Role of Sphingolipids in the Pathobiology of Lung Inflammation

Sphingolipid bioactivities in the respiratory airways and the roles of the proteins that handle them have been extensively investigated. Gas or inhaled particles or microorganisms come into contact with mucus components, epithelial cells, blood barrier, and immune surveillance within the airways. Lung structure and functionality rely on a complex interplay of polar and hydrophobic structures forming the surfactant layer and governing external-internal exchanges, such as glycerol-phospholipids sphingolipids and proteins. Sphingolipids act as important signaling mediators involved in the control of cell survival and stress response, as well as secreted molecules endowed with inflammation-regulatory activities. Most successful respiratory infection and injuries evolve in the alveolar compartment, the critical lung functional unit involved in gas exchange. Sphingolipid altered metabolism in this compartment is closely related to inflammatory reaction and ceramide increase, in particular, favors the switch to pathological hyperinflammation. This short review explores a few mechanisms underlying sphingolipid involvement in the healthy lung (surfactant production and endothelial barrier maintenance) and in a selection of lung pathologies in which the impact of sphingolipid synthesis and metabolism is most apparent, such as acute lung injury, or chronic pathologies such as cystic fibrosis and chronic obstructive pulmonary disease. A Brief Overview on Sphingolipids within the Lung Environment The interest in sphingolipid presence and bioactivities in the respiratory airways has produced a steady number of reports since the 1970s. However, a host of publications in the last few years have provided an increasingly detailed picture of the role played in the lungs by this class of lipids and by the proteins that handle them. As vital respiratory organs that mediate air-blood gas exchanges, lungs must undergo delicate and tightly controlled developmental transitions. Antenatally, a 20-week human fetus displays lungs that have branched to generate all airways, but it is not before ∼28 weeks of gestation that alveolarization begins from primordial saccular structures and type I alveolar cells differentiate from the cuboidal epithelium. Concomitantly, at this stage endothelial cells shape the alveolar capillary bed and type II alveolar cells appear, to demarcate alveolar septal junctions. Type II cells start producing surfactant, which accumulates to increasing concentrations by term. The initiation of autonomous ventilation at birth represents a dramatic switch in postnatal lung function. While throughout gestation a chloride-ion driven liquid secretion creates a positive pressure that distends the lungs and stimulates growth, a sudden reversal from net secretion to net adsorption takes place at birth under the effect of O 2 and hormones (epinephrine, glucocorticoids, and thyroid hormones), enabling the rapid elimination of lung liquid. From this moment on, lung lumen will maintain a low-level chloride-ion based liquid secretion to generate a surface liquid layer, known as surfactant and formed by specific secreted lipids and proteins, and a robust absorptive capacity will prevent alveolar flooding and edema. Equally important, being permanently exposed to inhaled particles and microorganisms from birth, pulmonary immunity must be tuned to effectively dispose of them, while minimizing immunopathology to preserve appropriate gas exchange. Thus, the first-line lung defenses, prior to immunity, are based on mechanical weapons including cilia, mucus, and the cough reflex, which concur to prevent pathogen access to the lower airways and in so doing avoid an overt inflammatory response. This is one of the major reasons why lungs are particularly sensitive to the sphingolipid (and Hindawi Publishing Corporatio

Infant immunization coverage in Italy (2000-2016)

BackgroundIn Italy, national-level immunization polices are included in the National Immunization Prevention Plan (PNPV), whose latest edition - 2017-2019 PNPV- was approved in February 2017. Immunization coverage is a key measure of immunization system performance; it can inform and support national and regional immunization polices’ implementation monitoring, as well as measure the impact of interventions aimed at increase vaccine uptake. MethodsWe collected, analysed and critically interpreted 2000-2015 Italian national infant immunization coverage trends, by different vaccine, target population, and by Region. Data were provided by the Directorate General for Prevention of the Italian Ministry of Health.ResultsIn 2015, none of mandatory or recommended vaccines reached the 95% national coverage target set in the PNPV. Weighted average national coverage for mandatory vaccines (against polio, tetanus, diphtheria, hepatitis B) and other antigens included in the hexavalent vaccine (pertussis, and Haemophilus influenzae type b) in 2015 was 93.3%; it was lower for measles, mumps and rubella vaccines (85.2%), pneumococcal (88.7%) and meningococcal C conjugate vaccines (76.6%), with a high degree of heterogeneity by Region. Both hexavalent and MMR vaccines coverage rates have been decreasing since 2012, with an annual decrease of, respectively 1% and 1.5%.DiscussionFurther efforts are needed to increase vaccine uptake in Italy, to improve data collection and reporting, as well as to fight the growing phenomenon of the vaccine hesitancy so that PNPV objectives and target can be met in the near future.Ep

