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1.
Brain Inj ; 32(13-14): 1866-1878, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30346868

RESUMEN

Blast-induced traumatic brain injury (blast-TBI) is associated with vestibulomotor dysfunction, persistent post-traumatic headaches and post-traumatic stress disorder, requiring extensive treatments and reducing quality-of-life. Treatment and prevention of these devastating outcomes require an understanding of their underlying pathophysiology through studies that take advantage of animal models. Here, we report that cranium-directed blast-TBI in rats results in signs of pain that last at least 8 weeks after injury. These occur without significantly elevated behavioural markers of anxiety-like conditions and are not associated with glial up-regulation in sensory thalamic nuclei. These injuries also produce transient vestibulomotor abnormalities that resolve within 3 weeks of injury. Thus, blast-TBI in rats recapitulates aspects of the human condition.


Asunto(s)
Lesiones Encefálicas/complicaciones , Dolor Facial/etiología , Reflejo Vestibuloocular/fisiología , Trastornos de la Sensación/etiología , Análisis de Varianza , Animales , Traumatismos por Explosión/complicaciones , Lesiones Encefálicas/etiología , Adaptación a la Oscuridad/fisiología , Modelos Animales de Enfermedad , Conducta Exploratoria/fisiología , Hiperalgesia/diagnóstico , Hiperalgesia/etiología , Masculino , Aprendizaje por Laberinto , Neuroglía/metabolismo , Neuroglía/patología , Dimensión del Dolor , Umbral del Dolor/fisiología , Estimulación Física/efectos adversos , Equilibrio Postural , Ratas , Ratas Long-Evans , Prueba de Desempeño de Rotación con Aceleración Constante , Tálamo/patología , Factores de Tiempo
2.
Neurocrit Care ; 29(2): 253-263, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-29700692

RESUMEN

BACKGROUND: Spontaneous intracerebral hemorrhage (ICH) leaves most survivors dependent at follow-up. The importance of promoting M2-like microglial responses is increasingly recognized as a key element to ameliorate brain injury following ICH. The osmotherapeutic agents, mannitol and hypertonic saline (HTS), which are routinely used to reduce intracranial pressure, have been shown to reduce neuroinflammation in experimental ischemic and traumatic brain injury, but anti-inflammatory effects of osmotherapies have not been investigated in ICH. METHODS: We studied the effects of iso-osmotic mannitol and HTS in rat models of ICH utilizing high-dose and moderate-dose collagenase injections into the basal ganglia, associated with high and low mortality, respectively. We studied the effects of osmotherapies, first given 5 h after ICH induction, and then administered every 12 h thereafter (4 doses total). Immunohistochemistry was used to quantify microglial activation and polarization. RESULTS: Compared to controls, mannitol and HTS increased plasma osmolarity 1 h after infusion (301 ± 1.5, 315 ± 4.2 and 310 ± 2.0 mOsm/kg, respectively), reduced mortality at 48 h (82, 36 and 53%, respectively), and reduced hemispheric swelling at 48 h (32, 21, and 17%, respectively). In both perihematomal and contralateral tissues, mannitol and HTS reduced activation of microglia/macrophages (abundance and morphology of Iba1 + cells), and in perihematomal tissues, they reduced markers of the microglia/macrophage M1-like phenotype (nuclear p65, TNF, and NOS2), increased markers of the microglia/macrophage M2-like phenotype (arginase, YM1, and pSTAT3), and reduced infiltration of CD45 + cells. CONCLUSIONS: Repeated dosing of osmotherapeutics at regular intervals may be a useful adjunct to reduce neuroinflammation following ICH.


Asunto(s)
Edema Encefálico/tratamiento farmacológico , Hemorragia Cerebral/tratamiento farmacológico , Diuréticos Osmóticos/farmacología , Inflamación/tratamiento farmacológico , Macrófagos/efectos de los fármacos , Manitol/farmacología , Microglía/efectos de los fármacos , Solución Salina Hipertónica/farmacología , Animales , Edema Encefálico/etiología , Hemorragia Cerebral/complicaciones , Modelos Animales de Enfermedad , Diuréticos Osmóticos/administración & dosificación , Humanos , Inflamación/etiología , Inflamación/metabolismo , Masculino , Ratas , Ratas Wistar , Solución Salina Hipertónica/administración & dosificación
3.
Brain Sci ; 14(3)2024 Feb 28.
Artículo en Inglés | MEDLINE | ID: mdl-38539619

RESUMEN

In human stroke, brain swelling is an important predictor of neurological outcome and mortality, yet treatments to reduce or prevent brain swelling are extremely limited, due in part to an inadequate understanding of mechanisms. In preclinical studies on cerebroprotection in animal models of stroke, historically, the focus has been on reducing infarct size, and in most studies, a reduction in infarct size has been associated with a corresponding reduction in brain swelling. Unfortunately, such findings on brain swelling have little translational value for treating brain swelling in patients with stroke. This is because, in humans, brain swelling usually becomes evident, either symptomatically or radiologically, days after the infarct size has stabilized, requiring that the prevention or treatment of brain swelling target mechanism(s) that are independent of a reduction in infarct size. In this problematizing review, we highlight the often-neglected concept that brain edema and brain swelling are not simply secondary, correlative phenomena of stroke but distinct pathological entities with unique molecular and cellular mechanisms that are worthy of direct targeting. We outline the advances in approaches for the study of brain swelling that are independent of a reduction in infarct size. Although straightforward, the approaches reviewed in this study have important translational relevance for identifying novel treatment targets for post-ischemic brain swelling.

