Mauro Maniscalco

Early treatment with noninvasive positive pressure ventilation prolongs survival in Amyotrophic Lateral Sclerosis patients with nocturnal respiratory insufficiency

BackgroundAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disease, which rapidly leads to chronic respiratory failure requiring mechanical ventilation. Currently, forced vital capacity (FVC) < 50% is considered as physiologic marker for admitting patients to Noninvasive Positive Pressure Ventilation (NPPV) intervention, although it has been recently shown the median survival of patients with baseline FVC < 75% much shorter than median survival of patients with baseline FVC > 75%, independently by any treatment.AimTo assess the role of NPPV in improving outcome of ALS, a retrospective analysis was performed to investigate 1 year survival of ALS patients with FVC < 75% and nocturnal respiratory insufficiency, treated with NPPV, compared to a well-matched population of ALS patients, who refused or was intolerant to NPPV.MethodsWe investigated seventy-two consecutive ALS patients who underwent pulmonary function test. Forty-four presented a FVC > 75% and served as control group. Twenty-eight patients presented a FVC < 75% and showed, at polysomnography analysis, nocturnal respiratory insufficiency, requiring NPPV; sixteen were treated with NPPV, while twelve refused or were intolerant.ResultsIncreased survival rate at 1 year in patients with FVC < 75% treated with NPPV, as compared to those who refused or could not tolerate NPPV (p = 0.02), was observed. The median rate of decline in FVC% was slower in NPPV patients than in patients who did not use NPPV (95% CI: 0.72 to 1.85; p < 0.0001).ConclusionThis report demonstrates that early treatment with NPPV prolongs survival and reduces decline of FVC% in ALS.

Effect of nitric oxide inhibition on nasal airway resistance after nasal allergen challenge in allergic rhinitis

Background Nitric oxide has been detected by chemiluminescence in the lumen of nasal airway, which is increased in nasal breathing in patients with seasonal rhinitis during a chronic exposure. The purpose of this study was to determinate the effect of a NO‐synthase inhibitor NGL‐arginine methyl ester (L‐NAME) on nasal airway resistance (NAR) in patients with seasonal allergic rhinitis after an acute challenge to the allergen.

Endothelin-1 Induces Proliferation of Human Lung Fibroblasts and IL-11 Secretion Through an ET A Receptor-Dependent Activation of Map Kinases

Endothelin‐1 (ET‐1) is implicated in the fibrotic responses characterizing interstitial lung diseases, as well as in the airway remodeling process occurring in asthma. Within such a context, the aim of our study was to investigate, in primary cultures of normal human lung fibroblasts (NHLFs), the ET‐1 receptor subtypes, and the intracellular signal transduction pathways involved in the proliferative effects of this peptide. Therefore, cells were exposed to ET‐1 in the presence or absence of an overnight pre‐treatment with either ETA or ETB selective receptor antagonists. After cell lysis, immunoblotting was performed using monoclonal antibodies against the phosphorylated, active forms of mitogen‐activated protein kinases (MAPK). ET‐1 induced a significant increase in MAPK phosphorylation pattern, and also stimulated fibroblast proliferation and IL‐6/IL‐11 release into cell culture supernatants. All these effects were inhibited by the selective ETA antagonist BQ‐123, but not by the specific ETB antagonist BQ‐788. The stimulatory influence of ET‐1 on IL‐11, but not on IL‐6 secretion, was prevented by MAPK inhibitors. Therefore, such results suggest that in human lung fibroblasts ET‐1 exerts a profibrogenic action via an ETA receptor‐dependent, MAPK‐mediated induction of IL‐11 release and cell proliferation.

