Astragaloside IV alleviates stroke-triggered early brain injury by modulating neuroinflammation and ferroptosis via the Nrf2/HO-1 signaling pathway

Purpose: Stroke is an acute cerebrovascular disease. Astragaloside IV (AS-IV) is an active ingredient extracted from Astragalus membranaceus with an established therapeutic effect on central nervous system diseases. This study examined the neuroprotective properties and possible mechanisms of AS-IV in stroke-triggered early brain injury (EBI) in a rat transient middle cerebral artery occlusion (MCAO) model. Methods: The neurological scores and brain water content were analyzed. 2,3,5-triphenyl tetrazolium chloride (TTC) staining was utilized to determine the infarct volume, neuroinflammatory cytokine levels, and ferroptosis-related genes and proteins, and neuronal damage and molecular mechanisms were evaluated by terminal deoxynucleotidyl transferase dutp nickend labeling (TUNEL) staining, western blotting, and real-time polymerase chain reaction. Results: AS-IV administration decreased the infarct volume, brain edema, neurological deficits, and inflammatory cytokines TNF-α, interleukin-1ß (IL-1ß), IL-6, and NF-κB, increased the levels of SLC7A11 and glutathione peroxidase 4 (GPX4), decreased lipid reactive oxygen species (ROS) levels, and prevented neuronal ferroptosis. Meanwhile, AS-IV triggered the Nrf2/HO-1 signaling pathway and alleviated ferroptosis due to the induction of stroke. Conclusion: Hence, the findings of this research illustrate that AS-IV administration can improve delayed ischemic neurological deficits and decrease neuronal death by modulating nuroinflammation and ferroptosis via the Nrf2/HO-1 signaling pathway.

Ulinastatin alleviates early brain injury after traumatic brain injury by inhibiting oxidative stress and apoptosis

Purpose: Traumatic brain injury (TBI) remains a major public health problem and cause of death. Ulinastatin (UTI), a serine protease inhibitor, has been reported to have an anti-inflammatory effect and play a role in immunoregulation and organ protection by reducing reactive oxygen species (ROS) production, oxidative stress and inflammation. However, the neuroprotective of UTI in TBI has not been confirmed. Therefore, this study aimed to investigate the neuroprotection and potential molecular mechanisms of UTI in TBI-induced EBI in a C57BL/6 mouse model. Methods: The neurological score and brain water content were evaluated. Enzyme-linked immunosorbent assay was used to detect neuroinflammatory cytokine levels, ROS and malondialdehyde detection to evaluate oxidative stress levels, and TUNEL staining and western blotting to examine neuronal damages and their related mechanisms. Results: Treatment with UTI markedly increased the neurological score; alleviated brain oedema; decreased the inflammatory cytokine tumour necrosis factor a, interleukin-1ß (IL-1ß), IL-6 and nuclear factor kappa B (NF-kB) levels; inhibited oxidative stress; decreased caspase-3 and Bax protein expressions; and increased the Bcl-2 levels, indicating that UTI-mediated inhibition of neuroinflammation, oxidative stress and apoptosis ameliorated neuronal death after TBI. The neuroprotective capacity of UTI is partly dependent on the TLR4/NF-kB/p65 signalling pathway. Conclusions: Therefore, this study reveals that UTI improves neurological outcomes in mice and reduces neuronal death by protecting against neural neuroinflammation, oxidative stress and apoptosis.

Healing of brain lesions in sheep recovered from amprolium-induced polioencephalomalacia / Cicatrização das lesões cerebrais em ovinos recuperados de polioencefalomalacia induzida por amprólio

To evaluate the outcome of acute lesions in the brains of sheep that completely clinically recover from acute polioencephalomalacia (PEM), ten sheep were used in this experiment. Eight of those sheep received varying doses of amprolium to induce PEM. Four sheep were treated intramuscularly with 40mg/kg/body weight with thiamine to allow recovery and four sheep were left untreated. Two control sheep did not receive either amprolium or thiamine and were kept along with the other eight sheep for the duration of the experiment. Except for the two drugs, the diet and water source were the same for the ten sheep. Two sheep receiving high daily doses of amprolium and one sheep receiving a lower dose had acute deaths and developed acute brain lesions consisting of neuronal laminar cortical necrosis (red neurons), edema, reactive astrocytes, swollen endothelial cells and gitter cells infiltration. Four sheep that recovered from lower doses of amprolium-induced PEM after being treated with thiamine and another one that recovered spontaneously were euthanatized six months after clinical recovery and had gross changes consisting of segmental absence of cortical tissue. Histologically these segmental cortex-deprived areas corresponded to quasi-empty spaces where only vessels and gitter cells existed. No changes were seen in the brains of the two control sheep.(AU)

