Acute modulation of brain connectivity in Parkinson disease after automatic mechanical peripheral stimulation: A pilot study

The present study shows the results of a double-blind sham-controlled pilot trial to test whether measurable stimulus-specific functional connectivity changes exist after Automatic Mechanical Peripheral Stimulation (AMPS) in patients with idiopathic Parkinson Disease.Eleven patients (6 women and 5 men) with idiopathic Parkinson Disease underwent brain fMRI immediately before and after sham or effective AMPS. Resting state Functional Connectivity (RSFC) was assessed using the seed-ROI based analysis. Seed ROIs were positioned on basal ganglia, on primary sensory-motor cortices, on the supplementary motor areas and on the cerebellum. Individual differences for pre- and post-effective AMPS and pre- and post-sham condition were obtained and first entered in respective one-sample t-test analyses, to evaluate the mean effect of condition.Effective AMPS, but not sham stimulation, induced increase of RSFC of the sensory motor cortex, nucleus striatum and cerebellum. Secondly, individual differences for both conditions were entered into paired group t-test analysis to rule out sub-threshold effects of sham stimulation, which showed stronger connectivity of the striatum nucleus with the right lateral occipital cortex and the cuneal cortex (max Z score 3.12) and with the right anterior temporal lobe (max Z score 3.42) and of the cerebellum with the right lateral occipital cortex and the right cerebellar cortex (max Z score 3.79).Our results suggest that effective AMPS acutely increases RSFC of brain regions involved in visuo-spatial and sensory-motor integration.This study provides Class II evidence that automatic mechanical peripheral stimulation is effective in modulating brain functional connectivity of patients with Parkinson Disease at rest.Clinical Trials.gov NCT01815281

Surfactant Nebulization Therapy During NIPPV Ventilation in Surfactant-Deficient Newborn Piglets

Background In recent years, nasal intermittent positive pressure ventilation (NIPPV) has been growing in popularity as a form of noninvasive ventilation for respiratory support in the initial treatment of neonates with surfactant (SF) deficiency. The combination of this type of ventilation with noninvasive SF administration (by nebulization) is an attractive treatment option for respiratory distress syndrome (RDS)-associated pathophysiology of the neonatal lungs. In this study, we aimed to test the tolerability and efficacy of SF nebulization during NIPPV for the treatment of neonatal RDS. Methods Spontaneously-breathing newborn piglets (n = 6/group) with bronchoalveolar lavage (BAL)-induced RDS were assigned to receive during NIPPV (180 min): poractant alfa (400 mg/kg) via an investigational customized vibrating-membrane nebulizer (eFlow-Neos) or poractant alfa (200 mg/kg) as a bolus using the Insure method or no surfactant (controls). Measurement and results We assessed pulmonary, hemodynamic and cerebral effects and performed histological analysis of lung and brain tissue. After repeated BAL, newborn piglets developed severe RDS (FiO2: 1, pH  70 mmHg, PaO2< 70 mmHg, Cdyn < 0.5 ml/cmH2O/kg). In both SF-treated groups, we observed rapid improvement in pulmonary status and also similar hemodynamic, cerebral behavior, and lung and brain injury scores. Conclusion Our results in newborn piglets with severe BAL-induced RDS show the administration of nebulized poractant alfa using the eFlow-Neos nebulizer during NIPPV to be well tolerated and efficacious, suggesting that this noninvasive SF administration option should be explored further.Drs. Rey-Santano, Mielgo, and Gomez-Solaetxe's institutions received funding from Chiesi Farmaceutici and Carlos III Health Institute (PI18/00166) (co-funded by ERDF/ESF, "Investing in your future") and GIU19/026 (University of the Basque Country Research Group

Lung ultrasound features and relationships with respiratory mechanics of evolving BPD in preterm rabbits and human neonates

