TY - JOUR AB - In this study, we demonstrate that mice deficient in TNFR1 (TNFR1(-/-)) were resistant to LPS-induced encephalopathy. Systemic administration of lipopolysaccharide (LPS) induces a widespread inflammatory response similar to that observed in sepsis. Following LPS administration TNFR1(-/-) mice had less caspase-dependent apoptosis in brain cells and fewer neutrophils infiltrating the brain (p<0.039), compared to control C57Bl6 (TNFR1(+/+)) mice. TNFR1-dependent increase in aquaporin (AQP)-4 mRNA and protein expression was observed with a concomitant increase in water content, in brain (18% increase in C57Bl6 mice treated with LPS versus those treated with saline), similar to cerebral edema observed in sepsis. Furthermore, absence of TNFR1 partially but significantly reduced the activation of astrocytes, as shown by immunofluorescence and markedly inhibited iNOS mRNA expression (p<0.01). Septic encephalopathy is a devastating complication of sepsis. Although, considerable work has been done to identify the mechanism causing the pathological alterations in this setting, the culprit still remains an enigma. Our results demonstrate for the first time that endotoxemia leads to inflammation in brain, with alteration in blood-brain barrier, up-regulation of AQP4 and associated edema, neutrophil infiltration, astrocytosis, as well as apoptotic cellular death, all of which appear to be mediated by TNF-alpha signaling through TNFR1. AD - Department of Medicine, University of Chicago, 5841 South Maryland Avenue, MC5100, Chicago, IL 60637, USA. jalexand@medicine.bsd.uchicago.edu AN - 17884256 AU - Alexander, J. J. AU - Jacob, A. AU - Cunningham, P. AU - Hensley, L. AU - Quigg, R. J. DA - Feb DO - S0197-0186(07)00229-X [pii] 10.1016/j.neuint.2007.08.006 DP - NLM ET - 2007/09/22 KW - Animals Apoptosis/genetics Aquaporin 4/genetics/metabolism Astrocytes/metabolism Blood-Brain Barrier/metabolism/physiopathology Brain/ metabolism/physiopathology Brain Diseases, Metabolic/ metabolism/pathology/physiopathology Brain Edema/genetics/metabolism/physiopathology Chemotaxis, Leukocyte/genetics Encephalitis/ metabolism/microbiology/physiopathology Gliosis/genetics/metabolism/physiopathology Inflammation Mediators/metabolism Lipopolysaccharides Mice Mice, Inbred C57BL Mice, Knockout Nitric Oxide Synthase Type II/genetics RNA, Messenger/metabolism Receptors, Tumor Necrosis Factor, Type I/genetics/ metabolism Sepsis/ complications Tumor Necrosis Factor-alpha/ metabolism LA - eng IS - 3 N1 - Alexander, Jessy J Jacob, Alexander Cunningham, Patrick Hensley, Lauren Quigg, Richard J R01AI43579/AI/NIAID NIH HHS/United States R01DK41873/DK/NIDDK NIH HHS/United States R01DK55357/DK/NIDDK NIH HHS/United States Research Support, N.I.H., Extramural England Neurochemistry international Neurochem Int. 2008 Feb;52(3):447-56. Epub 2007 Aug 17. PY - 2008 SN - 0197-0186 (Print) 0197-0186 (Linking) SP - 447-56 ST - TNF is a key mediator of septic encephalopathy acting through its receptor, TNF receptor-1 T2 - Neurochem Int TI - TNF is a key mediator of septic encephalopathy acting through its receptor, TNF receptor-1 VL - 52 ID - 77 ER - TY - JOUR AB - In this study, we demonstrate that mice deficient in TNFR1 (TNFR1(-/-)) were resistant to LPS-induced encephalopathy. Systemic administration of lipopolysaccharide (LPS) induces a widespread inflammatory response similar to that observed in sepsis. Following LPS administration TNFR1(-/-) mice had less caspase-dependent apoptosis in brain cells and fewer neutrophils infiltrating the brain (p<0.039), compared to control C57Bl6 (TNFR1(+/+)) mice. TNFR1-dependent increase in aquaporin (AQP)-4 mRNA and protein expression was observed with a concomitant increase in water content, in brain (18% increase in C57Bl6 mice treated with LPS versus those treated with saline), similar to cerebral edema observed in sepsis. Furthermore, absence of TNFR1 partially but significantly reduced the activation of astrocytes, as shown by immunofluorescence and markedly inhibited iNOS mRNA expression (p<0.01). Septic encephalopathy is a devastating complication of sepsis. Although, considerable work has been done to identify the mechanism causing the pathological alterations in this setting, the culprit still remains an enigma. Our results demonstrate for the first time that endotoxemia leads to inflammation in brain, with alteration in blood-brain barrier, up-regulation of AQP4 and associated edema, neutrophil infiltration, astrocytosis, as well as apoptotic cellular death, all of which appear to be mediated by TNF-alpha signaling through TNFR1. AD - Department of Medicine, University of Chicago, 5841 South Maryland Avenue, MC5100, Chicago, IL 60637, USA. jalexand@medicine.bsd.uchicago.edu AN - 17884256 AU - Alexander, JJ AU - Jacob, A AU - Cunningham, P AU - Hensley, L AU - Quigg, RJ DA - Feb DO - S0197-0186(07)00229-X [pii] 10.1016/j.neuint.2007.08.006 KW - Animals Apoptosis Aquaporin 4 Astrocytes Blood-Brain Barrier Brain Brain Diseases, Metabolic Brain Edema Chemotaxis, Leukocyte Encephalitis Gliosis Inflammation Mediators Lipopolysaccharides Mice Mice, Inbred C57BL Mice, Knockout Nitric Oxide Synthase Type II RNA, Messenger Receptors, Tumor Necrosis Factor, Type I Sepsis Tumor Necrosis Factor-alpha L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17884256 LA - eng IS - 3 PY - 2008 SN - 0197-0186 SP - 447-56 ST - TNF is a key mediator of septic encephalopathy acting through its receptor, TNF receptor-1. T2 - Neurochem Int TI - TNF is a key mediator of septic encephalopathy acting through its receptor, TNF receptor-1. UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17884256 VL - 52 ID - 35 ER - TY - JOUR AB - The intimate mechanisms of sepsis-induced delirium are unknown. Among the potential contributing factors, the breakdown of the blood-brain barrier is considered a key determinant of brain dysfunction. The complement activation is paramount to an appropriate activation of the central nervous system during stress. C3a and C5a have been extensively studied and may be involved in sepsis-induced delirium. Here we discuss the pro and con for inhibiting C5a to attenuate brain damage during sepsis. In particular, we discuss the hypothesis that C5a increased blood-brain barrier permeability amy ease the brain to mount an appropriate response to sepsis. Thus, blockade of C5a may be detrimental, resulting in an attenuated response of the stress system. AD - General Intensive Care Unit, Raymond Poincare Hospital (AP-HP), University of Versailles SQY (UniverSud Paris), 104 boulevard Raymond Poincare, 92380 Garches, France. djillali.annane@rpc.aphp.fr AN - 19439043 AU - Annane, D. C2 - 2689478 DO - cc7754 [pii] 10.1186/cc7754 DP - NLM ET - 2009/05/15 KW - Animals Blood-Brain Barrier Complement C5a/ antagonists & inhibitors/metabolism Delirium/ etiology/metabolism Mice Sepsis/ complications/metabolism LA - eng IS - 2 N1 - Annane, Djillali Comment England Critical care (London, England) Crit Care. 2009;13(2):135. Epub 2009 Apr 22. PY - 2009 SN - 1466-609X (Electronic) 1364-8535 (Linking) SP - 135 ST - Sepsis-associated delirium: the pro and con of C5a blockade T2 - Crit Care TI - Sepsis-associated delirium: the pro and con of C5a blockade VL - 13 ID - 69 ER - TY - JOUR AB - Septic encephalopathy is a complication of sepsis, and it is closely associated with the increased mortality of the sufferers. Pathophysiology of septic encephalopathy is not still completely understood. In an attempt to provide insight into the pathogenesis of septic encephalopathy, a light and electron microscopic investigation has been carried out in a rat model of intraperitoneal sepsis. Experimental fecal peritonitis was induced in Wistar rats which have been monitored for 6 h and sacrificed to harvest the samples of frontal cortex. Vital parameters and morphometric data obtained from investigation of the microvessels were then compared with the sham-operated and unoperated controls. In addition to the discernible drop in the blood pressure and in rectal temperature following initial increases, unstable but usually increased heart rate and marked respiratory failure were recorded. Estimation of the percentage of the microvessel area occupied by edema revealed the presence of significantly more perimicrovascular edema in the experimental fecal peritonitis group compared to both sham-operated and unoperated controls, while no significant difference was present between the latter two groups. Electron microscopic investigation confirmed the presence of distinctive perimicrovascular edema in the fecal peritonitis group although the endothelial cells were linked by tight junctions which appeared morphologically intact. Although it might be premature to draw any strict parallels between the septic encephalopathy in humans and the findings observed in the present model, the results may suggest that the edema observed around the microvessels would bare a role in the pathogenesis of the septic encephalopathy probably by affecting the exchange of oxygen and nutrients with carbon dioxide and waste products between the blood and brain parenchyma. AD - Department of Anatomy, Uludag University Medical Faculty, Bursa 16059, Turkey. AN - 16423349 AU - Ari, I AU - Kafa, IM AU - Kurt, MA DA - Mar DO - S0014-4886(05)00457-7 [pii] 10.1016/j.expneurol.2005.12.001 KW - Analysis of Variance Animals Bacterial Infections Blood Pressure Blood Vessels Body Temperature Brain Edema Diagnostic Imaging Disease Models, Animal Frontal Lobe Heart Rate Male Microscopy, Electron, Transmission Rats Rats, Wistar Respiration Sepsis L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16423349 LA - eng IS - 1 PY - 2006 SN - 0014-4886 SP - 242-9 ST - Perimicrovascular edema in the frontal cortex in a rat model of intraperitoneal sepsis. T2 - Exp Neurol TI - Perimicrovascular edema in the frontal cortex in a rat model of intraperitoneal sepsis. UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16423349 VL - 198 ID - 45 ER - TY - JOUR AB - BACKGROUND AND PURPOSE: The cause of "posterior reversible encephalopathy syndrome" (PRES) is not established. We recently encountered several patients who developed PRES in the setting of severe infection. In this study, we comprehensively reviewed the clinical and imaging features in a large cohort of patients who developed PRES, with particular attention to those with isolated infection, sepsis, or shock (I/S/S). METHODS: The clinical/imaging features of 106 patients who developed PRES were comprehensively evaluated. In 25 of these patients, PRES occurred in association with severe I/S/S separate from transplantation. The clinical/imaging features (computer tomography, MR imaging, and MR angiography [MRA]) of the patients with I/S/S were further evaluated, including organ/tissue/blood culture results, mean arterial blood pressure (MAP) at toxicity, extent of cerebral edema, and presence of vasospasm. RESULTS: PRES occurred in association with I/S/S in 25 of 106 patients (23.6%), in addition to 4 other major clinical settings, including cyclosporine/FK-506 (post-transplant) neurotoxicity (46.2%), autoimmune disease (10.4%), postchemotherapy (3.7%), and eclampsia (10.4%). In the 25 patients with I/S/S, available cultures demonstrated a predominance of gram-positive organisms (84%). Blood pressure was "normal" at toxicity in 10 patients (MAP, 95 mm Hg); "severe" hypertension was present in 15 patients (MAP, 137 mm Hg). Extent of brain edema graded on imaging studies was greater in the normal MAP group compared with the severe hypertension group (P < .05). MRA demonstrated vasospasm in patients with severe hypertension and vessel "pruning" in the normal MAP group. CONCLUSION: Infection/sepsis/shock may be an important cause of PRES, particularly in relation to infection with gram-positive organisms. AD - Department of Radiology, Division of Neuroradiology, Presbyterian University Hospital, University of Pittsburgh, Pittsburgh, PA 15213, USA. bartynskiws@upmc.edu AN - 17110690 AU - Bartynski, W. S. AU - Boardman, J. F. AU - Zeigler, Z. R. AU - Shadduck, R. K. AU - Lister, J. DA - Nov-Dec DO - 27/10/2179 [pii] DP - NLM ET - 2006/11/18 KW - Adolescent Adult Aged Brain Diseases/diagnosis/etiology Brain Edema/ diagnosis/ etiology Female Gram-Positive Bacterial Infections/ complications Humans Magnetic Resonance Imaging Male Middle Aged Sepsis/ complications Shock, Septic/ complications Syndrome Tomography, X-Ray Computed LA - eng IS - 10 N1 - Bartynski, W S Boardman, J F Zeigler, Z R Shadduck, R K Lister, J United States AJNR. American journal of neuroradiology AJNR Am J Neuroradiol. 2006 Nov-Dec;27(10):2179-90. PY - 2006 SN - 0195-6108 (Print) 0195-6108 (Linking) SP - 2179-90 ST - Posterior reversible encephalopathy syndrome in infection, sepsis, and shock T2 - AJNR Am J Neuroradiol TI - Posterior reversible encephalopathy syndrome in infection, sepsis, and shock VL - 27 ID - 86 ER - TY - JOUR AB - BACKGROUND AND PURPOSE: The cause of "posterior reversible encephalopathy syndrome" (PRES) is not established. We recently encountered several patients who developed PRES in the setting of severe infection. In this study, we comprehensively reviewed the clinical and imaging features in a large cohort of patients who developed PRES, with particular attention to those with isolated infection, sepsis, or shock (I/S/S). METHODS: The clinical/imaging features of 106 patients who developed PRES were comprehensively evaluated. In 25 of these patients, PRES occurred in association with severe I/S/S separate from transplantation. The clinical/imaging features (computer tomography, MR imaging, and MR angiography [MRA]) of the patients with I/S/S were further evaluated, including organ/tissue/blood culture results, mean arterial blood pressure (MAP) at toxicity, extent of cerebral edema, and presence of vasospasm. RESULTS: PRES occurred in association with I/S/S in 25 of 106 patients (23.6%), in addition to 4 other major clinical settings, including cyclosporine/FK-506 (post-transplant) neurotoxicity (46.2%), autoimmune disease (10.4%), postchemotherapy (3.7%), and eclampsia (10.4%). In the 25 patients with I/S/S, available cultures demonstrated a predominance of gram-positive organisms (84%). Blood pressure was "normal" at toxicity in 10 patients (MAP, 95 mm Hg); "severe" hypertension was present in 15 patients (MAP, 137 mm Hg). Extent of brain edema graded on imaging studies was greater in the normal MAP group compared with the severe hypertension group (P < .05). MRA demonstrated vasospasm in patients with severe hypertension and vessel "pruning" in the normal MAP group. CONCLUSION: Infection/sepsis/shock may be an important cause of PRES, particularly in relation to infection with gram-positive organisms. AD - Department of Radiology, Division of Neuroradiology, Presbyterian University Hospital, University of Pittsburgh, Pittsburgh, PA 15213, USA. bartynskiws@upmc.edu AN - 17110690 AU - Bartynski, WS AU - Boardman, JF AU - Zeigler, ZR AU - Shadduck, RK AU - Lister, J DA - 2006 Nov-Dec DO - 27/10/2179 [pii] KW - Adolescent Adult Aged Brain Diseases Brain Edema Female Gram-Positive Bacterial Infections Humans Magnetic Resonance Imaging Male Middle Aged Sepsis Shock, Septic Syndrome Tomography, X-Ray Computed L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17110690 LA - eng IS - 10 PY - 2006 SN - 0195-6108 SP - 2179-90 ST - Posterior reversible encephalopathy syndrome in infection, sepsis, and shock. T2 - AJNR Am J Neuroradiol TI - Posterior reversible encephalopathy syndrome in infection, sepsis, and shock. UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17110690 VL - 27 ID - 39 ER - TY - JOUR AB - OBJECTIVE: To evaluate plasma amino acid concentrations and markers of inflammation in the early stage and the course of septic encephalopathy. DESIGN: Prospective, case series of patients with well-defined septic encephalopathy. SETTING: Surgical department and intensive care unit of a university hospital. PATIENTS: Seventeen patients with sepsis according to the ACCP/SCCM consensus conference criteria and encephalopathy based on neuropsychological tests, compared to a control group undergoing uncomplicated thoracic surgery. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: SOFA score, blood samples for plasma amino acids, procalcitonin and interleukin-6. Sepsis was determined to be the cause of encephalopathy in 14 of the 17 patients. Six patients developed septic shock, four died within the study period of 28 days. Within 12 h of the onset of septic encephalopathy, mean values of PCT and IL-6 were elevated ( p<0.001) and the amino acids unbalanced (the ratio of branched-chain to aromatic amino acids was decreased, p<0.001). During the course of sepsis the decreased amino acid ratio was significantly, but moderately, correlated with elevated PCT and IL-6 levels. On study days when PCT was higher than 2 ng/ml, the amino acid ratio was significantly lower. In no patient was severe liver dysfunction seen. CONCLUSIONS: Metabolic disturbances with changes in amino acid levels can occur early in septic patients, without serious liver abnormalities. The present data suggest a possible role of amino acids in the pathogenesis of septic encephalopathy. AD - Klinik fur Anaesthesiologie und Intensivtherapie, University Hospital, Bachstrasse 18, 07743 Jena, Germany. AN - 11904658 AU - Basler, T. AU - Meier-Hellmann, A. AU - Bredle, D. AU - Reinhart, K. DA - Mar DO - 10.1007/s00134-002-1217-6 DP - NLM ET - 2002/03/21 KW - Amino Acids/ blood Biological Markers Brain Diseases, Metabolic/ blood Calcitonin/blood Case-Control Studies Female Humans Inflammation/blood Intensive Care Units Interleukin-6/blood Liver/metabolism Male Middle Aged Multiple Organ Failure/ blood Prospective Studies Protein Precursors/blood Sepsis/ blood/diagnosis LA - eng IS - 3 N1 - Basler, Thomas Meier-Hellmann, Andreas Bredle, Don Reinhart, Konrad United States Intensive care medicine Intensive Care Med. 2002 Mar;28(3):293-8. Epub 2002 Feb 8. PY - 2002 SN - 0342-4642 (Print) 0342-4642 (Linking) SP - 293-8 ST - Amino acid imbalance early in septic encephalopathy T2 - Intensive Care Med TI - Amino acid imbalance early in septic encephalopathy VL - 28 ID - 99 ER - TY - JOUR AB - Neurological problems are common among critically ill patients; they often signal that other organs are failing, but are themselves important causes of morbidity and mortality. Cognitive function may suffer as a consequence of septic encephalopathy, the pathophysiology of which is poorly understood; however, the affected patients usually return to their baseline when sepsis resolves. Seizures and cerebrovascular disorders are also common in the intensive care unit. Neuromuscular complications are important causes of failure to wean from mechanical ventilation and lead to substantial long-term morbidity. AD - Department of Neurology, University of Virginia School of Medicine, Charlottesville, Virginia 22908-0394, USA. tbleck@virginia.edu AN - 16791754 AU - Bleck, TP DA - Jun DO - 10.1055/s-2006-945531 KW - Diagnosis, Differential Humans Intensive Care Units Multicenter Studies as Topic Nervous System Diseases Prognosis Prospective Studies L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16791754 LA - eng IS - 3 PY - 2006 SN - 1069-3424 SP - 201-9 ST - Neurological disorders in the intensive care unit. T2 - Semin Respir Crit Care Med TI - Neurological disorders in the intensive care unit. UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16791754 VL - 27 ID - 40 ER - TY - JOUR AB - Brain dysfunction is frequently observed in sepsis as a consequence of changes in cerebral structure and metabolism, resulting in worse outcome and reduced life-quality of surviving patients. However, the mechanisms of sepsis-associated encephalopathy development and a better characterization of this syndrome in vivo are lacking. Here, we used magnetic resonance imaging (MRI) techniques to assess brain morphology and metabolism in a murine sepsis model (cecal ligation and puncture, CLP). Sham-operated and CLP mice were subjected to a complete MRI session at baseline, 6 and 24 h after surgery. Accumulation of vasogenic edematic fluid at the base of the brain was observed in T(2)-weighted image at 6 and 24 h after CLP. Also, the water apparent diffusion coefficients in both hippocampus and cortex were decreased, suggesting a cytotoxic edema in brains of nonsurvival septic animals. Moreover, the N-acetylaspartate/choline ratio was reduced in brains of septic mice, indicating neuronal damage. In conclusion, noninvasive assessment by MRI allowed the identification of new aspects of brain damage in sepsis, including cytotoxic and vasogenic edema as well as neuronal damage. These findings highlight the potential applications of MRI techniques for the diagnostic and therapeutic studies in sepsis. AD - ICU, Instituto de Pesquisa Clinica Evandro Chagas, Fundacao Oswaldo Cruz, Rio de Janeiro, Brazil. AN - 19844239 AU - Bozza, F. A. AU - Garteiser, P. AU - Oliveira, M. F. AU - Doblas, S. AU - Cranford, R. AU - Saunders, D. AU - Jones, I. AU - Towner, R. A. AU - Castro-Faria-Neto, H. C. DA - Feb DO - jcbfm2009215 [pii] 10.1038/jcbfm.2009.215 DP - NLM ET - 2009/10/22 KW - Animals Brain Diseases/etiology/ pathology Brain Mapping/ methods Diffusion Magnetic Resonance Imaging Mice Protons Sepsis/ complications LA - eng IS - 2 N1 - Bozza, Fernando A Garteiser, Philippe Oliveira, Marcus F Doblas, Sabrina Cranford, Rebecca Saunders, Debra Jones, Inna Towner, Rheal A Castro-Faria-Neto, Hugo C Research Support, Non-U.S. Gov't United States Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism J Cereb Blood Flow Metab. 