Different resuscitation strategies and novel pharmacologic treatment with valproic acid in traumatic brain injury.

Traumatic brain injury (TBI) is a leading cause of death in young adults, and effective treatment strategies have the potential to save many lives. TBI results in coagulopathy, endothelial dysfunction, inflammation, cell death, and impaired epigenetic homeostasis, ultimately leading to morbidity and/or mortality. Commonly used resuscitation fluids such as crystalloids or colloids have several disadvantages and might even be harmful when administered in large quantities. There is a need for next-generation treatment strategies (especially in the prehospital setting) that minimize cellular damage, improve survival, and enhance neurological recovery. Pharmacologic treatment with histone deacetylase inhibitors, such as valproic acid, has shown promising results in animal studies of TBI and may therefore be an excellent example of next-generation therapy. This review briefly describes traditional resuscitation strategies for TBI combined with hemorrhagic shock and describes preclinical studies on valproic acid as a new pharmacologic agent in the treatment of TBI. It finally discusses limitations and future directions on the use of histone deacetylase inhibitors for the treatment of TBI.

Improvement of Blood-Brain Barrier Integrity in Traumatic Brain Injury and Hemorrhagic Shock Following Treatment With Valproic Acid and Fresh Frozen Plasma.

OBJECTIVE: Combined traumatic brain injury and hemorrhagic shock are highly lethal. Following injuries, the integrity of the blood-brain barrier can be impaired, contributing to secondary brain insults. The status of the blood-brain barrier represents a potential factor impacting long-term neurologic outcomes in combined injuries. Treatment strategies involving plasma-based resuscitation and valproic acid therapy have shown efficacy in this setting. We hypothesize that a component of this beneficial effect is related to blood-brain barrier preservation. DESIGN: Following controlled traumatic brain injury, hemorrhagic shock, various resuscitation and treatment strategies were evaluated for their association with blood-brain barrier integrity. Analysis of gene expression profiles was performed using Porcine Gene ST 1.1 microarray. Pathway analysis was completed using network analysis tools (Gene Ontology, Ingenuity Pathway Analysis, and Parametric Gene Set Enrichment Analysis). SUBJECTS: Female Yorkshire swine were subjected to controlled traumatic brain injury and 2 hours of hemorrhagic shock (40% blood volume, mean arterial pressure 30-35 mmHg). INTERVENTIONS: Subjects were resuscitated with 1) normal saline, 2) fresh frozen plasma, 3) hetastarch, 4) fresh frozen plasma + valproic acid, or 5) hetastarch + valproic acid (n = 5 per group). After 6 hours of observation, brains were harvested for evaluation. MEASUREMENTS AND MAIN RESULTS: Immunofluoroscopic evaluation of the traumatic brain injury site revealed significantly increased expression of tight-junction associated proteins (zona occludin-1, claudin-5) following combination therapy (fresh frozen plasma + valproic acid and hetastarch + valproic acid). The extracellular matrix protein laminin was found to have significantly improved expression with combination therapies. Pathway analysis indicated that valproic acid significantly modulated pathways involved in endothelial barrier function and cell signaling. CONCLUSIONS: Resuscitation with fresh frozen plasma results in improved expression of proteins essential for blood-brain barrier integrity. The addition of valproic acid provides significant improvement to these protein expression profiles. This is likely secondary to activation of key pathways related to endothelial functions.

Relationship between tissue perfusion and coagulopathy in traumatic brain injury.

