RESUMEN
PURPOSE: It is becoming increasingly clear that genetic factors play a role in traumatic brain injury (TBI), whether in modifying clinical outcome after TBI or determining susceptibility to it. MicroRNAs are small RNA molecules involved in various pathophysiological processes by repressing target genes at the post- transcriptional level, and TBI alters microRNA expression levels in the hippocampus and cortex. This study was designed to detect differentially expressed microRNAs in the cerebrospinal fluid (CSF) of TBI patients remaining unconscious two weeks after initial injury and to explore related single nucleotide polymorphisms (SNPs). METHODS: We used a microarray platform to detect differential microRNA expression levels in CSF samples from patients with post-traumatic coma compared with samples from controls. A bioinformatic scan was performed covering microRNA gene promoter regions to identify potential functional SNPs. RESULTS: Totally 26 coma patients and 21 controls were included in this study, with similar distribution of age and gender between the two groups. Microarray showed that fourteen microRNAs were differentially expressed, ten at higher and four at lower expression levels in CSF of traumatic coma patients compared with controls (p<0.05). One SNP (rs11851174 allele: C/T) was identified in the motif area of the microRNA hsa-miR-431-3P gene promoter region. CONCLUSION: The altered microRNA expression levels in CSF after brain injury together with SNP identified within the microRNA gene promoter area provide a new perspective on the mechanism of impaired consciousness after TBI. Further studies are needed to explore the association between the specific microRNAs and their related SNPs with post-traumatic unconsciousness.
Asunto(s)
Lesiones Traumáticas del Encéfalo/líquido cefalorraquídeo , Biología Computacional , MicroARNs/líquido cefalorraquídeo , Polimorfismo de Nucleótido Simple , Adulto , Lesiones Traumáticas del Encéfalo/genética , Humanos , Masculino , MicroARNs/genética , Persona de Mediana Edad , Inconsciente en PsicologíaRESUMEN
PURPOSE: To investigate the in vitro effect of short interfering RNAs (siRNAs) against Nogo receptor (NgR) on neurite outgrowth under an inhibitory substrate of central nervous system (CNS) myelin. METHODS: Three siRNA sequences against NgR were designed and transfected into cerebellar granule cells (CGCs) to screen for the most effcient sequence of NgR siRNA by using reverse transcription polymerase chain reaction (RT-PCR) and immunofluorescence staining. NgR siRNA sequence 1 was found the most efficient which was then transfected into the CGCs grown on CNS myelin substrate to observe its disinhibition for neurite outgrowth. RESULTS: Compared with the scrambled control sequence of siRNA, the NgR siRNA sequence 1 significantly decreased NgR mRNA level at 24 h and 48 h (p <0.05), which was recovered by 96 h after transfection. NgR immunoreactivity was also markedly reduced at 24 and 48 h after the transfection of siRNA sequence 1 compared with that before transfection (p<0.05). The NgR immunoreactivity was recovered after 72 h post-transfection. Moreover, the neurite outgrowth on the myelin substrate was greatly improved within 72 h after the transfection with siRNA sequence 1 compared with the scrambled sequence-transfected group or non-transfected group (p<0.05). CONCLUSION: siRNA-mediated knockdown of NgR expression contributes to neurite outgrowth in vitro.
Asunto(s)
Vaina de Mielina/fisiología , Proyección Neuronal/fisiología , Receptor Nogo 1/fisiología , Animales , Células Cultivadas , Receptor Nogo 1/antagonistas & inhibidores , Receptor Nogo 1/genética , ARN Interferente Pequeño , Ratas , Ratas Sprague-DawleyRESUMEN
The global prevalence rate for congenital hydrocephalus (CH) is approximately one out of every five hundred births with multifaceted predisposing factors at play. Genetic influences stand as a major contributor to CH pathogenesis, and epidemiological evidence suggests their involvement in up to 40% of all cases observed globally. Knowledge about an individual's genetic susceptibility can significantly improve prognostic precision while aiding clinical decision-making processes. However, the precise genetic etiology has only been pinpointed in fewer than 5% of human instances. More occurrences of CH cases are required for comprehensive gene sequencing aimed at uncovering additional potential genetic loci. A deeper comprehension of its underlying genetics may offer invaluable insights into the molecular and cellular basis of this brain disorder. This review provides a summary of pertinent genes identified through gene sequencing technologies in humans, in addition to the 4 genes currently associated with CH (two X-linked genes L1CAM and AP1S2, two autosomal recessive MPDZ and CCDC88C). Others predominantly participate in aqueduct abnormalities, ciliary movement, and nervous system development. The prospective CH-related genes revealed through animal model gene-editing techniques are further outlined, focusing mainly on 4 pathways, namely cilia synthesis and movement, ion channels and transportation, Reissner's fiber (RF) synthesis, cell apoptosis, and neurogenesis. Notably, the proper functioning of motile cilia provides significant impulsion for cerebrospinal fluid (CSF) circulation within the brain ventricles while mutations in cilia-related genes constitute a primary cause underlying this condition. So far, only a limited number of CH-associated genes have been identified in humans. The integration of genotype and phenotype for disease diagnosis represents a new trend in the medical field. Animal models provide insights into the pathogenesis of CH and contribute to our understanding of its association with related complications, such as renal cysts, scoliosis, and cardiomyopathy, as these genes may also play a role in the development of these diseases. Genes discovered in animals present potential targets for new treatments but require further validation through future human studies.
