Exhaled nitric oxide in relation to asthma control: A real-life survey

BACKGROUND: Asthma is characterised by chronic airway inflammation, a complex cascade of events, mostly sustained by eosinophil recruitment and activation. Fractional exhaled nitric oxide (FeNO) is a surrogate marker of airway inflammation closely associated with bronchial eosinophilia. FeNO is used to define asthma phenotype, to assess eosinophilic inflammatory severity and to predict corticosteroid responsiveness. OBJECTIVE: The aim of this study was to investigate whether FeNO may be associated with some clinical and functional factors in asthmatics evaluated in a real life setting. METHODS: Globally 363 patients (150 males, mean age 46.3 years) with asthma were consecutively evaluated. The following parameters were assessed: history, including comorbidities, physical examination, body mass index (BMI), lung function, asthma control grade, asthma control test (ACT), and FeNO. RESULTS: FeNO values were significantly higher in patients with poorly controlled asthma (p < 0.01), asthma symptoms (p = 0.015), wheezing (p < 0.001), rhinitis diagnosis, (p = 0.049) and rhinitis symptoms (p = 0.019), but lower in patients with GERD (p = 0.024) and pneumonia history (p = 0.048). FeNO values increased in patients with the lowest corticosteroid dose (p = 0.031). FeNO values > 25 ppb were associated with poorly controlled asthma (OR 3.71), asthma signs (OR 3.5) and symptoms (OR 1.79). A FeNO value cut-off of 29.9 ppb was fairly predictive of (AUC 0.7) poorly controlled asthma. CONCLUSIONS: FeNO assessment in clinical practice may be a useful tool for monitoring asthmatics as it is associated with several clinical factors, including asthma control

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Exhaled nitric oxide in relation to asthma control: A real-life survey.

BACKGROUND: Asthma is characterised by chronic airway inflammation, a complex cascade of events, mostly sustained by eosinophil recruitment and activation. Fractional exhaled nitric oxide (FeNO) is a surrogate marker of airway inflammation closely associated with bronchial eosinophilia. FeNO is used to define asthma phenotype, to assess eosinophilic inflammatory severity and to predict corticosteroid responsiveness. OBJECTIVE: The aim of this study was to investigate whether FeNO may be associated with some clinical and functional factors in asthmatics evaluated in a real life setting. METHODS: Globally 363 patients (150 males, mean age 46.3 years) with asthma were consecutively evaluated. The following parameters were assessed: history, including comorbidities, physical examination, body mass index (BMI), lung function, asthma control grade, asthma control test (ACT), and FeNO. RESULTS: FeNO values were significantly higher in patients with poorly controlled asthma (p<0.01), asthma symptoms (p=0.015), wheezing (p<0.001), rhinitis diagnosis, (p=0.049) and rhinitis symptoms (p=0.019), but lower in patients with GERD (p=0.024) and pneumonia history (p=0.048). FeNO values increased in patients with the lowest corticosteroid dose (p=0.031). FeNO values>25ppb were associated with poorly controlled asthma (OR 3.71), asthma signs (OR 3.5) and symptoms (OR 1.79). A FeNO value cut-off of 29.9ppb was fairly predictive of (AUC 0.7) poorly controlled asthma. CONCLUSIONS: FeNO assessment in clinical practice may be a useful tool for monitoring asthmatics as it is associated with several clinical factors, including asthma control.

Bradykinin B2 receptor expression in the bronchial mucosa of allergic asthmatics: the role of NF-kB.

BACKGROUND: Bradykinin (BK) mediates acute allergic asthma and airway remodelling. Nuclear factor-kappa B (NF-kB) is potentially involved in BK B2 receptor (B2R) regulation. OBJECTIVE: In this observational cross-sectional study, B2R and NF-kB expression was evaluated in bronchial biopsies from mild asthmatics (after diluent/allergen challenge) and healthy controls, examining the role of NF-kB in B2R expression in primary human fibroblasts from normal and asthmatic subjects (HNBFb and HABFb). METHODS: B2R and NF-kB (total and nuclear) expression was analysed by immunohistochemistry in biopsies from 10 mild intermittent asthmatics (48 h after diluent/allergen challenge) and 10 controls undergoing bronchoscopy. B2R co-localization in 5B5(+) and αSMA(+) mesenchymal cells was studied by immunofluorescence/confocal microscopy, and B2R expression in HABFb/HNBFb incubated with interleukin (IL)-4/IL-13 with/without BK, and after NF-kB inhibitor, by Western blotting. RESULTS: Bronchial mucosa B2R and nuclear NF-kB expression was higher in asthmatics after diluent (B2R only) and allergen challenge than in controls (P < 0.05), while B2R and NF-kB (total and nuclear) increased after allergen compared with after diluent (P < 0.05). Allergen exposure increased B2R expression in 5B5(+) and αSMA(+) cells. Constitutive B2R protein expression was higher in HABFb than in HNBFb (P < 0.05) and increased in both cell types after IL-13 or IL-4/IL-13 and BK treatment. This increase was suppressed by a NF-kB inhibitor (P < 0.05). CONCLUSIONS & CLINICAL RELEVANCE: Bronchial B2R expression is constitutively elevated in allergic asthma and is further increased after allergen exposure together with NF-kB expression. NF-kB inhibitor blocked IL-4/IL-13-induced increase in B2R expression in cultured fibroblasts, suggesting a role as potential anti-asthma drug.