BACKGROUND: Traumatic brain injury (TBI)-related coagulopathy appears to be most prevalent in patients with tissue hypoperfusion, but evidence for this association is scarce. This study investigated the relationship between tissue perfusion and hemostatic derangements in TBI patients. MATERIALS AND METHODS: Coagulation parameters were measured on emergency department admission in patients with TBI (head abbreviated injury scale ≥ 3). The level of hypoperfusion was simultaneously assessed by near-infrared spectroscopy (NIRS) at the forehead and arm, and by base excess and lactate. Coagulopathy was defined as an international normalized ratio > 1.2 and/or activated partial thromboplastin time > 40 s and/or thrombocytopenia (<120 × 10(9)/L). RESULTS: TBI patients with coagulopathy (42%) had more signs of tissue hypoperfusion as indicated by increased lactate levels (2.1 [1.1-3.2] mmol/L versus 1.2 [1.0-1.7] mmol/L; P = 0.017) and a larger base deficit (-3.0 [-4.6 to -2.0] mmol/L versus -0.1 [-2.5 to 1.8] mmol/L; P < 0.001). There was no difference in the cerebral or somatic tissue oxygenation index. However, there was a distinct trend toward a moderate inverse association between the cerebral tissue oxygenation index and D-dimer levels (r=-0.40; P = 0.051) as marker of fibrinolysis. The presence of coagulopathy was associated with an increased inhospital mortality rate (45.5% versus 6.7%; P = 0.002). CONCLUSIONS: This is the first study to investigate the relationship between hemostatic derangements and tissue oxygenation using NIRS in TBI patients. This study showed that TBI-related coagulopathy is more profound in patients with metabolic acidosis and increased lactate levels. Although there was no direct relationship between tissue oxygenation and coagulopathy, we observed an inverse relationship between NIRS tissue oxygenation levels and fibrinolysis.

Low Cerebral Oxygenation Levels during Resuscitation in Out-of-hospital Cardiac Arrest Are Associated with Hyperfibrinolysis.

BACKGROUND: The authors investigated whether patients with out-of-hospital cardiac arrest with an initial low cerebral oxygen level during cardiopulmonary resuscitation are more prone to develop hyperfibrinolysis than patients with normal cerebral oxygenation levels and which part of the fibrinolytic system is involved in this response. METHODS: In 46 patients, hyperfibrinolysis was diagnosed immediately upon emergency department admission using rotational thromboelastometry and defined as a lysis more than 15%. Simultaneously, initial cerebral tissue oxygenation was measured using near-infrared spectroscopy, and oxygen desaturation was defined as a tissue oxygenation index (TOI) of 50% or less. Blood sample analysis included markers for hypoperfusion and fibrinolysis. RESULTS: There was no difference in prehospital cardiopulmonary resuscitation duration between patients with or without hyperfibrinolysis. An initial TOI of 50% or less was associated with more clot lysis (91% [17 to 100%; n = 16]) compared with patients with a normal TOI (6% [4 to 11%]; n = 30; P < 0.001), with lower levels of plasminogen (151.6 ± 61.0 vs. 225.3 ± 47.0 µg/ml; P < 0.001) and higher levels of tissue plasminogen activator (t-PA; 18.3 ± 7.4 vs. 7.9 ± 4.7 ng/ml; P < 0.001) and plasminogen activator inhibitor-1 (19.3 ± 8.9 vs. 12.1 ± 6.1 ng/ml; P = 0.013). There were no differences in (activated) protein C levels among groups. The initial TOI was negatively correlated with t-PA (r = -0.69; P < 0001). Mortality rates were highest in patients with hyperfibrinolysis. CONCLUSION: Activation of the fibrinolytic system is more common in out-of-hospital cardiac arrest patients with an initial cerebral tissue oxygenation value of 50% or less during resuscitation and is linked to increased levels of t-PA rather than involvement of protein C.

Hypothermia and valproic acid activate prosurvival pathways after hemorrhage.

