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The diagnostic and prognostic value of systems biology research in major traumatic and thermal injury: a review

Burns & Trauma 2016年第3期4卷 169-179页

作者： Jon Hazeldine Peter Hampson janet m.lord NIHR Surgical Reconstruction and microbiology Research Centre Institute of Inflammation and AgeingBirmingham University Medical SchoolBirmingham B152TTUK NIHR Surgical Reconstruction and microbiology Research Centre Institute of Inflammation and AgeingBirmingham University Medical SchoolBirmingham B152TTUK Healing Foundation Centre for Burns Research Queen Elizabeth HospitalBirmingham B152WBUK

As secondary complications remain a significant cause of morbidity and mortality amongst hospitalised trauma patients,the need to develop novel approaches by which to identify patients at risk of adverse outcome is becoming increasingly *** on the idea that patients who experience"poor"outcome post trauma elicit a response to injury that is distinct from those who experience"good"outcome,tailored therapeutics is an emerging concept aimed at improving current treatment regimens by promoting patient-specific *** use of recent advancements in the fields of genomics,proteomics and metabolomics,numerous groups have undertaken a systems-based approach to analysing the acute immune and inflammatory response to major traumatic and thermal injury in an attempt to uncover a single or combination of biomarkers that can identify patients at risk of adverse *** results are encouraging,with all three approaches capable of discriminating patients with"good"outcome from those who develop nosocomial infections,sepsis and multiple organ failure,with differences apparent in blood samples acquired as early as 2 h post *** particular,genomic data is proving to be highly informative,identifying patients at risk of"poor"outcome with a higher degree of sensitivity and specificity than statistical models built upon data obtained from existing anatomical and physiological scoring ***,focussing predominantly upon human-based research,we provide an overview of the findings of studies that have investigated the immune and inflammatory response to major traumatic and thermal injury at the genomic,protein and metabolite level,and consider both the diagnostic and prognostic potential of these approaches.

关键词： Burns Cytokines Genomics Inflammation mortality Sepsis Trauma

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Vitamin D status and its influence on outcomes following major burn injury and critical illness

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Burns & Trauma 2018年第2期6卷 82-92页

作者： Khaled Al-Tarrah martin Hewison Naiem moiemen janet m.lord Institute of Inflammation and Ageing Birmingham University Medical SchoolBirmingham B15 2TTUK Scar Free Foundation Centre for Burns Research University Hospital Birmingham Foundation TrustBirmingham B15 2WBUK Institute of metabolism and Systems Research and Centre for Endocrinology Diabetes and metabolism The University of BirminghamBirmingham B15 2TTUK

Vitamin D deficiency is common among the general population. It is also observed in up to 76% of critically ill *** the high prevalence of hypovitaminosis D in critical illness, vitamin D is often overlooked by medical staff as the clinical implications and consequences of vitamin D deficiency in acute contexts remain to be fully *** D has a broad range of pleotropic effects on various processes and systems including the immuneinflammatory response. 1α,25-dihydroxyvitamin D (1,25(OH)2D), has been shown to promote a tolerogenic immune response limiting deleterious inflammatory effects, modulation of the innate immune system, and enhancement of anti-microbial peptides. Vitamin D deficiency is frequently observed in critically ill patients and has been related to extrinsic causes (i.e., limited sunlight exposure), magnitude of injury/illness, or the treatment started by medical doctors including fluid resuscitation. Low levels of vitamin D in critically ill patients have been associated with sepsis, organ failure, and mortality. Despite this, there are subpopulations of critical illness, such as burn patients, where the literature regarding vitamin D status and its influence on outcomes remain insufficient. Thermal injury results in damage to both burned and non-burned tissues, as well as induces an exaggerated and persistent immune-inflammatory and hypermetabolic response. In this review, we propose potential mechanisms in which burn injury affects the vitamin D status and summarizes current literature investigating the influence of vitamin D status on outcomes. In addition, wereviewed the literature and trials investigating vitamin D supplementation in critically ill patients and discuss the therapeutic potential of vitamin D supplementation in burn and critically ill patients. We also highlight current limitations of studies that have investigated vitamin D status and supplementation in critical illness. Thermal injury influences vitamin

