ORCID Profile
0000-0003-0135-134X
Current Organisation
James Cook University
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: Springer Science and Business Media LLC
Date: 12-2014
Publisher: Elsevier BV
Date: 2021
Publisher: SAGE Publications
Date: 07-2017
Abstract: Our aim was to examine the effect of low-volume 0.9% NaCl adenosine, lidocaine and Mg 2+ (ALM) ‘drip’ on early immune-inflammatory activation after a single laparotomy with no further manipulation. Male Sprague–Dawley rats were anesthetized and randomly assigned to one of the groups, baseline, 1 h infusion 0.9% NaCl ± ALM and metrics, 1 h infusion and 6-h metrics, and 6 h continuous infusion and metrics. Complete blood count, acid–base balance, systemic levels of IL-6 and IL-10, and coagulation status were measured. After 1 h, there was a disproportionate increase in circulating neutrophils between saline and ALM groups despite an identical 45% fall in lymphocytes. Disproportionate increases also occurred in platelet counts 1 h after surgery, and saline controls had increased respiratory alkalosis at 6 h with higher lactate. Systemic inflammation was also evident after 1 h in both groups (plasma IL-6 increase) and was lified in saline-controls after 6 h. The ALM group increased anti-inflammatory cytokine IL-10. Surgery was not associated with acute coagulopathy however, there were significant reductions in fibrinolysis. Following a single laparotomy, ALM infusion appeared to reduce stress-induced release of neutrophils and platelets into the circulation, and reduced acid–base disturbance. After 1 h, both groups had similar IL-6 levels, but ALM animals had increased IL-10, indicating improved inflammatory balance. The uncoupling of inflammation and coagulation activation but not fibrinolysis may offer a unique opportunity to investigate differential activation of innate immunity in response to sterile injury in this model.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-06-2019
DOI: 10.1097/TA.0000000000002397
Abstract: Noncompressible torso hemorrhage is a leading cause of traumatic death. Our aim was to examine survival time and the expression of key master genes of cellular metabolism after 3% NaCl adenosine, lidocaine, and Mg 2+ (ALM) bolus and 4 hours 0.9% NaCl/ALM “drip” in a rat model of uncontrolled hemorrhagic shock. Male Sprague-Dawley rats (425 ± 8 g) were anesthetized and randomly assigned to saline controls (n = 10) or ALM therapy (n = 10). Hemorrhage was induced by liver resection (60% left lateral lobe). After 15 minutes, a single intravenous bolus of 3% NaCl ± ALM (0.7 mL/kg) was administered (Phase 1), and after 60 minutes, a 0.9% NaCl ± ALM stabilization “drip” (0.5 mL/kg per hour) was infused for 4 hours (Phase 2) with 72 hours monitoring. Mean arterial pressure and lactate were measured. After 72 hours (or high moribund score), tissues were freeze-cl ed and stored at −80°C. Total RNA was extracted in heart, brain, and liver, and the relative expressions of -k, mtCO3, PGC-1α, and sirt-1 genes were determined. Kaplan-Meier survival curves showed that controls had a mean survival time of 22.6 ± 4.5 hours, and ALM animals, 72 ± 0 hours ( p 0.05). Death in controls was accompanied by approximately sevenfold increase in lactate, while ALM animals maintained lactates similar to baseline over 72 hours. The relative expression of -k, PGC-1α, and sirt-1 in heart and brain was 1.5-fold and 2.7-fold higher in the ALM group compared with controls ( p 0.05), with the exception of mitochondrial encoded cytochrome C oxidase III pseudogene 1 in heart, which was 19-fold higher. In contrast, -k, sirt-1, and mtCO3 gene expression in liver was significantly 29–41% lower in the ALM group compared with controls, and PGC-1α was 75% lower. Small-volume ALM therapy led to 3.3-times longer survival time compared with saline controls after hemorrhagic shock. A hallmark of the ALM-survival phenotype in heart and brain was an upregulation of -k, PGC-1α, sirt-1, and mtCO3 to presumably “boost” mitochondrial function and ATP production, and a contrasting downregulation in liver. These central-peripheral differences in gene expression require further investigation.