BACKGROUND: Therapeutic hypothermia (hypo) and valproic acid (VPA, a histone deacetylase inhibitor) have independently been shown to be protective in models of trauma and hemorrhagic shock but require logistically challenging doses to be effective. Theoretically, combined treatment may further enhance effectiveness, allowing us to use lower doses of each modality. The aim of this study was to determine whether a combination of mild hypo and VPA treatments would offer better cytoprotection compared with that of individual treatments in a hemorrhage model. MATERIALS AND METHODS: Male Sprague-Dawley rats were subjected to 40% volume-controlled hemorrhage, kept in shock for 30 min, and assigned to one of the following treatment groups: normothermia (36°C-37°C), hypo (30 ± 2°C), normothermia + VPA (300 mg/kg), and hypo + VPA (n = 5 per group). After 3 h of observation, the animals were sacrificed, liver tissue was harvested and subjected to whole cell lysis, and levels of key proteins in the prosurvival Akt pathway were measured using Western blot. RESULTS: Activation of the proapoptotic protein cleaved caspase-3 was significantly lower in the combined treatment group relative to normothermia (P < 0.05). Levels of the prosurvival Bcl-2 was significantly higher in the combined treatment group relative to sham, normothermia, and normothermia + VPA groups (P < 0.005). The downstream prosurvival protein phospho-GSK-3ß was significantly higher in the sham, hypo, and combined treatment groups compared with that in normothermia groups with or without VPA (P < 0.05). Levels of the prosurvival ß-catenin were significantly higher in the combined treatment group relative to normothermia (P < 0.01). CONCLUSIONS: This is the first in vivo study to demonstrate that combined treatment with VPA and hypo offers better cytoprotection than these treatments given independently.

Treatment with a histone deacetylase inhibitor, valproic acid, is associated with increased platelet activation in a large animal model of traumatic brain injury and hemorrhagic shock.

BACKGROUND: We have previously shown that resuscitation with fresh frozen plasma (FFP) in a large animal model of traumatic brain injury (TBI) and hemorrhagic shock (HS) decreases the size of the brain lesion, and that addition of a histone deacetylase inhibitor, valproic acid (VPA), provides synergistic benefits. In this study, we hypothesized that VPA administration would be associated with a conservation of platelet function as measured by increased platelet activation after resuscitation. MATERIALS AND METHODS: Ten swine (42-50 kg) were subjected to TBI and HS (40% blood loss). Animals were left in shock for 2 h before resuscitation with either FFP or FFP+VPA (300 mg/kg). Serum levels of platelet activation markers transforming growth factor beta, CD40 L, P-selectin, and platelet endothelial cell adhesion molecule (PECAM) 1 were measured at baseline, postresuscitation, and after a 6-h observation period. Platelet activation markers were also measured in the brain whole cell lysates and immunohistochemistry. RESULTS: Circulating P-selectin levels were significantly higher in the FFP+VPA group compared with the FFP alone group (70.85±4.70 versus 48.44±7.28 ng/mL; P<0.01). Likewise, immunohistochemistry data showed elevated P-selectin in the VPA treatment group (22.30±10.39% versus 8.125±3.94%, P<0.01). Serum sCD40L levels were also higher in the FFP+VPA group (3.21±0.124 versus 2.38±0.124 ng/mL; P<0.01), as was brain sCD40L levels (1.41±0.15 versus 1.22±0.12 ng/mL; P=0.05). Circulating transforming growth factor beta levels were elevated in the FFP+VPA group, but this did not reach statistical significance (11.20±1.46 versus 8.09±1.41 ng/mL; P=0.17). Brain platelet endothelial cell adhesion molecule 1 levels were significantly lower in the FFP+VPA group compared with the FFP group (5.22±2.00 pg/mL versus 7.99±1.13 pg/mL; P=0.03). CONCLUSIONS: In this clinically relevant large animal model of combined TBI+HS, the addition of VPA to FFP resuscitation results in an early upregulation of platelet activation in the circulation and the brain. The previously observed neuroprotective effects of VPA may be due to a conservation of platelet function as measured by a higher platelet activation response after resuscitation.

Using Measurable Residual Disease to Optimize Management of AML, ALL, and Chronic Myeloid Leukemia.

In this review, we discuss the use of measurable residual disease (MRD) in AML, ALL, and chronic myeloid leukemia (CML). Our aims were to review the different methodologies for MRD assessment; describe the clinical relevance and medical decision making on the basis of MRD; compare and contrast the usage of MRD across AML, ALL, and CML; and discuss what patients need to know about MRD as it relates to their disease status and treatment. Finally, we discuss ongoing challenges and future directions with the goal of optimizing MRD usage in leukemia management.

