Publications by authors named "Dalton Dietrich"

249 Publications

Hyperoxia-activated circulating extracellular vesicles induce lung and brain injury in neonatal rats.

Sci Rep 2021 Apr 22;11(1):8791. Epub 2021 Apr 22.

Division of Neonatology and Batchelor Children's Research Institute, Department of Pediatrics, University of Miami Miller School of Medicine, P. O. Box 016960, Miami, FL, 33101, USA.

Hyperoxia-induced lung injury plays a key role in the development of bronchopulmonary dysplasia (BPD), characterized by inflammatory injury and impaired lung development in preterm infants. Although BPD is a predictor of poor neurodevelopmental outcomes, currently it is uncertain how lung injury contributes to brain injury in preterm infants. Extracellular vesicles (EVs) are a heterogeneous group of cell-derived membranous structures that regulate intercellular and inter-organ communications. Gasdermin D (GSDMD) has emerged as a key executor of inflammasome-mediated cell death and inflammation. In this study, we utilized a neonatal rat model of BPD to assess if hyperoxia stimulates lung release of circulating EVs and if these EVs induce lung and brain injury. We found that hyperoxia-exposed rats had elevated numbers of plasma-derived EVs compared to rats maintained in room air. These EVs also had increased cargos of surfactant protein C, a marker of type II alveolar epithelial cells (AEC), and the active (p30) form of GSDMD. When these EVs were adoptively transferred into normal newborn rats via intravenous injection, they were taken up both by lung and brain tissues. Moreover, EVs from hyperoxic animals induced not only the pathological hallmarks of BPD, but also brain inflammatory injury in recipient rats, as well as inducing cell death in cultured pulmonary vascular endothelial cells and neural stem cells (NSC). Similarly, hyperoxia-exposed cultured AEC-like cells released EVs that also contained increased GSDMD-p30 and these EVs induced pyroptotic cell death in NSC. Overall, these data indicate that hyperoxia-activated circulating EVs mediate a lung to brain crosstalk resulting in brain injury and suggest a mechanism that links lung injury and neurodevelopmental impairment in BPD infants.
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http://dx.doi.org/10.1038/s41598-021-87706-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062626PMC
April 2021

Kollidon VA64 Treatment in Traumatic Brain Injury: Operation Brain Trauma Therapy.

J Neurotrauma 2021 May 14. Epub 2021 May 14.

Department of Neurological Surgery, Brain Trauma Research Center, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.

Loss of plasmalemmal integrity may mediate cell death after traumatic brain injury (TBI). Prior studies in controlled cortical impact (CCI) indicated that the membrane resealing agent Kollidon VA64 improved histopathological and functional outcomes. Kollidon VA64 was therefore selected as the seventh therapy tested by the Operation Brain Trauma Therapy consortium, across three pre-clinical TBI rat models: parasagittal fluid percussion injury (FPI), CCI, and penetrating ballistic-like brain injury (PBBI). In each model, rats were randomized to one of four exposures (7-15/group): (1) sham; (2) TBI+vehicle; (3) TBI+Kollidon VA64 low-dose (0.4 g/kg); and (4) TBI+Kollidon VA64 high-dose (0.8 g/kg). A single intravenous VA64 bolus was given 15 min post-injury. Behavioral, histopathological, and serum biomarker outcomes were assessed over 21 days generating a 22-point scoring matrix per model. In FPI, low-dose VA64 produced zero points across behavior and histopathology. High-dose VA64 worsened motor performance compared with TBI-vehicle, producing -2.5 points. In CCI, low-dose VA64 produced intermediate benefit on beam balance and the Morris water maze (MWM), generating +3.5 points, whereas high-dose VA64 showed no effects on behavior or histopathology. In PBBI, neither dose altered behavior or histopathology. Regarding biomarkers, significant increases in glial fibrillary acidic protein (GFAP) levels were seen in TBI versus sham at 4 h and 24 h across models. Benefit of low-dose VA64 on GFAP was seen at 24 h only in FPI. Ubiquitin C-terminal hydrolase-L1 (UCH-L1) was increased in TBI compared with vehicle across models at 4 h but not at 24 h, without treatment effects. Overall, low dose VA64 generated +4.5 points (+3.5 in CCI) whereas high dose generated -2.0 points. The modest/inconsistent benefit observed reduced enthusiasm to pursue further testing.
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http://dx.doi.org/10.1089/neu.2021.0089DOI Listing
May 2021

Phase 1 Safety Trial of Autologous Human Schwann Cell Transplantation in Chronic Spinal Cord Injury.

J Neurotrauma 2021 May 3. Epub 2021 May 3.

The Miami Project to Cure Paralysis, Departments of University of Miami, Miami, Florida, USA.

