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Background In about 5% of patients with hereditary angioedema due to C1-inhibitor deficiency (C1-INH-HAE) no mutation in the SERPING1 gene is detected. Methods C1-INH-HAE cases with no mutation in the coding region of SERPING1 after conventional genotyping were examined for defects in the intronic or untranslated regions of the gene. Using a next-generation sequencing (NGS) platform targeting the entire SERPING1, 14 unrelated C1-INH-HAE patients with no detectable mutations in the coding region of the gene were sequenced. Detected variants with a global minor allele frequency lower than the frequency of C1-INH-HAE (0.002%), were submitted to in silico analysis using ten different bioinformatics tools. Pedigree analysis and examination of their pathogenic effect on the RNA level were performed for filtered in variants. Results In two unrelated patients, the novel mutation c.-22-155G > T was detected in intron 1 of the SERPING1 gene by the use NGS and confirmed by Sanger sequencing. All bioinformatics tools predicted that the variant causes a deleterious effect on the gene and pedigree analysis showed its co-segregation with the disease. Degradation of the mutated allele was demonstrated by the loss of heterozygosity on the cDNA level. According to the American College of Medical Genetics and Genomics 2015 guidelines the c.-22-155G > T was curated as pathogenic. Conclusions For the first time, a deep intronic mutation that was detected by NGS in the SERPING1 gene, was proven pathogenic for C1-INH-HAE. Therefore, advanced DNA sequencing methods should be performed in cases of C1-INH-HAE where standard approaches fail to uncover the genetic alteration.

Hereditary angioedema (HAE) is a rare inherited autosomal dominant disease caused by deficiency or dysfunction of C1 inhibitor (C1INH). Clinical symptoms include recurrent subcutaneous and submucosal angioedema of the internal organs. Abdominal attacks affect more than 90% of patients, are often misdiagnosed and result in unnecessary surgical procedures.To analyse the utility of imaging studies (USG, CT) in patients with C1INH-HAE during an abdominal attack and remission.We enrolled 40 patients with type I and II HAE (30 women, 10 men; mean age 39 years). The diagnosis of C1INH-HAE was based on patient and family history, significantly reduced values of C1INH serum level and activity. Abdominal and pelvic ultrasound were performed in patients within the first 6 h of the abdominal attack and repeated during remission. Moreover, 23 cases underwent abdominal or pelvic computed tomography during acute abdominal symptoms. The most common ultrasound and CT findings showed the transient presence of a significant amount of fluid in the free abdominal cavity and intestinal oedema during the symptom progression and spontaneously disappearing during the seizure in 90% and 50% of patients, respectively. CT revealed also an enlargement of the mesenteric lymph nodes as well as a fat stranding along the bowel wall thickening.Ultrasound or CT imaging facilitates the diagnosis of the patient suspected of having an abdominal attack due to C1INH-HAE. They allow to identify transitional presence of an abundant fluid in the free abdominal cavity and intestinal swelling which spontaneously disappear with a symptoms attack.

The ‘Wieliczka’ Salt Mine with specific stable, microclimatic conditions is a unique place, where pulmonary and allergy-related diseases are treated. The aim of this study was to determine the occurrence of biological particles in the air of the ‘Wieliczka’ Salt Mine in relation to the location and time. Twenty measurements were taken quarterly in 2012–2016, in four salt chambers. The volumetric and impact methods were used to measure microbiological contamination, while the mite and cat allergens were measured using FEIA assay. The statistically significant differences among the study sites and time of measurements, treated as the following seasons, for spores and bacteria were found. Pollen grains were observed in the underground chambers rarely and in significantly lower quantities than outdoors. No statistically significant differences between the content of Der p1 and Fel d1 allergens among the study locations, seasons and patient presence/absence were found. The qualitative content of micro-organisms in the air of salt chambers seems to be related to the biological material carrying in by patients and staff.

SERPING1 genotyping of subjects suspicious for hereditary angioedema due to C1-INH deficiency (C1-INH-HAE) is important for clinical practice as well as for research reasons. Conventional approaches towards the detection of C1-INH-HAE-associated SERPING1 variants are cumbersome and time-demanding with many pitfalls. To take advantage of the benefits of next-generation sequencing (NGS) technology, we developed and validated a custom NGS platform that, by targeting the entire SERPING1 gene, facilitates genetic testing of C1-INH-HAE patients in clinical practice. In total, 135 different C1-INH-HAE-associated SERPING1 variants, out of the approximately 450 reported, along with 115 negative controls and 95 randomly selected DNA samples from affected family members of C1-INH-HAE index patients, were included in the forward and reverse validation processes of this platform. Our platform's performance, i.e. analytical sensitivity of 98.96%, a false negative rate of 1.05%, analytical specificity 100%, a false positive rate equal to zero, accuracy of 99.35%, and repeatability of 100% recommends its implementation as a first line approach for the genetic testing of C1-INH-HAE patients or as a confirmatory method. A noteworthy advantage of our platform is the concomitant detection of single nucleotide variants and copy number variations throughout the whole length of the SERPING1 gene, moreover providing information about the size and the localization of the latter. During our study, 15 novel C1-INH-HAE-related SERPING1 variants were detected.