Para avaliar a evolução das lesões agudas no cérebro de ovinos que se recuperam clinicamente de polioencefalomalacia aguda (PEM), dez ovinos foram usados neste experimento. Oito desses ovinos receberam doses variáveis de amprólio para induzir PEM. Quatro ovinos foram tratados intramuscularmente com 40mg/kg/peso corporal de tiamina para permitir a recuperação, e outros quatro ficaram sem tratamento. Dois ovinos controles não receberam amprólio nem tiamina e foram mantidos com os outros oito ovinos durante a duração do experimento. Exceto pelas duas drogas, a dieta e a fonte de água eram as mesmas para os dez ovinos. Dois ovinos que receberam doses diárias altas de amprólio, e um que recebeu doses menores, tiveram mortes agudas e desenvolveram lesões cerebrais constituídas por necrose neuronal laminar cortical (neurônios vermelhos), edema, tumefação de células endoteliais, astrócitos reativos, tumefação de células endoteliais e infiltração por células gitter. Quatro ovinos que se recuperam da PEM induzida por amprólio, após tratamento com tiamina, e outro que se recuperou espontaneamente, permaneceram clinicamente normais e foram submetidos a eutanásia seis meses após a recuperação clínica. Na necropsia, apresentavam alterações macroscópicas caracterizadas por ausência segmentar de tecido corticocerebral. Histologicamente, essas áreas privadas de tecido cortical consistiam de espaços praticamente vazios onde apenas vasos e células gitter eram vistos. Não foram encontradas alterações no encéfalo das duas ovelhas controle.(AU)

Cardiovascular Effects of Shock and Trauma in Experimental Models. A Review

Abstract Experimental models of human pathology are useful guides to new approaches towards improving clinical and surgical treatments. A systematic search through PubMed using the syntax (shock) AND (trauma) AND (animal model) AND (cardiovascular) AND ("2010/01/01"[PDat]: "2015/12/31"[PDat]) found 88 articles, which were reduced by manual inspection to 43 entries. These were divided into themes and each theme is subsequently narrated and discussed conjointly. Taken together, these articles indicate that valuable information has been developed over the past 5 years concerning endothelial stability, mesenteric lymph, vascular reactivity, traumatic injuries, burn and sepsis. A surviving interest in hypertonic saline resuscitation still exists.

The role of necroptosis in neurosurgical diseases

Programmed necrosis or necroptosis is an alternative form of cell death that is executed through a caspase-independent pathway. Necroptosis has been implicated in many pathological conditions. Genetic or pharmacological inhibition of necroptotic signaling has been shown to confer neuroprotection after traumatic and ischemic brain injury. Therefore, the necroptotic pathway represents a potential target for neurological diseases that are managed by neurosurgeons. In this review, we summarize recent advances in the understanding of necroptotic signaling pathways and explore the role of necroptotic cell death in craniocerebral trauma, brain tumors, and cerebrovascular diseases.

Factors associated with providing social security benefits for traumatic brain injury resulting from occupational accidents / Fatores associados à concessão de benefício previdenciário por traumatismo cranioencefálico decorrente de acidente de trabalho

INTRODUCTION: The Occupational Accident (OA) is considered to be an important public health problem in Brazil. Traumatic Brain Injury (TBI) is the most common among them. The TBI is associated with high morbidity and mortality rates among workers. OBJECTIVE: To identify factors associated with providing social security benefits for TBI due to occupational accidents according to the specific type of economic activity in Brazil, in 2009. METHODS: This is a cross-sectional study that was conducted with all workers who were part of the General Regime of Social Security (RGPS) of Brazil. Secondary data were obtained from the National Information System Benefit, from the Synchronized National Register of the Ministry of Finance and from the General Register of Employed and Unemployed Persons. Data were analyzed using the multiple logistic regression method. RESULTS: We analyzed 2,006 cases of social security benefits for traumatic brain injury due to Occupational Accident. Factors associated with the concession of the benefit according to the economic activity of the Company of the beneficiary were identified. Associations were found with sex, income and the region of the Company. CONCLUSION: Factors associated with the concession of social security benefits by TBI resulting from OA differ depending on the type of economic activity in the study. Understanding these factors may contribute to the planning of preventive policies. .