A phase 1 open-label, non-randomized clinical trial was conducted to determine feasibility and safety of autologous human Schwann cell (ahSC) transplantation accompanied by rehabilitation in participants with chronic spinal cord injury (SCI). Magnetic resonance imaging (MRI) was used to screen eligible participants to estimate an individualized volume of cell suspension to be implanted. The trial incorporated standardized multi-modal rehabilitation before and after cell delivery. Participants underwent sural nerve harvest, and ahSCs were isolated and propagated in culture. The dose of culture-expanded ahSCs injected into the chronic spinal cord lesion of each individual followed a cavity-filling volume approach. Primary outcome measures for safety and trend-toward efficacy were assessed. Two participants with American Spinal Injury Association Impairment Scale (AIS) A and two participants with incomplete chronic SCI (AIS B, C) were each enrolled in cervical and thoracic SCI cohorts ( = 8 total). All participants completed the study per protocol, and no serious adverse events related to sural nerve harvest or ahSC transplantation were reported. Urinary tract infections and skin abrasions were the most common adverse events reported. One participant experienced a 4-point improvement in motor function, a 6-point improvement in sensory function, and a 1-level improvement in neurological level of injury. Follow-up MRI in the cervical (6 months) and thoracic (24 months) cohorts revealed a reduction in cyst volume after transplantation with reduced effect over time. This phase 1 trial demonstrated the feasibility and safety of ahSC transplantation combined with a multi-modal rehabilitation protocol for participants with chronic SCI.
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http://dx.doi.org/10.1089/neu.2020.7590DOI Listing
May 2021

Netosis and Inflammasomes in Large Vessel Occlusion Thrombi.

Front Pharmacol 2020 22;11:607287. Epub 2021 Jan 22.

Department of Neurological Surgery and the Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL, United States.

The inflammatory response appears to play a critical role in clotting in which neutrophil extracellular traps (NETs) are the major drivers of thrombosis in acute ischemic stroke (AIS). The inflammasome is an innate immune complex involved in the activation of interleukin (IL)-18 and IL-1β through caspase-1, but whether the inflammasome plays a role in NETosis in AIS remains poorly understood. Here we assessed the levels of inflammasome signaling proteins in NETs and their association with clinical and procedural outcomes of mechanical thrombectomy for AIS. Electron microscopy and immunofluorescence indicate the presence of NETs in thrombi of patients with AIS. Moreover, the inflammasome signaling proteins caspase-1 and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) were also present in clots associated with the marker of NETosis citrullinated histone H (CitH3). Analysis of protein levels by a simple plex assay show that caspase-1, ASC and interleukin (IL)-1β were significantly elevated in clots when compared to plasma of AIS patients and healthy controls, while IL-18 levels were lower. Moreover, multivariate analyses show that IL-1β levels in clots contribute to the number of passes to achieve complete recanalization, and that ASC, caspase-1 and IL-18 are significant contributors to time to recanalization. Thus, inflammasome proteins are elevated in NETs present in thrombi of patients with AIS that contribute to poor outcomes following stroke.
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http://dx.doi.org/10.3389/fphar.2020.607287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868597PMC
January 2021

Neurophysiological Changes in the First Year After Cell Transplantation in Sub-acute Complete Paraplegia.

Front Neurol 2020 18;11:514181. Epub 2021 Jan 18.

The Miami Project to Cure Paralysis, Miller School of Medicine, The University of Miami, Miami, FL, United States.

Neurophysiological testing can provide quantitative information about motor, sensory, and autonomic system connectivity following spinal cord injury (SCI). The clinical examination may be insufficiently sensitive and specific to reveal evolving changes in neural circuits after severe injury. Neurophysiologic data may provide otherwise imperceptible circuit information that has rarely been acquired in biologics clinical trials in SCI. We reported a Phase 1 study of autologous purified Schwann cell suspension transplantation into the injury epicenter of participants with complete subacute thoracic SCI, observing no clinical improvements. Here, we report longitudinal electrophysiological assessments conducted during the trial. Six participants underwent neurophysiology screening pre-transplantation with three post-transplantation neurophysiological assessments, focused on the thoracoabdominal region and lower limbs, including MEPs, SSEPs, voluntarily triggered EMG, and changes in GSR. We found several notable signals not detectable by clinical exam. In all six participants, thoracoabdominal motor connectivity was detected below the clinically assigned neurological level defined by sensory preservation. Additionally, small voluntary activations of leg and foot muscles or positive lower extremity MEPs were detected in all participants. Voluntary EMG was most sensitive to detect leg motor function. The recorded MEP amplitudes and latencies indicated a more caudal thoracic level above which amplitude recovery over time was observed. In contrast, further below, amplitudes showed less improvement, and latencies were increased. Intercostal spasms observed with EMG may also indicate this thoracic "motor level." Galvanic skin testing revealed autonomic dysfunction in the hands above the injury levels. As an open-label study, we can establish no clear link between these observations and cell transplantation. This neurophysiological characterization may be of value to detect therapeutic effects in future controlled studies.
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http://dx.doi.org/10.3389/fneur.2020.514181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7848788PMC
January 2021

The complement cascade at the Utah microelectrode-tissue interface.

Biomaterials 2021 Jan 7;268:120583. Epub 2020 Dec 7.

Department of Biomedical Engineering, University of Miami, FL, USA; The Miami Project to Cure Paralysis, University of Miami, FL, USA. Electronic address:

Devices implanted within the central nervous system (CNS) are subjected to tissue reactivity due to the lack of biocompatibility between implanted material and the cells' microenvironment. Studies have attributed blood-brain barrier disruption, inflammation, and oxidative stress as main contributing factors that lead to electrode recording failure. The complement cascade is a part of the innate immunity that focuses on recognizing and targeting foreign objects; however, its role in the context of neural implants is substantially unknown. In this study, we implanted a non-functional 4x4 Utah microelectrode array (UEA) into the somatosensory cortex and studied the complement cascade via combined gene and immunohistochemistry quantification at acute (48-h), sub-acute (1-week), and early chronic (4-weeks) time points. The results of this study demonstrate the activation and continuation of the complement cascade at the electrode-tissue interface, illustrating the therapeutic potential of modulating the foreign body response via the complement cascade.
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http://dx.doi.org/10.1016/j.biomaterials.2020.120583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856077PMC
January 2021

The End of a Challenging Year.