Evolving bronchopulmonary dysplasia (BPD) is characterized by impaired alveolarization leading to lung aeration inhomogeneities. Hyperoxia-exposed preterm rabbits have been proposed to mimic evolving BPD; therefore, we aimed to verify if this model has the same lung ultrasound and mechanical features of evolving BPD in human neonates. Semiquantitative lung ultrasound and lung mechanics measurement was performed in 25 preterm rabbits (28days of gestation) and 25 neonates (mean gestational age approximate to 26wk) with evolving BPD. A modified rabbit lung ultrasound score (rLUS) and a validated neonatal lung ultrasound score (WS) were used. Lung ultrasound images were recorded and evaluated by two independent observers blinded to each other's evaluation. Lung ultrasound findings were equally heterogeneous both in rabbits as in human neonates and encompassed all the classical lung ultrasound semiology. Lung ultrasound and histology examination were also performed in 13 term rabbits kept under normoxia as further control and showed the absence of ultrasound and histology abnormalities compared with hyperoxia-exposed preterm rabbits. The interrater absolute agreement for the evaluation of lung ultrasound images in rabbits was very high [ICC: 0.989 (95%Cl: 0.975-0.995); P &lt; 0.0001], and there was no difference between the two observers. Lung mechanics parameters were similarly altered in both rabbits and human neonates. There were moderately significant correlations between airway resistances and lung ultrasound scores in rabbits (rho = 0.519; P = 0.008) and in neonates (rho = 0.409; P = 0.042). In conclusion, the preterm rabbit model fairly reproduces the lung ultrasound and mechanical characteristics of preterm neonates with evolving BPD.NEW &amp; NOTEWORTHY We have reported that hyperoxia-exposed preterm rabbits and human preterm neonates with evolving BPD have the same lung ultrasound appearance, and that lung ultrasound can be fruitfully applied on this model with a brief training. The animal model and human neonates also presented the same relationship between semiquantitative ultrasound-assessed lung aeration and airway resistances. In conclusion, this animal model fairly reproduce evolving BPD as it is seen in clinical practice

Sample preparation strategy for the detection of steroid-like compounds using MALDI mass spectrometry imaging: pulmonary distribution of budesonide as a case study

10openInternationalItalian coauthor/editorCorticosteroids as budesonide can be effective in reducing topic inflammation processes in different organs. Therapeutic use of budesonide in respiratory diseases, like asthma, chronic obstructive pulmonary disease, and allergic rhinitis is well known. However, the pulmonary distribution of budesonide is not well understood, mainly due to the difficulties in tracing the molecule in lung samples without the addition of a label. In this paper, we present a matrix-assisted laser desorption/ionization mass spectrometry imaging protocol that can be used to visualize the pulmonary distribution of budesonide administered to a surfactant-depleted adult rabbit. Considering that budesonide is not easily ionized by MALDI, we developed an on-tissue derivatization method with Girard’s reagent P followed by ferulic acid deposition as MALDI matrix. Interestingly, this sample preparation protocol results as a very effective strategy to raise the sensitivity towards not only budesonide but also other corticosteroids, allowing us to track its distribution and quantify the drug inside lung samples.openZecchi, Riccardo; Franceschi, Pietro; Tigli, Laura; Amidani, Davide; Catozzi, Chiara; Ricci, Francesca; Salomone, Fabrizio; Pieraccini, Giuseppe; Pioselli, Barbara; Mileo, ValentinaZecchi, R.; Franceschi, P.; Tigli, L.; Amidani, D.; Catozzi, C.; Ricci, F.; Salomone, F.; Pieraccini, G.; Pioselli, B.; Mileo, V

Structural and haemodynamic evaluation of less invasive surfactant administration during nasal intermittent positive pressure ventilation in surfactant-deficient newborn piglets

The most recent approaches to the initial treatment of respiratory distress syndrome (RDS)- involve non-invasive ventilation (NIV) and less-invasive surfactant (SF) administration (LISA). Combining these techniques has been proven a useful treatment option for SF-defi- cient neonates. The objective of this study was to explore the impact on the brain (using cerebral near infrared spectroscopy, NIRS) of different LISA methods during NIV, using nasal intermittent positive pressure ventilation (NIPPV) for treating neonatal RDS. For this, we used five groups of spontaneously breathing newborn piglets (n = 6/group) with bronch- oalveolar lavage (BAL)-induced respiratory distress which received NIPPV only (controls), poractant-alfa using the INSURE-like method (bolus delivery) followed by NIPPV, or porac- tant-alfa using one of three LISA devices, 1) a nasogastric tube (NT), 2) a vascular catheter (VC) or 3) the LISAcath® catheter. We assessed pulmonary, hemodynamic and cerebral effects, and performed histological analysis of lung and brain tissue. Following BALs, the piglets developed severe RDS (pH70 mmHg, PaO2<70 mmHg, dynamic com- pliance<0.5 ml/cmH2O/kg at FiO2 = 1). Poractant-alfa administration using different LISA techniques during NIPPV was well tolerated and efficacious in newborn piglets. In our study, although all groups showed normal physiological ranges of total lung injury score and bio- chemical lung analysis, VC and LISAcath® catheters were associated with better values of lung compliance and lower values of lung damage than NIPPV, NT or INSURE-like meth- ods. Moreover, neither of the SF administration methods used (LISA or INSURE-like) had a significant impact on the histological neonatal brain injury score. Of note, the LISAcath® has been recently withdrawn from the market.Drs. Rey-Santano, Mielgo, and Gomez- Solaetxe’s institutions received funding from Chiesi Farmaceutici (Number 10391902) and the Carlos III Health Institute (PI18/00166) (co-financed by the European Regional Development Fund “A way to make Europe”) and GIU19/026 (University of the Basque Country Research Group). Fabrizio Salomone and Francesca Ricci disclose that they are Chiesi employees. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Physiological, biochemical, and biophysical characterization of the lung-lavaged spontaneously-breathing rabbit as a model for respiratory distress syndrome