Asunto(s)
Hidrocefalia , Humanos , Hidrocefalia/genética , Hidrocefalia/etiología , Animales , Predisposición Genética a la EnfermedadRESUMEN
OBJECTIVE: To evaluate all the possible therapeutic measures concerning the acute management of traumatic brain injury (TBI) mentioned in Cochrane Systematic Reviews published in the Cochrane Database of Systematic Reviews (CDSR). METHODS: An exhausted literature search for all published Cochrane Systematic Reviews discussing therapeutic rather than prevention or rehabilitative interventions of TBI was conducted. We retrieved such databases as CDSR and Cochrane Injury Group, excluded the duplications, and eventually obtained 20 results, which stand for critical appraisal for as many as 20 different measures for TBI patients. The important data of each systematic review, including total population, intervention, outcome, etc, were collected and presented in a designed table. Besides, we also tried to find out the possible weakness of these clinical trials included in each review. RESULTS: Analysis of these reviews yielded meanfuling observations: (1) The effectiveness of most ordinary treatments in TBI is inconclusive except that corticosteroids are likely to be ineffective or harmful, and tranexamic acid, nimodipine and progesterone show a promising effect in bleeding trauma, traumatic subarachnoid hemorrhage, TBI or severe TBI. (2) A majority of the systematic reviews include a small number of clinical trials and the modest numbers of patients, largely due to the uncertainty of the effectiveness. (3) The quality of most trials reported in the systematic reviews is more or less questionable. (4) In addition, lots of other complex factors together may lead to the inconclusive results demonstrated in the Cochrane Systematic Reviews. CONCLUSIONS: For clinical physicians, to translate these conclusions into practice with caution is essential. Basic medication and nursing care deserve additional attention as well and can be beneficial. For researchers, high quality trials with perfect design and comprehensive consideration of various factors are urgently required.
Asunto(s)
Lesiones Encefálicas , Revisiones Sistemáticas como Asunto , Ácido Tranexámico , Hemorragia , HumanosRESUMEN
Objective: To evaluate the value of the correlation coefficient between the ICP wave amplitude and the mean ICP level (RAP) and the resistance to CSF outflow (Rout) in predicting the outcome of patients with post-traumatic hydrocephalus (PTH) selected for shunting. Materials and Methods: As a training set, a total of 191 patients with PTH treated with VP shunting were retrospectively analyzed to evaluate the potential predictive value of Rout, collected from pre-therapeutic CSF infusion test, for a desirable recovery level (dRL), standing for the modified rankin scale (mRS) of 0-2. Eventually, there were 70 patients with PTH prospectively included as a validation set to evaluate the value of Rout-combined RAP as a predictor of dRL. We calculated Rout from a CSF infusion test and collected RAP during continuous external lumbar drainage (ELD). Maximum RAP (RAPmax) and its changes relative to the baseline (ΔRAPmax%) served as specific parameters of evaluation. Results: In the training set, Rout was proved to be a significant predictor of dRL to shunting, with the area under the curve (AUC) of 0.686 (p < 0.001) in receiver-operating characteristic (ROC) analysis. In the validation set, Rout alone did not present a significant value in the prediction of desirable recovery level (dRL). ΔRAPmax% after 1st or 2nd day of ELD both showed significance in predicting of dRL to shunting with the AUC of 0.773 (p < 0.001) and 0.786 (p < 0.001), respectively. Significantly, Rout increased the value of ΔRAPmax% in the prediction of dRL with the AUC of 0.879 (p < 0.001), combining with ΔRAPmax% after the 1st and 2nd days of ELD. RAPmax after the 1st and 2nd days of ELD showed a remarkable predictive value for non-dRL (Levels 3-6 in Modified Rankin Scale) with the AUC of 0.891 (p < 0.001) and 0.746 (p < 0.001). Conclusion: Both RAP and Rout can predict desirable recovery level (dRL) to shunting in patients with PTH in the early phases of treatment. A RAP-combined Rout is a better dRL predictor for a good outcome to shunting. These findings help the neurosurgeon predict the probability of dRL and facilitate the optimization of the individual treatment plan in the event of ineffective or unessential shunting.