Ther Hypothermia Temp Manag 2020 12 25;10(4):191. Epub 2020 Nov 25.

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http://dx.doi.org/10.1089/ther.2020.29077.wddDOI Listing
December 2020

Glibenclamide Treatment in Traumatic Brain Injury: Operation Brain Trauma Therapy.

J Neurotrauma 2021 Mar 18;38(5):628-645. Epub 2020 Dec 18.

Safar Center for Resuscitation Research, Department of Critical Care Medicine, Anesthesiology, and Clinical and Translational Science, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

Glibenclamide (GLY) is the sixth drug tested by the Operation Brain Trauma Therapy (OBTT) consortium based on substantial pre-clinical evidence of benefit in traumatic brain injury (TBI). Adult Sprague-Dawley rats underwent fluid percussion injury (FPI;  = 45), controlled cortical impact (CCI;  = 30), or penetrating ballistic-like brain injury (PBBI;  = 36). Efficacy of GLY treatment (10-μg/kg intraperitoneal loading dose at 10 min post-injury, followed by a continuous 7-day subcutaneous infusion [0.2 μg/h]) on motor, cognitive, neuropathological, and biomarker outcomes was assessed across models. GLY improved motor outcome versus vehicle in FPI (cylinder task,  < 0.05) and CCI (beam balance,  < 0.05; beam walk,  < 0.05). In FPI, GLY did not benefit any other outcome, whereas in CCI, it reduced 21-day lesion volume versus vehicle ( < 0.05). On Morris water maze testing in CCI, GLY worsened performance on hidden platform latency testing versus sham ( < 0.05), but not versus TBI vehicle. In PBBI, GLY did not improve any outcome. Blood levels of glial fibrillary acidic protein and ubiquitin carboxyl terminal hydrolase-1 at 24 h did not show significant treatment-induced changes. In summary, GLY showed the greatest benefit in CCI, with positive effects on motor and neuropathological outcomes. GLY is the second-highest-scoring agent overall tested by OBTT and the only drug to reduce lesion volume after CCI. Our findings suggest that leveraging the use of a TBI model-based phenotype to guide treatment (i.e., GLY in contusion) might represent a strategic choice to accelerate drug development in clinical trials and, ultimately, achieve precision medicine in TBI.
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http://dx.doi.org/10.1089/neu.2020.7421DOI Listing
March 2021

The Inflammasome in Times of COVID-19.

Front Immunol 2020 8;11:583373. Epub 2020 Oct 8.

Department of Neurological Surgery and The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL, United States.

Coronaviruses (CoVs) are members of the genus Betacoronavirus and the Coronaviridiae family responsible for infections such as severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and more recently, coronavirus disease-2019 (COVID-19). CoV infections present mainly as respiratory infections that lead to acute respiratory distress syndrome (ARDS). However, CoVs, such as COVID-19, also present as a hyperactivation of the inflammatory response that results in increased production of inflammatory cytokines such as interleukin (IL)-1β and its downstream molecule IL-6. The inflammasome is a multiprotein complex involved in the activation of caspase-1 that leads to the activation of IL-1β in a variety of diseases and infections such as CoV infection and in different tissues such as lungs, brain, intestines and kidneys, all of which have been shown to be affected in COVID-19 patients. Here we review the literature regarding the mechanism of inflammasome activation by CoV infection, the role of the inflammasome in ARDS, ventilator-induced lung injury (VILI), and Disseminated Intravascular Coagulation (DIC) as well as the potential mechanism by which the inflammasome may contribute to the damaging effects of inflammation in the cardiac, renal, digestive, and nervous systems in COVID-19 patients.
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http://dx.doi.org/10.3389/fimmu.2020.583373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7580384PMC
November 2020

Use of Machine Learning to Re-Assess Patterns of Multivariate Functional Recovery after Fluid Percussion Injury: Operation Brain Trauma Therapy.

J Neurotrauma 2021 Jan 13. Epub 2021 Jan 13.

Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA.