4.
J Clin Med ; 12(16)2023 Aug 08.
Artículo en Inglés | MEDLINE | ID: mdl-37629211

RESUMEN

Over 38 million people worldwide are living with HIV/AIDS, and more than half of them are affected by HIV-associated neurocognitive disorders (HAND). Such disorders are characterized by chronic neuroinflammation, neurotoxicity, and central nervous system deterioration, which lead to short- or long-term memory loss, cognitive impairment, and motor skill deficits that may show gender disparities. However, the underlying mechanisms remain unclear. Our previous study suggested that HIV-1 infection and viral protein R (Vpr) upregulate the SUR1-TRPM4 channel associated with neuroinflammation, which may contribute to HAND. The present study aimed to explore this relationship in a mouse model of HAND. This study employed the HIV transgenic Tg26 mouse model, comparing Tg26 mice with wildtype mice in various cognitive behavioral and memory tests, including locomotor activity tests, recognition memory tests, and spatial learning and memory tests. The study found that Tg26 mice exhibited impaired cognitive skills and reduced learning abilities compared to wildtype mice, particularly in spatial memory. Interestingly, male Tg26 mice displayed significant differences in spatial memory losses (p < 0.001), while no significant differences were identified in female mice. Consistent with our early results, SUR1-TRPM4 channels were upregulated in Tg26 mice along with glial fibrillary acidic protein (GFAP) and aquaporin 4 (AQP4), consistent with reactive astrocytosis and neuroinflammation. Corresponding reductions in neurosynaptic responses, as indicated by downregulation of Synapsin-1 (SYN1) and Synaptophysin (SYP), suggested synaptopathy as a possible mechanism underlying cognitive and motor skill deficits. In conclusion, our study suggests a possible relationship between SUR1-TRPM4-mediated neuroinflammation and synaptopathy with impairments of learning and memory in mice with HAND. These findings could help to develop new therapeutic strategies for individuals living with HAND.

5.
Sci Rep ; 13(1): 5635, 2023 04 06.
Artículo en Inglés | MEDLINE | ID: mdl-37024509

RESUMEN

Endoplasmic reticulum (ER) stress and mitochondrial dysfunction are found in lesions of multiple sclerosis (MS) and animal models of MS such as experimental autoimmune encephalomyelitis (EAE), and may contribute to the neuronal loss that underlies permanent impairment. We investigated whether glatiramer acetate (GA) can reduce these changes in the spinal cords of chronic EAE mice by using routine histology, immunostaining, and electron microscopy. EAE spinal cord tissue exhibited increased inflammation, demyelination, mitochondrial dysfunction, ER stress, downregulation of NAD+ dependent pathways, and increased neuronal death. GA reversed these pathological changes, suggesting that immunomodulating therapy can indirectly induce neuroprotective effects in the CNS by mediating ER stress.


Asunto(s)
Encefalomielitis Autoinmune Experimental , Esclerosis Múltiple , Ratones , Animales , Acetato de Glatiramer/farmacología , Acetato de Glatiramer/uso terapéutico , Péptidos/farmacología , Inmunomodulación , Estrés del Retículo Endoplásmico , Mitocondrias/metabolismo , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad
6.
Cells ; 12(18)2023 09 06.
Artículo en Inglés | MEDLINE | ID: mdl-37759444

RESUMEN

Brain swelling is a major cause of death and disability in ischemic stroke. Drugs of the gliflozin class, which target the Na+-coupled D-glucose cotransporter, SGLT2, are approved for type 2 diabetes mellitus (T2DM) and may be beneficial in other conditions, but data in cerebral ischemia are limited. We studied murine models of cerebral ischemia with middle cerebral artery occlusion/reperfusion (MCAo/R). Slc5a2/SGLT2 mRNA and protein were upregulated de novo in astrocytes. Live cell imaging of brain slices from mice following MCAo/R showed that astrocytes responded to modest increases in D-glucose by increasing intracellular Na+ and cell volume (cytotoxic edema), both of which were inhibited by the SGLT2 inhibitor, canagliflozin. The effect of canagliflozin was studied in three mouse models of stroke: non-diabetic and T2DM mice with a moderate ischemic insult (MCAo/R, 1/24 h) and non-diabetic mice with a severe ischemic insult (MCAo/R, 2/24 h). Canagliflozin reduced infarct volumes in models with moderate but not severe ischemic insults. However, canagliflozin significantly reduced hemispheric swelling and improved neurological function in all models tested. The ability of canagliflozin to reduce brain swelling regardless of an effect on infarct size has important translational implications, especially in large ischemic strokes.