Exhaled and arterial levels of endothelin-1 are increased and correlate with pulmonary systolic pressure in COPD with pulmonary hypertension

BackgroundEndothelin-1 (ET-1) and Nitric Oxide (NO) are crucial mediators for establishing pulmonary artery hypertension (PAH). We tested the hypothesis that their imbalance might also occur in COPD patients with PAH.MethodsThe aims of the study were to measure exhaled breath condensate (EBC) and circulating levels of ET-1, as well as exhaled NO (FENO) levels by, respectively, a specific enzyme immunoassay kit, and by chemiluminescence analysis in 3 groups of subjects: COPD with PAH (12), COPD only (36), and healthy individuals (15). In order to evaluate pulmonary-artery systolic pressure (PaPs), all COPD patients underwent Echo-Doppler assessment.ResultsSignificantly increased exhaled and circulating levels of ET-1 were found in COPD with PAH compared to both COPD (p < 0.0001) only, and healthy controls (p < 0.0001). In COPD with PAH, linear regression analysis showed good correlation between ET-1 in EBC and PaPs (r = 0.621; p = 0.031), and between arterial levels of ET-1 and PaPs (r = 0.648; p = 0.022), while arterial levels of ET-1 inversely correlated with FEV1%, (r = -0.59, p = 0.043), and PaPs negatively correlated to PaO2 (r = -0.618; p = 0.032). Significantly reduced levels of FENO were found in COPD associated with PAH, compared to COPD only (22.92 ± 11.38 vs.35.07 ± 17.53 ppb; p = 0.03). Thus, we observed an imbalanced output in the breath between ET-1 and NO, as expression of pulmonary endothelium and epithelium impairment, in COPD with PAH compared to COPD only. Whether this imbalance is an early cause or result of PAH due to COPD is still unknown and deserves further investigations.

Influence of subclinical hypothyroidism and T4 treatment on the prevalence and severity of obstructive sleep apnoea syndrome (OSAS)

Background: Obstructive sleep apnoea (OSA) and subclinical hypothyroidism are relatively frequent disorders that may be causally linked. However, discordant results exist on the prevalence and severity of OSA in subclinical hypothyroidism. The aim of this study was to compare the prevalence and severity of sleep-dis-ordered breathing in individuals with or without subclinical hypothyroidism, and to investigate the possible effect of levothyroxine treatment on these patients. Patients and Methods: One hundred and eight subjects were consecutively enrolled and divided in 3 groups, according to the TSH levels and levothyroxine therapy. The first group (Group A) was represented by 63 subjects with normal TSH and thyroid function. The other two groups included patients affected by subclinical hypothyroidism; one group (Group B) treated with levothyroxine, while the other group (Group C) was never treated with levothyroxine. Anthropometric, respiratory and polysomnographic data were evaluated in all individuals. Results: The percentage of OSA, neck circumference, and body mass index (BMI) were not statistically different among the 3 groups. Respiratory disturbance index (RDI) as well as the percentage of the total number of events (apnoea-hypopnoea) by total sleep time (TST) with <90% oxyhemoglobin saturation (TSTSaO2 <90%) were not different among the groups. When we observed OSA patients, the only significant difference between groups B and C was represented by the Epworth Sleepiness Scale (ESS) (p=0.005). Conclusion: This study shows that subclinical hypothyroidism and treatment with levothyroxine do not influence the prevalence and severity of OSA, while sleep propensity is increased by untreated subclinical hypothyroidism.

Transient Decrease of Exhaled Nitric Oxide after Acute Exposure to Passive Smoke in Healthy Subjects

Abstract Nitric oxide (NO) is produced and detected in the exhalate from the respiratory tract where it plays important regulatory functions. Exhaled nitric oxide (eNO) concentrations are reduced in active cigarette smokers between cigarettes and in nonsmoking subjects during short-term exposure to environmental tobacco smoke. In this study, the authors evaluated eNO before and after an acute exposure to environmental tobacco smoke in healthy, nonsmoking subjects (n = 12). Baseline eNO levels were measured by chemiluminescence at baseline (1 hr before exposure), shortly after the end of exposure, and 10 and 30 min after the end of exposure. Mean room air NO concentration increased from 3 ppb to 4 ppm (range, 560 ppb-8.5 ppm) during the exposure period. Carboxyhemoglobin levels were assessed before and after the exposure with spectrophotometry. All subjects had decreased eNO with exposure to environmental tobacco smoke (mean ± standard error of the mean: 16.65 ± 1.35 ppb to 13.86 ± 1.33 ppb; p < .001). These concentrations remained significantly decreased at 10 min and recovered within 30 min. No modifications in airway resistance or increase in carboxyhemoglobin levels were observed. Exposure to environmental tobacco smoke transiently–but consistently–decreased eNO concentration in healthy, nonsmoking subjects, suggesting that second-hand smoke can directly affect NO in the airway environment.