Next-generation sequencing-based MRD in adults with ALL undergoing hematopoietic cell transplantation.

Measurable residual disease (MRD) is an adverse prognostic factor in adult patients with acute lymphoblastic leukemia (ALL) undergoing hematopoietic cell transplant (HCT). Next-generation sequencing (NGS) can detect MRD with a sensitivity of 10-6, but the prognostic value of NGS-based MRD in adult patients with ALL undergoing HCT remains minimally studied. To evaluate the prognostic value of NGS-based MRD in adult patients with ALL undergoing HCT, patients aged ≥18 years with ALL who underwent allogeneic HCT at Stanford University or Oregon Health & Science University between January 2014 and April 2021 and were evaluated for MRD using the NGS-based clonoSEQ assay were included in this study. MRD was assessed before HCT (MRDpre) and up to 1 year after HCT (MRDpost). Patients were followed up for leukemia relapse and survival for up to 2 years after HCT. In total, 158 patients had a trackable clonotype for MRD monitoring. The cumulative incidence of relapse was increased at all levels of MRDpre, including in patients who had low MRDpre of <10-4 (hazard ratio [HR], 3.56; 95% confidence interval [95% CI], 1.39-9.15). In multivariable analysis, MRDpre level remained significantly prognostic; however, detectable MRDpost was the strongest predictor of relapse (HR, 4.60; 95% CI, 3.01-7.02). In exploratory analyses limited to patients with B-cell ALL, the detection of post-HCT immunoglobulin H (IgH) MRD clonotypes, rather than non-IgH MRD clonotypes, was associated with relapse. In this analysis across 2 large transplant centers, we found that the detection of MRD by NGS at a level of 10-6 offers significant prognostic value in adults with ALL undergoing HCT.

SOHO State of the Art Updates and Next Questions: Measurable Residual Disease in Acute Lymphoblastic Leukemia - Optimization and Innovation in 2022 and Beyond.

Measurable residual disease (MRD) is an established component of acute lymphoblastic leukemia (ALL) management in both children and adults. Society guidelines and expert consensus documents include assessment of MRD as the standard of care following induction therapy, consolidation therapy, and at additional time points, depending on the treatment regimen administered. Further, the approval of blinatumomab for MRD+ B-ALL has advanced the concept of MRD response as a clinical endpoint in ALL. Although the utility of MRD in ALL has been well defined over the last decades, several questions remain. In this review we focus on areas of ongoing controversy and exploration in ALL MRD, including the following: (1) Does increasing the depth of MRD assessment add prognostic value? (2) Is there a role for ongoing MRD monitoring once patients achieve MRD response? (3) Can MRD assessment of the peripheral blood be substituted for bone marrow? (4) Should MRD assays be applied to the analysis of the central nervous system (CNS)? Ongoing studies should answer the majority of these questions in the coming years.

Challenging clinical scenarios for therapeutic anticoagulation: A practical approach.

Therapeutic anticoagulation remains a fundamental backbone in the treatment and prevention of venous thromboembolism. However, while modern therapies are increasingly safe, anticoagulation is not without risks, particularly in those at high risk for or with recent bleeding. When weighing concurrent risks and benefits in each challenging clinical scenario, an individualized assessment of the risk and acuity of bleeding should be balanced by the indication for anticoagulation. Addressing modifiable risk factors and routine re-evaluation of any changes in this balance is critical. This review outlines available data and current guidelines for the management of anticoagulation in high-risk populations, including those with thrombocytopenia, elderly and high-fall risk, inherited bleeding disorders, and in acute coronary syndrome. We also examine management after clinically significant bleeding episodes, including intracranial hemorrhage, gastrointestinal bleeding, hemoptysis, retroperitoneal bleeding, hematuria, and abnormal uterine bleeding. The aim is to provide a comprehensive review of available literature to guide clinicians in providing optimal, safe, and individualized care for patients in these challenging scenarios.