Publisher: Public Library of Science (PLoS)
Date: 16-11-2017
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2021
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2013
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2017
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2018
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2019
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-09-2020
DOI: 10.1097/SHK.0000000000001630
Abstract: The effect of analgesia on physiological systems has received little attention in trauma research. Our aim was to examine the effect of two different analgesics, buprenorphine and carprofen, on adenosine, lidocaine, and magnesium (ALM) resuscitation in a rat model of laparotomy and non-compressible hemorrhage. Male Sprague-Dawley rats were randomly assigned to Saline Carprieve, ALM Carprieve, Saline Buprenorphine, or ALM Buprenorphine (all n = 10). Anesthetized animals underwent surgical placement of chronic catheters and laparotomy, then hemorrhage was induced by liver resection (60% left lateral lobe). After 15 min, animals received 0.7 mL/kg 3% NaCl ± ALM bolus, and after 60 min, 4 h 0.5 mL/kg/h 0.9% NaCl±ALM drip with 72 h monitoring. Carprieve groups received 5 mg/kg s.c. every 24 h and Buprenorphine groups received 0.05 mg/kg Temgesic every 6 to 12 h. Survival, hemodynamics, blood chemistry, and hematology were measured. ALM Carprieve led to 100% survival compared to 40% survival in ALM Buprenorphine group ( P = 0.004). In Saline-treated rats, buprenorphine reduced median survival time by 91% (22 h to 2 h). Recovery of mean arterial pressure (MAP) at 60 min was lower in the buprenorphine versus Carprieve groups (83% vs. 101% for ALM and 62% vs. 95% for Saline groups). Buprenorphine was also associated with higher blood lactates and potassium. No analgesic-related differences were found in total white cells, lymphocytes, platelet count, hyperthermia, weight loss, or pica. We conclude that reduced survival and MAP recovery appears to a buprenorphine effect on cardiovascular function. Until the underlying mechanisms can be elucidated, buprenorphine should be used with caution in small and possibly large models of trauma and shock.
Publisher: Springer Science and Business Media LLC
Date: 15-04-2019
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 16-10-2019
Publisher: Frontiers Media SA
Date: 22-01-2021
DOI: 10.3389/FIMMU.2020.610131
Abstract: We present a brief history of the immune response and show that Metchnikoff’s theory of inflammation and phagocytotic defense was largely ignored in the 20 th century. For decades, the immune response was believed to be triggered centrally, until Lafferty and Cunningham proposed the initiating signal came from the tissues. This shift opened the way for Janeway’s pattern recognition receptor theory, and Matzinger’s danger model. All models failed to appreciate that without inflammation, there can be no immune response. The situation changed in the 1990s when cytokine biology was rapidly advancing, and the immune system’s role expanded from host defense, to the maintenance of host health. An inflammatory environment, produced by immune cells themselves, was now recognized as mandatory for their attack, removal and repair functions after an infection or injury. We explore the cellular programs of the immune response, and the role played by cytokines and other mediators to tailor the right response, at the right time. Normally, the immune response is robust, self-limiting and restorative. However, when the antigen load or trauma exceeds the body’s internal tolerances, as witnessed in some COVID-19 patients, excessive inflammation can lead to increased sympathetic outflows, cardiac dysfunction, coagulopathy, endothelial and metabolic dysfunction, multiple organ failure and death. Currently, there are few drug therapies to reduce excessive inflammation and immune dysfunction. We have been developing an intravenous (IV) fluid therapy comprising adenosine, lidocaine and Mg 2+ (ALM) that confers a survival advantage by preventing excessive inflammation initiated by sepsis, endotoxemia and sterile trauma. The multi-pronged protection appears to be unique and may provide a tool to examine the intersection points in the immune response to infection or injury, and possible ways to prevent secondary tissue damage, such as that reported in patients with COVID-19.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2014
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2015
Publisher: Oxford University Press (OUP)
Date: 21-08-2023
DOI: 10.1093/JBCR/IRAD127
Abstract: The management of severe burns remains a complex challenge. Adenosine, lidocaine and magnesium (ALM) resuscitation therapy has been shown to protect against hemorrhagic shock and traumatic injury. The aim of the present study was to investigate the early protective effects of small-volume ALM fluid resuscitation in a rat model of 30% total body surface area (TBSA) thermal injury. Male Sprague-Dawley rats (320-340g n=25) were randomly assigned to: 1) Sham (surgical instrumentation and saline infusion, without burn, n=5), 2) Saline resuscitation group (n=10), or 3) ALM resuscitation group (n=10). Treatments were initiated 15-min after burn trauma, including 0.7ml/kg 3% NaCl±ALM bolus and 0.25-0.5ml/kg/h 0.9% NaCl±ALM drip, with animals monitored to 8.25-hr post-burn. Hemodynamics, cardiac function, blood chemistry, hematology, endothelial injury markers and histopathology were assessed. Survival was 100% for Shams and 90% for both ALM and Saline groups. Shams underwent significant physiological, immune and hematological changes over time as a result of surgical traums. ALM significantly reduced malondialdehyde levels in the lungs compared to Saline (p=0.023), and showed minimal alveolar destruction and inflammatory cell infiltration (p& .001). ALM also improved cardiac function and oxygen delivery (21%, p=0.418 vs Saline), reduced gut injury (p& .001 vs Saline), and increased plasma adiponectin (p& .001 vs baseline). Circulating levels of the acute phase protein alpha 1-acid glycoprotein (AGP) increased 1.6-times (p& .001), which may have impacted ALM’s therapeutic efficacy. We conclude that small-volume ALM therapy significantly reduced lung oxidative stress and preserved alveolar integrity following severe burn trauma. Further studies are required to assess higher ALM doses with longer monitoring periods.