RESUMEN
BACKGROUND: Previous studies have demonstrated that long non-coding RNA maternally expressed gene 3 (MEG3) emerged as a key regulator in development and tumorigenesis. This study aims to investigate the function and mechanism of MEG3 in osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and explores the use of MEG3 in skull defects bone repairing. METHODS: Endogenous expression of MEG3 during BMSCs osteogenic differentiation was detected by quantitative real-time polymerase chain reaction (qPCR). MEG3 was knockdown in BMSCs by lentiviral transduction. The proliferation, osteogenic-related genes and proteins expression of MEG3 knockdown BMSCs were assessed by Cell Counting Kit-8 (CCK-8) assay, qPCR, alizarin red and alkaline phosphatase staining. Western blot was used to detect ß-catenin expression in MEG3 knockdown BMSCs. Dickkopf 1 (DKK1) was used to block wnt/ß-catenin pathway. The osteogenic-related genes and proteins expression of MEG3 knockdown BMSCs after wnt/ß-catenin inhibition were assessed by qPCR, alizarin red and alkaline phosphatase staining. MEG3 knockdown BMSCs scaffold with PHMG were implanted in a critical-sized skull defects of rat model. Micro-computed tomography(micro-CT), hematoxylin and eosin staining and immunohistochemistry were performed to evaluate the bone repairing. RESULTS: Endogenous expression of MEG3 was increased during osteogenic differentiation of BMSCs. Downregulation of MEG3 could promote osteogenic differentiation of BMSCs in vitro. Notably, a further mechanism study revealed that MEG3 knockdown could activate Wnt/ß-catenin signaling pathway in BMSCs. Wnt/ß-catenin inhibition would impair MEG3-induced osteogenic differentiation of BMSCs. By using poly (3-hydroxybutyrate-co-3-hydroxyhexanoate, PHBHHx)-mesoporous bioactive glass (PHMG) scaffold with MEG3 knockdown BMSCs, we found that downregulation of MEG3 in BMSCs could accelerate bone repairing in a critical-sized skull defects rat model. CONCLUSIONS: Our study reveals the important role of MEG3 during osteogenic differentiation and bone regeneration. Thus, MEG3 engineered BMSCs may be effective potential therapeutic targets for skull defects.
RESUMEN
External ventricular drainage (EVD) is widely used in patients with a traumatic brain injury (TBI). However, the EVD weaning trial protocol varies and insufficient studies focus on the intracranial pressure (ICP) during the weaning trial. We aimed to establish the relationship between ICP during an EVD weaning trial and the outcomes of TBI. We enrolled 37 patients with a TBI with an EVD from July 2018 to September 2019. Among them, 26 were allocated to the favorable outcome group and 11 to the unfavorable outcome group (death, post-traumatic hydrocephalus, persistent vegetative state, and severe disability). Groups were well matched for sex, pupil reactivity, admission Glasgow Coma Scale score, Marshall computed tomography score, modified Fisher score, intraventricular hemorrhage, EVD days, cerebrospinal fluid output before the weaning trial, and the complications. Before and during the weaning trial, we recorded the ICP at 1-hour intervals to calculate the mean ICP, delta ICP, and ICP burden, which was defined as the area under the ICP curve. There were significant between-group differences in the age, surgery types, and intensive care unit days (p = 0.045, p = 0.028, and p = 0.004, respectively). During the weaning trial, 28 (75.7%) patients had an increased ICP. Although there was no significant difference in the mean ICP before and during the weaning trial, the delta ICP was higher in the unfavorable outcome group (p = 0.001). Moreover, patients who experienced death and hydrocephalus had a higher ICP burden, which was above 20 mmHg (p = 0.016). Receiver operating characteristic analyses demonstrated the predictive ability of these variables (area under the curve [AUC] = 0.818 [p = 0.002] for delta ICP and AUC = 0.758 [p = 0.038] for ICP burden > 20 mmHg). ICP elevation is common during EVD weaning trials in patients with TBI. ICP-related parameters, including delta ICP and ICP burden, are significant outcome predictors. There is a need for larger prospective studies to further explore the relationship between ICP during EVD weaning trials and TBI outcomes.
