Calcitonin gene-related peptide inhibits neuronal apoptosis in heatstroke rats via PKA/p-CREB pathway / 中华创伤杂志(英文版)

PURPOSE@#The incidence of heatstroke (HS) is not particularly high; however, once it occurs, the consequences are serious. It is reported that calcitonin gene-related peptide (CGRP) is protective against brain injury in HS rats, but detailed molecular mechanisms need to be further investigated. In this study, we further explored whether CGRP inhibited neuronal apoptosis in HS rats via protein kinase A (PKA)/p-cAMP response element-binding protein (p-CREB) pathway.@*METHODS@#We established a HS rat model in a pre-warmed artificial climate chamber with a temperature of (35.5 ± 0.5) °C and a relative humidity of 60% ± 5%. Heatstress was stopped once core body temperature reaches above 41 °C. A total of 25 rats were randomly divided into 5 groups with 5 animals each: control group, HS group, HS+CGRP group, HS+CGRP antagonist (CGRP8-37) group, and HS+CGRP+PKA/p-CREB pathway blocker (H89) group. A bolus injection of CGRP was administered to each rat in HS+CGRP group, CGRP8-37 (antagonist of CGRP) in HS+CGRP8-37 group, and CGRP with H89 in HS+CGRP+H89 group. Electroencephalograms were recorded and the serum concentration of S100B, neuron-specific enolase (NSE), neuron apoptosis, activated caspase-3 and CGRP expression, as well as pathological morphology of brain tissue were detected at 2 h, 6 h, and 24 h after HS in vivo. The expression of PKA, p-CREB, and Bcl-2 in rat neurons were also detected at 2 h after HS in vitro. Exogenous CGRP, CGRP8-37, or H89 were used to determine whether CGRP plays a protective role in brain injury via PKA/p-CREB pathway. The unpaired t-test was used between the 2 samples, and the mean ± SD was used for multiple samples. Double-tailed p < 0.05 was considered statistically significant.@*RESULTS@#Electroencephalogram showed significant alteration of θ (54.50 ± 11.51 vs. 31.30 ± 8.71, F = 6.790, p = 0.005) and α wave (16.60 ± 3.21 vs. 35.40 ± 11.28, F = 4.549, p = 0.020) in HS group compared to the control group 2 h after HS. The results of triphosphate gap terminal labeling (TUNEL) showed that the neuronal apoptosis of HS rats was increased in the cortex (9.67 ± 3.16 vs. 1.80 ± 1.10, F = 11.002, p = 0.001) and hippocampus (15.73 ± 8.92 vs. 2.00 ± 1.00, F = 4.089, p = 0.028), the expression of activated caspase-3 was increased in the cortex (61.76 ± 25.13 vs. 19.57 ± 17.88, F = 5.695, p = 0.009) and hippocampus (58.60 ± 23.30 vs. 17.80 ± 17.62, F = 4.628, p = 0.019); meanwhile the expression of serum NSE (5.77 ± 1.78 vs. 2.35 ± 0.56, F = 5.174, p = 0.013) and S100B (2.86 ± 0.69 vs. 1.35 ± 0.34, F = 10.982, p = 0.001) were increased significantly under HS. Exogenous CGRP decreased the concentrations of NSE and S100B, and activated the expression of caspase-3 (0.41 ± 0.09 vs. 0.23 ± 0.04, F = 32.387, p < 0.001) under HS; while CGRP8-37 increased NSE (3.99 ± 0.47 vs. 2.40 ± 0.50, F = 11.991, p = 0.000) and S100B (2.19 ± 0.43 vs. 1.42 ± 0.30, F = 4.078, p = 0.025), and activated the expression caspase-3 (0.79 ± 0.10 vs. 0.23 ± 0.04, F = 32.387, p < 0.001). For the cell experiment, CGRP increased Bcl-2 (2.01 ± 0.73 vs. 2.15 ± 0.74, F = 8.993, p < 0.001), PKA (0.88 ± 0.08 vs. 0.37 ± 0.14, F = 20.370, p < 0.001), and p-CREB (0.87 ± 0.13 vs. 0.29 ± 0.10, F = 16.759, p < 0.001) levels; while H89, a blocker of the PKA/p-CREB pathway reversed the expression.@*CONCLUSIONS@#CGRP can protect against HS-induced neuron apoptosis via PKA/p-CREB pathway and reduce activation of caspase-3 by regulating Bcl-2. Thus CGRP may be a new target for the treatment of brain injury in HS.

Research progress on mechanism of traumatic brain injury promoting fracture healing / 中国修复重建外科杂志

OBJECTIVE@#To summarize the research progress on the mechanism related to traumatic brain injury (TBI) to promote fracture healing, and to provide theoretical basis for clinical treatment of fracture non-union.@*METHODS@#The research literature on TBI to promote fracture healing at home and abroad was reviewed, the role of TBI in fracture healing was summarized from three aspects of nerves, body fluids, and immunity, to explore new ideas for the treatment of fracture non-union.@*RESULTS@#Numerous studies have shown that fracture healing is faster in patients with fracture combined with TBI than in patients with simple fracture. It is found that the expression of various cytokines and hormones in the body fluids of patients with fracture and TBI is significantly higher than that of patients with simple fracture, and the neurofactors released by the nervous system reaches the fracture site through the damaged blood-brain barrier, and the chemotaxis and aggregation of inflammatory cells and inflammatory factors at the fracture end of patients with combined TBI also differs significantly from those of patients with simple fracture. A complex network of humoral, neural, and immunomodulatory networks together promote regeneration of blood vessels at the fracture site, osteoblasts differentiation, and inhibition of osteoclasts activity.@*CONCLUSION@#TBI promotes fracture healing through a complex network of neural, humoral, and immunomodulatory, and can treat fracture non-union by intervening in the perifracture microenvironment.