Publisher: Springer Science and Business Media LLC
Date: 28-06-2019
DOI: 10.1038/S41598-019-45871-Z
Abstract: Specific-pathogen free (SPF) animals were introduced in the 1960s to minimize disease and infection as variables in biomedical research. Our aim was to examine differences in physiological response in rat colonies bred and housed in a conventional versus SPF facility, and implications for research. Sprague-Dawley rats were anesthetized and catheterized for blood and pressure monitoring, and electrocardiogram (ECG) leads implanted. Hematology was assessed, and coagulation profile using rotational thromboelastometry. Health screening was outsourced to Cerberus Sciences. SPF rats had significantly lower pulse pressure (38% decrease), arrhythmias and prolonged QTc (27% increase) compared to conventional rats. No arrhythmias were found in conventional rats. SPF rats had significantly higher white cell, monocyte, neutrophil and lymphocyte counts, and were hyperfibrinolytic, indicated by EXTEM maximum lysis %. Independent assessment revealed similar pathogen exclusion between colonies, with the exception of Proteus in SPF animals. Returning to a conventional facility restored normal host physiology. We conclude that SPF animals displayed an abnormal hemodynamic, hematological and hemostatic phenotype in response to anesthesia and surgery, and provide a number of recommendations to help standardize research outcomes and translation.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2017
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2013
Publisher: Elsevier BV
Date: 05-2016
DOI: 10.1016/J.THROMRES.2016.03.007
Abstract: The mechanisms of early traumatic-induced coagulopathy are not well understood. Our aim was to examine the role of platelets and fibrinogen to early coagulopathy in the rat after hemorrhagic shock. Adult Sprague-Dawley rats were anesthetized and randomly assigned to: 1) Baseline, 2) Hemorrhage or 3) Shock (n=10 each). Controlled phlebotomy occurred over 20min and animals were left in shock 60min. Coagulation was assessed using PT, aPTT, ROTEM and ELISAs. PT and aPTT increased 5 to 7 times following hemorrhage and shock. Prolongation of EXTEM and INTEM clotting times, lower clot elasticity and increased EXTEM lysis index (LI) indicated a hypocoagulopathy. After 20min hemorrhage, LI(30-60) in FIBTEM was ~100%, EXTEM 83-87% and APTEM 80-82% indicating a platelet contribution to the coagulopathy with no hyperfibrinolysis. After 60min shock, the situation was reversed with fibrinogen loss being a contributor. This apparent switch from a platelet- to a fibrinogen-based coagulopathy, with fibrinolysis, was supported by ≥15% in maximum lysis (ML), a threefold increase in plasma PAI-1 after hemorrhage, and undetectable levels after shock. Curiously, the relative contribution of fibrinogen latelet ratio to clot litude, determined from FIBTEM/EXTEM A10 ratio (and MCF), remained unchanged at ~1:5 for baseline, hemorrhage and shock despite a progressive hypocoagulopathy. Significant increases in P-selectin, acidosis and lactate indicated systemic endothelial damage and tissue hypoperfusion. Hypocoagulopathy following severe hemorrhage and shock in the rat appeared to involve a two-step process of platelet dysfunction followed by fibrinogen impairment, possibly linked to progressive endothelial dysfunction.
