Phosphate and tension homology-induced kinase 1/Parkin signaling mediates cognitive dysfunction in sepsis-associated encephalopathy through activation of hippocampal mitochondrial autophagy / 中华危重病急救医学

OBJECTIVE@#To investigate the effects of gene of phosphate and tension homology (PTEN)-induced putative kinase 1 (PINK1)/Parkin pathway on hippocampal mitophagy and cognitive function in mice with sepsis-associated encephalopathy (SAE) and its possible mechanism.@*METHODS@#A total of 80 male C57BL/6J mice were randomly divided into Sham group, cecal ligation puncture (CLP) group, PINK1 plasmid transfection pretreatment groups (p-PINK1+Sham group, p-PINK1+CLP group), empty vector plasmid transfection control group (p-vector+CLP group), with 16 mice in each group. The mice in CLP groups were treated with CLP to reproduce SAE models. The mice in the Sham groups were performed laparotomy only. Animals in the p-PINK1+Sham and p-PINK1+CLP groups were transfected with PINK1 plasmid through the lateral ventricle at 24 hours before surgery, while mice in the p-vector+CLP group were transfected with the empty plasmid. Morris water maze experiment was performed 7 days after CLP. The hippocampal tissues were collected, the pathological changes were observed under a light microscope after hematoxylin-eosin (HE) staining, and the mitochondrial autophagy was observed under a transmission electron microscopy after uranyl acetate and lead citrate staining. The expressions of PINK1, Parkin, Beclin1, interleukins (IL-6, IL-1β) and microtubule-associated protein 1 light chain 3 (LC3) were detected by Western blotting.@*RESULTS@#Compared with the Sham group, CLP group mice in Morris water maze experiment had longer escape latency, shorter target quadrant residence time, and fewer times of crossing the platform at 1-4 days. Under the light microscope, the hippocampal structure of the mouse was injured, the neuronal cells were arranged in disorder, and the nuclei were pyknotic. Under the electron microscope, the mitochondria appeared swollen, round, and wrapped by bilayer or multilayer membrane structures. Compared with the Sham group, CLP group had higher expressions of PINK1, Parkin, Beclin1, LC3II/LC3I ratio, IL-6 and IL-1β in hippocampus, indicating that sepsis induced by CLP could activated inflammatory response and caused PINK1/Parkin-mediated mitophagy. Compared with the CLP group, p-PINK1+CLP group had shorter escape latencies, spent more time in the target quadrant and had more number of crossings in the target quadrant at 1-4 days. Under the light microscope, the hippocampal structures of mice was destroyed, the neurons were arranged disorderly, and the nuclei were pyknotic. Under transmission electron microscope, swollen and rounded mitochondria and mitochondrial structure wrapped by double membrane or multilayer membrane structure were observed. Compared with the CLP group, the levels of PINK1, Parkin, Beclin1 and LC3II/LC3 ratio in the p-PINK1+CLP group were significantly increased [PINK1 protein (PINK1/β-actin): 1.95±0.17 vs. 1.74±0.15, Parkin protein (Parkin/β-actin): 2.06±0.11 vs. 1.78±0.12, Beclin1 protein (Beclin1/β-actin): 2.11±0.12 vs. 1.67±0.10, LC3II/LC3I ratio: 3.63±0.12 vs. 2.27±0.10, all P < 0.05], while the levels of IL-6 and IL-1β were significantly decreased [IL-6 protein (IL-6/β-actin): 1.69±0.09 vs. 2.00±0.11, IL-1β protein (IL-1β/β-actin): 1.11±0.12 vs. 1.65±0.12, both P < 0.05], suggesting that overexpression of PINK1 protein could further activate mitophagy and reduce the inflammatory response caused by sepsis. There was no statistically significant difference in the above pathological changes and related indicators between Sham group and p-PINK1+Sham group, CLP group and p-vector+CLP group.@*CONCLUSIONS@#PINK1 overexpression can further activate CLP-induced mitophagy by upregulating Parkin, thereby inhibiting inflammation response and alleviate cognitive function impairment in SAE mice.

