Ventilation, oxidative stress and risk of brain injury in preterm newborn

Preterm infants have an increased risk of cognitive and behavioral deficits and cerebral palsy compared to term born babies. Especially before 32 weeks of gestation, infants may require respiratory support, but at the same time, ventilation is known to induce oxidative stress, increasing the risk of brain injury. Ventilation may cause brain damage through two pathways: localized cerebral inflammatory response and hemodynamic instability. During ventilation, the most important causes of pro-inflammatory cytokine release are oxygen toxicity, barotrauma and volutrauma. The purpose of this review was to analyze the mechanism of ventilation-induced lung injury (VILI) and the relationship between brain injury and VILI in order to provide the safest possible respiratory support to a premature baby. As gentle ventilation from the delivery room is needed to reduce VILI, it is recommended to start ventilation with 21-30% oxygen, prefer a non-invasive respiratory approach and, if mechanical ventilation is required, prefer low Positive End-Expiratory Pressure and tidal volume

Oxidative stress and respiratory diseases in preterm newborns

Premature infants are exposed to an increased generation of reactive oxygen species, and on the other hand, they have a deficient antioxidant defense system. Oxidative insult is a salient part of lung injury that begins as acute inflammatory injury in respiratory distress disease and then evolves into chronic and structural scar leading to bronchopulmonary dysplasia. Oxidative stress is also involved in the pathogenesis of pulmonary hypertension in the newborn through the modulation of the vascular tone and the response to pulmonary vasodilators, with consequent decrease in the density of the pulmonary vessels and thickening of the pulmonary arteriolar walls. Oxidative stress has been recognized as both a trigger and an endpoint for several events, including inflammation, hypoxia, hyperoxia, drugs, transfusions and mechanical ventilation, with im-pairment of pulmonary function and prolonged lung damage. Redoxomics is the most fascinating new measure to address the lung damage due to oxidative stress. The new challenge is to use omics data to discover a set of biomarkers useful in diagnoses, prognoses and in formulating optimal and individualized neonatal care. The aim of this review was to examine the most recent evidences on the relationship between oxidative stress and lung diseases in preterm newborns. What is cur-rently known regarding oxidative stress related- lung injury pathogenesis and the available preventive and therapeutic strategies are also discusse

Design, Synthesis, and in Vitro Evaluation of 4-(4-Hydroxyphenyl)piperazine-Based Compounds Targeting Tyrosinase

Melanin biosynthesis is enzymatically regulated by tyrosinase (TYR, EC 1.14.18.1), which is efficiently inhibited by natural and synthetic phenols, demonstrating potential therapeutic application for the treatment of several human diseases. Herein we report the inhibitory effects of a series of (4-(4-hydroxyphenyl)piperazin-1-yl)arylmethanone derivatives, that were designed, synthesised and assayed against TYR from Agaricus bisporus (AbTYR). The best inhibitory activity was predominantly found for compounds bearing selected hydrophobic ortho-substituents on the aroyl moiety (IC50 values in the range of 1.5–4.6 μM). They proved to be more potent than the reference compound kojic acid (IC50=17.8 μM) and displayed competitive mechanism of inhibition of diphenolase activity of AbTYR. Docking simulation predicted their binding mode into the catalytic cavities of AbTYR and the modelled human TYR. In addition, these compounds displayed antioxidant activity combined with no cytotoxicity in MTT tests. Notably, the best inhibitor affected tyrosinase activity in α-MSH-stimulated B16F10 cells, thus demonstrating anti-melanogenic activity

Rational design of small molecules able to inhibit α-synuclein amyloid aggregation for the treatment of Parkinson's disease

Parkinson's disease is one of the most common neurodegenerative disorders in elderly age. One of the mechanisms involved in the neurodegeneration appears related to the aggregation of the presynaptic protein alpha synuclein (α-syn) into toxic oligomers and fibrils. To date, no highly effective treatment is currently available; therefore, there is an increasing interest in the search of new therapeutic tools. The modulation of α-syn aggregation represents an emergent and promising disease-modifying strategy for reducing or blocking the neurodegenerative process. Herein, by combining in silico and in vitro screenings we initially identified 3-(cinnamylsulfanyl)-5-(4-pyridinyl)-1,2,4-triazol-4-amine (3) as α-syn aggregation inhibitor that was then considered a promising hit for the further design of a new series of small molecules. Therefore, we rationally designed new hit-derivatives that were synthesised and evaluated by biological assays. Lastly, the binding mode of the newer inhibitors was predicted by docking studies