Traumatic brain injury (TBI) is a leading cause of death and disability. Yet, despite immense research efforts, treatment options remain elusive. Translational failures in TBI are often attributed to the heterogeneity of the TBI population and limited methods to capture these individual variabilities. Advances in machine learning (ML) have the potential to further personalized treatment strategies and better inform translational research. However, the use of ML has yet to be widely assessed in pre-clinical neurotrauma research, where data are strictly limited in subject number. To better establish ML's feasibility, we utilized the fluid percussion injury (FPI) portion of the rich, rat data set collected by Operation Brain Trauma Therapy (OBTT), which tested multiple pharmacological treatments. Previous work has provided confidence that both unsupervised and supervised ML techniques can uncover useful insights from this OBTT pre-clinical research data set. As a proof-of-concept, we aimed to better evaluate the multi-variate recovery profiles afforded by the administration of nine different experimental therapies. We assessed supervised pairwise classifiers trained on a pre-processed data set that incorporated metrics from four feature groups to determine their ability to correctly identify specific drug treatments. In all but one of the possible pairwise combinations of minocycline, levetiracetam, erythropoietin, nicotinamide, and amantadine, the baseline was outperformed by one or more supervised classifiers, the exception being nicotinamide versus amantadine. Further, when the same methods were employed to assess different doses of the same treatment, the ML classifiers had greater difficulty in understanding which treatment each sample received. Our data serve as a critical first step toward identifying optimal treatments for specific subgroups of samples that are dependent on factors such as types and severity of traumatic injuries, as well as informing the prediction of therapeutic combinations that may lead to greater treatment effects than individual therapies.
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http://dx.doi.org/10.1089/neu.2020.7357DOI Listing
January 2021

Development and Evaluation of Machine Learning Models for Recovery Prediction after Treatment for Traumatic Brain Injury.

Annu Int Conf IEEE Eng Med Biol Soc 2020 07;2020:2416-2420

Traumatic brain injury (TBI) is a leading cause of death and disability yet treatment strategies remain elusive. Advances in machine learning present exciting opportunities for developing personalized medicine and informing laboratory research. However, their feasibility has yet to be widely assessed in animal research where data are typically limited or in the TBI field where each patient presents with a unique injury. The Operation Brain Trauma Therapy (OBTT) has amassed an animal dataset that spans multiple types of injury, treatment strategies, behavioral assessments, histological measures, and biomarker screenings. This paper aims to analyze these data using supervised learning techniques for the first time by partitioning the dataset into acute input metrics (i.e. 7 days post-injury) and a defined recovery outcome (i.e. memory retention). Preprocessing is then applied to transform the raw OBTT dataset, e.g. developing a class attribute by histogram binning, eliminating borderline cases, and applying principal component analysis (PCA). We find that these steps are also useful in establishing a treatment ranking; Minocycline, a therapy with no significant findings in the OBTT analyses, yields the highest percentage recovery in our ranking. Furthermore, of the seven classifiers we have evaluated, Naïve Bayes achieves the best performance (67%) and yields significant improvement over our baseline model on the preprocessed dataset with borderline elimination. We also investigate the effect of testing on individual treatment groups to evaluate which groups are difficult to classify, and note the interpretive qualities of our model that can be clinically relevant.Clinical Relevance- These studies establish methods for better analyzing multivariate functional recovery and understanding which measures affect prognosis following traumatic brain injury.
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http://dx.doi.org/10.1109/EMBC44109.2020.9175658DOI Listing
July 2020

Scientific Advancements During the COVID-19 Pandemic.

Ther Hypothermia Temp Manag 2020 09 28;10(3):130. Epub 2020 Jul 28.

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http://dx.doi.org/10.1089/ther.2020.29075.wddDOI Listing
September 2020

Age as a determinant of inflammatory response and survival of glia and axons after human traumatic spinal cord injury.

Exp Neurol 2020 10 13;332:113401. Epub 2020 Jul 13.

Krembil Research Institute, University Health Network, Toronto, Ontario, Canada; Department of Surgery, Division of Neurosurgery, University of Toronto, Toronto, Ontario, Canada.

Despite the shift in the demographics of traumatic spinal cord injury (SCI) with increased proportion of injuries in the elderly, little is known on the potential effects of old age on the pathobiology of SCI. Since there is an assumption that age adversely affects neural response to SCI, this study examines the clinically relevant question on whether age is a key determinant of inflammatory response, oligodendroglial apoptosis and axonal survival after traumatic SCI. This unique study includes post-mortem spinal cord tissue from 64 cases of SCI (at cervical or high-thoracic levels) and 38 control cases without CNS injury. Each group was subdivided into subgroups of younger and elderly individuals (65 years of age or older at the SCI onset). The results of this study indicate that age at the SCI onset does not adversely affect the cellular inflammatory response to, oligodendroglial apoptosis and axonal survival after SCI. These results support the conclusion that elderly individuals have similar neurobiological responses to SCI as younger people and, hence, treatment decisions should be based on an assessment of the individual patient and not an arbitrary assumption that "advanced age" should exclude patients with an acute SCI from access to advanced care and translational therapies.
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http://dx.doi.org/10.1016/j.expneurol.2020.113401DOI Listing
October 2020

Enoxaparin Attenuates Acute Lung Injury and Inflammasome Activation after Traumatic Brain Injury.

J Neurotrauma 2021 Mar 11;38(5):646-654. Epub 2020 Aug 11.

Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA.