Value of cerebral hypoxic-ischemic injury markers in the early diagnosis of sepsis associated encephalopathy in burn patients with sepsis / 中华烧伤杂志

Objective: To explore the value of cerebral hypoxic-ischemic injury markers in the early diagnosis of sepsis associated encephalopathy (SAE) in burn patients with sepsis. Methods: A retrospective case series study was conducted. From October 2018 to May 2021, 41 burn patients with sepsis who were admitted to Zhengzhou First People's Hospital met the inclusion criteria, including 23 males and 18 females, aged 18-65 (35±3) years. According to whether SAE occurred during hospitalization, the patients were divided into SAE group (21 cases) and non-SAE group (20 cases). The gender, age, deep partial-thickness burn area, full-thickness burn area, and acute physiology and chronic health evaluation Ⅱ (APACHE Ⅱ) scores of patients were compared between the two groups. The serum levels of central nervous system specific protein S100β and neuron specific enolase (NSE) at 12, 24, and 48 h after sepsis diagnosis (hereinafter referred to as after diagnosis), the serum levels of interleukin-6 (IL-6), IL-10, tumor necrosis factor α (TNF-α), Tau protein, adrenocorticotropic hormone (ACTH), and cortisol at 12, 24, 48, 72, 120, and 168 h after diagnosis, and the mean blood flow velocity of middle cerebral artery (VmMCA), pulsatility index, and cerebral blood flow index (CBFi) on 1, 3, and 7 d after diagnosis of patients in the two groups were counted. Data were statistically analyzed with chi-square test, analysis of variance for repeated measurement, independent sample t test, and Bonferroni correction. The independent variables to predict the occurrence of SAE was screened by multi-factor logistic regression analysis. The receiver operating characteristic (ROC) curve was drawn for predicting the occurrence of SAE in burn patients with sepsis, and the area under the curve (AUC), the best threshold, and the sensitivity and specificity under the best threshold were calculated. Results: The gender, age, deep partial-thickness burn area, full-thickness burn area, and APACHE Ⅱ score of patients in the two groups were all similar (χ2=0.02, with t values of 0.71, 1.59, 0.91, and 1.07, respectively, P>0.05). At 12, 24, and 48 h after diagnosis, the serum levels of S100β and NSE of patients in SAE group were all significantly higher than those in non-SAE group (with t values of 37.74, 77.84, 44.16, 22.51, 38.76, and 29.31, respectively, P<0.01). At 12, 24, 48, 72, 120, and 168 h after diagnosis, the serum levels of IL-10, Tau protein, and ACTH of patients in SAE group were all significantly higher than those in non-SAE group (with t values of 10.68, 13.50, 10.59, 8.09, 7.17, 4.71, 5.51, 3.20, 3.61, 3.58, 3.28, 4.21, 5.91, 5.66, 4.98, 4.69, 4.78, and 2.97, respectively, P<0.01). At 12, 24, 48, 72, and 120 h after diagnosis, the serum levels of IL-6 and TNF-α of patients in SAE group were all significantly higher than those in non-SAE group (with t values of 8.56, 7.32, 2.08, 2.53, 3.37, 4.44, 5.36, 5.35, 6.85, and 5.15, respectively, P<0.05 or P<0.01). At 12, 24, and 48 h after diagnosis, the serum level of cortisol of patients in SAE group was significantly higher than that in non-SAE group (with t values of 5.44, 5.46, and 3.55, respectively, P<0.01). On 1 d after diagnosis, the VmMCA and CBFi of patients in SAE group were significantly lower than those in non-SAE group (with t values of 2.94 and 2.67, respectively, P<0.05). On 1, 3, and 7 d after diagnosis, the pulsatile index of patients in SAE group was significantly higher than that in non-SAE group (with t values of 2.56, 3.20, and 3.12, respectively, P<0.05 or P<0.01). Serum IL-6 at 12 h after diagnosis, serum Tau protein at 24 h after diagnosis, serum ACTH at 24 h after diagnosis, and serum cortisol at 24 h after diagnosis were the independent risk factors for SAE complicated in burn patients with sepsis (with odds ratios of 2.42, 1.38, 4.29, and 4.19, 95% confidence interval of 1.76-3.82, 1.06-2.45, 1.37-6.68, and 3.32-8.79, respectively, P<0.01). For 41 burn patients with sepsis, the AUC of ROC of serum IL-6 at 12 h after diagnosis for predicting SAE was 0.92 (95% confidence interval was 0.84-1.00), the best threshold was 157 pg/mL, the sensitivity was 81%, and the specificity was 89%. The AUC of ROC of serum Tau protein at 24 h after diagnosis for predicting SAE was 0.92 (95% confidence interval was 0.82-1.00), the best threshold was 6.4 pg/mL, the sensitivity was 97%, and the specificity was 99%. The AUC of ROC of serum ACTH at 24 h after diagnosis for predicting SAE was 0.96 (95% confidence interval was 0.89-1.00), the best threshold was 14.7 pg/mL, the sensitivity was 90%, and the specificity was 94%. The AUC of ROC of serum cortisol at 24 h after diagnosis for predicting SAE was 0.93 (95% confidence interval was 0.86-1.00), the best threshold was 89 nmol/L, the sensitivity was 94%, and the specificity was 97%. Conclusions: Serum Tau protein, ACTH, and cortisol have high clinical diagnostic value for SAE complicated in burn patients with sepsis.