Transcriptional and Cytotoxic Responses of Human Intestinal Organoids to IFN Types I, II, and III.

The three types of IFN have roles in antimicrobial immunity and inflammation that must be properly balanced to maintain tissue homeostasis. For example, IFNs are elevated in the context of inflammatory bowel disease and may synergize with inflammatory cytokines such as TNF-α to promote tissue damage. Prior studies suggest that in mouse intestinal epithelial cells (IECs), type III IFNs are preferentially produced during viral infections and are less cytotoxic than type I IFN. In this study, we generated human IEC organoid lines from biopsies of ileum, ascending colon, and sigmoid colon of three healthy subjects to establish the baseline responses of normal human IECs to types I, II, and III IFN. We found that all IFN types elicited responses that were qualitatively consistent across intestinal biopsy sites. However, IFN types differed in magnitude of STAT1 phosphorylation and identity of genes in their downstream transcriptional programs. Specifically, there was a core transcriptional module shared by IFN types, but types I and II IFN stimulated unique transcriptional modules beyond this core gene signature. The transcriptional modules of type I and II IFN included proapoptotic genes, and expression of these genes correlated with potentiation of TNF-α cytotoxicity. These data define the response profiles of healthy human IEC organoids across IFN types, and they suggest that cytotoxic effects mediated by TNF-α in inflamed tissues may be amplified by a simultaneous high-magnitude IFN response.

Early Treatment With a Single Dose of Mesenchymal Stem Cell Derived Extracellular Vesicles Modulates the Brain Transcriptome to Create Neuroprotective Changes in a Porcine Model of Traumatic Brain Injury and Hemorrhagic Shock.

BACKGROUND: Cell-based therapies using mesenchymal stem cell derived extracellular vesicles (EVs) improve neurologic outcomes in animal models of traumatic brain injury (TBI), stroke, and hemorrhage. Using a porcine 7-day survival model of TBI and hemorrhagic shock (HS), we previously demonstrated that EV-treatment was associated with reduced brain lesion size, neurologic severity score, and cerebral inflammation. However, the underlying cellular and genomic mechanisms remain poorly defined. We hypothesize that EV treatment modulates the brain transcriptome to enhance neuroprotection and neurorestoration following TBI + HS. METHODS: Swine were subjected to severe TBI (8-mm cortical impact) and HS (40% blood volume). After 1 h of shock, animals were randomized (n = 4/group) to treatment with either lactated Ringer's (LR) or LR + EV. Both groups received fluid resuscitation after 2 h of shock, and autologous packed red blood cells 5 h later.After 7-days, brains were harvested and RNA-sequencing was performed. The transcriptomic data were imported into the iPathway pipeline for bioinformatics analyses. RESULTS: 5,273 genes were differentially expressed in the LR + EV group versus LR alone (total 9,588 measured genes). Genes with the greatest upregulation were involved in synaptic transmission and neuronal development and differentiation, while downregulated genes were involved in inflammation. GO-terms experiencing the greatest modulation were involved in inflammation, brain development, and cell adhesion. Pathway analysis revealed significant modulation in the glutamatergic and GABAergic systems. Network analysis revealed downregulation of inflammation, and upregulation of neurogenesis, and neuron survival and differentiation. CONCLUSIONS: In a porcine model of TBI + HS, EV treatment was associated with an attenuation of cerebral inflammatory networks and a promotion of neurogenesis and neuroplasticity. These transcriptomic changes could explain the observed neuroprotective and neurorestorative properties associated with EV treatment.

Treatment and Prevention of Acute Hepatitis B Virus.

This article reviews the incidence of acute hepatitis B virus (HBV) infection, its clinical course, strategies to prevent acute HBV infection in susceptible individuals, and the management of patients with acute HBV.

Modulation of Brain Transcriptome by Combined Histone Deacetylase Inhibition and Plasma Treatment Following Traumatic Brain Injury and Hemorrhagic Shock.