Asunto(s)
Lesiones Traumáticas del Encéfalo/fisiopatología , Lesiones Traumáticas del Encéfalo/terapia , Ventrículos Cerebrales/fisiopatología , Drenaje , Presión Intracraneal/fisiología , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
AIMS: Ferroptosis, a new form of iron-dependent programmed cell death, has been shown to be involved in a range of diseases. However, the role of ferroptosis in traumatic brain injury (TBI) has yet to be elucidated. We aimed to investigate whether ferroptosis is induced after TBI and whether the inhibition of ferroptosis would protect against traumatic brain injury in a controlled cortical impact injury (CCI) mouse model. METHODS: After establishing the TBI model in mice, we determined the biochemical and morphological changes associated with ferroptosis, including iron accumulation with Perl's staining, neuronal cell death with Fluoro-Jade B (FJB) staining, iron metabolism dysfunction with Western blotting, reactive oxygen species (ROS) accumulation with malondialdehyde (MDA) assays, and shrunken mitochondria with transmission electron microscopy. Furthermore, a specific inhibitor of ferroptosis, ferrostatin-1(fer-1), was administrated by cerebral ventricular injection after CCI. We used cresyl violet (CV) staining to assess lesion volume, along with the Morris water maze and beam walk test to evaluate long-term outcomes. RESULTS: TBI was followed by iron accumulation, dysfunctional iron metabolism, the upregulation of ferroptosis-related genes, reduced glutathione peroxidase (GPx) activity, and the accumulation of lipid-reactive oxygen species (ROS). Three days (d) after TBI, transmission electron microscopy (TEM) confirmed that the mitochondria had shrunk a typical characteristic of ferroptosis. Importantly, the administration of Fer-1 by cerebral ventricular injection significantly reduced iron deposition and neuronal degeneration while attenuating injury lesions and improving long-term motor and cognitive function. CONCLUSION: This study demonstrated an effective method with which to treat TBI by targeting ferroptosis.
Asunto(s)
Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Lesiones Traumáticas del Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Ciclohexilaminas/uso terapéutico , Ferroptosis/efectos de los fármacos , Fenilendiaminas/uso terapéutico , Animales , Encéfalo/patología , Lesiones Traumáticas del Encéfalo/patología , Ciclohexilaminas/farmacología , Ferroptosis/fisiología , Hierro/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Fenilendiaminas/farmacología , Especies Reactivas de Oxígeno/antagonistas & inhibidores , Especies Reactivas de Oxígeno/metabolismo , Resultado del TratamientoRESUMEN
China has more patients with traumatic brain injury (TBI) than most other countries in the world, making this condition a major public health concern. Population-based mortality of TBI in China is estimated to be approximately 13 cases per 100â000 people, which is similar to the rates reported in other countries. The implementation of various measures, such as safety legislation for road traffic, establishment of specialised neurosurgical intensive care units, and the development of evidence-based guidelines, have contributed to advancing prevention and care of patients with TBI in China. However, many challenges remain, which are augmented further by regional differences in TBI care. High-level care, such as intracranial pressure monitoring, is not universally available yet. In the past 30 years, the quality of TBI research in China has substantially improved, as evidenced by an increasing number of clinical trials done. The large number of patients with TBI and specialised trauma centres offer unique opportunities for TBI research in China. Furthermore, the formation and development of research collaborations between China and international groups are considered essential to advancing the quality of TBI care and research in China, and to improve quality of life in patients with this condition.
Asunto(s)
Lesiones Traumáticas del Encéfalo/epidemiología , Lesiones Traumáticas del Encéfalo/etiología , Lesiones Traumáticas del Encéfalo/terapia , China/epidemiología , Humanos , Prevalencia , Resultado del TratamientoRESUMEN
A prospective observational study collected temperature data from 51 patients in 11 neurosurgical centers and follow-up outcome information at 6 months in 49 patients. Brain temperature (Tbr) was measured directly by an intraventricular temperature sensor. Axillary temperature (Tax) and rectal temperature (Tre) were measured by electric thermometers. Tbr was 0.4 to 1.5°C higher than body temperature. Tre correlated well with the Tbr (coefficient: 0.7378; p < 0.05). Among all patients, Glasgow Coma Scale (GCS) scores on admission were significantly lower in the patients with post-operatively extreme peak temperature (Tpeak, < 37°C or >39°C in first 24 h) and major temperature variation (Tvari > 1°C in first 12 h; p < 0.05, p < 0.01, respectively). Among the patients with no temperature intervention, the extreme Tpeak group showed a lower Glasgow Outcome Scale-Extended (GOS-E) score at 6 months (p < 0.05) with lower GCS scores on admission (p < 0.01), compared with the moderate Tpeak group. Remarkably, the major Tvari group showed significantly lower GOS-E scores (p < 0.05) with the same GCS scores as the minor Tvari group. Thus, Tre is the better candidate to estimate Tbr. Spontaneously extreme Tpeak in TBI represents both more serious injury on admission and worse prognosis, and Tvari might be used as a novel prognostic parameter in TBI. Brain temperature is therefore one of the critical indicators evaluating injury severity, prognostication, and monitoring in the management of TBI. This prospective observational study has been registered in ClinicalTrials.gov ( https://clinicaltrials.gov ), and the registration number is NCT03068143.