Asunto(s)
Edema Encefálico , Isquemia Encefálica , Diabetes Mellitus Tipo 2 , Accidente Cerebrovascular Isquémico , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Animales , Ratones , Canagliflozina/farmacología , Canagliflozina/uso terapéutico , Edema Encefálico/tratamiento farmacológico , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Astrocitos , Transportador 2 de Sodio-Glucosa , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Glucosa , Iones , Isquemia Encefálica/tratamiento farmacológico , Infarto
7.
Sci Signal ; 16(788): eadd6364, 2023 06 06.
Artículo en Inglés | MEDLINE | ID: mdl-37279286

RESUMEN

Brain swelling causes morbidity and mortality in various brain injuries and diseases but lacks effective treatments. Brain swelling is linked to the influx of water into perivascular astrocytes through channels called aquaporins. Water accumulation in astrocytes increases their volume, which contributes to brain swelling. Using a mouse model of severe ischemic stroke, we identified a potentially targetable mechanism that promoted the cell surface localization of aquaporin 4 (AQP4) in perivascular astrocytic endfeet, which completely ensheathe the brain's capillaries. Cerebral ischemia increased the abundance of the heteromeric cation channel SUR1-TRPM4 and of the Na+/Ca2+ exchanger NCX1 in the endfeet of perivascular astrocytes. The influx of Na+ through SUR1-TRPM4 induced Ca2+ transport into cells through NCX1 operating in reverse mode, thus raising the intra-endfoot concentration of Ca2+. This increase in Ca2+ stimulated calmodulin-dependent translocation of AQP4 to the plasma membrane and water influx, which led to cellular edema and brain swelling. Pharmacological inhibition or astrocyte-specific deletion of SUR1-TRPM4 or NCX1 reduced brain swelling and improved neurological function in mice to a similar extent as an AQP4 inhibitor and was independent of infarct size. Thus, channels in astrocyte endfeet could be targeted to reduce postischemic brain swelling in stroke patients.


Asunto(s)
Edema Encefálico , Accidente Cerebrovascular Isquémico , Canales Catiónicos TRPM , Humanos , Edema Encefálico/genética , Edema Encefálico/metabolismo , Astrocitos/metabolismo , Acuaporina 4/genética , Acuaporina 4/metabolismo , Accidente Cerebrovascular Isquémico/metabolismo , Agua/metabolismo , Cationes/metabolismo , Canales Catiónicos TRPM/metabolismo
8.
Ther Hypothermia Temp Manag ; 12(2): 90-102, 2022 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-35675523

RESUMEN

Spinal cord injury (SCI) is a devastating neurological condition with no effective treatment. Hypothermia induced by physical means (cold fluid) is established as an effective therapy in animal models of SCI, but its clinical translation to humans is hampered by several constraints. Hypothermia induced pharmacologically may be noninferior or superior to physically induced hypothermia for rapid, convenient systemic temperature reduction, but it has not been investigated previously in animal models of SCI. We used a rat model of SCI to compare outcomes in three groups: (1) normothermic controls; (2) hypothermia induced by conventional physical means; (3) hypothermia induced by intravenous (IV) dihydrocapsaicin (DHC). Male rats underwent unilateral lower cervical SCI and were treated after a 4-hour delay with physical cooling or IV DHC (∼0.60 mg/kg total) cooling (both 33.0 ± 1.0°C) lasting 4 hours; controls were kept normothermic. Telemetry was used to monitor temperature and heart rate during and after treatments. In two separate experiments, one ending at 48 hours, the other at 6 weeks, "blinded" investigators evaluated rats in the three groups for neurological function followed by histopathological evaluation of spinal cord tissues. DHC reliably induced systemic cooling to 32-33°C. At both the time points examined, the two modes of hypothermia yielded similar improvements in neurological function and lesion size compared with normothermic controls. Our results indicate that DHC-induced hypothermia may be comparable with physical hypothermia in efficacy, but more clinically feasible to administer than physical hypothermia.


Asunto(s)
Hipotermia Inducida , Hipotermia , Traumatismos de la Médula Espinal , Animales , Capsaicina/análogos & derivados , Hipotermia/terapia , Hipotermia Inducida/métodos , Masculino , Ratas , Ratas Sprague-Dawley , Médula Espinal/patología , Traumatismos de la Médula Espinal/terapia
9.
J Trauma ; 70(5): 1096-103, 2011 May.
Artículo en Inglés | MEDLINE | ID: mdl-21610426

