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1.
Shock ; 57(2): 281-290, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-34798633

RESUMO

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.


Assuntos
Lesões Encefálicas Traumáticas/terapia , Vesículas Extracelulares/transplante , Células-Tronco Mesenquimais/ultraestrutura , Choque Hemorrágico/terapia , Animais , Encéfalo , Modelos Animais de Doenças , Intervenção Médica Precoce , Neuroproteção/genética , Suínos , Transcriptoma
2.
Clin Liver Dis ; 25(4): 711-724, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34593149

RESUMO

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.


Assuntos
Vírus da Hepatite B , Hepatite B , Antivirais/uso terapêutico , Hepatite B/tratamento farmacológico , Hepatite B/epidemiologia , Hepatite B/prevenção & controle , Humanos
3.
Shock ; 55(1): 110-120, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-32925172

RESUMO

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.


Assuntos
Lesões Encefálicas Traumáticas/prevenção & controle , Inibidores de Histona Desacetilases/uso terapêutico , Plasma , Choque Hemorrágico/prevenção & controle , Transcriptoma/efeitos dos fármacos , Ácido Valproico/uso terapêutico , Animais , Transfusão de Componentes Sanguíneos , Lesões Encefálicas Traumáticas/metabolismo , Lesões Encefálicas Traumáticas/patologia , Modelos Animais de Doenças , Inibidores Enzimáticos/uso terapêutico , Feminino , Choque Hemorrágico/metabolismo , Choque Hemorrágico/patologia , Suínos
4.
J Trauma Acute Care Surg ; 89(3): 536-543, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32658440

RESUMO

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.


Assuntos
Barreira Hematoencefálica/patologia , Lesões Encefálicas Traumáticas/terapia , Exossomos/transplante , Células-Tronco Mesenquimais/citologia , Choque Hemorrágico/terapia , Adulto , Animais , Lesões Encefálicas Traumáticas/patologia , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Neuroproteção , Ressuscitação/métodos , Choque Hemorrágico/patologia , Suínos , Fatores de Tempo , Resultado do Tratamento
5.
Ann Otol Rhinol Laryngol ; 129(12): 1168-1173, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32363889

RESUMO

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.


Assuntos
Resinas Acrílicas , Teste de Materiais , Modelos Anatômicos , Procedimentos Cirúrgicos Otológicos/educação , Cimento de Policarboxilato , Estereolitografia , Osso Temporal/cirurgia , Butadienos , Humanos , Mastoidectomia/educação , Neuro-Otologia/educação , Polímeros , Poliestirenos , Impressão Tridimensional , Treinamento por Simulação , Tomografia Computadorizada por Raios X
6.
J Trauma Acute Care Surg ; 89(2): 388-396, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32218019

RESUMO

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.


Assuntos
Lesões Encefálicas Traumáticas/fisiopatologia , Lesões Encefálicas Traumáticas/terapia , Exossomos , Neuroproteção , Choque Hemorrágico/fisiopatologia , Choque Hemorrágico/terapia , Animais , Apoptose , Barreira Hematoencefálica , Lesões Encefálicas Traumáticas/patologia , Citocinas/sangue , Modelos Animais de Doenças , Feminino , Hemodinâmica , Inflamação/patologia , Células-Tronco Mesenquimais/citologia , NF-kappa B/sangue , Choque Hemorrágico/patologia , Transdução de Sinais , Suínos , Resultado do Tratamento , Proteína X Associada a bcl-2/sangue
7.
J Trauma Acute Care Surg ; 88(2): 207-218, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31804413

RESUMO

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.


