Pressure injuries, also known as pressure ulcers, are regions of localized damage to the skin and/or underlying tissue. Repeated rounds of ischemia-reperfusion (I/R) have a major causative role for ...tissue damage in pressure injury. Ischemia prevents oxygen/nutrient supply, and restoration of blood flow induces a burst of reactive oxygen species that damages blood vessels, surrounding tissues and can halt blood flow return. Minimizing the consequences of repeated I/R is expected to provide a protective effect against pressure injury. Sulfaphenazole (SP), an off patent sulfonamide antibiotic, is a potent CYP 2C6 and CYP 2C9 inhibitor, functioning to decrease post-ischemic vascular dysfunction and increase blood flow. The therapeutic effect of SP on pressure injury was therefore investigated in apolipoprotein E knockout mice, a model of aging susceptible to ischemic injury, which were subjected to repeated rounds of I/R-induced skin injury. SP reduced overall severity, improved wound closure and increased wound tensile strength compared to vehicle-treated controls. Saliently, SP restored tissue perfusion in and around the wound rapidly to pre-injury levels, decreased tissue hypoxia, and reduced both inflammation and fibrosis. SP also demonstrated bactericidal activity through enhanced M1 macrophage activity. The efficacy of SP in reducing thermal injury severity was also demonstrated. SP is therefore a potential therapeutic option for pressure injury and other ischemic skin injuries.
The objective of the current cross-sectional study was to examine Achilles tendon transverse stiffness in a group of recreational runners with Achilles tendinopathy, in comparison to an asymptomatic ...group of runners with similar training history. We also aimed to determine the between-week intra-individual reliability of this measurement technique.
Cross-sectional cohort study.
A hand-held dynamometer was used to assess the transverse stiffness of the Achilles tendon (AT) in twenty-five recreational runners. In ten people with midportion Achilles tendinopathy (5 men, 5 women), measurements were taken directly over the most symptomatic location. In 15 people who were free of AT symptoms (7 men, 8 women), measurements were taken at an equivalent location on the tendon. Participants returned after one week to determine measurement reliability (intra-class correlation coefficient/ICC and minimum detectable change/MDC95). We also collected information about people's tendon loading activities, tendon thickness (ultrasound mesaurement), and symptoms (Victorian Institute of Sports Assessment-Achilles / VISA-A score).
The AT transverse stiffness was lower in people with Achilles tendinopathy (777 N/m ± 86) compared to those who were asymptomatic (873 N/m ± 72) (p < 0.05). AT transverse stiffness was negatively correlated with age and tendon thickness, and positively correlated with VISA-A score and waist circumference. Reliability was good, with ICC of 0.81 in people with tendinopathy and 0.80 in healthy controls, and an MDC95 of 118 and 87N/m in these two respective groups.
Transverse Achilles tendon stiffness can be reliably measured in people with midportion Achilles tendinopathy, and appears to be lower in people who are older, more symptomatic, and with more extensive tendon thickening. The potential clinical utility of monitoring tendon stiffness in the management of tendon injuries merits further study.
Abstract
Chronic high-thoracic and cervical spinal cord injury (SCI) results in a complex phenotype of cardiovascular consequences, including impaired left ventricular (LV) contractility. Here, we ...aim to determine whether such dysfunction manifests immediately post-injury, and if so, whether correcting impaired contractility can improve spinal cord oxygenation (SCO
2
), blood flow (SCBF) and metabolism. Using a porcine model of T2 SCI, we assess LV end-systolic elastance (contractility) via invasive pressure-volume catheterization, monitor intraparenchymal SCO
2
and SCBF with fiberoptic oxygen sensors and laser-Doppler flowmetry, respectively, and quantify spinal cord metabolites with microdialysis. We demonstrate that high-thoracic SCI acutely impairs cardiac contractility and substantially reduces SCO
2
and SCBF within the first hours post-injury. Utilizing the same model, we next show that augmenting LV contractility with the β-agonist dobutamine increases SCO
2
and SCBF more effectively than vasopressor therapy, whilst also mitigating increased anaerobic metabolism and hemorrhage in the injured cord. Finally, in pigs with T2 SCI survived for 12 weeks post-injury, we confirm that acute hemodynamic management with dobutamine appears to preserve cardiac function and improve hemodynamic outcomes in the chronic setting. Our data support that cardio-centric hemodynamic management represents an advantageous alternative to the current clinical standard of vasopressor therapy for acute traumatic SCI.