Publisher: Wiley
Date: 11-11-2022
DOI: 10.1111/ANEC.12910
Abstract: Many primary prevention heart failure (HF) patients with an implantable cardiac defibrillator (ICD) rarely experience life‐threatening ventricular arrhythmias (VA). New strategies are required to identify patients most at risk of VA and sudden cardiac death who would benefit from an ICD. One potential method is the detection of fragmented QRS (fQRS) on the electrocardiogram. The aim was to assess the predictive capacity of fQRS for VA and mortality in ischemic (ICM) and non‐ischemic cardiomyopathy (NICM) primary prevention HF patients. A systematic review and meta‐analysis of studies examining fQRS in HF patients with or without an ICD who met primary prevention indications with reduced ejection fraction ≤40%. Outcome measures were VA (or appropriate ICD therapy) and all‐cause mortality. Ten studies involving 3885 patients were included for analysis. Most patients were male with non‐fQRS patients being significantly younger (−1.5[−2.66, −0.42], p = .03). Diabetes was more likely in fQRS patients (1.12[1.01, 1.25], p = .03) while non‐fQRS patients were 28% more likely to have a history of atrial fibrillation (0.82[0.67,1.00], p = .05). Ventricular arrhythmias were significantly 1.5 times more likely in patients with fQRS (1.51[1.02, 2.25], p = .04). HF patients were 1.7 times more likely to die of any cause if fQRS was present (1.68[1.13, 2.52], p = .01). NICM patients with fQRS have a significant 2.6‐fold increased incidence of death compared with ICM patients (2.55[1.63, 3.98], p .0001). fQRS is associated with VA and all‐cause mortality and may be a novel marker in the risk stratification of primary prevention HF patients indicated for ICD implantation.
Publisher: Springer Science and Business Media LLC
Date: 10-11-2020
DOI: 10.1186/S13018-020-02042-5
Abstract: No validated pre-operative cardiac risk stratification tool exists that is specific for total hip and total knee arthroplasty (THA and TKA, respectively). To reduce the risk of post-operative cardiac complication, surgeons need clear guidance on which patients are likely to benefit from pre-operative cardiac optimisation. This is particularly important for asymptomatic patients, where the need is harder to determine. Primary THA and TKA performed between January 1, 2010, and December 31, 2017, were identified from a single orthopaedic practice. Over 25 risk factors were evaluated as predictors for patients requiring additional cardiac investigation beyond an ECG and echocardiogram, and for cardiac abnormality detected upon additional investigation. A multivariate logistic regression was conducted using significant predictor variables identified from inferential statistics. A series of predictive scores were constructed and weighted to identify the influence of each variable on the ability to predict the detection of cardiac abnormality pre-operatively. Three hundred seventy-four patients were eligible for inclusion. Increasing age ( p 0.001), history of cerebrovascular accident ( p = 0.018), family history of cardiovascular disease (FHx of CVD) ( p 0.001) and decreased ejection fraction (EF) ( p 0.001) were significant predictors of additional cardiac investigation being required. Increasing age ( p = 0.003), male gender ( p = 0.042), FHx of CVD ( p = 0.001) and a reduced EF ( p 0.001) were significantly predictive for the detection of cardiac abnormality upon additional cardiac investigation. Increasing age, male gender, FHx of CVD and decreased ejection fraction are important risk factors to consider for pre-operative cardiac optimisation in THA and TKA patients. These findings can be applied towards future predictive models, to determine which asymptomatic patients are likely to benefit from pre-operative cardiac referral.
Publisher: Elsevier BV
Date: 03-2019
Publisher: Elsevier BV
Date: 09-2017
Publisher: Elsevier BV
Date: 09-2017
DOI: 10.1016/J.JSS.2017.05.006
Abstract: Tranexamic acid (TXA) is increasingly used during major surgery with the goal to reduce excessive bleeding, transfusion requirements, and reexploration. Our aim was to examine the effect of TXA on coagulation at different times during cardiac surgery using rotational thromboelastometry. Nineteen adult males (EuroSCORE 4-5) were recruited consecutively for first-time cardiopulmonary bypass (CPB) surgery. Ten patients received TXA at anesthesia and nine received no TXA. Rotational thromboelastometry analysis occurred before anesthesia (baseline), after sternotomy, after CPB-heparinization and surgery, and after protamine administration-sternal closure. A median sternotomy had no effect on clot time (CT), formation, litude, or lysis in non-TXA patients. In contrast, TXA patients had twofold prolonged clotting time (all-tests) and ∼30% reduced FIBTEM (A5-30) and maximum clot firmness, indicating reduced thrombin generation and lower clot fibrinogen. After CPB, CTs in both groups were prolonged, possibly linked to overheparinization. In addition, TXA patients had significantly decreased EXTEM (A5-30), suggesting lower clot strength. After protamine-sternal closure, clotting time remained prolonged in both groups, and TXA patients had a persistently 25%-33% lower FIBTEM (A5-30) and maximum clot firmness. TXA patients also had significantly reduced platelet numbers (37% from baseline), which continued Days 1 and 2. Maximum clot lysis was <10% indicating little or no hyperfibrinolysis during cardiac surgery. In this nonrandomized, nonblinded, observational trial, patients in the TXA group displayed prolonged CTs and clot fibrinogen (FIBTEM A5-30) after sternotomy, decreased clot strength (EXTEM) after CPB/surgery, and acute thrombocytopenia after protamine-sternal closure. There was no significant decrease in clot lysis, questioning the need for TXA in this medium-risk group.