RESUMEN

BACKGROUND: There is little that can be done to treat or reverse the primary injury that occurs at the time of a traumatic brain injury (TBI). Initial management of the patient with severe TBI focuses on prevention of subsequent secondary insults, namely, intracranial hypertension (ICH) and cerebral hypoperfusion (CH). Currently, there is no reliable way to predict which patients will develop ICH and CH other than clinical acumen; therefore, indicators of impending secondary intracranial insults may be useful in predicting these events and allowing for prevention and early intervention. This study was undertaken to investigate the relationship of cytokine levels with intracranial pressure (ICP) and cerebral perfusion pressure (CPP) in patients with severe TBI. METHODS: Patients at the R Adams Cowley Shock Trauma Center were prospectively enrolled for a 6-month period. Inclusion criteria were older than 17 years, admission within the first 6 hours after injury, Glasgow Coma Scale<9 on admission, and placement of a clinically indicated ICP monitor. Serum and cerebrospinal fluid, when available, were collected on admission and twice daily for 7 days. Cytokine levels of interleukin (IL)-1ß, IL-6, IL-8, IL-10, and tumor necrosis factor (TNF)-α were analyzed by multiplex bead array assays. Hourly values for ICP and CPP were recorded, and means, minimum (for CPP) or maximum (for ICP) values, percentage time ICP>20 mm Hg (%ICP20) and CPP<60 mm Hg (%CPP60), and cumulative Pressure Times Time Dose (PTD; mm Hg·h) for ICP>20 mm Hg (PTD ICP20) and CPP<60 mm Hg (PTD CPP60) were compared with the serum and cerebrospinal fluid levels that were drawn before 12-hour time periods (PRE) and after 12-hour time periods (POST) of monitoring. RESULTS: Twenty-four patients were enrolled. In-hospital mortality was 12.5%, and good functional outcome was noted in 58%. Two hundred and seventy-five serum samples were taken and analyzed. IL-6 levels in the serum were found in the highest concentration of the cytokines measured. PTD ICP20 and PTD CPP60 were moderately correlated with increased PRE IL-8 levels (r=0.34, p<0.001; r=0.53, p<0.001). PTD ICP20 was also correlated with PRE TNF-α levels (r=0.27, p<0.001) as was PTD CPP60 (r=0.25, p<0.001). POST IL-8 levels were found to be correlated with PTD ICP20 (r=0.46, p<0.001) and PTD CPP60 (r=0.54, p<0.001). POST TNF-α was associated with PTD ICP20 (r=0.45, p<0.001). PTD CPP60 was also moderately correlated with POST TNF-α levels (r=0.26, p<0.001). When comparing patients with good versus poor outcome, median daily serum IL-8 levels were associated with poor outcome. CONCLUSIONS: IL-8 and, to a lesser extent, TNF-α demonstrated the most promise in this study to be candidate serum markers of impending ICH and CH. The clinical relevance of this is the suggestion that we may be able to predict impending secondary insults after TBI before the clinical manifestation of these events. Given the known morbidity of ICH and CH, early intervention and prevention may have a significant impact on outcome. This becomes even more important when decisions must be made about timing of interventions. Increased levels of IL-8 and TNF-α in the serum during episodes of ICH and CH imply there are significant systemic effects of these events. These serum biomarkers are promising as diagnostic targets. In addition, further study of the precise role of these molecules may have significant implications for inflammatory system manipulation in the management of severe TBI.


Asunto(s)
Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Lesiones Encefálicas/complicaciones , Isquemia Encefálica/fisiopatología , Circulación Cerebrovascular/fisiología , Hipertensión Intracraneal/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Lesiones Encefálicas/diagnóstico , Lesiones Encefálicas/fisiopatología , Isquemia Encefálica/etiología , Isquemia Encefálica/metabolismo , Citocinas/sangre , Citocinas/líquido cefalorraquídeo , Femenino , Estudios de Seguimiento , Humanos , Hipertensión Intracraneal/etiología , Hipertensión Intracraneal/fisiopatología , Presión Intracraneal , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Índices de Gravedad del Trauma , Adulto Joven
10.
Ann Plast Surg ; 66(4): 403-9, 2011 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-21042180

RESUMEN

Biologic prostheses have emerged to address the limitations of synthetic materials for ventral hernia repairs; however, they lack experimental comparative data. Fifteen swine were randomly assigned to 1 of 3 bioprosthetic groups (DermaMatrix, AlloDerm, and Permacol) after creation of a full thickness ventral fascial defect. At 15 weeks, host incorporation, hernia recurrence, adhesion formation, neovascularization, inflammation, and biomechanical properties were assessed. No animals had hernia recurrence or eventration. DermaMatrix and Alloderm implants demonstrated more adhesions, greater inflammatory infiltration, and more longitudinal laxity, but near identical neovascularization and tensile strength to Permacol. We found that porcine acellular dermal products (Permacol) contain following essential properties of an ideal ventral hernia repair material: low inflammation, less elastin and stretch, lower adhesion rates and cost, and more contracture. The addition of lower cost xenogeneic acellular dermal products to the repertoire of available acellular dermal products demonstrates promise, but requires long-term clinical studies to verify advantages and efficacy.