Research on the dynamic changes of neurological dysfunction and cognitive function impairment in traumatic brain injury / 解剖学报

Objective To explore the dynamic changes and mechanisms of neurological and cognitive functions in mice with traumatic brain injury (TBI). Methods Totally 60 12⁃month⁃old Balb/ c mice were divided into control group (10 in group) and TBI group (50 in group). TBT model mice were divided into 5 subgroups according to the time of model construction, including model 1 day, model 1 day, model 3 day, model 7 day, model 14 days and model 28 days group with 10 in each group. At the 29th day of the experiment, neurological scores and step down tests were carried out. After the test, the mice were sacrificed for brains which were detected by immunohistochemistry staining, inflammatory cytokine tests and Western blotting. Results Compared with the control group, the neurological scores of mice in TBI group increased, and then decreased after the 7th day when the scores reached the peak. However, the latency of step down errors was lower than control group, and the number of step down errors was higher than control group which had no changes. Compared with the control group, the expression of lonized calcium⁃binding adapter molecule 1(IBA1), chemokine C⁃X3⁃C⁃motif ligand1 (CX3CL1), C⁃X3⁃C chemokine receptor 1(CX3CR1), NOD⁃like receptor thermal protein domain associated protein 3 (NLRP3), and phosphorylation nuclear factor(p⁃NF)⁃κB in TBI group increased and reached to the peak at the 7th day, and then started to decrease. At the same time, the levels of inflammatory cytokines interleukin⁃6(IL⁃6) and tumor necrosis factor⁃α(TNF⁃α) first increased to the peak, and then began to decrease. However, compared with the control group, the expression of amyloid β(Aβ) protein and p⁃Tau protein in the model group continued to increase at all time. Conclusion The TBI model caused continuous activation of microglia along with inflammatory response, which first increased and then decreased, resultsing in neurological scores changes. In addition, the inflammatory response may act as a promoter of Aβ protein deposition and Tau protein phosphorylation, leading to cognitive impairment in mice.

Recent progress of targeting Nrf2-ferroptosis to treat brain injury after ischemic stroke / 中国临床药理学与治疗学

Emerging evidences suggest that ferroptosis plays a vital role in the pathophysiological process of brain injury after Ischemic stroke. Accumulating evidence supports pharmacological inhibition of ferroptosis as a therapeutic target for brain injury after Ischemic stroke through activating nuclear factor erythroid 2-related factor 2 (Nrf2), which transcriptionally controls many key components of the ferroptosis pathway. In this review, briefly describe ferroptosis processes and the roles they play in contributing to brain injury after ischemic stroke in the brain. We then provide a critical overview of the relationship between Nrf2 signalling and ferroptosis. With a focus on discuss how therapeutic modulation of the Nrf2 pathway is a viable strategy to explore in the treatment of ferroptosis-driven brain injury after Ischemic stroke.

Impairment of Autophagic Flux After Hypobaric Hypoxia Potentiates Oxidative Stress and Cognitive Function Disturbances in Mice / 神经科学通报·英文版

Acute hypobaric hypoxic brain damage is a potentially fatal high-altitude sickness. Autophagy plays a critical role in ischemic brain injury, but its role in hypobaric hypoxia (HH) remains unknown. Here we used an HH chamber to demonstrate that acute HH exposure impairs autophagic activity in both the early and late stages of the mouse brain, and is partially responsible for HH-induced oxidative stress, neuronal loss, and brain damage. The autophagic agonist rapamycin only promotes the initiation of autophagy. By proteome analysis, a screen showed that protein dynamin2 (DNM2) potentially regulates autophagic flux. Overexpression of DNM2 significantly increased the formation of autolysosomes, thus maintaining autophagic flux in combination with rapamycin. Furthermore, the enhancement of autophagic activity attenuated oxidative stress and neurological deficits after HH exposure. These results contribute to evidence supporting the conclusion that DNM2-mediated autophagic flux represents a new therapeutic target in HH-induced brain damage.

Adult human neural cells in culture following traumatic brain injury

Objective: The present study aims to evaluate the viability of adult human neural cells in culture obtained from traumatized brain tissues collected in emergency surgery procedures. Methods: Exploratory, descriptive, quantitative and cross-sectional study evaluating samples obtained from patients who underwent traumatic brain injury with extrusion of brain tissue submitted to cell culture in a standardized medium, being preserved during 168h. After observation under phase contrast microscopy and immunohistochemical processing for neuronal (MAP-2) and glial (GFAP) markers, morphometric parameters of neural cells (cell body area, dendritic field length and fractal dimension) were evaluated using ImageJ software, with data obtained after 24, 72 and 168h being compared using non-parametric Kruskal Wallis test, followed by Dunn's post hoc test. Results: The explant of the nervous tissue revealed a consolidated pattern of cell migration into the culture medium. Cell proliferation, upon reaching confluence, presented an aspect of cellular distribution juxtaposed along the culture medium at all time points analyzed. Both neurons and glial cells remained viable after 168h in culture, with their morphologies not varying significantly throughout the time points evaluated. Immunohistochemistry for MAP-2 showed a relatively well-preserved cytoskeletal organization. GFAP immunoreactivity revealed activated astrocytes especially at the later time point. Conclusions: Our results point out the viability of cell culture from traumatized human nervous tissue, opening up perspectives for the use of substances of natural origin that may contribute neuroprotectively to neuronal maintenance in culture, allowing future translational approach.