[b]Abstract Introduction and objective[/b]. Gluten proteins (gliadins and glutenins) are polymorphic wheat storage proteins of allergenic properties. Significant differences in chemical composition between both protein groups allow to expect highly specific immunological response of individual subunits and fractions in reactions with IgE sera of people allergic to wheat. The aim of these studies was to identify and characterize the most allergenic gluten proteins (GP) and nongluten proteins (NGP) occurred in two closely related wheat hybrid genotypes. [b]Materials and method.[/b] 3xC and 3xN wheat hybrids, which differ strongly in regard of gliadin composition, were analyzed. Seven people manifesting different symptoms of wheat allergy donated sera for the experiment. The technique of immunoblotting after SDS-PAGE was used for identification of allergenic subunits and fractions among GP and NGP. Immunologically active protein bands were visualized by chemiluminescence. [b]Results[/b]. Great variation of immunodetection spectra was observed. Results of immunoblotting showed LMW glutenins to be of highest, gliadins of medium, while NGP of lowest allergenicity for selected patients. The 43-kDa and 47-kDa LMW glutenin subunits, 40-kDa and 43-kDa γ-gliadin fractions and 49-kDa NGP can be considered as the most immunoreactive among all protein bands [b]separated by SDS-PAGE. Conclusion [/b] The observed differentiation of immunodetection spectra allows to model highly specific IgE-binding profiles of allergenic wheat proteins attributed to individual patients with symptoms of gluten intolerance. Highly immunoreactive subunits and fractions among GP and NGP were identified. The observed immunoreactivity of 49 kDa NGP is worth to emphasize, as it has never been reported as wheat allergenic protein before.

Background: Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) may affect health-related quality of life (HRQoL). A specific HRQoL questionnaire for adult patients with C1-INH-HAE, the HAE-QoL, has recently been developed in Spain. Objective: The objective of this study was to perform a cross-cultural validation and psychometric study of the HAE-QoL in an international setting. Methods: Cross-cultural adaptation of the Spanish HAE-QoL draft version and an international rating phase with experts were performed. The resultant version of the HAE-QoL, a clinical questionnaire, and Short Form 36-item Health Survey Version 2.0 (SF-36v2) were pilot tested internationally. Item reduction was based on both descriptive and exploratory factor analysis. Psychometric properties were assessed. Results: Cross-cultural adaptation of the HAE-QoL was performed in 18 countries. The draft version of the HAE-QoL was pilot tested in 332 patients, and accurate data were obtained from 290 patients from 11 countries. The reduction process resulted in a new version with 25 items and 7 dimensions (treatment difficulties, physical functioning and health, disease-related stigma, emotional role and social functioning, concern about offspring, perceived control over illness, and mental health). Strong psychometric properties were observed (Cronbach´s α 0.92; test-retest reliability 0.87). Convergent validity showed mild to moderate correlations with SF-36v2 physical and mental component summaries (0.45 and 0.64, respectively) and with SF-36v2 dimensions (P < .004). HAE-QoL scores discriminated significantly among severity groups (median: asymptomatic 133.5 vs severe 84.0; P < .001); between patients with and without long-term prophylaxis (median: 101 vs 90; P = .001); and between patients with and without psychiatric and/or psychological care (median: 74 vs 103; P ≤ .001). Conclusions: The HAE-QoL, currently available in 18 languages, showed good reliability and validity evidence. Fil: Prior, Nieves. Hospital Universitario Severo Ochoa; España Fil: Remor, Eduardo. Universidad Autónoma de Madrid; España Fil: Pérez Fernández, Elia. Fundacion Hospital Alcorcon; España Fil: Caminoa, Magdalena. Instituto de Investigacion Hospital Universitario la Paz ; España Fil: Gómez-Traseira, Carmen. Instituto de Investigacion Hospital Universitario la Paz ; España Fil: Gayá, Francisco. Instituto de Investigacion Hospital Universitario la Paz ; España Fil: Aabom, Anne. Odense University Hospital; Dinamarca Fil: Aberer, Werner. Medical University; Austria Fil: Betschel, Stephen. Saint Michael's Hospital; Canadá Fil: Boccon Gibod, Isabelle. Joseph Fourier University; Francia. Grenoble University Hospital; Francia Fil: Bouillet, Laurence. Joseph Fourier University; Francia. Grenoble University Hospital; Francia Fil: Bygum, Anette. Odense University Hospital; Dinamarca Fil: Csuka, Dorottya. Semmelweis University; Hungría Fil: Farkas, Henriette. Semmelweis University; Hungría Fil: Gomide, Maria. Universidade de Sao Paulo; Brasil Fil: Grumach, Anete. Universidade de Sao Paulo; Brasil Fil: Leibovich, Iris. Chaim Sheba Medical Center; Israel Fil: Malbrán, Alejandro. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud "Dr. C. G. Malbrán"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Moldovan, Dumitru. Mures County Hospital; Rumania Fil: Mihaly, Eniko. Mures County Hospital; Rumania Fil: Obtulowicz, Krystyna. Jagiellonian University; Polonia Fil: Perpén, Cecilia. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud "Dr. C. G. Malbrán"; Argentina Fil: Peveling Oberhag, Adriane. University Medical Center Mainz; Alemania Fil: Porebski, Grzegorz. Jagiellonian University; Polonia Fil: Chavannes, Celine Rayonne. Saint Michael's Hospital; Canadá Fil: Reshef, Avner. Chaim Sheba Medical Center; Israel Fil: Staubach, Petra. University Medical Center Mainz; Alemania Fil: Wiednig, Michaela. Medizinische University; Austria Fil: Caballero, Teresa. Instituto de Investigacion Hospital Universitario la Paz ; España