Asunto(s)
Materiales Biocompatibles/uso terapéutico , Bioprótesis , Colágeno/administración & dosificación , Colágeno/uso terapéutico , Hernia Ventral/cirugía , Piel Artificial , Mallas Quirúrgicas , Animales , Modelos Animales , Procedimientos Quirúrgicos Operativos/métodos , Técnicas de Sutura , Porcinos , Resultado del Tratamiento
11.
Am Surg ; 76(3): 317-20, 2010 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-20349664

RESUMEN

Our objective was to evaluate the hemostatic efficacy of a newly modified chitosan in a porcine grade V liver injury model. Fifteen Yorkshire pigs underwent standardized grade V liver injuries with a specially designed liver clamp and were randomized to either modified chitosan (MC) patch treatment or standard gauze packing. Free bleeding was allowed for 30 seconds. Fluid resuscitation was infused as necessary to reestablish a mean arterial pressure (MAP) within at least 80 per cent of the preinjury MAP. Animals were observed for 90 minutes or until death. Endpoints were survival, total blood loss, time to hemostasis, and resuscitation MAP, and resuscitation volume. Total mean blood loss was less in the MC patch group (464 +/- 267 mL vs 1234 +/- 78 mL, P < 0.001). Time to hemostasis was significantly less (4.8 +/- 2.5 minutes in the MC patch group vs 9.6 +/- 2.5 minutes, P < 0.01). Fluid resuscitation was less (1098 +/- 459 mL in the MC patch group vs 1770 +/- 172 mL, P < 0.01). Survival was 100 per cent in the MC patch group and 80 per cent in the gauze packing group. MC patches demonstrate the continued hemostatic agent evolution for improved control of lethal solid organ bleeding.


Asunto(s)
Quitosano/administración & dosificación , Hemostasis Quirúrgica/métodos , Hemostáticos/administración & dosificación , Animales , Modelos Animales de Enfermedad , Femenino , Porcinos
12.
PLoS One ; 15(11): e0242427, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33186383

RESUMEN

BACKGROUND: Gulf War (GW) Illness (GWI) is a debilitating condition with a complex constellation of immune, endocrine and neurological symptoms, including cognitive impairment, anxiety and depression. We studied a novel model of GWI based on 3 known common GW exposures (GWE): (i) intranasal lipopolysaccharide, to which personnel were exposed during desert sand storms; (ii) pyridostigmine bromide, used as prophylaxis against chemical warfare; and (iii) chronic unpredictable stress, an inescapable element of war. We used this model to evaluate prophylactic treatment with the PPARγ agonist, rosiglitazone (ROSI). METHODS: Rats were subjected to the three GWE for 33 days. In series 1 and 2, male and female GWE-rats were compared to naïve rats. In series 3, male rats with GWE were randomly assigned to prophylactic treatment with ROSI (GWE-ROSI) or vehicle. After the 33-day exposures, three neurofunctional domains were evaluated: cognition (novel object recognition), anxiety-like behaviors (elevated plus maze, open field) and depression-like behaviors (coat state, sucrose preference, splash test, tail suspension and forced swim). Brains were analyzed for astrocytic and microglial activation and neuroinflammation (GFAP, Iba1, tumor necrosis factor and translocator protein). Neurofunctional data from rats with similar exposures were pooled into 3 groups: naïve, GWE and GWE-ROSI. RESULTS: Compared to naïve rats, GWE-rats showed significant abnormalities in the three neurofunctional domains, along with significant neuroinflammation in amygdala and hippocampus. There were no differences between males and females with GWE. GWE-ROSI rats showed significant attenuation of neuroinflammation and of some of the neurofunctional abnormalities. CONCLUSION: This novel GWI model recapitulates critical neurofunctional abnormalities reported by Veterans with GWI. Concurrent prophylactic treatment with ROSI was beneficial in this model.


Asunto(s)
Síndrome del Golfo Pérsico/tratamiento farmacológico , Síndrome del Golfo Pérsico/metabolismo , Rosiglitazona/farmacología , Animales , Ansiedad/metabolismo , Astrocitos/metabolismo , Encéfalo/metabolismo , Cognición/fisiología , Modelos Animales de Enfermedad , Femenino , Hipocampo/metabolismo , Lipopolisacáridos/farmacología , Masculino , PPAR gamma/agonistas , PPAR gamma/metabolismo , Síndrome del Golfo Pérsico/fisiopatología , Bromuro de Piridostigmina/efectos adversos , Ratas , Ratas Wistar , Rosiglitazona/metabolismo , Estrés Psicológico/fisiopatología
13.
Ann Emerg Med ; 53(6): 804-10, 2009 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-19321227

