A polymorphism in ORMDL3 is associated not only with asthma without rhinitis but also with chronic obstructive pulmonary disease.

BACKGROUND: Asthma is a heterogeneous disease, and asthmatic patients without rhinitis more commonly have fixed airway obstruction, a feature that is also typical of chronic obstructive pulmonary disease (COPD). The Dutch hypothesis suggests that both COPD and asthma have common genetic risk factors. The purpose of this study was to assess the association between the polymorphism rs4795405 in the known asthma candidate gene ORMDL3 and asthma with and without rhinitis. We also analyzed COPD in order to investigate whether, in addition to a clinical overlap, there might also be a genetic overlap between COPD and asthma. METHODS: The population of this genetic association study comprised 493 Slovenian adults, distributed as follows: 131 patients with asthma (59 had asthma with rhinitis and 72 asthma without rhinitis), 59 patients with rhinitis only, 133 patients with COPD, and 170 controls. Genotypes for rs4795405 were determined using the TaqMan genotyping assay. RESULTS: rs4795405 was specifically associated with asthma without rhinitis. Assuming a recessive genetic model, we found the CC genotype in 26% of healthy controls, in 24% of patients with asthma with rhinitis (P = .862), and in 44% of patients with asthma without rhinitis (P = .006). Polymorphism rs4795405 was also associated with COPD, for which the CC genotype was found in 37% of cases (P = .045). CONCLUSIONS: rs4795405 was strongly associated with asthma without rhinitis, a subtype of asthma for which a higher degree of airway obstruction was found. These results show the importance of analyzing different asthma phenotypes in genetic association studies. We also observed a genetic overlap between COPD and asthma without rhinitis.

Airway angiogenesis in stable and exacerbated chronic obstructive pulmonary disease.

Angiogenesis is a prominent feature of structural tissue remodelling that occurs in chronic airway diseases, including chronic obstructive pulmonary disease (COPD). The aim of this study was to evaluate the airway levels of VEGF, angiogenin, IL-8 and TNF-α in patients with COPD during the stable phase and during acute exacerbation of the disease. We analysed induced sputum samples from 28 patients with COPD. Thirteen of these patients were followed up and second samples of sputum were obtained during acute exacerbation of the disease. The two control groups consisted of 12 healthy smokers and seven healthy non-smokers, all with normal lung function tests. Concentrations of VEGF, angiogenin, IL-8, TNF-α and bFGF were measured by cytometric bead array. In the induced sputum of patients with stable COPD, concentrations of VEGF (P < 0.001, P = 0.02), angiogenin (P < 0.0001, P < 0.0001), IL-8 (P < 0.0001, P = 0.0021) and TNF-α (P < 0.001, P = 0.03) were significantly elevated in comparison with healthy smokers and non-smokers. No additional elevation of angiogenic factors was demonstrated at the time of exacerbation. There was a significant negative correlation between FEV1 and VEGF (P < 0.05, r = -0.38), angiogenin (P < 0.0001, r = -0.68) and IL-8 (P < 0.001, r = -0.54) among smokers (smoking COPD patients and healthy smokers). No significant differences were observed between groups of healthy smokers and non-smokers. These results showed increased airway angiogenesis in patients with COPD. Moreover, VEGF, IL-8 and angiogenin negatively correlated with pulmonary function, which suggests their important role in COPD airway remodelling. However, no additional angiogenic activation was found during exacerbation of COPD.

Anxiety and depression during hospital treatment of exacerbation of chronic obstructive pulmonary disease.

This study investigated the prevalence, risk factors and rate of recognition of anxiety and depression in 50 patients hospitalized for exacerbation of chronic obstructive pulmonary disease (COPD). Using the Primary Care Evaluation of Mental Disorders questionnaire, 13 patients were identified as having depression, four had anxiety and eight had a combination of the two. Patients with anxiety and/or depression had a significantly higher partial pressure of oxygen and pH, and a lower partial pressure of carbon dioxide, in arterial blood on admission, more severe dyspnoea after a 6-min walk test and less improvement of dyspnoea from admission to discharge than COPD patients without anxiety and/or depression. Two patients were referred to a mental health specialist during their hospitalization, indicating a low rate of recognition. The results suggest that patients with mental disorders are referred and admitted to hospital earlier in the course of a COPD exacerbation due to earlier and more intense perception of dyspnoea.

Airway angiogenesis in patients with rhinitis and controlled asthma.