Myriocin modulates the altered lipid metabolism and storage in cystic fibrosis.

Cystic fibrosis (CF) is a hereditary disease mostly related to ΔF508 CFTR mutation causing a proteinopathy that is characterized by multiple organ dysfunction, primarily lungs chronic inflammation, and infection. Defective autophagy and accumulation of the inflammatory lipid ceramide have been proposed as therapeutic targets. Accumulation of lipids and cholesterol was reported in the airways of CF patients, together with altered triglycerides and cholesterol levels in plasma, thus suggesting a disease-related dyslipidemia. Myriocin, an inhibitor of sphingolipids synthesis, significantly reduces inflammation and activates TFEB-induced response to stress, enhancing fatty acids oxidation and promoting autophagy. Myriocin ameliorates the response against microbial infection in CF models and patients' monocytes. Here we show that CF broncho-epithelial cells exhibit an altered distribution of intracellular lipids. We demonstrated that lipid accumulation is supported by an enhanced synthesis of fatty acids containing molecules and that Myriocin is able to reduce such accumulation. Moreover, Myriocin modulated the transcriptional profile of CF cells in order to restore autophagy, activate an anti-oxidative response, stimulate lipid metabolism and reduce lipid peroxidation. Moreover, lipid storage may be altered in CF cells, since we observed a reduced expression of lipid droplets related proteins named perilipin 3 and 5 and seipin. To note, Myriocin up-regulates the expression of genes that are involved in lipid droplets biosynthesis and maturation. We suggest that targeting sphingolipids de novo synthesis may counteract lipids accumulation by modulating CF altered transcriptional profile, thus restoring autophagy and lipid metabolism homeostasis

SARS-CoV-2/COVID-19 Testing: The Tower of Babel

Background and aim: Testing represents one of the main pillars of public health response to SARS-CoV-2/COVID-19 pandemic. This paper shows how accuracy and utility of testing programs depend not just on the type of tests, but on the context as well. Methods: We describe the testing methods that have been developed and the possible testing strategies; then, we focus on two possible methods of population-wide testing, i.e., pooled testing and testing with rapid antigen tests. We show the accuracy of split-pooling method and how, in different pre-test probability scenarios, the positive and negative predictive values vary using rapid antigen tests. Results: Split-pooling, followed by retesting of negative results, shows a higher sensitivity than individual testing and requires fewer tests. In case of low pre-test probability, a negative result with antigen test could allow to rule out the infection, while, in case of a positive result, a confirmatory molecular test would be necessary. Conclusions: Test performance alone is not enough to properly choose which test to use; goals and context of the testing program are essential. We advocate the use of pooled strategies when planning population-wide screening, and the weekly use of rapid tests for close periodic monitoring in low-prevalence populations

Knowledge and beliefs on vaccines among a sample of Italian pregnant women: results from the NAVIDAD study