RESUMEN

STUDY OBJECTIVE: Rapid hemostasis is crucial in controlling severe extremity hemorrhage. Our objective is to evaluate the hemostatic efficacy of a newly modified amylopectin powder in a model of severe extremity arterial hemorrhage. METHODS: Anesthetized pigs underwent severe, reproducible femoral artery injuries. Animals were randomized (nonblinded) to either modified amylopectin powder (n=10) or standard gauze application (n=6). Each hemostatic agent was applied through a pool of blood with manual compression for 3-minute intervals until hemostasis was achieved. Fluid resuscitation was infused as necessary to reestablish a mean arterial pressure within at least 80% of the preinjury mean arterial pressure if possible. The primary measured outcome was total blood loss. Secondary endpoints were survival, time to hemostasis, resuscitation mean arterial pressure, and resuscitation volume. RESULTS: Pretreatment blood losses were similar in both groups. Median (absolute average deviation of the median) posttreatment blood loss was significantly less in the modified amylopectin powder group than in the gauze group, 275 (108) mL versus 1,312 (171) mL. Resuscitation mean arterial pressure at 180 minutes after injury was 68% of preinjury mean arterial pressure in the modified amylopectin powder group and undetectable in all control animals. Fluid volume required for resuscitation was 1,962 (258) mL in the modified amylopectin powder group and 2,875 (150) mL in the gauze group. Time to hemostasis was 9.0 (2.1) minutes in the modified amylopectin powder group. Hemostasis was not achieved in any animal in the gauze group. Survival was 100% in the modified amylopectin powder group, whereas no animals survived in the gauze group. CONCLUSION: Modified amylopectin powder demonstrates the ability to control major vascular bleeding in a lethal arterial injury model during a 3-hour period.


Asunto(s)
Amilopectina/administración & dosificación , Arteria Femoral/lesiones , Hemorragia/tratamiento farmacológico , Hemostáticos/administración & dosificación , Administración Tópica , Animales , Femenino , Fluidoterapia , Polvos , Sus scrofa
14.
Neurobiol Pain ; 6: 100030, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31223145

RESUMEN

Explosive blast-induced traumatic brain injury (blast-TBI) in military personnel is a leading cause of injury and persistent neurological abnormalities, including chronic pain. We previously demonstrated that chronic pain after spinal cord injury results from central sensitization in the posterior thalamus (PO). The presence of persistent headaches and back pain in veterans with blast-TBI suggests a similar involvement of thalamic sensitization. Here, we tested the hypothesis that pain after blast-TBI is associated with abnormal increases in activity of neurons in PO thalamus. We developed a novel model with two unique features: (1) blast-TBI was performed in awake, un-anesthetized rats, to simulate the human experience and to eliminate confounds of anesthesia and surgery inherent in other models; (2) only the cranium, rather than the entire body, was exposed to a collimated blast wave, with the blast wave striking the posterior cranium in the region of the occipital crest and foramen magnum. Three weeks after blast-TBI, rats developed persistent, ongoing spontaneous pain. Contrary to our hypothesis, we found no significant differences in the activity of PO neurons, or of neurons in the spinal trigeminal nucleus. There were also no significant changes in gliosis in either of these structures. This novel model will allow future studies on the pathophysiology of chronic pain after blast-TBI.

15.
J Trauma ; 65(4): 778-82; discussion 782-4, 2008 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-18849790

RESUMEN

BACKGROUND: Glial fibrillary acidic protein (GFAP) is an intermediate filament protein found in the cytoskeleton of astroglia. Recent work has indicated that GFAP may serve as a serum marker of traumatic brain injury (TBI) that is released after central nervous system cell damage. METHODS: Serum from 51 critically injured trauma patients was prospectively collected on admission and on hospital day 2. All patients underwent an admission head computed tomography (CT) scan as a part of their clinical evaluation. Patients with facial fractures in the absence of documented TBI and patients with spinal cord injury were excluded. Demographic and outcome data were collected prospectively. Serum GFAP was measured in duplicate using enzyme-linked immunosorbent assay techniques. RESULTS: Thirty-nine (76%) of the 51 patients had CT-documented TBI. The study cohort was 72.5% men with a mean age of 43 years and mean Injury Severity Score (ISS) of 30.2. There were no statistically significant demographic differences between the two groups. At admission day, the mean GFAP level in non-TBI patients was 0.07 pg/mL compared with 6.77 pg/mL in TBI patients (p = 0.002). On day 2 the mean GFAP level was 0.02 in non-TBI patients compared with 2.17 in TBI patients (p = 0.003). Using regression analysis to control for age, sex, and ISS, the Head Abbreviated Injury Scale was predictive of the level of GFAP on both days 1 and 2 (p values 0.006 and 0.026, respectively). Although GFAP levels were not predictive of increased hospital length of stay, intensive care unit length of stay, or ventilator days, high GFAP levels on hospital day 2 were predictive of mortality when controlling for age, sex, and ISS (odds ratio 1.45, p value 0.028). The area under the receiver operating characteristic curve for GFAP was 0.90 for day 1 and 0.88 for day 2. A GFAP cutoff point of 1 pg/mL yielded 100% specificity and 50% to 60% sensitivity for TBI. CONCLUSIONS: GFAP is a serum marker of TBI, and persistent elevation on day 2 is predictive of increased mortality. Excellent specificity for CT-documented brain injury was found using a cutoff point of 1 pg/mL.


