Role of Toll-like receptor 4 and Janus kinase and signal transducer and activator of transcription signal transduction pathway in sepsis-induced brain damage

The Janus kinase and signal transducer and activator of transcription （JAK/STAT） signal transduction pathway is involved in sepsis-induced functional damage to the heart, liver, kidney, and other organs. However, the cellular and molecular mechanisms underlying sepsis-induced brain damage remain elusive. In the present study, we found severe loss of neurons in the hippocampal CA1 region in rats with sepsis-induced brain damage following intraperitoneal injection of endotoxin, The expression of toll-like receptor 4, tumor necrosis factor a, and interleukin-6 was significantly increased in brain tissues following lipopolysaccharide exposure. AG490 （JAK2 antagonist） and rapamycin （STAT3 antagonist） significantly reduced neuronal loss and suppressed the increased expression of toll-like receptor 4, tumor necrosis factor a, and interleukin-6 in the hippocampal CA1 region in sepsis-induced brain damaged rats. Overall, these data suggest that blockade of the JAK/STAT signal transduction pathway is neuroprotective in sepsis-induced brain damage via the inhibition of toll-like receptor 4, tumor necrosis factor a, and interleukin-6 exoression.

Mutant amyloid precursor protein and presenilin-1 genes effect on ischemia vulnerability via calcium homeostasis disturbance

BACKGROUND： Previous studies have demonstrated that mutant amyloid precursor protein （APP） or presenilin-1 （PS1） genes increase susceptibility to ischemic brain damage induced by middle cerebral artery occlusion. Possible mechanisms include over-production of beta-amyloid peptide （Aβ）. OBJECTIVE： Because Aβ is over-produced in the APP/PS1 double-transgenic mouse, the present study focused on mechanisms of increased ischemic damage due to mutant APP and PS1 genes by measuring oxidative stress, mitochondrial function, and calcium homeostasis. DESIGN, TIME AND SETTING： The non-randomized, controlled, in vivo and in vitro experiments were performed at the Medical Research Center, Second Clinical College, Jinan University between May and October 2008. MATERIALS： Male APP transgenic mice carrying the mutant 695swe gene and female PS1 transgenic mice carrying the mutant Leu235Pro gene were donated from the University of Hong Kong. SHSY5Y human neureblastoma cells were purchased from ATCC （Manassas, VA, USA）, and Aβ1-42 was obtained from Sigma-Aldrich （St. Louis, MO, USA）. METHODS： APP transgenic mice were mated with PS1 transgenic mice to produce APP/PS1 double-transgenic mice and wildtype littermates mice. The photothrombotic stroke model was induced in six APP/PS1 double-transgenic and 6 wildtype littermates mice. SHSY5Y human neuroblastoma cells were cultured in vitro, and were divided into 4 groups： Aβ group, cells were exposed to 5 pmol/L Aβ for 24 hours; oxygen-glucose deprivation （OGD） group, cells were exposed to OGD for 1 hour after treatment with sterile, ultra-pure water for 24 hours; OGD＋Aβ group, cells were exposed to OGD and Aβfor 1 hour after treatment with 5 pmol/L Aβ for 24 hours; sham control group： cells were exposed to sterile, ultra-pure water for 25 hours. OGD was achieved by exposing the cells to glucose-free DMEM and placing the cells in an anaerobic chamber flushed with 5% CO2 and 95% N2 （v/v） at 37 ℃ for 1 hour. MAIN OUTCOME MEASURES： TTC staining was used to measure infarct volume 7 days after photothrombotic stroke. Cell viability was evaluated using the MTT kit. Opening of the mitochondrial permeability transition pore, intracellular concentration of superoxide anion, and calcium after OGD were detected with fluorescence intensity of calcein-AM, hydroethidine, and fluo-3/AM. RESULTS： At 7 days after stroke, total infarct volume and cortical infarct volume were significantly greater in the APP/PS1 transgenic mice compared with the wildtype littermates mice （P 〈 0.01）. Aβ, OGD, and Aβ ＋ OGD significantly decreased cell viability and increased fluorescence intensity of hydroethidine and fluo-3/AM （P 〈 0.01）. Compared with the Aβ or OGD group, Aβ ＋ OGD significantly decreased cell viability （P 〈 0.01） and significantly increased fluorescence intensity of calcein-AM, hydroethidine, and fluo-3/AM （P 〈 0.01 or P 〈 0.05）. CONCLUSION： The APP/PS1 double-transgenic mice were more vulnerable to ischemia. The possible mechanisms included enhanced opening of the mitochondrial permeability transition pore, overproduction of superoxide anion due to pore opening, and disturbed calcium homeostasis induced by excess superoxide anion.