Predictors of Mortality and Functional recovery after severe traumatic brain injury: protocol for a prospective cohort study

Introduction: traumatic brain injury is a global public health problem due to its severity and high rates of morbimortality worldwide. Identifying predictors associated with increased mortality and unfavorable functional outcomes after the traumatic brain injury event is crucial for minimizing morbidity and mortality rates. Therefore, this study aims to establish a protocol to investigate the predictors of mortality and functional recovery after severe traumatic brain injury in Brazil.Methods: The study will include all patients admitted for severe traumatic brain injury (Glasgow Coma Scale ≤ 8) at the State Hospital of Urgency and Emergency, which is the referral trauma hospital of Espirito Santo. The outcomes of interest are hospital mortality and functional recovery 24 months after hospital discharge. Subjects will be followed up at seventy-two hours, three months, six months, twelve months, and twenty-four months after the trauma. Morbidity will be determined by assessing: 1) the level of motor and cognitive disability, 2) functional impairment and quality of life, and 3) aspects of rehabilitation treatment. Additionally, the traumatic brain injury load, estimated by the years of life lost, will be calculated. Discussion: the results of this study will help identify variables that can predict morbidity and mortality, as well as diagnostic and therapeutic targets for patients with severe traumatic brain injury. Furthermore, the findings will have practical implications for: 1) the development of public policies, 2) investments in hospital infrastructure 3) understanding the socioeconomic impact of functional loss in the individuals.Study registration: the study received approval from the Ethics Committee of the Federal University of Espirito Santo under protocol number 4.222.002 on August 18, 2020.

Introdução: traumatismo cranioencefálico é um problema global de saúde pública devido à sua gravidade e altas taxas de morbimortalidade em todo o mundo. Identificar preditores associados ao aumento da mortalidade e desfechos funcionais desfavoráveis após o evento do traumatismo craniencefálico é primordial para minimizar as taxas de morbidade e mortalidade. Portanto, este estudo tem como objetivo estabelecer um protocolo para investigar os preditores de mortalidade e recuperação funcional após traumatismo cranioencefálico grave no Brasil. Métodos: este estudo tem como objetivo investigar os preditores de mortalidade e recuperação funcional em pacientes com traumatismo cranioencefálico, além de fornecer uma visão geral do traumatismo cranioencefálico no estado do Espírito Santo. O estudo abrangerá todos os pacientes internados por traumatismo cranioencefálico grave (Escala de Coma de Glasgow ≤ 8) no Hospital Estadual de Urgência e Emergência, o hospital de referência para traumas no Espírito Santo. Os desfechos de interesse incluem mortalidade hospitalar e recuperação funcional após 24 meses da alta hospitalar. Os participantes serão acompanhados em setenta e duas horas, três meses, seis meses, doze meses e vinte e quatro meses após o trauma. A morbidade será determinada pela avaliação de: 1) nível de incapacidade motora e cognitiva, 2) comprometimento funcional e qualidade de vida, e 3) aspectos do tratamento e reabilitação. Além disso, a carga de traumatismo cranioencefálico, estimada em anos de vida perdidos, será calculada. Discussão: os resultados deste estudo ajudarão a identificar variáveis que podem predizer a morbidade e a mortalidade após traumatismo cranioencefálico grave. Além disso, as descobertas terão implicações práticas para: 1) o desenvolvimento de políticas públicas, 2) investimentos em infraestrutura hospitalar e 3) compreensão do impacto socioeconômico da perda funcional nesses indivíduos. Registro do estudo: o estudo recebeu aprovação do Comitê de Ética da Universidade Federal do Espírito Santo sob o número de protocolo 4.222.002 em 18 de agosto de 2020

Septic complications in patients of traumatic brain injury: An impact on clinical and functional outcome

Background: Septic complications in traumatic brain injury causes short- and long-term cerebral dysregulation by disruption of blood brain barrier, reduced brain perfusion, neuroinflammation and deposition of amyloid. Materials and methods: The present study attempted to observe patients of traumatic brain injury for the development of septic complications during the hospital stay. 89 patients were included in the study with different grades of brain injury (Injury Severity Score (ISS) range, 9-72). The patients were managed according to the trauma protocol and classified into 3 groups based on the severity of trauma (ISS 9-17 (moderate), 18-30 (severe), and >32 (most severe)). The patients were observed for the development of major septic complications during the course of their hospital stay, which impacted on the morbidity and mortality while determining the clinical and functional outcome at the end. Results: Mean age of the study population was 33.5 years. TBI was more common in younger age groups with severe grades of injury, those with multiplicity of head injuries, sepsis with a pulmonary focus, prolonged ICU and in-hospital stay together with high mortality. Septic complications were also more common in cases with higher grades of TBI and more prolonged hospital stay. Patients requiring intubation had a higher risk of developing infectious complications. 69 patients (77.5%) required intubation and mechanical ventilation. Pneumonia was the most common source of sepsis leading to the respiratory failure while the most common cause being aspiration at the time of injury Genitourinary complications were also common leading to urosepsis. Most common organisms isolated were Staphylococcus aureus, Acinetobacter, klebsiella and Pseudomonas. Conclusion: Traumatic brain injury (TBI) when complicated by sepsis and multi organ failure increases the mortality and morbidity with less favorable clinical and functional outcome together with increased duration of ICU and hospital stay.

