Plasma proteins elevated in severe asthma despite oral steroid use and unrelated to Type-2 inflammation.

RATIONALE: Asthma phenotyping requires novel biomarker discovery. OBJECTIVES: To identify plasma biomarkers associated with asthma phenotypes by application of a new proteomic panel to samples from two well-characterised cohorts of severe (SA) and mild-to-moderate (MMA) asthmatics, COPD subjects and healthy controls (HCs). METHODS: An antibody-based array targeting 177 proteins predominantly involved in pathways relevant to inflammation, lipid metabolism, signal transduction and extracellular matrix was applied to plasma from 525 asthmatics and HCs in the U-BIOPRED cohort, and 142 subjects with asthma and COPD from the validation cohort BIOAIR. Effects of oral corticosteroids (OCS) were determined by a 2-week, placebo-controlled OCS trial in BIOAIR, and confirmed by relation to objective OCS measures in U-BIOPRED. RESULTS: In U-BIOPRED, 110 proteins were significantly different, mostly elevated, in SA compared to MMA and HCs. 10 proteins were elevated in SA versus MMA in both U-BIOPRED and BIOAIR (alpha-1-antichymotrypsin, apolipoprotein-E, complement component 9, complement factor I, macrophage inflammatory protein-3, interleukin-6, sphingomyelin phosphodiesterase 3, TNF receptor superfamily member 11a, transforming growth factor-ß and glutathione S-transferase). OCS treatment decreased most proteins, yet differences between SA and MMA remained following correction for OCS use. Consensus clustering of U-BIOPRED protein data yielded six clusters associated with asthma control, quality of life, blood neutrophils, high-sensitivity C-reactive protein and body mass index, but not Type-2 inflammatory biomarkers. The mast cell specific enzyme carboxypeptidase A3 was one major contributor to cluster differentiation. CONCLUSIONS: The plasma proteomic panel revealed previously unexplored yet potentially useful Type-2-independent biomarkers and validated several proteins with established involvement in the pathophysiology of SA.

Upregulation of citrullination pathway: From Autoimmune to Idiopathic Lung Fibrosis.

BACKGROUND: Increased protein citrullination and peptidylarginine deiminases (PADIs), which catalyze the citrullination process, are central in Rheumatoid arthritis pathogenesis and probably involved in the initial steps towards autoimmunity. Approximately, 10% of RA patients develop clinically significantly ILD. A possible shared role of protein citrullination in rheumatoid arthritis associated interstitial lung disease (RA-ILD), and idiopathic pulmonary fibrosis (IPF) pathogenesis remains unclear. METHODS: We evaluated PADI2 and PADI4 mRNA expression in bronchoalveolar lavage fluid (BALF) cells of 59 patients with IPF, 27 patients RA-ILD and 10 healthy controls. PADI 2 and 4 expression was analyzed by western blot and immunohistochemistry. Citrullinated protein levels were also quantified. RESULTS: PADI4 mRNA and protein levels were higher in RA-ILD and IPF than controls. Furthermore, PADI4 mRNA levels showed an increase among smokers in RA-ILD. PADI4 expression was detected in granulocytes and macrophages in all groups, with the strongest cytoplasmic expression observed in granulocytes in RA-ILD and IPF. PADI2 mRNA and immunostaining of BAL cells, were similar in all groups among smokers. Overall, stronger staining was observed in current smokers. Citrullinated peptides were significantly increased in IPF compared to RA-ILD and controls. In RA-ILD, protein citrullination strongly correlated with PADI4 expression and anti-citrullinated protein antibodies (ACPAs). CONCLUSIONS: These results suggest that the citrullination pathway is upregulated in IPF and in RA-ILD.

NLRP3 inflammasome expression in idiopathic pulmonary fibrosis and rheumatoid lung.

