Endothelium-targeted delivery of dexamethasone by anti-VCAM-1 SAINT-O-Somes in mouse endotoxemia

Microvascular endothelial cells play a pivotal role in the pathogenesis of sepsis-induced inflammatory responses and multiple organ failure. Therefore, they represent an important target for pharmacological intervention in the treatment of sepsis. Glucocorticosteroids were widely used in the treatment of sepsis but vast evidence to support their systemic use is lacking. The limited effects of glucocorticoids in the treatment of sepsis may be explained by differential effects of drug initiated NF-κB inhibition in different cell types and insufficient drug delivery in target cells. The current study aimed therefore to investigate the effects of an endothelial targeted delivery of dexamethasone in a mouse model of endotoxemia induced by two consecutive i.p. injections of lipopolysaccharide (LPS). To achieve endothelial cell specific delivery of dexamethasone, we modified SAINT-O-Somes, a new generation of liposomes that contain the cationic amphiphile SAINT-C18 (1-methyl-4-(cis-9-dioleyl) methyl-pyridinium chloride, with antibodies against vascular cell adhesion molecule-1 (VCAM-1). In LPS challenged mice, the systemic administration of free dexamethasone had negligible effects on the microvascular inflammatory endothelial responses. Dexamethasone-loaded anti-VCAM-1 SAINT-O-Somes specifically localized at VCAM-1 expressing endothelial cells in the microvasculature of inflamed organs. This was associated with a marginal attenuation of the expression of a few pro-inflammatory genes in kidney and liver, while no effects in the lung were observed. This study reveals that, although local accumulation of the targeted drug was achieved, endothelial targeted dexamethasone containing anti-VCAM-1 SAINT-O-Somes exhibited marginal effects on inflammatory endothelial cell activation in a model of endotoxemia. Studies with more potent drugs encapsulated into anti-VCAM-1 SAINT-O-Somes will in the future reveal whether this delivery system can be further developed for efficacious endothelial directed delivery of drugs in the treatment of sepsis

Introducing European Law Open

Published online: 06 April 2022These lines start on Page 1 of Issue 1 of Volume 1 of European Law Open, and are written with a sense of occasion of new beginnings, and in deep gratitude for the support of the academic community and the trust placed in us by Cambridge University Press. Launching a new open access journal of European law in times of COVID-19, economic slumps and widespread financial pressures on higher education is not a decision to be taken lightly, and it has not been taken lightly. Surely, there is a place, indeed a need, for contextual and critical approaches to European law. Many of us have dedicated years to fostering such work as editors and Board members of a certain other journal in another place, which we left collectively in early 2020. It is a heritage we are proud of, and a tradition we will build on. It is also clear, however, that over the decades – in no small measure thanks to that other journal – contextual approaches have become mainstream in EU law, and that, as a consequence, ‘European law in context’ as a description of a particular style of scholarship has lost much of its clarity and purpose. Not entirely in jest, we sometimes joke that the new frontier, the really cool, edgy stuff in EU law these days would consist of good old-fashioned doctrinal work. If only it existed

Gecompliceerde fractuur en antisepsis

Bij het bestudeeren van de geschiedenis der geneeskunde blijkt. dat pas na de vinding van de antiseptische methode door Lister. ± 1865. van cen doeltreffende behandeling van gecompliceerde fracturen sprake heeft kunnen zijn. Was het v66r dien Hjd een zeldzaamheid, dat een ernstig gecompliceerde fractuur zonder amputatie genas, na Lister kan men omgekeerd zeggen. dat de noodzakelijkheid tot amputatie uitzondering werd. Bij de genezing van gecompliceerde £racturen, waarvoor dus vergelijkingsmateriaal met vroeger ontbrak. bleek to en echter de consolidatie veelal lang op zich te laten wachten. ... Zie: Samenvatting

Extended Interval Dosing Natalizumab and impact on neuropsychological deficits in Relapsing-Remitting Multiple Sclerosis

Background: Cognitive impairment and neuropsychiatric symptoms are frequently reported in Relapsing-Remitting Multiple Sclerosis (RRMS). Natalizumab (NTZ) is usually administered on a 4-weekly Standard Interval Dosing (SID) schedule. However, Extended Interval Dosing (EID) at 6–8 weekly intervals has been proven non-inferior regarding relapse risk, with a lower risk of Progressive Multifocal Leukoencephalopathy (PML). The impact of EID NTZ on neuropsychological deficits in RRMS has not been studied. Objective: To determine if EID NTZ demonstrates an improvement in neuropsychological parameters in RRMS patients. Method: We performed a retrospective, observational analysis of 34 RRMS patients treated between August 2015–2017. Patients underwent baseline neuropsychological testing before commencing EID NTZ. A second evaluation was performed, on average 28 months after commencing treatment. Results: Z scores at the initial assessment showed baseline cognitive impairment in multiple domains. 14/20 Z-scores showed an improvement post-NTZ and 5/14 reached statistical significance; namely Trails A (visual attention/processing speed), Line-orientation (visual-spatial), Picture-naming (word finding), Digital-Span (attention, executive function and memory) and Story-recall (memory). The Hospital Anxiety and Depression Scale (HADS) data remained unchanged. Correlation matrix showed no association between HADS scores, the time between assessments and the changes in Z scores. Conclusion: This data suggests the efficacy of EID NTZ in improving cognitive impairment in RRMS. A prospective observational study is warranted. </jats:p