2010 Feb;30(2):440-8. Epub 2009 Oct 21. PY - 2010 SN - 1559-7016 (Electronic) 0271-678X (Linking) SP - 440-8 ST - Sepsis-associated encephalopathy: a magnetic resonance imaging and spectroscopy study T2 - J Cereb Blood Flow Metab TI - Sepsis-associated encephalopathy: a magnetic resonance imaging and spectroscopy study VL - 30 ID - 55 ER - TY - JOUR AB - Brain dysfunction is frequently observed in sepsis as a consequence of changes in cerebral structure and metabolism, resulting in worse outcome and reduced life-quality of surviving patients. However, the mechanisms of sepsis-associated encephalopathy development and a better characterization of this syndrome in vivo are lacking. Here, we used magnetic resonance imaging (MRI) techniques to assess brain morphology and metabolism in a murine sepsis model (cecal ligation and puncture, CLP). Sham-operated and CLP mice were subjected to a complete MRI session at baseline, 6 and 24 h after surgery. Accumulation of vasogenic edematic fluid at the base of the brain was observed in T(2)-weighted image at 6 and 24 h after CLP. Also, the water apparent diffusion coefficients in both hippocampus and cortex were decreased, suggesting a cytotoxic edema in brains of nonsurvival septic animals. Moreover, the N-acetylaspartate/choline ratio was reduced in brains of septic mice, indicating neuronal damage. In conclusion, noninvasive assessment by MRI allowed the identification of new aspects of brain damage in sepsis, including cytotoxic and vasogenic edema as well as neuronal damage. These findings highlight the potential applications of MRI techniques for the diagnostic and therapeutic studies in sepsis. AD - ICU, Instituto de Pesquisa Clínica Evandro Chagas, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil. AN - 19844239 AU - Bozza, FA AU - Garteiser, P AU - Oliveira, MF AU - Doblas, S AU - Cranford, R AU - Saunders, D AU - Jones, I AU - Towner, RA AU - Castro-Faria-Neto, HC DA - Feb DO - jcbfm2009215 [pii] 10.1038/jcbfm.2009.215 KW - Animals Brain Diseases Brain Mapping Diffusion Magnetic Resonance Imaging Mice Protons Sepsis L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19844239 LA - eng IS - 2 PY - 2010 SN - 1559-7016 SP - 440-8 ST - Sepsis-associated encephalopathy: a magnetic resonance imaging and spectroscopy study. T2 - J Cereb Blood Flow Metab TI - Sepsis-associated encephalopathy: a magnetic resonance imaging and spectroscopy study. UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19844239 VL - 30 ID - 13 ER - TY - JOUR AB - Encephalopathy associated with septic shock as well as psychiatric disorders can be caused by the central nervous formation of reactive oxygen species (ROS) associated with inflammation. The systemic application of lipopolysaccharide (LPS, 100 mug/kg i.p.) also serves as a model for major depression and results in enhanced inflammatory processes. which are characterized by the stimulation of microglia or macrophages that then impair normal brain function. The aim of the present study was to analyze the effect of peripherally applied LPS on the central nervous formation of ROS and IL-6 in wild-type mice and in mice lacking the NADPH oxidase Nox2 subunit gp91phox. Microdialysis was performed in the striatum of the mice. Central nervous ROS were detected by electron spin resonance spectroscopy using 1-hydroxy-3-methoxycarbonyl-2,2,5,5-tetramethylpyrrolidine (CMH) as reactant, which was infused via a microdialysis probe. IL-6 was measured in microdialysis samples by an immunoassay. Finally, blood samples were taken by heart puncture to detect IL-6 in plasma. In the wild-type mice, LPS significantly increased the ROS formation in the striatum of wild-type mice and resulted in a significantly enhanced IL-6 production. In the mice lacking the NADPH oxidase Nox2 subunit gp91phox, LPS did not enhance ROS formation, while central IL-6 was significantly increased. IL-6 plasma values were enhanced in both types of mice. In conclusion, the gp91phox-containing NADPH oxidase complex is involved in the central nervous ROS formation after peripheral LPS stimulation and might be a pharmacological target in patients with septic shock. AD - Department of Child and Adolescent Psychiatry, University of Freiburg, Freiburg, Germany. hans-willi.clement@uniklinik-freiburg.de AN - 19866338 AU - Clement, HW AU - Vazquez, JF AU - Sommer, O AU - Heiser, P AU - Morawietz, H AU - Hopt, U AU - Schulz, E AU - von Dobschütz, E DA - Jan DO - 10.1007/s00702-009-0327-5 KW - Animals Brain Corpus Striatum Extracellular Space Interleukin-6 Lipopolysaccharides Male Membrane Glycoproteins Mice Mice, Inbred C57BL Mice, Knockout Microdialysis NADPH Oxidase Neuroimmunomodulation Reactive Oxygen Species Time Factors L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19866338 LA - eng IS - 1 PY - 2010 SN - 1435-1463 SP - 13-22 ST - Lipopolysaccharide-induced radical formation in the striatum is abolished in Nox2 gp91phox-deficient mice. T2 - J Neural Transm TI - Lipopolysaccharide-induced radical formation in the striatum is abolished in Nox2 gp91phox-deficient mice. UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19866338 VL - 117 ID - 12 ER - TY - JOUR AB - Sepsis is a major disease entity with important clinical implications. It is associated with a high mortality rate in humans. Recently, several studies have demonstrated that Intensive Care Unit survivors present long-term cognitive impairment, including alterations in memory, attention, concentration and/or global loss of cognitive function. The pathogenesis of septic encephalopathy and cognitive impairment are still poorly known and further understanding of these processes is necessary for the development of effective preventive and therapeutic interventions. Here we discuss the clinical presentation and underlying pathophysiology of the encephalopathy and neurobiology of the cognitive impairment associated with sepsis. AD - Laboratorio de Neurociencias and Instituto Nacional de Ciencia e Tecnologia Translacional em Medicina, Programa de Pos-Graduacao em Ciencias da Saude, Unidade Academica de Ciencias da Saude, Universidade do Extremo Sul Catarinense, SC, Brazil AN - 19534717 AU - Comim, C. M. AU - Constantino, L. C. AU - Barichello, T. AU - Streck, E. L. AU - Quevedo, J. AU - Dal-Pizzol, F. DA - Aug DO - AI/CNR-6/3-7 [pii] DP - NLM ET - 2009/06/19 KW - Animals Brain Diseases/drug therapy/ etiology Cognition Disorders/drug therapy/ etiology/pathology Disease Models, Animal Humans Models, Biological Neurobiology Sepsis/ complications/drug therapy/pathology LA - eng IS - 3 N1 - Comim, Clarissa M Constantino, Leandra C Barichello, Tatiana Streck, Emilio L Quevedo, Joao Dal-Pizzol, Felipe Research Support, Non-U.S. Gov't Review Netherlands Current neurovascular research Curr Neurovasc Res. 2009 Aug;6(3):194-203. Epub 2009 Aug 1. PY - 2009 SN - 1875-5739 (Electronic) SP - 194-203 ST - Cognitive impairment in the septic brain T2 - Curr Neurovasc Res TI - Cognitive impairment in the septic brain VL - 6 ID - 64 ER - TY - JOUR AB - Sepsis is a major disease entity with important clinical implications. It is associated with a high mortality rate in humans. Recently, several studies have demonstrated that Intensive Care Unit survivors present long-term cognitive impairment, including alterations in memory, attention, concentration and/or global loss of cognitive function. The pathogenesis of septic encephalopathy and cognitive impairment are still poorly known and further understanding of these processes is necessary for the development of effective preventive and therapeutic interventions. Here we discuss the clinical presentation and underlying pathophysiology of the encephalopathy and neurobiology of the cognitive impairment associated with sepsis. AD - Laboratório de Neurociências and Instituto Nacional de Ciência e Tecnologia Translacional em Medicina, Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, SC, Brazil AN - 19534717 AU - Comim, CM AU - Constantino, LC AU - Barichello, T AU - Streck, EL AU - Quevedo, J AU - Dal-Pizzol, F DA - Aug DO - AI/CNR-6/3-7 [pii] KW - Animals Brain Diseases Cognition Disorders Disease Models, Animal Humans Models, Biological Neurobiology Sepsis L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19534717 LA - eng IS - 3 PY - 2009 SN - 1875-5739 SP - 194-203 ST - Cognitive impairment in the septic brain. T2 - Curr Neurovasc Res TI - Cognitive impairment in the septic brain. UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19534717 VL - 6 ID - 16 ER - TY - JOUR AB - BACKGROUND: Chronic neurodegeneration results in microglial activation, but the contribution of inflammation to the progress of neurodegeneration remains unclear. We have shown that microglia express low levels of proinflammatory cytokines during chronic neurodegeneration but are "primed" to produce a more proinflammatory profile after systemic challenge with bacterial endotoxin (lipopolysaccharide [LPS]). METHODS: Here, we investigated whether intraperitoneal (IP) challenge with LPS, to mimic systemic infection, in the early stages of prion disease can 1) produce exaggerated acute behavioral (n = 9) and central nervous system (CNS) inflammatory (n = 4) responses in diseased animals compared with control animals, and 2) whether a single LPS challenge can accelerate disease progression (n = 34-35). RESULTS: Injection of LPS (100 microg/kg), at 12 weeks postinoculation (PI), resulted in heightened CNS interleukin-1 beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), and interferon-beta (IFN-beta) transcription and microglial IL-1beta translation in prion-diseased animals relative to control animals. This inflammation caused exaggerated impairments in burrowing and locomotor activity, and induced hypothermia and cognitive changes in prion-diseased animals that were absent in LPS-treated control animals. At 15 weeks PI, LPS (500 microg/kg) acutely impaired motor coordination and muscle strength in prion-diseased but not in control animals. After recovery, these animals also showed earlier onset of disease-associated impairments on these parameters. CONCLUSIONS: These data demonstrate that transient systemic inflammation superimposed on neurodegenerative disease acutely exacerbates cognitive and motor symptoms of disease and accelerates disease progression. These deleterious effects of systemic inflammation have implications for the treatment of chronic neurodegeneration and associated delirium. AD - Department of Biochemistry, Trinity College Institute of Neuroscience, Trinity College Dublin, Republic of Ireland. colm.cunningham@tcd.ie AN - 18801476 AU - Cunningham, C. AU - Campion, S. AU - Lunnon, K. AU - Murray, C. L. AU - Woods, J. F. AU - Deacon, R. M. AU - Rawlins, J. N. AU - Perry, V. H. C2 - 2633437 DA - Feb 15 DO - S0006-3223(08)00895-0 [pii] 10.1016/j.biopsych.2008.07.024 DP - NLM ET - 2008/09/20 KW - Animals Behavior, Animal/ physiology Body Temperature/drug effects Cognition/ physiology Female Immunohistochemistry Inflammation/ complications/ psychology Infusions, Parenteral Lipopolysaccharides/pharmacology Longitudinal Studies Maze Learning/drug effects Mice Mice, Inbred C57BL Motor Activity/drug effects Neurodegenerative Diseases/ etiology/ psychology Psychomotor Performance/physiology Reverse Transcriptase Polymerase Chain Reaction LA - eng IS - 4 N1 - Cunningham, Colm Campion, Suzanne Lunnon, Katie Murray, Carol L Woods, Jack F C Deacon, Robert M J Rawlins, J Nicholas P Perry, V Hugh Wellcome Trust/United Kingdom Research Support, Non-U.S. Gov't United States Biological psychiatry Biol Psychiatry. 2009 Feb 15;65(4):304-12. Epub 2008 Sep 18. PY - 2009 SN - 1873-2402 (Electronic) 0006-3223 (Linking) SP - 304-12 ST - Systemic inflammation induces acute behavioral and cognitive changes and accelerates neurodegenerative disease T2 - Biol Psychiatry TI - Systemic inflammation induces acute behavioral and cognitive changes and accelerates neurodegenerative disease VL - 65 ID - 115 ER - TY - JOUR AB - The contribution of inflammation to the progression of neurodegenerative diseases such as Alzheimer's, Parkinson's, and prion diseases is poorly understood. Brain inflammation in animal models of these diseases is dominated by chronic microglial activation with minimal proinflammatory cytokine expression. However, these inflammatory cells are "primed" to produce exaggerated inflammatory responses to subsequent lipopolysaccharide (LPS) challenges. We show that, using the ME7 model of prion disease, intracerebral challenge with LPS results in dramatic interleukin-1beta (IL-1beta) expression, neutrophil infiltration, and inducible nitric oxide synthase expression in the brain parenchyma of prion-diseased mice compared with the same challenge in normal mice. Systemic inflammation evoked by LPS also produced greater increases in proinflammatory cytokines, pentraxin 3, and inducible nitric oxide synthase transcription in prion-diseased mice than in control mice and induced microglial expression of IL-1beta. These systemic challenges also increased neuronal apoptosis in the brains of ME7 animals. Thus, both central and peripheral inflammation can exacerbate local brain inflammation and neuronal death. The finding that a single acute systemic inflammatory event can induce neuronal death in the CNS has implications for therapy in neurodegenerative diseases. AD - CNS Inflammation Group, School of Biological Sciences, Southampton, Hampshire SO16 7PX, United Kingdom. C.Cunningham@soton.ac.uk AN - 16207887 AU - Cunningham, C. AU - Wilcockson, D. C. AU - Campion, S. AU - Lunnon, K. AU - Perry, V. H. DA - Oct 5 DO - 25/40/9275 [pii] 10.1523/jneurosci.2614-05.2005 DP - NLM ET - 2005/10/07 KW - Animals C-Reactive Protein/metabolism Caspase 3 Caspases/metabolism Cell Count/methods Cell Death/ drug effects Chronic Disease Cytokines/metabolism Disease Models, Animal Drug Administration Routes Endotoxins/administration & dosage/ toxicity Female Gene Expression Regulation/drug effects Immunohistochemistry/methods In Situ Nick-End Labeling/methods Inflammation/chemically induced/physiopathology Interleukin-1/metabolism Lipopolysaccharides/ administration & dosage Mice Mice, Inbred C57BL Microglia/drug effects/metabolism/pathology Neurodegenerative Diseases/ pathology Neurofilament Proteins/metabolism Neurons/ drug effects/pathology Neutrophil Infiltration/drug effects/physiology Phosphopyruvate Hydratase/metabolism RNA, Messenger/metabolism Reverse Transcriptase Polymerase Chain Reaction/methods Serum Amyloid P-Component/metabolism Signal Transduction/drug effects LA - eng IS - 40 N1 - Cunningham, Colm Wilcockson, David C Campion, Suzanne Lunnon, Katie Perry, V Hugh Wellcome Trust/United Kingdom Comparative Study Research Support, Non-U.S. Gov't United States The Journal of neuroscience : the official journal of the Society for Neuroscience J Neurosci. 2005 Oct 5;25(40):9275-84. PY - 2005 SN - 1529-2401 (Electronic) 0270-6474 (Linking) SP - 9275-84 ST - Central and systemic endotoxin challenges exacerbate the local inflammatory response and increase neuronal death during chronic neurodegeneration T2 - J Neurosci TI - Central and systemic endotoxin challenges exacerbate the local inflammatory response and increase neuronal death during chronic neurodegeneration VL - 25 ID - 116 ER - TY - JOUR AB - Septic encephalopathy is associated with breakdown of the blood-brain barrier and cerebral oedema. These features are also common properties of brain tumours. Perimicrovessel oedema, disruption of associated astrocyte end feet and neuronal injury occur in a porcine model of acute septic encephalopathy. The adrenergic system has been implicated in the inflammatory response to sepsis and may play a role in controlling blood-brain barrier permeability, since the beta2-adrenoceptor agonist dopexamine inhibits perimicrovessel oedema formation whereas the alpha1-adrenoceptor agonist methoxamine provokes it. Electron microscopy revealed tight junction opening in high-grade astrocytoma microvessels. Expression of the tight junction protein occludin is reduced in these microvessels and this reduction is inversely correlated with the degree of cerebral oedema. Normal astrocytes secrete factors that induce barrier properties in endothelial cells, whereas high-grade astrocytomas secrete vascular endothelial growth factor, which stimulates angiogenesis, down regulates occludin and increases endothelial cell permeability. The water channel protein aquaporin-4 is normally expressed in astrocyte foot processes around cerebral microvessels. Its expression is massively up-regulated in high-grade astrocytoma and around metastatic adenocarcinoma. There is a significant correlation between aquaporin-4 expression and the degree of cerebral oedema, but it is not clear whether increased aquaporin-4 expression enhances oedema formation or clearance. These results suggest that the pathophysiology of brain oedema is multifactorial, but that there may be common processes operating regardless of the aetiology. AD - Department of Anatomy and Developmental Biology, St George's Hospital Medical School, Tooting, London, UK. daviesdc@sghms.ac.uk AN - 12162731 AU - Davies, D. C. C2 - 1570752 DA - Jun DP - NLM ET - 2002/08/07 KW - Aquaporin 4 Aquaporins/metabolism Astrocytoma/metabolism/ pathology Blood-Brain Barrier Brain Edema/metabolism/ microbiology/ pathology Brain Neoplasms/metabolism/ pathology Endothelium, Vascular/metabolism/ ultrastructure Humans Membrane Proteins/metabolism Sepsis/metabolism/ pathology Tight Junctions/metabolism LA - eng IS - 6 N1 - Davies, D C Review England Journal of anatomy J Anat. 2002 Jun;200(6):639-46. PY - 2002 SN - 0021-8782 (Print) 0021-8782 (Linking) SP - 639-46 ST - Blood-brain barrier breakdown in septic encephalopathy and brain tumours T2 - J Anat TI - Blood-brain barrier breakdown in septic encephalopathy and brain tumours VL - 200 ID - 97 ER - TY - JOUR AB - Reduced level of consciousness is a common clinical finding in acutely sick patients. In the majority of cases a cause for the encephalopathy is readily identifiable,whilst in a minority the aetiology is more difficult to ascertain. Frequently the onset of encephalopathy is associated with, or follows, infection. The mechanisms through which infection leads to encephalopathy are diverse. They range from direct microbial invasion of the brain or its supporting structures, to remote, infection-triggered mechanisms such as acute disseminated encephalomyelitis. Most common however, is the encephalopathy caused through a remote effect of systemic sepsis-septic encephalopathy. This article discusses the clinical presentation and underlying pathogeneses of the acute encephalopathies associated with infection, aiming to aid both their recognition and treatment. AD - Department of Neurology, Guy's & St Thomas' Hospitals NHS Trust, London, UK. nicholas.davies@kcl.ac.uk AN - 16715200 AU - Davies, N. W. AU - Sharief, M. K. AU - Howard, R. S. DA - Jul DO - 10.1007/s00415-006-0092-4 DP - NLM ET - 2006/05/23 KW - Brain/microbiology/pathology/ physiopathology Central Nervous System Bacterial Infections/diagnosis/ physiopathology/therapy Central Nervous System Viral Diseases/diagnosis/ physiopathology/therapy Demyelinating Diseases/diagnosis/physiopathology/therapy Encephalitis/diagnosis/ physiopathology/therapy Encephalomyelitis, Acute Disseminated/diagnosis/physiopathology/therapy Humans Nerve Fibers, Myelinated/pathology Systemic Inflammatory Response Syndrome/complications/physiopathology LA - eng IS - 7 N1 - Davies, N W S Sharief, M K Howard, R S Research Support, Non-U.S. Gov't Review Germany Journal of neurology J Neurol. 