Expert consensus on the glycemic management of critically ill patients

Introduction The incidence of hyperglycemia is 40-60%in critically ill patients and is up to 60-80%in those who have undergone car-diac surgery.[1]The results of an epidemiological study in the United States showed that 28.6%of diabetic patients and 9.3%of non-diabetic patients had elevated mean daily glucose on the day of ICU admission.[2]In critically ill patients,elevated blood glucose is primarily the result of stress,and stress-induced hy-perglycemia is an independent risk factor associated with prog-nosis,regardless of a previous diagnosis of diabetes.Nutritional therapy has become an integral treatment option for patients in the ICU,[3,4]though nearly 30%of patients with enteral nu-trition and 44-50%with parenteral nutrition(PN)experience elevated glucose.[5,6]Intensive insulin therapy(IIT)is an impor-tant treatment for controlling hyperglycemia in critically ill pa-tients,but it also carries a corresponding risk of hypoglycemia.

Impaired ATP Release from Brain Astrocytes May be a Cause of Major Depression

Major depressive disease(MDD)is one of the most common mental disorders and a leading cause of disability[1].Core symptoms include depressed mood,increased apathy,and a general loss of interest.In consequence,it represents not only a personal hardship for the patients themselves,but also a major socio-economic burden for society as a whole.

Analysis of the correlation between the longitudinal trajectory of SOFA scores and prognosis in patients with sepsis at 72 hour after admission based on group trajectory modeling

Background:To identify the distinct trajectories of the Sequential Organ Failure Assessment(SOFA)scores at 72 h for patients with sepsis in the Medical Information Mart for Intensive Care(MIMIC)-IV database and determine their effects on mortality and adverse clinical outcomes.Methods:A retrospective cohort study was carried out involving patients with sepsis from the MIMIC-IV database.Group-based trajectory modeling(GBTM)was used to identify the distinct trajectory groups for the SOFA scores in patients with sepsis in the intensive care unit(ICU).The Cox proportional hazards regression model was used to investigate the relationship between the longitudinal change trajectory of the SOFA score and mortality and adverse clinical outcomes.Results:A total of 16,743 patients with sepsis were included in the cohort.The median survival age was 66 years(interquartile range:54-76 years).The 7-day and 28-day in-hospital mortality were 6.0%and 17.6%,respectively.Five different trajectories of SOFA scores according to the model fitting standard were determined:group 1(32.8%),group 2(30.0%),group 3(17.6%),group 4(14.0%)and group 5(5.7%).Univariate and multivariate Cox regression analyses showed that,for different clinical outcomes,trajectory group 1 was used as the reference,while trajectory groups 2-5 were all risk factors associated with the outcome(P<0.001).Subgroup analysis revealed an interaction between the two covariates of age and mechanical ventilation and the different trajectory groups of patients’SOFA scores(P<0.05).Conclusion:This approach may help identify various groups of patients with sepsis,who may be at different levels of risk for adverse health outcomes,and provide subgroups with clinical importance.

Convergence to diffusion waves for solutions of Euler equations with time-depending damping on quadrant

This paper is concerned with the asymptotic behavior of the solution to the Euler equations with time-depending damping on quadrant(x,t)∈R^+×R^+,with the null-Dirichlet boundary condition or the null-Neumann boundary condition on u. We show that the corresponding initial-boundary value problem admits a unique global smooth solution which tends timeasymptotically to the nonlinear diffusion wave. Compared with the previous work about Euler equations with constant coefficient damping, studied by Nishihara and Yang(1999), and Jiang and Zhu(2009, Discrete Contin Dyn Syst), we obtain a general result when the initial perturbation belongs to the same space. In addition,our main novelty lies in the fact that the cut-off points of the convergence rates are different from our previous result about the Cauchy problem. Our proof is based on the classical energy method and the analyses of the nonlinear diffusion wave.