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BACKGROUND AND AIMS: Aging is associated with an increased risk of developing atherosclerosis. Subjects over 80 years of age without cardiovascular disease provide a model to investigate the protective factors increasing their resistance to atherosclerotic disease. Platelet-activating factor acetylhydrolase (PAF-AH) is an enzyme associated with low density lipoprotein (LDL) and high density lipoprotein (HDL) inactivating plateletactivating factor (PAF) and preventing LDL oxidation by hydrolysis of oxidized phospholipids. The aim of the present study was to evaluate the contribution of the PAFAH gene Arg92His, Ile198Thr and Ala379Val polymorphisms to resistance toward developing cardiovascular events in healthy Sicilian octogenarians. METHODS: Distribution of PAF-AH genotypes and activity, and biochemical parameters, were compared between 100 octogenarians and 200 healthy adults. RESULTS: The individuals in the elderly group displayed significantly higher levels of HDL-C (p<0.001) and plasma (p<0.001) and HDL (p<0.001) PAF-AH activity. Analysis of PAFAH genotype distributions showed no significant differences between octogenarians and controls. No differences among PAF-AH genotypes with respect to plasma and HDL PAF-AH activity were found in either group. CONCLUSIONS: Our results provide no evidence of a significant association between the PAF-AH gene Arg92His, Ile198Thr and Ala379Val polymorphisms and successful aging in Sicilians. They also emphasize that, in these subjects, aging is characterized by increased levels of PAF-AH activity and HDL-C. [ABSTRACT FROM AUTHOR]

Cystic fibrosis (CF) is a genetic disorder that alters chloride transport in mucous membranes. Recent studies have demonstrated that treatment with modulators of the chloride channel reduces inflammatory markers, restoring, among others, the imbalance of lipids. In this study, we analyzed the serum samples of treated and non-treated patients with modulators with Raman spectroscopy. Nineteen (eight treated an eleven non-treated) patients were considered. The main difference between the two groups appeared in the 3020-2800 cm -1 range. A Voigt deconvolution fit was performed, and nine sub-bands were identified. To distinguish between treated and non-treated patients, the area ratio between the CH 3 and CH 2 vibration modes was calculated for each patient. The results were validated using statistical analyses. In particular, receiver operating characteristic (ROC) curves and Youden index (Y) were calculated (Area Under Curve (AUC): 0.977; Y: 3.30). An ROC curve represents the performance of the classification, illustrating the diagnostic ability of Raman spectroscopy. It was demonstrated that Raman spectroscopy is able to highlight peculiar differences between elexacaftor/tezacaftor/ivacaftor (ETI)-treated and non-treated patients, in relation with lipids biomarkers.

Background: Cystic fibrosis is caused by mutations impairing expression, trafficking, stability and/or activity of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. The G1244E mutation causes a severe gating defect that it is not completely rescued by ivacaftor but requires the use of a second compound (a co-potentiator). Recently, it has been proposed that the corrector elexacaftor may act also as a co-potentiator., Methods: By using molecular, biochemical and functional analyses we performed an in-depth characterization of the G1244E-CFTR mutant in heterologous and native cell models., Results: Our studies demonstrate that processing and function of the mutant protein, as well as its pharmacological sensitivity, are markedly dependent on cell background. In heterologous expression systems, elexacaftor mainly acted on G1244E-CFTR as a co-potentiator, thus ameliorating the gating defect. On the contrary, in the native nasal epithelial cell model, elexacaftor did not act as a co-potentiator, but it increased mature CFTR expression possibly by improving mutant's defective stability at the plasma membrane., Conclusions: Our study highlights the importance of the cell background in the evaluation of CFTR modulator effects. Further, our results draw attention to the need for the development of novel potentiators having different mechanisms with respect to ivacaftor to improve channel activity for mutants with severe gating defect., Competing Interests: Conflicts of Interest The authors declare no conflict of interest., (Copyright © 2022. Published by Elsevier B.V.)

Background: C3 glomerulonephritis is a rare glomerulopathy characterized at renal biopsy by C3 deposition, alone or with scanty immunoglobulins, as well as by an electron-dense material in mesangium, subendothelial and subepithelial space. An abnormal systemic activation of the alternative pathway of the complement cascade is responsible for the development of the disease if triggered by several possible environmental conditions. We report the first case in literature of a patient affected by cystic fibrosis and C3GN., Case Presentation: Our case involves a young woman with cystic fibrosis, who had persistent microscopic hematuria, proteinuria and hypocomplementemia C3 for over three months. Renal biopsy confirmed the diagnosis of C3 glomerulopathy. Complement system dysregulation was tested and resulted in a strong terminal pathway activation proved by high levels of sC5b-9 complex, amounting to 1588 ng/ml (normal value < 400 ng/ml). Next generation sequencing (NGS) showed polymorphism in CFH (p.V62I in SCR1) and THBD (p.A473V), already known as pathogenic for C3GN, as well as a mutation in C3 (p.R102G) associated only with age-related macular degeneration (AMD) so far. Treatment was based on ACE inhibitors and kidney function is currently stable (GFR 50 ml/min, serum creatinine 1.7)., Conclusions: The co-existence of C3 glomerulopathy in a patient with CF, which is characterized by chronic infection/inflammation, makes this case an interesting model of chronic altered systemic activation of the alternative pathway of the complement cascade.