2006 Jul;253(7):833-45. Epub 2006 May 24. PY - 2006 SN - 0340-5354 (Print) 0340-5354 (Linking) SP - 833-45 ST - Infection-associated encephalopathies: their investigation, diagnosis, and treatment T2 - J Neurol TI - Infection-associated encephalopathies: their investigation, diagnosis, and treatment VL - 253 ID - 88 ER - TY - JOUR AB - Reduced level of consciousness is a common clinical finding in acutely sick patients. In the majority of cases a cause for the encephalopathy is readily identifiable,whilst in a minority the aetiology is more difficult to ascertain. Frequently the onset of encephalopathy is associated with, or follows, infection. The mechanisms through which infection leads to encephalopathy are diverse. They range from direct microbial invasion of the brain or its supporting structures, to remote, infection-triggered mechanisms such as acute disseminated encephalomyelitis. Most common however, is the encephalopathy caused through a remote effect of systemic sepsis-septic encephalopathy. This article discusses the clinical presentation and underlying pathogeneses of the acute encephalopathies associated with infection, aiming to aid both their recognition and treatment. AD - Department of Neurology, Guy's & St Thomas' Hospitals NHS Trust, London, UK. nicholas.davies@kcl.ac.uk AN - 16715200 AU - Davies, NW AU - Sharief, MK AU - Howard, RS DA - Jul DO - 10.1007/s00415-006-0092-4 KW - Brain Central Nervous System Bacterial Infections Central Nervous System Viral Diseases Demyelinating Diseases Encephalitis Encephalomyelitis, Acute Disseminated Humans Nerve Fibers, Myelinated Systemic Inflammatory Response Syndrome L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16715200 LA - eng IS - 7 PY - 2006 SN - 0340-5354 SP - 833-45 ST - Infection-associated encephalopathies: their investigation, diagnosis, and treatment. T2 - J Neurol TI - Infection-associated encephalopathies: their investigation, diagnosis, and treatment. UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16715200 VL - 253 ID - 42 ER - TY - JOUR AB - OBJECTIVE: Sepsis-associated delirium is a common and poorly understood neurological complication of sepsis. This review provides an update of the diagnostic criteria and treatment strategies and the current knowledge about the mechanisms involved in sepsis associated brain dysfunction. DATA SOURCES: Articles published between 1981 and 2006 were identified through a Medline search for "encephalopathy" and "sepsis" and by hand searching of articles cited in the identified publications. The immune response to sepsis results in multiorgan failure including brain dysfunction. DISCUSSION: The potential mechanisms for sepsis-associated delirium include vascular damage, endothelial activation, breakdown of the blood-brain barrier, metabolic disorders, brain inflammation and apoptosis. On the other hand, there is evidence for distinct neuroprotective factors, such as anti-inflammatory mediators and glial cell activity. CONCLUSIONS: The diagnosis of sepsis-associated delirium relies mainly on clinical and electrophysiological criteria, and its treatment is entirely based on general management of sepsis. AD - Universite de Versailles Saint Quentin, Service de Reanimation Medicale, Hopital Raymond Poincare (AP-HP), 104 Boulevard Raymond Poincare, 92380 Garches, France. AN - 17410344 AU - Ebersoldt, M. AU - Sharshar, T. AU - Annane, D. DA - Jun DO - 10.1007/s00134-007-0622-2 DP - NLM ET - 2007/04/06 KW - Delirium/ etiology France Humans Sepsis/complications/ psychology LA - eng IS - 6 N1 - Ebersoldt, Marion Sharshar, Tarek Annane, Djillali Review United States Intensive care medicine Intensive Care Med. 2007 Jun;33(6):941-50. Epub 2007 Apr 5. PY - 2007 SN - 0342-4642 (Print) 0342-4642 (Linking) SP - 941-50 ST - Sepsis-associated delirium T2 - Intensive Care Med TI - Sepsis-associated delirium VL - 33 ID - 83 ER - TY - JOUR AB - OBJECTIVE: To investigate antibiotic-mediated release of tumour necrosis factor (TNF)-alpha and norharman in patients with hospital-acquired pneumonia with and without additional septic encephalopathy. DESIGN: Prospective observational study with a retrospective post hoc analysis. SETTING: Surgical intensive care unit (ICU) at a university hospital. PATIENTS: Thirty-seven patients were consecutively included (9 patients with hospital-acquired pneumonia, 11 patients with hospital-acquired pneumonia and septic encephalopathy, 17 control patients) in the study. Pneumonia was defined according to the criteria of the American Thoracic Society. INTERVENTIONS: Patients received cephalosporins for antibiotic treatment of hospital-acquired pneumonia. Blood samples were taken before, immediately after and 4 h after application of cephalosporins. MEASUREMENTS AND RESULTS: Of the pneumonia patients, 55% developed septic encephalopathy. ICU stay, complications and mortality were significantly increased. An increased release of TNF-alpha was immediately seen in all pneumonia patients after antibiotics compared to controls, whereas the level did not differ between patients with and without septic encephalopathy. Norharman was significantly increased in pneumonia patients 4 h after antibiotic treatment, in tendency more enhanced in the pneumonia patients without encephalopathy. CONCLUSIONS: Patients with hospital-acquired pneumonia and septic encephalopathy had a significantly longer ICU stay with higher mortality rate compared to patients with hospital-acquired pneumonia alone. Antibiotic-mediated TNF-alpha release may induce the kynurenine pathway. TNF-alpha activates indolamine-2,3-dioxygenase with neurotoxic quinolinic acid as the end product. Norharman seems to counteract this mechanism and seems to play a role in neuroprotection. The worse outcome of patients with encephalopathy expresses the need to investigate protective factors and mechanisms. AD - Department of Anaesthesiology and Intensive Care Medicine, University Hospital Charite, Campus Mitte, Humboldt University Berlin, Schumannstrasse 20/21, 10117, Berlin, Germany. AN - 15112034 AU - Eggers, V. AU - Fugener, K. AU - Hein, O. V. AU - Rommelspacher, H. AU - Heyes, M. P. AU - Kox, W. J. AU - Spies, C. D. DA - Aug DO - 10.1007/s00134-004-2285-6 DP - NLM ET - 2004/04/28 KW - Adult Aged Aged, 80 and over Brain Diseases/ blood/etiology Cephalosporins/ therapeutic use Chi-Square Distribution Cross Infection/ blood/complications/ drug therapy Female Harmine/ analogs & derivatives/ blood Humans Intensive Care Units Male Middle Aged Pneumonia/ blood/complications/ drug therapy Prospective Studies Retrospective Studies Sepsis/ blood/etiology Statistics, Nonparametric Tumor Necrosis Factor-alpha/ metabolism LA - eng IS - 8 N1 - Eggers, Verena Fugener, Katja Hein, Ortrud Vargas Rommelspacher, Hans Heyes, Melvyn P Kox, Wolfgang J Spies, Claudia D United States Intensive care medicine Intensive Care Med. 2004 Aug;30(8):1544-51. Epub 2004 Apr 27. PY - 2004 SN - 0342-4642 (Print) 0342-4642 (Linking) SP - 1544-51 ST - Antibiotic-mediated release of tumour necrosis factor alpha and norharman in patients with hospital-acquired pneumonia and septic encephalopathy T2 - Intensive Care Med TI - Antibiotic-mediated release of tumour necrosis factor alpha and norharman in patients with hospital-acquired pneumonia and septic encephalopathy VL - 30 ID - 90 ER - TY - JOUR AB - INTRODUCTION: Permeability changes in the blood-brain barrier (BBB) and their possible contribution to brain edema formation have a crucial role in the pathophysiology of septic encephalopathy. Magnesium sulfate has been shown to have a protective effect on BBB integrity in multiple experimental models. In this study we determine whether magnesium sulfate administration could have any protective effects on BBB derangement in a rat model of sepsis. METHODS: This randomized controlled experimental study was performed on adult male Sprague-Dawley rats. Intraperitoneal sepsis was induced by using the infected fibrin-thrombin clot model. To examine the effect of magnesium in septic and sham-operated rats, a dose of 750 micromol/kg magnesium sulfate was given intramuscularly immediately after surgery. Control groups for both infected and sham-operated rats were injected with equal volume of saline. Those rats surviving for 24 hours were anesthetized and decapitated for the investigation of brain tissue specific gravity and BBB integrity by the spectrophotometric assay of Evans blue dye extravasations. Another set of experiments was performed for hemodynamic measurements and plasma magnesium level analysis. Rats were allocated into four parallel groups undergoing identical procedures. RESULTS: Sepsis significantly increased BBB permeability to Evans blue. The dye content of each hemisphere was significantly lower in the magnesium-treated septic rats (left hemisphere, 0.00218 +/- 0.0005; right hemisphere, 0.00199 +/- 0.0007 [all results are means +/- standard deviation]) than in control septic animals (left hemisphere, 0.00466 +/- 0.0002; right hemisphere, 0.00641 +/- 0.0003). In septic animals treated with magnesium sulfate, specific gravity was higher (left hemisphere, 1.0438 +/- 0.0007; right hemisphere, 1.0439 +/- 0.0004) than in the untreated septic animals (left hemisphere, 1.0429 +/- 0.0009; right hemisphere, 1.0424 +/- 0.0012), indicating less edema formation with the administration of magnesium. A significant decrease in plasma magnesium levels was observed 24 hours after the induction of sepsis. The dose of magnesium that we used maintained the baseline plasma magnesium levels in magnesium-treated septic rats. CONCLUSIONS: Magnesium administration attenuated the increased BBB permeability defect and caused a reduction in brain edema formation in our rat model of intraperitoneal sepsis. AD - University of Istanbul, Istanbul Faculty of Medicine, Department of Anesthesiology and Intensive Care, Istanbul, Turkey. esenf@istanbul.edu.tr AN - 15693962 AU - Esen, F AU - Erdem, T AU - Aktan, D AU - Orhan, M AU - Kaya, M AU - Eraksoy, H AU - Cakar, N AU - Telci, L C2 - PMC1065104 DA - Feb DO - cc3004 [pii] 10.1186/cc3004 KW - Animals Anticonvulsants Blood Pressure Blood-Brain Barrier Brain Edema Cell Membrane Permeability Magnesium Magnesium Sulfate Male Rats Rats, Sprague-Dawley Sepsis L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15693962 LA - eng IS - 1 PY - 2005 SN - 1466-609X SP - R18-23 ST - Effect of magnesium sulfate administration on blood-brain barrier in a rat model of intraperitoneal sepsis: a randomized controlled experimental study. T2 - Crit Care TI - Effect of magnesium sulfate administration on blood-brain barrier in a rat model of intraperitoneal sepsis: a randomized controlled experimental study. UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15693962 VL - 9 ID - 49 ER - TY - JOUR AB - BACKGROUND: During sepsis, the dysfunction of blood-brain barrier (BBB) was mediated by inflammation and subsequently caused sepsis-associated encephalopathy. Hydroxyethyl starch (HES, 130/0.4) is most widely used for volume replacement to maintain or improve tissue perfusion in patients with sepsis, trauma, and shock. This study was undertaken to investigate the effects of HES on BBB permeability, brain edema, inflammatory response and clinical outcome in septic rats. METHODS: Using the cecal ligation and puncture (CLP) model, Sprague-Dawley rats were treated with 15 ml/kg HES or normal saline 4h after the operation. Two hours later, expressions of brain toll-like receptor (TLR)-2, TLR4 and intercellular adhesion molecule (ICAM)-1 mRNA was determined by real-time reverse transcription-polymerase chain reaction; inflammatory cytokines like tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 by enzyme-linked immunosorbent assay; activity of nuclear factor-kappa B (NF-kappaB) by electrophoretic mobility shift assay; BBB permeability by Evans blue extravasation method; brain edema by wet/dry weight ratio. Weight loss, and clinical symptoms were also observed. RESULTS: Without obvious influence on systemic macrohemodynamics, HES could markedly attenuate BBB dysfunction and brain edema. Meanwhile, HES could significantly reduce TNF-alpha, IL-6, and ICAM-1 mRNA, inhibit NF-kappaB activation, and down-regulate TLR2 and TLR4 expression in the brain. In addition, CLP-induced increase in weight loss, and clinical symptoms was not reduced after treatment with HES. CONCLUSIONS: HES could ameliorate BBB dysfunction and inflammation mediators by modulating brain TLR2 and TLR4 expression during sepsis. However, HES could not improve clinical outcome. AD - Department of Anesthesiology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, PR China. AN - 20451670 AU - Feng, X AU - Zhang, F AU - Dong, R AU - Wang, H AU - Liu, J AU - Liu, X AU - Li, W AU - Yao, J AU - Xu, J AU - Yu, B DA - Aug DO - S1567-5769(10)00134-7 [pii] 10.1016/j.intimp.2010.04.020 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=20451670 LA - eng IS - 8 PY - 2010 SN - 1878-1705 SP - 859-64 ST - Effects of hydroxyethyl starch (130 kD) on brain inflammatory response and outcome during normotensive sepsis. T2 - Int Immunopharmacol TI - Effects of hydroxyethyl starch (130 kD) on brain inflammatory response and outcome during normotensive sepsis. UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=20451670 VL - 10 ID - 5 ER - TY - JOUR AB - A 48 year old woman, status post renal transplantation six years earlier, died after a two week illness characterised by fever, recurrent seizures, and coma. Widespread abnormalities were seen on neuroimaging. A diagnosis of septic encephalopathy was established on postmortem. We describe the magnetic resonance imaging findings of bilateral basal ganglia, thalamic, cerebellar, brainstem, and cerebral abnormalities in this patient, which correlate with the pathophysiology of septic encephalopathy. AD - Departments of Neurology and Pathology, Hartford Hospital, University of Connecticut School of Medicine, Hartford 06102-5037, USA. Pfinell@harthosp.org AN - 15258229 AU - Finelli, PF AU - Uphoff, DF C2 - PMC1739149 DA - Aug DO - 75/8/1189 [pii] 10.1136/jnnp.2003.030833 KW - Brain Brain Diseases Female Humans Magnetic Resonance Imaging Middle Aged Sepsis L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15258229 LA - eng IS - 8 PY - 2004 SN - 0022-3050 SP - 1189-91 ST - Magnetic resonance imaging abnormalities with septic encephalopathy. T2 - J Neurol Neurosurg Psychiatry TI - Magnetic resonance imaging abnormalities with septic encephalopathy. UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15258229 VL - 75 ID - 50 ER - TY - JOUR AB - The exact cellular and molecular mechanisms of sepsis-induced encephalopathy remain elusive. The breakdown of the blood-brain barrier (BBB) is considered a focal point in the development of sepsis-induced brain damage. Contributing factors for the compromise of the BBB include cytokines and chemokines, activation of the complement cascade, phagocyte-derived toxic mediators, and bacterial products. To date, we are far from fully understanding the neuropathology that develops as a secondary remote organ injury as a consequence of sepsis. However, recent studies suggest that bacterial proteins may readily cross the functional BBB and trigger an inflammatory response in the subarachnoid space, in absence of a bacterial invasion. A better understanding of the pathophysiological events leading to septic encephalopathy appears crucial to advance the clinical care for this vulnerable patient population. AD - Department of Orthopaedic Surgery, University of Colorado School of Medicine, Denver Health Medical Center, 777 Bannock Street, Denver, CO 80204, USA. michael.flierl@dhha.org AN - 20565858 AU - Flierl, M. A. AU - Rittirsch, D. AU - Huber-Lang, M. S. AU - Stahel, P. F. C2 - 2911737 DO - cc9035 [pii] 10.1186/cc9035 DP - NLM ET - 2010/06/23 LA - eng IS - 3 N1 - Flierl, Michael A Rittirsch, Daniel Huber-Lang, Markus S Stahel, Philip F Comment England Critical care (London, England) Crit Care. 2010;14(3):165. Epub 2010 Jun 16. PY - 2010 SN - 1466-609X (Electronic) 1364-8535 (Linking) SP - 165 ST - Pathophysiology of septic encephalopathy--an unsolved puzzle T2 - Crit Care TI - Pathophysiology of septic encephalopathy--an unsolved puzzle VL - 14 ID - 56 ER - TY - JOUR AB - INTRODUCTION: Septic encephalopathy secondary to a breakdown of the blood-brain barrier (BBB) is a known complication of sepsis. However, its pathophysiology remains unclear. The present study investigated the effect of complement C5a blockade in preventing BBB damage and pituitary dysfunction during experimental sepsis. METHODS: Using the standardised caecal ligation and puncture (CLP) model, Sprague-Dawley rats were treated with either neutralising anti-C5a antibody or pre-immune immunoglobulin (Ig) G as a placebo. Sham-operated animals served as internal controls. RESULTS: Placebo-treated septic rats showed severe BBB dysfunction within 24 hours, accompanied by a significant upregulation of pituitary C5a receptor and pro-inflammatory cytokine expression, although gene levels of growth hormone were significantly attenuated. The pathophysiological changes in placebo-treated septic rats were restored by administration of neutralising anti-C5a antibody to the normal levels of BBB and pituitary function seen in the sham-operated group. CONCLUSIONS: Collectively, the neutralisation of C5a greatly ameliorated pathophysiological changes associated with septic encephalopathy, implying a further rationale for the concept of pharmacological C5a inhibition in sepsis. AD - Department of Orthopaedic Surgery, Denver Health Medical Center, University of Colorado School of Medicine, Denver, CO 80204, USA. michael.flierl@dhha.org AN - 19196477 AU - Flierl, M. A. AU - Stahel, P. F. AU - Rittirsch, D. AU - Huber-Lang, M. AU - Niederbichler, A. D. AU - Hoesel, L. M. AU - Touban, B. M. AU - Morgan, S. J. AU - Smith, W. R. AU - Ward, P. A. AU - Ipaktchi, K. C2 - 2688129 DO - cc7710 [pii] 10.1186/cc7710 DP - NLM ET - 2009/02/07 KW - Animals Blood-Brain Barrier/drug effects/ metabolism Complement C5a/ antagonists & inhibitors/ immunology Immunoglobulin G/pharmacology/therapeutic use Male Pituitary Diseases/ metabolism/physiopathology/ prevention & control Rats Rats, Sprague-Dawley Receptor, Anaphylatoxin C5a/antagonists & inhibitors/biosynthesis Sepsis/complications/drug therapy/ metabolism LA - eng IS - 1 N1 - Flierl, Michael A Stahel, Philip F Rittirsch, Daniel Huber-Lang, Markus Niederbichler, Andreas D Hoesel, L Marco Touban, Basel M Morgan, Steven J Smith, Wade R Ward, Peter A Ipaktchi, Kyros Comparative Study England Critical care (London, England) Crit Care. 2009;13(1):R12. Epub 2009 Feb 6. PY - 2009 SN - 1466-609X (Electronic) 1364-8535 (Linking) SP - R12 ST - Inhibition of complement C5a prevents breakdown of the blood-brain barrier and pituitary dysfunction in experimental sepsis T2 - Crit Care TI - Inhibition of complement C5a prevents breakdown of the blood-brain barrier and pituitary dysfunction in experimental sepsis VL - 13 ID - 70 ER - TY - JOUR AB - The exact cellular and molecular mechanisms of sepsis-induced encephalopathy remain elusive. The breakdown of the blood-brain barrier (BBB) is considered a focal point in the development of sepsis-induced brain damage. Contributing factors for the compromise of the BBB include cytokines and chemokines, activation of the complement cascade, phagocyte-derived toxic mediators, and bacterial products. To date, we are far from fully understanding the neuropathology that develops as a secondary remote organ injury as a consequence of sepsis. However, recent studies suggest that bacterial proteins may readily cross the functional BBB and trigger an inflammatory response in the subarachnoid space, in absence of a bacterial invasion. A better understanding of the pathophysiological events leading to septic encephalopathy appears crucial to advance the clinical care for this vulnerable patient population. AD - Department of Orthopaedic Surgery, University of Colorado School of Medicine, Denver Health Medical Center, 777 Bannock Street, Denver, CO 80204, USA. michael.flierl@dhha.org AN - 20565858 AU - Flierl, MA AU - Rittirsch, D AU - Huber-Lang, MS AU - Stahel, PF C2 - PMC2911737 DO - cc9035 [pii] 10.1186/cc9035 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=20565858 LA - eng IS - 3 PY - 2010 SN - 1466-609X SP - 165 ST - Pathophysiology of septic encephalopathy--an unsolved puzzle. T2 - Crit Care TI - Pathophysiology of septic encephalopathy--an unsolved puzzle. UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=20565858 VL - 14 ID - 3 ER - TY - JOUR AB - INTRODUCTION: Septic encephalopathy secondary to a breakdown of the blood-brain barrier (BBB) is a known complication of sepsis. However, its pathophysiology remains unclear. The present study investigated the effect of complement C5a blockade in preventing BBB damage and pituitary dysfunction during experimental sepsis. METHODS: Using the standardised caecal ligation and puncture (CLP) model, Sprague-Dawley rats were treated with either neutralising anti-C5a antibody or pre-immune immunoglobulin (Ig) G as a placebo. Sham-operated animals served as internal controls. RESULTS: Placebo-treated septic rats showed severe BBB dysfunction within 24 hours, accompanied by a significant upregulation of pituitary C5a receptor and pro-inflammatory cytokine expression, although gene levels of growth hormone were significantly attenuated. The pathophysiological changes in placebo-treated septic rats were restored by administration of neutralising anti-C5a antibody to the normal levels of BBB and pituitary function seen in the sham-operated group. CONCLUSIONS: Collectively, the neutralisation of C5a greatly ameliorated pathophysiological changes associated with septic encephalopathy, implying a further rationale for the concept of pharmacological C5a inhibition in sepsis. AD - Department of Orthopaedic Surgery, Denver Health Medical Center, University of Colorado School of Medicine, Denver, CO 80204, USA. michael.flierl@dhha.org AN - 19196477 AU - Flierl, MA AU - Stahel, PF AU - Rittirsch, D AU - Huber-Lang, M AU - Niederbichler, AD AU - Hoesel, LM AU - Touban, BM AU - Morgan, SJ AU - Smith, WR AU - Ward, PA AU - Ipaktchi, K C2 - PMC2688129 DO - cc7710 [pii] 10.1186/cc7710 KW - Animals Blood-Brain Barrier Complement C5a Immunoglobulin G Male Pituitary Diseases Rats Rats, Sprague-Dawley Receptor, Anaphylatoxin C5a Sepsis L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19196477 LA - eng IS - 1 PY - 2009 SN - 1466-609X SP - R12 ST - Inhibition of complement C5a prevents breakdown of the blood-brain barrier and pituitary dysfunction in experimental sepsis. T2 - Crit Care TI - Inhibition of complement C5a prevents breakdown of the blood-brain barrier and pituitary dysfunction in experimental sepsis. UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19196477 VL - 13 ID - 18 ER - TY - JOUR AB - Relapsing fever (RF) is a multisystemic borrelial infection with frequent neurologic involvement referred to as neuroborreliosis. The absence of an effective antibody response results in persistent infection. To study the consequences to the brain of persistent infection with the RF spirochete Borrelia turicatae, we studied B cell (Igh6-/-) and B and T (Rag1-/-) cell-deficient mice inoculated with isogenic serotypes 1 (Bt1) or 2 (Bt2). We found that Bt1 was more tissue tropic than Bt2, not only for brain but also for heart. Igh6-/- mice developed more severe clinical disease than Rag1-/- mice. Bt1-infected brains had widespread microgliosis/brain macrophage activation despite localization of spirochetes in the leptomeninges rather than the brain parenchyma itself. Oligoarray analysis revealed that CXCL13 was the most upregulated gene in the brain of Bt1-infected Igh6-/- mice. CXCL13 was also the most abundant of the chemokines we measured in infected blood. Persistent infection did not result in injury to the brain. Treatment with exogenous interleukin-10 reduced microgliosis in the brain and production of CXCL13 in the blood. We concluded that brain involvement in B cell-deficient mice persistently infected with B. turicatae is characterized by prominent microgliosis and production of CXCL13 without detectable injury. AD - Department of Neurology and Neuroscience and Center for Emerging Pathogens, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, New Jersey, USA. AN - 17356382 AU - Gelderblom, H. AU - Londono, D. AU - Bai, Y. AU - Cabral, E. S. AU - Quandt, J. AU - Hornung, R. AU - Martin, R. AU - Marques, A. AU - Cadavid, D. DA - Mar DO - 10.1097/01.jnen.0000248556.30209.6d 00005072-200703000-00005 [pii] DP - NLM ET - 2007/03/16 KW - Animals B-Lymphocytes/physiology Borrelia/classification Borrelia Infections/ metabolism/microbiology/pathology Brain/ metabolism/microbiology Chemokine CXCL13 Chemokines, CXC/ metabolism Enzyme-Linked Immunosorbent Assay/methods Gene Expression Regulation, Bacterial/drug effects Heart/microbiology Interleukin-10/pharmacology Mice Mice, Inbred C57BL Oligonucleotide Array Sequence Analysis/methods RNA, Messenger/biosynthesis Relapsing Fever/ metabolism/microbiology/ pathology Reverse Transcriptase Polymerase Chain Reaction/methods Statistics, Nonparametric LA - eng IS - 3 N1 - Gelderblom, Harald Londono, Diana Bai, Yunhong Cabral, Erik S Quandt, Jacqueline Hornung, Ron Martin, Roland Marques, Adriana Cadavid, Diego N01-CO-12400/CO/NCI NIH HHS/United States Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't United States Journal of neuropathology and experimental neurology J Neuropathol Exp Neurol. 