Rheological effects of hypertonic saline and sodium bicarbonate solutions on cystic fibrosis sputum in vitro.

BACKGROUND: Cystic fibrosis (CF) is a life-threatening multiorgan genetic disease, particularly affecting the lungs, where recurrent infections are the main cause of reduced life expectancy. In CF, mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein impair transepithelial electrolyte and water transport, resulting in airway dehydration, and a thickening of the mucus associated with abnormal viscoelastic properties. Our aim was to develop a rheological method to assess the effects of hypertonic saline (NaCl) and NaHCO3 on CF sputum viscoelasticity in vitro, and to identify the critical steps in sample preparation and in the rheological measurements. METHODS: Sputum samples were mixed with hypertonic salt solutions in vitro in a ratio of either 10:4 or 10:1. Distilled water was applied as a reference treatment. The rheological properties of sputum from CF patients, and the effects of these in vitro treatments, were studied with a rheometer at constant frequency and strain, followed by frequency sweep tests, where storage modulus (G'), loss modulus (G″) and loss factor were determined. RESULTS: We identified three distinct categories of sputum: (i) highly elastic (G' > 100,000 Pa), (ii) elastic (100,000 Pa > G' > 1000 Pa), and (iii) viscoelastic (G' < 1000). At the higher additive ratio (10:4), all of the added solutions were found to significantly reduce the gel strength of the sputum, but the most pronounced changes were observed with NaHCO3 (p < 0.001). Samples with high elasticity exhibited the greatest changes while, for less elastic samples, a weakening of the gel structure was observed when they were treated with water or NaHCO3, but not with NaCl. For the viscoelastic samples, the additives did not cause significant changes in the parameters. When the lower additive ratio (10:1) was used, the mean values of the rheological parameters usually decreased, but the changes were not statistically significant. CONCLUSION: Based on the rheological properties of the initial sputum samples, we can predict with some confidence the treatment efficacy of each of the alternative additives. The marked differences between the three categories suggest that it is advisable to evaluate each sample individually using a rheological approach such as that described here.

Novel duplication in the F12 gene in a patient with recurrent angioedema.

Edema formation is mediated by histamine or bradykinin release and may have several hereditary and acquired causes. In hereditary forms of bradykinin-mediated angioedemas, mutations in the genes encoding C1-inhibitor (SERPING1) as well as coagulation factor XII (F12) have been described. We present a novel F12 gene mutation, a duplication of 18 base pairs (c.892_909dup) in a 37-year-old woman with recurrent angioedema and normal C1-inhibitor level. A single episode of facial edema in the family of the patient showed co-segregation with the mutation. This duplication is causing the repeated presence of 6 amino acids (p.298-303) in the same region of factor XII, as those three mutations described previously in cases of hereditary angioedema with normal C1-INH function. These results may confirm the importance of the proline-rich region of factor XII protein in edema formation.

[Genetic revision of the Hungarian Cystic Fibrosis Registry]. / A magyar Cystás Fibrosis Regiszter genetikai revíziója.

INTRODUCTION: Cystic fibrosis (CF) is one of the most common monogenic diseases. Genetic testing is becoming increasingly reasoned to establish or confirm the diagnosis by detecting abnormal mutations. OBJECTIVE: In order to develop a diagnostic strategy for cystic fibrosis and to facilitate mutation-specific treatments, the genetic revision of the Hungarian Cystic Fibrosis Registry was performed. METHOD: 582 patients' data and samples were used for the revision (528 originally included in the register and 54 received during the revision). First we reviewed the patients' existing genetic findings. Wherever necessary, a comprehensive three-level genetic analysis of the CFTR gene was done. RESULTS: According to our study, of the 528 patients present in the Registry, 395 (74.8%) had 2 pathogenic CFTR mutations. We completed and corrected 94 patients' previously incomplete genetic status. 73 different pathogenic variants were described, in which 1 aberration was not previously reported (c.3130G>A). The 5 most common mutations were: F508del (68.4%); CFTRdele2,3 (3.7%); G542X (3.2%); 2184insA (2.7%); W1282X (2.3%). Based on genotype and age, in Hungary 211 patients are eligible for the available lumacaftor-ivacaftor combination therapy, and 361 patients for the ivacaftor-tezacaftor-elexacaftor therapy. CONCLUSION: Due to the revision, we could identify the patients who can benefit from mutation-specific drugs instead of symptomatic therapy. In addition, the data obtained have been used to map the Hungarian distribution of mutations in the CFTR gene, which will help to develop a diagnostic strategy. Orv Hetil. 2022; 163(51): 2052-2059.

[Role of the TNF system in the pathomechanism of bronchial asthma]. / A tumornecrosis faktor (TNF) rendszer szerepe az asthma bronchiale patomehanizmusában.

INTRODUCTION: The activation of the TNF system during asthmatic attack has already been proved. AIMS: The aim of the study was to reveal the role of the tumor necrosis factor (TNF) system in the pathomechanism of bronchial asthma. PATIENTS/METHODS: Childhood asthmatic lately symptom-free adults (n:39) and their non-asthmatic offspring were examined (n:42). According to the methacholin airway challenge test, patients were divided into bronchial hyperreactive (n:44) and non-hyperreactive (n:37) groups. Tumor necrosis factor alpha (TNF-alpha) and its soluble receptors 55 (sTNF-R1) and 75 kDa (sTNF-R2) were measured by ELISA. RESULTS: Among the hyperreactive patients (n:44) significantly higher TNF-alpha (mean +/- SD: 5.13 +/- 1.37 vs. 3.91 +/- 0.61 pg/ml, p < 0.0001), sTNF-R1 (mean +/- SD: 1.37 +/- 0.28 vs. 1.16 +/- 0.13 ng/ml, p = 0.0002) and sTNF-R2 (mean +/- SD: 0.78 +/- 0.42 vs. 0.43 +/- 0.41 ng/ml, p < 0.0001) values were measured compared to the non-hyperreactives (n:37). In hyperreactive patients there was a significant correlation between the cytokine and cytokine receptor levels (TNF-alpha-sTNF-R1 p = 0.0184, r = 0.3541; TNF-alpha-sTNF-R2 p < 0.0001, r = 0.6468). Significant negative correlation was detected between the serum TNF-alpha and sTNF-R2 concentrations and PD20 FEV1 methacholin (dose of methacholin resulting in a 20% reduction of forced exspiratory volume in 1 second) in hyperreactive patients. CONCLUSION: According to our results the activation of the TNF system may contribute to the bronchial hyperreactivity. It can be observed in asthmatic patients having been symptom-free for years and in their non-asthmatic offspring as well. These results refer to the presence of a minimal allergic inflammation.