Objective: Cystic fibrosis (CF) is the most common autosomal recessive disease affecting the Caucasian population, with a birth incidence ranging between 1:2,500 and 1:1,800. It is caused by mutations in the CF transmembrane regulator gene which is localized on 7 chromosomes. Renal disease is reported as a relatively rare complication in adult patient with CF. We evaluated proteinuria and chronic renal failure (CRF) in a population of patients with CF., Methods: A retrospective study was carried out in a referral center for CF at University of Messina in Italy. We identified all patients with renal disease, characterized by proteinuria and/or CRF, during the period 2007 to 2012 and reviewed their medical records to assess influence on renal disease of genotype, number of pulmonary exacerbation, pancreatic insufficiency, pulmonary function, CF-related diabetes, and antibiotics courses., Results: From a population of 77 adult patients with CF, we identified 9 patients with proteinuria (11.7%), and 11 patients (14.28%) with CRF. Mean age was 35.6 (+5.1 standard deviation) years, 55% were female and 33% had diabetes mellitus. Renal biopsy was performed in 3 patients because of nephrotic syndrome in 1 patient and proteinuria with renal failure in the other 2 patients. Renal amyloidosis was disclosed in 2, whereas IgA nephropathy in 1 patient. The ΔF508 mutation in homozygosis was present in 44% of patients with proteinuria (vs. 27% of our CF population, relative risk 2.07), whereas genotype ΔF508/N1303K in 22%. ΔF508 allele mutation was present in 77.7% of proteinuric patients., Conclusions: Our study shows a higher prevalence of renal disease in patients with CF, than was previously described. The main reason may be related to increased life expectancy because of better management. Moreover, patients with ΔF508 homozygosis had higher risk of proteinuria., (Copyright © 2017 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Some studies have shown a direct relationship between nutritional status and survival in Cystic Fibrosis (CF) patients. Body wasting, defined as a percentage of the ideal body weight for age, has been shown to be an independent predictor of mortality in CF. With respect to height only two studies were performed and these studies suggested that stunting is an important determinant of survival but both did not adjust statistical analysis for confounding variables. We aimed at determining the association between stunting and risk of mortality in CF patients., Methods: 393 CF patients older than 6 years of age, 95 deceased, as cases, and 298 live, as controls, were enrolled in a nested case-control study. Stunting was defined by a height percentile < 5th. We performed a multivariate statistical analysis including height percentile and the following possible confounding variables: age, gender, Body Mass Index (BMI), Forced Expiratory Volume in 1 s (FEV1), genotype, pancreatic status, CF-related diabetes, colonization with Pseudomonas aeruginosa and/or Burkholderia cepacia., Results: In the adjusted analyses stunting (OR 2.22 [IC 95%1.10-4.46]), wasting (OR 5.27 [IC 95% 2.66-10.41]), and FEV1 < 40% of predicted (OR 10.60 [IC 95% 5.43-20.67]) resulted the covariates that significantly predict the risk of mortality., Conclusions: Our study shows, for the first time, that stunting is a significant and independent risk factor for mortality in CF patients, and warrants an intervention of nutritional rehabilitation. Considering that nutritional interventions in stunted patients should be prolonged, are invasive and expensive, and might affect self-esteem and body image, their efficacy should be fully assessed by Randomised Controlled Trials., (Copyright © 2012 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Purpose: The aim of this study was to assess the incidence of late onset complications of totally implantable venous access devices (TIVAD) in patients with cystic fibrosis (CF) and to investigate possible associations between the rate of complications and different policies of TIVAD management., Methods: A multicenter prospective cohort study was performed in 11 Italian CF Centers. Patients with CF and a TIVAD were recruited and followed-up., Results: The study commenced on May 2008 and ended on September 2010. Eighty subjects were studied (77.5% women--mean age 27.2 years). Eighteen late complications of ports were observed (22.5%; incidence 0.96 per 1000 days of observation): three lumen occlusions, seven catheter-related infections , three port-related venous thrombosis, in addition to five other complications. A statistically significant association was found between the onset of catheter-related infection and the presence of CF-related diabetes (CFRD) (P=.0064), Conclusions: Our data suggest that TIVADs represent a safe and effective device for the intermittent IV administration of drugs in people with CF. However, people with CFRD have a higher risk of developing TIVAD-related infection.

Background: Atherosclerosis is a complex, chronic disease that usually arises from the converging action of several pathogenic processes, including hypertension, hyperlipidemia, obesity, and the accumulation of oxidized LDL. Platelet-activating factor acetylhydrolase (PAF-AH) is a LDL- and HDL-bound enzyme that hydrolyzes and inactivates PAF and prevents LDL-cholesterol oxidation, thus delaying the onset of atherosclerotic disease., Methods: We evaluated the relationship between variants of the PAF-AH gene polymorphisms Arg92His, Ile198Thr, and Ala379Val and the presence of carotid atherosclerosis in 190 hypercholesterolemic Sicilian individuals. Carotid artery intima-media wall thickness (IMT) was measured as an indicator of early atherosclerotic disease. The participants were classified according to having normal (< or =1 mm) or abnormal (> or =1 mm) IMT and were also investigated for physical characteristics and biochemical indices, including PAF-AH activity., Results: PAF-AH activity and LDL concentrations were significantly correlated in hypercholesterolemic patients, but plasma PAF-AH activity and HDL were not significantly correlated in either IMT group. No significant differences were detected among the PAF-AH gene polymorphisms in both groups after correction for age, sex, body mass index, plasma glucose and lipid concentrations, PAF-AH activity, blood pressure, and smoking habits. The analysis of PAF-AH genotype distribution showed no significant differences in percentage of 92, 198, and 379 genotypes in both IMT groups., Conclusion: Our data provided no evidence that PAF-AH polymorphisms influence PAF-AH activity and atherosclerosis in hypercholesterolemic Sicilian patients.