In this study we investigated the implication of NLRP3 inflammasomes in the pathogenesis of idiopathic pulmonary fibrosis (IPF) and rheumatoid arthritis-usual interstitial pneumonia (RA-UIP).NLRP3 inflammasome activation at baseline and following stimulation with lipopolysaccharide/ATP was evaluated by measuring interleukin (IL)-1ß and IL-18 levels released in the bronchoalveolar lavage fluid (BALF) fluid and by cultures of BALF cells. IL-1ß and IL-18 levels were significantly elevated in the BALF and BALF macrophage cultures from RA-UIP patients, consistent with pre-existing inflammasome activation in these patients. In contrast, in IPF, BALF levels of IL-1ß were significantly less elevated relative to RA-UIP and IL-18 was lower than controls. Furthermore, upon inflammasome stimulation, IPF BALF macrophage cultures failed to upregulate IL-1ß and partly IL-18 secretion, in contrast to controls, which showed robust IL-1ß and IL-18 upregulation. Interestingly, RA-UIP BALF cell cultures treated with lipopolysaccharide/ATP showed a potent stimulation of IL-18 secretion but not IL-1ß, the latter being already elevated in the unstimulated cultures, while examination of the intracellular IL-1ß levels in RA-UIP BALF cells upon NLRP3 inflammasome stimulation showed a significant upregulation of IL-1ß suggesting the NLRP3 pathway could be further activated.Taken together, our results suggest distinct inflammasome activation profiles between autoimmune and idiopathic lung fibrosis.

Expression of YKL-40 and MIP-1a proteins in exudates and transudates: biomarkers for differential diagnosis of pleural effusions? A pilot study.

BACKGROUND: YKL-40 is an extracellular matrix glycoprotein with a significant role in tissue inflammation and remodeling. MIP-1a has chemotactic and pro-inflammatory properties, and is induced by YKL-40 in several lung disorders. The aim of this study was to determine the levels of YKL-40 and MIP-1a in blood serum and pleural fluids of various pulmonary diseases, and to evaluate their potential role as differential diagnosis biomarkers. METHODS: We recruited 60 patients (age: 62.5 ± 20.6 years) with pleural effusions: 49 exudates and 11 transudates (T). Exudates were further classified based on the underlying disease: ten with tuberculosis (TB), 13 with lung cancer (LCa), 15 with metastatic cancer (MCa) of non-lung origin and 11 with parapneumonic (PN) effusions. YKL-40 and MIP-1a levels were measured by ELISA. RESULTS: Pleural YKL-40 levels (ng/ml) were similar among all patient groups (TB: 399 ± 36, LCa: 401 ± 112, MCa: 416 ± 34, PN: 401 ± 50, T: 399 ± 42, p = 0.92). On the contrary, YKL-40 was significantly lower in the serum of TB patients (TB: 58 ± 22, LCa: 212 ± 106, MCa: 254 ± 140, PN: 265 ± 140, T: 229 ± 123, p < 0.001). Pleural MIP-1a protein levels (ng/ml) were statistically lower only in patients with LCa (TB: 25.0 ± 20.2, LCa: 7.3 ± 6.0, MCa: 16.1 ± 14.9, PN: 25.4 ± 27.9, T: 18.5 ± 7.9, p = 0.012), a finding also observed in serum MIP-1a levels (TB: 17.1 ± 7.6, LCa: 9.4 ± 7.0, MCa: 28.7 ± 28.7, PN: 33.3 ± 24.0, T: 22.9 ± 8.7, p = 0.003). CONCLUSIONS: Our data suggest that both YKL-40 and MIP-1a, particularly in serum, could prove useful for the differentiation of pleural effusions in clinical practice, especially of TB or LCa origin. However, large-scale studies are needed to validate these findings.

Intensive versus standard follow-up to improve continuous positive airway pressure compliance.