Development and validation of a patient-reported outcome tool to assess cancer-related financial toxicity in Italy

Introduction. Financial toxicity (FT) is a well-recognized problem in oncology. US-based studies have shown that: (a) cancer patients have a 2.7 times risk of bankruptcy; (b) patients who declare bankruptcy have a 79% greater hazard of death; (c) financial burden significantly impairs quality of life (QoL), and (d) reduces compliance and adherence to treatment prescriptions. The aim of the project is to develop and validate a patient-reported-outcome (PRO) measure to assess FT of cancer patients in Italy, where, despite the universal health coverage given by the national health service, FT is an emerging issue. Methods and analysis. Our hypothesis is that a specific FT measure, which considers the relevant socio-cultural context and health care system, would allow to understand the main determinants of cancer-related financial toxicity in Italy and to contrast them. According to the International Society for Pharmaco-economics and Outcomes Research (ISPOR) guidelines on PROs, the project will include the following steps: (1) concept elicitation (from focus groups with patients and caregivers; literature; oncologists; nurses) and analysis, creating a coding library; (2) item generation (using a format that includes a question and a response on a 4-point Likert scale) and analysis through patients’ cognitive interviews of item importance within different coding categories to produce the draft instrument; (3) factor analysis and internal validation (with Cronbach’s alpha and test-retest for reliability) to produce the final instrument; (4) external validation with QoL anchors and depression scales. The use of the FT measure in prospective trials is also planned. Ethics and dissemination. The protocol is approved by the ethical committees of all the participating centres. The project will tentatively produce a validated tool by the spring 2021.The project might also represent a model and the basis for future cooperation with other European countries, with different health care systems and socio-economic conditions

Efficacy of a new technique - INtubate-RECruit-SURfactant-Extubate - "IN-REC-SUR-E" - in preterm neonates with respiratory distress syndrome: Study protocol for a randomized controlled trial

Background: Although beneficial in clinical practice, the INtubate-SURfactant-Extubate (IN-SUR-E) method is not successful in all preterm neonates with respiratory distress syndrome, with a reported failure rate ranging from 19 to 69 %. One of the possible mechanisms responsible for the unsuccessful IN-SUR-E method, requiring subsequent re-intubation and mechanical ventilation, is the inability of the preterm lung to achieve and maintain an "optimal" functional residual capacity. The importance of lung recruitment before surfactant administration has been demonstrated in animal studies showing that recruitment leads to a more homogeneous surfactant distribution within the lungs. Therefore, the aim of this study is to compare the application of a recruitment maneuver using the high-frequency oscillatory ventilation (HFOV) modality just before the surfactant administration followed by rapid extubation (INtubate-RECruit-SURfactant-Extubate: IN-REC-SUR-E) with IN-SUR-E alone in spontaneously breathing preterm infants requiring nasal continuous positive airway pressure (nCPAP) as initial respiratory support and reaching pre-defined CPAP failure criteria. Methods/design: In this study, 206 spontaneously breathing infants born at 24+0-27+6 weeks' gestation and failing nCPAP during the first 24 h of life, will be randomized to receive an HFOV recruitment maneuver (IN-REC-SUR-E) or no recruitment maneuver (IN-SUR-E) just prior to surfactant administration followed by prompt extubation. The primary outcome is the need for mechanical ventilation within the first 3 days of life. Infants in both groups will be considered to have reached the primary outcome when they are not extubated within 30 min after surfactant administration or when they meet the nCPAP failure criteria after extubation. Discussion: From all available data no definitive evidence exists about a positive effect of recruitment before surfactant instillation, but a rationale exists for testing the following hypothesis: a lung recruitment maneuver performed with a step-by-step Continuous Distending Pressure increase during High-Frequency Oscillatory Ventilation (and not with a sustained inflation) could have a positive effects in terms of improved surfactant distribution and consequent its major efficacy in preterm newborns with respiratory distress syndrome. This represents our challenge. Trial registration: ClinicalTrials.gov identifier: NCT02482766. Registered on 1 June 2015