Asunto(s)
Lesiones Encefálicas/sangre , Lesiones Encefálicas/mortalidad , Causas de Muerte , Proteína Ácida Fibrilar de la Glía/sangre , Adolescente , Adulto , Biomarcadores/sangre , Lesiones Encefálicas/diagnóstico por imagen , Estudios de Casos y Controles , Femenino , Escala de Coma de Glasgow , Humanos , Puntaje de Gravedad del Traumatismo , Modelos Lineales , Modelos Logísticos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Probabilidad , Estudios Prospectivos , Curva ROC , Valores de Referencia , Medición de Riesgo , Sensibilidad y Especificidad , Estadísticas no Paramétricas , Análisis de Supervivencia , Tomografía Computarizada por Rayos X
16.
J Neurotrauma ; 35(17): 2136-2142, 2018 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-29566593

RESUMEN

Primary blast traumatic brain injury (bTBI) accounts for a significant proportion of wartime trauma. Previous studies have demonstrated direct brain injury by blast waves, but the effect of the location of the blast epicenter on the skull with regard to brain injury remains poorly characterized. In order to investigate the role of the blast epicenter location, we modified a previously established rodent model of cranium-only bTBI to evaluate two specific blast foci: a rostrally focused blast centered on bregma (B-bTBI), which excluded the foramen magnum region, and a caudally focused blast centered on the occipital crest, which included the foramen magnum region (FM-bTBI). At all blast overpressures studied (668-1880 kPa), rats subjected to FM-bTBI demonstrated strikingly higher mortality, increased durations of both apnea and hypoxia, and increased severity of convexity subdural hematomas, than rats subjected to B-bTBI. Together, these data suggest a unique role for the foramen magnum region in mortality and brain injury following blast exposure, and emphasize the importance of the choice of blast focus location in experimental models of bTBI.


Asunto(s)
Traumatismos por Explosión/patología , Lesiones Traumáticas del Encéfalo/patología , Foramen Magno/lesiones , Foramen Magno/patología , Animales , Apnea/etiología , Apnea/patología , Traumatismos por Explosión/mortalidad , Lesiones Traumáticas del Encéfalo/mortalidad , Modelos Animales de Enfermedad , Hematoma Subdural/patología , Hipoxia Encefálica/etiología , Hipoxia Encefálica/patología , Masculino , Hueso Occipital/lesiones , Ratas , Ratas Long-Evans , Insuficiencia Respiratoria/etiología
17.
PLoS One ; 13(7): e0201831, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30063749

RESUMEN

[This corrects the article DOI: 10.1371/journal.pone.0171163.].

18.
Biochem J ; 397(1): 77-87, 2006 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-16551274

RESUMEN

Apoptosis occurs within crypts and at the intestinal luminal surface and plays a critical role in mucosal homoeostasis. NF-kappaB (nuclear factor-kappaB) is the central regulator of the transcription of genes involved in apoptosis, and its activity is highly regulated in the intestinal mucosa. We have recently demonstrated that TRPC1 (transient receptor potential canonical-1) is expressed in IECs (intestinal epithelial cells) and functions as a Ca2+ permeable channel activated by Ca2+ store depletion. The present study tests the hypothesis that TRPC1 channels are implicated in the regulation of apoptosis by inhibiting NF-kappaB through the induction of TRPC1-mediated Ca2+ influx in the IEC-6 line. The expression of TRPC1 induced by stable transfection of IEC-6 cells with the wild-type TRPC1 gene (IEC-TRPC1 cells) increased Ca2+ influx after Ca2+ store depletion and repressed NF-kappaB transactivation, which was associated with an increase in susceptibility to apoptosis induced by exposure to TNFalpha (tumour necrosis factor-alpha) plus CHX (cycloheximide) (TNF-alpha/CHX), or STS (staurosporine). By contrast, the induction of endogenous NF-kappaB activity, by the depletion of cellular polyamines, promoted resistance to apoptosis, which was prevented by the ectopic expression of the IkappaBalpha super-repressor. Furthermore, inhibition of TRPC1 expression by transfection with siRNA (small interfering RNA) targeting TRPC1 (siTRPC1) decreased Ca2+ influx, increased NF-kappaB transactivation, and prevented the increased susceptibility of IEC-TRPC1 cells to apoptosis. Decreasing Ca2+ influx by exposure to a Ca2+-free medium also induced NF-kappaB activity and blocked the increased susceptibility to apoptosis of stable IEC-TRPC1 cells. These results indicate that induced TRPC1 expression sensitizes IECs to apoptosis by inhibiting NF-kappaB activity as a result of the stimulation of Ca2+ influx.