Adverse drug reaction profile of patients taking amantadine for traumatic brain injury in a tertiary care hospital

Background: Amantadine is found to be effective for the treatment of complications associated with traumatic brain injury. Drug-related side effects are common with Amantadine especially when combined with other drugs. Comprehensive information about the incidence and severity of these adverse effects is not available. Aim and Objectives: The aim of the study was to analyze the pattern of occurrence of adverse drug reactions (ADRs) in patients receiving Amantadine for traumatic brain injury in a tertiary care hospital. We also assessed the causality, severity and preventability of ADRs. Materials and Methods: This prospective cohort study was conducted among patients taking Amantadine for a continuous period of 1 month for traumatic brain injury in neurosurgery department between June 2020 and December 2020. Tools used were ADR Reporting form of National Pharmacovigilance Centre, WHO causality scale, Hartwig and Siegel scale, and Schumock and Thornton scale. Descriptive statistics were used and the values were expressed in numbers and percentages. Results: ADRs were experienced in 55 patients (36.7%) out of 150 patients and all the patients were on combination therapy. ADR was present more in male patients (63.6%) compared to females (36.4%). The most common ADRs were headache, ankle edema and dry mouth. Majority of ADRs belonged to the possible category according to the WHO causality assessment scale. Majority of the ADRs (61.9%) were mild level 1 according to severity scale. All the ADRs came under the definitely or probably preventable category. Conclusion: ADRs with Amantadine are common but mild and preventable.

Neurocritical care management supported by multimodal brain monitoring after acute brain injury / Abordagem de cuidados neurocríticos apoiada por monitorização cerebral multimodal após lesão cerebral aguda

ABSTRACT Objective: To evaluate the association between different intensive care units and levels of brain monitoring with outcomes in acute brain injury. Methods: Patients with traumatic brain injury and subarachnoid hemorrhage admitted to intensive care units were included. Neurocritical care unit management was compared to general intensive care unit management. Patients managed with multimodal brain monitoring and optimal cerebral perfusion pressure were compared with general management patients. A good outcome was defined as a Glasgow outcome scale score of 4 or 5. Results: Among 389 patients, 237 were admitted to the neurocritical care unit, and 152 were admitted to the general intensive care unit. Neurocritical care unit management patients had a lower risk of poor outcome (OR = 0.228). A subgroup of 69 patients with multimodal brain monitoring (G1) was compared with the remaining patients (G2). In the G1 and G2 groups, 59% versus 23% of patients, respectively, had a good outcome at intensive care unit discharge; 64% versus 31% had a good outcome at 28 days; 76% versus 50% had a good outcome at 3 months (p < 0.001); and 77% versus 58% had a good outcome at 6 months (p = 0.005). When outcomes were adjusted by SAPS II severity score, using good outcome as the dependent variable, the results were as follows: for G1 compared to G2, the OR was 4.607 at intensive care unit discharge (p < 0.001), 4.22 at 28 days (p = 0.001), 3.250 at 3 months (p = 0.001) and 2.529 at 6 months (p = 0.006). Patients with optimal cerebral perfusion pressure management (n = 127) had a better outcome at all points of evaluation. Mortality for those patients was significantly lower at 28 days (p = 0.001), 3 months (p < 0.001) and 6 months (p = 0.001). Conclusion: Multimodal brain monitoring with autoregulation and neurocritical care unit management were associated with better outcomes and should be considered after severe acute brain injury.

RESUMO Objetivo: Avaliar a associação entre diferentes tipos de unidades de cuidados intensivos e os níveis de monitorização cerebral com desfechos na lesão cerebral aguda. Métodos: Foram incluídos doentes com traumatismo craniencefálico e hemorragia subaracnoide internados em unidades de cuidados intensivos. A abordagem na unidade de cuidados neurocríticos foi comparada à abordagem na unidade de cuidados intensivos polivalente geral. Os doentes com monitorização cerebral multimodal e pressão de perfusão cerebral ótima foram comparados aos que passaram por tratamento geral. Um bom desfecho foi definido como pontuação de 4 ou 5 na Glasgow outcome scale. Resultados: Dos 389 doentes, 237 foram admitidos na unidade de cuidados neurocríticos e 152 na unidade de cuidados intensivos geral. Doentes com abordagem em unidades de cuidados neurocríticos apresentaram menor risco de um mau desfecho (Odds ratio = 0,228). Um subgrupo de 69 doentes com monitorização cerebral multimodal (G1) foi comparado aos demais doentes (G2). Em G1 e G2, respectivamente, 59% e 23% dos doentes apresentaram bom desfecho na alta da unidade de cuidados intensivos; 64% e 31% apresentaram bom desfecho aos 28 dias; 76% e 50% apresentaram bom desfecho aos 3 meses (p < 0,001); e 77% e 58% apresentaram bom desfecho aos 6 meses (p = 0,005). Quando os desfechos foram ajustados para o escore de gravidade do SAPS II, usando o bom desfecho como variável dependente, os resultados foram os seguintes: para o G1, em comparação ao G2, a odds ratio foi de 4,607 na alta da unidade de cuidados intensivos (p < 0,001), 4,22 aos 28 dias (p = 0,001), 3,250 aos 3 meses (p = 0,001) e 2,529 aos 6 meses (p = 0,006). Os doentes com abordagem da pressão de perfusão cerebral ótima (n = 127) apresentaram melhor desfecho em todos os momentos de avaliação. A mortalidade desses doentes foi significativamente menor aos 28 dias (p = 0,001), aos 3 meses (p < 0,001) e aos 6 meses (p = 0,001). Conclusão: A monitorização cerebral multimodal com autorregulação e abordagem na unidade de cuidados neurocríticos foi associado a melhores desfechos e deve ser levado em consideração após lesão cerebral aguda grave.