BACKGROUND: Vaccine hesitancy is an emerging phenomenon in European countries and leads to decreasing trends in infant vaccine coverage. The aim of this study was to analyze the level of confidence and correct awareness about immunizations, which are crucial for the success of vaccination programmes. METHODS: As part of the NAVIDAD multicentre study, we examined vaccination confidence and complacency among a sample of 1820 pregnant women from 14 Italian cities. The questionnaire assessed the interviewee's knowledge, beliefs and misconceptions, as well as their socioeconomic status, information sources about vaccines and confidence in the Italian National Healthcare Service. RESULTS: Only 9% of women completely believed to the efficacy, necessity and safety of vaccinations. Almost 20% of them had misconceptions on most of the themes. There was a significant difference in the level of knowledge considering educational level: women with a high educational level have less probability of obtaining a low knowledge score (odds ratio (OR) 0.43 [95% confidence interval (CI) 0.34-0.54]). The level of knowledge was also influenced by the sources of information: women who received information from their general practitioner (GP) and from institutional websites had a significantly lower chance of having misconceptions (OR 0.74 [95% CI 0.58-0.96]; OR 0.59 [95% CI 0.46-0.74]). Finally, the results underlined the influence of trust in healthcare professional information on the likelihood of having misconceptions (OR 0.49 [95% CI 0.27-0.89]). CONCLUSIONS: The data suggest the efficacy of GPs and institutional websites as a source of information to contrast misconceptions and underline the importance of confidence in the healthcare system to increase complacency and confidence in vaccines

Metformin +/- cyclic fasting mimicking diet in combination with platinum-pemetrexed chemotherapy for advanced LKB1 inactive lung adenocarcinoma: The FAME trial

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The interplay among psychopathology, personal resources, context-related factors and real-life functioning in schizophrenia: stability in relationships after 4 years and differences in network structure between recovered and non-recovered patients

Improving real-life functioning is the main goal of the most advanced integrated treatment programs in people with schizophrenia. The Italian Network for Research on Psychoses previously explored, by using network analysis, the interplay among illness-related variables, personal resources, context-related factors and real-life functioning in a large sample of patients with schizophrenia. The same research network has now completed a 4-year follow-up of the original sample. In the present study, we used network analysis to test whether the pattern of relationships among all variables investigated at baseline was similar at follow-up. In addition, we compared the network structure of patients who were classified as recovered at follow-up versus those who did not recover. Six hundred eighteen subjects recruited at baseline could be assessed in the follow-up study. The network structure did not change significantly from baseline to follow-up, and the overall strength of the connections among variables increased slightly, but not significantly. Functional capacity and everyday life skills had a high betweenness and closeness in the network at follow-up, as they had at baseline, while psychopathological variables remained more peripheral. The network structure and connectivity of non-recovered patients were similar to those observed in the whole sample, but very different from those in recovered subjects, in which we found few connections only. These data strongly suggest that tightly coupled symptoms/dysfunctions tend to maintain each other's activation, contributing to poor outcome in schizophrenia. Early and integrated treatment plans, targeting variables with high centrality, might prevent the emergence of self-reinforcing networks of symptoms and dysfunctions in people with schizophrenia

The interplay among psychopathology, personal resources, context-related factors and real-life functioning in schizophrenia: stability in relationships after 4 years and differences in network structure between recovered and non-recovered patients

Improving real-life functioning is the main goal of the most advanced integrated treatment programs in people with schizophrenia. The Italian Network for Research on Psychoses previously explored, by using network analysis, the interplay among illness-related variables, personal resources, context-related factors and real-life functioning in a large sample of patients with schizophrenia. The same research network has now completed a 4-year follow-up of the original sample. In the present study, we used network analysis to test whether the pattern of relationships among all variables investigated at baseline was similar at follow-up. In addition, we compared the network structure of patients who were classified as recovered at follow-up versus those who did not recover. Six hundred eighteen subjects recruited at baseline could be assessed in the follow-up study. The network structure did not change significantly from baseline to follow-up, and the overall strength of the connections among variables increased slightly, but not significantly. Functional capacity and everyday life skills had a high betweenness and closeness in the network at follow-up, as they had at baseline, while psychopathological variables remained more peripheral. The network structure and connectivity of non-recovered patients were similar to those observed in the whole sample, but very different from those in recovered subjects, in which we found few connections only. These data strongly suggest that tightly coupled symptoms/dysfunctions tend to maintain each other's activation, contributing to poor outcome in schizophrenia. Early and integrated treatment plans, targeting variables with high centrality, might prevent the emergence of self-reinforcing networks of symptoms and dysfunctions in people with schizophrenia