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Beautiful creatures : dark secrets will come to light
\"Lena has just moved to the small, Southern town of Gatlin, where the only person who seems to understand her, or dream of bigger places or ideas, is a cute guy named Ethan Wate, who recognizes her instantly from the cryptic dreams he's been having every night. Lena is an orphan, and she's come to stay with her mysterious uncle, Macon Ravenwood, the patriarch of her powerful family. Powerful, because The Ravenwood clan are Casters, born with powers that ordinary mortals don't have, like the ability to move objects, control the elements, and even step out of normal space and time to communicate only with each other. But just as Lena feels ready to open up to Ethan, she discovers that their love is in imminent danger, because when female Casters turn 16, their destiny as either good or evil is revealed. Unwilling to let her nature be dictated by forces outside her control, Lena and Ethan set out together to uncover the strange, secret lore of their families' intertwined histories dating back to the Civil War, and figure out how to grant Lena the power to choose her own destiny\"--Allmovie.com, September 28, 2018.
DVD
Key early proinflammatory signaling molecules encapsulated within circulating exosomes following traumatic injury
Background
Assessment of immune status in critically ill patients is often based on serial tracking of systemic cytokine levels and clinical laboratory values. Exosomes are extracellular vesicles that can be secreted and internalized by cells to transport important cellular cargo in the regulation of numerous physiological and pathological processes. Here, we characterize the early compartmentalization profile of key proinflammatory mediators in serum exosomes in the steady state and following trauma. Adult male Sprague-Dawley rats (91 including naïve) were divided into one of four traumatic injury model groups incorporating whole-body blast, fracture, soft-tissue crush injury, tourniquet-induced ischemia, and limb amputation. Serum was collected at 1, 3, 6, and 24 h, and 3- and 7-day post-injury. Electrochemiluminescence-based immunoassays for 9 key proinflammatory mediators in whole serum, isolated serum exosomes, and exosome depleted serum were analyzed and compared between naïve and injured rats. Serum clinical chemistry analysis was performed to determine pathological changes.
Results
In naïve animals, substantial amounts of IL-1β, IL-10, and TNF-α were encapsulated, IL-6 was completely encapsulated, and CXCL1 freely circulating. One hour after blast injury alone, levels of exosome encapsulated IFN-γ, IL-10, IL-6, IL-13, IL-4, and TNF-α increased, whereas freely circulating and membrane-associated levels remained undetectable or low. Rats with the most severe polytraumatic injuries with end organ complications had the earliest rise and most pronounced concentration of IL-1β, IL-10, TNF-α, and IL-6 across all serum compartments. Moreover, CXCL1 levels increased in relation to injury severity, but remained almost entirely freely circulating at all timepoints.
Conclusion
These findings highlight that conventional ELISA-based assessments, which detect only free circulating and exosome membrane-bound mediators, underestimate the full immunoinflammatory response to trauma. Inclusion of exosome encapsulated mediators may be a better, more accurate and clinically useful early strategy to identify, diagnose, and monitor patients at highest risk for post-traumatic inflammation-associated complications.
Journal Article
Tranexamic acid decreases rodent hemorrhagic shock-induced inflammation with mixed end-organ effects
Beyond its anti-fibrinolytic mechanism, tranexamic acid has been suggested to have anti-inflammatory properties which may contribute to the survival benefit it provides to trauma patients. The objective of this study was to assess possible immunomodulatory effects of tranexamic acid as well as potential amelioration of end-organ injury in a rodent hemorrhagic shock model. Controlled hemorrhagic shock was induced in adult Sprague Dawley rats to a mean arterial pressure of 30 mmHg. Groups of 10 rats were administered intravenous tranexamic acid (300mg/kg) or vehicle control (normal saline) intravenously 15 minutes after the induction of shock. After 60 minutes of hemorrhagic shock, resuscitation was started. Animals were euthanized at six, 24, or 72 hours from the start of shock. Serum laboratory values to include inflammatory biomarkers were measured, and end organ histology was evaluated. Tranexamic acid treatment was associated with a significant decrease in serum IL-1β at six and 24 hours and IL-10 at 24 hours from start of shock compared to vehicle control. Histologic analysis demonstrated mild decreases in both perivascular pulmonary edema and follicular mesenteric lymph node hyperplasia in the tranexamic acid treatment group but also increased myocardial lymphocytic infiltration with necrosis and degeneration. Tranexamic acid was also associated with a small but significant increase in peripheral neutrophil count as well as a significant decrease in neutrophil aggregation in pulmonary tissue at six hours post-injury. These data thus demonstrate a mixed effect of tranexamic acid. While there was an improvement in pulmonary edema and a suppressive effect on several key inflammatory mediators, there was also increased myocardial degeneration and necrosis, which is possibly related to the pro-thrombotic effect of tranexamic acid.
