in several pathological processes of experimental SSc. Fasudil could be a promising therapeutic approach for the treatment of SSc.

Pulmonary hypertension (PH) is a complex disorder resulting from many etiologies that cause disturbances of normal pulmonary haemodynamics. Recent breakthroughs have led to a better understanding of the pathophysiology of the disease. In PH, haemodynamic disturbances are closely linked to structural changes and excessive remodeling of pulmonary vessels, leading to progressive narrowing of the pulmonary vascular lumen. Imbalances between pulmonary vasoconstrictors and vasodilators on the one hand, and factors favoring cell proliferation and apoptosis on the other hand, probably account for most cases of PH. This review aims to update readers with the current knowledge on the molecular physiopathology of PH and how this can progress the therapeutic of this disorder.

Nitric oxide metabolites (NOx) in serum, and alveolar concentration of NO (CA(NO)), are markers of inflammation and alveolitis, respectively, in systemic sclerosis (SSc). We prospectively evaluated the usefulness of both NOx and CA(NO) to assess lung involvement and skin fibrosis in SSc. Serum NOx, and CA(NO) measured by two different methods, namely the two-compartment (2CM) and the "trumpet" models (TM), were concomitantly assessed in 65 patients with SSc and 17 healthy controls. Whilst serum NOx remained comparable between groups, CA(NO) were significantly higher in SSc patients (n=65, 6.7ppb; 4.8-9.7 and 5.9ppb; 3.9-8.9) as compared with controls (n=17, 3.0ppb; 2.0-3.8 and 1.8ppb; 1.1-2.9, p

Exhaled nitric oxide (NO) is increased as a result of lung inflammation, which in turn causes subsequent interstitial lung disease in patients with systemic sclerosis (SSc). However, the exact time course of inflammatory and fibrotic changes in the SSc lung has not yet been described. Our objective was to assess the chronological evolution of lung inflammatory and fibrotic processes in mice pre-treated with hypochlorous acid (HOCl) or bleomycin. C57BL/6 mice were randomized into three groups receiving subcutaneous injections of HOCl, bleomycin, or PBS for 2, 4 or 6 weeks. Exhaled NO (eNO) was measured at the end of each injection period and after 2 resting weeks without injection (8 week group). Mice were then sacrificed to obtain skin and lung tissues to measure fibrotic changes and NO synthases (NOS) expression. Increased eNO, inducible NOS and nitrotyrosine expression in bronchial epithelium, lung neutrophils and macrophages were observed at early phases in both HOCl- and bleomycin-treated mice. Conversely, lung vascular endothelial NOS expression decreased significantly at 6th and 8th weeks. Skin fibrosis was significantly increased from the 4th week and lung fibrosis from 6th week. We conclude that lung inflammation occurs early after injury as reflected by increased exhaled NO and inducible NOS expression, and precedes fibrotic changes in skin and lungs of mice pre-treated with bleomycin and HOCl. Early detection and treatment of pulmonary inflammation might be useful in preventing subsequent occurrence of lung fibrosis in SSc patients.

Recent evidence suggests that activation of RhoA/Rho-kinase accounts for systemic and pulmonary endothelial dysfunction in smokers with normal lung function. However, its role in patients with chronic obstructive pulmonary disease (COPD) has not yet been investigated. The aim of this study was to evaluate the regulation of RhoA/Rho-kinase pathway and pulmonary endothelial dysfunction in patients with COPD. Pulmonary arteries were obtained from nonsmokers (control subjects) and patients with nonhypoxemic and hypoxemic COPD (n = 6-7/group). Endothelium-dependent and -independent relaxations were evaluated by acetylcholine and sodium nitroprusside, respectively. Gene and protein expressions of endothelial nitric oxide synthase (eNOS) were measured by RT-PCR, Western blot, and immunohistochemistry. Nitrate, cGMP, and endothelin-1 (ET-1) concentrations, as well as Rho-kinase activity were measured by ELISA. Protein expressions of total RhoA and GTP-RhoA were measured by Western blot and pull-down assay, respectively. Endothelium-dependent relaxation, and nitrate and cGMP levels were significantly reduced in pulmonary arteries of COPD patients as compared with control subjects. Conversely, activity of RhoA/Rho-kinase was increased in pulmonary arteries of COPD patients as compared with control subjects. In patients with COPD, pulmonary endothelial dysfunction was related to the downregulation of eNOS activity and upregulation of RhoA/Rho-kinase activity.