With increasingly complex and globalised supply chains, agricultural production and related impacts are often far removed from the point of final demand and difficult to trace. Accurately linking ...consumption to production is essential to understand drivers, key actors, and to facilitate actionable adaptation strategies to minimise negative impacts and guarantee food security. Here a hybridised multiregional input-output (MRIO) model, IOTA, is introduced. IOTA utilises sub-national and national level production, trade and environmental data, national scale commodity-use data, and a global economic MRIO, to link sub-national production and associated impacts to regional final consumption. In an example case-study, applying the model to Brazilian soy production and related land use for EU consumption, the relative levels of production in Brazilian states to meet EU demand differ from those of total production, and differ further still between the EU's constituent countries. Patterns can also vary considerably within a country's consumption profile depending on the sector of purchase. The linking of consumption to sub-national production and trade allows for more accurate and meaningful connections to be made between consumer behaviour and the associated impacts and risks. This enhanced understanding of consumption-driven impacts in turn informs, and allows for, more targeted and effective policy interventions to tackle the pressures and risks associated with agricultural commodity production for a global market.
DNA repair is important for maintaining genome integrity. In plants, DNA damage accumulated in the embryo of seeds is repaired early in imbibition, and is important for germination performance and ...seed longevity. An essential step in most repair pathways is the DNA ligase-mediated rejoining of single- and double-strand breaks. Eukaryotes possess multiple DNA ligase enzymes, each having distinct roles in cellular metabolism. Here, we report the characterization of DNA LIGASE VI, which is only found in plant species. The primary structure of this ligase shows a unique N-terminal region that contains a β-CASP motif, which is found in a number of repair proteins, including the DNA double-strand break (DSB) repair factor Artemis. Phenotypic analysis revealed a delay in the germination of atlig6 mutants compared with wild-type lines, and this delay becomes markedly exacerbated in the presence of the genotoxin menadione. Arabidopsis atlig6 and atlig6 atlig4 mutants display significant hypersensitivity to controlled seed ageing, resulting in delayed germination and reduced seed viability relative to wild-type lines. In addition, atlig6 and atlig6 atlig4 mutants display increased sensitivity to low-temperature stress, resulting in delayed germination and reduced seedling vigour upon transfer to standard growth conditions. Seeds display a rapid transcriptional DNA DSB response, which is activated in the earliest stages of water imbibition, providing evidence for the accumulation of cytotoxic DSBs in the quiescent seed. These results implicate AtLIG6 and AtLIG4 as major determinants of Arabidopsis seed quality and longevity.
In animals, the response to chronic hypoxia is mediated by prolyl hydroxylases (PHDs) that regulate the levels of hypoxia-inducible transcription factor α (HIFα). PHD homologues exist in other types ...of eukaryotes and prokaryotes where they act on non HIF substrates. To gain insight into the factors underlying different PHD substrates and properties, we carried out biochemical and biophysical studies on PHD homologues from the cellular slime mold, Dictyostelium discoideum, and the protozoan parasite, Toxoplasma gondii, both lacking HIF. The respective prolyl-hydroxylases (DdPhyA and TgPhyA) catalyze prolyl-hydroxylation of S-phase kinase-associated protein 1 (Skp1), a reaction enabling adaptation to different dioxygen availability. Assays with full-length Skp1 substrates reveal substantial differences in the kinetic properties of DdPhyA and TgPhyA, both with respect to each other and compared with human PHD2; consistent with cellular studies, TgPhyA is more active at low dioxygen concentrations than DdPhyA. TgSkp1 is a DdPhyA substrate and DdSkp1 is a TgPhyA substrate. No cross-reactivity was detected between DdPhyA/TgPhyA substrates and human PHD2. The human Skp1 E147P variant is a DdPhyA and TgPhyA substrate, suggesting some retention of ancestral interactions. Crystallographic analysis of DdPhyA enables comparisons with homologues from humans, Trichoplax adhaerens, and prokaryotes, informing on differences in mobile elements involved in substrate binding and catalysis. In DdPhyA, two mobile loops that enclose substrates in the PHDs are conserved, but the C-terminal helix of the PHDs is strikingly absent. The combined results support the proposal that PHD homologues have evolved kinetic and structural features suited to their specific sensing roles.
Pericytes are mural cells closely associated with endothelial cells in capillaries and microvessels. They are precursors of mesenchymal stem/stromal cells that have historically been retrospectively ...characterized in culture. We established a protocol, described in this chapter, to characterize and isolate pericytes from multiple human organs by flow cytometry and fluorescence-activated cell sorting. This prospective purification of pericytes brings us a step forward in the development of strategies for their use in the clinic.
Pericytes are found in all vascularized organs and are defined anatomically as perivascular cells that closely surround endothelial cells in capillaries and microvessels and are embedded within the ...same basement membrane. They have been shown to have diverse physiological and pathological functions including regulation of blood pressure, and tissue regeneration and scarring. Fundamental to understanding the role these cells play in these diverse processes is the ability to accurately identify and localize them in vivo. To do this, we have developed multicolor immunohistochemistry protocols described in this chapter.
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