We aimed to compare the effect of intensive versus standard interventions on continuous positive airway pressure (CPAP) adherence 2 years after CPAP initiation, as well as on sleepiness, quality of life, depression, hospitalisation and death rate due to cardiovascular disease (CVD). 3100 patients with newly diagnosed sleep apnoea were randomised into the standard group, with usual follow-up care, or the intensive group, with additional visits, telephone calls and education. Subjective daytime sleepiness (Epworth Sleepiness Scale; ESS), quality of life (36-item Short Form Health Survey; SF-36) and the patient's level of depression (Beck Depression Inventory; BDI) were recorded before and 2 years after CPAP initiation, together with CVD hospitalisations and death rate. 2 years after CPAP initiation, the intensive group used CPAP significantly more than the standard group (6.9 versus 5.2 h per night; p<0.001). ESS, SF-36 and BDI scores were also significantly better in the intensive group. Furthermore, the standard group had significantly more deaths and hospitalisations due to CVD. CPAP usage can be improved by both intensive and standard patient support. However, the patients who received intensive CPAP support had significantly better ESS, BDI and SF-36 scores, and lower cardiovascular morbidity and mortality, suggesting that an intensive programme could be worthwhile.

Comparative mortality risk of tiotropium administered via handihaler or respimat in COPD patients: are they equivalent?

BACKGROUND: Tiotropium bromide, once daily, long-acting anticholinergic bronchodilator is either administered by handihaler metered dose inhaler or by respimat soft mist inhaler. It has been proved to improve lung function, daily symptoms and quality of life and to decrease the exacerbation and hospitalisation rate of patients with Chronic Obstructive Pulmonary Disease (COPD). Although the efficacy of both formulations is undeniable, concerns have been raised on their effect on cardiovascular and general mortality. METHODS: Two independent authors systematically reviewed Medline, Scopus, Cochrane Library and ClinicalTrials.gov to collect clinical trials, observational studies and meta-analyses studying the safety of tiotropium. The reference list of all the included studies were also reviewed. RESULTS: Limited, early studies suggested a potential increase in cardiovascular and general mortality associated with tiotropium handihaler, but these data were outweighed by following larger trials, real-life studies and meta-analyses which proved the opposite. On the other hand, data on tiotropium respimat (5 µg) have been contradictory, with different studies suggesting increased cardiovascular and general mortality compared to handihaler (18 µg) or placebo, especially in patients with comorbid diseases. TIOSPIR trial suggests comparable safety of the two formulations. However the exclusion of patients with pre-existing unstable cardiovascular disease, moderate or severe kidney disease or any other significantly disease may limit the generizability of these results. CONCLUSION: Although the two tiotropium formulations have similar efficacy, current data cannot prove safety equivalence, since respimat may be associated with increased cardiovascular and general mortality, especially in patients with comorbid diseases.

Abnormal cytokine profile in patients with obstructive sleep apnea-hypopnea syndrome and erectile dysfunction.

Patients with obstructive sleep apnea-hypopnea syndrome (OSAHS) show a high prevalence of erectile dysfunction (ED). Although the underlying pathogenesis is still unknown, endothelial dysfunction, induced by inflammatory cytokines, chemokines, and adhesion molecules, has been proposed as a possible mechanism. The aim of this study was to assess whether OSAHS is associated with activation of the inflammatory cytokine system in patients with ED compared to the matched OSAHS patients with normal sexual function. Thirty-one patients with severe OSAHS and ED were included. Fifteen patients with severe OSAHS and without ED served as controls. Serum concentrations of high-sensitivity C-reactive protein (hsCRP), tumor necrosis factor-α (TNF-a), interleukin-6 (IL-6), interleukin-8 (IL-8), and adiponectin were measured after the diagnostic polysomnography. We found that hsCRP levels were significantly elevated in OSAHS patients with ED compared to controls. Similarly, TNF-a levels, IL-6, and IL-8 were elevated in OSAHS patients with ED compared to controls. Serum adiponectin levels were lower in OSAHS-ED patients, but the difference did not reach statistical significance. The presence of ED in patients with severe OSAHS is associated with elevated levels of inflammatory markers, underlining a possible involvement of endothelial dysfunction in the pathogenesis of ED.

Molecular profiling of EGFR family in chronic obstructive pulmonary disease: correlation with airway obstruction.