Publisher: Medknow
Date: 2018
Publisher: Springer Science and Business Media LLC
Date: 18-06-2018
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2011
Publisher: Elsevier BV
Date: 12-2019
DOI: 10.1016/J.SEMARTHRIT.2019.03.008
Abstract: Osteoarthritis (OA) is a leading cause of global disability that affects more than half of the population over 65. It is not a single disease but a progressive, inflammatory- and immune-altering multi-disease that affects the whole joint. OA has many risk factors including age, obesity, gender, lifestyle, joint morphology, metabolic dysfunction and genetic disposition. A major stumbling block in treating clinical OA has been the inability to detect its early onset and disease progression. This gap in understanding may arise from our failure to recognize that the OA patient exhibits a vulnerability to dysregulation of central feedback circuits that control sympathetic tone, inflammation, circadian rhythms (central and peripheral clocks), gut microbiome, metabolic redox and whole joint pathology. Early detection of OA and slowing its progression may come from discoveries outside the joint targeting these potentially modifiable upstream targets. We argue that future treatments may benefit from moving from a knee-centric viewpoint to a more systems-based, whole-body approach. The challenge, however, will be to better characterize these key circuits and apply this knowledge to develop new therapies and interventions.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2011
Publisher: American Society for Microbiology
Date: 11-2016
DOI: 10.1128/CVI.00390-16
Abstract: Innovative host-directed drug therapies are urgently required to treat sepsis. We tested the effect of a small-volume 0.9% NaCl adenosine, lidocaine, and Mg 2+ (ALM) bolus and a 4-h intravenous infusion on survivability in the rat model of polymicrobial sepsis over 6 days. ALM treatment led to a significant increase in survivability (88%) compared to that of controls (25%). Four controls died on day 2 to 3, and two died on day 5. Early death was associated with elevated plasma and lung inflammatory markers (interleukin-6 [IL-6], IL-1β, C-reactive protein), reduced white blood cell (WBC) count, hypoxemia, hypercapnia, acidosis, hyperkalemia, and elevated lactate, whereas late death was associated with a massive cytokine storm, a neutrophil-dominated WBC rebound/overshoot, increased lung oxidant injury, edema, and persistent ischemia. On day 6, seven of eight ALM survivors had inflammatory and immunological profiles not significantly different from those of sham-treated animals. We conclude in the rat model of experimental sepsis that small-volume ALM treatment led to higher survivability at 6 days (88%) than that of controls (25%). Early death in controls (day 2 to 3) was associated with significantly elevated plasma levels of IL-1β, IL-6, and C-reactive protein, severe plasma lymphocyte deficiency, reduced neutrophils, and acute lung injury. Late death (day 5) was associated with a massive neutrophil inflammatory storm, increased lung injury, and persistent ischemia. Possible mechanisms of ALM protection are discussed.
Publisher: Elsevier BV
Date: 04-2014
Publisher: The Company of Biologists
Date: 15-09-2019
DOI: 10.1242/BIO.045203
Abstract: Prosthetic joint infection (PJI) following total knee arthroplasty (TKA) remains the leading cause for revision surgery, with Staphylococcus aureus the bacterium most frequently responsible. We describe a novel rat model of implant-associated S. aureus infection of the knee using orthopaedic materials relevant to modern TKA. Male Sprague-Dawley rats underwent unilateral knee implant surgery, which involved placement of a cementless, porous titanium implant into the femur, and an ultra-highly cross-linked polyethyelene (UHXLPE) implant into the proximal tibia within a mantle of gentamicin-laden bone cement. S. aureus biofilms were established on the surface of titanium implants prior to implantation into the femur of infected animals, whilst control animals received sterile implants. Compared to controls, the time taken to full weight-bear and recover pre-surgical body weight was greater in the infected group. Neutrophils and C-reactive protein levels were significantly higher in infected compared to control animals at day 5 post surgery, returning to baseline levels for the remainder of the 28-day experimental period. Blood cultures remained negative and additional plasma inflammatory markers were comparable for control and infected animals, consistent with the clinical presentation of delayed-onset PJI. S. aureus was recovered from joint tissue and implants at day 28 post surgery from all animals that received pre-seeded titanium implants, despite the use of antibiotic-laden cement. Persistent localised infection was associated with increased inflammatory responses and radiological changes in peri-implant tissue. The availability of a preclinical model that is reproducible based on the use of current TKA materials and consistent with clinical features of delayed-onset PJI will be valuable for evaluation of innovative therapeutic approaches.
