A follow-up survey of patients with acquired angioedema due to C1-inhibitor deficiency.

BACKGROUND: Acquired angioedema due to C1-inhibitor deficiency (C1-INH-AAE) is a rare form of bradykinin-mediated angioedema. It is diagnosed by complement testing; its treatment consists of the management of angioedema (AE) attacks and of underlying disease. OBJECTIVE: Evaluate the results of the clinical follow-up of patients with C1-INH-AAE. METHODS: Between 1999 and 2020, 3938 patients with angioedema were evaluated, and 17 diagnosed with acquired C1-INH deficiency were followed-up. RESULTS: Mean age of the 17 patients was 61 years at diagnosis. In 33%, ACE inhibitors provoked AE attacks. Autoantibodies against C1-INH were detected in 10 patients at diagnosis and in a further patient during follow-up. The AE attacks involved the skin in 70.6%, the upper airways in 41.2% and the tongue/lip in 52.9% of patients. Twelve of the 17 patients had an underlying condition, mainly (n = 11) lymphoproliferative disease. In 10 patients diagnosed with a haematological disorder, AAE symptoms preceded the onset of the latter. One patient has not experienced an AE attack since diagnosis. Twelve patients were treated for angioedema attacks, and 32% of the attacks required acute treatment. PdC1-INH was used to relieve AE attacks, and rituximab for the treatment of underlying disease (in six patients). Six patients had multiple AE attacks before any treatment. The symptom-free period increased in five patients after the on-demand administration of pdC1-INH concentrate and following treatment of the underlying disease in two patients. CONCLUSION: Early diagnosis of C1-INH-AAE and underlying disease is indispensable to reduce disease burden by introducing appropriate, individualized treatment and regular follow-up.

Systematic derivatization, mass fragmentation and acquisition studies in the analysis of chlorophenols, as their silyl derivatives by gas chromatography-mass spectrometry.

An exhaustive GC-MS sample preparation, derivatization, mass fragmentation and acquisition study was performed, for the simultaneous analysis of chlorophenols (CPs). Selected species were 2-CP, 3-CP, 4-CP, 3,5-dichlorophenol (diCP), 2,5-diCP, 2,6-diCP, 2,4-diCP, 2,3-diCP, 3,4-diCP 2,4,6-trichlorophenol (triCP), 2,4,5-triCP, 2,3,4-triCP, 2,3,4,6-tetrachlorophenol (tetraCP) and pentachlorophenol (pentaCP), in total 14 compounds. As novelties to the field, basic researches, like systematic derivatization, mass fragmentation and acquisition methods have been optimized for the trimethylsilyl (TMS) ether derivatives of CPs. The reactivity of chlorophenols with silylating agents has not been systematically analyzed. Here, we studied the reactivity of 14 chlorophenols with five silylating reagents. The three acquisition techniques, the full scan (FS), the multiple ion monitoring (MIM), and the currently optimized multiple reaction monitoring (MRM) methods, have been compared. We developed a new analytical approach, simultaneously monitoring the fragmentation pattern of the (35)Cl and the (37)Cl containing fragment ions both as precursor and as product ions. This principle resulted in remarkable specificity and sensitivity of detection and quantification; particularly in the cases of the tetraCP and pentaCP derivatives containing the (35)Cl and the (37)Cl fragment ions at an approximate ratio of <1:1. Detailed documentation of the loss of HCl via fragmentation processes, without decomposition of the benzene ring, was attributed to the "ring-walk" mechanism described first for monochlorophenol. Critical evaluation of the derivatization and acquisition protocols was collated and validated with the same characteristics. Data of six point calibration along with the corresponding relative standard deviation percentage (RSD%) values, in the line of FS, MIM and MRM methods (r(2): 0.9987, 0.9992, 0.9989; RSD%: 8.7, 5.6, 8.1), proved to be independent on the acquisition processes. The practical utility of the optimized MRM acquisition techniques was confirmed by the quantitation of the CP contents of Danube River, tap water and distilled water samples. Results confirmed at the first time the primary importance of the MRM acquisition method, even in comparison to the MIM one: we revealed that distilled water contains higher chlorophenol content than tap water, which might have a great significance for the water industry.

The role of the acquisition methods in the analysis of natural and synthetic steroids and cholic acids by gas chromatography-mass spectrometry.