Nasal continuous positive airway pressure (nCPAP) is a widely accepted technique of non-invasive respiratory support in spontaneously-breathing premature infants with respiratory distress syndrome (RDS). Surfactant administration techniques compatible with nCPAP ventilation strategy are actively investigated. Our aim is to set up and validate a respiratory distress animal model that can be managed on nCPAP suitable for surfactant administration techniques studies. Surfactant depletion was induced by bronchoalveolar lavages (BALs) on 18 adult rabbits. Full depletion was assessed by surfactant component analysis on the BALs samples. Animals were randomized into two groups: Control group (nCPAP only) and InSurE group, consisting of a bolus of surfactant (Poractant alfa, 200 mg/kg) followed by nCPAP. Arterial blood gases were monitored until animal sacrifice, 3 hours post treatment. Lung mechanics were evaluated just before and after BALs, at the time of treatment, and at the end of the procedure. Surfactant phospholipids and protein analysis as well as surface tension measurements on sequential BALs confirmed the efficacy of the surfactant depletion procedure. The InSurE group showed a significant improvement of blood oxygenation and lung mechanics. On the contrary, no signs of recovery were appreciated in animals treated with just nCPAP. The surfactant-depleted adult rabbit RDS model proved to be a valuable and efficient preclinical tool for mimicking the clinical scenario of preterm infants affected by mild/moderate RDS who spontaneously breathe and do not require mechanical ventilation. This population is of particular interest as potential target for the non-invasive administration of surfactant

Surfactant-assisted distal pulmonary distribution of Budesonide revealed by mass spectrometry imaging

13openInternationalBothDirect lung administration of budesonide in combination with surfactant reduces the incidence of bronchopulmonary dysplasia. Although the therapy is currently undergoing clinical development, the lung distribution of budesonide throughout the premature neonatal lung has not yet been investigated. Here, we applied mass spectrometry imaging (MSI) to investigate the surfactant-assisted distal lung distribution of budesonide. Unlabeled budesonide was either delivered using saline as a vehicle (n = 5) or in combination with a standard dose of the porcine surfactant Poractant alfa (n = 5). These lambs were ventilated for one minute, and then the lungs were extracted for MSI analysis. Another group of lambs (n = 5) received the combination of budesonide and Poractant alfa, followed by two hours of mechanical ventilation. MSI enabled the label-free detection and visualization of both budesonide and the essential constituent of Poractant alfa, the porcine surfactant protein C (SP-C). 2D ion intensity images revealed a non-uniform distribution of budesonide with saline, which appeared clustered in clumps. In contrast, the combination therapy showed a more homogeneous distribution of budesonide throughout the sample, with more budesonide distributed towards the lung periphery. We found similar distribution patterns for the SP-C and budesonide in consecutive lung tissue sections, indicating that budesonide was transported across the lungs associated with the exogenous surfactant. After two hours of mechanical ventilation, the budesonide intensity signal in the 2D ion intensity maps dropped dramatically, suggesting a rapid lung clearance and highlighting the relevance of achieving a uniform surfactant-assisted lung distribution of budesonide early after delivery to maximize the anti-inflammatory and maturational effects throughout the lungopenZecchi, Riccardo; Franceschi, Pietro; Tigli, Laura; Pioselli, Barbara; Mileo, Valentina; Murgia, Xabier; Salomone, Fabrizio; Pieraccini, Giuseppe; Usada, Haruo; Schmidt, Augusto F; Hillman, Noah H.; Kemp, Matthew W.; Jobe, Alan H.Zecchi, R.; Franceschi, P.; Tigli, L.; Pioselli, B.; Mileo, V.; Murgia, X.; Salomone, F.; Pieraccini, G.; Usada, H.; Schmidt, A.F.; Hillman, N.H.; Kemp, M.W.; Jobe, A.H