Traumatic brain injury (TBI) patients frequently develop cardiopulmonary system complications such as acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). However, the mechanism by which TBI causes ALI/ARDS is not fully understood. Here, we used a severe TBI model to examine the effects of a low-molecular-weight heparin, enoxaparin, on inflammasome activation and lung injury damage. We investigated whether enoxaparin inhibits ALI and inflammasome signaling protein expression in the brain and lungs after TBI in mice. C57/BL6 mice were subjected to severe TBI and were treated with vehicle or 1 mg/kg of enoxaparin 30 min after injury. Lung and brain tissue were collected 24 h post-TBI and were analyzed by immunoblotting for expression of the inflammasome proteins, caspase-1 and interleukin (IL)-1β. In addition, lung tissue was collected for histological analysis to determine ALI scoring and neutrophil and macrophage infiltration post-injury. Our data show that severe TBI induces increased expression of inflammasome proteins caspase-1 and IL-1β in the brain and lungs of mice after injury. Treatment with enoxaparin attenuated inflammasome expression in the brain and lungs 24 h after injury. Enoxaparin significantly decreased ALI score as well as neutrophil and macrophage infiltration in lungs at 24 h after injury. This study demonstrates that enoxaparin attenuates ALI and inhibits inflammasome expression in the brain and lungs after TBI. These findings support the hypothesis that inhibition of the neural-respiratory inflammasome axis that is activated after TBI may have therapeutic potential.
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http://dx.doi.org/10.1089/neu.2020.7257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898405PMC
March 2021

The Inflammasome Adaptor Protein ASC in Mild Cognitive Impairment and Alzheimer's Disease.

Int J Mol Sci 2020 Jun 30;21(13). Epub 2020 Jun 30.

Department of Neurological Surgery and The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL 33136, USA.

Mild cognitive impairment (MCI) is characterized by memory loss in the absence of dementia and is considered the translational stage between normal aging and early Alzheimer's disease (AD). Patients with MCI have a greater risk of advancing to AD. Thus, identifying early markers of MCI has the potential to increase the therapeutic window to treat and manage the disease. Protein levels of the inflammasome signaling proteins apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and interleukin (IL)-18 were analyzed in the serum of patients with MCI, AD and healthy age-matched donors as possible biomarkers, as well as levels of soluble amyloid precursor proteins α/β (sAPP α/β) and neurofilament light (NfL). Cut-off points and positive and negative predictive values, as well as receiver operator characteristic (ROC) curves, likelihood ratios and accuracy were determined for these proteins. Although the levels of ASC were higher in MCI and AD than in age-matched controls, protein levels of ASC were higher in MCI than in AD cases. For control vs. MCI, the area under the curve (AUC) for ASC was 0.974, with a cut-off point of 264.9 pg/mL. These data were comparable to the AUC for sAPP α and β of 0.9687 and 0.9068, respectively, as well as 0.7734 for NfL. Moreover, similar results were obtained for control vs. AD and MCI vs. AD. These results indicate that ASC is a promising biomarker of MCI and AD.
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http://dx.doi.org/10.3390/ijms21134674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7370034PMC
June 2020

A New Way of Thinking About Therapeutic Hypothermia.

Ther Hypothermia Temp Manag 2020 09 25;10(3):129. Epub 2020 Jun 25.

Department of Neurological Surgery, The Miami Project to Cure Paralysis University of Miami Miller School of Medicine.

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http://dx.doi.org/10.1089/ther.2020.29074.cfpDOI Listing
September 2020

Stay Safe and Healthy.

Ther Hypothermia Temp Manag 2020 06 8;10(2):85. Epub 2020 May 8.

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http://dx.doi.org/10.1089/ther.2020.29073.wddDOI Listing
June 2020

IC100: a novel anti-ASC monoclonal antibody improves functional outcomes in an animal model of multiple sclerosis.

J Neuroinflammation 2020 May 4;17(1):143. Epub 2020 May 4.

University of Miami Miller School of Medicine, Miami, FL, 33136, USA.

Background: The inflammasome adaptor apoptosis-associated speck-like protein containing a CARD (ASC) is involved in immune signaling by bridging the interactions between inflammasome sensors and caspase-1. Strong experimental evidence has shown that ASC mice are protected from disease progression in animal models of multiple sclerosis (MS), suggesting that targeting inflammasome activation via ASC inhibition may be a promising therapeutic strategy in MS. Thus, the goal of our study is to test the efficacy of IC100, a novel humanized antibody targeting ASC, in preventing and/or suppressing disease in the experimental autoimmune encephalomyelitis (EAE) model of MS.

Methods: We employed the EAE model of MS where disease was induced by immunization of C57BL/6 mice with myelin oligodendrocyte glycoprotein peptide 35-55 (MOG). Mice were treated with vehicle or increasing doses of IC100 (10, 30, and 45 mg/kg) and clinical disease course was evaluated up to 35 days post EAE induction. Immune cell infiltration into the spinal cord and microglia responses were assessed.

Results: We show that IC100 treatment reduced the severity of EAE when compared to vehicle-treated controls. At a dose of 30 mg/kg, IC100 significantly reduced the number of CD4 and CD8 T cells and CD11bMHCII activated myeloid cells entering the spinal cord from the periphery, and reduced the number of total and activated microglia.

Conclusions: These data indicate that IC100 suppresses the immune-inflammatory response that drives EAE development and progression, thereby identifying ASC as a promising target for the treatment of MS as well as other neurological diseases with a neuroinflammatory component.
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http://dx.doi.org/10.1186/s12974-020-01826-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7199312PMC
May 2020

An Exploratory Report on Electrographic Changes in the Cerebral Cortex Following Mild Traumatic Brain Injury with Hyperthermia in the Rat.

Ther Hypothermia Temp Manag 2021 Mar 5;11(1):10-18. Epub 2020 May 5.

The Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Miami, Florida, USA.