Publisher: Elsevier BV
Date: 2019
Publisher: Elsevier BV
Date: 08-2018
DOI: 10.1016/J.JOCA.2018.04.018
Abstract: The history of osteoarthritis (OA) is important because it can help broaden our perspective on past and present controversies. The naming of OA, beginning with Heberden's nodes, is itself a fascinating story. According to Albert Hoffa, R. Llewellyn Jones and Archibald Edward Garrod, the name OA was introduced in the mid-nineteenth century by surgeon Richard von Volkmann who distinguished it from rheumatoid arthritis and gout. Others preferred the terms 'chronical rheumatism', 'senile arthritis', 'hypertrophic arthritis' or 'arthritis deformans'. A similar narrative applies to the concept of OA affecting the whole joint vs the 'wear-and-tear' hypothesis, inflammation and the role of the central nervous system (CNS). In the late nineteenth and early twentieth centuries, the Garrods (father and son) and Hermann Senator argued that OA was a whole joint disease, and that inflammation played a major role in its progression. Garrod Jnr and John Spender also linked OA to a neurogenic lesion 'outside the joint'. The remaining twentieth century was no less dynamic, with major advances in basic science, diagnostics, treatments, surgical interventions and technologies. Today, OA is characterized as a multi-disease with inflammation, immune and CNS dysfunction playing central roles in whole joint damage, injury progression, pain and disability. In the current 'omics' era (genomics, proteomics and metabolomics), we owe a great debt to past physicians and surgeons who dared to think 'outside-the-box' to explain and treat OA. Over 130 years later, despite these developments, we still don't fully understand the underlying complexities of OA, and we still don't have a cure.
Publisher: Georg Thieme Verlag KG
Date: 18-02-2020
Abstract: Traumatic-induced coagulopathy (TIC) is often associated with significant bleeding, transfusion requirements, inflammation, morbidity, and mortality. This review considers TIC as a systems failure, not as a single-event manifestation of trauma. After briefly reviewing the meaning of TIC and the bewildering array of fibrinolysis phenotypes, we will discuss the role of platelets and fibrinogen in coagulopathy. Next, we will review the different TIC hypotheses and drill down to a single mechanistic domain comprising (1) thrombin's differential binding to thrombomodulin, (2) the expression of annexin II-S100A10 complex, and (3) the functional integrity of the endothelial glycocalyx. This triad forms the basis of the “switch” hypothesis of TIC. We will next address the potential limitations of current practice in treating a coagulation or fibrinolytic defect, and the next defect, and so on down the line, which often leads to what U.S. surgeon William C. Shoemaker considered “an uncoordinated and sometimes contradictory therapeutic outcome.” The treat-as-you-go approach using sequential, single-target treatments appears to be a by-product of decades of highly reductionist thinking and research. Lastly, we will present a unified systems hypothesis of TIC involving three pillars of physiology: the central nervous system (CNS)–cardiovascular system, the endothelial glycocalyx, and mitochondrial integrity. If CNS control of ventriculoarterial coupling is maintained close to unity following trauma, we hypothesize that the endothelium will be protected, mitochondrial energetics will be maintained, and TIC (and inflammation) will be minimized. The Systems Hypothesis of Trauma (SHOT) also helps to answer why certain groups of severely bleeding trauma patients are still dying despite receiving the best care. Currently, no drug therapy exists that targets the whole system.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2018
DOI: 10.1097/TA.0000000000001874
Abstract: Currently, no drug therapy prevents secondary injury progression after traumatic brain injury (TBI). Our aim was to investigate the effects of small-volume intravenous adenosine, lidocaine, and Mg 2+ (ALM) resuscitation fluid after moderate TBI in a rat fluid–percussion injury model. Anesthetized, mechanically ventilated male Sprague-Dawley rats (449 ± 5 g) were randomly assigned to one of four groups: (1) sham (craniotomy without TBI), (2) no-treatment, (3) saline-control, or (4) ALM therapy groups (all n = 16). A subdural probe was implanted in eight animals per group to measure cerebral blood flow. Fifteen minutes after moderate TBI was induced with lateral fluid percussion injury (2.57 atm), a single 3% NaCl ± ALM bolus (0.7 mL/kg) was injected intravenously, and after 60 minutes (Phase 1), 0.9% NaCl ± ALM stabilization “drip” (0.5 mL/kg per hour) was administered for 3 hours (Phase 2). Mortality (without subdural brain probe) was 25% (saline controls) and 0% (ALM). Sixty minutes after bolus, ALM significantly increased cardiac