BACKGROUND: Growth factors mediate various cellular responses to environmental stimuli. Specifically, exposure of lung epithelium to oxidative stress induced by cigarette smoke stimulates aberrant epidermal growth factor receptor (ERBB) family activation. This study's objective was to evaluate the expression of ERBB1-4 receptors in the lung tissue of smokers with or without chronic obstructive pulmonary disease (COPD). MATERIALS AND METHODS: ERBBs expression was measured by microarray analysis in lung tissue samples from five patients with COPD and five non-COPD smokers, and by quantitative real-time PCR in additional 20 patients with COPD (GOLD stage II), 15 non-COPD smokers and 10 nonsmoker controls. RESULTS: Microarray data analysis revealed that ERBB receptors expression was elevated in patients with COPD compared to non-COPD smokers, ranging from 1·62- to 2·45-fold, (P < 0·01). Real-time qPCR verified that patients with COPD had higher ERBB1-3 expression levels compared with non-COPD smokers (PERBB1  < 0·001; PERBB2  = 0·003; PERBB3  = 0·003) and nonsmokers (PERBB1  = 0·019; PERBB2  = 0·005; PERBB3  = 0·011). On the other hand, ERBB4 mRNA levels gradually increased from nonsmokers (0·74 ± 0·19) to non-COPD smokers (1·11 ± 0·05) to patients with COPD (1·57 ± 0·28) and were correlated with the degree of airflow obstruction (PFEV1  < 0·001). DISCUSSION: These data suggest that ERBB1-3 overexpression is not related only to smoking exposure but probably to epithelial remodelling and mucociliary system distortion, characterizing COPD. Additionally, the inverse correlation of ERBB4 with FEV1 exhibits a possible link between ERBB4 and COPD severity.

Smoking-related emphysema is associated with idiopathic pulmonary fibrosis and rheumatoid lung.

BACKGROUND AND OBJECTIVE: A combined pulmonary fibrosis/emphysema syndrome has been proposed, but the basis for this syndrome is currently uncertain. The aim was to evaluate the prevalence of emphysema in idiopathic pulmonary fibrosis (IPF) and rheumatoid lung (rheumatoid arthritis-interstitial lung disease (RA-ILD)), and to compare the morphological features of lung fibrosis between smokers and non-smokers. METHODS: Using high-resolution computed tomography, the prevalence of emphysema and the pack-year smoking histories associated with emphysema were compared between current/ex-smokers with IPF (n = 186) or RA-ILD (n = 46), and non-chronic obstructive pulmonary disease (COPD) controls (n = 103) and COPD controls (n = 34). The coarseness of fibrosis was compared between smokers and non-smokers. RESULTS: Emphysema, present in 66/186 (35%) patients with IPF and 22/46 (48%) smokers with RA-ILD, was associated with lower pack-year smoking histories than in control groups (P < 0.05 for all comparisons). The presence of emphysema in IPF was positively linked to the pack-year smoking history (odds ratio 1.04, 95% confidence interval (CI) 1.02-1.06, P < 0.0005). In IPF, fibrosis was coarser in smokers than in non-smokers on univariate and multivariate analysis (P < 0.01 for all comparisons). In RA-ILD, fibrosis was coarser in patients with emphysema but did not differ significantly between smokers and non-smokers. CONCLUSIONS: In IPF and RA-ILD, a high prevalence of concurrent emphysema, in association with low pack-year smoking histories, and an association between coarser pulmonary fibrosis and a history of smoking in IPF together provide support for possible pathogenetic linkage to smoking in both diseases.

Molecular response of the human diaphragm on different modes of mechanical ventilation.