关键词： Vitamin D Critical care Burns Trauma Thermal injury Critically ill

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Traumatic injury is associated with reduced deoxyribonuclease activity and dysregulation of the actin scavenging system

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Burns & Trauma 2021年第1期9卷 558-572页

作者： Jon Hazeldine Robert J.Dinsdale David N.Naumann Animesh Acharjee Jonathan R.B.Bishop janet m.lord Paul Harrison Institute of Inflammation and Ageing University of BirminghamEdgbastonBirminghamWest MidlandsB152TTUnited Kingdom National Institute for Health Research Surgical Reconstruction and microbiology Research Centre Heritage BuildingQueen Elizabeth Hospital BirminghamMindelsohnWayEdgbastonBirminghamWest MidlandsB152THUnited Kingdom Scar Free Foundation Birmingham Centre for Burns Research University Hospital Birmingham Foundation TrustQueen Elizabeth Hospital BirminghamMindelsohnWayEdgbastonBirminghamWest MidlandsB152THUnited Kingdom Academic Department of military Surgery and Trauma Royal Centre for Defence MedicineQueen Elizabeth Hospital BirminghamMindelsohnWayEdgbastonBirminghamWest MidlandsB152THUnited Kingdom Institute of Cancer and Genomic Sciences Centre for Computational BiologyUniversity of BirminghamEdgbastonBirminghamWest MidlandsB152TTUnited Kingdom

Background:Traumatic injury is associated with increased concentrations of cell-free DNA(cfDNA)in the circulation,which contribute to post-injury *** endonuclease deoxyribonuclease 1(DNase-1)is responsible for removing 90%of circulating ***,DNase activity was reported to be significantly reduced following major non-traumatic brain injury(TBI),but the processes responsible were not ***,it is not known how quickly following injury DNase activity is reduced and whether this also occurs after ***:At 3 post-injury time points(≤1,4–12 and 48–72 hours),blood samples were obtained from 155 adult trauma patients that had sustained an isolated TBI(n=21),TBI with accompanying extracranial injury(TBI^(+))(n=53)or an extracranial injury only(ECI)(n=81).In addition to measuring cfDNA levels and the activity and expression of DNase,circulating concentrations of monomeric globular action(G-actin),an inhibitor of DNase-1,and the actin scavenging proteins gelsolin(GSN)and vitamin D binding protein(VDBP)were determined and values compared to a cohort of healthy ***:Significantly elevated concentrations of plasma cfDNA were seen in TBI,TBI^(+)and ECI patients at all study time points when compared to healthy *** levels were significantly higher at≤1 hour post-injury in ECI patients who subsequently developed multiple organ dysfunction syndrome when compared to those who did *** DNase-1 protein was significantly elevated in all patient groups at all sampling time *** contrast,DNase enzyme activity was significantly reduced,with this impaired function evident in TBI^(+)patients within minutes of *** concentrations of G-actin were elevated in all patient cohorts in the immediate aftermath of injury and this was accompanied by a significant reduction in the levels of GSN and ***:The post-traumatic increase in circulating cfDNA that occurs following extracranial trauma and TBI

关键词： Cell-free DNA Deoxyribonuclease Extracellular actin scavenging system Pre-hospital Trauma

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Heparin resistance in severe thermal injury:a prospective cohort study

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Burns & Trauma 2021年第1期9卷 157-169页

作者： Liam D Cato Benjamin Bailiff Joshua Price Christos Ermogeneous Jon Hazeldine William Lester Gillian Lowe Christopher Wearn Jonathan RB Bishop janet m lord Naiem moiemen Paul Harrison Scar Free Foundation Birmingham Centre for Burns Research University Hospitals Birmingham Foundation TrustQueen Elizabeth Hospital BirminghamMindelsohn WayBirminghamB152WBUK Department of Haematology University Hospitals Birmingham Foundation TrustMindelsohnWayBirminghamB152WBUK Institute of Inflammation and Ageing University of BirminghamBirminghamB152TTUK NIHR Surgical Reconstruction and microbiology Research Centre University Hospitals Birmingham Foundation TrustMindelsohn WayBirminghamB152WBUK