Assuntos
Barreira Hematoencefálica/patologia , Lesões Encefálicas Traumáticas/terapia , Exossomos/transplante , Células-Tronco Mesenquimais/citologia , Choque Hemorrágico/terapia , Animais , Lesões Encefálicas Traumáticas/etiologia , Lesões Encefálicas Traumáticas/patologia , Modelos Animais de Doenças , Feminino , Humanos , Ressuscitação/métodos , Choque Hemorrágico/etiologia , Choque Hemorrágico/patologia , Sus scrofa , Fatores de Tempo , Resultado do Tratamento
8.
Oper Neurosurg (Hagerstown) ; 16(3): 395, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30010956

RESUMO

This 3-dimensional operative video illustrates resection of a thoracic hemangioblastoma in a 30-year-old female with a history of Von Hippel-Lindau disease. The patient presented with right lower extremity numbness and flank pain. Magnetic resonance imaging (MRI) demonstrated an enhancing intradural intramedullary lesion at T 7 consistent with a hemangioblastoma. The patient underwent a thoracic laminectomy with a midline dural opening for tumor resection. This case demonstrates the principles of intradural intramedullary spinal cord tumor resection. In this particular case, internal debulking was untenable owing to the vascular nature of hemangioblastomas. The operative video demonstrates en bloc tumor removal. Postoperative MRI demonstrated gross total resection. The postoperative course was uneventful. The natural history of this disease, treatment options, and potential complications are discussed.

9.
Oper Neurosurg (Hagerstown) ; 16(2): 274, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-29873783

RESUMO

This 3-dimensional operative video illustrates resection of 2 cervical spine schwannomas in a 19-yr-old female with neurofibromatosis type 2. The patient presented with lower extremity hyperreflexity and hypertonicity. Magnetic resonance imaging (MRI) demonstrated 2 contrast-enhancing intradural extramedullary cervical spine lesions causing spinal cord compression at C4 and C5. The patient underwent a posterior cervical laminoplasty with a midline dural opening for tumor resection. Curvilinear spine cord compression is demonstrated in the operative video. After meticulous dissection, the tumors were resected without complication. The dural closure was performed in watertight fashion followed by laminoplasty using osteoplastic titanium miniplates and screws. Postoperative MRI demonstrated gross total resection with excellent decompression of the spinal cord. The postoperative course was uneventful. The natural history of this disease, treatment options, and potential complications are discussed.

10.
Oper Neurosurg (Hagerstown) ; 16(3): 360-367, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30169851

RESUMO

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.


Assuntos
Craniotomia/métodos , Osso Frontal/cirurgia , Seio Frontal/cirurgia , Órbita/cirurgia , Humanos
11.
Oper Neurosurg (Hagerstown) ; 16(5): 640, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30169866

RESUMO

This 3-dimensional operative video illustrates resection of a lumbar schwannoma in a 57-yr-old female who presented with right lower extremity numbness, paresthesias, as well as a long history of lower back pain with rest. On magnetic resonance imaging (MRI), there was evidence of an intradural extramedullary enhancing lesion at L5, nearly completely encompassing the spinal canal. This video demonstrates the natural history, treatment options, surgical procedure, risks, and complications of treatment of these types of tumors. The patient underwent a posterior lumbar laminectomy with a midline dural opening for tumor resection. The tumor was encountered intradurally and electromyography recording confirmed that the tumor arose from a lumbar sensory nerve root. The sensory root was then divided and the tumor was then removed. The mass was removed en bloc and histopathologic analysis was consistent with a schwannoma. Postoperative MRI demonstrated gross total resection of the patient's neoplasm with excellent decompression of the spinal cord. The patient had an uneventful postoperative course with full recovery and complete resolution of her back pain and leg paresthesias.

12.
Oper Neurosurg (Hagerstown) ; 16(3): 392, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30107430

RESUMO

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.