Alveolar concentration of nitric oxide (C A NO) is a non invasive prognostic marker of systemic sclerosis (SSc) lung disease. There is, however, as yet no direct evidence showing concomitant increase of C A NO and the presence of inflammatory cells in alveoli. We have therefore measured C A NO and performed broncho-alveolar lavage (BAL) in SSc patients. Exhaled NO was measured, by the means of two different models, the two-compartment model (2CM) and the trumpet model with axial diffusion (TMAD), in 22 SSc patients and compared with 15 healthy controls. BAL was performed in all SSc patients. Alveolitis was defined as lymphocytes >14%, polymorphonuclears >4%, or eosinophils >3% on cell count in BAL fluid. Comparisons of C A NO levels were made between SSc patients with, and without, alveolitis. Levels of C A NO were significantly higher in SSc patients as compared with controls ( p A NO was significantly higher in SSc patients with alveolitis as compared with SSc patients without alveolitis (8.4 ppb; 1st and 3rd interquartile range: 6.0–10.5 vs 3.3 ppb; 2.2–3.5; p = 0.004 for 2CM and 5.4 ppb; 3.2–9.2 vs 3.2 ppb; 1.4–3.3, p = 0.02 for TMAD), while bronchial airway output of NO ( J′ awNO, p = 0.19), and fractional exhaled NO (F E NO, p = 0.12) were comparable. C A NO was consistently high in SSc patients with alveolitis irrespective of the methods chosen (TMAD or 2CM). Our findings showed that increased C A NO was associated with alveolitis in patients with SSc. We submit that C A NO could be used as a reliable non-invasive surrogate biomarker of alveolitis in scleroderma lung disease.

Respiratory failure is a life-threatening and unpredictable complication of systemic sclerosis (SSc). A study was undertaken to assess the value of alveolar nitric oxide (NO) in predicting the risk of lung function deterioration leading to respiratory failure or death in patients with SSc.105 patients with SSc were enrolled in this prospective cohort and were followed longitudinally over a 3-year period during which the risk of occurrence of deleterious events was analysed according to alveolar concentration (C(A)NO), conducting airway output (J'(aw)NO) and fractional concentration (F(E)NO(0.05)) of exhaled NO measured at inclusion. Comparison was made between each NO parameter to predict the occurrence of deleterious events, defined as a 10% decrease in total lung capacity or forced vital capacity from baseline, or death.The area under the receiver operating characteristic curve of C(A)NO to predict the occurrence of the combined events was 0.84 (95% CI 0.76 to 0.92; p0.001), which was significantly higher than those of J'(aw)NO and F(E)NO(0.05) (p0.001). A cut-off of C(A)NO of 5.3 ppb had a sensitivity of 88% and a specificity of 62% for the prediction of the occurrence of combined events during follow-up, and was validated in an independent cohort of patients with SSc. Combined events occurred more frequently in patients whose C(A)NO was5.3 ppb. The adjusted HR for patients with C(A)NO5.3 ppb was 6.06 (95% CI 2.36 to 15.53; p0.001). C(A)NO accurately predicted the occurrence of combined events irrespective of forced vital capacity values or the presence of interstitial lung disease at baseline.Increased C(A)NO accurately identifies patients with SSc with a high risk of developing lung function deterioration and may help to initiate early appropriate treatment.