BACKGROUND: The mechanical stress that the human diaphragm is exposed to during mechanical ventilation affects a variety of processes, including signal transduction, gene expression, and angiogenesis. OBJECTIVES: The study aim was to assess the change in the production of major angiogenic regulators [vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF2), and transforming growth factor beta 1 (TGFB1)] on the human diaphragm before and after contraction/relaxation cycles during mechanical ventilation. METHODS: This observational study investigates the diaphragmatic mRNA expression of VEGF, FGF2, and TGFB1 in surgical patients receiving general anesthesia with controlled mechanical ventilation (CMV) with muscle relaxation (group A, n = 13), CMV without muscle relaxation (group B, n = 10), and pressure support of spontaneous breathing (group C, n = 9). Diaphragmatic samples were obtained from each patient at two time points: 30 min after the induction of anesthesia (t1) and 90 min after the first specimen collection (t2). RESULTS: No significant changes in the mRNA expression of VEGF, FGF2, and TGFB1 were documented in groups A and C between time points t1 and t2. In contrast, in group B, the mRNA levels of the above angiogenic factors were increased in time point t2 compared to t1, a finding which was statistically significant (pVEGF = 0.003, pFGF2 = 0.028, pTGFB1 = 0.001). CONCLUSIONS: These findings suggest that the molecular response of the human diaphragm before and after application of diverse modes of mechanical ventilation is different. Angiogenesis via the expression of VEGF, FGF2, and TGFB1 was only promoted in CMV without muscle relaxation, and this may have important clinical implications.

Translation and validation of Berlin questionnaire in primary health care in Greece.

BACKGROUND: The aim of our study was to validate a Greek translation of the Berlin Questionnaire (BQ) for obstructive sleep apnoea syndrome (OSAS) and to explore whether this screening questionnaire could be used to help identify primary care patients at greater risk of having OSAS. METHODS: We recruited 189 patients visiting a primary health care setting on the island of Crete, Greece. They all completed the Greek Version of the BQ. Patients were then referred to a Sleep Disorders Unit for evaluation of suspected sleep-disordered breathing. RESULTS: A PSG study was performed in 129 of the 189 subjects (68.3%). BQ identified 74.4% (n = 96) of the patients as high-risk for OSAS and the remaining 25.6% (n = 33) as low-risk. The sensitivity and specificity of BQ for OSAS diagnosis were 76% and 40%, respectively, for an apnoea-hypopnoea index (AHI) ≥5 per hour but <15 per hour, 84% and 61% for an AHI ≥15 per hour but ≤30 per hour, and 79% and 39% for an AHI >30 per hour. CONCLUSIONS: In conclusion, the Greek Version of the BQ is a useful instrument for identifying patients at risk for OSAS in primary health care in Greece. The findings of our study confirm that such screening tools should be used by primary care clinicians for OSAS prediction.

Effect of Mediterranean diet versus prudent diet combined with physical activity on OSAS: a randomised trial.

We aimed to evaluate the effect of the Mediterranean diet (MD) compared with a prudent diet (PD) combined with physical activity on obese obstructive sleep apnoea syndrome (OSAS) patients who were treated with continuous positive airway pressure. 900 patients were evaluated and 40 obese patients (body mass index ≥ 30.0 kg · m(-2)) who met the inclusion criteria, with moderate-to-severe OSAS (apnoea-hypopnoea index (AHI) >15 events · h(-1) and Epworth Sleepiness Scale score >10) based on overnight attended polysomnography, were included in the study. After randomisation, 20 patients followed the MD and 20 a PD for a 6-month period. All patients were counselled to increase their physical activity. Concerning sleep parameters, only AHI during rapid eye movement (REM) sleep was reduced to a statistically significant degree, by mean ± SD 18.4 ± 17.6 events · h(-1) in the MD group and by 2.6 ± 23.7 events · h(-1) in the PD group (p<0.05). The MD group also showed a greater reduction in waist circumference (WC) (-8.7 ± 3.6 cm), WC/height ratio (-0.04 ± 0.02 cm · m(-1)) and WC/hip ratio (-0.04 ± 0.03 cm · cm(-1)), compared with the other group (-2.6 ± 1.7 events · h(-1), -5.7 ± 3.8 cm, -0.03 ± 0.02 cm · m(-1) and 0.02 ± 0.02 cm · cm(-1), respectively; p<0.05). Our results showed that the MD combined with physical activity for a 6-month period was effective in reducing the AHI during REM sleep without any statistically significant effect in the other sleep parameters, compared with a PD in obese adults with moderate-to-severe OSAS.

