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Newborn screening for Cystic Fibrosis (CF) is associated with situations where the diagnosis of CF or CFTR related disorders (CFTR-RD) cannot be clearly ruled out.We report a case series of 23 children with unconclusive diagnosis after newborn screening for CF and a mean follow-up of 7.7 years (4-13). Comprehensive investigations including whole CFTR gene sequencing, in vivo intestinal current measurement (ICM), nasal potential difference (NPD), and in vitro functional studies of variants of unknown significance, helped to reclassify the patients.Extensive genetic testing identified, in trans with a CF causing mutation, variants with varying clinical consequences and 3 variants of unknown significance (VUS). Eighteen deep intronic variants were identified by deep resequencing of the whole CFTR gene in 13 patients and were finally considered as non-pathogenic. All patients had normal CFTR dependent chloride transport in ICM. NPD differentiated 3 different profiles: CF-like tracings qualifying the patients as CF, such as F508del/D1152H patients; normal responses, suggesting an extremely low likelihood of developing a CFTR-RD such as F508del/TG11T5 patients; partial CFTR dysfunction above 20% of the normal, highlighting a remaining risk of developing CFTR-RD such as F508del/F1052V patients. The 3 VUS were reclassified as variant with defective maturation (D537N), defective expression (T582I) or with no clinical consequence (M952T).This study demonstrates the usefulness of combining genetic and functional investigations to assess the possibility of evolving to CF or CFTR-RD in babies with inconclusive diagnosis at neonatal screening.

(1) Background: Pulmonary exacerbation (PEx) is one of the main factors affecting the quality of life and life expectancy in patients with cystic fibrosis (CF). Our study aimed to evaluate the change in selected pulmonary function parameters, including lung clearance index (LCI), in patients with CF diagnosed with PEx. (2) Methods: We enrolled 40 children with CF aged 6–17. They performed spirometry and multiple breath nitrogen washout (MBNW) tests during a stable condition period at the beginning and the end of intravenous antibiotic treatment. (3) Results: LCI increased by 65% and FEV1 decreased by ≥10% in 40% of patients with CF during PEx. An absolute change in LCI between a stable condition period and PEx was 1.05 (±1.92) units, which corresponds to a relative change of 11.48% (±18.61) of the baseline. The relative decrease in FEV1 was −9.22% (±12.00) and the z-score was −0.67 (±1.13). After the PEx treatment, FEV1 increased by 11.05% (±9.04) on average, whereas LCI decreased by 1.21 ± 1.59 units on average, which represented 9.42% ± 11.40 compared to the value at the beginning of PEx. (4) Conclusions: The change in LCI captures a higher proportion of events with functional impairment than FEV1 in school-age children with CF.

Introduction Lung disease in cystic fibrosis (CF) begins early in life but the capabilities for detecting abnormalities of pulmonary dysfunction in children remain limited. Objective The study aimed to evaluate the early progression of lung function by the analysis of pulmonary hyperinflation, ventilation inhomogeneity (VI), trapped gas and airway obstruction with age. Methods One hundred CF children aged 7 to 18, divided into two groups aged 7 to 12 (n = 40) and 13 to 18 (n = 60), were enrolled. Patients performed multiple-breath nitrogen washout (MBNW) tests and plethysmography for measurements of lung clearance index (LCI), functional residual capacity (FRCpleth , FRCMBNW ), volume of trapped gas (VT ), total resistance, and effective and specific effective airway resistance (Reff , sReff ). Results We obtained a positive correlation of FRCpleth , FRCMBNW , and LCI with age. A linear correlation between FRCMBNW and FRCpleth (P 2 (z-score) was present in 58% of all subjects (50% and 63.3%, respectively). Pulmonary hyperinflation (FRCpleth >2 z-score) was observed in 33% of all patients: 25% and 36.6%, respectively. Trapped gas (VT > 2 z-score) was present in 18% of all children: 30% and 10%, respectively. Conclusion A gradual decline in lung function is associated with an increase in VI, airway obstruction, pulmonary hyperinflation and development of trapped gas. In children who cannot perform either spirometry or plethysmography, MBNW can deliver a measurement of LCI connecting with VI as well as FRCMBNW to indicate indirectly the increase of hyperinflation.