Traumatic brain injury (TBI) has the potential to perturb perception by disrupting electrical propagation within and between the thalamus and cerebral cortex. Moderate and severe TBI may result in posttraumatic epilepsy, a condition characterized by convulsive tonic-clonic seizures. Spike/wave discharges (SWDs) of generalized nonconvulsive seizures, also called absence seizures, may also occur as a consequence of brain trauma. As mild hyperthermia has been reported to exacerbate histopathological and behavioral outcomes, we used an unbiased algorithm to detect periodic increases in power across different frequency bands following single or double closed head injury (CHI) under normothermia and hyperthermia conditions. We demonstrated that mild TBI did not significantly alter the occurrence of events containing increases in power between the delta (0.5-4 Hz), theta (4-8 Hz), alpha (8-12 Hz), and beta1 (12-20 Hz) frequency bands in the Sprague Dawley rat 12 weeks after injury. However, when hyperthermia (39°C) was induced before and after CHI, electrographic events containing a similar waveform and harmonic frequency to SWDs were observed in a subset of animals. Further experiments utilizing chronic recordings will need to be performed to determine if these trends lead to absence seizures.
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http://dx.doi.org/10.1089/ther.2020.0002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910421PMC
March 2021

Additive Protective Effects of Delayed Mild Therapeutic Hypothermia and Antioxidants on PC12 Cells Exposed to Oxidative Stress.

Ther Hypothermia Temp Manag 2020 Apr 17. Epub 2020 Apr 17.

Department of Otolaryngology, University of Miami, Miami, Florida, USA.

Mild therapeutic hypothermia is protective against several cellular stresses, but the mechanisms underlying this protection are not completely resolved. In the present study, we used an model to investigate whether therapeutic hypothermia at 33°C applied following a peroxide-induced oxidative stress would protect PC12 cells. A 1-hour exposure to tert-butyl peroxide increased cell death measured 24 hours later. This cell death was dose-dependent in the range of 100-1000 μM tert-butyl peroxide with ∼50% cell death observed at 24 hours from 500 μM peroxide exposure. Cell survival/death was measured with an alamarBlue viability assay, and propidium iodide/Hoechst imaging for counts of living and dead cells. Therapeutic hypothermia at 33°C applied for 2 hours postperoxide exposure significantly increased cell survival measured 24 hours postperoxide-induced stress. This protection was present even when delayed hypothermia, 15 minutes after the peroxide washout, was applied. Addition of any of the three FDA-approved antioxidants (Tempol, EUK134, Edaravone at 100 μM) in combination with hypothermia improved cell survival. With the therapeutic hypothermia treatment, a significant downregulation of caspases-3 and -8 and tumor necrosis factor-α was observed at 3 and 24 hours poststress. Consistent with this, a cell-permeable pan-caspase inhibitor Z-VAD-FMK applied in combination with hypothermia significantly increased cell survival. Overall, these results suggest that the antioxidants quenching of reactive oxygen species likely works with hypothermia to reduce mitochondrial damage and/or apoptotic mechanisms. Further studies are required to confirm and extend these results to other cell types, including neuronal cells, and other forms of oxidative stress as well as to optimize the critical parameters of hypothermia treatment such as target temperature and duration.
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http://dx.doi.org/10.1089/ther.2019.0034DOI Listing
April 2020

Therapeutic hypothermia reduces cortical inflammation associated with utah array implants.

J Neural Eng 2020 04 29;17(2):026035. Epub 2020 Apr 29.

Department of Biomedical Engineering, University of Miami, FL, United States of America.

Objective: Neuroprosthetics hold tremendous promise to restore function through brain-computer interfaced devices. However, clinical applications of implantable microelectrodes remain limited given the challenges of maintaining neuronal signals for extended periods of time and with multiple biological mechanisms negatively affecting electrode performance. Acute and chronic inflammation, oxidative stress, and blood brain barrier disruption contribute to inconsistent electrode performance. We hypothesized that therapeutic hypothermia (TH) applied at the microelectrode insertion site will positively modulate both inflammatory and apoptotic pathways, promoting neuroprotection and improved performance in the long-term.

Approach: A custom device and thermoelectric system were designed to deliver controlled TH locally to the cortical implant site at the time of microelectrode array insertion and immediately following surgery. The TH paradigm was derived from in vivo cortical temperature measurements and finite element modeling of temperature distribution profiles in the cortex. Male Sprague-Dawley rats were implanted with non-functional Utah microelectrodes arrays (UMEA) consisting of 4 × 4 grid of 1.5 mm long parylene-coated silicon shanks. In one group, TH was applied to the implant site for two hours following the UMEA implantation, while the other group was implanted under normothermic conditions without treatment. At 48 h, 72 h, 7 d and 14 d post-implantation, mRNA expression levels for genes associated with inflammation and apoptosis were compared between normothermic and hypothermia-treated groups.

Main Results: The custom system delivered controlled TH to the cortical implant site and the numerical models confirmed that the temperature decrease was confined locally. Furthermore, a one-time application of TH post UMEA insertion significantly reduced the acute inflammatory response with a reduction in the expression of inflammatory regulating cytokines and chemokines.

Significance: This work provides evidence that acutely applied hypothermia is effective in significantly reducing acute inflammation post intracortical electrode implantation.
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http://dx.doi.org/10.1088/1741-2552/ab85d2DOI Listing
April 2020

2020: A New Decade for Therapeutic Hypothermia and Temperature Management.