Teoría de la Mente en pacientes Traumatizados Craneoencefálico

Antecedentes: Uno de los impedimentos más importantes en los traumatismos craneoencefálicos (TEC), revistan en las dificultades de interacción social, la Teoría de la Mente (ToM) es un factor fundamental de la cognición social, que permite una interacción satisfactoria del sujeto. Objetivo: Observar la capacidad de ToM en pacientes TEC moderado o severo, y su relación con dominios neurocognitivos. Método: Pacientes diagnosticados con TEC moderado o severo, evaluados neuropsicológicamente, edad 16 y 45 años, se aplicaron Test de la Mirada (TdlM) e Historias Extrañas (HT). Resultados: Se encontraron correlaciones entre TdlM y HT con memoria y funciones ejecutivas. Pacientes lesionados izquierdos, rinden significativamenie menos en HT. Conclusiones: Pacientes con TEC moderado o grave tienen una disminución de la capacidad de ToM. Existe una relación entre memoria episódica y ToM, podría deberse a que esta última requiere información a experiencias pasadas. Durante la infancia la ToM depende de la memoria episódica, pero cuando ambas se desarrollan adecuadamente, son independientes. Existe una relación entre funciones ejecutivas y ToM. Ambos constructos están vinculados en la infancia, pero luego comienzan a ser más independientes. Sin embargo, la ToM igualmente va a requerir de las funciones ejecutivas.

Background: One of the most important impediments in traumatic brain injuries (TBI), are the difficulties of social and family interaction. The Theory of Mind (ToM) is a fundamental factor of social cognition, which allows a satisfactory interaction of the individual with his environment. Objetive: To observe the ability of ToM in moderate or severe TBI patients, and its relationship with neurocognitive domains. Methods: Outpatients with diagnosis of moderate or severe TBI, evaluated neuropsychologically, age between 16 and 45 years, were applied Eyes Test (ET) and the Hinting task (HT). Results: Correlations were found between ET and HT with memory and executive functions. Injured left, perform significantly less in HT Patients with moderate or severe TBI have a decrease in ToM capacity. Conclusions: There is a relationship between episodic memory and ToM, which could be due to the latter 's need to request information from past experiences through episodic memory. During childhood ToM depends on episodic memory, but when both are achieved and developed properly, they are independent. There is a relationship between executive functions and ToM. Both constructs are linked in childhood, but then they begin to be more independent. However, ToM tasks will also require executive functions.

Experimental study on high-frequency subharmonic scattering characteristics of ultrasound contrast agent microbubbles under low ambient pressure / 生物医学工程学杂志

Correlation between nonlinear subharmonic scattering of ultrasound contrast agent microbubbles and ambient pressure is expected to be used for local brain tissue pressure monitoring. Although high-frequency ultrasound has achieved high-resolution imaging of intracranial microvessels, the research on high-frequency subharmonic scattering characteristics of microbubbles is insufficient at present, which restricts the research progress of estimating local brain tissue pressure based on high-frequency subharmonic scattering of microbubbles. Therefore, under the excitation of 10 MHz high-frequency ultrasound, the effects of different acoustic pressures and ambient pressures on the high-frequency subharmonic scattering characteristics of three different ultrasound contrast agents including SonoVue, Sonazoid and Huashengxian were investigated in this in vitro study. Results showed that the subharmonic scattering amplitudes of the three microbubbles increased with the increase of ambient pressure at the peak negative acoustic pressures of 696, 766 and 817 kPa, and there was a favorable linear correlation between subharmonic amplitude and ambient pressure. Under the above three acoustic pressures, the highest correlation coefficient of SonoVue was 0.948 ( P = 0.03), the highest sensitivity of pressure measurement was 0.248 dB/mm Hg and the minimum root mean square error (RMSE) was 2.64 mm Hg. Sonazoid's highest correlation coefficient was 0.982 ( P < 0.01), the highest sensitivity of pressure measurement was 0.052 dB/mm Hg and the minimum RMSE was 1.51 mm Hg. The highest correlation coefficient of Huashengxian was 0.969 ( P = 0.02), the highest sensitivity of pressure measurement was 0.098 dB/mm Hg and the minimum RMSE was 2.00 mm Hg. The above in vitro experimental results indicate that by selecting ultrasound contrast agent microbubbles and optimizing acoustic pressure, the correlation between high-frequency subharmonic scattering of microbubbles and ambient pressure can be improved, the sensitivity of pressure measurement can be upgraded, and the measurement error can be reduced to meet the clinical demand for local brain tissue pressure measurement, which provided an important experimental basis for subsequent research in vivo.

Effect of aqueous extract of Corni Fructus on Aβ_(25-35)-induced brain injury and neuroinflammation in mice with Alzheimer's disease / 中国中药杂志