2007 Mar;66(3):208-17. PY - 2007 SN - 0022-3069 (Print) 0022-3069 (Linking) SP - 208-17 ST - High production of CXCL13 in blood and brain during persistent infection with the relapsing fever spirochete Borrelia turicatae T2 - J Neuropathol Exp Neurol TI - High production of CXCL13 in blood and brain during persistent infection with the relapsing fever spirochete Borrelia turicatae VL - 66 ID - 103 ER - TY - JOUR AB - Sepsis associated encephalopathy (SAE) is a poorly understood condition that is associated with severe sepsis and appears to have a negative influence on survival. The incidence of encephalopathy secondary to sepsis is unknown. Amino acid derangements, blood-brain barrier disruption, abnormal neurotransmitters, and direct CNS effect are possible causes of septic encephalopathy. Research has not defined the pathogenesis of SAE. AD - Critical Care Medicine, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71130, USA. AN - 14977574 AU - Green, R. AU - Scott, L. K. AU - Minagar, A. AU - Conrad, S. DA - May 1 DP - NLM ET - 2004/02/24 KW - Amino Acids/metabolism Blood-Brain Barrier/metabolism Brain Diseases/epidemiology/etiology/ microbiology Humans Incidence Neurotransmitter Agents/metabolism Sepsis/ complications/epidemiology LA - eng N1 - Green, Rebecca Scott, L Keith Minagar, Alireza Conrad, Steven Review United States Frontiers in bioscience : a journal and virtual library Front Biosci. 2004 May 1;9:1637-41. PY - 2004 SN - 1093-4715 (Electronic) 1093-4715 (Linking) SP - 1637-41 ST - Sepsis associated encephalopathy (SAE): a review T2 - Front Biosci TI - Sepsis associated encephalopathy (SAE): a review VL - 9 ID - 91 ER - TY - JOUR AB - Severe septic illness is often associated with cerebral manifestations such was disturbed consciousness and delirium. Little was known about its effect on the CNS. This is the first study in children that has assessed the direct mediators of brain inflammation and injury with sepsis. The serum and CSF concentrations of soluble intracellular adhesion molecule-1 (sICAM-1) (marker of endothelium-leukocyte interaction), nitric oxide (NO) and lipid peroxide (LPO) (markers for lipid peroxidation) and S-100B protein (marker of astrocytes activation and injury), were measured in 40 children with sepsis of whom 40% had moderate to severe septic encephalopathy. Serum from 25 normal children was used for comparison. Serum values of sICAM-1, NO, LPO and S100B were elevated in patients compared to controls. The greater elevation of the CSF:serum albumin ratio suggests loss of blood-brain barrier integrity. After normalising for CSF:serum albumin ratio, we demonstrated a significant intrathecal synthesis of NO, LPO and S100B. Patients with encephalopathy had elevated serum and CSF levels of sICAM-1, NO, LPO and S100B compared to sepsis only. This study indicates that the brain is vulnerable in children with sepsis. It also suggests that coordinated interactions between immune system, vascular endothelial cells, CNS barriers, astrocytes and brain lipid peroxides, may contribute to septic encephalopathy. AD - Department of Neurology, Assiut University Hospital, Assiut, Egypt. AN - 19809934 AU - Hamed, S. A. AU - Hamed, E. A. AU - Abdella, M. M. DA - Apr DO - 10.1055/s-0029-1231054 DP - NLM ET - 2009/10/08 KW - Adolescent Analysis of Variance Brain Diseases/blood/cerebrospinal fluid/enzymology/etiology/microbiology Cell Adhesion Molecules/blood/cerebrospinal fluid Child Child, Preschool Enzyme-Linked Immunosorbent Assay/methods Female Humans Infant Infant, Newborn Lipid Peroxides/blood/cerebrospinal fluid Male Nerve Growth Factors/blood/cerebrospinal fluid S100 Proteins/blood/cerebrospinal fluid Sepsis/ complications Statistics, Nonparametric LA - eng IS - 2 N1 - Hamed, S A Hamed, E A Abdella, M M Germany Neuropediatrics Neuropediatrics. 2009 Apr;40(2):66-72. Epub 2009 Oct 6. PY - 2009 SN - 1439-1899 (Electronic) 0174-304X (Linking) SP - 66-72 ST - Septic encephalopathy: relationship to serum and cerebrospinal fluid levels of adhesion molecules, lipid peroxides and S-100B protein T2 - Neuropediatrics TI - Septic encephalopathy: relationship to serum and cerebrospinal fluid levels of adhesion molecules, lipid peroxides and S-100B protein VL - 40 ID - 67 ER - TY - JOUR AB - Severe septic illness is often associated with cerebral manifestations such was disturbed consciousness and delirium. Little was known about its effect on the CNS. This is the first study in children that has assessed the direct mediators of brain inflammation and injury with sepsis. The serum and CSF concentrations of soluble intracellular adhesion molecule-1 (sICAM-1) (marker of endothelium-leukocyte interaction), nitric oxide (NO) and lipid peroxide (LPO) (markers for lipid peroxidation) and S-100B protein (marker of astrocytes activation and injury), were measured in 40 children with sepsis of whom 40% had moderate to severe septic encephalopathy. Serum from 25 normal children was used for comparison. Serum values of sICAM-1, NO, LPO and S100B were elevated in patients compared to controls. The greater elevation of the CSF:serum albumin ratio suggests loss of blood-brain barrier integrity. After normalising for CSF:serum albumin ratio, we demonstrated a significant intrathecal synthesis of NO, LPO and S100B. Patients with encephalopathy had elevated serum and CSF levels of sICAM-1, NO, LPO and S100B compared to sepsis only. This study indicates that the brain is vulnerable in children with sepsis. It also suggests that coordinated interactions between immune system, vascular endothelial cells, CNS barriers, astrocytes and brain lipid peroxides, may contribute to septic encephalopathy. AD - Department of Neurology, Assiut University Hospital, Assiut, Egypt. AN - 19809934 AU - Hamed, SA AU - Hamed, EA AU - Abdella, MM DA - Apr DO - 10.1055/s-0029-1231054 KW - Adolescent Analysis of Variance Brain Diseases Cell Adhesion Molecules Child Child, Preschool Enzyme-Linked Immunosorbent Assay Female Humans Infant Infant, Newborn Lipid Peroxides Male Nerve Growth Factors S100 Proteins Sepsis Statistics, Nonparametric L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19809934 LA - eng IS - 2 PY - 2009 SN - 1439-1899 SP - 66-72 ST - Septic encephalopathy: relationship to serum and cerebrospinal fluid levels of adhesion molecules, lipid peroxides and S-100B protein. T2 - Neuropediatrics TI - Septic encephalopathy: relationship to serum and cerebrospinal fluid levels of adhesion molecules, lipid peroxides and S-100B protein. UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19809934 VL - 40 ID - 14 ER - TY - JOUR AB - Sepsis-associated encephalopathy is an early manifestation of sepsis, resulting in a diffuse dysfunction of the brain. Recently, nitric oxide (NO) has been proposed to be one of the key molecules involved in the modulation of inflammatory responses in the brain. The aim of this study was to assess the role of NO in cerebrovascular endothelial cell activation/dysfunction during the early onsets of sepsis. To this end, we employed an in vitro model of sepsis in which cultured mouse cerebrovascular endothelial cells (MCVEC) were challenged with blood plasma (20% vol/vol) obtained from sham or septic (feces-induced peritonitis, FIP; 6 h) mice. Exposing MCVEC to FIP plasma for 1 h resulted in increased production of reactive oxygen species and NO as assessed by intracellular oxidation of oxidant-sensitive fluorochrome, dihydrorhodamine 123 (DHR 123), and nitrosation of NO-specific probe, DAF-FM, respectively. The latter events were accompanied by dissociation of tight junction protein, occludin, from MCVEC cytoskeletal framework and a subsequent increase in FITC-dextran (3-kDa mol mass) flux across MCVEC grown on the permeable cell culture supports, whereas Evans blue-BSA (65-kDa mol mass) or FITC-dextran (10-kDa mol mass) flux were not affected. FIP plasma-induced oxidant stress, occludin rearrangement, and MCVEC permeability were effectively attenuated by antioxidant, 1-pyrrolidinecarbodithioic acid (PDTC; 0.5 mM), or interfering with nitric oxide synthase (NOS) activity [0.1 mM nitro-L-arginine methyl ester (L-NAME) or endothelial NOS (eNOS)-deficient MCVEC]. However, treatment of MCVEC with PDTC failed to interfere with NO production, suggesting that septic plasma-induced oxidant stress in MCVEC is primarily a NO-dependent event. Taken together, these data indicate that during early sepsis, eNOS-derived NO exhibits proinflammatory characteristics and contributes to the activation and dysfunction of cerebrovascular endothelial cells. AD - Centre for Critical Illness Research, Lawson Health Research Institute, London, Ontario, Canada. AN - 18723768 AU - Handa, O. AU - Stephen, J. AU - Cepinskas, G. C2 - 2593506 DA - Oct DO - 00476.2008 [pii] 10.1152/ajpheart.00476.2008 DP - NLM ET - 2008/08/30 KW - Animals Antioxidants/pharmacology Brain/ blood supply Cell Membrane Permeability/drug effects Cells, Cultured Disease Models, Animal Endothelium, Vascular/drug effects/ enzymology/physiopathology Enzyme Inhibitors/pharmacology Membrane Proteins/metabolism Mice Mice, Inbred C57BL Mice, Knockout Nitric Oxide/ metabolism Nitric Oxide Synthase Type II/antagonists & inhibitors/deficiency/genetics/ metabolism Nitric Oxide Synthase Type III Oxidative Stress Reactive Oxygen Species/metabolism Sepsis/blood/ enzymology/physiopathology Time Factors LA - eng IS - 4 N1 - Handa, Osamu Stephen, Jancy Cepinskas, Gediminas Research Support, Non-U.S. Gov't United States American journal of physiology. Heart and circulatory physiology Am J Physiol Heart Circ Physiol. 2008 Oct;295(4):H1712-9. Epub 2008 Aug 22. PY - 2008 SN - 0363-6135 (Print) 0363-6135 (Linking) SP - H1712-9 ST - Role of endothelial nitric oxide synthase-derived nitric oxide in activation and dysfunction of cerebrovascular endothelial cells during early onsets of sepsis T2 - Am J Physiol Heart Circ Physiol TI - Role of endothelial nitric oxide synthase-derived nitric oxide in activation and dysfunction of cerebrovascular endothelial cells during early onsets of sepsis VL - 295 ID - 73 ER - TY - JOUR AB - Sepsis-associated encephalopathy is an early manifestation of sepsis, resulting in a diffuse dysfunction of the brain. Recently, nitric oxide (NO) has been proposed to be one of the key molecules involved in the modulation of inflammatory responses in the brain. The aim of this study was to assess the role of NO in cerebrovascular endothelial cell activation/dysfunction during the early onsets of sepsis. To this end, we employed an in vitro model of sepsis in which cultured mouse cerebrovascular endothelial cells (MCVEC) were challenged with blood plasma (20% vol/vol) obtained from sham or septic (feces-induced peritonitis, FIP; 6 h) mice. Exposing MCVEC to FIP plasma for 1 h resulted in increased production of reactive oxygen species and NO as assessed by intracellular oxidation of oxidant-sensitive fluorochrome, dihydrorhodamine 123 (DHR 123), and nitrosation of NO-specific probe, DAF-FM, respectively. The latter events were accompanied by dissociation of tight junction protein, occludin, from MCVEC cytoskeletal framework and a subsequent increase in FITC-dextran (3-kDa mol mass) flux across MCVEC grown on the permeable cell culture supports, whereas Evans blue-BSA (65-kDa mol mass) or FITC-dextran (10-kDa mol mass) flux were not affected. FIP plasma-induced oxidant stress, occludin rearrangement, and MCVEC permeability were effectively attenuated by antioxidant, 1-pyrrolidinecarbodithioic acid (PDTC; 0.5 mM), or interfering with nitric oxide synthase (NOS) activity [0.1 mM nitro-L-arginine methyl ester (L-NAME) or endothelial NOS (eNOS)-deficient MCVEC]. However, treatment of MCVEC with PDTC failed to interfere with NO production, suggesting that septic plasma-induced oxidant stress in MCVEC is primarily a NO-dependent event. Taken together, these data indicate that during early sepsis, eNOS-derived NO exhibits proinflammatory characteristics and contributes to the activation and dysfunction of cerebrovascular endothelial cells. AD - Centre for Critical Illness Research, Lawson Health Research Institute, London, Ontario, Canada. AN - 18723768 AU - Handa, O AU - Stephen, J AU - Cepinskas, G C2 - PMC2593506 DA - Oct DO - 00476.2008 [pii] 10.1152/ajpheart.00476.2008 KW - Animals Antioxidants Brain Cell Membrane Permeability Cells, Cultured Disease Models, Animal Endothelium, Vascular Enzyme Inhibitors Membrane Proteins Mice Mice, Inbred C57BL Mice, Knockout Nitric Oxide Nitric Oxide Synthase Type II Nitric Oxide Synthase Type III Oxidative Stress Reactive Oxygen Species Sepsis Time Factors L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18723768 LA - eng IS - 4 PY - 2008 SN - 0363-6135 SP - H1712-9 ST - Role of endothelial nitric oxide synthase-derived nitric oxide in activation and dysfunction of cerebrovascular endothelial cells during early onsets of sepsis. T2 - Am J Physiol Heart Circ Physiol TI - Role of endothelial nitric oxide synthase-derived nitric oxide in activation and dysfunction of cerebrovascular endothelial cells during early onsets of sepsis. UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18723768 VL - 295 ID - 24 ER - TY - JOUR AB - The cause of brain dysfunction during sepsis and septic encephalopathy is still under ongoing research. Sepsis induced changes in cerebral protein expression may play a significant role in the understanding of septic encephalopathy. The aim of the present study was to explore cerebral proteome alterations in septic rats. Fifty-six male Wistar rats were randomly assigned to a sepsis group (coecal ligature and puncture, CLP) or a control group (sham). Surviving rats were killed 24 or 48 hours after surgery and whole-brain lysates were used for two-dimensional gel electrophoresis and subsequent protein identification. Differentially expressed proteins were identified by mass spectrometry. Using the Ingenuity Pathways Analysis (IPA) tool, the relationship and interaction between the identified proteins was analyzed. Mortality was 53 % in septic rats. No rat of the control group was lost. More than 1,100 spots per gel were discriminated of which 29 different proteins were significantly (2-fold, P<0.01) changed: 24 proteins down-regulated after 24 hours; two proteins up-regulated and three down-regulated after 48 hours. IPA identified 11 of 35 differentially regulated proteins allocating them to an existing inflammatory pathway. In the analysis of septic rat brains, multiple differentially expressed proteins associated with metabolism, signaling, and cell stress can be identified via proteome analysis, that may help to understand the development of septic encephalopathy. AD - Clinic for Anesthesiology and Intensive Care Medicine, University of Heidelberg, Medical Faculty Mannheim, Mannheim, Germany. jochen.hinkelbein@anaes.ma.uni-heidelberg.de AN - 18045154 AU - Hinkelbein, J. AU - Feldmann, R. E., Jr. AU - Peterka, A. AU - Schubert, C. AU - Schelshorn, D. AU - Maurer, M. H. AU - Kalenka, A. DA - Nov DP - NLM ET - 2007/11/30 KW - Animals Brain Chemistry/ physiology Cecum/pathology Disease Progression Electrophoresis, Gel, Two-Dimensional Energy Metabolism/ physiology Escherichia coli/metabolism Image Processing, Computer-Assisted Male Nerve Tissue Proteins/ biosynthesis Neural Networks (Computer) Proteomics Rats Rats, Wistar Sepsis/ metabolism/microbiology/mortality Signal Transduction/physiology LA - eng IS - 4 N1 - Hinkelbein, Jochen Feldmann, Robert E Jr Peterka, Anna Schubert, Charlotte Schelshorn, Dominik Maurer, Martin H Kalenka, Armin Netherlands Current neurovascular research Curr Neurovasc Res. 2007 Nov;4(4):280-8. PY - 2007 SN - 1567-2026 (Print) SP - 280-8 ST - Alterations in cerebral metabolomics and proteomic expression during sepsis T2 - Curr Neurovasc Res TI - Alterations in cerebral metabolomics and proteomic expression during sepsis VL - 4 ID - 82 ER - TY - JOUR AB - Sepsis is often complicated by encephalopathy, neuroendocrine dysfunction and cardiovascular autonomic failure. The cause of septic brain dysfunction is not fully understood. The aim of the present study is to explore whether septic brain dysfunction in a common septic model in the rat correlates with abnormalities either of local cerebral blood flow (LCBF) of defined brain areas or of whole brain blood flow (CBF). 45 male Wistar rats (320+/-13 g) were randomly assigned to a sepsis group (31 rats, cecal ligature and puncture, CLP) or a control group (14 rats, sham operation). Of these 45 rats, 16 rats were used for blood analysis; the remaining 29 rats were used for CBF/LCBF measurements. LCBF measurements were performed 24h after initial surgery using quantitative autoradiography with 4-iodo[N-methyl-(14)C]antipyrine, which allows to analyze CBF on a regional/local and global basis. In 42 different brain regions bilateral optical density measurements were performed. Septic rats (vs. control) presented tachycardia (507+/-37 vs. 452+/-44 min(-1), P<0.05), leukocytopenia (2.96+/-2.37 vs. 8.83+/-2.9710(9) x L(-1), P<0.05), hypocapnia (29.3+/-4.6 vs. 36.4+/-3.9 mmHg, P<0.05), and higher serum lactate concentrations (5.7+/-3.9 vs. 2.2+/-2.0 mmol x L(-1), P<0.05). LCBF of all 42 areas, as well as, CBF (116+/-59 vs. 115+/-52 m x 100 g(-1)min(-1), n.s.) did not differ. The results showed that severe sepsis (mortality rate of 43 %) did not induce alterations in mean CBF and LCBF. It is concluded that brain dysfunction is not reflected in changes of CBF during severe sepsis. AD - University Clinic for Anesthesiology and Intensive Care Medicine, University Hospital Mannheim, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany. jochen.hinkelbein@physiologie.uni-heidelberg.de AN - 17311543 AU - Hinkelbein, J. AU - Schroeck, H. AU - Peterka, A. AU - Schubert, C. AU - Kuschinsky, W. AU - Kalenka, A. DA - Feb DP - NLM ET - 2007/02/22 KW - Acid-Base Equilibrium/physiology Animals Autoradiography Brain/ blood supply/radionuclide imaging Brain Diseases/ physiopathology/radionuclide imaging Carbon Radioisotopes/diagnostic use Cecum Cerebrovascular Circulation/ physiology Disease Models, Animal Male Rats Rats, Wistar Sepsis/ physiopathology/radionuclide imaging Wounds, Stab LA - eng IS - 1 N1 - Hinkelbein, Jochen Schroeck, Helmut Peterka, Anna Schubert, Charlotte Kuschinsky, Wolfgang Kalenka, Armin Netherlands Current neurovascular research Curr Neurovasc Res. 2007 Feb;4(1):39-47. PY - 2007 SN - 1567-2026 (Print) SP - 39-47 ST - Local cerebral blood flow is preserved in sepsis T2 - Curr Neurovasc Res TI - Local cerebral blood flow is preserved in sepsis VL - 4 ID - 85 ER - TY - JOUR AB - The cause of brain dysfunction during sepsis and septic encephalopathy is still under ongoing research. Sepsis induced changes in cerebral protein expression may play a significant role in the understanding of septic encephalopathy. The aim of the present study was to explore cerebral proteome alterations in septic rats. Fifty-six male Wistar rats were randomly assigned to a sepsis group (coecal ligature and puncture, CLP) or a control group (sham). Surviving rats were killed 24 or 48 hours after surgery and whole-brain lysates were used for two-dimensional gel electrophoresis and subsequent protein identification. Differentially expressed proteins were identified by mass spectrometry. Using the Ingenuity Pathways Analysis (IPA) tool, the relationship and interaction between the identified proteins was analyzed. Mortality was 53 % in septic rats. No rat of the control group was lost. More than 1,100 spots per gel were discriminated of which 29 different proteins were significantly (2-fold, P<0.01) changed: 24 proteins down-regulated after 24 hours; two proteins up-regulated and three down-regulated after 48 hours. IPA identified 11 of 35 differentially regulated proteins allocating them to an existing inflammatory pathway. In the analysis of septic rat brains, multiple differentially expressed proteins associated with metabolism, signaling, and cell stress can be identified via proteome analysis, that may help to understand the development of septic encephalopathy. AD - Clinic for Anesthesiology and Intensive Care Medicine, University of Heidelberg, Medical Faculty Mannheim, Mannheim, Germany. jochen.hinkelbein@anaes.ma.uni-heidelberg.de AN - 18045154 AU - Hinkelbein, J AU - Feldmann, RE Jr AU - Peterka, A AU - Schubert, C AU - Schelshorn, D AU - Maurer, MH AU - Kalenka, A DA - Nov KW - Animals Brain Chemistry Cecum Disease Progression Electrophoresis, Gel, Two-Dimensional Energy Metabolism Escherichia coli Image Processing, Computer-Assisted Male Nerve Tissue Proteins Neural Networks (Computer) Proteomics Rats Rats, Wistar Sepsis Signal Transduction L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18045154 LA - eng IS - 4 PY - 2007 SN - 1567-2026 SP - 280-8 ST - Alterations in cerebral metabolomics and proteomic expression during sepsis. T2 - Curr Neurovasc Res TI - Alterations in cerebral metabolomics and proteomic expression during sepsis. UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18045154 VL - 4 ID - 33 ER - TY - JOUR AB - Sepsis is often complicated by encephalopathy, neuroendocrine dysfunction and cardiovascular autonomic failure. The cause of septic brain dysfunction is not fully understood. The aim of the present study is to explore whether septic brain dysfunction in a common septic model in the rat correlates with abnormalities either of local cerebral blood flow (LCBF) of defined brain areas or of whole brain blood flow (CBF). 