BACKGROUND: Airway angiogenesis may be an important part of structural remodelling in the pathogenesis of asthma. The development of asthma is frequently preceded by rhinitis. OBJECTIVE: We sought to determine whether the levels of angiogenesis-related factors are elevated in airways of patients with rhinitis or controlled asthma. METHODS: We analysed the induced sputum of 18 rhinitis patients, 16 asthmatic patients, and 15 healthy controls. The concentrations of angiogenin, vascular endothelial growth factor (VEGF), IL-8, fibroblast growth factor (bFGF), and TNF-alpha were measured by cytometric bead arrays. RESULTS: We found significantly increased angiogenin and VEGF concentrations in the induced sputum supernatant of both rhinitis and asthma patients compared with that of the healthy control group (P< or =0.0005). With the exception of TNF-alpha, there was no difference in the other angiogenic factors; TNF-alpha levels were higher in the rhinitis group than in the control group (P=0.02). CONCLUSION: These in vivo results suggest increased airway angiogenesis in patients with rhinitis without asthma as well as in corticosteroid-treated and well-controlled asthma patients.

Circadian and concentration profile of cathepsin S in sera from healthy subjects and asthmatic patients.

Cathepsin S (CS) has been proposed to be associated with asthma pathogenesis but its exact role is not established. In order to understand this proposed association our objective was to follow the 24-h concentration pattern of CS in sera from apparently healthy subjects and from steroid-independent and steroid-dependent asthmatics before and after one weeks' treatment with methylprednisolone (MP) and cyclosporin A (CsA), respectively. Blood samples were collected every 4 h over a 24-h period. Statistical evaluation of data for time effect was performed by one way ANOVA and least-squares fit of 24-h cosine. Little or no significant change of CS concentrations with time over a 24-h period was observed in healthy and asthmatic sera. CS concentrations were significantly lower in steroid-independent asthmatics compared to controls while there was no difference between healthy subjects and steroid-dependent asthmatics. After one week of therapy MP decreased CS concentrations while CsA had no effect. Our data suggest the involvement of CS in asthma pathogenesis and the potential use of CS levels as an additional biological parameter for monitoring the extent of disease and response to therapy.

Serum concentration and circadian profiles of cathepsins B, H and L, and their inhibitors, stefins A and B, in asthma.

BACKGROUND: In order to determine the effect of asthma on serum concentrations of cathepsins B, H and L, and stefins A and B, the circadian and concentration profiles were followed in steroid-independent and steroid-dependent asthmatics before and after 1-week treatment with methylprednisolone and cyclosporin A. METHODS: Serum samples were taken at 4-h intervals throughout a 24-h period. Cathepsin and stefin concentrations were assayed using specific ELISAs. Data were analysed by one-way ANOVA and least squares fit of 24-h cosine. RESULTS: Temporal analysis of these proteins revealed little or no significant changes with time over a 24-h period. In comparison to normal sera, cathepsin H concentrations were elevated in all asthmatic patients, concentrations of both stefins were decreased in steroid-independent asthmatics, and stefin A concentrations were increased in steroid-dependent asthmatics before therapy. The effect of methylprednisolone treatment was demonstrated on decreased cathepsin B and increased cathepsin L concentrations in post-therapy serum samples. On the other hand, cyclosporin A treatment led to increased concentrations of cathepsins H and L. However, concentrations of stefins A and B were unaffected. CONCLUSIONS: This study associated alterations in balance of serum cysteine proteinases and their inhibitors in asthmatic patients, which has raised the possibility of their involvement in asthma pathogenesis. Validated rhythms of cathepsins and stefins in asthmatic sera exhibited temporal differences, which are too small to influence the time of sampling for their quantitative measurement over the course of a day.

Serum cystatin C, a potent inhibitor of cysteine proteinases, is elevated in asthmatic patients.

The effect of asthma pathogenesis on serum cystatin C, a potent inhibitor of cysteine proteinases and a newly proposed marker of the renal function, has not been yet determined. The objectives were to determine the 24-h pattern of cystatin C and creatinine concentrations in sera of asthmatic patients in order to test whether their concentrations might reflect circadian rhythms, the disease severity and the effect of therapy. Serum concentrations of cystatin C and creatinine were determined in steroid-independent and steroid-dependent asthmatics before and after 1 week of treatment with methylprednisolone and cyclosporin A, respectively. Samples were collected every 4 h during a 24-h period. Little or no significant effects of time on cystatin C and creatinine concentrations over a 24-h period were observed in healthy and asthmatic sera. However, significantly higher cystatin C concentrations were found in asthmatic patients compared to controls which suggests its role in the pathogenesis of asthma. Methylprednisolone increased and cyclosporin A decreased serum cystatin C concentrations after 1 week of therapy. Additionally these results support the need for the evaluation of cystatin C as a marker of glomerular filtration rate determination in asthma.