Asunto(s)
Apoptosis , Calcio/metabolismo , FN-kappa B/antagonistas & inhibidores , Canales Catiónicos TRPC/biosíntesis , Canales Catiónicos TRPC/fisiología , Animales , Línea Celular , Mucosa Intestinal/citología , FN-kappa B/metabolismo , Ratas , Transfección
19.
PLoS One ; 12(2): e0171163, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28158198

RESUMEN

BACKGROUND: In adult humans, cerebral microbleeds play important roles in neurodegenerative diseases but in neonates, the consequences of cerebral microbleeds are unknown. In rats, a single pro-angiogenic stimulus in utero predisposes to cerebral microbleeds after birth at term, a time when late oligodendrocyte progenitors (pre-oligodendrocytes) dominate in the rat brain. We hypothesized that two independent pro-angiogenic stimuli in utero would be associated with a high likelihood of perinatal microbleeds that would be severely damaging to white matter. METHODS: Pregnant Wistar rats were subjected to intrauterine ischemia (IUI) and low-dose maternal lipopolysaccharide (mLPS) at embryonic day (E) 19. Pups were born vaginally or abdominally at E21-22. Brains were evaluated for angiogenic markers, microhemorrhages, myelination and axonal development. Neurological function was assessed out to 6 weeks. RESULTS: mRNA (Vegf, Cd31, Mmp2, Mmp9, Timp1, Timp2) and protein (CD31, MMP2, MMP9) for angiogenic markers, in situ proteolytic activity, and collagen IV immunoreactivity were altered, consistent with an angiogenic response. Vaginally delivered pups exposed to prenatal IUI+mLPS had spontaneous cerebral microbleeds, abnormal neurological function, and dysmorphic, hypomyelinated white matter and axonopathy. Pups exposed to the same pro-angiogenic stimuli in utero but delivered abdominally had minimal cerebral microbleeds, preserved myelination and axonal development, and neurological function similar to naïve controls. CONCLUSIONS: In rats, pro-angiogenic stimuli in utero can predispose to vascular fragility and lead to cerebral microbleeds. The study of microbleeds in the neonatal rat brain at full gestation may give insights into the consequences of microbleeds in human preterm infants during critical periods of white matter development.


Asunto(s)
Encéfalo/patología , Feto/patología , Hemorragias Intracraneales/patología , Isquemia/patología , Animales , Modelos Animales de Enfermedad , Femenino , Inmunohistoquímica , Lipopolisacáridos/toxicidad , Embarazo , Ratas , Ratas Wistar , Reacción en Cadena en Tiempo Real de la Polimerasa
20.
Behav Brain Res ; 333: 43-53, 2017 08 30.
Artículo en Inglés | MEDLINE | ID: mdl-28662892

RESUMEN

Blast traumatic brain injury (bTBI) affects both military and civilian populations, and often results in chronic deficits in cognition and memory. Chronic glial activation after bTBI has been linked with cognitive decline. Pharmacological inhibition of sulfonylurea receptor 1 (SUR1) with glibenclamide was shown previously to reduce glial activation and improve cognition in contusive models of CNS trauma, but has not been examined in bTBI. We postulated that glibenclamide would reduce chronic glial activation and improve long-term memory function after bTBI. Using a rat direct cranial model of bTBI (dc-bTBI), we evaluated the efficacy of two glibenclamide treatment paradigms: glibenclamide prophylaxis (pre-treatment), and treatment with glibenclamide starting after dc-bTBI (post-treatment). Our results show that dc-bTBI caused hippocampal astrocyte and microglial/macrophage activation that was associated with hippocampal memory dysfunction (rapid place learning paradigm) at 28days, and that glibenclamide pre-treatment, but not post-treatment, effectively protected against glial activation and memory dysfunction. We also report that a brief transient time-window of blood-brain barrier (BBB) disruption occurs after dc-bTBI, and we speculate that glibenclamide, which is mostly protein bound and does not normally traverse the intact BBB, can undergo CNS delivery only during this brief transient opening of the BBB. Together, our findings indicate that prophylactic glibenclamide treatment may help to protect against chronic cognitive sequelae of bTBI in warfighters and other at-risk populations.


Asunto(s)
Lesiones Traumáticas del Encéfalo/complicaciones , Gliburida/administración & dosificación , Hipoglucemiantes/administración & dosificación , Trastornos de la Memoria/etiología , Trastornos de la Memoria/prevención & control , Neuroglía/efectos de los fármacos , Animales , Apnea/etiología , Apnea/prevención & control , Barrera Hematoencefálica/fisiopatología , Peso Corporal/efectos de los fármacos , Peso Corporal/fisiología , Esquema de Medicación , Proteína Ácida Fibrilar de la Glía/metabolismo , Masculino , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Neuroglía/metabolismo , Oximetría , Consumo de Oxígeno/efectos de los fármacos , Consumo de Oxígeno/fisiología , Desempeño Psicomotor/efectos de los fármacos , Desempeño Psicomotor/fisiología , Ratas , Ratas Long-Evans , Aprendizaje Espacial/efectos de los fármacos , Aprendizaje Espacial/fisiología , Factores de Tiempo
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