Neven Tudorić

Decrease in CD23+ B Lymphocytes and Clinical Outcome in Asthmatic Patients Receiving Specific Rush Immunotherapy

Rush immunotherapy (RIT) has been documented as useful in the treatment of patients with allergic bronchial asthma. To investigate the mechanisms of its action, we studied changes in the serum levels of total IgE, allergen-specific IgE and IgG4, and expression of CD23 on peripheral blood B cells in patients receiving RIT. Twenty patients with perennial bronchial asthma were evaluated before the beginning of RIT, as well as 6 weeks and 6 months later. Compared to pretreatment values, the level of Der-p-specific IgG4 and IgE significantly increased after 6 weeks and 6 months of RIT, while the total serum IgE remained unchanged. Furthermore, after 6 months of RIT, the percentage of CD23+B cells and its CD23 receptor density significantly decreased. Since the symptom score improved and the need for medication decreased, we evaluated RIT as a useful procedure. After 6 months, 30% of patients did not have an asthma attack, with no medication in the last month, while 10% of them were asthma free for the last 3 months. No significant correlation between the clinical improvement, and in vitro changes was found. Furthermore, the observed in vitro changes were not significantly different in patients who responded with clinical improvement, compared to those with unchanged intensity of asthma. In conclusion, during specific RIT we found a significant increase in Der-p-specific IgE and IgG4 antibodies, as well as a moderate decrease in CD23+ B cells and its CD23 receptor density. These findings suggest a change in the lymphokine profile of patients receiving specific immunotherapy, and that the inhibition of IL-4-induced B cell stimulation may be hypothesized as the most important mechanism.

Effects of halothane and isoflurane on antigen‐ and leukotriene‐D4‐induced constriction of guinea pig trachea

We investigated the mechanism of the action of volatile anesthetics on the airway smooth muscle constricted by an antigen and leukotriene‐D4 (LTD4).

Phosphoramidon augments contraction of guinea pig tracheal smooth muscle induced by histamine and leukotriene-D4

Our previous studies have shown that the inhibition of neutral endopeptidase, an enzyme which degrades tachykinins, increases anaphylactic contraction of guinea pig tracheal smooth muscle. Anaphylactic release of tachykinin-like substances was indicated. To investigate this observation further, we examined the effects of phosphoramidon, an inhibitor of a neutral endopeptidase, on contraction induced by mediators of anaphylaxis. Phosphoramidon significantly increased histamine- and leukotriene D4-induced contractions of tracheal rings from unsensitized animals (by 14 and 48%, respectively), but failed to alter the contractile responses to prostaglandins D2 and F2 alpha. In tracheal rings preincubated with tachykinin antagonist-[D-Pro4, D-Trp7,9]-substance P(4-11), or in capsaicin-desensitized tracheal rings, phosphoramidon did not change histamine- and leukotriene D4-induced contractions. In the second part of the study, performed on tracheal rings obtained from ovalbumin-sensitized guinea pigs, we examined the effects of phosphoramidon on contractile responses to histamine and leukotrienes which are released after antigen challenge. The incubation of tracheal rings with H1-histamine receptor antagonist (diphenhydramine HCl) or leukotriene receptor antagonist (ICI 198.615) prevented a phosphoramidon-dependent increase of antigen-induced contraction. These results indicate that histamine and leukotrienes may be involved in the anaphylactic release of tachykinin-like substances or other neutral endopeptidase substratum.

Intraregional differences in asthma prevalence and risk factors for asthma among adolescents in Split-Dalmatia County, Croatia

Summary Background Our aim was to assess the differences in intraregional prevalence of asthma in adolescents in Split-Dalmatia County to determine asthma risk factors in our population and estimate the specificity and sensitivity of the questionnaire used. Material/Methods We conducted the study using the European Community Respiratory Health Survey II short questionnaire supplemented by some questions from the International Study of Asthma in Childhood questionnaire. The participants suspected to have asthma were invited for examination by an asthma specialist who established the final diagnosis of asthma according to the medical history, physical examination, skin-prick tests, and peak flow measurements. Results A total of 4027 students (51.2% male) participated in the study. According to the prevalence of wheezing during the last 12 months, asthma prevalence was estimated at 9.7%. The total prevalence of asthma confirmed by an asthma specialist in the selected population was 5.60% (95% CI, 4.93–6.36%); 6.18% in Split (95% CI, 5.37–7.09), 5.63% in Imotski (95% CI, 3.48–8.58), and 2.90% in Sinj (95% CI, 1.67–4.68) (P=0.0028). We found sensitization to aeroallergens and peanuts, and active smoking to be independent risk factors for asthma. Conclusions Split-Dalmatia County has moderate asthma prevalence, with a significant intraregional difference. Asthma prevalence estimated by a questionnaire (9.7%) overestimates the prevalence of asthma confirmed by an asthma specialist (5.6%) in adolescents in Croatia. Our data confirmed the need of a more complex questionnaire to evaluate the accurate prevalence of current asthma or the need for subsequent clinical evaluation of the questionnaire obtained data. Allergic sensitization to aeroallergens and active smoking were important risk factors for asthma.