function, cortical blood flow (CBF approximately threefold) and blunted systemic inflammation compared to saline controls. Three hours after infusion drip, ALM improved left ventricular function, supported higher CBF, decreased proinflammatory cytokines systemically (IL-1β, tumor necrosis factor α, and regulated on activation, normal T cell expressed and secreted [RANTES]), increased anti-inflammatory cytokines in brain tissue (IL-10, IL-4), lowered brain injury markers (neuron-specific enolase, Syndecan-1, HMGB-1), reduced coagulopathy, increased platelet aggregation, and maintained baseline fibrinogen levels. Saline-controls were proinflammatory (brain, heart, lung, and blood) and hypocoagulable with neurogenic enlargement of the right side of the heart. Survival time significantly correlated with plasma neuron-specific enolase ( p = 0.001) and CBF at 180 minutes ( p = 0.009), and CBF correlated with brain anti-inflammatory cytokines ( p = 0.001–0.034). After moderate TBI, ALM resuscitation fluid increased survival and protected against early secondary injury by reducing coagulopathy, inflammation, and platelet dysfunction.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2011
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2015
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-12-2019
Publisher: Springer Science and Business Media LLC
Date: 11-01-2019
Publisher: Elsevier BV
Date: 09-2020
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2020
DOI: 10.1097/SHK.0000000000001495
Abstract: Specific-pathogen free (SPF) animals were introduced into biomedical research in the early 1960s to reduce the incidence of disease into experimental design. The goal was to provide animals with selected microbiota compatible with sustained health. Sixty years later, SPF status has become a variable itself in biomedical research. Alterations in the gut microbiome–host relationship can profoundly influence basic physiology, immune/inflammatory function, susceptibility to infection and disease, and behavior. In addition, it can influence the translational success of a drug or technology from animal models to humans. We discuss this aspect of SPF status in animal models used for military or civilian trauma and shock research. Currently, there is a broad spectrum of SPF exclusion and inclusion criteria which vary from one supplier or animal husbandry facility. If translation to humans is the end-game of trauma research, we recommend replicating a gut microbiome similar to the wild-type for optimal success. We further suggest that at the end of each publication a URL access be provided on Animal Microbial/Pathogen Exclusion Status that a study was based upon. This may help address the differences in results within a single laboratory or between laboratories around the world and improve translation success.
Publisher: Wiley
Date: 29-08-2023
DOI: 10.1002/PRP2.1133
Abstract: The binding of drugs to plasma proteins is an important consideration in drug development. We have reported that the dose of adenosine, lidocaine, and magnesium (ALM) fluid therapy for resuscitation from hemorrhagic shock is nearly 3‐times higher for pigs than rats. Since lidocaine strongly binds to serum alpha‐1‐acid glycoprotein (AGP), the aim of the study was to investigate the effect of hemorrhagic shock on levels of AGP in rats and pigs. Healthy adult male Sprague–Dawley rats and female crossbred pigs ( n = 33 each) underwent tail vein and peripheral ear vein blood s ling, respectively, to collect plasma for AGP measurements. Rats ( n = 17) and pigs ( n = 16) underwent surgical instrumentation and uncontrolled hemorrhage via liver resection, and were treated with 3% NaCl ± ALM IV bolus followed 60 min later by 4 h 0.9% NaCl ± ALM IV drip. Rats were monitored for 72 h with blood s les taken post‐surgery, and at 5.25, 24, and 72 h. Pigs were monitored for 6 h with blood s les taken post‐surgery, and at 60 min and 6 h. Plasma AGP was measured with rat‐ and pig‐specific enzyme‐linked immunosorbent assay kits. Baseline AGP levels in rats were 3.91 μg/mL and significantly 83‐fold lower than in pigs (325 μg/mL). Surgical instrumentation was associated with ~10‐fold increases in AGP in rats and a 21% fall in pigs. AGP levels remained elevated in rats after hemorrhage and resuscitation (28–29 μg/mL). In contrast, no significant differences in plasma AGP were found in ALM‐ or Saline‐treated pigs over the monitoring period. We conclude that the trauma of surgery alone was associated with significant increases in AGP in rats, compared to a contrasting decrease in pigs. Higher levels of plasma AGP in pigs prior to hemorrhagic shock is consistent with the higher ALM doses required to resuscitate pigs compared with rats.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2016
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2014