Long-term omalizumab treatment in severe allergic asthma: the South-Eastern Mediterranean "real-life" experience.

BACKGROUND: Omalizumab is a recombinant humanized anti-IgE monoclonal antibody indicated as an add-on treatment for severe allergic asthma, inadequately controlled despite high dose of inhaled corticosteroids (ICS) and long-acting b2-agonists. OBJECTIVES: Medical registries were used to evaluate the 4 months, 1 and 4 years effectiveness of omalizumab treatment, in a non-interventional, observational "real-life" study. METHODS: Sixty patients with severe persistent allergic asthma from 5 South-Eastern Mediterranean centres from Crete and Cyprus were evaluated. Effectiveness outcomes included spirometry, severe asthma exacerbations rate, level of asthma control (ACT), and additional asthma medication (inhaled steroids). RESULTS: Outcome variables improved after 4 months and sustained after 1 and 4 years treatment with Omalizumab. FEV1 improved statistically significant at all time points versus baseline [ΔFEV1 (% pred.) = +21 p = 0.008 at 4 months, ΔFEV1 (% pred.) = +24.5 p < 0.0001 at 4 years after treatment]. Similarly, FVC increased statistically significant versus baseline [ΔFVC (% pred.) = +20 p = 0.002 at 4 months, ΔFVC (% pred.) = +22.6 p = 0.0002 at 4 years]. The level of asthma control as evaluated by ACT was significantly improved after treatment (+12% p = 0.001 at 4 months, +24% p < 0.0001 at 4 years). Omalizumab treatment reduced significantly asthma exacerbations rate (-65% p = 0.0002 at 1 year, and -70% p < 0.0001 at 4 years). The use of inhaled steroids decreased statistically significant after 4 months (p = 0.017), 1 year (p = 0.029) and 4 years (p = 0.014) of omalizumab treatment. CONCLUSIONS: This long-term "real-life" study demonstrated significant improvement in lung function and other clinical outcomes after omalizumab treatment, evident at 4 months, and sustained after 1 and 4 years suggesting its efficacy in severe allergic asthma, in the "real-life" practice.

Effect of Mediterranean diet on lipid peroxidation marker TBARS in obese patients with OSAHS under CPAP treatment: a randomised trial.

PURPOSE: The aim of our study was to examine the possible effect of the Mediterranean diet on thiobarbituric acid reacting substances (TBARS) in obese patients with obstructive sleep apnoea/hypopnoea syndrome (OSAHS) who are under continuous positive airway pressure treatment. METHODS: Nine hundred patients were evaluated during a 1-year period (November 2008-October 2009), and 21 obese patients who met the inclusion criteria, with moderate to severe OSAHS based on overnight attended polysomnography, were included in the study. After randomisation, 11 followed the Mediterranean diet and 10 a prudent diet for a 6-month period. TBARS were measured in serum. RESULTS: TBARS levels decreased notably in both groups (p < 0.05), but no difference was observed between them (p > 0.05). There were significant differences in other characteristics. The Mediterranean diet group showed a greater reduction in weight (-10.8 ± 3.8), body mass index (-3.9 ± 1.6), waist circumference (-9.9 ± 3.0) and percentage of body fat (-4.7 ± 2.3) compared with the other group (-6.9 ± 3.1, -2.5 ± 1.0, -5.3 ± 2.6 and -2.2 ± 1.5, respectively; p < 0.05). CONCLUSIONS: Our results showed that the Mediterranean diet did not reduce the TBARS more than the prudent diet.

DNA damage due to oxidative stress in Chronic Obstructive Pulmonary Disease (COPD).

