Chitosan-Coated Nanoparticles: Effect of Chitosan Molecular Weight on Nasal Transmucosal Delivery

Drug delivery to the brain represents a challenge, especially in the therapy of central nervous system malignancies. Simvastatin (SVT), as with other statins, has shown potential anticancer properties that are difficult to exploit in the central nervous system (CNS). In the present work the physico⁻chemical, mucoadhesive, and permeability-enhancing properties of simvastatin-loaded poly-ε-caprolactone nanocapsules coated with chitosan for nose-to-brain administration were investigated. Lipid-core nanocapsules coated with chitosan (LNCchit) of different molecular weight (MW) were prepared by a novel one-pot technique, and characterized for particle size, surface charge, particle number density, morphology, drug encapsulation efficiency, interaction between surface nanocapsules with mucin, drug release, and permeability across two nasal mucosa models. Results show that all formulations presented adequate particle sizes (below 220 nm), positive surface charge, narrow droplet size distribution (PDI < 0.2), and high encapsulation efficiency. Nanocapsules presented controlled drug release and mucoadhesive properties that are dependent on the MW of the coating chitosan. The results of permeation across the RPMI 2650 human nasal cell line evidenced that LNCchit increased the permeation of SVT. In particular, the amount of SVT that permeated after 4 hr for nanocapsules coated with low-MW chitosan, high-MW chitosan, and control SVT was 13.9 ± 0.8 μg, 9.2 ± 1.2 µg, and 1.4 ± 0.2 µg, respectively. These results were confirmed by SVT ex vivo permeation across rabbit nasal mucosa. This study highlighted the suitability of LNCchit as a promising strategy for the administration of simvastatin for a nose-to-brain approach for the therapy of brain tumors

Genetic landscape of a large cohort of Primary Ovarian Insufficiency : New genes and pathways and implications for personalized medicine

Background Primary Ovarian Insufficiency (POI), a public health problem, affects 1-3.7% of women under 40 yield-ing infertility and a shorter lifespan. Most causes are unknown. Recently, genetic causes were identified, mostly in single families. We studied an unprecedented large cohort of POI to unravel its molecular pathophysiology.Methods 375 patients with 70 families were studied using targeted (88 genes) or whole exome sequencing with pathogenic/likely-pathogenic variant selection. Mitomycin-induced chromosome breakages were studied in patients' lymphocytes if necessary. Findings A high-yield of 29.3% supports a clinical genetic diagnosis of POI. In addition, we found strong evidence of pathogenicity for nine genes not previously related to a Mendelian phenotype or POI: ELAVL2, NLRP11, CENPE, SPATA33, CCDC150, CCDC185, including DNA repair genes: C17orf53(HROB), HELQ, SWI5 yielding high chromo-somal fragility. We confirmed the causal role of BRCA2, FANCM, BNC1, ERCC6, MSH4, BMPR1A, BMPR1B, BMPR2, ESR2, CAV1, SPIDR, RCBTB1 and ATG7 previously reported in isolated patients/families. In 8.5% of cases, POI is the only symptom of a multi-organ genetic disease. New pathways were identified: NF-kB, post-translational regulation, and mitophagy (mitochondrial autophagy), providing future therapeutic targets. Three new genes have been shown to affect the age of natural menopause supporting a genetic link.Interpretation We have developed high-performance genetic diagnostic of POI, dissecting the molecular pathogene-sis of POI and enabling personalized medicine to i) prevent/cure comorbidities for tumour/cancer susceptibility genes that could affect life-expectancy (37.4% of cases), or for genetically-revealed syndromic POI (8.5% of cases), ii) predict residual ovarian reserve (60.5% of cases). Genetic diagnosis could help to identify patients who may benefit from the promising in vitro activation-IVA technique in the near future, greatly improving its success in treating infertility.Funding Universite? Paris Saclay, Agence Nationale de Biome?decine.Copyright (c) 2022 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)Peer reviewe

Road traffic accidents with vehicular entrapment: incidence of major injuries and need for advanced life support

10Road traffic accidents (RTAs) with entrapment are perceived as a challenge to emergency systems because of the severity of the ensuing traumas and the inherent complexity of the rescue procedures. To clarify these two aspects this prospective cohort study enrolling 244 entrapped trauma patients was conducted by a Regional Medical Helicopter Service. Forty-six victims (18.9%) were found dead, 101 (51%) of the 198 patients who reached the hospital alive had an injury severity score (ISS) > or = 16. The use of seat belts was associated with lower trauma severity. Out of the 101 severely traumatized patients (ISS > or = 16), 46 (42.6%) were intubated at road side, 12 required decompression of a tension pneumothorax on the scene and in 15 cases a pneumothorax was drained during the early intrahospital phase. Thirty-six (34.7%) patients had the first systolic blood pressure (SBP) < or = 90 mmHg and were then aggressively infused: in 75% of these cases, the SBP on arrival at the emergency department increased. The first SBP was significantly correlated with mortality. There was no correlation of extrication time, total rescue time and mortality. Fourteen patients (13.9%) died during hospitalization. These data demonstrate that a high percentage of entrapped patients require advanced life support (ALS), including on scene intubation and chest decompression. Aggressive field resuscitation and immediate transport to a level 1 trauma centre is associated with a mortality lower than that predicted by TRISS in spite of the prolonged prehospital time.nonemixedSanson G; Di Bartolomeo S; Nardi G; Albanese P, Diani A, Raffin L, Filippetto C, Cattarossi A, Scian E, Rizzi L.Sanson, G; Di Bartolomeo, S; Nardi, G; Albanese, P; Diani, A; Raffin, L; Filippetto, C; Cattarossi, A; Scian, E; Rizzi, L

Degree of importance of demographic and socio-cultural factors in environmental perception: bases for the design of public policies in Argentina and Spain

Environmental problems on a global scale (such as climate change) are of increasing concern in the scholar. However, it is unclear to what extent society is aware of the severity of these problems. The aim of this study is to advance our knowledge about the environmental perceptions of citizens, with the understanding that citizen participation and action are key to mitigating environmental problems. Specifically, we aim to determine the degree of importance of demographic and sociocultural factors in this perception. To this end, data from 506 questionnaires carried out in Spain and Argentina were analysed. Quantitative data were treated using multivariate analysis based on multiple logistic regression. The results showed that demographic variables, such as location and age, have a greater influence than sociocultural variables, such as profession and sources of environmental information, in the perception of environmental problems. Our findings show that the analysis of environmental perception is a useful tool both for incorporating the point of view of local actors in public policies and for defining effective strategies for action in participatory management. They also show that the different age, occupation and profession of the population must be taken into account and that, to address specific environmental problems, it is necessary to carry out diagnoses focussed on demographic factors, mainly to find out which aspects should be strengthened through programmes and projects aimed at solving environmental problems. It is important to bear in mind that the behaviour of local actors is related to their environmental perception.Universidad Complutense de MadridDepto. de Estadística e Investigación OperativaFac. de Ciencias MatemáticasTRUEpu