Publisher: Cold Spring Harbor Laboratory
Date: 22-10-2023
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 28-05-2020
DOI: 10.1097/TA.0000000000002810
Abstract: Surgical management of trauma in the last 20 years has evolved in parallel with the military's experience in the current conflicts. Therapies such as widespread tourniquet use, empiric administration of fresh frozen plasma, and airborne intensive care units had been viewed skeptically but are now common practice. There is an opportunity to expand the envelope of care even further through similarly innovative approaches and varied avenues of research. As the molecular biology of trauma is elucidated, research methodologies must also be developed to capitalize on innovative approaches to resuscitation. Blood component therapy and control of bleeding remain as the fundamental concepts in trauma care. The inflammo-immune response to injury, however, plays an increasingly recognized role in recovery of organ function. Perhaps the inflammatory cascade of trauma can be manipulated to extend the treatment envelope of at risk trauma patients. In trauma, the additional challenge of delivering effective treatment, often required very early after injury, necessitates the development of treatments to be implemented on the front lines of trauma care that are cost-effective, portable, and environmentally stable. Future conflicts may not offer ready access to high-level surgical care therefore, resuscitative therapies will be needed for wounded service members because they are evacuated to the surgeon. Manipulation of the inflammatory response to trauma may offer a solution. As our understanding of the immune response continues to develop, the potential for improved outcomes for the wounded expands. A review of basic concepts in immunology is necessary to appreciate any potential impact of immunotherapeutic approaches to trauma and inflammation. An overview of current options will focus on outcome benefits of available therapies and suggest possible areas for future investigation. Quantitative approaches will leverage basic science to identify high-yield strategies to improve care of the injured combatant. Review, level III.
Publisher: Public Library of Science (PLoS)
Date: 26-12-2019
Publisher: Frontiers Media SA
Date: 20-10-2017
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2012
Publisher: BMJ
Date: 18-10-2013
DOI: 10.1136/JRAMC-2013-000145
Abstract: In 1984, Col. Ronald Bellamy launched a worldwide challenge to develop a new resuscitation fluid to aid survival after catastrophic blood loss on the battlefield. In 1996, after careful compromise among need, cube weight and efficacy, the US military and later coalition forces adopted 6% hetastarch (HES) fluids for early resuscitation. In the intervening years, evidence has amassed indicating that the HES fluids may not be safe, and in June 2013 the US Food and Drug Administration issued a warning that HES solutions should not be used to treat patients with hypovolaemia or the critically ill. We review the unique challenges of early battlefield resuscitation, why the 'Bellamy challenge' remains open and discuss a number of forward-looking strategies that may help to solve the problem. The first two pillars of resuscitation that we believe have not been adequately addressed are rescuing and stabilising the heart (and brain) and the vascular system. The 'ideal' resuscitation fluid needs to nurture the heart and body slowly back to health, and not 'shock' it a second time with unnatural colloids or large volumes of unphysiological saline-based solutions.
Publisher: Frontiers Media SA
Date: 27-10-2020
Publisher: BMJ
Date: 09-2022
DOI: 10.1136/OPENHRT-2022-002075
Abstract: Identifying patients with high-risk heart failure (HF) who would benefit from an implantable cardioverter-defibrillator (ICD) remains controversial. A potential marker for arrhythmic sudden death is fragmented QRS (fQRS). fQRS is the notching and slurring of the QRS complex in a 12-lead ECG and it indicates abnormal ventricular depolarisation and myocardial scarring and fibrosis. However, before fQRS complex can be included into selection criteria for ICD therapy, more complete reporting is required on their association with malignant arrhythmias, left ventricular remodelling and myocardial scarring/fibrosis in patients with HF. The molecular basis of the fQRS-arrhythmia-fibrosis connection in HF also needs to be explored. It is not widely appreciated that changes in the QRS complex and phases 0 and 1 of the ventricular action potential occur before contraction and predetermine Ca 2+ release during contraction and later Ca 2+ sparks. It is currently not known whether the different zig-zag patterns of the QRS are associated with aberrant Ca 2+ cycling and arrhythmogenic sparks in patients with HF.
No related grants have been discovered for Hayley Letson.