According to the American Thorasic Society (ATS)/European Respiratory Society (ERS) Statement, chronic obstructive pulmonary disease (COPD) is defined as a preventable and treatable disease with a strong genetic component, characterized by airflow limitation that is not fully reversible, but is usually progressive and associated with an enhanced inflammatory response of the lung to noxious particles or gases. The main features of COPD are chronic inflammation of the airways and progressive destruction of lung parenchyma and alveolar structure. The pathogenesis of COPD is complex due to the interactions of several mechanisms, such as inflammation, proteolytic/antiproteolytic imbalance, oxidative stress, DNA damage, apoptosis, enhanced senescence of the structural cells and defective repair processes. This review focuses on the effects of oxidative DNA damage and the consequent immune responses in COPD. In susceptible individuals, cigarette smoke injures the airway epithelium generating the release of endogenous intracellular molecules or danger-associated molecular patterns from stressed or dying cells. These signals are captured by antigen presenting cells and are transferred to the lymphoid tissue, generating an adaptive immune response and enhancing chronic inflammation.

Utility of formulas predicting the optimal nasal continuous positive airway pressure in a Greek population.

BACKGROUND: There have been reports that optimal CPAP pressure can be predicted from a previously derived formula, with the Hoffstein formula being the most accurate and accepted in the literature so far. However, the validation of this predictive model has not been applied in different clinical settings. Our aim was to compare both the Hoffstein prediction formula and a newly derived formula to the CPAP pressure setting assessed during a formal CPAP titration study. METHODS: We prospectively studied 1,111 patients (871 males/240 females) with obstructive sleep apnea hypopnea syndrome (OSAHS) undergoing a CPAP titration procedure. In this large population sample, we tested the Hoffstein formula, utilizing body mass index (BMI), neck circumference and apnea/hypopnea index (AHI), and we compared it with our new formula that included not only AHI and BMI but also smoking history and gender adjustment. RESULTS: We found that using the Hoffstein prediction formula, successful prediction (predicted CPAP pressure within ±2 cm H(2)O compared to the finally assessed optimum CPAP pressure during titration) was accomplished in 873 patients (79%), with significant correlation between CPAP predicted pressure (CPAPpred(1)) and the optimum CPAP pressure (CPAPopt) [r = 0.364, p < 0.001]. With the new formula, including smoking history and gender adjustment, successful prediction was accomplished in 1,057 patients (95%), with significant correlation between CPAP predicted pressure (CPAPpred(2)) and the CPAPopt (r = 0.392, p < 0.001). However, there was a highly significant correlation between the two formulas (r = 0.918, p < 0.001). CONCLUSIONS: We conclude that the level of CPAP necessary to abolish sleep apnea can be successfully predicted from both equations, using common clinical measurements and prediction formulas that may be useful in calculating the starting pressure for initiating CPAP titration. It may also be possible to shorten CPAP titration and perhaps in selected cases to combine it with the initial diagnostic study.

Prediction of obstructive sleep apnea syndrome in a large Greek population.

PURPOSE: We aimed to evaluate the predictive value of anthropometric measurements and self-reported symptoms of obstructive sleep apnea syndrome (OSAS) in a large number of not yet diagnosed or treated patients. Commonly used clinical indices were used to derive a prediction formula that could identify patients at low and high risk for OSAS. METHODS: Two thousand six hundred ninety patients with suspected OSAS were enrolled. We obtained weight; height; neck, waist, and hip circumference; and a measure of subjective sleepiness (Epworth sleepiness scale--ESS) prior to diagnostic polysomnography. Excessive daytime sleepiness severity (EDS) was coded as follows: 0 for ESS ≤ 3 (normal), 1 for ESS score 4-9 (normal to mild sleepiness), 2 for score 10-16 (moderate to severe sleepiness), and 3 for score >16 (severe sleepiness). Multivariate linear and logistic regression analysis was used to identify independent predictors of apnea-hypopnea index (AHI) and derive a prediction formula. RESULTS: Neck circumference (NC) in centimeters, body mass index (BMI) in kilograms per square meter, sleepiness as a code indicating EDS severity, and gender as a constant were significant predictors for AHI. The derived formula was: AHIpred = NC × 0.84 + EDS × 7.78 + BMI × 0.91 - [8.2 × gender constant (1 or 2) + 37]. The probability that this equation predicts AHI greater than 15 correctly was 78%. CONCLUSIONS: Gender, BMI, NC, and sleepiness were significant clinical predictors of OSAS in Greek subjects. Such a prediction formula can play a role in prioritizing patients for PSG evaluation, diagnosis, and initiation of treatment.