Inhibition of neutral endopeptidase augments anaphylactic constriction of guinea pig tracheal smooth muscle.

To determine whether tachykinins participate in antigen-induced constriction of tracheal smooth muscle, we examined the effects of a neutral endopeptidase inhibitor, phosphoramidon, the tachykinin antagonist (D-Pro4, D-Trp7,9,10)-substance P(4-11), and capsaicin-induced tachykinin depletion on the responses to antigen in tracheal rings from ovalbumin-sensitized guinea pigs. In these preparations, the antigen (ovalbumin, 0.1 microgram/ml) produced reproducible and durable constriction of tracheal smooth muscle. Incubation with phosphoramidon (10 min, 10 microM) prior to antigen challenge significantly augmented the magnitude of ovalbumin-induced constriction by 22% after 30 min and by 31% after 45 min. The addition of phosphoramidon at the plateau level of antigen-induced constriction produced a similar, significant increase in the magnitude of the constriction. Following incubation with tachykinin antagonist (D-Pro4,D-Trp7,9,10)-substance P(4-11) (5 microM), the contractile response of the tracheal rings to the antigen was not altered. Furthermore, the addition of phosphoramidon (10 microM) did not significantly affect this contraction. Similarly, neither tachykinin antagonist nor phosphoramidon altered the ovalbumin-induced constriction of the tracheal rings from capsaicin-treated guinea pigs. Based on these findings, we hypothesize that tachykinins or similar broncho-constricting neutral endopeptidase substrates were released from tachykinin-containing nerve endings during immediate hypersensitivity reaction in airways, manifesting a modest and delayed constrictive effect. Following alteration of endopeptidase activity, these substances could modulate the anaphylactic constriction of the airway smooth muscle.

Phosphoramidon Modulates Effects of the 5-Lipoxygenase Inhibition on Anaphylactic Contraction of the Guinea Pig Trachea

Our previous studies have shown that the inhibition of neutral endopeptidase, an enzyme which degrades tachykinins, increases anaphylactic contraction of guinea pig tracheal smooth muscle. It was suggested that anaphylactic release of tachykinin-like substances is likely to be responsible for the observed increases in tracheal contractions. To obtain additional information on the mechanisms responsible for anaphylactic release of tachykinins in guinea pig trachea, we examined the effects of phosphoramidon, an inhibitor of neutral endopeptidase, on contractile response to antigen after preincubation with the selective 5-lipoxygenase inhibitor AA-861. AA-861 (5 microM) significantly reduced ovalbumin-induced contraction, although the effect was not constant. A marked spontaneous increase in contraction was observed. Phosphoramidon (10 microM) produced significant increase of this contraction (27% after 30 min, and 33% after 45 min). The addition of H1-histamine receptor antagonist (diphenhydramine HCl, 10 microM) produced additional inhibition of the initial phase of antigen-induced contraction, while its later phase, apart from a spontaneous increment in magnitude, remained similar. Phosphoramidon (10 microM) increased the contraction by 26% after 30 min, and by 34% after 45 min. Since the effects of histamine and 5-lipoxygenase pathway products were prevented, we hypothesize that cyclooxygenase pathway products are responsible for the phosphoramidon-dependent increase in antigen-induced contraction. In accordance with previously reported ineffectiveness of contractile prostaglandins, we suggest that the relaxant prostaglandins are most important in mediating the release of tachykinins during the immediate hypersensitivity reaction in guinea pig trachea.

Evaluation of nutritional status, disease severity and anxiety/depression in COPD patients with different exercise capacity

Background: Reduced physical activity and nutritional status abnormalities are frequent in patients with chronic obstructive pulmonary disease (COPD). Aim: To compare disease severity, daily physical activity, nutritional and psychological status in COPD patients with normal and poor exercise capacity (EC). Methods: Patients (n = 91) with moderate to very severe COPD were included in this cross-sectional study. Six-minute walk distance (6MWD) ® . Results: Patients with poor EC had lower forced expiratory volume in 1 sec (FEV 1 ), higher CAT score, worse dyspnea, lower lean and fat-free mass index, bone mineral content, bone mineral density (BMD), T-score, MNA score, lower daily step count, and higher HADS-Depression score (all comparisons p 1 (OR=1.073, p=0.012) and BMD (OR=2.866, p=0.039) were independently and significantly associated to better EC. Conversely, older age (OR=0.834, p=0.004) and higher mMRC dyspnea level (OR=0.137, p=0.001) decrease the probability of normal EC. Conclusion: Not only severity of COPD, age and low physical activity impact the EC, but also nutritional status is an important factor that has to be considered, especially in patients with impaired EC.