Developing Experimental Models of Non-Traumatic Spinal Cord Injury

Over 50% of non-traumatic spinal cord injuries (NTSCI) are caused by mechanical compression either due to osteophytes in degenerative disease, or tumours (New et al., 2014). The pathophysiology of NTSCI is poorly understood, with no distinct injury cascade (Karadimas et al., 2013). The aim of this project was to evaluate cellular responses to mechanical insults in the context of NTSCI. In-vitro, a model was developed to apply high and low velocity compression to astrocyte-seeded collagen hydrogels. Outcomes included hydrogel contraction, GFAP expression, cellular shape, and cytokine release. In-vivo a balloon lesion model was modified to induce a non-traumatic ventral lesion, by developing an injection port and inflating over 3 days. Functional deficits and histological outcomes were assessed. In-vitro, 100 mm.s-1 compression elicited an astrogliotic and inflammatory response from day 11, indicative of TSCI. This comprised a significant increase in GFAP area per cell, astrocyte ramification, and IL-6 expression. Conversely, at <100 mm.s-1, no differences were observed. The findings of this study suggest slow compression of astrocytes alone does not induce NTSCI. In-vivo, surgery was undertaken on 10 animals (including 3 shams). In injury groups, functional deficits were observed , which increased with each inflation. Animals were grouped into mild and severe based on their motor function (severe animals exhibited paraplegia). Minimum motor function correlated with minimum cross-sectional area, and greater parenchyma disruption. In the severe group only, there was a trend of mild astrogliosis, demyelination and vasculature narrowing at the epicentre. This corresponds with the wider literature, where demyelination and disruption to the vasculature are hypothesised to be involved in NTSCI pathology. Overall, in-vitro and in-vivo models of NTSCI have been successfully developed. Physiological changes were observed in both models, with differences to TSCI. Further investigations can be undertaken to understand the pathology of NTSCI

Indole-containing arene-ruthenium complexes with broad spectrum activity against antibiotic-resistant bacteria

Antimicrobial resistant (AMR) bacteria are emerging and spreading globally, threatening our ability to treat common infectious diseases. The development of new classes of antibiotics able to kill or inhibit the growth of such AMR bacteria through novel mechanisms of action is therefore urgently needed. Here, a new family of indole-containing arene ruthenium organometallic compounds are screened against several bacterial species and drug resistant strains. The most active complex [(p-cym)Ru(O-cyclohexyl-1H-indole-2-carbothioate)Cl] (3) shows growth inhibition and bactericidal activity against different organisms (Acinetobacter baumannii, Mycobacterium abscessus, Mycobacterium tuberculosis, Staphylococcus aureus, Salmonella enterica serovar typhi and Escherichia coli), demonstrating broad-spectrum inhibitory activity. Importantly, this compound series exhibits low toxicity against human cells. Owing to the novelty of the antibiotic family, their moderate cytotoxicity, and their inhibitory activity against Gram positive, Gram negative and acid-fast, antibiotic resistant microorganisms, this series shows significant promise for further development

Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome

Purpose: Pathogenic variants in SETD1B have been associated with a syndromic neurodevelopmental disorder including intellectual disability, language delay, and seizures. To date, clinical features have been described for 11 patients with (likely) pathogenic SETD1B sequence variants. This study aims to further delineate the spectrum of the SETD1B-related syndrome based on characterizing an expanded patient cohort. Methods: We perform an in-depth clinical characterization of a cohort of 36 unpublished individuals with SETD1B sequence variants, describing their molecular and phenotypic spectrum. Selected variants were functionally tested using in vitro and genome-wide methylation assays. Results: Our data present evidence for a loss-of-function mechanism of SETD1B variants, resulting in a core clinical phenotype of global developmental delay, language delay including regression, intellectual disability, autism and other behavioral issues, and variable epilepsy phenotypes. Developmental delay appeared to precede seizure onset, suggesting SETD1B dysfunction impacts physiological neurodevelopment even in the absence of epileptic activity. Males are significantly overrepresented and more severely affected, and we speculate that sex-linked traits could affect susceptibility to penetrance and the clinical spectrum of SETD1B variants. Conclusion: Insights from this extensive cohort will facilitate the counseling regarding the molecular and phenotypic landscape of newly diagnosed patients with the SETD1B-related syndrome

BET 1: To debrief or not debrief

A short cut review was carried out to establish whether a staff debriefing session after involvement in a traumatic resuscitation reduces stress and anxiety, reduces sickness, improves team working and morale and improves staff retention. Four papers presented the best evidence to answer the question. The author, date and country of publication, group studied, study type, relevant outcomes, results and study weaknesses of these papers are tabulated. It is concluded that there is no evidence about the efficacy of team debriefing in the ED. However, there is some desire among staff for it to occur. Further research is needed and in the meantime local advice should be followed.</jats:p