Journal Article
Tourniquet use following blast-associated complex lower limb injury and traumatic amputation promotes end organ dysfunction and amplified heterotopic ossification formation
Background
Traumatic heterotopic ossification (tHO) is characterized by ectopic bone formation in extra-skeletal sites leading to impaired wound healing, entrapment of neurovascular structures, pain, and reduced range of motion. HO has become a signature pathology affecting wounded military personnel who have sustained blast-associated traumatic amputations during the recent conflicts in Iraq and Afghanistan and can compound recovery by causing difficulty with prosthesis limb wearing. Tourniquet use to control catastrophic limb hemorrhage prior to surgery has become almost ubiquitous during this time, with the recognition the prolonged use may risk an ischemia reperfusion injury and associated complications. While many factors influence the formation of tHO, the extended use of tourniquets to limit catastrophic hemorrhage during prolonged field care has not been explored.
Methods
Utilizing an established pre-clinical model of blast-associated complex lower limb injury and traumatic amputation, we evaluated the effects of tourniquet use on tHO formation. Adult male rats were subjected to blast overpressure exposure, femur fracture, and soft tissue crush injury. Pneumatic tourniquet (250–300 mmHg) applied proximal to the injured limb for 150-min was compared to a control group without tourniquet, before a trans-femoral amputation was performed. Outcome measures were volume to tHO formation at 12 weeks and changes in proteomic and genomic markers of early tHO formation between groups.
Results
At 12 weeks, volumetric analysis with microCT imaging revealed a 70% increase in total bone formation (
p
= 0.007) near the site of injury compared to rats with no tourniquet time in the setting of blast-injuries. Rats subjected to tourniquet usage had increased expression of danger-associated molecular patterns (DAMPs) and end organ damage as early as 6 h and as late as 7 days post injury. The expressions of pro-inflammatory cytokines and chemokines and osteochondrogenic genes using quantitative RT-PCR similarly revealed increased expression as early as 6 h post injury, and these genes along with hypoxia associated genes remained elevated for 7 days compared to no tourniquet use.
Conclusion
These findings suggest that tourniquet induced ischemia leads to significant increases in key transcription factors associated with early endochondral bone formation, systemic inflammatory and hypoxia, resulting in increased HO formation.
Journal Article
Alarming Cargo: The Role of Exosomes in Trauma-Induced Inflammation
Severe polytraumatic injury initiates a robust immune response. Broad immune dysfunction in patients with such injuries has been well-documented; however, early biomarkers of immune dysfunction post-injury, which are critical for comprehensive intervention and can predict the clinical course of patients, have not been reported. Current circulating markers such as IL-6 and IL-10 are broad, non-specific, and lag behind the clinical course of patients. General blockade of the inflammatory response is detrimental to patients, as a certain degree of regulated inflammation is critical and necessary following trauma. Exosomes, small membrane-bound extracellular vesicles, found in a variety of biofluids, carry within them a complex functional cargo, comprised of coding and non-coding RNAs, proteins, and metabolites. Composition of circulating exosomal cargo is modulated by changes in the intra- and extracellular microenvironment, thereby serving as a homeostasis sensor. With its extensively documented involvement in immune regulation in multiple pathologies, study of exosomal cargo in polytrauma patients can provide critical insights on trauma-specific, temporal immune dysregulation, with tremendous potential to serve as unique biomarkers and therapeutic targets for timely and precise intervention.
Journal Article
Systemic inflammation following traumatic injury and its impact on neuroinflammatory gene expression in the rodent brain
Background
Trauma can result in systemic inflammation that leads to organ dysfunction, but the impact on the brain, particularly following extracranial insults, has been largely overlooked.
