Application of Dual Task Performance in Pediatrics and Adults with Traumatic Brain Injury: A Systematic Review

Purpose: The aim of this systematic review of the literature is to investigate the application of cognitive and motor dual task paradigms in the physical therapy management of moderate to severe TBI population across the lifespan in physical therapy practice.https://jdc.jefferson.edu/dptcapstones/1001/thumbnail.jp

iTAP, a novel iRhom interactor, controls TNF secretion by policing the stability of iRhom/TACE

The apical inflammatory cytokine TNF regulates numerous important biological processes including inflammation and cell death, and drives inflammatory diseases. TNF secretion requires TACE (also called ADAM17), which cleaves TNF from its transmembrane tether. The trafficking of TACE to the cell surface, and stimulation of its proteolytic activity, depends on membrane proteins, called iRhoms. To delineate how the TNF/TACE/iRhom axis is regulated, we performed an immunoprecipitation/mass spectrometry screen to identify iRhom-binding proteins. This identified a novel protein, that we name iTAP (iRhom Tail-Associated Protein) that binds to iRhoms, enhancing the cell surface stability of iRhoms and TACE, preventing their degradation in lysosomes. Depleting iTAP in primary human macrophages profoundly impaired TNF production and tissues from iTAP KO mice exhibit a pronounced depletion in active TACE levels. Our work identifies iTAP as a physiological regulator of TNF signalling and a novel target for the control of inflammation.info:eu-repo/semantics/publishedVersio

Senescence of the cellular immune response in Drosophila melanogaster

Immune system effectiveness generally declines as animals age, compromising disease resistance. In Drosophila, expression of a variety of immune-related genes elevates during ageing; however how this is linked to increasing pathogen susceptibility in older flies has remained unclear. We investigated whether changes in the Drosophila cellular immune response might contribute to immunosenescence. Experiments studied fly cohorts of different ages and compared the numbers and activity of the circulating haemocytes involved in pathogen defence. In female wildtype Samarkand and Oregon R flies the haemocyte population fell by 31.8% and 10.2% respectively during the first four weeks of adulthood. Interestingly we detected no such decline in male flies. The impact of ageing on the phagocytic activity of haemocytes was investigated by injecting flies with fluorescently labelled microbes or latex beads and assessing the ability of haemocytes to engulf them. For all immune challenges the proportion of actively phagocytosing haemocytes decreased as flies aged. Whilst 24.3% ± 1.15% of haemocytes in one-week-old flies phagocytosed Escherichia coli bacteria or Beauveria bassiana fungal spores, this decreased to 16.7% ± 0.99% in four-week-old flies. This clear senescence of the Drosophila cellular immune response may underpin increased disease susceptibility in older flies

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Neutrophil extracellular traps can serve as platforms for processing and activation of IL-1 family cytokines

Activated neutrophils can undergo a mode of regulated cell death, called NETosis, that results in the extrusion of chromatin into the extracellular space, thereby acting as extracellular traps for microorganisms. Neutrophil-derived extracellular traps (NETs) are comprised of DNA decorated with histones, antimicrobial proteins and neutrophil granule proteases, such as elastase and cathepsin G (Cat G). NET-associated factors are thought to enhance the antimicrobial properties of these structures and localisation of antimicrobial molecules on NETs may serve to increase their local concentration. Because neutrophil-derived proteases have been implicated in the processing and activation of several members of the extended interleukin (IL)-1 family, we wondered whether neutrophil NETs could also serve as platforms for the activation of proinflammatory cytokines. Here, we show that neutrophil NETs potently processed and activated IL-1 as well as IL-36 subfamily cytokines through NET-associated Cat G and elastase. Thus, in addition to their role as antimicrobial traps, NETs can also act as local sites of cytokine processing and activation

RIPK1 can function as an inhibitor rather than an initiator of RIPK3-dependent necroptosis

Tumour necrosis factor and lipopolysaccharide can promote a regulated form of necrosis, called necroptosis, upon inhibition of caspase activity in cells expressing receptor-interacting serine/threonine kinase (RIPK) 3. Because inhibitors of RIPK1 kinase activity such as necrostatin-1 block necroptosis in many settings, RIPK1 is thought to be required for activation of RIPK3, leading to necroptosis. However, here we show that, although necrostatin potently inhibited tumour necrosis factor-induced, lipopolysaccharide-induced and polyIC-induced necroptosis, RIPK1 knockdown unexpectedly potentiated this process. In contrast, RIPK3 knockdown potently suppressed necroptosis under the same conditions. Significantly, necrostatin failed to block necroptosis in the absence of RIPK1, indicating that its ability to suppress necroptosis was indeed RIPK1-dependent. These data argue that RIPK1 is dispensable for necroptosis and can act as an inhibitor of this process. Our observations also suggest that necrostatin enhances the inhibitory effects of RIPK1 on necroptosis, as opposed to blocking its participation in this process

Neutrophil extracellular traps can serve as platforms for processing and activation of IL

Activated neutrophils can undergo a mode of regulated cell death, called NETosis, that results in the extrusion of chromatin into the extracellular space, thereby acting as extracellular traps for microorganisms. Neutrophil-derived extracellular traps (NETs) are comprised of DNA decorated with histones, antimicrobial proteins and neutrophil granule proteases, such as elastase and cathepsin G (Cat G). NET-associated factors are thought to enhance the antimicrobial properties of these structures and localisation of antimicrobial molecules on NETs may serve to increase their local concentration. Because neutrophil-derived proteases have been implicated in the processing and activation of several members of the extended interleukin (IL)-1 family, we wondered whether neutrophil NETs could also serve as platforms for the activation of proinflammatory cytokines. Here, we show that neutrophil NETs potently processed and activated IL-1 as well as IL-36 subfamily cytokines through NET-associated Cat G and elastase. Thus, in addition to their role as antimicrobial traps, NETs can also act as local sites of cytokine processing and activation

Structural basis of human IL-18 sequestration by the decoy receptor IL-18 binding protein in inflammation and tumor immunity

Human Interleukin-18 (IL-18) is an omnipresent proinflammatory cytokine of the IL-1 family with central roles in autoimmune and inflammatory diseases and serves as a staple biomarker in the evaluation of inflammation in physiology and disease, including the inflammatory phase of COVID-19. The sequestration of IL-18 by its soluble decoy receptor IL-18-Binding Protein (IL-18BP) is critical to the regulation of IL-18 activity. Since an imbalance in expression and circulating levels of IL-18 is associated with disease, structural insights into how IL-18BP outcompetes binding of IL-18 by its cognate cell-surface receptors are highly desirable; however, the structure of human IL-18BP in complex with IL-18 has been elusive. Here, we elucidate the sequestration mechanism of human IL-18 mediated by IL-18BP based on the crystal structure of the IL-18:IL-18BP complex. These detailed structural snapshots reveal the interaction landscape leading to the ultra-high affinity of IL-18BP toward IL-18 and identify substantial differences with respect to previously characterized complexes of IL-18 with IL-18BP of viral origin. Furthermore, our structure captured a fortuitous higher-order assembly between IL-18 and IL-18BP coordinated by a disulfide-bond distal to the binding surface connecting IL-18 and IL-18BP molecules from different complexes, resulting in a novel tetramer with 2:2 stoichiometry. This tetrapartite assembly was found to restrain IL-18 activity more effectively than the canonical 1:1 complex. Collectively, our findings provide a framework for innovative, structure-driven therapeutic strategies and further functional interrogation of IL-18 in physiology and disease