Background:Low molecular-weight heparin(LmWH)is routinely administered to burn patients for *** studies have reported heparin resistance,yet the mechanism(s)and prevalence have not been systematically *** hypothesized that nucleosomes,composed of histone structures with associated DNA released from injured tissue and activated immune cells in the form of neutrophil extracellular traps(NETs or NETosis),neutralize LmWH resulting in suboptimal anticoagulation,assessed by reduction in anti-factor Xa ***:Blood was sampled from>15%total body surface area(TBSA)burn patients receiving LmWH on days 5,10 and *** anti-factor Xa(AFXa)activity,anti-thrombin(ATIII)activity,cellfree DNA(cfDNA)levels and nucleosome levels were *** effects regression was adjusted for multiple confounders,including injury severity and ATIII activity,and was used to test the association between nucleosomes and ***:A total of 30 patients with severe burns were *** TBSA 43%(SD 17).Twentythree(77%)patients were affected by heparin resistance(defined by AFXa activitymL).mean peak AFXa activity across samples was 0.18 IU/mL(SD 0.11).mean ATIII was 81.9%activity(SD 20.4).Samples taken at higher LWmH doses were found to have significantly increased AFXa activity,though the effect was not observed at all doses,at 8000 IU no samples were heparin *** levels were negatively correlated with AFXa(r=−0.29,p=0.050)consistent with the *** final model,with peak AFXa as the response variable,was adjusted for nucleosome levels(p=0.0453),ATIII activity(p=0.0053),LmWH dose pre-sample(p=0.0049),drug given(enoxaparin or tinzaparin)(p=0.03),and other confounders including severity of injury,age,gender,time point of ***:Heparin resistance is a prevalent issue in severe *** levels were increased post-burn,and showed an inverse association with AFXa consistent with the hypothesis that they ma

关键词： Burn Heparin resistance Low molecular-weight heparin Nucleosomes Neutrophil extracellular traps Factor-Xa Thrombosis Enoxaparin NETosis

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Dehydroepiandrosterone:a potential therapeutic agent in the treatment and rehabilitation of the traumatically injured patient

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Burns & Trauma 2019年第1期7卷 248-260页

作者： Conor Bentley Jon Hazeldine Carolyn Greig janet lord mark Foster NIHR Surgical Reconstruction and microbiology Research Centre University Hospital BirminghamBirmingham B152WBUK School of Sport Exercise and Rehabilitation SciencesUniversity of BirminghamBirminghamUK mRC-Arthritis Research UK Centre for musculoskeletal Ageing Research Institute of Inflammation and AgeingBirmingham University Medical SchoolBirmingham B152TTUK NIHR Biomedical Research Centre University Hospital BirminghamBirminghamUK Royal Centre for Defence medicine Birmingham Research ParkBirmingham B152SQUK.

Severe injuries are the major cause of death in those aged under 40,mainly due to road traffic ***,metabolic and immune pathways respond to limit the tissue damage sustained and initiate wound healing,repair and regeneration ***,depending on age and sex,the response to injury and patient prognosis differ *** are catabolic and immunosuppressive and are produced as part of the stress response to injury leading to an intra-adrenal shift in steroid biosynthesis at the expense of the anabolic and immune enhancing steroid hormone dehydroepiandrosterone(DHEA)and its sulphated metabolite dehydroepiandrosterone sulphate(DHEAS).The balance of these steroids after injury appears to influence outcomes in injured humans,with high cortisol:DHEAS ratio associated with increased morbidity and *** models of trauma,sepsis,wound healing,neuroprotection and burns have all shown a reduction in proinflammatory cytokines,improved survival and increased resistance to pathological challenges with DHEA *** supplementation studies,which have focused on post-menopausal females,older adults,or adrenal insufficiency have shown that restoring the cortisol:DHEAS ratio improves wound healing,mood,bone remodelling and psychological ***,there are no DHEA or DHEAS supplementation studies in trauma patients,but we review here the evidence for this potential therapeutic agent in the treatment and rehabilitation of the severely injured patient.