INTRODUÇÃO: O Acidente de Trabalho (AT) é considerado um importante agravo à saúde do trabalhador no Brasil, sendo o Traumatismo Cranioencefálico (TCE) o mais comum dentre eles. O TCE está associado a altas taxas de morbidade e mortalidade entre trabalhadores. OBJETIVO: Verificar os fatores associados à concessão de benefícios previdenciários por TCE decorrentes de acidente de trabalho de acordo com o ramo de atividade econômica específica, no Brasil, em 2009. MÉTODOS: Trata-se de estudo epidemiológico de corte transversal que foi conduzido com todos os trabalhadores que integram o Regime Geral da Previdência Social (RGPS) do Brasil. Dados secundários foram obtidos do Sistema Único de Informações de Benefícios, do Cadastro Sincronizado Nacional do Ministério da Fazenda e do Cadastro Geral de Empregados e Desempregados e analisados utilizando-se regressão logística múltipla. RESULTADOS: Foram analisados 2.006 casos de benefícios previdenciários por TCE decorrentes de AT no Brasil, e identificaram-se fatores associados à concessão do benefício diferenciados de acordo com a seção da Classificação Nacional de Atividades Econômicas à qual o beneficiário estava vinculado. Foram encontradas associações com o sexo, a renda e a região da empresa. CONCLUSÃO: Os fatores associados à concessão de benefícios previdenciários por TCE decorrentes de AT diferem a depender da CNAE em estudo. A compreensão desses fatores poderá contribuir com o planejamento de políticas públicas de caráter preventivo. .

Associacao entre o indice de respiracao rapida e superficial e o sucesso da extubacao em pacientes com traumatismo cranioencefalico / Association between the rapid shallow breathing index and extubation success in patients with traumatic brain injury

OBJETIVO: Verificar a associação entre o índice de respiração rápida e superficial e o sucesso da extubação em pacientes com traumatismo cranioencefálico. MÉTODOS: Estudo prospectivo, formado por pacientes com traumatismo cranioencefálico, de ambos os gêneros, ventilados mecanicamente por pelo menos 2 dias, que obtiveram sucesso no teste de respiração espontânea. Foram mensurados, por meio da ventilometria, o volume-minuto e a frequência respiratória, sendo calculado o índice de respiração rápida e superficial (frequência respiratória/volume corrente). A variável dependente foi o resultado da extubação: reintubação em 48 horas (falha da extubação) ou não (sucesso da extubação). A variável independente foi o índice de respiração rápida e superficial mensurado após o sucesso no teste de respiração espontânea. RESULTADOS: A amostra foi constituída por 119 pacientes, sendo 111 (93,3%) do gênero masculino. A média da idade foi de 35,0±12,9 anos. O tempo médio de ventilação mecânica foi de 8,1±3,6 dias. Cento e quatro (87,4%) pacientes obtiveram sucesso na extubação. Não foi observada associação entre o índice de respiração rápida e superficial e o sucesso da extubação. CONCLUSÃO: O índice de respiração rápida e superficial não esteve associado ao sucesso da extubação em pacientes com traumatismo cranioencefálico. .

OBJECTIVE: To investigate the association between the rapid shallow breathing index and successful extubation in patients with traumatic brain injury. METHODS: This study was a prospective study conducted in patients with traumatic brain injury of both genders who underwent mechanical ventilation for at least two days and who passed a spontaneous breathing trial. The minute volume and respiratory rate were measured using a ventilometer, and the data were used to calculate the rapid shallow breathing index (respiratory rate/tidal volume). The dependent variable was the extubation outcome: reintubation after up to 48 hours (extubation failure) or not (extubation success). The independent variable was the rapid shallow breathing index measured after a successful spontaneous breathing trial. RESULTS: The sample comprised 119 individuals, including 111 (93.3%) males. The average age of the sample was 35.0±12.9 years old. The average duration of mechanical ventilation was 8.1±3.6 days. A total of 104 (87.4%) participants achieved successful extubation. No association was found between the rapid shallow breathing index and extubation success. CONCLUSION: The rapid shallow breathing index was not associated with successful extubation in patients with traumatic brain injury. .