13.
Oper Neurosurg (Hagerstown) ; 16(4): 516-517, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30107551

RESUMO

This operative video illustrates resection of a cervical ependymoma in a 40-yr-old female with numbness of upper and lower extremities and ataxia. Magnetic resonance imaging (MRI) demonstrated an enhancing intramedullary intradural spinal mass at C2-3. The patient underwent a posterior cervical laminoplasty for tumor resection. This video highlights the natural history of this disease, treatment options, surgical procedure, potential risks and complications, and postoperative management of ependymomas. A posterior midline skin incision was made from the inion to the level of C4 which exposed the posterolateral elements of C1-3. C2 and C3 lamina were removed as a single piece using the high-speed drill. A C1 laminectomy was then also performed to provide adequate superior exposure. The dura was opened widely in the midline. Careful midline myelotomy was then performed overlying the tumor. The tumor is noted to be densely adherent to the surrounding spinal cord. Gross total resection was completed using ultrasonic aspiration and microdissection. The dura was closed in a watertight fashion followed by a synthetic dural sealant. The bony elements of C2, C3 were then reconstructed using osteoplastic laminoplasty, titanium miniplates, and screws at C2-3. The wound was closed in multiple layers using sutures. Specimens were sent for frozen and permanent pathological analysis, eventually demonstrating WHO grade II ependymoma. There were no complications. Postoperative MRI demonstrated gross total resection. The patient had an uneventful postoperative course. The strength was at baseline at long term follow-up, with small sensory deficit.

14.
World Neurosurg ; 119: 176-182, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30092467

RESUMO

OBJECTIVE: The transtentorial extension of the retrosigmoid approach allows for improved visualization of the brainstem and petroclival region. This approach is an important tool in the skull base surgeon's armamentarium for pathologies involving the petroclival region. It has been shown that the addition of tentorial transection improves the exposed surface area of the brainstem. However, no data have been reported regarding the depth of the additional anterior and medial exposure. The goal of the present study was to describe the additional depth of exposure gained by performing tentorial transection. This information allows surgeons to preoperatively estimate the amount of operative exposure gained by this technique. METHODS: Five preserved cadaveric heads were dissected using frameless image guidance. A standard retrosigmoid craniotomy was performed, followed by tentorial transection. The boundaries of the surgical exposure and depth of the surgical field were compared before and after tentorial transection. RESULTS: After transection, we found a 20.1-mm increase in anterior exposure (P < 0.01) and a 13-mm increase in medial exposure (P < 0.01). No significant difference was found in the extent of the superior (P = 0.32) or lateral (P = 0.07) exposure. The surgical working distance increased significantly from 68.8 to 90.3 mm (P < 0.01). CONCLUSIONS: When performing retrosigmoid craniotomy, the addition of tentorial transection allows for a significant increase in anterior and medial exposure with no significant increase in superior or lateral exposure.


Assuntos
Craniotomia/métodos , Base do Crânio/cirurgia , Cerebelo , Endoscopia/métodos , Humanos , Base do Crânio/diagnóstico por imagem , Medula Espinal
15.
Crit Care Med ; 46(1): e59-e66, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29095204

RESUMO

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.


Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/fisiologia , Lesões Encefálicas Traumáticas/fisiopatologia , Modelos Animais de Doenças , Plasma , Ressuscitação/métodos , Choque Hemorrágico/fisiopatologia , Ácido Valproico/farmacologia , Animais , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiopatologia , Feminino , Suínos
16.
J Neurosci Res ; 96(4): 711-719, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28742231

RESUMO

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.


Assuntos
Lesões Encefálicas Traumáticas/tratamento farmacológico , Inibidores de Histona Desacetilases/farmacologia , Ressuscitação/métodos , Choque Hemorrágico/tratamento farmacológico , Ácido Valproico/farmacologia , Acetilação , Lesões Encefálicas Traumáticas/metabolismo , Epigênese Genética , Humanos , Choque Hemorrágico/metabolismo
17.
World Neurosurg ; 104: 180-185, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28479521