关键词： Dehydroepiandrosterone Dehydroepiandrosterone sulphate Traumatic injury Intensive care Immune Rehabilitation

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Thiopurine use associated with reduced B and natural killer cells in inflammatory bowel disease

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World Journal of Gastroenterology 2017年第18期23卷 3240-3251页

作者： James D lord Donna m Shows Translational Research Program Benaroya Research Institute Gastroenterology Division Virginia Mason Medical Center

To identify which blood and mucosal lymphocyte populations are specifically depleted by thiopurine use in *** thiopurines azathioprine and 6-mercaptopurine have been a mainstay of inflammatory bowel disease (IBD) therapy for decades, but their mechanism of action in vivo remains obscure. Although thiopurines are lymphotoxic at high doses, and have been reported to cause T cell apoptosis in vitro, their ability to control IBD at lower doses suggests that they may selectively deplete particular lymphocyte populations. Blood cells from 19 IBD patients on a thiopurine, 19 IBD patients not on a thiopurine, and 38 matched healthy control subjects were analyzed by multiple multi-color flow cytometry panels to quantify the immune cell subsets contained therein, both as a percent of cells, and as an absolute cell count. Similar analyses were performed on colon biopsies from 17 IBD patients on a thiopurine, 17 IBD patients not on a thiopurine, and 49 healthy screening colonoscopy *** blood counts revealed lower lymphocyte, but not monocyte or granulocyte, counts in IBD patients who were taking thiopurines at the time of sampling. This reduction was restricted to CD3-negative lymphocytes, wherein both natural killer (NK) and B cells were significantly reduced among thiopurine recipients. Among CD19+ B cells, the transitional B cells were particularly depleted, being nearly absent in both blood and colon biopsies of thiopurine recipients. No differences were associated with thiopurine use in CD8+ T cells, mucosa-associated invariant T (mAIT) cells, invariant natural killer T (iNKT) cells, gamma/delta T cells, Th1, Th17, regulatory T cells (Tregs) or naïve CD4+ T cells. However, patients with IBD had significantly more circulating FOXP3+, Helios+ Tregs and fewer iNKT and mAIT cells than healthy *** use is associated with reduced B and NK cell, but not T cell, subpopulations in the blood of IBD patients.

关键词： Thiopurine Azathioprine mercaptopurine Lymphocyte Natural killer cell Transitional B cell Inflammatory bowel disease

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Towards high strength cast mg-RE based alloys:Phase diagrams and strengthening mechanisms

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Journal of magnesium and Alloys 2022年第6期10卷 1401-1427页

作者： janet m.meier Josh Caris Alan A.Luo Department of materials Science and Engineering The Ohio State UniversityColumbusOH 43210USA Terves LLC EuclidOH 44117USA Department of Integrated Systems Engineering The Ohio State UniversityColumbusOH 43210USA

mg-rare earth(RE)based systems provide several important commercial alloys and many alloy development opportunities for high strength applications,especially in aerospace and defense *** phase diagrams,microstructure,and strengthening mechanisms of these multicomponent systems are very complex and often not well understood in *** have calculated phase diagrams of important binary,ternary,and multicomponent RE-containing alloy systems,using CALPHAD(CALculation of PHAse Diagrams).Based on these phase diagrams,this paper offers a critical overview on phase equilibria and strengthening mechanisms in these alloy systems,including precipitation,long period stacking order(LPSO),and other intermetallic *** review also summarized several promising mg-RE based cast alloys in comparison with commercial WE54 and WE43 alloys;and explored new strategies for future alloy development for high strength *** is pointed out that the combination of precipitation and LPSO phases can lead to superior strength and ductility in mg-RE based cast *** precipitates and LPSO phases can form a complex three-dimensional network that effectively impedes dislocation motion on the basal and non-basal *** LPSO phases can also prevent the coarsening of precipitates when they interact,thus providing good thermal stability at elevated *** research is needed to determine how the combination of these two types of phases can be used in alloy design and industrial scale applications.