45 male Wistar rats (320+/-13 g) were randomly assigned to a sepsis group (31 rats, cecal ligature and puncture, CLP) or a control group (14 rats, sham operation). Of these 45 rats, 16 rats were used for blood analysis; the remaining 29 rats were used for CBF/LCBF measurements. LCBF measurements were performed 24h after initial surgery using quantitative autoradiography with 4-iodo[N-methyl-(14)C]antipyrine, which allows to analyze CBF on a regional/local and global basis. In 42 different brain regions bilateral optical density measurements were performed. Septic rats (vs. control) presented tachycardia (507+/-37 vs. 452+/-44 min(-1), P<0.05), leukocytopenia (2.96+/-2.37 vs. 8.83+/-2.9710(9) x L(-1), P<0.05), hypocapnia (29.3+/-4.6 vs. 36.4+/-3.9 mmHg, P<0.05), and higher serum lactate concentrations (5.7+/-3.9 vs. 2.2+/-2.0 mmol x L(-1), P<0.05). LCBF of all 42 areas, as well as, CBF (116+/-59 vs. 115+/-52 m x 100 g(-1)min(-1), n.s.) did not differ. The results showed that severe sepsis (mortality rate of 43 %) did not induce alterations in mean CBF and LCBF. It is concluded that brain dysfunction is not reflected in changes of CBF during severe sepsis. AD - University Clinic for Anesthesiology and Intensive Care Medicine, University Hospital Mannheim, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany. jochen.hinkelbein@physiologie.uni-heidelberg.de AN - 17311543 AU - Hinkelbein, J AU - Schroeck, H AU - Peterka, A AU - Schubert, C AU - Kuschinsky, W AU - Kalenka, A DA - Feb KW - Acid-Base Equilibrium Animals Autoradiography Brain Brain Diseases Carbon Radioisotopes Cecum Cerebrovascular Circulation Disease Models, Animal Male Rats Rats, Wistar Sepsis Wounds, Stab L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17311543 LA - eng IS - 1 PY - 2007 SN - 1567-2026 SP - 39-47 ST - Local cerebral blood flow is preserved in sepsis. T2 - Curr Neurovasc Res TI - Local cerebral blood flow is preserved in sepsis. UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17311543 VL - 4 ID - 38 ER - TY - JOUR AB - BACKGROUND: The pathogenesis and mechanisms of septic encephalopathy are not completely understood. We compared two different models of sepsis: lipopolysaccharide-induced endotoxemia and cecal ligation and puncture (CLP) bacteremia in rats with respect to changes in endothelial expression of the adhesion molecules intercellular adhesion molecule-1 (ICAM-1), platelet-endothelial cell adhesion molecule-1 (PECAM-1), and of cerebral albumin extravasation as a marker for capillary breakdown of the blood brain barrier. MATERIAL AND METHODS: Male Wistar rats were divided into control, endotoxemia, or CLP-group. Mean arterial blood pressure was measured via femoral artery catheterization. Brain tissue for immunohistochemistry was harvested at 1 h, 6 h, and 24 h after induction of sepsis. RESULTS: The CLP-group showed a decrease in mean arterial pressure after 24 h in comparison with the sham-group (P < 0.05). Cerebral ICAM-1 expression was at its maximum 24 h after induction of sepsis, with the highest expression in the CLP-group. There was no difference in PECAM-1 expression between the groups. Cerebral albumin extravasation increased early after 6 h in both septic groups with a maximum at 24 h after induction of sepsis. CONCLUSION: These results suggest that there are early changes in the integrity of the blood-brain barrier in the central nervous system in an ongoing septic progress. This provides evidence that these changes are due to inflammatory mediators, and not to the presence of live bacteria. Increased ICAM-1 expression might be an early factor involved in these pathogenic events. Although the role of PECAM-1 cannot conclusively be determined, we were able to show its expression on cerebral endothelium in all groups. AD - Department of Anesthesiology, University of Heidelberg, Heidelberg, Germany. AN - 18164036 AU - Hofer, S. AU - Bopp, C. AU - Hoerner, C. AU - Plaschke, K. AU - Faden, R. M. AU - Martin, E. AU - Bardenheuer, H. J. AU - Weigand, M. A. DA - May 15 DO - S0022-4804(07)00482-9 [pii] 10.1016/j.jss.2007.07.021 DP - NLM ET - 2008/01/01 KW - Albumins/cerebrospinal fluid Animals Antigens, CD31/ biosynthesis Biological Markers Blood-Brain Barrier/ injuries Disease Models, Animal Endothelium, Vascular/ metabolism Intercellular Adhesion Molecule-1/ biosynthesis Male Rats Rats, Wistar Sepsis/ genetics/microbiology Up-Regulation LA - eng IS - 2 N1 - Hofer, Stefan Bopp, Christian Hoerner, Christian Plaschke, Konstanze Faden, Rita M Martin, Eike Bardenheuer, Hubert J Weigand, Markus A In Vitro United States The Journal of surgical research J Surg Res. 2008 May 15;146(2):276-81. Epub 2007 Aug 23. PY - 2008 SN - 0022-4804 (Print) 0022-4804 (Linking) SP - 276-81 ST - Injury of the blood brain barrier and up-regulation of icam-1 in polymicrobial sepsis T2 - J Surg Res TI - Injury of the blood brain barrier and up-regulation of icam-1 in polymicrobial sepsis VL - 146 ID - 75 ER - TY - JOUR AB - BACKGROUND: The pathogenesis and mechanisms of septic encephalopathy are not completely understood. We compared two different models of sepsis: lipopolysaccharide-induced endotoxemia and cecal ligation and puncture (CLP) bacteremia in rats with respect to changes in endothelial expression of the adhesion molecules intercellular adhesion molecule-1 (ICAM-1), platelet-endothelial cell adhesion molecule-1 (PECAM-1), and of cerebral albumin extravasation as a marker for capillary breakdown of the blood brain barrier. MATERIAL AND METHODS: Male Wistar rats were divided into control, endotoxemia, or CLP-group. Mean arterial blood pressure was measured via femoral artery catheterization. Brain tissue for immunohistochemistry was harvested at 1 h, 6 h, and 24 h after induction of sepsis. RESULTS: The CLP-group showed a decrease in mean arterial pressure after 24 h in comparison with the sham-group (P < 0.05). Cerebral ICAM-1 expression was at its maximum 24 h after induction of sepsis, with the highest expression in the CLP-group. There was no difference in PECAM-1 expression between the groups. Cerebral albumin extravasation increased early after 6 h in both septic groups with a maximum at 24 h after induction of sepsis. CONCLUSION: These results suggest that there are early changes in the integrity of the blood-brain barrier in the central nervous system in an ongoing septic progress. This provides evidence that these changes are due to inflammatory mediators, and not to the presence of live bacteria. Increased ICAM-1 expression might be an early factor involved in these pathogenic events. Although the role of PECAM-1 cannot conclusively be determined, we were able to show its expression on cerebral endothelium in all groups. AD - Department of Anesthesiology, University of Heidelberg, Heidelberg, Germany. AN - 18164036 AU - Hofer, S AU - Bopp, C AU - Hoerner, C AU - Plaschke, K AU - Faden, RM AU - Martin, E AU - Bardenheuer, HJ AU - Weigand, MA DA - May DO - S0022-4804(07)00482-9 [pii] 10.1016/j.jss.2007.07.021 KW - Albumins Animals Antigens, CD31 Biological Markers Blood-Brain Barrier Disease Models, Animal Endothelium, Vascular Intercellular Adhesion Molecule-1 Male Rats Rats, Wistar Sepsis Up-Regulation L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18164036 LA - eng IS - 2 PY - 2008 SN - 0022-4804 SP - 276-81 ST - Injury of the blood brain barrier and up-regulation of icam-1 in polymicrobial sepsis. T2 - J Surg Res TI - Injury of the blood brain barrier and up-regulation of icam-1 in polymicrobial sepsis. UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18164036 VL - 146 ID - 31 ER - TY - JOUR AB - OBJECTIVE: To determine whether known serum markers of neurologic injury are increased in children with septic shock. DESIGN: Prospective, observational study. SETTING: Tertiary-care, pediatric intensive care unit. PATIENTS: Two cohorts of children (n = 24) with septic shock were prospectively enrolled within 24 hrs of their diagnosis. In cohort 1, serum markers (S100beta, neuron-specific enolase [NSE], and glial fibrillary acidic protein [GFAP]) were determined (n = 18). In cohort 2, in addition to serum markers, urine S100beta and GFAP were determined, and continuous electroencephalography (cEEG) was performed. Children who presented to the emergency room with a fever served as controls (n = 32). Children with known neurologic conditions were excluded. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Serum and urine were collected daily for up to 7 days or until pediatric intensive care unit discharge. Biomarker concentrations were determined by commercially available enzyme-linked immunosorbent assays. cEEG was performed on days 1, 2, 4, and 7 in a 16-channel montage for at least 6 hrs. Physical examinations did not reveal focal neurologic deficits. Children with septic shock demonstrated increased serum S100beta and NSE compared with controls (mean +/- SEM: 10.5 microg/L +/- 2.4 vs. .9 microg/L +/- .1, p < .001; 96.6 microg/L +/- 8.9 vs. 4.0 microg/L +/- 1.3, p < .001, respectively). Serum GFAP was detectable in five septic children and none of the controls. In cohort 2, urine of four patients demonstrated measurable S100beta levels, and GFAP was detected in one child (nonsurvivor). cEEG demonstrated moderate to severe encephalopathy in all children studied. CONCLUSIONS: Markers of neurologic injuries are increased in children with septic shock. This may indicate subclinical injuries that are either transient or permanent. Studies that correlate the long-term neurologic outcome of children with these markers are needed to identify children at risk for neurologic injuries from septic shock. AD - Division of Critical Care Medicine, Children's Research Institute, Children's National Medical Center, Washington, DC, USA. ahsu@cnmc.org AN - 18446104 AU - Hsu, AA AU - Fenton, K AU - Weinstein, S AU - Carpenter, J AU - Dalton, H AU - Bell, MJ DA - May DO - 10.1097/PCC.0b013e3181727b22 KW - Adolescent Biological Markers Brain Injuries Case-Control Studies Child Child, Preschool Electroencephalography Enzyme-Linked Immunosorbent Assay Glial Fibrillary Acidic Protein Humans Infant Nerve Growth Factors Phosphopyruvate Hydratase Prospective Studies S100 Proteins Shock, Septic L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18446104 LA - eng IS - 3 PY - 2008 SN - 1529-7535 SP - 245-51 ST - Neurological injury markers in children with septic shock. T2 - Pediatr Crit Care Med TI - Neurological injury markers in children with septic shock. UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18446104 VL - 9 ID - 26 ER - TY - JOUR AB - A 41-year-old man with a previous kidney transplant was referred for arterial hypertension and acute renal failure. Initial neurological examination was normal. Laboratory data showed a high serum cyclosporine A concentration. A few hours later, he developed generalised tonic-clonic seizures. The brain computed tomogram was not remarkable, but Glasgow Coma Scale score remained at 8. Mechanical ventilation was required for rapidly progressive hypoxaemia related to Staphylococcus aureus pneumonia and septicaemia. Noradrenaline infusion was needed for only nine hours, with no major drop in mean arterial blood pressure. On day three his Glasgow Coma Scale score was 3/15, with fixed dilated pupils. The brain computed tomogram revealed bilateral hypodense lesions in the posterior areas together with cerebral oedema and the patient was subsequently declared brain dead. We discuss the possibility of a posterior reversible encephalopathy syndrome, likely triggered by a gram-positive septicaemia in addition to other risk factors. AD - Department of Intensive Care, Cliniques St-Luc, Université Catholique de Louvain, Brussels, Belgium. AN - 20014613 AU - Huberlant, V AU - Cosnard, G AU - Hantson, PE DA - Nov KW - Adult Bacteremia Brain Brain Death Glasgow Coma Scale Gram-Positive Bacterial Infections Humans Male Posterior Leukoencephalopathy Syndrome Respiration, Artificial Risk Factors Tomography, X-Ray Computed L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=20014613 LA - eng IS - 6 PY - 2009 SN - 0310-057X SP - 1017-20 ST - Brain death in a septic patient: possible relationship with posterior reversible encephalopathy syndrome? T2 - Anaesth Intensive Care TI - Brain death in a septic patient: possible relationship with posterior reversible encephalopathy syndrome? UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=20014613 VL - 37 ID - 10 ER - TY - JOUR AB - The spectrum of para-infectious neurological symptoms was examined by a retrospective study of 57 patients admitted with acute neurological symptoms which were eventually interpreted as secondary to urinary tract infection. The symptoms encountered most frequently were confusion, gait disturbances, and drowsiness. Patients with Parkinson's disease, multiple sclerosis or a previous stroke often experienced a deterioration of their preexisting neurological deficits. We suggest that para-infectious encephalopathy (PE) is a mild form of septic encephalopathy with a distinct clinical pattern. AD - Abteilung fur Neurologie, Verbundkrankenhaus Bernkastel-Wittlich, Wittlich, Germany. a.hufschmidt@t-online.de AN - 20197663 AU - Hufschmidt, A. AU - Shabarin, V. AU - Rauer, S. AU - Zimmer, T. DO - 000289098 [pii] 10.1159/000289098 DP - NLM ET - 2010/03/04 KW - Aged Aged, 80 and over Brain Diseases/ etiology Female Humans Male Middle Aged Multiple Sclerosis/complications Parkinson Disease/complications Retrospective Studies Urinary Tract Infections/ complications LA - eng IS - 3 N1 - Hufschmidt, Andreas Shabarin, Vsevolod Rauer, Sebastian Zimmer, Thomas Switzerland European neurology Eur Neurol. 2010;63(3):180-3. Epub 2010 Feb 27. PY - 2010 SN - 1421-9913 (Electronic) 0014-3022 (Linking) SP - 180-3 ST - Neurological symptoms accompanying urinary tract infections T2 - Eur Neurol TI - Neurological symptoms accompanying urinary tract infections VL - 63 ID - 61 ER - TY - JOUR AB - The spectrum of para-infectious neurological symptoms was examined by a retrospective study of 57 patients admitted with acute neurological symptoms which were eventually interpreted as secondary to urinary tract infection. The symptoms encountered most frequently were confusion, gait disturbances, and drowsiness. Patients with Parkinson's disease, multiple sclerosis or a previous stroke often experienced a deterioration of their preexisting neurological deficits. We suggest that para-infectious encephalopathy (PE) is a mild form of septic encephalopathy with a distinct clinical pattern. AD - Abteilung für Neurologie, Verbundkrankenhaus Bernkastel-Wittlich, Wittlich, Germany. a.hufschmidt@t-online.de AN - 20197663 AU - Hufschmidt, A AU - Shabarin, V AU - Rauer, S AU - Zimmer, T DO - 000289098 [pii] 10.1159/000289098 KW - Aged Aged, 80 and over Brain Diseases Female Humans Male Middle Aged Multiple Sclerosis Parkinson Disease Retrospective Studies Urinary Tract Infections L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=20197663 LA - eng IS - 3 PY - 2010 SN - 1421-9913 SP - 180-3 ST - Neurological symptoms accompanying urinary tract infections. T2 - Eur Neurol TI - Neurological symptoms accompanying urinary tract infections. UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=20197663 VL - 63 ID - 9 ER - TY - JOUR AD - Ruprecht-Karls-Universitat, Heidelberg. ernst_hund@med.uni-heidelberg.de AN - 17286220 AU - Hund, E. DA - Feb 16 DO - 10.1055/s-2007-959328 DP - NLM ET - 2007/02/09 KW - Anti-Bacterial Agents/therapeutic use Brain Diseases/diagnosis/drug therapy/ etiology Coma/etiology Diagnosis, Differential Humans Prognosis Sepsis/ complications/diagnosis/drug therapy Severity of Illness Index LA - ger IS - 7 N1 - Hund, E Review Germany Deutsche medizinische Wochenschrift (1946) Dtsch Med Wochenschr. 2007 Feb 16;132(7):322-4. OP - Septische Enzephalopathie. PY - 2007 SN - 0012-0472 (Print) 0012-0472 (Linking) SP - 322-4 ST - [Septic encephalopathy] T2 - Dtsch Med Wochenschr TI - [Septic encephalopathy] VL - 132 ID - 84 ER - TY - JOUR AB - Sepsis is often complicated by an acute and reversible deterioration of mental status, which is associated with increased mortality and is consistent with delirium but can also be revealed by a focal neurologic sign. Sepsis-associated encephalopathy is accompanied by abnormalities of electroencephalogram and somatosensory-evoked potentials, increased in biomarkers of brain injury (i.e., neuron-specific enolase, S-100 beta-protein) and, frequently, by neuroradiological abnormalities, notably leukoencephalopathy. Its mechanism is highly complex, resulting from both inflammatory and noninflammatory processes that affect all brain cells and induce blood-brain barrier breakdown, dysfunction of intracellular metabolism, brain cell death, and brain injuries. Its diagnosis relies essentially on neurologic examination that can lead one to perform specific neurologic tests. Electroencephalography is required in the presence of seizure; neuroimaging in the presence of seizure, focal neurologic signs or suspicion of cerebral infection; and both when encephalopathy remains unexplained. In practice, cerebrospinal fluid analysis should be performed if there is any doubt of meningitis. Hepatic, uremic, or respiratory encephalopathy, metabolic disturbances, drug overdose, withdrawal of sedatives or opioids, alcohol withdrawal delirium, and Wernicke's encephalopathy are the main differential diagnoses of sepsis-associated encephalopathy. Patient management is based mainly on controlling infection, organ system failure, and metabolic homeostasis, at the same time avoiding neurotoxic drugs. AD - General Intensive Care Unit, Fermo Hospital Ancona, Italy. AN - 20046118 AU - Iacobone, E. AU - Bailly-Salin, J. AU - Polito, A. AU - Friedman, D. AU - Stevens, R. D. AU - Sharshar, T. DA - Oct DO - 10.1097/CCM.0b013e3181b6ed58 00003246-200910001-00007 [pii] DP - NLM ET - 2010/02/06 KW - Blood-Brain Barrier/metabolism Brain Diseases/ diagnosis/etiology/ therapy Brain Diseases, Metabolic/diagnosis Brain Injuries/diagnosis Brain Mapping/methods Critical Care/methods Critical Illness Diagnosis, Differential Electroencephalography Encephalitis/diagnosis Humans Intensive Care Units Neurologic Examination/methods Risk Factors Sepsis/complications/ diagnosis/ therapy LA - eng IS - 10 Suppl N1 - Iacobone, Emanuele Bailly-Salin, Juliette Polito, Andrea Friedman, Diane Stevens, Robert D Sharshar, Tarek Review United States Critical care medicine Crit Care Med. 2009 Oct;37(10 Suppl):S331-6. PY - 2009 SN - 1530-0293 (Electronic) 0090-3493 (Linking) SP - S331-6 ST - Sepsis-associated encephalopathy and its differential diagnosis T2 - Crit Care Med TI - Sepsis-associated encephalopathy and its differential diagnosis VL - 37 ID - 109 ER - TY - JOUR AB - We present a 7-year-old boy diagnosed as having salmonella encephalopathy. He developed severe consciousness disturbance following enterocolitis. Electroencephalography showed diffuse and high-voltage slow activity but MR images of the brain were normal. Examination of inflammatory cytokines in serum and cerebrospinal fluid revealed high levels of interleukin-6, -8, and -10, and interferon gamma. Salmonella typhimurium was detected in a stool specimen. He was diagnosed as having salmonella-associated encephalopathy that had features of septic encephalopathy and quickly responded to high-dose methylpredonisolone therapy. High-dose methylpredonisolone was considered to be an effective treatment for hypercytokine-mediated S. encephalopathy. AD - Department of Pediatrics, Yokohama City University Medical Center, 4-57 Urafune-cho, Minami-ku, Yokohama 232-0024, Japan. k-ichi@urahp.yokohama-cu.ac.jp AN - 19216041 AU - Ichikawa, K. AU - Kajitani, A. AU - Tsutsumi, A. AU - Takeshita, S. DA - Nov DO - S0387-7604(08)00302-1 [pii] 10.1016/j.braindev.2008.12.019 DP - NLM ET - 2009/02/14 KW - Child Electroencephalography Encephalitis/ drug therapy/etiology Humans Japan Male Methylprednisolone/ administration & dosage Salmonella Infections/complications/ drug therapy Salmonella typhimurium LA - eng IS - 10 N1 - Ichikawa, Kazushi Kajitani, Akiko Tsutsumi, Akiko Takeshita, Saoko Netherlands Brain & development Brain Dev. 2009 Nov;31(10):782-4. Epub 2009 Feb 11. PY - 2009 SN - 1872-7131 (Electronic) 0387-7604 (Linking) SP - 782-4 ST - Salmonella encephalopathy successfully treated with high-dose methylpredonisolone therapy T2 - Brain Dev TI - Salmonella encephalopathy successfully treated with high-dose methylpredonisolone therapy VL - 31 ID - 63 ER - TY - JOUR AB - The complement system normally eliminates bacteria and has a protective effect. However, in an inflammatory setting such as sepsis, an exaggerated or insufficient activation of this cascade can have deleterious effect through the activation of glial cells, secretion of proinflammatory cytokines and generation of other toxic products. The aim of the present study was to investigate the role of the complement cascade in septic encephalopathy, through the passive injection of endotoxin/lipopolysaccharide (LPS) into mice overexpressing the potent complement inhibitor, CR1-related y (Crry-tg). Increased gliosis occurred in brains of endotoxemic mice. Concomitant with this, there was a significant rise in mRNA expression of GFAP, CD45 and proinflammatory molecules, TLR4, TNF-alpha and NO, in these brains. Consistent with the capacity of these inflammatory mediators, there was increased apoptosis as determined by DNA fragmentation and TUNEL staining on LPS treatment, which occurred through the Akt pathway. In addition, there was increased water content in brain, similar to cerebral edema observed in sepsis. Relative to wild-type mice, complement-inhibited mice had an attenuated inflammatory response, decreased edema and reduced apoptosis. Therefore, we demonstrate for the first time that the complement cascade appears to be one of the key players that cause brain pathology in an endotoxemic setting and therefore is a viable therapeutic target. AD - Department of Medicine, University of Chicago, Chicago, IL 60637, USA. AN - 17922019 AU - Jacob, A. AU - Hensley, L. K. AU - Safratowich, B. D. AU - Quigg, R. J. AU - Alexander, J. J. DA - Dec DO - 3700686 [pii] 10.1038/labinvest.3700686 DP - NLM ET - 2007/10/09 KW - Animals Antigens, CD45/biosynthesis Apoptosis Brain Diseases/etiology/ immunology/pathology Brain Edema/etiology/immunology Complement Activation In Situ Nick-End Labeling Lipopolysaccharides/pharmacology Mice Mice, Inbred C57BL Nitric Oxide/metabolism Proto-Oncogene Proteins c-akt/metabolism Receptors, Complement/genetics/metabolism Sepsis/etiology/ immunology/pathology Signal Transduction Toll-Like Receptor 4/metabolism Tumor Necrosis Factor-alpha/biosynthesis LA - eng IS - 12 N1 - Jacob, Alexander Hensley, Lauren K Safratowich, Bryan D Quigg, Richard J Alexander, Jessy J R01DK041873/DK/NIDDK NIH HHS/United States R01DK055357/DK/NIDDK NIH HHS/United States Research Support, N.I.H., Extramural United States Laboratory investigation; a journal of technical methods and pathology Lab Invest. 