Sputum and nasal lavage lung-specific biomarkers before and after smoking cessation.

BACKGROUND: Little is known about the effect of smoking cessation on airway inflammation. Secretory Leukocyte Protease Inhibitor (SLPI), Clara Cell protein 16 (CC16), elafin and human defensin beta-2 (HBD-2) protect human airways against inflammation and oxidative stress. In this longitudinal study we aimed to investigate changes in sputum and nasal lavage SLPI, CC16, elafin and HBD-2 levels in healthy smokers after 6 and 12 months of smoking cessation. METHODS: Induced sputum and nasal lavage was obtained from healthy current smokers (n = 76) before smoking cessation, after 6 months of smoking cessation (n = 29), after 1 year of smoking cessation (n = 22) and from 10 healthy never smokers. SLPI, CC16, elafin and HBD-2 levels were measured in sputum and nasal lavage supernatants by commercially available ELISA kits. RESULTS: Sputum SLPI and CC-16 levels were increased in healthy smokers before smoking cessation versus never-smokers (p = 0.005 and p = 0.08 respectively). SLPI and CC16 levels did not differ before and 6 months after smoking cessation (p = 0.118 and p = 0.543 respectively), neither before and 1 year after smoking cessation (p = 0.363 and p = 0.470 respectively). Nasal lavage SLPI was decreased 12 months after smoking cessation (p = 0.033). Nasal lavage elafin levels were increased in healthy smokers before smoking cessation versus never-smokers (p = 0.007), but there were no changes 6 months and 1 year after smoking cessation. CONCLUSIONS: Only nasal lavage SLPI decrease after 1 year after smoking cessation. We may speculate that there is an ongoing inflammatory process stimulating the production of counter-regulating proteins in the airways of healthy ex-smokers.

Role of VEGF-stromal cell-derived factor-1alpha/CXCL12 axis in pleural effusion of lung cancer.

CONTEXT AND OBJECTIVE: It has been suggested that stromal cell-derived factor-1alpha ((SDF-1alpha) or CXCL12, both transcripts, TR1 and TR2) and its cognate receptor CXCR4 may regulate cancer metastasis. We have investigated the role of vascular endothelial growth factor (VEGF), angiopoietins (Ang-1 and Ang-2) and the biological axis of CXCL12-CXCR4, in patients with malignant pleural effusions (PEs). MATERIAL AND METHODS: Twenty five patients, seven with transudative PEs due to heart failure and 18 with exudative malignant PEs (7 with small cell lung cancer (SCLC) and 11 with nonsmall cell lung cancer (NSCLC)) were included in the study. Expression analysis of the mediators was performed in pleural fluid pellet using real-time reverse transcription-PCR. Protein expression has been evaluated by western blot analysis. RESULTS: SDF-TR1 (P = 0.02) but not SDF-TR2 (P = 0.23) or CXCR4 levels (P = 0.23) were higher in malignant PEs than in transudates. SDF-TR1 (P = 0.04) and SDF- TR2 levels (P = 0.04) but not CXCR4 levels (P = 0.123) were higher in SCLC PEs than in heart failure PEs. SDF-TR1 (P = 0.03) but not SDF-TR2 levels (P = 0.6) and CXCR4 levels (P = 0.4) were higher in NSCLC PEs than in transudates. Ang-1 has not been expressed in PEs, whereas no significant difference has been detected in VEGF and Ang-2 expression between malignant PEs and transudates. However, protein expression showed increased VEGF and SDF expression in malignant PEs. CONCLUSIONS: These results suggest that elevated SDF-1alpha/CXCL12 levels would be suggestive of a link to metastasis and may participate in pleural trafficking in lung cancer.