An exhaustive GC-MS acquisition study was performed, for the simultaneous analysis of natural and synthetic steroids and cholic acids (in order to insert them into the last tierce of our multiresidue analysis system), such as androsterone, ß-estradiol, transdehydroandro-sterone, transdehyroandrosterone, mestranol, dihydrotestosterone, ethinylestradiol, testosterone, norethisterone, estriol, 4-androstene-3,17-dione, gestodene, levonorgestrel, etonogestrel, coprostanol, progesterone, cholesterol, medroxyprogesterone-acetate, lithocholic acid, stigmasterol, cholic acid, chenodeoxycholic acid, ß-sitosterol, ursodeoxycholic acid, 3-hydroxy-7-ketocholic acid and dehydrocholic acid, in total 26 compounds. As novelties to the field, for the trimethylsilyl (TMS) oxime ether/ester derivatives of steroids and cholic acids, at first, a tandem mass spectrometric (MS/MS), multiple reaction monitoring (MRM) type acquisition method has been developed in a single run; also for the first time, the three acquisition techniques, the full scan (FS), the selective ion monitoring (SIM), in our case the multiple ion monitoring (MIM) and the currently optimized MRM methods, have been compared; all three, in parallel, under strictly the same derivatization/instrumental conditions, both in matrix free solutions and municipal wastewater from two Hungarian wastewater treatment plants (WWTPs). Critical evaluation of the three acquisition protocols was collated on their analytical performances and validated under the same conditions. The data of six point calibration curves for FS, MIM and MRM methods, showed that both R² (0.9995, 0.9858, 0.9975) and RSD (5.3, 5.8, 5.0), for two parallel derivatizations, each injected three times, proved to be independent of the acquisition processes. Whereas, for the method limit of quantification (LOQ) and the instrument limit of quantification (ILQ) values showed considerable differences. LOQ data, were decreasing in the FS, MIM, MRM line (expressed in ng/L), for all steroids and cholic acids. The same trend was determined in terms of the ILQ values. The practical utility of the optimized acquisition techniques was confirmed by the quantitation of the steroids and cholic acids contents of wastewater samples. Results confirmed the importance of the MRM acquisition method, even in comparison to the MIM one: with particular interest in selected cases: avoiding the extreme overestimation of the ß-estradiol (156-1325%) and that of the ethinylestradiol (582-831%) concentrations in the wastewater samples.

Derivatization and fragmentation pattern analysis of natural and synthetic steroids, as their trimethylsilyl (oxime) ether derivatives by gas chromatography mass spectrometry: analysis of dissolved steroids in wastewater samples.

This paper reports the extension of our multiresidue analysis (MA) procedure with 18 natural and synthetic steroids; permitting the identification and quantification, in total of 81 pollutants from one solution, by a single injection, as their trimethylsilyl (TMS)-oxime ether/ester derivatives, by gas chromatography-mass spectrometry (GC-MS), within 31 min. As a novelty to the field, basic researches, such as fragmentation pattern analysis and derivatization optimization studies were performed for androsterone, transdehydroandrosterone, transandrosterone, mestranol, dihydrotestosterone, ethinylestradiol, testosterone, norethisterone, estriol, 4-androstene-3,17-dione, gestodene, levonorgestrel, etonogestrel, coprostanol, progesterone, cholesterol, medroxy-progesterone-acetate, stigmasterol and ß-sitosterol. Results confirmed that (i) the TMS oxime-ether derivatives of the keto steroids provide from 1.40 times (gestodene) up to 4.25 times (norethisterone) higher responses compared to their TMS-ether ones, and (ii) the distribution of syn/anti oximes is characteristic to the ketosteroid species examined. Based on our optimized mass fragmentation, solid phase extraction (SPE) and derivatization studies separations have been performed in the total ion current (TIC) mode, identification and quantification of compounds have been carried out on the basis of their selective fragment ions. Responses, obtained with derivatized standards proved to be linear (hydroxysteroids), or have been calculated from calibration curves (ketosteroids) in the range of 1.88-750ng/L levels. Limit of quantitation (LOQ) values varied between 1.88ng/L and 37.5ng/L concentrations. The most important practical messages of this work are the high androsterone (0.744-4.28µg/L), transandrosterone (0.138-4.00µg/L), coprostanol (2.11-302µg/L), cholesterol (0.308-41µg/L), stigmasterol (1.21-8.40µg/L) and ß-sitosterol (1.12-11.0µg/L) contents of influent wastewaters. ß-Estradiol (100ng/L) and estriol (54ng/L) were found in one influent sample, only. Reproducibilities, characterized with the relative standard deviation percentages (RSD%) of measurements, varied between 1.73 RSD% (ß-estradiol) and 5.4 RSD% (stigmasterol), with an average of 4.82 RSD%.