Methods
Building upon our prior findings, we aimed to understand the impact of systemic inflammation on neuroinflammatory gene transcripts in eight brain regions in rats exposed to (1) blast overpressure exposure [BOP], (2) cutaneous thermal injury [BU], (3) complex extremity injury, 3 hours (h) of tourniquet-induced ischemia, and hind limb amputation [CEI+tI+HLA], (4) BOP+BU or (5) BOP+CEI and delayed HLA [BOP+CEI+dHLA] at 6, 24, and 168 h post-injury (hpi).
Results
Globally, the number and magnitude of differentially expressed genes (DEGs) correlated with injury severity, systemic inflammation markers, and end-organ damage, driven by several chemokines/cytokines (
Csf3, Cxcr2, Il16, and Tgfb2
), neurosteroids/prostaglandins (
Cyp19a1, Ptger2, and Ptger3
), and markers of neurodegeneration (
Gfap
,
Grin2b
, and
Homer1
). Regional neuroinflammatory activity was least impacted following BOP. Non-blast trauma (in the BU and CEI+tI+HLA groups) contributed to an earlier, robust and diverse neuroinflammatory response across brain regions (up to 2–50-fold greater than that in the BOP group), while combined trauma (in the BOP+CEI+dHLA group) significantly advanced neuroinflammation in all regions except for the cerebellum. In contrast, BOP+BU resulted in differential activity of several critical neuroinflammatory-neurodegenerative markers compared to BU. t-SNE plots of DEGs demonstrated that the onset, extent, and duration of the inflammatory response are brain region dependent. Regardless of injury type, the thalamus and hypothalamus, which are critical for maintaining homeostasis, had the most DEGs. Our results indicate that neuroinflammation in all groups progressively increased or remained at peak levels over the study duration, while markers of end-organ dysfunction decreased or otherwise resolved.
Conclusions
Collectively, these findings emphasize the brain's sensitivity to mediators of systemic inflammation and provide an example of immune-brain crosstalk. Follow-on molecular and behavioral investigations are warranted to understand the short- to long-term pathophysiological consequences on the brain, particularly the mechanism of blood–brain barrier breakdown, immune cell penetration–activation, and microglial activation.
Journal Article
Inhibition of focal adhesion kinase 2 results in a macrophage polarization shift to M2 which attenuates local and systemic inflammation and reduces heterotopic ossification after polysystem extremity trauma
Heterotopic ossification (HO) is a complex pathology often observed in combat injured casualties who have sustained severe, high energy polytraumatic extremity injuries. Once HO has developed, prophylactic therapies are limited outside of surgical excision. Tourniquet-induced ischemia injury (IR) exacerbates trauma-mediated musculoskeletal tissue injury, inflammation, osteogenic progenitor cell development and HO formation. Others have shown that focal adhesion kinase-2 (FAK2) plays a key role in regulating early inflammatory signaling events. Therefore, we hypothesized that targeting FAK2 prophylactically would mitigate extremity trauma induced IR inflammation and HO formation.
We tested whether the continuous infusion of a FAK2 inhibitor (Defactinib, PF-573228; 6.94 µg/kg/min for 14 days) can mitigate ectopic bone formation (HO) using an established blast-related extremity injury model involving femoral fracture, quadriceps crush injury, three hours of tourniquet-induced limb ischemia, and hindlimb amputation through the fracture site. Tissue inflammation, infiltrating cells, osteogenic progenitor cell content were assessed at POD-7. Micro-computed tomography imaging was used to quantify mature HO at POD-56.
In comparison to vehicle control-treated rats, FAK2 administration resulted in no marked wound healing complications or weight loss. FAK2 treatment decreased HO by 43%. At POD-7, marked reductions in tissue proinflammatory gene expression and assayable osteogenic progenitor cells were measured, albeit no significant changes in expression patterns of angiogenic, chondrogenic and osteogenic genes. At the same timepoint, injured tissue from FAK-treated rats had fewer infiltrating cells. Additionally, gene expression analyses of tissue infiltrating cells resulted in a more measurable shift from an M1 inflammatory to an M2 anti-inflammatory macrophage phenotype in the FAK2 inhibitor-treated group.
Our findings suggest that FAK2 inhibition may be a novel strategy to dampen trauma-induced inflammation and attenuate HO in patients at high risk as a consequence of severe musculoskeletal polytrauma.