Asunto(s)
Temperatura Corporal/fisiología , Lesiones Traumáticas del Encéfalo/fisiopatología , Lesiones Traumáticas del Encéfalo/terapia , Encéfalo/fisiopatología , Adulto , Anciano , Femenino , Escala de Coma de Glasgow , Escala de Consecuencias de Glasgow , Humanos , Hipotermia Inducida , Masculino , Persona de Mediana Edad , Pronóstico , Estudios ProspectivosRESUMEN
Circular RNAs (circRNAs) are involved in a variety of diseases. However, the roles of circRNAs in traumatic brain injury (TBI) remain unknown. In this study, circRNA microarray was used to profile the altered circRNAs in the rat hippocampus following TBI. A total of 192 circRNAs were observed to be differentially expressed (fold change [FC] ≥1.5 and p < 0.05) after TBI, including 98 upregulated and 94 downregulated. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated that many messenger RNAs (mRNAs) transcribed from the host genes of altered circRNAs were implicated in brain damage and neural regeneration. CircRNA/microRNA (miRNA) interaction was predicted using Arraystar's homemade miRNA target prediction software based on TargetScan and miRanda. Thus, our studies have demonstrated altered circRNA expression pattern in the rat hippocampus after TBI, which may play important roles in post-TBI physiological and pathological processes. These findings may provide not only a new direction for studying the molecular mechanisms underlying TBI but also a new possibility for the treatment of TBI by modulating circRNAs.
Asunto(s)
Lesiones Traumáticas del Encéfalo/genética , Hipocampo , ARN/análisis , ARN/genética , Transcriptoma , Animales , Masculino , ARN Circular , Ratas , Ratas Sprague-DawleyRESUMEN
Mild therapeutic hypothermia is a candidate for the treatment of traumatic brain injury (TBI). However, the role of mild hypothermia in neuronal sprouting after TBI remains obscure. We used a fluid percussion injury (FPI) model to assess the effect of mild hypothermia on pericontusion neuronal sprouting after TBI in rats. Male Sprague-Dawley rats underwent FPI or sham surgery, followed by mild hypothermia treatment (33°C) or normothermia treatment (37°C) for 3 h. All the rats were euthanized at 7 days after FPI. Neuronal sprouting that was confirmed by an increase in growth associated protein-43 (GAP-43) expression was evaluated using immunofluorescence and Western blot assays. The expression levels of several intrinsic and extrinsic sprouting-associated genes such as neurite outgrowth inhibitor A (NogoA), phosphatase and tensin homolog (PTEN), and suppressor of cytokine signaling 3 (SOCS3) were analyzed by quantitative real-time polymerase chain reaction (RT-PCR). Our results revealed that mild hypothermia significantly increased the expression level of GAP-43 and dramatically suppressed the expression level of interleukin-6 (IL-6) and SOCS3 at 7 days after FPI in the ipsilateral cortex compared with that of the normothermia TBI group. These data suggest that post-traumatic mild hypothermia promotes pericontusion neuronal sprouting after TBI. Moreover, the mechanism of hypothermia-induced neuronal sprouting might be partially associated with decreased levels of SOCS3.
Asunto(s)
Lesiones Traumáticas del Encéfalo/metabolismo , Lesiones Traumáticas del Encéfalo/terapia , Corteza Cerebral/metabolismo , Proteína GAP-43/metabolismo , Hipotermia Inducida/métodos , Interleucina-6/metabolismo , Neuronas/metabolismo , Proteína 3 Supresora de la Señalización de Citocinas/metabolismo , Animales , Contusión Encefálica/metabolismo , Contusión Encefálica/terapia , Modelos Animales de Enfermedad , Masculino , Proteínas Nogo/metabolismo , Fosfohidrolasa PTEN/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
Traumatic brain injury (TBI) causes a primary insult and initiates a secondary injury cascade. The mechanisms underlying the secondary injury are multifactorial and may include the aberrant expression of long non-coding RNA (lncRNA) post-TBI. Here, lncRNA microarray analysis was performed to profile the altered lncRNAs in the rat hippocampus after TBI. A total of 271 lncRNA probe sets and 1046 messenger RNA (mRNA) probe sets were differentially expressed after TBI. Gene ontology analysis showed that the main components of the most significantly changed categories were inflammation, DNA transcription, apoptosis, and necroptosis. Additionally, the pathway analysis and the pathway relation network revealed correlated pathways mainly involving inflammation, cell cycle, and apoptosis. A co-expression network of these aberrantly expressed lncRNAs and mRNAs was further constructed to predict the potential function of individual lncRNAs. Sub-co-expression networks were formed for the top three lncRNAs: NR_002704, ENSRNOT00000062543, and Zfas1. Thus, our study demonstrated differential expression of a series of lncRNAs in the rat hippocampus after TBI, which may be correlated with post-TBI physiological and pathological processes. The findings also may provide novel targets for further investigation of both the molecular mechanisms underlying TBI and potential therapeutic interventions.