Ther Hypothermia Temp Manag 2020 03 13;10(1). Epub 2020 Jan 13.

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http://dx.doi.org/10.1089/ther.2019.29067.wddDOI Listing
March 2020

Sexually dimorphic microglia and ischemic stroke.

CNS Neurosci Ther 2019 12 20;25(12):1308-1317. Epub 2019 Nov 20.

Peritz Scheinberg Cerebral Vascular Disease Research Laboratory, Department of Neurology, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA.

Ischemic stroke kills more women compared with men thus emphasizing a significant sexual dimorphism in ischemic pathophysiological outcomes. However, the mechanisms behind this sexual dimorphism are yet to be fully understood. It is well established that cerebral ischemia activates a variety of inflammatory cascades and that microglia are the primary immune cells of the brain. After ischemic injury, microglia are activated and play a crucial role in progression and resolution of the neuroinflammatory response. In recent years, research has focused on the role that microglia play in this sexual dimorphism that exists in the response to central nervous system (CNS) injury. Evidence suggests that the molecular mechanisms leading to microglial activation and polarization of phenotypes may be influenced by sex, therefore causing a difference in the pro/anti-inflammatory responses after CNS injury. Here, we review advances highlighting that sex differences in microglia are an important factor in the inflammatory responses that are seen after ischemic injury. We discuss the main differences between microglia in the healthy and diseased developing, adult, and aging brain. We also focus on the dimorphism that exists between males and females in microglial-induced inflammation and energy metabolism after CNS injury. Finally, we describe how all of the current research and literature regarding sex differences in microglia contribute to the differences in poststroke responses between males and females.
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http://dx.doi.org/10.1111/cns.13267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6887716PMC
December 2019

December's Wintry Breath.

Ther Hypothermia Temp Manag 2019 12 14;9(4):223. Epub 2019 Nov 14.

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http://dx.doi.org/10.1089/ther.2019.29066.wddDOI Listing
December 2019

Neural-respiratory inflammasome axis in traumatic brain injury.

Exp Neurol 2020 01 15;323:113080. Epub 2019 Oct 15.

Department of Neurological Surgery, University of Miami Miller School of Medicine, United States of America; Miami Project to Cure Paralysis, United States of America; Department of Physiology and Biophysics, University of Miami Miller School fo Medicine, 1600 NW10th Avenue, Miami, FL 33136, United States of America. Electronic address:

Traumatic brain injury (TBI) is a leading cause of morbidity and mortality. Approximately 20-25% of TBI subjects develop Acute Lung Injury (ALI), but the pathomechanisms of TBI-induced ALI remain poorly defined. Currently, mechanical ventilation is the only therapeutic intervention for TBI-induced lung injury. Our recent studies have shown that the inflammasome plays an important role in the systemic inflammatory response leading to lung injury-post TBI. Here, we outline the role of the extracellular vesicle (EV)-mediated inflammasome signaling in the etiology of TBI-induced ALI. Furthermore, we evaluate the efficacy of a low molecular weight heparin (Enoxaparin, a blocker of EV uptake) and a monoclonal antibody against apoptosis speck-like staining protein containing a caspase recruitment domain (anti-ASC) as therapeutics for TBI-induced lung injury. We demonstate that activation of an EV-mediated Neural-Respiratory Inflammasome Axis plays an essential role in TBI-induced lung injury and disruption of this axis has therapeutic potential as a treatment strategy.
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http://dx.doi.org/10.1016/j.expneurol.2019.113080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6981270PMC
January 2020

Fall Is in the Air.

Ther Hypothermia Temp Manag 2019 09 22;9(3):167. Epub 2019 Aug 22.

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http://dx.doi.org/10.1089/ther.2019.29063.wddDOI Listing
September 2019

Summer Time for the Journal.

Ther Hypothermia Temp Manag 2019 Jun 23;9(2):97. Epub 2019 May 23.

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http://dx.doi.org/10.1089/ther.2019.29059.wddDOI Listing
June 2019

Caspase-1 Inhibition Attenuates Hyperoxia-induced Lung and Brain Injury in Neonatal Mice.

Am J Respir Cell Mol Biol 2019 09;61(3):341-354

Division of Neonatology and.

Hyperoxia plays a key role in the development of bronchopulmonary dysplasia (BPD), a chronic lung disease of preterm infants. Infants with BPD often have brain injury that leads to long-term neurodevelopmental impairment, but the underlying mechanisms that control BPD-induced neurodevelopmental impairment remain unclear. Our previous studies have shown that hyperoxia-induced BPD in rodents is associated with lung inflammasome activation. Here, we tested the hypothesis that hyperoxia-induced lung and brain injury is mediated by inflammasome activation, and that inhibition of caspase-1, a key component of the inflammasome, attenuates hyperoxia-induced lung and brain injury in neonatal mice. C57/BL6 mouse pups were randomized to receive daily intraperitoneal injections of Ac-YVAD-CMK, an irreversible caspase-1 inhibitor, or placebo during exposure to room air or hyperoxia (85% O) for 10 days. We found that hyperoxia activated the NLRP1 inflammasome, increased production of mature IL-1β, and upregulated expression of p30 gasdermin-D (GSDMD), the active form of GSDMD that is responsible for the programmed cell death mechanism of pyroptosis in both lung and brain tissue. Importantly, we show that inhibition of caspase-1 decreased IL-1β activation and p30 GSDMD expression, and improved alveolar and vascular development in hyperoxia-exposed lungs. Moreover, caspase-1 inhibition also promoted cell proliferation in the subgranular zone and subventricular zone of hyperoxia-exposed brains, resulting in lessened atrophy of these zones. Thus, the inflammasome plays a critical role in hyperoxia-induced neonatal lung and brain injury, and targeting this pathway may be beneficial for the prevention of lung and brain injury in preterm infants.
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http://dx.doi.org/10.1165/rcmb.2018-0192OCDOI Listing
September 2019