The purpose of this study was to investigate the effect of aqueous extract of Corni Fructus on β-amyloid protein 25-35(Aβ_(25-35))-induced brain injury and neuroinflammation in Alzheimer's disease(AD) mice to provide an experimental basis for the treatment of AD by aqueous extract of Corni Fructus. Sixty C57BL/6J male mice were randomly divided into a sham group, a model group, a positive control group(huperizine A, 0.2 mg·kg~(-1)), a low-dose aqueous extract of Corni Fructus group(1.3 g·kg~(-1)), a medium-dose aqueous extract of Corni Fructus group(2.6 g·kg~(-1)), and a high-dose aqueous extract of Corni Fructus group(5.2 g·kg~(-1)). The AD model was induced by lateral ventricular injection of Aβ_(25-35) in mice except for those in the sham group, and AD model mice were treated with corresponding drugs by gavage for 24 days. The behavioral test was performed one week before animal dissection. Hematoxylin-eosin(HE) staining was performed to observe the morphology of neurons in the hippocampal region. Flow cytometry was used to detect the apoptosis level of primary hippocampal cells in mice. ELISA kits were used to detect the levels of β-amyloid protein 1-42(Aβ_(1-42)) and phosphorylated microtubule-associated protein Tau(p-Tau) in mouse brain tissues. Immunofluorescence and Western blot were used to detect the expression of related proteins in mouse brain tissues. MTT assay was used to detect the effect of compounds in aqueous extract of Corni Fructus on Aβ_(25-35)-induced N9 cell injury. Molecular docking was employed to analyze the interactions of caffeic acid, trans-p-hydroxy cinnamic acid, isolariciresinol-9'-O-β-D-glucopyranoside, esculetin, and(+)-lyoniresinol with β-amyloid precursor protein(APP), interleukin-6(IL-6), and tumor necrosis factor-α(TNF-α). Aqueous extract of Corni Fructus could improve the learning and memory abilities of Aβ_(25-35)-induced mice by increasing the duration of the autonomous activity, the rate of autonomous alternation, the preference coefficient, and the discrimination coefficient, and reduce Aβ_(25-35)-induced brain injury and neuroinflammation in mice by increasing the expression levels of interleukin-10(IL-10) and B-cell lymphoma-2(Bcl-2) in brain tissues, decreasing the expression levels of Aβ_(1-42), p-Tau, IL-6, TNF-α, cysteine aspartate-specific protease 3(caspase-3), cysteine aspartate-specific protease 9(caspase-9), and Bcl-2-associated X protein(Bax), and decreasing the number of activated glial cells in brain tissues. The results of cell experiments showed that esculetin and(+)-lyoniresinol could improve Aβ_(25-35)-induced N9 cell injury. Molecular docking results showed that caffeic acid, trans-p-hydroxy cinnamic acid, isolariciresinol-9'-O-β-D-glucopyranoside, esculetin, and(+)-lyoniresinol had good binding affinity with APP and weak binding affinity with IL-6 and TNF-α. Aqueous extract of Corni Fructus could ameliorate cognitive dysfunction and brain damage in Aβ_(25-35)-induced mice by reducing the number of apoptotic cells and activated glial cells in the brain and decreasing the expression level of inflammatory factors. Caffeic acid, trans-p-hydroxy cinnamic acid, isolariciresinol-9'-O-β-D-glucopyranoside, esculetin, and(+)-lyoniresinol may be the material basis for the anti-AD effect of aqueous extract of Corni Fructus.

Long-term impact of mild traumatic brain injury on oculomotor parameters / 国际眼科杂志(Guoji Yanke Zazhi)

AIM: To evaluate the long-term impact of mild traumatic brain injury(mTBI)on oculomotor parameters.METHODS: Prospective study. A total of 46 patients from 6 to 12mo after mTBI who visited Tianjin Eye Hospital from February to August 2021 were collected. According to the score of the Brain Injury Vision Sympton Survey(BIVSS)Questionnaire, they were divided into the symptomatic group of mTBI(BIVSS total score ≥32, n=24)and the asymptomatic group of mTBI(BIVSS total score &#x0026;#x003C;32, n=22). In addition, healthy people without mTBI were selected as the control group(n=23). All of the subjects accepted test of oculomotor parameters to evaluate binocular vision.RESULTS: Monocular accommodation amplitude, monocular accommodation facility, the absolute value of phoria at near, BI recovery point of fusional range at near and saccades were different among the three groups(P&#x0026;#x003C;0.05); There were no significant differences in near point of convergence, the absolute value of distance phoria, BI blur, BO blur and recovery of fusional range at near among the three groups(P&#x0026;#x003E;0.05). The incidence of accommodative abnormality, convergence abnormality, and saccadic dysfunction were different among the three groups(P&#x0026;#x003C;0.01). The incidence of accommodative abnormality in the symptomatic group was significantly higher than that in the asymptomatic and control groups(all P&#x0026;#x003C;0.0167); the incidence of convergence dysfunction in the symptomatic and the asymptomatic groups were higher than that in the control group(all P&#x0026;#x003C;0.0167); the incidence of saccadic dysfunction in the symptomatic group was significantly higher than that in the asymptomatic and control groups(all P&#x0026;#x003C;0.0167).CONCLUSION: Accommodation, convergence, and saccades functions in the mTBI symptomatic group were lower, and some of the binocular vision in the asymptomatic group was also affected. It is suggested that mTBI has a long-term impact on oculomotor parameters, and comprehensive oculomotor assessment is necessary for mTBI patients.

Feature Deconstruction Strategy Based Identification of Acute Features Associated With Impairment of Activities of Daily Living in Patients With Traumatic Brain Injury / 中山大学学报(医学科学版)