2007 Dec;87(12):1186-94. Epub 2007 Oct 8. PY - 2007 SN - 1530-0307 (Electronic) 0023-6837 (Linking) SP - 1186-94 ST - The role of the complement cascade in endotoxin-induced septic encephalopathy T2 - Lab Invest TI - The role of the complement cascade in endotoxin-induced septic encephalopathy VL - 87 ID - 81 ER - TY - JOUR AB - The complement system normally eliminates bacteria and has a protective effect. However, in an inflammatory setting such as sepsis, an exaggerated or insufficient activation of this cascade can have deleterious effect through the activation of glial cells, secretion of proinflammatory cytokines and generation of other toxic products. The aim of the present study was to investigate the role of the complement cascade in septic encephalopathy, through the passive injection of endotoxin/lipopolysaccharide (LPS) into mice overexpressing the potent complement inhibitor, CR1-related y (Crry-tg). Increased gliosis occurred in brains of endotoxemic mice. Concomitant with this, there was a significant rise in mRNA expression of GFAP, CD45 and proinflammatory molecules, TLR4, TNF-alpha and NO, in these brains. Consistent with the capacity of these inflammatory mediators, there was increased apoptosis as determined by DNA fragmentation and TUNEL staining on LPS treatment, which occurred through the Akt pathway. In addition, there was increased water content in brain, similar to cerebral edema observed in sepsis. Relative to wild-type mice, complement-inhibited mice had an attenuated inflammatory response, decreased edema and reduced apoptosis. Therefore, we demonstrate for the first time that the complement cascade appears to be one of the key players that cause brain pathology in an endotoxemic setting and therefore is a viable therapeutic target. AD - Department of Medicine, University of Chicago, Chicago, IL 60637, USA. AN - 17922019 AU - Jacob, A AU - Hensley, LK AU - Safratowich, BD AU - Quigg, RJ AU - Alexander, JJ DA - Dec DO - 3700686 [pii] 10.1038/labinvest.3700686 KW - Animals Antigens, CD45 Apoptosis Brain Diseases Brain Edema Complement Activation In Situ Nick-End Labeling Lipopolysaccharides Mice Mice, Inbred C57BL Nitric Oxide Proto-Oncogene Proteins c-akt Receptors, Complement Sepsis Signal Transduction Toll-Like Receptor 4 Tumor Necrosis Factor-alpha L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17922019 LA - eng IS - 12 PY - 2007 SN - 1530-0307 SP - 1186-94 ST - The role of the complement cascade in endotoxin-induced septic encephalopathy. T2 - Lab Invest TI - The role of the complement cascade in endotoxin-induced septic encephalopathy. UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17922019 VL - 87 ID - 34 ER - TY - JOUR AB - OBJECTIVE: Gc globulin (vitamin D-binding protein) is a component of the extracellular actin scavenger system. The level of Gc globulin is reduced in patients with fulminant hepatic failure, septic shock and trauma. Furthermore, low levels of Gc globulin in patients with fulminant hepatic failure and multiple trauma have been found to correlate with the morbidity and mortality of patients. Owing to a large increase in the turnover of Gc globulin upon complex formation with actin, it may be important to determine both the total Gc globulin concentration and the degree of complexing with actin for estimating the clinical prognosis of a patient. For this reason, we have compared a crossed immuno-electrophoresis method (CIE), suitable for visualizing the degree of complexing with actin, with a rocket immuno-electrophoresis method (RIE), previously used for determination of the complex degree. MATERIAL AND METHODS: Sera from healthy donors and from patients with acetaminophen-induced liver disease or trauma were investigated using CIE, RIE and enzyme-linked immunosorbent assay (ELISA). RESULTS: Using the CIE, no Gc globulin-actin complexes were detected among healthy donors. Complexes were present in 21 of 39 patients with liver disease and 3 of 37 trauma patients. High complex ratios (> 20 %) were found in 6 of 7 patients with hepatic encephalopathy. Using the RIE, complexes were detected in most samples. CONCLUSION: The results show that the CIE method may be used for determining the degree of actin complexing in conjunction with ELISA or RIE in determining the levels of total Gc globulin. AD - Department of Bacteriology, Mycology and Parasitology, Statens Serum Institut, Copenhagen, Denmark. csv@ssi.dk AN - 17852808 AU - Jørgensen, CS AU - Schiødt, FV AU - Dahl, B AU - Laursen, I AU - Houen, G DO - 779455454 [pii] 10.1080/00365510701326909 KW - Acetaminophen Actins Calibration Drug-Induced Liver Injury Enzyme-Linked Immunosorbent Assay Gelsolin Hepatic Encephalopathy Humans Immunoelectrophoresis Immunoelectrophoresis, Two-Dimensional Liver Diseases Protein Binding Reproducibility of Results Temperature Vitamin D-Binding Protein Wounds and Injuries L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17852808 LA - eng IS - 7 PY - 2007 SN - 0036-5513 SP - 767-77 ST - Comparison of rocket and crossed immuno-electrophoresis assays for determination of the level of actin complexing of Gc globulin. T2 - Scand J Clin Lab Invest TI - Comparison of rocket and crossed immuno-electrophoresis assays for determination of the level of actin complexing of Gc globulin. UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17852808 VL - 67 ID - 36 ER - TY - JOUR AB - Encephalopathy is a common complication of sepsis. However, little is known about the morphological changes that occur in the brain during sepsis. In this study, fecal peritonitis was induced in Wistar rats, which had been monitored for 4 h before their brains were removed and samples from the CA1 area taken. In addition to higher blood pressure with a decreasing pattern and a significant drop in rectal temperature, an increased heart rate and marked respiratory failure were observed. The tissue was investigated and compared with corresponding hippocampal samples taken from sham-operated and not operated control groups. Significantly more peri-microvascular edema was found in the hippocampal CA1 area in the septic group. The percentages of the peri-microvascular edema were 158.57 +/- 3.6%, 122.84 +/- 1.5% and 120.24 +/- 1.9% in the fecal peritonitis group, sham-operated and not operated control groups, respectively. The results may suggest that the edema observed around the microvessels may participate in the pathogenesis of the septic encephalopathy probably by causing in the microvascular permeability characteristics. AD - Uludag University, Faculty of Medicine, Anatomy Department, Bursa, Turkey. imkafa@uludag.edu.tr AN - 17645234 AU - Kafa, IM AU - Ari, I AU - Kurt, MA DA - Jun KW - Animals Brain Edema Disease Models, Animal Hippocampus Image Processing, Computer-Assisted Male Microcirculation Peritonitis Rats Rats, Wistar Sepsis L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17645234 LA - eng IS - 3 PY - 2007 SN - 0919-6544 SP - 213-20 ST - The peri-microvascular edema in hippocampal CA1 area in a rat model of sepsis. T2 - Neuropathology TI - The peri-microvascular edema in hippocampal CA1 area in a rat model of sepsis. UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17645234 VL - 27 ID - 37 ER - TY - JOUR AB - Sepsis and septic shock are the commonest causes of death in the intensive care units. Although recent research have improved our understanding of the progress and pathophysiology of sepsis and septic shock, underlying mechanisms in sepsis-associated encephalopathy is still poorly understood. The incidence of sepsis-associated encephalopathy has been reported to vary from 8% to 70% of septic patients. We aimed at investigating the brain's electrical activity using somatosensory-evoked potentials and electrocorticographical recordings in cecal ligation and puncture rat model of sepsis. Significant decrease in mean arterial pressure, increase in heart rate, deteriorated neurological reflexes together with positive blood cultures results, thrombocytopenia and increased blood lactate levels suggesting the successful induction of sepsis in the present study. Elongated latencies and increased amplitudes were observed in somatosensory recordings of septic group, while electrocorticograms revealed slight decrease in median and spectral edge frequencies amplitudes and significantly increased delta activities in 50% of the septic rats. These results would suggest that the studies based on the investigation of the sepsis-associated encephalopathy in animal models needs to be combined with the electrophysiological confirmations of the brain dysfunction following the induction of sepsis. AD - Department of Anatomy, Uludag University, School of Medicine, Bursa, Turkey. imkafa@uludag.edu.tr AN - 20674556 AU - Kafa, IM AU - Bakirci, S AU - Uysal, M AU - Kurt, MA DA - Oct DO - S0006-8993(10)01639-2 [pii] 10.1016/j.brainres.2010.07.049 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=20674556 LA - eng PY - 2010 SN - 1872-6240 SP - 217-26 ST - Alterations in the brain electrical activity in a rat model of sepsis-associated encephalopathy. T2 - Brain Res TI - Alterations in the brain electrical activity in a rat model of sepsis-associated encephalopathy. UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=20674556 VL - 1354 ID - 1 ER - TY - JOUR AB - Metabolic encephalopathies, usually multifactorial in origin, may be important complications of many diseases of patients treated in a critical care unit. In many cases these complications arise from more than one cause. Neurological signs of metabolic encephalopathies, ancillary tests and differential diagnosis, etiology and pathophysiology are discussed. In this context major single causes for metabolic encephalopathies are referred to. Metabolic encephalopathies as diseases per se (e. g. Wernicke's encephalopathy) and encephalopathies as consequences of deteriorating known diseases (e. g. renal or hepatic diseases) and encephalopathies as complications in patients treated with other diseases in the ICU have to be differentiated. Encephalopathies are known to be the most common complication of a large group of diseases treated in the ICU; on the other hand, manifestation of metabolic encephalopathy can be taken as a warning of deterioration or beginning organ dysfunction. So it would be misleading so far to reduce the clinical concept of metabolic encephalopathies in ICH to septic encephalopathy only. AD - Neurologische Universitatsklinik Hamburg - Eppendorf, Martinistr. 52, 20246 Hamburg, Germany. kunze@uke.uni-hamburg.de AN - 12242532 AU - Kunze, K. DA - Sep DO - 10.1007/s00415-002-0869-z DP - NLM ET - 2002/09/21 KW - Animals Brain Diseases, Metabolic/classification/ etiology/ physiopathology Humans Hypoxia-Ischemia, Brain/complications/physiopathology Systemic Inflammatory Response Syndrome/complications/physiopathology LA - eng IS - 9 N1 - Kunze, Klaus Research Support, Non-U.S. Gov't Review Germany Journal of neurology J Neurol. 2002 Sep;249(9):1150-9. PY - 2002 SN - 0340-5354 (Print) 0340-5354 (Linking) SP - 1150-9 ST - Metabolic encephalopathies T2 - J Neurol TI - Metabolic encephalopathies VL - 249 ID - 96 ER - TY - JOUR AD - Department of Pediatrics, College of Medicine, The Catholic University of Korea, Our Lady of Mercy Hospital, Pupyung-dong Pupyung-gu, Incheon, Korea. AN - 19131864 AU - Lee, S. Y. AU - Lee, K. H. AU - Hwang, H. S. AU - Jeong, D. C. AU - Chung, S. Y. AU - Kang, J. H. DA - Jan DO - 10.1097/PCC.0b013e3181937125 00130478-200901000-00045 [pii] DP - NLM ET - 2009/01/10 KW - Appendectomy/methods Appendicitis/ complications/diagnosis/surgery Child, Preschool Electroencephalography Encephalitis/diagnosis/ etiology/therapy Female Follow-Up Studies Glasgow Coma Scale Humans Intensive Care Units, Pediatric Magnetic Resonance Imaging Risk Assessment Sepsis/ complications/diagnosis Severity of Illness Index Treatment Outcome LA - eng IS - 1 N1 - Lee, Soo Young Lee, Keun-Ho Hwang, Hui Sung Jeong, Dae Chul Chung, Seung Yun Kang, Jin Han Case Reports United States Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies Pediatr Crit Care Med. 2009 Jan;10(1):e11-3. PY - 2009 SN - 1529-7535 (Print) 1529-7535 (Linking) SP - e11-3 ST - Septic encephalopathy complicating acute appendicitis T2 - Pediatr Crit Care Med TI - Septic encephalopathy complicating acute appendicitis VL - 10 ID - 71 ER - TY - JOUR AD - Department of Pediatrics, College of Medicine, The Catholic University of Korea, Our Lady of Mercy Hospital, Pupyung-dong Pupyung-gu, Incheon, Korea. AN - 19131864 AU - Lee, SY AU - Lee, KH AU - Hwang, HS AU - Jeong, DC AU - Chung, SY AU - Kang, JH DA - Jan DO - 00130478-200901000-00045 [pii] 10.1097/PCC.0b013e3181937125 KW - Appendectomy Appendicitis Child, Preschool Electroencephalography Encephalitis Female Follow-Up Studies Glasgow Coma Scale Humans Intensive Care Units, Pediatric Magnetic Resonance Imaging Risk Assessment Sepsis Severity of Illness Index Treatment Outcome L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19131864 LA - eng IS - 1 PY - 2009 SN - 1529-7535 SP - e11-3 ST - Septic encephalopathy complicating acute appendicitis. T2 - Pediatr Crit Care Med TI - Septic encephalopathy complicating acute appendicitis. UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19131864 VL - 10 ID - 20 ER - TY - JOUR AB - OBJECTIVE: Septic encephalopathy is associated with an increased mortality rate in septic patients. We have previously shown that a peripheral lipopolysaccharide (LPS) injection induces neuronal activation in the brain-stem nuclei of rats. Nitric oxide (NO) and superoxide are involved in LPS-induced brain damage. Hyperbaric oxygenation (HBO) provides protective effects against systemic oxidative stress and mortality in animals with septic shock. We examined the effects of HBO on neuronal activation and oxidative stress in the brain-stem nuclei of LPS-treated rats. DESIGN AND INTERVENTIONS: Wistar rats were randomly distributed into six groups for the following treatments:(a) normal saline injection (NS); (b) HBO; (c) LPS; (d) LPS-HBO; (e) LPS-aminoguanidine (AG, an inhibitor of inducible nitric oxide synthase); or (f) hydralazine (HYD, a direct vasodilator). The HYD induces prolonged hypotension and was used as a comparison for LPS stimulation. The AG was used as a comparison for HBO treatment. Two HBO sessions were administered, 1 and 4[Symbol: see text]h after LPS. RESULTS: HBO and AG significantly reversed the overproduction of c-Fos induced by LPS in the brain stems of rats, with greater reversal in the nucleus tractus solitarii (NTS) by HBO. Although AG did not reduce the superoxide level, HBO significantly abolished superoxide production and NADPH diaphorase expression in the brain stems of LPS-treated rats. The HYD induced much lower c-Fos expression in the brain-stem nuclei than that in LPS-treated animals and caused no significant increase in NADPH diaphorase expression or superoxide formation. CONCLUSION: HBO protects against endotoxin-related neuronal activation and oxidative stress in the brain-stem nuclei of rats. AD - Department of Pharmacology, National Defense Medical Center, No. 161 Section 6 Min-Chuan East Road, 114 Taipei, Taiwan. hclin@ndmctsgh.edu.tw AN - 18193191 AU - Lin, HC AU - Wan, FJ DA - Jun DO - 10.1007/s00134-007-0986-3 KW - Analysis of Variance Animals Brain Stem Guanidines Hydralazine Hyperbaric Oxygenation Hypotension Immunoenzyme Techniques Lipopolysaccharides Male NADP Oxidative Stress Proto-Oncogene Proteins c-fos Random Allocation Rats Rats, Wistar Shock, Septic Superoxides L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18193191 LA - eng IS - 6 PY - 2008 SN - 0342-4642 SP - 1122-32 ST - Hyperbaric oxygenation reduces overexpression of c-Fos and oxidative stress in the brain stem of experimental endotoxemic rats. T2 - Intensive Care Med TI - Hyperbaric oxygenation reduces overexpression of c-Fos and oxidative stress in the brain stem of experimental endotoxemic rats. UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18193191 VL - 34 ID - 30 ER - TY - JOUR AB - Sepsis is the most common cause of mortality in intensive care units. Although sepsis-associated encephalopathy (SAE) is reported to be a leading manifestation of sepsis, its pathogenesis remains unclear. In our previous studies, we showed that heat shock pretreatment can reduce mortality in polymicrobial septic rats and protect the cerebral cortical function during hypoxia or drug-induced convulsion. In the present study, we investigated to what extent heat shock pretreatment might affect the development of SAE in septic rats and the possible mechanism behind its effect was discussed. To do this, we used lipopolysaccharide (LPS) to induce septic response in a SAE animal model. Heat shock pretreatment was performed and rectal temperature maintained between 41 and 42 degrees C for 15 min using an electric heating pad. Electroencephalography (EEG) activity, a sensitive electrophysiological recording of electrical activity in the brain, was used as an indicator of cerebral cortical dysfunction in SAE. In LPS rats not pretreated with heat shock, the EEG background activity decreased 10 min after intraperitoneal administration of LPS. However, in rats pretreated with heat shock, this decrease was significantly attenuated. Untreated septic rats were also found to have earlier, more frequent epileptic spikes. In summary, we found that heat shock could attenuate the electro-cortical dysfunction in rats with LPS-induced septic response, suggesting that heat shock response might potentially be used to prevent SAE in sepsis. AD - Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan. AN - 19574006 AU - Lin, LC AU - Chen, YY AU - Lee, WT AU - Chen, HL AU - Yang, RC DA - May DO - S0387-7604(09)00169-7 [pii] 10.1016/j.braindev.2009.06.002 KW - Animals Brain Diseases Electroencephalography HSP72 Heat-Shock Proteins Heat-Shock Response Hot Temperature Humans Lipopolysaccharides Rats Rats, Sprague-Dawley Seizures Sepsis L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19574006 LA - eng IS - 5 PY - 2010 SN - 1872-7131 SP - 371-7 ST - Heat shock pretreatment attenuates sepsis-associated encephalopathy in LPS-induced septic rats. T2 - Brain Dev TI - Heat shock pretreatment attenuates sepsis-associated encephalopathy in LPS-induced septic rats. UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19574006 VL - 32 ID - 15 ER - TY - JOUR AB - The current view is that bacteria need to enter the brain to cause inflammation. However, in mice infected with the spirochete Borrelia turicatae, we observed widespread cerebral inflammation despite a paucity of spirochetes in the brain parenchyma at times of high bacteremia. Here we studied the possibility that bacterial lipoproteins may be capable of disseminating from the periphery across the blood-brain barrier to inflame the brain. For this we injected normal and infected mice intraperitoneally with lanthanide-labeled variable outer membrane lipoproteins of B. turicatae and measured their localization in blood, various peripheral organs, and whole and capillary-depleted brain protein extracts at various times. Lanthanide-labeled nonlipidated lipoproteins of B. turicatae and mouse albumin were used as controls. Brain inflammation was measured by TaqMan RT-PCR amplification of genes known to be up-regulated in response to borrelial infection. The results showed that the two lipoproteins we studied, LVsp1 and LVsp2, were capable of inflaming the brain after intraperitoneal injection to different degrees: LVsp1 was better than LVsp2 and Bt1 spirochetes at moving from blood to brain. The dissemination of LVsp1 from the periphery to the brain occurred under normal conditions and significantly increased with infection. In contrast, LVsp2 disseminated better to peripheral organs. We conclude that some bacterial lipoproteins can disseminate from the periphery to inflame the brain. AD - Department of Neurology and Neuroscience and Center for Emerging Pathogens, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey, USA. AN - 20431027 AU - Londono, D. AU - Cadavid, D. C2 - 2877846 DA - Jun DO - ajpath.2010.091235 [pii] 10.2353/ajpath.2010.091235 DP - NLM ET - 2010/05/01 KW - Animals Antigens, Bacterial/ immunology Bacterial Outer Membrane Proteins/ immunology Blood-Brain Barrier/immunology Borrelia/chemistry/pathogenicity Borrelia Infections/ immunology Brain/immunology/microbiology/pathology Female Immunologic Factors/immunology Lipoproteins/ immunology Mice Mice, Inbred Strains Spirochaetales/immunology LA - eng IS - 6 N1 - Londono, Diana Cadavid, Diego R21 NS053997/NS/NINDS NIH HHS/United States R21 NS057545-02/NS/NINDS NIH HHS/United States Research Support, N.I.H., Extramural United States The American journal of pathology Am J Pathol. 