The impact of infections caused by bacteria, especially Gram-negative, on the progression of lung disease in cystic fibrosis is well established. Decline in pulmonary function commence already at early age. In this group of patients, the lung clearance index seems to be a better marker than FEV1 allowing non-invasive monitoring of changes in small airways. The aim of this study was to investigate the association between the microbiological status and LCI derived from multiple breath washout (MBW) technique as well as FEV1 and FVC in children suffering from cystic fibrosis. Over the 1-year recruitment period, 136 CF patients aged 5-18 with: Staphylococcus aureus (n-27), Pseudomonas aeruginosa (first time (n-27), intermittent (n-9), and chronic (34) infection), Aspergillus fumigatus (n-6) and without pathogenic flora (n-33) were included in the study. Patients had performed a spirometry and MBW test during the visit at outpatient clinic. The study showed that the lung clearance index in patients infected with Aspergillus fumigatus was significantly higher (P 70% and FEV1 < 70%. In conclusion, LCI was associated with microbiological status of CF patients. Chronic lung infections, especially Aspergillus fumigatus and Pseudomonas aeruginosa, were associated with increased LCI. Early eradication of pathological flora positively affects the maintenance of lower LCI.

This study is a continuation of a research program aimed at identifying potent drugs against bacterial infections, in which a series of organic compounds: dicarboxylic acid imides and thioimides, isoquinoline derivatives and open chain compounds, were examined for antimicrobial properties against Staphylococcus auneus and Escheiichia coli. In effect of this investigation, the most active compounds (35-40, 47) were selected for in vitiv tests against fourteen clinically important pathogenic isolates, the methicillin resistant Staphylococcus aueus (MRSA) and several reference Gram-negative bacteria: Prteus vulgaris, Pseudomonas aeruginosa, Klebsiella pneumonia, Stenonophoinonas inaltophilia, and Acinetobacter baumannii. The obtained data revealed that seven compounds (three dithioimides, 35, 39, 47, and four thioimides, 36-38, 40) exhibit effective antibacterial activity against the tested Staphylococcus auirus MSSA and MRSA strains. Among them, dicarboxylic acid thioimides 37 and 38 were proven to be the most active.

Secondary metabolites obtained from Actinomycetales provide a potential source of many new antibacterial, antitumour, antifungal, antiviral, antiparasitic compounds and others. The majority of discovered substances are widely used as medicines for combating multidrug-resistant Gram-positive and Gram-negative bacterial strains, as well as in veterinary practice, agriculture and industry. Members of the Streptomyces genus are outstanding producers of already known secondary metabolites. In our study we isolated a new metabolite from Streptomyces badius fermentation broth. This compound, 2-acetamido-5-hydroxybenzoic acid (1) was already described in literature, however, not yet discovered as Streptomyces badius product. The compound was firstly isolated from fermentation broth and purified by chromatography methods (ion exchange resin DowexWX40, Solid Phase Extraction C18 Polar Plus; HPLC, dC18). Then, the chemical structure of metabolite was determined by 1H NMR, 13C NMR and 2D homo- and heteronuclear (1H-13C HSQC, 1H-13C HMBC) NMR. The molecular formula of (1), C9H9NO4 was identified by high resolution ESI-MS. The chemical structure was analyzed by the UV and IR methods, as well. Biological activities of 2-acetamido-5-hydroxybenzoic acid were evaluated. The compound shows moderate DD-peptidase 64-575 inhibitory activity as well as antioxidative properties (ABTS radical scavenging). Such chemical moiety may serve as model compound for further modern drug discovery and be a source of active substance in anti-ageing cosmetics.

Secondary metabolites obtained from Actinomycetales provide a potential source of many novel compounds with antibacterial, antitumour, antifungal, antiviral, antiparasitic and other properties. The majority of these compounds are widely used as medicines for combating multidrug-resistant Gram-positive and Gram-negative bacterial strains. Members of the genus Streptomyces are profile producers of previously-known secondary metabolites. Actinomycetes have been isolated from terrestrial soils, from the rhizospheres of plant roots, and recently from marine sediments. This review demonstrates the diversity of secondary metabolites produced by actinomycete strains with respect to their chemical structure, biological activity and origin. On the basis of this diversity, this review concludes that the discovery of new bioactive compounds will continue to pose a great challenge for scientists.

N-acetyl-3,4-dihydroxy- L -phenylalanine, a second identified bioactive metabolite produced by Streptomyces sp. 8812

A series of 3,4-dihydroisoquinoline-3-carboxylic acid derivatives were synthesised and tested for their free-radical scavenging activity using 2,2-diphenyl-1-picrylhydrazyl radical (DPPH·), 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radical (ABTS·+), superoxide anion radical (O2·−) and nitric oxide radical (·NO) assays. We also studied d-amino acid oxidase (DAAO), acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activity. Almost each of newly synthesised compounds exhibited radical scavenging capabilities. Moreover, several compounds showed moderate inhibitory activities against DAAO, AChE and BuChE. Compounds with significant free-radical scavenging activity may be potential candidates for therapeutics used in oxidative-stress-related diseases.