ROC trials update on prehospital hypertonic saline resuscitation in the aftermath of the US-Canadian trials

The objectives of this review are to assess the current state of hypertonic saline as a prehospital resuscitation fluid in hypotensive trauma patients, particularly after the 3 major Resuscitation Outcomes Consortium trauma trials in the US and Canada were halted due to futility. Hemorrhage and traumatic brain injury are the leading causes of death in both military and civilian populations. Prehospital fluid resuscitation remains controversial in civilian trauma, but small-volume resuscitation with hypertonic fluids is of utility in military scenarios with prolonged or delayed evacuation times. A large body of pre-clinical and clinical literature has accumulated over the past 30 years on the hemodynamic and, most recently, the anti-inflammatory properties of hypertonic saline, alone or with dextran-70. This review assesses the current state of hypertonic fluid resuscitation in the aftermath of the failed Resuscitation Outcomes Consortium trials.

Analysis of cranio-cerebral injuries by blunt force.

Despite current advances in public education and in automobile safety requirements, cranio-cerebral injuries continues to be a major cause of morbidity and mortality and accounts for significant portion of health care costs today. Trauma respects neither geography nor body systems. Consequently head injury occurs every 15 seconds and a patient dies from a head injury every 12 minutes, a day doesn’t pass that an emergency department physician is not confronted with a head injured patient. The present work is based on the observation and study made on 117 cases collected. These cases include 39 cases who died before being admitted to any hospital and were sent directly by the police to postmortem, Mysore Medical College, Mysore, and 78 cases that died in the hospital under medical care. Clinical data are available for 78 cases that died in the hospital after undergoing some treatment. An attempt is made in these cases to correlate clinical findings with the autopsy findings.

Selective therapeutic hypothermia: A review of invasive and noninvasive techniques / Hipotermia terapêutica seletiva: uma revisão de técnicas invasivas e não invasivas

OBJECTIVE: Therapeutic hypothermia is a promising treatment to prevent secondary neurologic injury. Clinical utility is limited by systemic complications of global hypothermia. Selective brain cooling remains a largely uninvestigated application. We review techniques of inducing selective brain cooling. METHOD: Literature review. RESULTS: Strategies of inducing selective brain cooling were divided between non-invasive and invasive techniques. Non-invasive techniques were surface cooling and cooling via the upper airway. Invasive cooling methods include transvascular and compartmental (epidural, subdural, subarachnoid and intraventricular) cooling methods to remove heat from the brain. CONCLUSION: Selective brain cooling may offer the best strategy for achieving hypothermic neuroprotection. Non-invasive strategies have proven disappointing in human trials. There is a paucity of human experiments using invasive methods of selective brain cooling. Further application of invasive cooling strategies is needed.

OBJETIVO: A hipotermia terapêutica é uma estratégia promissora para prevenção do dano neurológico secundário. Sua utilidade clínica é limitada por complicações sistêmicas da hipotermia global. Resfriamento cerebral seletivo (RCS), entretanto, permanece uma técnica pouco estudada. Revisamos aqui as diferentes técnicas de indução de RCS. MÉTODO: Revisão de literatura. RESULTADOS: As estratégias de indução de RCS foram divididas em invasivas e não-invasivas. Métodos de remoção de calor do cérebro não-invasivos incluem o resfriamento de superfície e o de vias aéreas superiores; as técnicas invasivas incluem resfriamento transvascular e compartimental (epidural, subdural, subaracnóideo e intraventricular). CONCLUSÃO: RCS pode oferecer a melhor estratégia para alcançar neuroproteção hipotérmica. Estratégias não-invasivas têm se mostrado ineficazes em estudos clínicos. Técnicas invasivas foram raramente estudadas em humanos e necessitam ser mais investigadas para tornarem-se úteis.