Asunto(s)
Apoptosis/fisiología , Lesiones Traumáticas del Encéfalo/metabolismo , Ciclo Celular/fisiología , Hipocampo/lesiones , ARN Largo no Codificante/metabolismo , Animales , Lesiones Traumáticas del Encéfalo/genética , Perfilación de la Expresión Génica , Hipocampo/metabolismo , Inflamación/genética , Inflamación/metabolismo , Masculino , Análisis de Secuencia por Matrices de Oligonucleótidos , ARN Largo no Codificante/genética , Ratas , Ratas Sprague-DawleyRESUMEN
To compare the effect of long-term mild hypothermia versus short-term mild hypothermia on the outcome of 215 severe traumatic brain injured patients with cerebral contusion and intracranial hypertension. At three medical centers, 215 patients aged 18 to 45 years old with an admission Glasgow Coma Scale < or =8 within 4 h after injury were randomly divided into two groups: long-term mild hypothermia group (n = 108) for 5+/-1.3 days mild hypothermia therapy and short-term mild hypothermia group (n = 107) for 2+/-0.6 days mild hypothermia therapy. All patients had intracranial hypertension and frontotemporoparietal contusion with midline shift >1 cm confirmed on computed tomographic scan. Glasgow Outcome Scale at 6-month follow-up, 47 cases had favorable outcome (43.5%), and other 61 cases had unfavorable outcome (56.5%) in the long-term mild hypothermia group. However, only 31 cases had favorable outcome (29.0%), and other 76 cases had unfavorable outcome (71.0%) in the short-term mild hypothermia group (P < 0.05). The intracranial pressure significantly rebounded after rewarming in the short-term mild hypothermia group, but not in the long-term mild hypothermia (P < 0.05). Furthermore, the incidence of stress ulcer, epilepsy, pulmonary infection, intracranial infection did not significantly differ between the two groups (P > 0.05). Compared with short-term mild hypothermia, long-term mild hypothermia significantly improves the outcome of severe traumatic brain injured patients with cerebral contusion and intracranial hypertension without significant complications. Our data suggest that 5 days of long-term cooling is more efficacious than 2 days of short-term cooling when mild hypothermia is used to control refractory intracranial hypertension in patients with severe traumatic brain injury.
Asunto(s)
Lesiones Encefálicas/terapia , Hipotermia Inducida , Adolescente , Adulto , Lesiones Encefálicas/complicaciones , Femenino , Escala de Consecuencias de Glasgow , Humanos , Hipertensión Intracraneal/etiología , Hipertensión Intracraneal/terapia , Masculino , Recuperación de la Función , Factores de Tiempo , Resultado del TratamientoRESUMEN
Hypothermia has been demonstrated to protect the brain from ischemia or traumatic brain injury. Achieving profound hypothermia has relied on techniques requiring total body cooling, which may result in serious cardiovascular and pulmonary complications. A technique to selectively cool the brain could conceivably exert a marked protection on cerebral structures and provide a relatively bloodless operative surgical field without systemic complications. Accordingly, this approach was tried in 7 rhesus monkeys after induction of general anesthesia. The right internal carotid artery and both internal jugular veins were each occlusively cannulated and connected to a circulation pump. The left internal carotid artery, both external carotid arteries, and both external jugular veins were temporarily clamped to establish severe cerebral ischemia. Using a closed-circuit system, cooled Ringer's lactate liquid (4 degrees C) was infused through right internal carotid artery with outflow draining though both internal jugular veins. Cooled perfusate decreased cerebral temperature to the target temperature of 15 degrees C. Thereafter, pump flow was discontinued, and brains were rewarmed spontaneously, while the temporarily clamped carotid arteries and jugular veins were opened to resume normal cerebral blood circulation. Neurological functions were recorded daily and cerebral histology was examined at the conclusion of the experiment. Magnetic resonance (MR) scans were routinely taken before and 3 weeks after ischemia. In the normothermia control group of five rhesus monkeys, Ringer's solution at 37 degrees C was infused in the same manner as the cold solution with cerebral temperature maintained at 36.7 +/- 0.32 degrees C. Right cerebral temperature decreased from 36.5 +/- 0.49 to 15.5 +/- 2.29 degrees C, and simultaneously the left cerebral temperature decreased from 36.4 +/- 0.38 to 16.3 +/- 2.4 degrees C for 62.8 +/- 9.76 min during selective cerebral cooled Ringer's liquid perfusion. In contrast, rectal temperature was only reduced to 32.4 +/- 0.96 degrees C from a baseline of 37.2 +/- 0.76 degrees C. Internal jugular vein hematocrit was 38.2 +/- 0.31% before perfusion and 2.82 +/- 0.46% at the end of perfusion in profound hypothermia group; hematocrit was 39.7 +/- 0.62% before perfusion and 3.42 +/- 0.38% at the end of perfusion in the normothermia group. In the hypothermic group, neurological functions were normal during 6 months of follow-up, and microscopic examination of brain tissue did not show evidence of pathological changes in hippocampus or medulla. MR scans did not show any cerebral infarction. In contrast, none of the monkeys in normothermia group survived for more than several hours, and microscopic examination of the brain revealed extensive neuronal necrosis within the medulla. Selective cerebral profound hypothermia provides significant histologic and neurologic protection after severe cerebral ischemia. In addition, there were no major complications, and the operative field remained relatively bloodless in the profound hypothermic group.