Nasal IL-17F is related to bronchial IL-17F/neutrophilia and exacerbations in stable atopic severe asthma.

Severe asthma (SA) is associated with neutrophil recruitment and T helper (TH )17 chemokine overexpression in bronchial biopsies. We aimed to evaluate IL-17A and IL-17F expression in nasal/bronchial lamina propria of atopic mild-to-severe asthmatics and controls in relation to neutrophilia and asthma exacerbations. Cryostat sections of nasal/bronchial biopsies obtained from 14 SA and 14 mild asthma (MA) stable atopic patients with rhinitis, and seven healthy controls were analyzed by immunohistochemistry for neutrophils, IL-17A and IL-17F expression. Atopic SA showed an increase in asthma exacerbations number, IL-17F and IL-17A expression in nasal/bronchial lamina propria compared to MA and controls, and a higher expression of bronchial neutrophils in SA compared to MA and controls. In all asthmatics, significant relationships were found between bronchial IL-17F and neutrophils/FEV1 , nasal IL-17F and bronchial neutrophil/IL-17 markers and between the latter and exacerbations, suggesting that nasal IL-17F might be informative on bronchial IL17-driven neutrophilia in atopic SA.

TNF-alpha, IL-4R-alpha and IL-4 polymorphisms in mild to severe asthma from Italian Caucasians.

Asthma is a chronic airway inflammatory disease associated with airway hyperresponsiveness which affects subjects with genetic predisposition. An association has been reported between some polymorphisms in various cytokine genes and asthma. Most of them are single nucleotide polymorphisms (SNPs). These polymorphisms are detected in the protein coding sequence or in the promoter region thus influencing cytokine production. We investigated the involvement of SNP mapping in 5 cytokine genes in mild to severe asthmatics of Italian Caucasians. The frequency of alleles and genotypes, relatively to 10 allelic specificities of the cytokine genes, was defined in 57 asthmatics and in 124 control subjects by a Polymerase Chain Reaction-Sequence Specific Primer method. TNF-alpha -308A and TNF-alpha -238A allele frequencies were higher in asthmatics than in controls (p less than 0.001). Significant differences in the frequency of IL-4 -590T allele and of IL-4Ralpha +1902A allele were also detected in asthmatics in comparison with controls (pless than 0.001 and p=0.005, respectively). Similarly, IL-1alpha -889C allele was present in 84.1 percent of asthmatics and in 70.2 percent of controls (p=0.013). Furthermore, the IL-4Ralpha +1902A/A and IL-1alpha -889C/C homozygous conditions and the TNF-alpha -308G/A, TNF-alpha -238G/A, IL-4 -590T/C and IL-10 -1082G/A heterozygous conditions were significantly associated with asthma (p less than 0.05). ACA haplotype of IL-10 was observed only in asthmatic patients. This study reports, for the first time, the frequency of 10 different single nucleotide polymorphisms in 5 cytokine genes in the Italian Caucasians. Furthermore, we also indicate that in our population some single nucleotide polymorphisms are associated with mild to severe bronchial asthma.

Headache and multiple sclerosis: a population-based case-control study in Catania, Sicily.

We carried out a population-based case-control study to evaluate the association between multiple sclerosis (MS) and headache. We had previously determined the incidence of MS during 1990-1999 in Catania, Sicily, identifying 155 incident MS patients; these subjects underwent a telephone interview using a standardized questionnaire for headache. Diagnosis and classification of headaches were made according to International Headache Society criteria (1988). A control group was selected from the general population through random digit dialling. One hundred and one (65.2%) MS patients, of the 155 identified, and 101 controls were screened for headaches. Fifty-eight (57.4%) MS patients and 38 (37.2%) controls fulfilled the diagnostic criteria of headache. A significant association between MS and headache was found with an adjusted odds ratio, estimated by logistic regression, of 2.18 (95% confidence interval 1.27, 3.93). Frequency of headaches in our MS population is higher than in the general population, supporting the hypothesis of a possible association between these two conditions.