RESUMO

OBJECTIVE: The anatomic area exposed through exposure of Trautmann triangle may not be sufficient. We studied the additional exposure provided by skeletonizing the sigmoid sinus (SS). METHODS: In 5 human cadaveric heads, thin-cut computed tomography images of 2 sides of the temporal bone were obtained for a total of 10 sides. The estimated surgical working angle was calculated based on the relationship of the SS to the posterior semicircular canal (PSC), superior petrosal sinus, and jugular bulb on imaging. Mastoidectomy was performed, and heads with and without SS skeletonization were remeasured. RESULTS: Working angle calculated on computed tomography was 56° ± 11.3. Skeletonization of the SS increased the distance between the PSC and SS by 5 mm (P = 0.01) and between the lateral semicircular canal and SS by 4 mm (P = 0.01). Skeletonization and retraction of the SS significantly increased the distance between the PSC and lateral semicircular canal to the SS. On images obtained after mastoidectomy, skeletonizing the SS helped improve anterior visibility on most samples that had an SS that was lateral to the PSC on axial imaging. In samples in which the SS was medial to the PSC or had only minimal lateral displacement, skeletonizing the SS did not markedly improve visibility of the retrolabyrinthine space. CONCLUSIONS: Working area and visibility improved as the PSC and SS approached the same plane on axial imaging. Preoperative evaluation of the laterality of the SS to the PSC may assist a surgeon in determining the need for skeletonizing the SS and avoiding possible vascular injuries.


Assuntos
Pontos de Referência Anatômicos/anatomia & histologia , Pontos de Referência Anatômicos/diagnóstico por imagem , Ângulo Cerebelopontino/anatomia & histologia , Ângulo Cerebelopontino/cirurgia , Craniotomia/métodos , Osso Temporal/anatomia & histologia , Osso Temporal/cirurgia , Adulto , Pontos de Referência Anatômicos/cirurgia , Cadáver , Ângulo Cerebelopontino/diagnóstico por imagem , Cavidades Cranianas/anatomia & histologia , Cavidades Cranianas/diagnóstico por imagem , Cavidades Cranianas/cirurgia , Feminino , Humanos , Masculino , Osso Temporal/diagnóstico por imagem
18.
Blood Coagul Fibrinolysis ; 28(6): 479-484, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28230635

RESUMO

: Trauma-induced coagulopathy is associated with adverse patient outcome. Animal models demonstrate that histone deacetylase inhibitors, such as valproic acid (VPA), improve survival following injury. While in-vivo data suggest that improved survival may in part be because of an attenuation of coagulopathy, it remains unknown whether this is a direct effect of the drug, or the establishment of an overall prosurvival phenotype. We thus conducted an ex-vivo experiment to determine if VPA has an effect on coagulation and platelet function. Ten swine were subjected to traumatic brain injury (TBI) and hemorrhagic shock (HS). Blood samples were drawn prior to TBI+HS insult (Healthy group) and 2 h following TBI+HS (Shock group). Samples were incubated with VPA or vehicle controls for 1 h. Platelet aggregation was analyzed via impedance aggregometry and coagulation was measured using thromboelastography. Addition of VPA to the healthy blood did not affect platelet aggregation or coagulation parameters. In shock blood, incubation with VPA significantly reduced collagen-(P = 0.050), arachidonic acid-(P = 0.005), and adenosine diphosphate-(P = 0.023) induced platelet aggregation. VPA also significantly increased the clot strength (P = 0.002) and clot formation rate (P = 0.011). This is the first study to investigate the effect of VPA on platelet function ex vivo. Our results suggest that VPA has no effect on normal blood, but it decreases platelet activation and improves clot dynamics (strength and rate of formation) in blood from shocked animals. This suggests that VPA is capable of exerting a selective platelet sparing effect while enhancing the clot integrity.


Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Agregação Plaquetária/efeitos dos fármacos , Ácido Valproico/farmacologia , Animais , Plaquetas/efeitos dos fármacos , Lesões Encefálicas/sangue , Choque Hemorrágico/sangue , Suínos , Trombose
19.
World Neurosurg ; 100: 444-449, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27693767

RESUMO

BACKGROUND: Facial nerve schwannomas are rare, benign, nerve-sheath tumors. They can occur in any segment of the facial nerve and often clinically and radiographically mimic the common vestibular schwannoma when extending into the cerebellopontine angle. The optimal treatment strategy for intracranial facial nerve schwannomas remains controversial. METHODS: We review the literature and discuss the natural history, clinical features, diagnosis and current management of facial nerve schwannoma. RESULTS: Complete tumor resection with facial nerve preservation can be achieved in fewer cases. In most cases, the affected segment of facial nerve must be removed if the goal is to achieve complete tumor section. Regardless of type of facial nerve repair, patients can expect no better than an eventual HB grade III palsy. Stereotactic radiosurgery has good results in tumor control and facial function outcome. CONCLUSIONS: Treatment for intracranial facial nerve schwannomas depends on clinical presentation, tumor size, preoperative facial, and hearing function. Conservative management is recommended for asymptomatic patients with small tumors. Stereotactic radiosurgery may be an option for smaller and symptomatic tumors with good facial function. If tumor is large or the patient has facial paralysis, surgical resection should be indicated. If preservation of the facial nerve is not possible, total resection with nerve grafting should be performed for those patients with facial paralysis, whereas subtotal resection is best for those patients with good facial function.


Assuntos
Gerenciamento Clínico , Nervo Facial/diagnóstico por imagem , Nervo Facial/cirurgia , Neurilemoma/diagnóstico por imagem , Neurilemoma/cirurgia , Procedimentos Neurocirúrgicos/tendências , Humanos , Resultado do Tratamento
20.
J Am Coll Surg ; 224(1): 49-58, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27725221

RESUMO

BACKGROUND: Resuscitation with fresh frozen plasma (FFP) decreases brain lesion size and swelling in a swine model of traumatic brain injury and hemorrhagic shock. We hypothesized that brain gene expression profiles after traumatic brain injury and hemorrhagic shock would be modulated by FFP resuscitation. STUDY DESIGN: Fifteen swine underwent a protocol of traumatic brain injury and hemorrhagic shock and 2 hours of shock followed by resuscitation with FFP, normal saline, or hetastarch (5/group). After 6 hours, brain RNA was isolated and hybridized onto a porcine gene ST 1.1 microarray. Weighted gene correlation network analysis was used to identify clusters of highly coexpressed genes. Principal component analysis identified cluster eigenvectors, indicating overall direction and magnitude of cluster gene expression. Using linear regression, cluster eigenvectors were associated with treatment as well as brain lesion size and swelling. Results were post-hoc corrected using false discovery rate. Relevant gene clusters were subjected to pathway analysis using the Reactome tool. RESULTS: Network analysis identified 322 gene expression clusters (total of 12,462 coexpressed genes). Fresh frozen plasma resuscitation (but not normal saline or hetastarch) was positively associated with 2 distinct gene clusters (termed A and B) comprising 493 genes. Gene expression in both clusters was negatively associated with brain swelling, and cluster B was also negatively associated with lesion size. Pathway analysis revealed an upregulation of genes involved in metabolic and platelet signaling, as well as collagen formation and downregulation of inflammation. CONCLUSIONS: Fresh frozen plasma resuscitation in this model was associated with downregulation of inflammatory pathway genes and expression of gene clusters mapping to increased metabolic and platelet signaling, which, in turn, was reversely associated with brain swelling.


Assuntos
Lesões Encefálicas Traumáticas/genética , Lesões Encefálicas Traumáticas/terapia , Encéfalo , Plasma , Ressuscitação/métodos , Choque Hemorrágico/terapia , Transcriptoma , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Lesões Encefálicas Traumáticas/complicações , Análise por Conglomerados , Regulação para Baixo , Feminino , Perfilação da Expressão Gênica , Marcadores Genéticos , Modelos Lineares , Análise de Componente Principal , Choque Hemorrágico/etiologia , Choque Hemorrágico/genética , Suínos , Resultado do Tratamento , Regulação para Cima
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