Asunto(s)
Isquemia Encefálica/prevención & control , Hipotermia Inducida/métodos , Soluciones Isotónicas/administración & dosificación , Anestesia General , Animales , Temperatura Corporal , Isquemia Encefálica/patología , Arteria Carótida Interna , Frío , Circulación Extracorporea , Infusiones Intraarteriales , Macaca mulatta , Lactato de RingerRESUMEN
OBJECTIVE: The role of autophagy in moderate hypothermia in posttraumatic brain injury (post-TBI) remains elusive. In this study, we evaluated the protective role of autophagy in post-TBI moderate hypothermia. METHODS: Adult male Sprague-Dawley rats were randomly divided into 3 groups (n = 36/group): TBI with hypothermia group (sham), TBI with hypothermia and a single intracerebroventricular injection of saline (saline, 5 µL), and TBI with hypothermia and a single intracerebroventricular injection of 3-methyladenine (600 nmol, diluted in 0.9% saline to a final volume of 5 µL). All rats, except those in the behavioral tests, were killed at 24 hours after fluid percussion TBI. Immunohistochemistry staining, western blot, and transmission electron microscopy were performed to assess changes in apoptosis and autophagy after injection of 3-methyladenine. Motor function (beam-walk test) and spatial learning/memory (Morris water maze) were assessed on postoperative days 1-5 and 11-15, respectively. RESULTS: Our results showed downregulation of the expression level of microtubule-associated protein 1 light chain 3 and Beclin-1, aggravation of behavioral outcome, and increase of apoptosis. CONCLUSION: Our results suggest that the autophagy pathway is involved in the neuroprotective effect of post-TBI hypothermia and negative modulation of apoptosis may be 1 possible mechanism.
Asunto(s)
Adenina/análogos & derivados , Autofagia/efectos de los fármacos , Lesiones Encefálicas/fisiopatología , Lesiones Encefálicas/rehabilitación , Hipotermia Inducida/métodos , Recuperación de la Función/efectos de los fármacos , Adenina/administración & dosificación , Animales , Lesiones Encefálicas/patología , Masculino , Neuroprotección/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Resultado del TratamientoRESUMEN
Here, we evaluated changes in autophagy after post-traumatic brain injury (TBI) followed by moderate hypothermia in rats. Adult male Sprague-Dawley rats were randomly divided into four groups: sham injury with normothermia group (37 °C); sham injury with hypothermia group (32 °C); TBI with normothermia group (TNG; 37 °C); and TBI with hypothermia group (THG; 32 °C). Injury was induced by a fluid percussion TBI device. Moderate hypothermia (32 °C) was achieved by partial immersion in a water bath (0 °C) under general anesthesia for 4 h. All rats were killed at 24 h after fluid percussion TBI. The ipsilateral hippocampus in all rats was analyzed with hematoxylin and eosin staining; terminal deoxynucleoitidyl transferase-mediated nick end labeling staining was used to determine cell death in ipsilateral hippocampus. Immunohistochemistry and western blotting of microtubule-associated protein light chain 3 (LC3), Beclin-1, as well as transmission electron microscopy performed to assess changes in autophagy. At 24 h after TBI, the cell death index was 27.90 ± 2.36% in TNG and 14.90 ± 1.52% in THG. Expression level of LC3 and Beclin-1 were significantly increased after TBI and were further up-regulated after post-TBI hypothermia. Further, ultrastructural observations showed that there was a marked increase of autophagosomes and autolysosomes in ipsilateral hippocampus after post-TBI hypothermia. Our data demonstrated that moderate hypothermia significantly attenuated cell death and increased autophagy in ipsilateral hippocampus after fluid percussion TBI. In conclusion, autophagy pathway may participate in the neuroprotective effect of post-TBI hypothermia.