Expression level of glial fibrillary acidic protein and its clinical significance in patients with sepsis-associated encephalopathy / 中南大学学报(医学版)

To determine expression levels of glial fibrillary acidic protein in patients of sepsis-associated encephalopathy (SAE) and its clinical significance.
 Methods: Patients, admitted to intensive care units and diagnosed as sepsis, were recruited to our study from October 2016 to August 2018 in the Third Xiangya Hospital, Central South University. SAE is defined as a brain dysfunction secondary to sepsis and without evidence of a primary central nervous system infection or encephalopathy due to other reasons. The SAE group and non-SAE group were classed by Confusion Assessment Method for the ICU (CAM-ICU) score. We measured the levels of serum GFAP, S100β and neuron-specific enolase (NSE) within 24 hours after diagnosis of sepsis, and compared the patients' general clinical data, ICU stay time, 28-day and 180-day mortality.
 Results: Among 152 enrolled patients, 58 and 94 were assigned to the SAE group and the non-SAE group, respectively. There were a significantly higher Sequential Organ Failure Assessment (SOFA) scores, 28-day mortality rate, as well as 180-day mortality rate in the SAE group (all P<0.001). The levels of GFAP, NSE and S100β in the SAE group were significantly higher than those in the non-SAE group (all P<0.001). The diagnostic values of GFAP was 0.67 μg/L, with sensitivity at 75.9% and specificity at 77.7%. Area under the receiver operating characteristic curve (AUROC) of GFAP, NSE and S100β were 0.803, 0.795 and 0.750, respectively. Pearson analysis showed that serum GFAP level was positively correlated with Acute Physiology and Chronic Health Evaluation II (APACHE II) score, but it was negatively correlated with Glasgow Coma Scale (GCS) score, 28-day survival rate and 180-day survival rate.
 Conclusion: The level of serum GFAP is significantly increased in SAE, which shows certain correlation with incidence, severity and prognosis of the disease.

Sepsis Associated Encephalopathy Accompanied by Bilateral Corticospinal Tract Lesions in Diffusion Weighed Image

No abstract available.

Manejo de delirium no paciente em unidade de terapia intensiva oncológica: elaboração de protocolos de diretrizes de cuidados / Delirium management in intensive cancer care unit patients: elaboration of care guidelines protocols