INTRODUCTION: We previously showed that the addition of valproic acid (VPA), a histone deacetylase inhibitor, to fresh frozen plasma (FFP) resuscitation attenuates brain lesion size and swelling following traumatic brain injury (TBI) and hemorrhagic shock (HS). The goal of this study was to use computational biology tools to investigate the effects of FFP+VPA on the brain transcriptome following TBI+HS. METHODS: Swine underwent TBI+HS, kept in shock for 2 h, and resuscitated with FFP or FFP + VPA (n = 5/group). After 6 h of observation, brain RNA was isolated and gene expression was analyzed using a microarray. iPathwayGuide, Gene Ontology (GO), Gene-Set Enrichment Analysis, and Enrichment Mapping were used to identify significantly impacted genes and transcriptomic networks. RESULTS: Eight hundred differentially expressed (DE) genes were identified out of a total of 9,118 genes. Upregulated genes were involved in promotion of cell division, proliferation, and survival, while downregulated genes were involved in autophagy, cell motility, neurodegenerative diseases, tumor suppression, and cell cycle arrest. Seven hundred ninety-one GO terms were significantly enriched. A few major transcription factors, such as TP53, NFKB3, and NEUROD1, were responsible for modulating hundreds of other DE genes. Network analysis revealed attenuation of interconnected genes involved in inflammation and tumor suppression, and an upregulation of those involved in cell proliferation and differentiation. CONCLUSION: Overall, these results suggest that VPA treatment creates an environment that favors production of new neurons, removal of damaged cells, and attenuation of inflammation, which could explain its previously observed neuroprotective effects.

Comparison of Materials Used for 3D-Printing Temporal Bone Models to Simulate Surgical Dissection.

OBJECTIVE: To identify 3D-printed temporal bone (TB) models that most accurately recreate cortical mastoidectomy for use as a training tool by comparison of different materials and fabrication methods. BACKGROUND: There are several different printers and materials available to create 3D-printed TB models for surgical planning and trainee education. Current reports using Acrylonitrile Butadiene Styrene (ABS) plastic generated via fused deposition modeling (FDM) have validated the capacity for 3D-printed models to serve as accurate surgical simulators. Here, a head-to-head comparison of models produced using different materials and fabrication processes was performed to identify superior models for application in skull base surgical training. METHODS: High-resolution CT scans of normal TBs were used to create stereolithography files with image conversion for application in 3D-printing. The 3D-printed models were constructed using five different materials and four printers, including ABS printed on a MakerBot 2x printer, photopolymerizable polymer (Photo) using the Objet 350 Connex3 Printer, polycarbonate (PC) using the FDM-Fortus 400 mc printer, and two types of photocrosslinkable acrylic resin, white and blue (FLW and FLB, respectively), using the Formlabs Form 2 stereolithography printer. Printed TBs were drilled to assess the haptic experience and recreation of TB anatomy with comparison to the current paradigm of ABS. RESULTS: Surgical drilling demonstrated that FLW models created by FDM as well as PC and Photo models generated using photopolymerization more closely recreated cortical mastoidectomy compared to ABS models. ABS generated odor and did not represent the anatomy accurately. Blue resin performed poorly in simulation, likely due to its dark color and translucent appearance. CONCLUSIONS: PC, Photo, and FLW models best replicated surgical drilling and anatomy as compared to ABS and FLB models. These prototypes are reliable simulators for surgical training.

Early treatment with exosomes following traumatic brain injury and hemorrhagic shock in a swine model promotes transcriptional changes associated with neuroprotection.