Tumor necrosis factor-alpha in airway secretions from cystic fibrosis patients upregulate endothelial adhesion molecules and induce airway epithelial cell apoptosis: implications for cystic fibrosis lung disease.

Airway inflammation plays a crucial role in lung damage in cystic fibrosis (CF) and is characterized by a persistent influx of neutrophils into the airways. We hypothesized that the high levels of inflammatory products that accumulate in the microenvironment of the CF lung contribute to induce the persistent neutrophil recruitment and the airway epithelial damage. Thus, we evaluated the in vitro effect of sputum sol phase (SSP) from CF patients on a) adhesion molecule expression by human microvascular endothelial cells (HMECs) and b) apoptosis of human bronchial epithelial cells (HBECs), both wild-type and CFTR-defective. SSP was obtained from 7 clinically stable adult CF patients and 8 patients with an acute exacerbation. HMECs and HBECs were cultured in the absence or presence of SSP. Cell adhesion molecule expression was assessed by flow cytometry and cell death by the detection of histone-associated DNA fragments, caspase activation, and cytochrome c release. SSP obtained from CF patients, especially at the time of an acute exacerbation, induced a) an upregulation of endothelial adhesion molecules on cultured HMECs that was associated with an increase of neutrophil adhesion to these cells, and was mediated at least in part by TNF-alpha and IL-1 and b) apoptosis of airway epithelial cells, mainly activated by TNF- alpha pathway. These results suggest that the high concentrations of inflammatory mediators in CF airways contribute both to the chronic neutrophil influx and the airway damage, and support the crucial role of early anti-inflammatory treatment in the disease.

Possible increasing risk of multiple sclerosis in Catania, Sicily.

OBJECTIVE: To update prevalence and incidence rates of multiple sclerosis (MS) in Catania, Italy during 1990 to 1999 and evaluate their temporal profiles to assess a possible increase in the MS risk in our study population. METHODS: We studied the frequency of MS in Catania, Italy (population of 313,110 as reported in the 2001 census). The primary sources for the case ascertainment were the neurologic and motor-rehabilitation departments, the MS centers, the Italian MS Association, private neurologists, and family doctors. We considered as prevalent and incident cases all patients who satisfied Poser's criteria for clinically definite MS (CDMS), laboratory-supported definite MS (LSDMS), clinically probable MS (CPMS), and laboratory-supported probable MS (LSPMS). RESULTS: We found 288 subjects with MS who had onset of disease before December 31, 1999 (prevalence day) in a population of 313,110 inhabitants. The prevalence rate was 92.0/100,000 (95% CI 81.8 to 103.2) and was higher in women (102.4/100,000) than in men (80.4/100,000). The age-specific prevalence showed a peak in the group aged 35 to 44 years (208.2/100,000). From 1990 to 1999, 155 patients with MS had the clinical onset of the disease. The mean annual incidence was 4.7/100,000 (95% CI 4.0 to 5.5). Age-specific incidence showed a peak in the group aged 25 to 34 years (11.7/100,000). Mean annual incidence for 5-year intervals increased from 3.9/100,000 during 1990 to 1994 to 5.5/100,000 during 1995 to 1999. CONCLUSIONS: Prevalence and incidence rates of multiple sclerosis have further increased during the last decade.

Quantitative real-time RT-PCR analysis of eight novel estrogen-regulated genes in breast cancer.

BACKGROUND: Biological markers capable of predicting the risk of recurrence and the response to treatment in breast cancer are eagerly awaited. Estrogen and progesterone receptors (ER, PgR) in tumor cells mark cancers that are more likely to respond to endocrine treatment, but up to 40% of such patients do not respond. Here, the expression of a group of estrogen-regulated genes, previously identified by microarray analysis of in vitro models, was measured in breast tumors and possible associations with other clinicopathological variables were investigated. METHODS: The expression of CD24, CD44, HAT-1, BAK-1, G1P3, TIEG, NRP-1 and RXRalpha was measured by quantitative real-time RT-PCR on RNA from eighteen primary breast tumors. Statistical analyses were used to identify correlations among the eight genes and the available clinicopathological data. RESULTS: Variable expression levels of all the genes were observed in all the samples examined. Significant associations of CD24 with tumor size, CD44 with lymph node invasion, and HAT-1 and BAK-1 with ER positivity were found. The possible combinatorial value of these genes was assessed. Unsupervised hierarchical clustering analysis demonstrated that the expression profile of these genes was able to predict ER status with an acceptable approximation. CONCLUSIONS: Eight novel potential markers for breast cancer have been preliminarily characterized. As expected from in vitro data, their expression is able to discriminate ER- versus ER+ tumors.