Objetivo: propor diretrizes de cuidado de manejo de delirium em uma unidade de cuidados intensivos oncológica, utilizando as recomendações do Clinical Practice Guidelines for Pain, Agitation, and Delirium (PAD). Método: estudo transversal para avaliar a frequência de delirium no período de três meses e para avaliar e validar diretrizes a partir do PAD em prontuários. Foi realizado com 43 profissionais na unidade de cuidados intensiva oncológica de um hospital especializado em oncologia da rede pública do Estado do Rio de Janeiro, que é um roteiro para o desenvolvimento integrado, com base em evidências, e para a prevenção e tratamento da dor, agitação e delirium em pacientes críticos. O instrumento preliminar proposto foi avaliado/validado através da metodologia Delphi, obedecendo consenso de 80% e Índice de Validade de Conteúdo (IVC) para análise do grau de importância de 0.78. Durante os meses de outubro a dezembro de 2016. Resultados: Cento e trinta e cinco prontuários de pacientes internados na UTI/UPO foram incluídos no estudo. A média de dias que precedeu a internação destes pacientes na unidade de cuidados intensivos oncológica foi de 10,3 dias. Encontrou-se uma frequência de 39,3% de pacientes com delirium no período pesquisado. Considerando apenas os pacientes sob ventilação mecânica, a frequência de delirium foi de 64,6%. O resultado do teste U indicou diferença significativa entre os grupos conforme o tempo de permanência na unidade de cuidados intensivos oncológica (p < 0,01). Pacientes internados por até sete dias tiveram tempo médio (M= 0,36; DP= 0,89) de duração de delirium (em dias) significativamente inferior aos de pacientes internados por oito dias ou mais (M = 4,58; DP = 4,80). Na análise ajustada foi identificado que os pacientes submetidos a traqueostomia (OR = 4,15; IC95% 1,33 ­ 12,94; p = 0,01) e ventilação mecânica (OR = 7,64; IC95% 2,41 ­ 24,25; p < 0,01) apresentaram maiores chances de delirium do que os pacientes que não foram submetidos a tais procedimentos. Sobre as diretrizes todos os 19 itens avaliados obtiveram a concordância maior de 80% e IVC maior de 0,78, a validação dos juízes na etapa Delphi 1, com consenso de 19 itens, foi um resultado considerado positivo, em especial, pela extensão do protocolo e diversidades de temáticas envolvidas com o manejo de delirium com pacientes oncológicos em UTI, o que poderia ter aumentado as chances de inadequações, apesar da análise dos resultados obtidos na 1ª de rodada da Técnica Delphi obterem índice de concordância mínimo de 80%, a análise dos comentários e das sugestões realizados pelos juízes determinou a realização de alterações no conteúdo dos itens, que foram submetidas à nova avaliação do grupo, no Delphi 2 utilizando Método de Pascali com valores percentuais superiores a 90%. Isso atesta que as diretrizes se encontram competente, quanto ao seu conteúdo, para avaliar o que se propõem: o manejo do delirium em paciente oncológico na UTI. Conclusão, aplicabilidade e impacto: a elaboração e validação das diretrizes revelou-se pertinente pela alta concordância dos pares visando uma melhor gestão do delirium para qualidade em cuidado e melhores desfechos, manejos e incidência do delirium

Autophagy in hippocampal nerve cells from rats with sepsis-associated encephalopathy / 中南大学学报(医学版)

OBJECTIVE@#To show evidence of the autophagy in hippocampal nerve cells from rats with sepsis-associated encephalopathy (SAE) in vivo and to investigate the expression of microtubule-associated protein 1 light chain 3 (LC3). 
@*METHODS@#A rat model of sepsis was established by the cecal ligation and puncture (CLP). A total of 60 male Wistar rats (30 days old) were randomly divided into a sham group (n=10) and a CLP group (n=50). At 12 hours after CLP, the electroencephalogram (EEG) and somatosensory evoked potential (SEP) changes in rats were monitored and the neurobehavioral score was measured. According to the occurrence of SAE, the CLP group was further divided into an SAE(+) group and an SAE(-) group. Histopathological changes in hippocampus were observed by hematoxylin-eosin staining. An electron microscope was used to observe autophagosome formation and lysosome activation in the hippocampal nerve cells. Expressions of LC3-I and LC3-II protein were measured by Western blot. 
@*RESULTS@#Five of 50 rats in CLP group died in 12 hours after CLP. According to the low neurobehavioral score and abnormal EEG and SEP, 16 rats were diagnosed as SAE. The incidence of SAE was 35.56% (16/45). Compared with the sham group or the SAE(-) group, the frequency of α wave in SAE(+) group was significantly decreased at 12 hours after CLP, the δ wave increased, the P1 amplitude decreased, and the latency of SEP waves (P1 and N1) was prolonged (P<0.05). The morphology of hippocampal nerve cells was obvious in a status of edema. Pyramidal cells decreased significantly, even dissolved, and cell arrangement was in disorder in the SAE(+) group. But these cells were normal in the sham group and the SAE(-) group. The structure of hippocampal nerve cells was disordered, and the autophagy, granular matrix and square or rectangular crystals were found in the SAE(+) group. However, there was no autophagy both in the sham group and the SAE(-) group. LC3-II/LC3-I ratio in the hippocampal nerve cells was increased significantly at 12 hours after CLP in the SAE(+) group when compared with that in the sham or the SAE(-) group (P<0.05). 
@*CONCLUSION@#There is autophagy in hippocampal nerve cells from rats with SAE and the LC3-II/LC3-I ratio is increased significantly.