Montelukast versus salmeterol in patients with asthma and exercise-induced bronchoconstriction. Montelukast/Salmeterol Exercise Study Group.

BACKGROUND: Montelukast, a leukotriene receptor antagonist, and salmeterol, a long-acting beta(2)-receptor agonist, each have demonstrated benefits in the treatment of exercise-induced bronchoconstriction (EIB) in short-term studies. Direct comparisons between these agents in long-term studies are limited. OBJECTIVE: We sought to compare montelukast and salmeterol in the long-term treatment of EIB. METHODS: One hundred ninety-seven patients with mild asthma and a postexercise fall in FEV(1) of at least 18% were randomized (double-blind) to receive montelukast 10 mg once daily or salmeterol 50 microg twice daily for 8 weeks. Exercise challenge was repeated at day 3, week 4, and week 8 after randomization near the end of the dosing interval for both drugs. The primary efficacy endpoint was the maximal percent fall in postexercise FEV(1) at week 8. RESULTS: Montelukast was effective in treating EIB without inducing tolerance and provided superior (P

Flow cytometric analysis of lymphocytes isolated from nasal polyps.

We analyzed by flow cytometry the expression of IL-2 receptors (alpha subunit-CD25) and ICAM-1 adhesion molecules (CD54) on T cells and subsets (CD4, CD8) isolated from nasal polyp tissue in allergic and non-allergic patients. We found a significant increase in IL-2 receptor and ICAM-1 molecule expression on T cells isolated from nasal polyp tissue compared to peripheral blood lymphocytes. We also found a significantly increased expression of ICAM-1 molecules on CD8+ cells in non-allergic compared to allergic patients. The latter may reflect a difference in cytotoxic immune response between allergic and non-allergic patients, but the result should be confirmed in a more extensive study including cytokine and immunoglobulin analysis. We hope that it would enable us to obtain a deeper insight into the local immune events and further to clarify the etiology and pathogenesis of nasal polyps and their relation to allergy.

[Efficacy of the inhalation of warm mineral water from Moravci well MT-6 in patients with chronic obstructive lung disease]. / Proucavanje efikasnosti inhalacija termomineralne vode iz busotine MT-6 u Moravcima u bolesnika s hronicnim opstrukcionim plucnim obolenjem.

In 20 patients with chronic obstructive pulmonary disease (COPD) the effects of inhalation of Bisolvon (BS) were compared with the inhalations of thermomineral water of the well MT.6 of thermal spring Moravci (TMW). It was found that mean maximal expiratory flow during inhalations of TMW was statistically significantly higher from that during inhalation of BS (P less than 0.05). By visually-analogous scale the patients during inhalations of TMW were found to have statistically smaller dyspnea (P less than 0.001) and after inhalation of TMW they could expectorate much better (P less than 0.01) in comparison with the period of inhalations with BS. The authors consider the inhalations of TMW to be a good method of therapy of patients with COPD.

Evaluation of slow-release theophylline pharmacokinetics by Fourier's harmonic analysis.

Theophylline absorption from two sustained-release theophylline formulations was examined over 2 consecutive days during continuous therapy in 7 asthma patients. We compared two twice daily formulations of Teotard capsules (TC) and Teolin tablets (TT). Bioavailability for each 12-h period was defined as: BIO = (AUC oral/AUC iv) x (Dose iv/Dose oral)x100. The amount of theophylline absorbed during each 2-h interval was calculated using modified Wagner-Nelson equation for multiple dose drug administration. Mean serum theophylline concentrations were analysed by Fourier's harmonic analysis (FHA) and by F test. There were not statistically significant differences between TT and TC neither for BIO nor for fractional absorption calculated for 2-h sampling intervals. On the other hand FHA of mean SCT disclose more predictable theophylline absorption from TT compared to TC. We conclude that in order to obtain complete pharmacokinetic profile of slow-release formulation FHA should also be included into the calculations.

[Pharmacokinetics of Teolin 300 tablets and Teotard 350 capsules in asthma patients]. / Farmakokinetika tableta Teolin 300 i kapsula Teotard 350 u astmaticara.