BACKGROUND: We have shown that administration of mesenchymal stem cell-derived exosomes (single dose given within 1 hour) in models of traumatic brain injury (TBI) and hemorrhagic shock is neuroprotective. The precise mechanisms responsible for the neuroprotection are not fully understood. This study was designed to investigate the transcriptomic changes in the brain that are associated with this treatment strategy. METHODS: Yorkshire swine (40-45 kg) were subjected to a severe TBI (12-mm cortical impact) and hemorrhagic shock (40% estimated total blood volume). One hour into shock, animals were randomized (n = 5/cohort) to receive either lactated Ringer's (LR; 5 mL) or exosomes suspended in LR (LR + EXO; 1 × 10 exosome particles in 5 mL LR). Animals then underwent additional shock (1 hour) followed by normal saline resuscitation. After 6 hours of observation, brain swelling (% increase compared with the uninjured side) and lesion size (mm) were assessed. Periinjured brain tissue was processed for RNA sequencing, analyzed with high through-put RNA sequencing data analysis, and results compared between control and experimental groups. RESULTS: Exosome treatment significantly increased (p < 0.005) gene expression associated with neurogenesis, neuronal development, synaptogenesis, and neuroplasticity. It also significantly reduced (p < 0.005) genes associated with stroke, neuroinflammation, neuroepithelial cell proliferation, and nonneuronal cell proliferation contributing to reactive gliosis. Exosome treatment also significantly increased (p < 0.005) the genes that are associated with stability of blood-brain barrier. CONCLUSIONS: Administration of a single dose of exosomes induces transcriptomic changes suggestive of neuroprotection. Their use as a treatment for TBI is promising and requires further investigation for human translation.

Early single-dose exosome treatment improves neurologic outcomes in a 7-day swine model of traumatic brain injury and hemorrhagic shock.

BACKGROUND: Early single-dose treatment with human mesenchymal stem cell-derived exosomes promotes neuroprotection and promotes blood-brain barrier integrity in models of traumatic brain injury (TBI) and hemorrhagic shock (HS) in swine. The impact of an early single dose of exosomes on late survival (7 days), however, remains unknown. We sought to evaluate the impact of early single-dose exosome treatment on neurologic outcomes, brain lesion size, inflammatory cytokines, apoptotic markers, and mediators of neural plasticity in a 7-day survival model. METHODS: Yorkshire swine were subjected to a severe TBI (8-mm cortical impact) and HS (40% estimated total blood volume). After 1 hour of shock, animals were randomized (n = 4/cohort) to receive either lactated Ringer's (5 mL) or lactated Ringer's with exosomes (1 × 10 exosome particles). After an additional hour of shock, animals were resuscitated with normal saline. Daily neurologic severity scores were compared. At 7 days following injury, lesion size, inflammatory markers, and mediators of inflammation (NF-κB), apoptosis (BAX), and neural plasticity (brain-derived neurotrophic factor) in brain tissue were compared between groups. RESULTS: Exosome-treated animals had significantly lower neurologic severity scores (first 4 days; p < 0.05) and faster neurologic recovery. At 7 days, exosome-treated animals had significantly smaller (p < 0.05) brain lesion sizes. Exosome-treated animals also had significantly lower levels of inflammatory markers (interleukin [IL]-1, IL-6, IL-8, and IL-18) and higher granulocyte-macrophage colony-stimulating factor levels compared with the control animals, indicating specific impacts on various cytokines. The BAX and NF-κB levels were significantly lower (p < 0.05) in exosome-treated animals, while brain-derived neurotrophic factor levels were significantly higher (p < 0.05) in the exosome-treated animals. CONCLUSION: In a large animal model of TBI and HS, early single-dose exosome treatment attenuates neurologic injury, decreases brain lesion size, inhibits inflammation and apoptosis, and promotes neural plasticity over a 7-day period.

Early single-dose treatment with exosomes provides neuroprotection and improves blood-brain barrier integrity in swine model of traumatic brain injury and hemorrhagic shock.