Diagnostic and Predictive Levels of Calcium-binding Protein A8 and Tumor Necrosis Factor Receptor-associated Factor 6 in Sepsis-associated Encephalopathy: A Prospective Observational Study / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Despite its high prevalence, morbidity, and mortality, sepsis-associated encephalopathy (SAE) is still poorly understood. The aim of this prospective and observational study was to investigate the clinical significance of calcium-binding protein A8 (S100A8) in serum and tumor necrosis factor receptor-associated factor 6 (TRAF6) in peripheral blood mononuclear cells (PBMCs) in diagnosing SAE and predicting its prognosis.</p><p><b>METHODS</b>Data of septic patients were collected within 24 h after Intensive Care Unit admission from July 2014 to March 2015. Healthy medical personnel served as the control group. SAE was defined as cerebral dysfunction in the presence of sepsis that fulfilled the exclusion criteria. The biochemical indicators, Glasgow Coma Scale, Acute Physiology and Chronic Health Evaluation score II, TRAF6 in PBMC, serum S100A8, S100β, and neuron-specific enolase were evaluated in SAE patients afresh. TRAF6 and S100A8 were also measured in the control group.</p><p><b>RESULTS</b>Of the 57 enrolled patients, 29 were diagnosed with SAE. The S100A8 and TRAF6 concentrations in SAE patients were both significantly higher than that in no-encephalopathy (NE) patients, and higher in NE than that in controls (3.74 ± 3.13 vs. 1.08 ± 0.75 vs. 0.37 ± 0.14 ng/ml, P < 0.01; 3.18 ± 1.55 vs. 1.02 ± 0.63 vs. 0.47 ± 0.10, P < 0.01). S100A8 levels of 1.93 ng/ml were diagnostic of SAE with 92.90% specificity and 69.00% sensitivity in the receiver operating characteristic (ROC) curve, and the area under the curve was 0.86 (95% confidence interval [CI]: 0.76-0.95). TRAF6-relative levels of 1.44 were diagnostic of SAE with 85.70% specificity and 86.20% sensitivity, and the area under the curve was 0.94 (95% CI: 0.88-0.99). In addition, S100A8 levels of 2.41 ng/ml predicted 28-day mortality of SAE with 90.00% specificity and 73.70% sensitivity in the ROC curve, and the area under the curve was 0.88. TRAF6 relative levels of 2.94 predicted 28-day mortality of SAE with 80.00% specificity and 68.40% sensitivity, and the area under the curve was 0.77. Compared with TRAF6, the specificity of serum S100A8 in diagnosing SAE and predicting mortality was higher, although the sensitivity was low. In contrast, the TRAF6 had higher sensitivity for diagnosis.</p><p><b>CONCLUSIONS</b>Peripheral blood levels of S100A8 and TRAF6 in SAE patients were elevated and might be related to the severity of SAE and predict the outcome of SAE. The efficacy and specificity of S100A8 for SAE diagnosis were superior, despite its weak sensitivity. S100A8 might be a better biomarker for diagnosis of SAE and predicting prognosis.</p>

Treatment of Sepsis-associated Encephalopathy by Xingnaojing Injection: a Clinical Observation / 中国中西医结合杂志

<p><b>OBJECTIVE</b>To observe the efficacy of Xingnaojing Injection (XI) in treatment of sepsis-associated encephalopathy (SAE).</p><p><b>METHODS</b>Totally 65 SAE patients were retrospectively analyzed at EICU from September 2010 to September 2013. They were assigned to the control group (32 cases) and the treatment group (33 cases) according to whether they received XI. Patients in the control group received anti-infection and symptomatic support, while those in the treatment group were intravenously injected with XI at 20 mL per day for additional 7-10 days. The fever clearance time, Glasgow coma scale (GCS), C-reactive protein (CRP), neuron-specific enolase (NSE), and improvement of electroen-cephalogram (EEG) were observed in the two groups.</p><p><b>RESULTS</b>Compared with the control group, the fever clearance time was shortened, CRP levels decreased, GCS score and efficacy of EEG was alleviated in the treatment group after treatment with statistical difference (P < 0.05). No adverse reaction occurred during medication.</p><p><b>CONCLUSION</b>X1 was safe and effective in treatment of SAE.</p>

Septic encephalopathy: does inflammation drive the brain crazy?