2010 Jun;176(6):2848-57. Epub 2010 Apr 29. PY - 2010 SN - 1525-2191 (Electronic) 0002-9440 (Linking) SP - 2848-57 ST - Bacterial lipoproteins can disseminate from the periphery to inflame the brain T2 - Am J Pathol TI - Bacterial lipoproteins can disseminate from the periphery to inflame the brain VL - 176 ID - 101 ER - TY - JOUR AB - Spirochetal infections are an important cause of neurological disease. In previous studies of the pathogenesis of spirochetal brain infection, mice inoculated with Borrelia turicatae, an agent of tick-borne relapsing fever in North America, developed mild meningitis and parenchymal activation/infiltration by interleukin 10 (IL-10)-producing microglia/macrophages. Here, we investigated the neuroprotective effects of IL-10 during spirochetal infection by comparing the outcomes of B. turicatae infection in wild-type and IL-10-deficient RAG2-deficient mice. Mice were infected with either serotype 1 (Bt1), which causes more brain infection but lower bacteremia, or Bt2, which causes less brain infection but higher bacteremia. Interleukin 10 deficiency resulted in early death from subarachnoid/intraparenchymal brain hemorrhage in Bt2-infected mice. These mice had marked apoptosis of brain microvascular endothelial cells as assessed by terminal transferase-mediated DNA nick end-labeling staining. In contrast, Bt1 infection caused milder subarachnoid hemorrhage. Neuronal apoptosis was observed in mice infected with both serotypes and was prominent in the cerebellum. Neutralization of tumor necrosis factor prevented death and reduced morbidity and brain injury in mice infected by both serotypes. We conclude that IL-10 plays a critical role protecting the cerebral microcirculation from spirochetal injury possibly by inhibition effects of tumor necrosis factor. AD - Department of Neurology and Neuroscience and Center for Emerging Pathogens at UMDNJ-New Jersey Medical School, Newark, New Jersey 07103, USA. AN - 18800010 AU - Londono, D. AU - Carvajal, J. AU - Arguelles-Grande, C. AU - Marques, A. AU - Cadavid, D. C2 - 2712754 DA - Oct DO - 10.1097/NEN.0b013e318187a279 DP - NLM ET - 2008/09/19 KW - Animals Borrelia Infections/mortality/ pathology/ prevention & control Brain/ pathology Coloring Agents Cytokines/biosynthesis/genetics Female Hemorrhage/etiology/pathology In Situ Nick-End Labeling Interleukin-10/ genetics/ physiology Mice Mice, Inbred C57BL Mice, Knockout Microcirculation/ pathology Reverse Transcriptase Polymerase Chain Reaction Tumor Necrosis Factors/antagonists & inhibitors LA - eng IS - 10 N1 - Londono, Diana Carvajal, Jenny Arguelles-Grande, Carolina Marques, Adriana Cadavid, Diego 1R21NS053997-01/NS/NINDS NIH HHS/United States R21 NS057545-01A2/NS/NINDS NIH HHS/United States R21 NS057545-02/NS/NINDS NIH HHS/United States Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't United States Journal of neuropathology and experimental neurology Nihms96001 J Neuropathol Exp Neurol. 2008 Oct;67(10):976-83. PY - 2008 SN - 0022-3069 (Print) 0022-3069 (Linking) SP - 976-83 ST - Interleukin 10 protects the brain microcirculation from spirochetal injury T2 - J Neuropathol Exp Neurol TI - Interleukin 10 protects the brain microcirculation from spirochetal injury VL - 67 ID - 102 ER - TY - JOUR AB - OBJECTIVE: To investigate whether apoptosis is a possible mechanism of brain dysfunction occurring in septic syndrome. DESIGN: Experimental prospective study. SETTING: Laboratory of Surgical Research at the University of Athens. SUBJECTS: Male pathogen-free Wistar rats. INTERVENTIONS: Rats (n = 112) were subjected to sepsis by cecal ligation and puncture. Sham-operated animals (n = 40) underwent the same procedure but without ligation or puncture. Septic animals were either randomly divided (n = 62) in six groups and studied at 6, 12, 24, 36, 48, and 60 hrs after the operation or monitored (n = 50) for 48 hrs as a survival study group. Sham-operated animals were killed at 6, 12, 24, 36, 48, and 60 hrs after the procedure. Brain and cecum were then removed and postfixed in paraffin sections. Apoptosis was evaluated by light microscopy in hematoxylin and eosin-stained specimens and by transmission electron microscopy. In paraffin-embedded sections, immunostaining for bax, bcl-2, cytochrome c, and caspase-8 was done. MEASUREMENTS AND MAIN RESULTS: In septic rats, increased apoptosis was detected in neurons of the CA1 region of the hippocampus, in choroid plexus, and in Purkinje cells of the cerebellum. Bax immunopositivity was found decreased after the septic insult (p =.03). Bax immunoreactivity was altered as the septic syndrome evolved; it was up-regulated in the early stages (6-12 hrs) and progressively decreased in the late phases (p =.001). Cytochrome c presented a similar regional pattern of expression and was found to be the sole gene marker carrying an independent prognostic role (p =.03). Both bcl-2 and caspase-8 expression remained at constant levels at all times evaluated. CONCLUSIONS: There is evidence that more neurons undergo apoptosis during sepsis than in normal brain tissue in certain sites where the blood-brain barrier is compromised. In this phenomenon, mitochondrial gene regulators such as bax and products such as cytochrome c seem to play important regulating and prognostic roles, respectively. AD - Laboratory of Surgical Research, First Department of Propaedeutic Surgery, Athens Medical School, Hippokration Hospital, Athens, Greece. AN - 15286556 AU - Messaris, E. AU - Memos, N. AU - Chatzigianni, E. AU - Konstadoulakis, M. M. AU - Menenakos, E. AU - Katsaragakis, S. AU - Voumvourakis, C. AU - Androulakis, G. DA - Aug DO - 00003246-200408000-00020 [pii] DP - NLM ET - 2004/08/03 KW - Animals Apoptosis/genetics Caspase 8 Caspases/analysis Cecum/pathology Choroid Plexus/ pathology Cytochromes c/analysis Cytoplasm/chemistry/ultrastructure Disease Models, Animal Genes, bcl-2 Hippocampus/ pathology Male Mitochondria/ultrastructure Neurons/chemistry/ ultrastructure Prognosis Proto-Oncogene Proteins/analysis Proto-Oncogene Proteins c-bcl-2 Purkinje Cells/ ultrastructure Rats Rats, Wistar Sepsis/enzymology/ pathology Survival Analysis Time Factors bcl-2-Associated X Protein LA - eng IS - 8 N1 - Messaris, Evangelos Memos, Nicholas Chatzigianni, Emmy Konstadoulakis, Manousos M Menenakos, Evangelos Katsaragakis, Stylianos Voumvourakis, Constatine Androulakis, George Research Support, Non-U.S. Gov't United States Critical care medicine Crit Care Med. 2004 Aug;32(8):1764-70. PY - 2004 SN - 0090-3493 (Print) 0090-3493 (Linking) SP - 1764-70 ST - Time-dependent mitochondrial-mediated programmed neuronal cell death prolongs survival in sepsis T2 - Crit Care Med TI - Time-dependent mitochondrial-mediated programmed neuronal cell death prolongs survival in sepsis VL - 32 ID - 111 ER - TY - JOUR AB - The proinflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha), has been suggested to mediate septic encephalopathy through an effect on cerebral blood flow (CBF) and metabolism. The effect of an intravenous bolus of endotoxin on global CBF, metabolism, and net flux of cytokines and catecholamines was investigated in eight healthy young volunteers. Cerebral blood flow was measured by the Kety-Schmidt technique at baseline (during normocapnia and voluntary hyperventilation for calculation of subject-specific cerebrovascular CO reactivity), and 90 minutes after an intravenous bolus of a reference endotoxin. Arterial TNF-alpha peaked at 90 minutes, coinciding with a peak in subjective symptoms. At this time, CBF and Paco were significantly reduced compared to baseline; the CBF decrease was readily explained by hypocapnia. The cerebral metabolic rate of oxygen remained unchanged, and the net cerebral flux of TNF-alpha, interleukin (IL)-1beta, and IL-6 did not differ significantly from zero. Thus, high circulating levels of TNF-alpha during human endotoxemia do not induce a direct reduction in cerebral oxidative metabolism. AD - Department of Infectious Diseases, University Hospital Rigshospitalet, Copenhagen, Denmark. kirsten.moller@dadlnet.dk AN - 12368665 AU - Moller, K. AU - Strauss, G. I. AU - Qvist, J. AU - Fonsmark, L. AU - Knudsen, G. M. AU - Larsen, F. S. AU - Krabbe, K. S. AU - Skinhoj, P. AU - Pedersen, B. K. DA - Oct DO - 10.1097/00004647-200210000-00014 DP - NLM ET - 2002/10/09 KW - Adult Blood Flow Velocity/ physiology Brain Diseases/blood/metabolism/ physiopathology Cerebrovascular Circulation/ physiology Cytokines/blood Electrolytes/blood Endotoxemia/metabolism/ physiopathology Endotoxins/toxicity Female Hemoglobins/metabolism Humans Inflammation/blood/chemically induced/physiopathology Interleukin-1/blood Interleukin-6/blood Kidney Function Tests Leukocyte Count Liver Function Tests Male Oxygen Consumption/ physiology Reference Values Time Factors Tumor Necrosis Factor-alpha/metabolism LA - eng IS - 10 N1 - Moller, Kirsten Strauss, Gitte Irene Qvist, Jesper Fonsmark, Lise Knudsen, Gitte Moos Larsen, Fin Stolze Krabbe, Karen Suarez Skinhoj, Peter Pedersen, Bente Klarlund Research Support, Non-U.S. Gov't United States Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism J Cereb Blood Flow Metab. 2002 Oct;22(10):1262-70. PY - 2002 SN - 0271-678X (Print) 0271-678X (Linking) SP - 1262-70 ST - Cerebral blood flow and oxidative metabolism during human endotoxemia T2 - J Cereb Blood Flow Metab TI - Cerebral blood flow and oxidative metabolism during human endotoxemia VL - 22 ID - 95 ER - TY - JOUR AB - Stress doses of hydrocortisone are known to have immunomodulatory effects in patients with hyperdynamic septic shock. The prognosis correlates with the presence and severity of septic encephalopathy. However, neurological evaluation is influenced by the use of analgesia sedation during artificial ventilation. The objective of this study was to demonstrate the effect of stress doses of hydrocortisone during the initial phase of human septic shock on the serum values of the neurospecific protein S-100B in comparison to the inflammation markers interleukin (IL)-8 in serum and polymorphonuclear (PMN) elastase in plasma. A total of 24 consecutive patients, who met the American College of Chest Physicians/Society of Critical Care Medicine criteria for septic shock, were enrolled in this prospective, randomized, double-blind, single-center trial. The severity of illness at recruitment was graded using the Acute Physiology and Chronic Health Evaluation II and the Simplified Acute Physiology Score II scoring systems. Multi-organ dysfunction syndrome was described by the Sepsis-related Organ Failure Assessment (SOFA) score. All patients were prospectively randomized to receive either stress doses of hydrocortisone or placebo. Hydrocortisone was started in 12 patients with a loading dose of 100 mg and followed by a continuous infusion of 0.18 mg/kg/h for 6 days. Median S-100B serum levels of the hydrocortisone group decreased from 0.32 ng/mL at study entry to 0.07 ng/mL 6 days later without significant differences compared to the placebo group. Initial IL-8 serum levels were significantly higher in the hydrocortisone group up to 12 h after study entry, and significantly decreased from 715 to 17 pg/mL at the end of the observation period. Median PMN elastase plasma levels were not affected by hydrocortisone infusion. Patients with initial S-100B serum levels > 0.50 ng/mL revealed significantly higher SOFA scores up to 30 h, IL-8 serum levels up to 12 h, and PMN elastase plasma levels up to 36 h after study entry than those patients with < or = 0.50 ng/mL. These effects were independent of the amount of fluid correction for hemodilution. Starting S-100B, IL-8 and PMN elastase values of the hydrocortisone group were within the ranges already known in patients with out-of-hospital cardiac arrest or severe traumatic brain injury. Stress doses of hydrocortisone resulted in a significant reduction in IL-8 serum, but not in S-100B serum and PMN elastase plasma concentrations in patients with hyperdynamic septic shock. For the first time, a similar extent of S-100B increase in serum of septic patients at the time of diagnosis was shown as reported for cardiac arrest or severe traumatic brain injury. AD - Department of Surgery Innenstadt, Klinikum der Universität München, Munich, Germany. thomas.mussack@med.uni-muenchen.de AN - 15843228 AU - Mussack, T AU - Briegel, J AU - Schelling, G AU - Biberthaler, P AU - Jochum, M DO - 10.1515/CCLM.2005.044 KW - Adult Aged Anti-Inflammatory Agents Dose-Response Relationship, Drug Double-Blind Method Female Germany Humans Hydrocortisone Intensive Care Units Interleukin-8 Leukocyte Elastase Male Middle Aged Multiple Organ Failure Nerve Growth Factors Placebos Prognosis Prospective Studies S100 Proteins Sensitivity and Specificity Severity of Illness Index Shock, Septic Time Factors L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15843228 LA - eng IS - 3 PY - 2005 SN - 1434-6621 SP - 259-68 ST - Effect of stress doses of hydrocortisone on S-100B vs. interleukin-8 and polymorphonuclear elastase levels in human septic shock. T2 - Clin Chem Lab Med TI - Effect of stress doses of hydrocortisone on S-100B vs. interleukin-8 and polymorphonuclear elastase levels in human septic shock. UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15843228 VL - 43 ID - 47 ER - TY - JOUR AB - BACKGROUND: The prognosis in patients with hyperdynamic septic shock correlates with the presence and the severity of septic encephalopathy. However, the neurological evaluation is considerably influenced by the use of analgesia sedation during mechanical ventilation. An early concentration peak of the neuroprotein S-100B in serum reflects both cellular damage at an increased permeability of the blood-brain-barrier and a delayed renal elimination. Thus, the objective of this study was to analyze the effect of continuous veno-venous hemofiltration (CVVH) on early S-100B serum levels in septic shock patients, who were treated with either stress doses of hydrocortisone or placebo. METHODS: Twenty-four consecutive patients, who met the ACCP / SCCM criteria for septic shock, were enrolled in this prospective, randomised, double-blind, single-center trial. The severity of illness at recruitment was graded using the APACHE II and SAPS II scoring systems; the MODS was described by the SOFA score. All patients were prospectively randomised to receive either stress doses of hydrocortisone or placebo. Hydrocortisone was started in 12 patients with a loading dose of 100 mg and followed by a continuous infusion of 0.18 mg/kg/h for 6 days. RESULTS: Median S-100B serum levels of the hydrocortisone group decreased from 0.32 ng/ml (0.19-3.60) at study entry to 0.07 ng/ml (0.04 - 0.32) 6 days later without significant differences compared to the placebo group. Patients undergoing CVVH showed significantly higher S-100B serum values compared to patients without CVVH (p<0.001). However, initial median S-100B serum levels of the CVVH group even increased from 0.92 ng/ml (0.16 - 4.63) to 2.33 ng/ml (0.59 - 2.44) 30 hours after study entry, reaching data ranges already known in patients with out-of-hospital cardiac arrest or severe traumatic brain injury. CONCLUSION: Early S-100B serum levels in septic shock patients receiving either stress doses of hydrocortisone or placebo were not influenced by CVVH. For the first time, we observed a similar extent of S-100B serum increase in CVVH patients, who had significantly higher S-100B serum values compared to those without CVVH, as reported for out-of-hospital cardiac arrest or severe traumatic brain injury. Hypercortisolemia induced by the infusion of stress doses of hydrocortisone did not significantly reduce early S-100B serum concentrations with time. AD - Department of Surgery Innenstadt, Klinikum der Universität München, Germany. Thomas.Mussack@med.uni-muenchen.de AN - 15817428 AU - Mussack, T AU - Briegel, J AU - Schelling, G AU - Jochum, M DA - Feb KW - Adult Aged Anti-Inflammatory Agents Dose-Response Relationship, Drug Double-Blind Method Female Hemofiltration Humans Hydrocortisone Male Middle Aged Nerve Growth Factors Placebos Prognosis Prospective Studies S100 Proteins Sensitivity and Specificity Shock, Septic L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15817428 LA - eng IS - 2 PY - 2005 SN - 0949-2321 SP - 81-7 ST - Hemofiltration does not influence early S-100B serum levels in septic shock patients receiving stress doses of hydrocortisone or placebo. T2 - Eur J Med Res TI - Hemofiltration does not influence early S-100B serum levels in septic shock patients receiving stress doses of hydrocortisone or placebo. UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15817428 VL - 10 ID - 48 ER - TY - JOUR AB - BACKGROUND: Septic encephalopathy is a common term denoting the signs of progressing central nervous system dysfunction in septic patients. Metabolic alterations including amino acid imbalance are involved in the pathogenesis of septic encephalopathy. The aim of the present study was to determine whether the ratio of branched-chain amino acids to aromatic amino acids is altered in patients with septic encephalopathy and whether polymyxin B-immobilized fiber (PMX-F) hemoperfusion affects this balance. METHODS: 16 septic patients with encephalopathy, 10 septic patients without encephalopathy, and 20 healthy controls were included in this study. Sepsis was diagnosed according to the ACCP/SCCM Consensus Conference criteria. Plasma endotoxin levels, interleukin-6 (IL-6) levels, and amino acid ratios were measured before and after PMX-F treatment. RESULTS: Within 12 h of the onset of septic encephalopathy, plasma endotoxin and IL-6 levels were increased significantly in septic patients with encephalopathy in comparison to those in septic patients without encephalopathy (endotoxin, p < 0.05; IL-6, p < 0.01) and those in healthy controls (endotoxin; p < 0.001; IL-6, p < 0.001). The ratio of branched-chain amino acids to aromatic amino acids in septic patients with encephalopathy was decreased in comparison to the ratio in septic patients without encephalopathy (p < 0.05) and that in healthy controls (p < 0.01). PMX-F treatment reduced plasma endotoxin (p < 0.01) and IL-6 levels (p < 0.01) and increased the ratio of branched-chain amino acids to aromatic amino acids (p < 0.01). CONCLUSION: The amino acid imbalance in patients with septic encephalopathy may be a marker for the severity of the septic syndrome, and PMX-F hemoperfusion is effective in ameliorating the increased plasma endotoxin and IL-6 levels and the amino acid imbalance in these patients. AD - Department of Medicine, Shinmatsudo Central General Hospital, Chiba, Japan. AN - 12944727 AU - Nakamura, T. AU - Kawagoe, Y. AU - Matsuda, T. AU - Ebihara, I. AU - Koide, H. DO - 10.1159/000072546 BPU20030214_5282 [pii] DP - NLM ET - 2003/08/29 KW - Adult Aged Amino Acids/blood/ metabolism Amino Acids, Aromatic/blood Amino Acids, Branched-Chain/blood Brain Diseases/ etiology Endotoxins/blood Female Hemoperfusion/ methods Humans Interleukin-6/blood Male Middle Aged Polymyxin B/ therapeutic use Sepsis/blood/complications/ therapy LA - eng IS - 4-5 N1 - Nakamura, Tsukasa Kawagoe, Yasuhiro Matsuda, Takaharu Ebihara, Isao Koide, Hikaru Clinical Trial Controlled Clinical Trial Switzerland Blood purification Blood Purif. 