BACKGROUND: Administration of human mesenchymal stem cell (MSC)-derived exosomes can enhance neurorestoration in models of traumatic brain injury (TBI) and hemorrhagic shock (HS). The impact of early treatment with MSC-derived exosomes on brain injury in a large animal model remains unknown. We sought to evaluate the impact of early single-dose exosome treatment on brain swelling and lesion size, blood-based cerebral biomarkers, and blood-brain barrier (BBB) integrity. METHODS: Female Yorkshire swine were subjected to a severe TBI (12-mm cortical impact) and HS (40% estimated total blood volume). One hour into shock, animals were randomized (n = 5/cohort) to receive either lactated Ringer's (LR; 5 mL) or LR + exosomes (1 × 10 exosome particles in 5 mL LR). Animals then underwent additional shock (1 hour) followed by normal saline resuscitation. After 6 hours of observation, brain swelling (% increase compared with the uninjured side) and lesion size (mm) were assessed. Cerebral hemodynamics and blood-based biomarkers of brain injury were compared. Immunofluorescence and RNA sequencing with differential gene expression and pathway analysis were used to assess the integrity of the perilesion BBB. RESULTS: Exosome-treated animals had significantly less (p < 0.05) brain swelling and smaller lesion size. They also had significantly decreased (p < 0.05) intracranial pressures and increased cerebral perfusion pressures. Exosome-treated animals had significantly decreased (p < 0.05) albumin extravasation and significantly higher (p < 0.05) laminin, claudin-5, and zonula occludens 1 levels. Differential gene expression and pathway analysis confirmed these findings. Serum glial fibrillary acidic protein levels were also significantly lower (p < 0.05) in the exosome-treated cohort at the end of the experiment. CONCLUSION: In a large animal model of TBI and HS, early treatment with a single dose of MSC-derived exosomes significantly attenuates brain swelling and lesion size, decreases levels of blood-based cerebral biomarkers, and improves BBB integrity.

Posterior Cervical Laminoplasty for Resection Intradural Extramedullary Spinal Meningioma: 2-Dimensional Operative Video.

This operative video demonstrates a posterior cervical laminoplasty for the resection of a cervical intradural extramedullary meningioma. In addition, the natural history, treatment options, and potential complications are discussed. The patient is a 68-yr-old male who presented with left-hand grip weakness and paresthesias. Magnetic resonance imaging (MRI) demonstrated an enhancing mass that displacing the spinal cord anteriorly and causing severe flattening of the cord at C4 and C5. The patient underwent a posterior cervical laminoplasty for tumor resection. Removal of the dorsal elements with a high-speed drill was performed at C3, C4, and C5. A midline durotomy was performed and a large extra-axial intradural tumor was encountered. The tumor was resected en bloc and specimens were sent for permanent pathological analysis. The dura was closed in a watertight fashion using 6-0 Prolene sutures. The laminoplasty was performed by using titanium miniplates and screws to reconstruct the dorsal bony elements, and the wound was closed in layers using sutures. There were no complications. Final pathology was consistent with a WHO grade I meningioma. Postoperative MRI demonstrated gross total resection. The patient's perioperative course was uncomplicated and his preoperative weakness completely resolved by time of discharge.

Is the Supraorbital Notch a Reliable Landmark to Avoid the Frontal Sinus?

BACKGROUND: When performing a craniotomy involving the orbital bar, the supraorbital notch is a potential landmark to localize the lateral extent of the frontal sinus. Avoidance of the frontal sinus is important to reduce the risk of postoperative surgical site infection, epidural abscess formation, and mucocele development. OBJECTIVE: To determine the reliability of the supraorbital notch as a marker of the lateral location of the frontal sinus. METHODS: Cadaveric dissections were used with image guidance software to define the relationship between the frontal sinus and supraorbital foramen. RESULTS: The supraorbital notch was located 2.54 cm from midline and the lateral extent of the frontal sinus extended 2.84 mm lateral to the supraorbital notch. When performing a craniotomy extending medially to the supraorbital notch at a perpendicular angle, the frontal sinus was breached in 65% of craniotomies. When the craniotomy ended 10 mm lateral to the supraorbital notch, the rate of frontal sinus breach decreased to 10%. CONCLUSION: When performing a craniotomy involving the supraorbital notch, a lateral to medial trajectory that ends 15 mm to the supraorbital notch will minimize the risk of frontal sinus violation.