Sepsis and the multiorgan dysfunction syndrome are among the most common reasons for admission to an intensive care unit, and are a leading cause of death. During sepsis, the central nervous system (CNS) is one of the first organs affected, and this is clinically manifested as sepsis-associated encephalopathy (SAE). It is postulated that the common final pathway that leads to SAE symptoms is the deregulation of neurotransmitters, mainly acetylcholine. Thus, it is supposed that inflammation can affect neurotransmitters, which is associated with SAE development. In this review, we will cover the current evidence (or lack thereof) for the mechanisms by which systemic inflammation interferes with the metabolism of major CNS neurotransmitters, trying to explain how systemic inflammation drives the brain crazy.

Disfunção cerebral associada à sepse: papel das estatinas na prevenção do dano cognitivo em modelo de sepse experimental / Brain dysfunction associated with sepsis: role of statins in the reversal of cognitive impairment in experimental sepsis model

A sepse é um dos mais graves problemas de saúde pública mundial, apresentando uma estimativa de 19 milhões de casos por ano. [...] A disfunção no sistema nervoso central se manifesta tipicamente por delirium, déficit de atenção e dano cognitivo. As estatinas são fármacos que têm a capacidade de bloquear a enzima HMG-CoA redutase,reduzindo a síntese de colesterol endógeno. Recentemente, foi observado que asestatinas, apresentam efeitos anti-inflamatórios, com potencial para prevenir a disfunção cerebral em modelo experimental de malária cerebral. Objetivamos neste estudo avaliar a capacidade do tratamento das estatinas em reduzir a neuroinflamação e proteger do dano cognitivo no modelo (ISC) de sepse. Para isso,foi coletado o conteúdo cecal, diluído em solução salina, e centrifugado, sendo sobrenadante recolhido para administração nos animais por via (i.p.) na dose de 5mg/g (0,5 mL) (n = 5-8/grupo). Os controles receberam 0,5 mL de solução salina. Os animais foram tratados 6, 24 e 48 h após a indução da sepse com imipenem (30mg/kg de peso corporal, por via subcutânea – s.c.) e 1,0 ml de solução salina (s.c.).As estatinas (atorvastatina e sinvastatina) foram administrados v.o. 1 hora antes e 6,24 e 48 h após a infecção (20 mg/kg). A mortalidade foi observada por 96 h e um escore de gravidade avaliado. O perfil de citocinas inflamatórias, o dano oxidativo e os níveis de mieloperoxidase foram determinados em 6 e 24 h. Além disso, foramavaliados a adesão e rolamento de leucócitos foram avaliados no cérebro dos animais a ativação da microglia, a disfunção da barreira hematoencefálica e alterações na microcirculação vascular cerebral...

Sepsis is one of the most serious problems in worldwide public health, with anestimated 19 million cases a year. [...] Thedysfunction in the central nervous system (CNS) is typically manifested by delirium,cognitive impairment and attention deficit. The statins are drugs with the ability toinhibit the HMG-CoA reductase enzymatic activity, reducing endogenous cholesterolsynthesis. Recently, it was observed that statins have anti-inflammatory effects, withthe potential to prevent brain dysfunction in an experimental model of cerebralmalaria. We aimed in this study to evaluate the capacity of statins to reduceneuroinflammation and protect from cognitive impairment in an experimental modelof sepsis (CSI). For this purpose, the cecal content was collected, diluted in salinesolution and centrifuged, and the supernatant collected for administration in animals(i.p.) at a dose of 5 mg/g (0.5 mL) (n= 5-8/grupo). The controls received 0.5 mL ofsaline. The animals received antibiotic therapy 6, 24 and 48 hours after induction ofsepsis with imipenem (30 mg/kg, subcutaneously - s.c.) and 1.0 ml of saline (s.c.).Statins (atorvastatin and simvastatin) were administered orally 1 h before and 6, 24and 48 h post-infection (20 mg/kg). Mortality was observed for 96 h and a clinicalscore reported. The profile of cytokines, oxidative stress and myeloperoxidase levelswere determined at 6 and 24 h. Moreover, adhesion and rolling of leukocytes inbrain, microglial activation, dysfunction of the blood brain barrier (BBB) and vascularchanges in the cerebral microcirculation were assessed. After 15 days we analyzedthe cognitive impairment using behavioral tests of inhibitory avoidance task andMorris Water Maze...