Functional electrical stimulation improves brain perfusion in cranial trauma patients / A terapia com estímulo elétrico funcional pode melhorar a perfusão cerebral no SPECT em pacientes com trauma craniano

OBJECTIVE: Demonstrate brain perfusion changes due to neuronal activation after functional electrical stimulation (FES). METHOD: It was studied 14 patients with hemiplegia who were submitted to a program with FES during fourteen weeks. Brain perfusion SPECT was performed before and after FES therapy. These patients were further separated into 2 groups according to the hemiplegia cause: cranial trauma and major vascular insults. All SPECT images were analyzed using SPM. RESULTS: There was a significant statistical difference between the two groups related to patient's ages and extent of hypoperfusion in the SPECT. Patients with cranial trauma had a reduction in the hypoperfused area and patients with major vascular insult had an increase in the hypoperfused area after FES therapy. CONCLUSION: FES therapy can result in brain perfusion improvement in patients with brain lesions due to cranial trauma but probably not in patients with major vascular insults with large infarct area.

OBJETIVO: Demonstrar mudanças na perfusão cerebral devido à ativação neuronal depois de estimulação elétrica funcional (EEF). MÉTODO: Foram estudados 14 pacientes com hemiplegia submetidos a quatorze semanas de um programa com EEF. O SPECT de perfusão cerebral foi realizado antes e depois da terapia com EEF. Estes pacientes foram separados em 2 grupos com relação à causa da hemiplegia: trauma craniano e acidente vascular cerebral (AVC). As imagens de SPECT foram analisadas usando SPM. RESULTADOS: Houve diferença estatisticamente significativa entre os dois grupos relacionada a idade dos pacientes e extensão da hipoperfusão. Os pacientes com trauma craniano tiveram redução na área de hipoperfusão e pacientes com AVC tiveram aumento na área de hipoperfusão após terapia com EEF. CONCLUSÃO: A terapia com EEF pode levar a melhora na perfusão cerebral em pacientes com lesões cerebrais secundárias a trauma craniano; entretanto, provavelmente não em pacientes com extensas áreas de infarto secundárias a AVC.

Ventilación mecánica en el paciente con lesión cerebral aguda / Mechanical ventilation in patients with acute brain injury

In about20 percent of patients admitted to an Intensive Care Unit (ICU) the indica-tion of mechanical ventilation (MV) is a neurological disease. These patients have a prolonged MV stay and high mortality. The appropriate use of MV in patients with acute brain injury (ABI) is critica! considering that MV by itself is oble to induce or worsen an underlying lung injury. Patients with ABI have a higher risk to develop pulmonary complications. During endotracheal intubation the activation of airway reflexes should beprevented, because they may increase intracranialpressure. Tracheostomy is indicated to improve airway management and it is performed in about 33 percent of these patients. Indications for MV are loss of spontaneous respira-tory effort, changes in lung compliance, gas exchange impairment and ventilatory failure due to muscle fatigue or neuromuscular junction dysfunction. During MV, hypoxemia should be avoided. The pC0(2) level has a critica! role in cerebral blood flow regulation; therefore a normal pCO must be maintained in order to guarantee an optimal cerebral blood flow. Despite that, hypocapnia has been used in patients with increased intracranial pressure, at the present it is not recommended. Its use should be limited to the emergency management of intracranial hypertension, while the underlying cause is beingtreated. Non-conventional ventilatory modes asprone position ventilation, high-frequency oscillatory ventilation and extracorporeal C02 removal can be used in patients with ABI. All ofthem have specific risks and should be employed cautiously This paper reviews upper airway management and MV in patients with acute brain injury.

Selective hypothermia: an experimental study on traumatic brain injury in rats / Hipotermia seletiva: estudo experimental de traumatismo crânio-encefálico em ratos

OBJECTIVE: To evaluate the efficiency of selective hypothermia in the treatment of the traumatic brain injury in rats. METHOD: After the trauma produced for the model of cortical impact, a small craniectomy in the right frontoparietal region was carried through; after the procedure the animals had been divided in two groups of 15 each. Group A, without treatment with hypothermia (control group) and group B, treated with selective hypothermia for a period to 5 to 6 hours. After this time all the animals were sacrificed, their brains had been removed and histopathological analysis was carried through. RESULTS: Comparison between both groups was done using the counting of neurons injured for field. Counting in the control group n=15 had an average of 70.80 neurons injured for field against an average of 21.33 neurons injured for field in group B (submitted to the treatment with hypothermia), with n=15 also. The difference was statiscally significant. CONCLUSION: Based in the quantification of the neurons injured for field, the effectiveness of the treatment with selective hypothermia was demonstrated.