ObjectiveTo identify acute phase features associated with the prognosis of traumatic brain injury （TBI）. MethodsThrough two traditional strategies， correlation analysis and prediction model， and one innovative research strategy based on feature deconstruction， a retrospective analysis was conducted using demographic， acute phase and chronic phase features of 354 TBI patients to identify acute phase features associated with activities of daily living （ADL） in chronic phase of TBI. For feature deconstruction strategy， the LASSO （Least Absolute Shrinkage and Selection Operator） algorithm was used to build a prediction model that could effectively predict ADL based on non-ADL chronic phase features. The model could indicate the key chronic phase dimensions determining the ADL in TBI patients. We then identified demographic and acute phase variables that were significantly associated with these key chronic phase features. ResultsThe feature deconstruction strategy revealed that ADL could be deconstructed into chronic phase dimensions such as weak limbs in TBI population. Importantly， to the best of our knowledge， this strategy revealed for the first time the association of these important acute phase features with specific chronic phase impairment features. For example， TBI patients had a higher risk for chronic phase recent memory impairment if they had a prolonged coma time and low GCS scores at acute phase ［scaled coma time OR95%CI = 94.288 （35.095， 273.231）； scaled GCS OR95%CI = 0.068 （0.030， 0.147）］； the patients had a higher risk for insight impairment and disorientation at chronic phase if they had hydrocephalus at acute phase ［insight impairment OR95%CI = 6.760 （3.653，12.855） ； disorientation OR95%CI = 6.538 （3.530， 12.490）］. All strategies showed that the strongest risk factors for ADL damage in the chronic phase included prolonged coma time and low GCS scores as well as hydrocephalus. ConclusionThis study provides an innovative research strategy to establish the association between acute injury features and chronic recovery features， and to identify demographic and acute phase features associated with the prognosis of TBI.

Research Progress of Radiation-induced Brain Injury for Nasopharyngeal Carcinoma / 肿瘤防治研究

Radiation-induced brain injury (RBI) is a common long-term complication of radiotherapy for nasopharyngeal carcinoma (NPC) and seriously affects the quality of life and overall survival of patients. In the era of intensity-modulated radiation therapy (IMRT), the long-term complications after radiotherapy, especially RBI, are becoming increasingly concerning because a number of treated patients with NPC obtain long-term survival. At present, the understanding of RBI is still being explored, and its pathogenesis and treatment methods are continuously updated. This article reviews the research progress of RBI in patients with NPC.

Effects of scutellarin on neuroinflammation in rats with traumatic brain injury by regulating cGAS/STING signaling pathway / 中国药房

OBJECTIVE To investigate the improvement effects and mechanism of scutellarin （Scu） on neuroinflammation in rats with traumatic brain injury （TBI）. METHODS The modified Feeney method was applied to construct TBI rat model. The rats were randomly grouped into TBI group，Scu low-dose group （40 mg/kg），Scu high-dose group （80 mg/kg），cyclic guanylate- adenylate synthase （cGAS） inhibitor group （cGAS inhibitor RU.521，450 μg/kg），with 24 rats in each group. Other 24 rats were included in the sham operation group. The modified neurological deficit score （mNSS） method was applied to assess the neurological function of rats； the brain water content of rats was measured by dry/wet specific gravity method； hematoxylin-eosin and TdT-mediated dUTP nick-end labeling staining were applied to observe the pathological changes and apoptosis of brain tissue in rats； the levels of interferon-β （IFN-β），CXC chemokine ligand-10 （CXCL10），tumor necrosis factor-α （TNF-α） and interleukin-6 （IL-6） in rat brain tissue were detected by enzyme-linked immunosorbent assay； Western blot method was applied to detect the expression of cGAS/interferon gene stimulating protein （STING） signal pathway-related proteins in brain tissue of rats. RESULTS Compared with the sham operation group，the mNSS，brain water content，apoptosis rate，the contents of IFN-β，CXCL10，TNF-α and IL-6，and the relative expressions of cGAS and STING proteins in TBI group increased significantly （P＜0.05）； there were edema，bleeding and pathological damage to neurons in the brain tissue. Compared with TBI group，the above indicators and pathological changes of rats in administration groups were improved significantly （P＜0.05），and the effect of Scu was in a dose- dependent manner （P＜0.05）； however，there was no statistically obvious difference in the above indicators between the Scu high- dose group and the cGAS inhibitor group （P＞0.05）. CONCLUSIONS Scu may alleviate neuroinflammation，reduce brain tissue damage and apoptosis，and promote the recovery of neural function in TBI rats by inhibiting the activation of cGAS/STING signaling pathway.

Electroacupuncture in Treatment of Acute Gastrointestinal Injury in Patients with Severe Traumatic Brain Injury: A Multicenter Randomized Controlled Trial / 中国结合医学杂志

OBJECTIVE@#To evaluate whether electroacupuncture (EA) would improve gastrointestinal function and clinical prognosis in patients with severe traumatic brain injury (TBI) complicocted by acute gastrointestinal injury (AGI).@*METHODS@#This multicenter, single-blind trial included patients with TBI and AGI admitted to 5 Chinese hospitals from September 2018 to December 2019. A total of 500 patients were randomized to the control or acupuncture groups using a random number table, 250 cases in each group. Patients in the control group received conventional treatment, including mannitol, nutritional support, epilepsy and infection prevention, and maintenance of water, electrolytes, and acid-base balance. While patients in the acupuncture group received EA intervention at bilateral Zusanli (ST 36), Shangjuxu (ST 37), Xiajuxu (ST 39), Tianshu (ST 25), and Zhongwan (RN 12) acupoints in addition to the conventional treatment, 30 min per time, twice daily, for 7 d. The primary endpoint was 28-d mortality. The secondary endpoints were serum levels of D-lactic acid (D-lac), diamine oxidase (DAO), lipopolysaccharide (LPS), motilin (MTL) and gastrin (GAS), intra-abdominal pressure (IAP), bowel sounds, abdominal circumference, AGI grade, scores of gastrointestinal failure (GIF), Glasgow Coma Scale (GCS), Acute Physiology and Chronic Health Evaluation (APACHE II), Sequential Organ Failure Assessment (SOFA), and Multiple Organ Dysfunction Syndrome (MODS), mechanical ventilation time, intense care unit (ICU) stay, and the incidence of hospital-acquired pneumonia.@*RESULTS@#The 28-d mortality in the acupuncture group was lower than that in the control group (22.80% vs. 33.20%, P<0.05). Compared with the control group, the acupuncture group at 7 d showed lower GIF, APACHE II, SOFA, MODS scores, D-lac, DAO, LPS, IAP, and abdominal circumference and higher GCS score, MTL, GAS, and bowel sound frequency (all P<0.05). In addition, the above indices showed simillar changes at 7 d compared with days 1 and 3 (all P<0.05) in the EA group.@*CONCLUSION@#Early EA can improve gastrointestinal function and clinical prognosis in patients with severe TBI complicated by AGI. (Registration No. ChiCTR2000032276).