Imaging characteristics of chronic spinal cord injury identified during screening for a cell transplantation clinical trial.

Neurosurg Focus 2019 03;46(3):E8

Departments of1Neurological Surgery.

OBJECTIVEIn cell transplantation trials for spinal cord injury (SCI), quantifiable imaging criteria that serve as inclusion criteria are important in trial design. The authors' institutional experience has demonstrated an overall high rate of screen failures. The authors examined the causes for trial exclusion in a phase I, open-lab clinical trial examining the role of autologous Schwann cell intramedullary transplantation. Specifically, they reviewed the imaging characteristics in people with chronic SCI that excluded applicants from the trial, as this was a common cause of screening failures in their study.METHODSThe authors reviewed MRI records from 152 people with chronic (> 1 year) SCI who volunteered for intralesional Schwann cell transplantation but were deemed ineligible by prospectively defined criteria. Rostral-caudal injury lesion length was measured along the long axis of the spinal cord in the sagittal plane on T2-weighted MRI. Other lesion characteristics, specifically those pertaining to lesion cavity structure resulting in trial exclusion, were recorded.RESULTSImaging records from 152 potential participants with chronic SCI were reviewed, 42 with thoracic-level SCI and 110 with cervical-level SCI. Twenty-three individuals (55%) with thoracic SCI and 70 (64%) with cervical SCI were not enrolled in the trial based on imaging characteristics. For potential participants with thoracic injuries who did not meet the screening criteria for enrollment, the average rostral-caudal sagittal lesion length was 50 mm (SD 41 mm). In applicants with cervical injuries who did not meet the screening criteria for enrollment, the average sagittal lesion length was 34 mm (SD 21 mm).CONCLUSIONSWhile screening people with SCI for participation in a cell transplantation clinical trial, lesion length or volume can exclude potential subjects who appear appropriate candidates based on neurological eligibility criteria. In planning future cell-based therapy trials, the limitations incurred by lesion size should be considered early due to the screening burden and impact on candidate selection.
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http://dx.doi.org/10.3171/2018.12.FOCUS18593DOI Listing
March 2019

The role of microglial inflammasome activation in pyroptotic cell death following penetrating traumatic brain injury.

J Neuroinflammation 2019 Feb 8;16(1):27. Epub 2019 Feb 8.

Department of Physiology and Biophysics, University of Miami Miller School of Medicine, Miami, Florida, USA.

Background: Traumatic brain injury remains a significant cause of death and disability in the USA. Currently, there are no effective therapies to mitigate disability except for surgical interventions necessitating a need for continued research into uncovering novel therapeutic targets. In a recent study, we used a rodent model of penetrating traumatic brain injury known as penetrating ballistic-like brain injury (PBBI) to examine the role of innate immunity in post-traumatic secondary injury mechanisms. We previously reported that the inflammasome, a multiprotein complex composed of apoptosis-associated speck-like protein containing card and caspase-1, plays a role in secondary cell death mechanisms after PBBI, including inflammatory cell death (pyroptosis).

Methods: In the current study, we used flow cytometry analysis to evaluate activated microglia and CD11b-positive leukocytes after PBBI and assessed inflammasome activation and pyroptosis of specific cellular populations. Sprague-Dawley male rats underwent PBBI or sham-operated procedures and ipsilateral cortical regions processed for flow cytometry and cellular analysis. Flow cytometry results were compared using one-way ANOVA followed by Tukey's multiple comparisons.

Results: At 48 h following PBBI, there was an increase in activated microglia and infiltrating leukocytes compared to sham controls that were associated with increased caspase-1 activity. Using a florescent probe to identify caspase-1 activity and a fluorescent assay to determine cell viability, evidence for pyroptosis in CD11b+ cells was also determined. Finally, while post-traumatic treatment with an anti-ASC antibody had no effect on the number of activated microglia and infiltrating leukocytes, antibody treatment decreased caspase-1 activity in both resident microglia and infiltrating leukocytes and reduced pyroptotic CD11b+ cell death.

Conclusions: These results provide evidence for inflammasome activation in microglia and infiltrating leukocytes after penetrating traumatic brain injury and a role for pyroptotic cell death in the pathophysiology. In addition to inhibiting neuronal cell death, therapeutic treatments targeting inflammasome activation may also provide beneficial effects by reducing the potentially detrimental consequences of activated microglia and infiltrating CD11b+ leukocytes following penetrating traumatic brain injury.
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http://dx.doi.org/10.1186/s12974-019-1423-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6367831PMC
February 2019