OBJETIVO: Avaliar a eficiência da hipotermia seletiva no tratamento do traumatismo crânio-encefálico (TCe) em ratos. o trauma foi produzido por um modelo de impacto cortical desenvolvido exclusivamente para o estudo. MÉTODO: Após o TCE produzido pelo modelo de impacto cortical, foi realizada pequena craniectomia na região fronto-parietal direita; após o procedimento os animais foram divididos em dois grupos de 15 cada um. o grupo A, sem tratamento com hipotermia (grupo controle) e grupo B, tratado com hipotermia seletiva por período de 5 a 6 horas. depois deste tempo todos os animais foram sacrificados, seus encéfalos foram removidos e realizada a análise anatomopatológica. RESULTADOS: Na comparação entre o grupo tratado com hipotermia e o grupo controle utilizou-se a contagem de neurônios lesados por campo. Tal contagem no grupo A (controle/sem tratamento) com n=15 teve media de 70,80 neurônios lesados por campo contra a media de 21,33 nerônios lesados por campo no grupo B (submetido ao tratamento com hipotermia), com n=15 também. diferença estatísticamente significativa pôde ser demonstrada. CONCLUSÃO: A análise anatomopatológica dos encéfalos dos animais estudados, baseada na quantificação dos neurônios lesados por campo demonstrou efetividade do tratamento com hipotermia seletiva com diferença estatística significativa.

Optimized hyperventilation preserves 2,3-diphosphoglycerate in severe traumatic brain injury

INTRODUCTION: The concentration of 2,3-diphosphoglycerate (2,3-DPG/Hct) increases as a physiological occurrence to pH increase and hyperventilation. This response was tested in patients with severe traumatic brain injury (TBI). METHOD: The concentration of 2,3-DPG/Hct was measured daily for six days in eleven patients with severe TBI in need of optimized hyperventilation because of intracranial hypertension. RESULTS:There was correlation between pH and the concentration of DPG/Hct. The concentration of 2,3-DPG/Hct remained predominantly within normal levels with slight increase in the sixth day of the study. The concentration of 2,3-DPG/Hct correlated significantly with measured partial pressure of oxygen that saturates 50 percent the hemoglobin of the blood (P50st), confirming the consistency of our data. CONCLUSION: The expected physiological response of a progressive increase in concentration of 2,3-DPG/Hct to hyperventilation was not observed. This fact may be explained by the intermittent and not sustained hyperventilation as dictated by the protocol of optimized ventilation.

INTRODUÇÃO: A concentração de 2,3-difosfoglicerato nos eritrócitos (2,3-DPG/Hct) aumenta como ocorrência fisiológica ao aumento do pH e à hiperventilação. Esta resposta foi testada em pacientes com traumatismo craniencefálico (TCE) grave. MÉTODO: A concentração de 2,3-DPG/Hct foi medida diariamente, durante seis dias, em 11 pacientes com TCE grave necessitando de hiperventilação otimizada por causa da hipertensão intracraniana. RESULTADOS: Houve correlação entre o pH e a concentração de 2,3-DPG/Hct. A concentração de 2,3-DPG/Hct permaneceu predominantemente dentro da normalidade, com ligeira tendência à elevação no sexto dia de estudo. Houve correlação entre a concentração de 2,3-DPG/Hct e a pressão parcial de oxigênio que satura 50 por cento da hemoglobina (P50st), confirmando a consistência dos dados. CONCLUSÃO: A esperada resposta fisiológica de aumento progressivo da concentração de 2,3-DPG/Hct não foi observada. Este fato pode ser explicado pela aplicação intermitente e não sustentada de hiperventilação, como ditado pelo protocolo clínico de ventilação otimizada.

Neurocritical care and traumatic brain injury.

The majority of severely head injured children will not require neurosurgery. For the pediatrician, the central question must be whether medical interventions are effective in limiting morbidity and treating the problem of cerebral oedema. However, in order to address this issue we need to give some thought to the system of care in which we practice, how we assess the severity of brain injury and whether, in regard to pathophysiology, responses in children are significantly different from those seen in adults. In this regard, this review highlights some of the recent pediatric neurocritical care literature and provides, for the clinician, a framework on which to base ones medical management of severe traumatic brain injury occurring in childhood.