Xingnao Kaiqiao acupuncture on promoting wake-up of consciousness disorder in children with early severe traumatic brain injury / 中国针灸

OBJECTIVE@#To observe the awakening effect and safety of Xingnao Kaiqiao (regaining consciousness and opening orifices) acupuncture on consciousness disorder in children with early severe traumatic brain injury (STBI) based on western medicine treatment.@*METHODS@#A total of 62 children with STBI were randomly divided into an observation group (31 cases,1 case dropped off) and a control group (31 cases, 1 case dropped off). The control group was treated with routine rehabilitation therapy (6 times a week for 30 days), and intravenous drip of cattle encephalon glycoside and ignotin injection (once a day for 28 days). On the basis of the treatment in the control group, the observation group was treated with Xingnao Kaiqiao acupuncture at Neiguan (PC 6), Shuigou (GV 26), Yintang (GV 24+), Baihui (GV 20), Sanyinjiao (SP 6), Zusanli (ST 36), etc., and supplementary acupoints according to clinical symptoms, once a day, 6 times a week for 30 days. The scores of Glasgow coma scale (GCS), coma recovery scale-revised (CRS-R) and modified Barthel index (MBI) were observed before treatment and 10, 20 and 30 d into treatment. Electroencephalogram (EEG) grading before and after treatment was observed in the two groups, and safety was evaluated.@*RESULTS@#After 10, 20 and 30 days of treatment, the scores of GCS, CRS-R and MBI in the two groups were increased compared before treatment (P<0.05), and those in the observation group were higher than the control group (P<0.05). After treatment, EEG grading of both groups was improved compared with that before treatment (P<0.05), and the observation group was better than the control group (P<0.05). There were no adverse events or adverse reactions in the two groups during treatment.@*CONCLUSION@#On the basis of western medicine treatment, Xingnao Kaiqiao acupuncture plays a remarkable role in wakening the early STBI children, can improve the level of consciousness disorder and daily living ability, and it is safe and effective.

Effects of astaxanthin on oxidative stress and inflammatory reaction in rats with traumatic brain injury based on Nrf2/HO-1 signaling pathway / 中国药房

OBJECTIVE To investigate the effects of astaxanthin on oxidative stress and inflammatory reaction in rats with traumatic brain injury （TBI）. METHODS Male SD rats were randomly divided into sham operation group， model group， astaxanthin low-dose group （20 mg/kg）， astaxanthin high-dose group （40 mg/kg）， astaxanthin+ML385 group [astaxanthin 40 mg/kg+ nuclear factor-erythroid 2-related factor 2 （Nrf2） inhibitor ML385 30 mg/kg]， with 14 rats in each group. Except for the sham operation group， TBI model was induced by the modified Feeney free-fall impact method in other groups. The rats in each drug group were given the corresponding drug intragastrically or intraperitoneally， and the rats in the sham operation group and model group were intragastrically given a constant volume of normal saline. The neurological function of rats in each group was scored on the 1st， 3rd and 7th day after drug intervention； on the 7th day of drug intervention， the changes of cerebral histomorphology and inflammatory infiltration score were observed in each group， and the ultrastructure of nerve cells in brain tissue was also observed. The contents of oxidative stress indexes [superoxide dismutase （SOD）， catalase （CAT）， glutathione peroxidase （GSH-Px）， malondialdehyde （MDA）， nitric oxide （NO）] and inflammatory reaction indexes [tumor necrosis factor-α， interleukin-1β （IL-1β）， IL-6， inducible nitric oxide synthase] as well as protein and mRNA expressions of Nrf2， heme oxygenase-1 （HO-1） and NAD（P）H： quinone oxidoreductase 1 （NQO1） were detected in cerebral tissue. RESULTS Compared with the sham operation group， the brain edema of rats in the model group was obvious， accompanied by a large number of inflammatory cells infiltrated， the shape of organelles was damaged and their number was reduced， and the ultrastructure of nerve cells was seriously damaged. The neurological function score， the contents of SOD， CAT， GSH-Px and NO and the relative expression levels of Nrf2， HO-1 and NQO1 protein and mRNA in brain tissue were significantly decreased， while the inflammatory infiltration scores， the contents of MDA and inflammatory reaction indexes were significantly increased （P＜0.05）. Compared with the model group， low-dose and high-dose astaxanthin could significantly improve the pathological status of brain tissue and nerve cells and neurological function scores （except for the first day of drug intervention in the astaxanthin low-dose group）， increase the contents of SOD， CAT， GSH-Px and NO and the relative expression levels of Nrf2， HO-1， NQO1 protein and mRNA in brain tissue in a dose-dependent manner， and reduce inflammatory infiltration scores， the contents of MDA and inflammatory reaction indexes （P＜0.05）. ML385 could significantly inhibit the above effects of astaxanthin （P＜0.05）. CONCLUSIONS Astaxanthin may reduce the oxidative stress of TBI model rats， alleviate the neurological damage and reduce the level of inflammation reaction by activating the Nrf2/HO-1 signaling pathway.