关键词： magnesium alloys Phase diagrams Precipitation strengthening Long period stacking order(LPSO) Alloy development CALPHAD

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Analytical evaluation of steady-state solute distribution in through- diffusion and membrane behavior test under non-perfectly flushing boundary conditions

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Journal of Rock mechanics and Geotechnical Engineering 2024年第1期16卷 258-267页

作者： Guannian Chen Yuchao Li Kristin mSample-lord Shan Tong School of Civil&Environmental Engineering and Geography Science Ningbo UniversityNingbo315211China mOE Key Laboratory of Soft Soils and Geoenvironmental Engineering College of Civil Engineering and ArchitectureZhejiang UniversityHangzhou310058China Ningbo ZCONE High-tech Company Limited Ningbo315000China Department of Civil and Environmental Engineering Villanova UniversityVillanovaPAUSA

The through-diffusion and membrane behavior testing procedure using a closed-system apparatus has been widely used for concurrent measurement of diffusion and membrane efficiency coefficients of low-permeability clay-based barrier ***,the common assumption of perfectly flushing conditions at the specimen boundaries could induce errors in analyses of the diffusion coefficients and membrane *** this study,an innovative pseudo three-dimensional(3D)analytical method was proposed to evaluate solute distribution along the boundary surfaces of the soil-porous disks system,considering the non-perfectly flushing *** results were consistent with numerical models under two scenarios considering different inflow/outflow *** proposed model has been demonstrated to be an accurate and reliable method to estimate solute distributions along the *** calculated membrane efficiency coefficient and diffusion coefficient based on the proposed analytical method are more accurate,resulting in up to 50%less relative error than the traditional approach that adopts the arithmetic mean value of the influent and effluent *** retar-dation factor of the clay specimen also can be calculated with a revised cumulative mass ***,the simulated transient solute transport matched with experimental data from a multi-stage through-diffusion and membrane behavior test,validating the accuracy of the proposed method.

关键词： Diffusion testing membrane behavior Coupled transport Clay barrier Transport modeling

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Tuning the intentional corona of cerium oxide nanoparticles to promote angiogenesis via fibroblast growth factor 2 signalling

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Regenerative Biomaterials 2022年第1期9卷 963-978页

作者： Lu Fu Rupeng Li John m.Whitelock megan S.lord Graduate School of Biomedical Engineering UNSW SydneySydneyNSW 2052Australia School of minerals and Energy Resources Engineering UNSW SydneySydneyNSW 2052Australia

Inadequate angiogenesis is a hallmark of conditions including cardiovascular diseases,stroke and chronic diabetic wounds,which exhibit tissue ischaemia ensuring that therapeutic strategies to promote angiogenesis are of great ***,many angiogenic treatments involve the delivery of growth factors which have limited clinical success due to poor stability,high manufacturing cost and poor *** oxide nanoparticles(nanoceria)can either promote or inhibit angiogenesis depending on their surface corona ***,nanoceria were functionalized with an intentional heparin corona,a polysaccharide which binds and signals growth factors,of different chain lengths and surface grafting density to establish their effect on *** nanoparticles promoted angiogenesis in vivo with the surface grafting density positively correlated with angiogenesis over the widest concentration range;however,chain length did not play a *** heparin–nanoceria supported fibroblast growth factor 2(FGF2)signalling in vitro and promoted FGF2-mediated angiogenesis in *** nanoparticles were internalized by endothelial cells in vitro where they trafficked to the lysosomes and reduced cell viability suggesting that the angiogenic activity of heparin–nanoceria is mediated in the extracellular ***,this study adds to our knowledge of the angiogenic effects of heparin–nanoceria towards finding new angiogenic treatments.

关键词： cerium oxide nanoparticle endothelial angiogenesis

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materials and technology of Chinese jades dating to the Western Zhou period (1050―771 BCE)

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Science China(Technological Sciences) 2008年第4期51卷 467-480页

作者： janet G DOUGLAS Department of Conservation and Scientific Research Freer Gallery of Art / Arthur M. Sackler Gallery Smithsonian Institution

Excavated jades dating to the Western Zhou period (1050―771 BCE) from the Xi’an area in Shaanxi Province, China, and contemporaneous jades in the collections of the Arthur m. Sackler Gallery at the Smithsonian Institution have been studied to learn about the jade and stone materials and how they were worked during the Western Zhou period. materials identification was carried out using a combination of techniques such as Fourier-transform infrared spectroscopy and X-ray diffraction. Tool marks were studied using stereomicroscopy and examination of mold impressions using scanning electron microscopy. All of these objects were pro- duced through simple processes involving solid drilling, riffling, and sharp point abrasion; and no evidence was found for the use of rotary tools for incising or sawing.

关键词： jade nephrite stone China Western Zhou scanning electron microscopy materials technology tool marks

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