Pharmacokinetics of tablets Teolin 300 (TT) and capsules Teotard 350 (TC) was studied in 7 asthma patients. Serum theophylline concentrations (SCT) were measured in 2-h intervals over 2 consecutive days for each theophylline formulation. A randomized, crossover design was used. In 12-h one dose of TT was absorbed 89.76 +/- 32.76% (means +/- SD) and TC 83.76 +/- 49.48%; between them there were statistically no differences. Amplitudes of SCT (AMP) were in the range 0.31 to 2.7 and mean 24-h SCT in the range 19.8 to 119.3 mumol/L. AMP were reproducible only to TT (r = 0.97, p less than 0.001). Fourier's harmonic analysis applied to mean SCT disclosed statistically significant 12-h oscillations only for TT (p less than 0.05). Continuous therapy with slow-release theophylline should always be monitored with measurements of SCT which should be interpreted by pharmacokinetics data of applied sustained theophylline formulation.

[Comparison of the results of transthoracic needle biopsy of the lungs using the Nordenström and the Rotex needles]. / Uporedenje rezultata pertorakalne iglene biopsije pluca iglom prema Nordenströmu i Rotex iglom.

In the diagnostics of nodular and infiltrative lung lesions in 28 patients the transthoracic needle biopsy of the lung was performed both by Nordenström and Rotex needle. In confirming the cancer, both needles were equally satisfactory. By Rotex needle the tissue sample was obtained also from hard lesions from which the tissue sample with Nordenström needle couldn't be obtained. By transthoracic needle biopsy of the lung the diagnosis of benign disease was confirmed in two patients with isolation of Mycobacterium tuberculosis from the sample obtained by Rotex needle.

[Effect of salbutamol administered directly by a nebulizer or by means of a spacer on bronchodilation]. / Bronhodilatacioni efekat salbutamola aplikovanog direktno rasprsivacem i preko spacera.

During three successive days in 14 patients with bronchial asthma after application of Salbutamol directly from the metered-dose inhaler (MDI) or indirectly by spacer the changes of FEF and FEV1 were measured. For inhalation through spacer the double blind crossover trial with placebo was used. Out of 12 patients three of them responded with better flows (FEV1, FEF) after inhalation via MDI. In 7 of them there were no significant differences between ways of application while in two of them the flows by spacer were significantly better. Tachypnea, low lung volumes as well as poor co-operation of the patient, especially elderly, should speak in favour of the use of spacer. However, in young, co-operative asthmatic patients the MDI is suitable. Further controlled studies of new applications of inhalation therapy should be studied.

[Modulation of nonspecific bronchial hyperreactivity]. / Modulacija nespecificne bronhijalne hiperreaktivnosti.

Nonspecific bronchial hyperresponsiveness (NBHR) is a typical characteristic of asthmatic patients. The impairment of NBHR is due to the airway inflammations caused by the viruses, irritants from the air and especially by specific allergens from natural and working environment. NBHR is diminished by elimination of inflammatory triggers as well as by antiinflammatory measures, the most important being inhalatory glucocorticoids which should be administered for long-term period in order to achieve the successful decrease of NBHR.

The effect of food on the bronchial response in adult asthmatic patients, and the protective role of ketotifen.

The bronchial response and haemolytic complement were monitored for 8 hours after challenge in 24 asthmatics giving positive oral provocation tests (OPT) to various food. Double-blind oral provocation tests were carried out in 16 asthmatics and open food challenge in 8. The food in question was milk (10 patients), flour (5 patients), eggs (4 patients), potatoes (2 patients), beans (1 patient), tomatoes (1 patient) and beer (1 patient). Five patients gave an immediate type bronchial response, the reduction in PEFR being greatest in the first hour. Eighteen patients showed a non-immediate type response, the maximum decrease in PEFR being observed in the second hour in 8 patients, in the third hour in 7 patients and in the fourth hour in 3 patients. In 4 of the asthmatic patients a dual type of bronchial reaction was observed. The onset of bronchial response and the time to maximum change in PEFR did not depend on the food ingested. An open study with Ketotifen was carried out in 14 asthmatics. The mean reduction in PEFR in response to repeated OPT was smaller than the reduction induced by the initial OPT (p less than 0.001). The results indicated that Ketotifen afforded effective protection against the bronchial response to food challenge in asthmatics. The study confirmed that ingested food, i.e. flour, milk and eggs, may provoke asthmatic dyspnoea in chronic adult asthmatic patients.