Journal Article
The influence of microbial colonization on inflammatory versus pro-healing trajectories in combat extremity wounds
A combination of improved body armor, medical transportation, and treatment has led to the increased survival of warfighters from combat extremity injuries predominantly caused by blasts in modern conflicts. Despite advances, a high rate of complications such as wound infections, wound failure, amputations, and a decreased quality of life exist. To study the molecular underpinnings of wound failure, wound tissue biopsies from combat extremity injuries had RNA extracted and sequenced. Wounds were classified by colonization (colonized vs. non-colonized) and outcome (healed vs. failed) status. Differences in gene expression were investigated between timepoints at a gene level, and longitudinally by multi-gene networks, inferred proportions of immune cells, and expression of healing-related functions. Differences between wound outcomes in colonized wounds were more apparent than in non-colonized wounds. Colonized/healed wounds appeared able to mount an adaptive immune response to infection and progress beyond the inflammatory stage of healing, while colonized/failed wounds did not. Although, both colonized and non-colonized failed wounds showed increasing inferred immune and inflammatory programs, non-colonized/failed wounds progressed beyond the inflammatory stage, suggesting different mechanisms of failure dependent on colonization status. Overall, these data reveal gene expression profile differences in healing wounds that may be utilized to improve clinical treatment paradigms.
Journal Article
Progenitors in Peripheral Nerves Launch Heterotopic Ossification
Studies presented here, using a murine model of bone morphogenetic protein type 2 (BMP2)‐induced heterotopic ossification (HO) show that the protein initiates HO by signaling through progenitors in the endoneurium of peripheral nerves. In the mouse, these cells were identified in the endoneurium one day after BMP2 induction using antibody against phosphoSMAD (PS) 1, 5, and 8. Studies conducted in a tracking mouse that contains a tamoxifen‐regulated Wnt1‐Cre recombinase crossed with a td Tomato red (TR) reporter (Wnt1CreErt:Ai9Tm) confirmed their neural origin. In this model both BMP2 induction and tamoxifen are absolutely required to induce TR. SP7+(osterix+)TR+ cells were found in the endoneurium on day 1 and associated with bone on day 7. Quantification of TR+ and TR− cells isolated by fluorescence‐activated cell sorting showed that all SP7+ cells were found in the TR+ population, whereas only about 80% of the TR+ cells expressed SP7. Pre‐chondrocytes (Sox 9+) and transient brown fat (tBAT, UCP1+) also coexpressed TR, suggesting that the progenitor in nerves is multi‐potential. The endoneurium of human nerves near the site of HO contained many PS+ cells, and SP7+ cells were found in nerves and on bone in tissue from patients with HO. Control tissues and nerves did not contain these PS+ and SP7+ cells. Some osteoblasts on bone from patients with HO were positive for PS, suggesting the continued presence of BMP during bone formation. The data suggests that the progenitors for HO are derived from the endoneurium in both the mouse model of HO and in humans with HO. Stem Cells Translational Medicine 2017;6:1109–1119
Journal Article
Systematic Identification of the Optimal Housekeeping Genes for Accurate Transcriptomic and Proteomic Profiling of Tissues following Complex Traumatic Injury
Trauma triggers critical molecular and cellular signaling cascades that drive biological outcomes and recovery. Variations in the gene expression of common endogenous reference housekeeping genes (HKGs) used in data normalization differ between tissue types and pathological states. Systematically, we investigated the gene stability of nine HKGs (Actb, B2m, Gapdh, Hprt1, Pgk1, Rplp0, Rplp2, Tbp, and Tfrc) from tissues prone to remote organ dysfunction (lung, liver, kidney, and muscle) following extremity trauma. Computational algorithms (geNorm, Normfinder, ΔCt, BestKeeper, RefFinder) were applied to estimate the expression stability of each HKG or combinations of them, within and between tissues, under both steady-state and systemic inflammatory conditions. Rplp2 was ranked as the most suitable in the healthy and injured lung, kidney, and skeletal muscle, whereas Rplp2 and either Hprt1 or Pgk1 were the most suitable in the healthy and injured liver, respectively. However, the geometric mean of the three most stable genes was deemed the most stable internal reference control. Actb and Tbp were the least stable in normal tissues, whereas Gapdh and Tbp were the least stable across all tissues post-trauma. Ct values correlated poorly with the translation from mRNA to protein. Our results provide a valuable resource for the accurate normalization of gene expression in trauma-related experiments.
Journal Article