Γ-secretase inhibitor DAPT prevents neuronal death and memory impairment in sepsis associated encephalopathy in septic rats / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Brain dysfunction is a frequent complication of sepsis, usually defined as sepsis-associated encephalopathy (SAE). Although the Notch signaling pathway has been proven to be involved in both ischemia and neuronal proliferation, its role in SAE is still unknown. Here, the effect of the Notch signaling pathway involved γ-secretase inhibitor DAPT on SAE in septic rats was investigated in a cecal ligation and puncture (CLP) model.</p><p><b>METHODS</b>Fifty-nine Sprague-Dawley rats were randomly divided into four groups, with the septic group receiving the CLP operation. Twenty-four hours after CLP or sham treatment, rats were sacrificed and their hippocampus was harvested for Western blot analysis. TNF-α expression was determined using an enzyme-linked immunosorbent assay (ELISA) kit. Neuronal apoptosis was assessed by TUNEL staining, and neuronal cell death was detected by H&E staining. Finally, a novel object recognition experiment was used to evaluate memory impairment.</p><p><b>RESULTS</b>Our data showed that sepsis can increase the expression of hippocampal Notch receptor intracellular domain (NICD) and poly (adenosine diphosphate [ADP]-ribose) polymerase-1 (PARP-1), as well as the inflammatory response, neuronal apoptosis, neuronal death, and memory dysfunction in rats. The γ-secretase inhibitor N-[N-(3,5-difluorophenacetyl)-1-alanyl]-S-phenylglycine t-butyl ester (DAPT) can significantly decrease the level of NICD and PARP-1, reduce hippocampal neuronal apoptosis and death, attenuate TNF-α release and rescue cognitive impairment caused by CLP.</p><p><b>CONCLUSION</b>The neuroprotective effect of DAPT on neuronal death and memory impairment in septic rats, which could be a new therapeutic approach for treating SAE in the future.</p>

Biomarcadores na encefalopatia séptica: revisão sistemática dos estudos clínicos / Biomarkers in septic encephalopathy: a systematic review of clinical studies

OBJETIVO: O objetivo deste estudo foi revisar sistematicamente a importância da enolase específica neuronal e S100B para diagnóstico e monitorização da encefalopatia séptica. MÉTODOS: Foi realizada uma busca no banco de dados PubMed selecionando estudos que avaliaram níveis séricos de S 100 B e enolase específica neuronal em pacientes com sepse, publicados entre Janeiro de 2000 e Abril de 2012. Apenas estudos em humanos e que utilizaram um método adicional de avaliação neurológica foram selecionados. RESULTADOS: Foram identificados nove estudos, dos quais sete associaram concentrações elevadas de S100 beta e enolase específica neuronal ao desenvolvimento de encefalopatia séptica; quatro também as associaram ao aumento de mortalidade. Entretanto, dois trabalhos não encontraram essa associação quando avaliaram S100 beta e um deles não observou correlação entre a enolase específica neuronal e encefalopatia séptica. CONCLUSÃO: A S100 beta e enolase específica neuronal são biomarcadores promissores para diagnóstico e monitorização de pacientes com encefalopatia séptica, mas é necessária uma maior investigação.

OBJECTIVE: The aim of this study was to systematically review the importance of neuron-specific enolase and S100 beta for diagnosing and monitoring septic encephalopathy. METHODS: A PubMed database search was performed to identify studies that evaluated S100 beta and neuron-specific enolase serum levels in patients with sepsis and that were published between January 2000 and April 2012. Only human studies that employed an additional method of neurological assessment were selected. RESULTS: Nine studies were identified, seven of which associated high concentrations of S100 beta and neuron-specific enolase with the development of septic encephalopathy. Four studies also associated these concentrations with increased mortality. However, two studies did not find such an association when they evaluated S100 beta levels, and one of these studies did not observe a correlation between neuron-specific enolase and septic encephalopathy. CONCLUSION: S100 beta and neuron-specific enolase are promising biomarkers for diagnosing and monitoring patients with septic encephalopathy, but more research is necessary.