Right ventricular performance in severe obesity. Effect of weight loss.

Backgroundu2002 The effects of severe obesity on right ventricular function in the absence of associated cardiopulmonary disease are not well known. Right myocardial performance index (R‐MPI) is an echocardiographic index to non‐invasively assess the right ventricular function.

The effect of platelet‐activating factor (PAF) on nasal airway resistance in healthy subjects is not mediated by nitric oxide

Background: The nose is an important source of nitric oxide (NO) in man, but the relevance of NO production to the response to inflammatory mediators is not clear.

Extended analysis of exhaled and nasal nitric oxide for the evaluation of chronic cough.

INTRODUCTIONnChronic cough is usually defined as a cough that lasts for eight weeks or longer. Its etiological diagnosis is not always straightforward, and the measurement of exhaled nitric oxide (FeNO) has been proposed in patients evaluation. No studies have assessed the usefulness of extended exhaled NO measurement for the evaluation of chronic cough. Therefore, we aimed at evaluating the usefulness of an extended exhaled NO measurement and nasal NO for an initial evaluation of chronic cough.nnnMETHODSnWe studied 52 non-smoker patients with prolonged cough lasting more than eight weeks. Etiologies of cough were identified. Nasal NO and FeNO were assessed using multiple single-breath NO analysis at different constant expiratory flow-rates. From the fractional NO concentration measured at each flow-rate, the total NO flux between tissue and gas phase in the bronchial lumen (JawNO), and the alveolar NO concentration (Cano) were extrapolated.nnnRESULTSnThe patients were classified in four categories: cough variant asthma (CVA), nonasthmatic eosinophilic bronchitis (NAEB), upper airway cough syndrome (UACS) and gastro-esophageal reflux disease (GERD). Compared with UACS and GERD, both exhaled NO and JawNO were higher in CVA and NAEB, and no differences were found in Cano and nasal NO level among the four groups.nnnCONCLUSIONSnOur study suggests a potentially useful role for FeNO measurement in the etiological diagnosis of chronic cough. We did not find any additive value of performing exhaled NO at multiple flow-rates and nasal NO measurements.

Exhaled nitric oxide after inhalation of isotonic and hypotonic solutions in healthy subjects.

Airway nitric oxide (NO) homoeostasis is influenced by chemical and mechanical stimuli in humans; airway epithelium, which is an important site of NO production, is sensitive to osmotic challenge. The effect of inhaled hypotonic solutions on exhaled NO (eNO) is not known. In this study we evaluated the effect of ultrasonically nebulized distilled water (UNDW), a hypotonic indirect stimulus, on eNO levels. A total of 10 non-smoking healthy subjects were enrolled in the study. eNO was detected by chemiluminescence, and specific airway conductance (sGaw) was measured by plethysmography. Bronchial challenges with UNDW and with an isotonic solution were performed according to a double-blind experimental design. Baseline levels of eNO were 28.1+/-14.7 p.p.b. UNDW did not cause any significant change in sGaw (from 0.190+/-0.029 to 0.181+/-0.036 cm H(2)O x s(-1)). With respect to baseline values, the eNO concentration decreased significantly after inhalation of 8 or 16 ml of UNDW (from 26.0+/-13.1 to 17.2+/-8.5 and 16.6+/-7.7 p.p.b. respectively; P<0.001, n=10). After bronchial challenge with UNDW, eNO was significantly reduced in comparison with after inhalation of the isotonic solution. In five subjects, pretreatment with N(G)-nitro-L-arginine methyl ester (L-NAME), an inhibitor NO synthesis, decreased NO levels from 21.7+/-8.5 to 10.0+/-3.3 p.p.b. Subsequent inhalation of 16 ml of UNDW did not cause any further decrease in NO levels (10.1+/-3.7 p.p.b.; not significant compared with L-NAME). We conclude that inhalation of aqueous solutions decreases eNO levels in healthy subjects, and that this effect is not associated with any significant change in airway calibre. The UNDW-induced decrease in eNO is not enhanced by pretreatment with the NO synthase inhibitor L-NAME, suggesting that inhaled solutions may interfere with the airway NO pathway in humans.