Introduction: Hereditary angioedema (HAE) is a genetic disease caused by C1-esterase inhibitor deficiency, characterized by recurrent attacks of intense, massive, localized subcutaneous oedema that can involve all parts of the body. The aim of this study is a comparison of the clinical effectiveness of conestat alfa, human C1 esterase inhibitor (C1INH) and icatibant in the treatment of acute angioedema attacks in adults with HAE. Materials and methods: A systematic review of literature published up to May 2012 was performed to assess the efficacy and safety of conestat alfa, C1INH and icatibant in the treatment of acute angioedema attacks in adults with HAE. Databases were searched at MEDLINE (PubMed), EMBASE and Cochrane. The general search structure was designed as a combination of keywords or synonyms: (hereditary angioedema) AND (conestat alfa OR human C1 esterase inhibitor concentrate or synonyms OR icatibant). Only randomized clinical studies were selected. Results: Systematic review yielded no clinical trials directly comparing the therapeutic options mentioned. Two randomized clinical trials were found which compared each of the following: conestat alfa, C1INH and icatibant with placebo. Based on the gathered evidence it was demonstrated that taking any of the medicinal substances mentioned in the treatment of acute angioedema attack results in a shorter time to the start of symptom relief and the time to reduce symptoms, the probability of treatment response after 4 hours is increased and the safety profile is comparable to placebo. Conclusions: Due to the significant heterogeneity of the identified trials, the scientific evidence available was insufficient to identify the most effective therapeutic option in the treatment of acute oedemas in HAE.

Introduction Hereditary angioedema (HAE) is caused by mutations in the C1inh gene, leading to dysfunction of the C1-esterase inhibitor (C1-INH). C1-INH interacts with MASP-1 and MASP-2 proteases, participating in the mannan-binding lectin (MBL) pathway of complement activation. The aim of the study was to investigate the contribution of possible changes in MBL/MASP-2 complex activity and Helicobacter pylori, hepatitis B virus (HBV), and hepatitis C virus (HCV) infections to the severity and frequency of clinical symptoms of HAE. Materials and Methods The study was performed in 65 patients with HAE and 113 healthy persons. The parameters measured were C1-INH, C4, MBL concentration and MBL/MASP-2 complex activity, and serological markers of H. pylori, HBV, and HCV infection. Scores for the frequency and severity of HAE symptoms were determined. Results HAE scores were significantly higher in patients whose C1-INH activity did not exceed 10% than in patients with activity of 10-52% (p=0.016). No significant differences were found in the median levels of MBL concentration and MBL/MASP-2 complex activity between patients and the control group. There was a slight association between contact with H. pylori in patients and HAE symptom score (p=0.052, not significant). Adult patients showed a 2.6-times higher frequency of anti-HBc than the general population. HBV DNA was negative in anti-HBc(+) patients. Conclusions These results suggest that the MBL complement activation pathway itself does not contribute to the frequency of angioedema attacks. Infections with H. pylori and HBV may slightly influence the disease score (not significant).

Background: Patients with hereditary C1-inhibitor deficiency have recurrent attacks of angioedema, preferably treated with C1-inhibitor concentrate. A recombinant human C1-inhibitor (rHuC1INH) was developed, derived from milk from transgenic rabbits. This study was undertaken to investigate the effects of rHuC1INH in the treatment of acute angioedema attacks in patients with a hereditary C1-inhibitor deficiency. Study Design and Methods: Patients with hereditary C1-inhibitor deficiency were treated with rHuC1INH (at a dose of 100 U/kg) within 8 hours after onset of an acute attack. Time to initiation of relief and time to minimal symptoms were reported by both the patient and the treating physician. Results: Thirteen severe angioedema attacks in 9 patients with hereditary C1-inhibitor deficiency were treated with rHuC1INH. There was rapid improvement of clinical conditions for all attacks, with approximately 80 percent of treated patients experiencing symptom relief within 2 hours and minimal symptoms within 12 hours. There were no drug-related adverse events or immunogenic reactions to C1-inhibitor or rabbit proteins. Conclusion: The transgenically produced rHuC1INH was successfully used in the treatment of acute angioedema attacks in patients with hereditary C1-inhibitor deficiency.