Asunto(s)
Autofagia/fisiología , Lesiones Encefálicas/terapia , Hipocampo/patología , Hipotermia Inducida , Animales , Proteínas Reguladoras de la Apoptosis/metabolismo , Beclina-1 , Temperatura Corporal/fisiología , Lesiones Encefálicas/metabolismo , Lesiones Encefálicas/patología , Hipocampo/metabolismo , Masculino , Proteínas de la Membrana/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
Traumatic brain injury (TBI) treatment is a long-term process and requires repeated medicine administration, which, however, can cause high expense, infection, and hemorrhage to patients. To investigate how a long-term expression of nerve growth factor (Ngf) gene affects the injured hippocampus function post-TBI, in this study, a pseudo lentivirus carrying the ß-Ngf fusion gene, with green fluorescence protein (GFP) gene, was constructed to show the gene expression and its ability of protecting cells from oxidative damage in vitro. Then, the pseudo lentivirus-carried ß-Ngf fusion gene was directly injected into the injured brain to evaluate its influence on the injured hippocampus function post-TBI in vivo. We found that the expression of the pseudo lentivirus-delivered ß-Ngf fusion gene lasted more than four-week after the cell transduction and the encoded ß-NGF fusion protein could induce the neuron-like PC12 cell differentiation. Moreover, the hippocampal injection of the pseudo lentivirus-carried ß-Ngf fusion gene sped the injured cognitive function recovery of the rat subjected to TBI. Together, our findings indicate that the long-term expression of the ß-Ngf fusion gene, delivered by the pseudo lentivirus, can promote the neurite outgrowth of the neuron-like cells and protect the cells from the oxidative damage in vitro, and that the direct and single dose hippocampal injection of the pseudo lentivirus-carried ß-Ngf fusion gene is able to rescue the hippocampus function after the TBI in the rat.
Asunto(s)
Lesiones Encefálicas/genética , Lesiones Encefálicas/terapia , Cognición , Terapia Genética , Hipocampo/fisiopatología , Lentivirus/genética , Factor de Crecimiento Nervioso/genética , Animales , Lesiones Encefálicas/fisiopatología , Expresión Génica , Técnicas de Transferencia de Gen , Hipocampo/metabolismo , Humanos , Masculino , Neuritas/metabolismo , Neuritas/patología , Neurogénesis , Ratas , Ratas Sprague-Dawley , Transducción GenéticaRESUMEN
A number of factors, including Glasgow coma scale (GCS) score, age, pupillary response and size, hypoxia, hyperthermia, and high intracranial pressure, may play an important role in predicting the outcome of traumatic brain injury. Eight hundred forty-six cases of severe traumatic brain injury (GCS < or = 8) were analyzed retrospectively to clarify the effects of multiple factors on the prognosis of patients. At 1 year after injury, the outcomes in these cases were as follows: good recovery, 31.56%; moderate disability, 14.07%; severe disability 24.35%; vegetative status, 0.59%; and death, 29.43%. The outcomes were strongly correlated (p < 0.05) with GCS score, age, pupillary response and size, hypoxia, hyperthermia, and high intracranial pressure (ICP). These findings indicate that prevention of hypoxia, control of high ICP, and prevention of hyperthermia may be useful means for improving the outcome of patients with severe head injury.
Asunto(s)
Lesiones Encefálicas/diagnóstico , Evaluación de Resultado en la Atención de Salud , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Lesiones Encefálicas/complicaciones , Distribución de Chi-Cuadrado , Niño , Preescolar , Femenino , Fiebre/diagnóstico , Fiebre/etiología , Humanos , Hipoxia-Isquemia Encefálica/diagnóstico , Hipoxia-Isquemia Encefálica/etiología , Lactante , Hipertensión Intracraneal/diagnóstico , Hipertensión Intracraneal/etiología , Masculino , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud/métodos , Evaluación de Resultado en la Atención de Salud/estadística & datos numéricos , Pronóstico , Estudios RetrospectivosRESUMEN
The aim of this study was to evaluate the potential efficacy of SB-3CT, a matrix metallopeptidase 9 inhibitor, on behavioral and histological outcomes after traumatic brain injury (TBI) in rats. Adult male Sprague-Dawley rats were randomly divided into three groups (n=15/group): TBI with SB-3CT treatment, TBI with saline, and sham injury. The TBI model was induced by a fluid percussion TBI device. SB-3CT (50 mg/kg in 10% dimethyl sulfoxide) was administered intraperitoneally at 30 min, 6 h, and 12 h after the TBI. Motor function (beam-balance/beam-walk tests) and spatial learning/memory (Morris water maze) were assessed on post-operative Days 1-5 and 11-15, respectively. Fluoro-Jade staining, immunofluorescence, and cresyl violet-staining were carried out for histopathological evaluation at 24 h, 72 h, and 15 days after TBI, respectively. It was shown that TBI can result in significant behavioral deficit induced by acute neurodegeneration, increased expression of cleaved caspase-3, and long-term neuronal loss. SB-3CT intervention via the current regime provides robust behavioral protection and hippocampal neurons preservation from the deleterious effects of TBI. Hence, the efficacy of SB-3CT on TBI prognosis could be ascertained. It is believed that the current study adds to the growing literature in identifying SB-3CT as a potential therapy for human brain injury.