2003;21(4-5):282-6. PY - 2003 SN - 0253-5068 (Print) 0253-5068 (Linking) SP - 282-6 ST - Effects of polymyxin B-immobilized fiber hemoperfusion on amino acid imbalance in septic encephalopathy T2 - Blood Purif TI - Effects of polymyxin B-immobilized fiber hemoperfusion on amino acid imbalance in septic encephalopathy VL - 21 ID - 94 ER - TY - JOUR AB - OBJECTIVE: We investigated whether serum levels of neuron-specific enolase (NSE) and S-100beta protein could be used to evaluate cerebral injury and to predict outcome in severe sepsis and severe septic shock. DESIGN: Prospective study. SETTING: University hospital. PATIENTS AND MEASUREMENTS: In 170 consecutively enrolled patients with severe sepsis and septic shock, serum S-100beta and NSE were measured daily during four consecutive days after intensive care unit admission. Admission Glasgow Coma Scale before sedation and daily Sequential Organ Failure Assessment scores were recorded in all patients. Acute encephalopathy was defined as either a state of agitation, confusion, irritability, and convulsions (type A) or characterized by somnolence, stupor, and coma (type B) and persistently observed during 72 hrs after withdrawing sedation. When clinically indicated, contrast computed tomography or magnetic resonance imaging were performed to evaluate brain injury. MAIN RESULTS: S-100beta and NSE increased in, respectively, 72 (42%) and 90 (53%) patients. High biomarker levels were associated with the maximum Sequential Organ Failure Assessment scores (p = .001), and the highest values were found in patients who died early, within 4 days of inclusion (p = .005). Low consciousness encephalopathy type B was more frequently observed in patients with elevated S-100beta (p = .004). S-100beta levels of >or=4 microg/L were associated with severe brain ischemia or hemorrhage, and values of <2 microg/L were found in patients with diffuse cerebral embolic infarction lesions. High S-100beta levels were associated with higher intensive care unit mortality (p = .04) and represented the strongest independent predictor of intensive care unit survival, whereas NSE and the Glasgow Coma Scale failed to predict fatal outcome. CONCLUSIONS: S-100beta and NSE are frequently increased and associated with brain injury in patients with severe sepsis and septic shock. S-100beta levels more closely reflected severe encephalopathy and type of brain lesions than NSE and the Glasgow Coma Scale. AD - Critical Care Department, Vrije Universiteit Brussel, Brussels, Belgium. AN - 16607230 AU - Nguyen, D. N. AU - Spapen, H. AU - Su, F. AU - Schiettecatte, J. AU - Shi, L. AU - Hachimi-Idrissi, S. AU - Huyghens, L. DA - Jul DO - 10.1097/01.ccm.0000217218.51381.49 DP - NLM ET - 2006/04/12 KW - Adolescent Adult Aged Aged, 80 and over Biological Markers/ blood Brain Diseases/ blood/diagnosis/etiology Coma/diagnosis Female Glasgow Coma Scale Humans Intensive Care Units Magnetic Resonance Imaging Male Middle Aged Nerve Growth Factors/ blood Phosphopyruvate Hydratase/ blood Prospective Studies S100 Proteins/ blood Sepsis/ complications Shock, Septic/ complications Tomography, X-Ray Computed LA - eng IS - 7 N1 - Nguyen, Duc Nam Spapen, Herbert Su, Fuhong Schiettecatte, Johan Shi, Lin Hachimi-Idrissi, Said Huyghens, Luc Comparative Study United States Critical care medicine Crit Care Med. 2006 Jul;34(7):1967-74. PY - 2006 SN - 0090-3493 (Print) 0090-3493 (Linking) SP - 1967-74 ST - Elevated serum levels of S-100beta protein and neuron-specific enolase are associated with brain injury in patients with severe sepsis and septic shock T2 - Crit Care Med TI - Elevated serum levels of S-100beta protein and neuron-specific enolase are associated with brain injury in patients with severe sepsis and septic shock VL - 34 ID - 87 ER - TY - JOUR AB - OBJECTIVE: We investigated whether serum levels of neuron-specific enolase (NSE) and S-100beta protein could be used to evaluate cerebral injury and to predict outcome in severe sepsis and severe septic shock. DESIGN: Prospective study. SETTING: University hospital. PATIENTS AND MEASUREMENTS: In 170 consecutively enrolled patients with severe sepsis and septic shock, serum S-100beta and NSE were measured daily during four consecutive days after intensive care unit admission. Admission Glasgow Coma Scale before sedation and daily Sequential Organ Failure Assessment scores were recorded in all patients. Acute encephalopathy was defined as either a state of agitation, confusion, irritability, and convulsions (type A) or characterized by somnolence, stupor, and coma (type B) and persistently observed during 72 hrs after withdrawing sedation. When clinically indicated, contrast computed tomography or magnetic resonance imaging were performed to evaluate brain injury. MAIN RESULTS: S-100beta and NSE increased in, respectively, 72 (42%) and 90 (53%) patients. High biomarker levels were associated with the maximum Sequential Organ Failure Assessment scores (p = .001), and the highest values were found in patients who died early, within 4 days of inclusion (p = .005). Low consciousness encephalopathy type B was more frequently observed in patients with elevated S-100beta (p = .004). S-100beta levels of >or=4 microg/L were associated with severe brain ischemia or hemorrhage, and values of <2 microg/L were found in patients with diffuse cerebral embolic infarction lesions. High S-100beta levels were associated with higher intensive care unit mortality (p = .04) and represented the strongest independent predictor of intensive care unit survival, whereas NSE and the Glasgow Coma Scale failed to predict fatal outcome. CONCLUSIONS: S-100beta and NSE are frequently increased and associated with brain injury in patients with severe sepsis and septic shock. S-100beta levels more closely reflected severe encephalopathy and type of brain lesions than NSE and the Glasgow Coma Scale. AD - Critical Care Department, Vrije Universiteit Brussel, Brussels, Belgium. AN - 16607230 AU - Nguyen, DN AU - Spapen, H AU - Su, F AU - Schiettecatte, J AU - Shi, L AU - Hachimi-Idrissi, S AU - Huyghens, L DA - Jul DO - 10.1097/01.CCM.0000217218.51381.49 KW - Adolescent Adult Aged Aged, 80 and over Biological Markers Brain Diseases Coma Female Glasgow Coma Scale Humans Intensive Care Units Magnetic Resonance Imaging Male Middle Aged Nerve Growth Factors Phosphopyruvate Hydratase Prospective Studies S100 Proteins Sepsis Shock, Septic Tomography, X-Ray Computed L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16607230 LA - eng IS - 7 PY - 2006 SN - 0090-3493 SP - 1967-74 ST - Elevated serum levels of S-100beta protein and neuron-specific enolase are associated with brain injury in patients with severe sepsis and septic shock. T2 - Crit Care Med TI - Elevated serum levels of S-100beta protein and neuron-specific enolase are associated with brain injury in patients with severe sepsis and septic shock. UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16607230 VL - 34 ID - 43 ER - TY - JOUR AB - The blood-brain barrier (BBB) is highly restrictive of the transport of substances between blood and the central nervous system. Brain pericytes are one of the important cellular constituents of the BBB and are multifunctional, polymorphic cells that lie within the microvessel basal lamina. The present study aimed to evaluate the role of pericytes in the mediation of BBB disruption using a lipopolysaccharide (LPS)-induced model of septic encephalopathy in mice. ICR mice were injected intraperitoneally with LPS or saline and were sacrificed at 1, 3, 6, and 24 h after injection. Sodium fluorescein accumulated with time in the hippocampus after LPS injection; this hyperpermeability was supported by detecting the extravasation of fibrinogen. Microglia were activated and the number of microglia increased with time after LPS injection. LPS-treated mice exhibited a broken basal lamina and pericyte detachment from the basal lamina at 6-24 h after LPS injection. The disorganization in the pericyte and basal lamina unit was well correlated with increased microglial activation and increased cerebrovascular permeability in LPS-treated mice. These findings suggest that pericyte detachment and microglial activation may be involved in the mediation of BBB disruption due to inflammatory responses in the damaged brain. AD - Department of Pharmaceutical Care and Health Sciences, Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan. AN - 18987969 AU - Nishioku, T AU - Dohgu, S AU - Takata, F AU - Eto, T AU - Ishikawa, N AU - Kodama, KB AU - Nakagawa, S AU - Yamauchi, A AU - Kataoka, Y DA - May DO - 10.1007/s10571-008-9322-x KW - Animals Basement Membrane Blood-Brain Barrier Hippocampus Lipopolysaccharides Mice Mice, Inbred ICR Microglia Pericytes Sepsis L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18987969 LA - eng IS - 3 PY - 2009 SN - 1573-6830 SP - 309-16 ST - Detachment of brain pericytes from the basal lamina is involved in disruption of the blood-brain barrier caused by lipopolysaccharide-induced sepsis in mice. T2 - Cell Mol Neurobiol TI - Detachment of brain pericytes from the basal lamina is involved in disruption of the blood-brain barrier caused by lipopolysaccharide-induced sepsis in mice. UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18987969 VL - 29 ID - 21 ER - TY - JOUR AN - 18276654 AU - Panni, J. K. AU - Panni, M. K. DA - Mar DO - 100/3/419 [pii] 10.1093/bja/aen009 DP - NLM ET - 2008/02/16 KW - Biological Markers/blood Brain Diseases/ diagnosis Humans Nerve Growth Factors/ blood Prognosis S100 Proteins/ blood Sepsis/ complications LA - eng IS - 3 N1 - Panni, J K Panni, M K Comment Letter England British journal of anaesthesia Br J Anaesth. 2008 Mar;100(3):419; author reply 419-20. PY - 2008 SN - 1471-6771 (Electronic) 0007-0912 (Linking) SP - 419; author reply 419-20 ST - Changes in S100B levels rather than absolute values may be a better marker of severity of septic encephalopathy T2 - Br J Anaesth TI - Changes in S100B levels rather than absolute values may be a better marker of severity of septic encephalopathy VL - 100 ID - 76 ER - TY - JOUR AN - 18276654 AU - Panni, JK AU - Panni, MK DA - Mar DO - 100/3/419 [pii] 10.1093/bja/aen009 KW - Biological Markers Brain Diseases Humans Nerve Growth Factors Prognosis S100 Proteins Sepsis L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18276654 LA - eng IS - 3 PY - 2008 SN - 1471-6771 SP - 419; author reply 419-20 ST - Changes in S100B levels rather than absolute values may be a better marker of severity of septic encephalopathy. T2 - Br J Anaesth TI - Changes in S100B levels rather than absolute values may be a better marker of severity of septic encephalopathy. UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18276654 VL - 100 ID - 29 ER - TY - JOUR AB - Systemic infection or inflammation gives rise to signals that communicate with the brain and leads to changes in metabolism and behaviour collectively known as sickness behaviour. In healthy young individuals, these changes are normally transient with no long-term consequences. The microglia are involved in the immune to brain signalling pathways. In the aged or diseased brain, the microglia have a primed phenotype as a consequence of changes in their local microenvironment. Systemic inflammation impacts on these primed microglia and switches them from a relatively benign to an aggressive phenotype with the enhanced synthesis of pro-inflammatory mediators. Recent evidence suggests that systemic inflammation contributes to the exacerbation of acute symptoms of chronic neurodegenerative disease and may accelerate disease progression. The normal homeostatic role that microglia play in signalling about systemic infections and inflammation becomes maladaptive in the aged and diseased brain and this offers a route to therapeutic intervention. Prompt treatment of systemic inflammation or blockade of signalling pathways from the periphery to the brain may help to slow neurodegeneration and improve the quality of life for individuals suffering from chronic neurodegenerative disease. AD - School of Biological Sciences, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK. vhp@soton.ac.uk AN - 20644946 AU - Perry, V. H. DA - Sep DO - 10.1007/s00401-010-0722-x DP - NLM ET - 2010/07/21 LA - eng IS - 3 N1 - Perry, V Hugh Medical Research Council/United Kingdom Wellcome Trust/United Kingdom Research Support, Non-U.S. Gov't Germany Acta neuropathologica Acta Neuropathol. 2010 Sep;120(3):277-86. Epub 2010 Jul 20. PY - 2010 SN - 1432-0533 (Electronic) 0001-6322 (Linking) SP - 277-86 ST - Contribution of systemic inflammation to chronic neurodegeneration T2 - Acta Neuropathol TI - Contribution of systemic inflammation to chronic neurodegeneration VL - 120 ID - 114 ER - TY - JOUR AB - INTRODUCTION: In sepsis the brain is frequently affected although there is no infection of the CNS (septic encephalopathy). One possible cause of septic encephalopathy is failure of the blood-brain barrier. Brain edema has been documented in animal models of sepsis. Aggressive fluid resuscitation in the early course of sepsis improves survival and is standard practice. We hypothesized that aggressive fluid administration will increase intracranial pressure (ICP) and may cause critical reductions in cerebral perfusion pressure (CPP). MATERIALS AND METHODS: Patients with sepsis were investigated daily on up to four consecutive days in the intensive care unit. Mean arterial blood pressure (MAP) and blood flow velocity in the middle cerebral artery were monitored for one hour each day. ICP was calculated non-invasively from MAP and flow velocity data. S-100beta was determined daily. FINDINGS: Fifty-two measurements were performed in 16 patients. ICP could be determined in 45 measurements in 15 patients. Seven patients had an ICP > 15 mmHg and 11 patients had a CPP < 60 mmHg on at least 1 day. We found no significant correlation between ICP and fluid administration, but low CPP was significantly correlated with elevated S-100beta (r = -0.47, p = 0.001). CONCLUSIONS: Further research is needed to determine the role of ICP/CPP monitoring in patients with sepsis. AD - Department of Anaesthesia, Operative Intensive Care Unit, University Hospital Basel, Spitalstrasse 21, CH-4031 Basel, Switzerland. AN - 19388291 AU - Pfister, D. AU - Schmidt, B. AU - Smielewski, P. AU - Siegemund, M. AU - Strebel, S. P. AU - Ruegg, S. AU - Marsch, S. C. AU - Pargger, H. AU - Steiner, L. A. DP - NLM ET - 2008/01/01 KW - Aged Blood Pressure/physiology Cerebrovascular Circulation/ physiology Female Humans Intracranial Pressure/ physiology Male Middle Aged Pulsatile Flow/physiology Sepsis/ physiopathology Statistics, Nonparametric Ultrasonography, Doppler, Transcranial/methods LA - eng N1 - Pfister, D Schmidt, B Smielewski, P Siegemund, M Strebel, S P Ruegg, S Marsch, S C U Pargger, H Steiner, L A Austria Acta neurochirurgica. Supplement Acta Neurochir Suppl. 2008;102:71-5. PY - 2008 SN - 0065-1419 (Print) 0065-1419 (Linking) SP - 71-5 ST - Intracranial pressure in patients with sepsis T2 - Acta Neurochir Suppl TI - Intracranial pressure in patients with sepsis VL - 102 ID - 78 ER - TY - JOUR AB - INTRODUCTION: In sepsis the brain is frequently affected although there is no infection of the CNS (septic encephalopathy). One possible cause of septic encephalopathy is failure of the blood-brain barrier. Brain edema has been documented in animal models of sepsis. Aggressive fluid resuscitation in the early course of sepsis improves survival and is standard practice. We hypothesized that aggressive fluid administration will increase intracranial pressure (ICP) and may cause critical reductions in cerebral perfusion pressure (CPP). MATERIALS AND METHODS: Patients with sepsis were investigated daily on up to four consecutive days in the intensive care unit. Mean arterial blood pressure (MAP) and blood flow velocity in the middle cerebral artery were monitored for one hour each day. ICP was calculated non-invasively from MAP and flow velocity data. S-100beta was determined daily. FINDINGS: Fifty-two measurements were performed in 16 patients. ICP could be determined in 45 measurements in 15 patients. Seven patients had an ICP > 15 mmHg and 11 patients had a CPP < 60 mmHg on at least 1 day. We found no significant correlation between ICP and fluid administration, but low CPP was significantly correlated with elevated S-100beta (r = -0.47, p = 0.001). CONCLUSIONS: Further research is needed to determine the role of ICP/CPP monitoring in patients with sepsis. AD - Department of Anaesthesia, Operative Intensive Care Unit, University Hospital Basel, Spitalstrasse 21, CH-4031 Basel, Switzerland. AN - 19388291 AU - Pfister, D AU - Schmidt, B AU - Smielewski, P AU - Siegemund, M AU - Strebel, SP AU - Rüegg, S AU - Marsch, SC AU - Pargger, H AU - Steiner, LA KW - Aged Blood Pressure Cerebrovascular Circulation Female Humans Intracranial Pressure Male Middle Aged Pulsatile Flow Sepsis Statistics, Nonparametric Ultrasonography, Doppler, Transcranial L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19388291 LA - eng PY - 2008 SN - 0065-1419 SP - 71-5 ST - Intracranial pressure in patients with sepsis. T2 - Acta Neurochir Suppl TI - Intracranial pressure in patients with sepsis. UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19388291 VL - 102 ID - 32 ER - TY - JOUR AB - The pathogenesis of sepsis associated encephalopathy (SAE) is not yet clear: the blood-brain barrier (BBB) disruption has been indicated among the possible causative mechanisms. S100B, a calcium binding protein, originates in the central nervous system but it can be also produced by extra-cerebral sources; it is passively released from damaged glial cells and neurons; it has limited passage through the BBB. We aimed to demonstrate BBB damage as part of the pathogenesis of SAE by cerebral spinal fluid (CSF) and serum S100B measurements and by magnetic resonance imaging (MRI). This paper describes four septic patients in whom SAE was clinically evident, who underwent MRI and S100B measurement. We have not found any evidence of CSF-S100B increase. Serum S100B increase was found in three out of four patients. MRI did not identify images attributable to BBB disruption but vasogenic edema, probably caused by an alteration of autoregulation, was diagnosed. S100B does not increase in CSF of septic patients; S100B increase in serum may be due to extracerebral sources and does not prove any injury of BBB. MRI can exclude other cerebral pathologies causing brain dysfunction but is not specific of SAE. BBB damage may be numbered among the contributors of SAE, which aetiology is certainly multifactorial: an interplay between the toxic mediators involved in sepsis and the indirect effects of hyperthermia, hypossia and hypoperfusion. AD - Dipartimento di Scienze Chirurgiche Anestesiologiche Rianimatorie e dell'Emergenza, Universita degli Studi di Napoli Federico II, via Pansini 5, 80131, Naples, Italy. orpiazza@unina.it AN - 19132530 AU - Piazza, O. AU - Cotena, S. AU - De Robertis, E. AU - Caranci, F. AU - Tufano, R. DA - Jul DO - 10.1007/s11064-008-9907-2 DP - NLM ET - 2009/01/10 KW - Adult Blood-Brain Barrier/physiology Brain Diseases/cerebrospinal fluid/etiology Fatal Outcome Female Humans Magnetic Resonance Imaging Male Middle Aged Nerve Growth Factors/ cerebrospinal fluid S100 Proteins/ cerebrospinal fluid Sepsis/ cerebrospinal fluid/complications/ metabolism Shock, Septic/complications LA - eng IS - 7 N1 - Piazza, Ornella Cotena, Simona De Robertis, Edoardo Caranci, Ferdinando Tufano, Rosalba Case Reports United States Neurochemical research Neurochem Res. 2009 Jul;34(7):1289-92. Epub 2009 Jan 9. PY - 2009 SN - 1573-6903 (Electronic) 0364-3190 (Linking) SP - 1289-92 ST - Sepsis associated encephalopathy studied by MRI and cerebral spinal fluid S100B measurement T2 - Neurochem Res TI - Sepsis associated encephalopathy studied by MRI and cerebral spinal fluid S100B measurement VL - 34 ID - 65 ER - TY - JOUR AB - The pathogenesis of sepsis associated encephalopathy (SAE) is not yet clear: the blood-brain barrier (BBB) disruption has been indicated among the possible causative mechanisms. S100B, a calcium binding protein, originates in the central nervous system but it can be also produced by extra-cerebral sources; it is passively released from damaged glial cells and neurons; it has limited passage through the BBB. We aimed to demonstrate BBB damage as part of the pathogenesis of SAE by cerebral spinal fluid (CSF) and serum S100B measurements and by magnetic resonance imaging (MRI). This paper describes four septic patients in whom SAE was clinically evident, who underwent MRI and S100B measurement. We have not found any evidence of CSF-S100B increase. Serum S100B increase was found in three out of four patients. MRI did not identify images attributable to BBB disruption but vasogenic edema, probably caused by an alteration of autoregulation, was diagnosed. S100B does not increase in CSF of septic patients; S100B increase in serum may be due to extracerebral sources and does not prove any injury of BBB. MRI can exclude other cerebral pathologies causing brain dysfunction but is not specific of SAE. BBB damage may be numbered among the contributors of SAE, which aetiology is certainly multifactorial: an interplay between the toxic mediators involved in sepsis and the indirect effects of hyperthermia, hypossia and hypoperfusion. AD - Dipartimento di Scienze Chirurgiche Anestesiologiche Rianimatorie e dell'Emergenza, Università degli Studi di Napoli Federico II, via Pansini 5, 80131, Naples, Italy. orpiazza@unina.it AN - 19132530 AU - Piazza, O AU - Cotena, S AU - De Robertis, E AU - Caranci, F AU - Tufano, R DA - Jul DO - 10.1007/s11064-008-9907-2 KW - Adult Blood-Brain Barrier Brain Diseases Fatal Outcome Female Humans Magnetic Resonance Imaging Male Middle Aged Nerve Growth Factors S100 Proteins Sepsis Shock, Septic L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19132530 LA - eng IS - 7 PY - 2009 SN - 1573-6903 SP - 1289-92 ST - Sepsis associated encephalopathy studied by MRI and cerebral spinal fluid S100B measurement. T2 - Neurochem Res TI - Sepsis associated encephalopathy studied by MRI and cerebral spinal fluid S100B measurement. UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19132530 VL - 34 ID - 19 ER - TY - JOUR AB - PURPOSE OF REVIEW: Septic encephalopathy is a frequent complication in severe sepsis, the pathogenesis and mechanisms of which are not fully understood. Here, we review recent advances in our understanding of septic encephalopathy, from molecular mechanisms to behavioral alterations, from diagnostic tools to potential therapeutic agents. RECENT FINDINGS: Recent insights into septic encephalopathy include: microcirculatory failure precedes changes in evoked potential responses; blood-brain barrier alteration is prevented by reducing intercellular adhesion molecule expression and pericyte detachment; reducing infiltration of CD68 macrophages and inhibiting complement activation alleviates neuroinflammation in septic encephalopathy; and reducing mitochondrial dysfunction and inducible nitric oxide synthase expression can restore altered brain function. In addition, other factors such as the circulating levels of growth hormone are independent predictors for mortality and correlate with the severity of sepsis. Similar to humans, septic rats present recognition memory impairment and depressive-like symptoms but not anxiety-like behavior and will serve as efficient models to study the underlying mechanisms of septic encephalopathy. SUMMARY: Septic encephalopathy is a dynamic disease caused by a complex network of systems and pathways going awry. More insights into the pathogenesis of septic encephalopathy are expected to lead to new cellular and molecular targets, which in turn will permit design of specific septic encephalopathy-alleviating drugs and prevent its negative influence on survival. AD - Department of Pathology, University of Chicago, Chicago, Illinois 60637, USA. AN - 19387342 AU - Pytel, P. AU - Alexander, J. J. DA - Jun DO - 10.1097/WCO.0b013e32832b3101 DP - NLM ET - 2009/04/24 KW - Animals Biological Markers/metabolism Blood-Brain Barrier/physiology Central Nervous System Bacterial Infections/drug therapy/ etiology/immunology/ physiopathology Complement Activation Disease Models, Animal Humans Hypoxia-Ischemia, Brain/pathology/physiopathology Microcirculation Sepsis/ complications/drug therapy/immunology/ physiopathology LA - eng IS - 3 N1 - Pytel, Peter Alexander, Jessy J Review England Current opinion in neurology Curr Opin Neurol. 2009 Jun;22(3):283-7. PY - 2009 SN - 1473-6551 (Electronic) 1080-8248 (Linking) SP - 283-7 ST - Pathogenesis of septic encephalopathy T2 - Curr Opin Neurol TI - Pathogenesis of septic encephalopathy VL - 22 ID - 66 ER - TY - JOUR AB - PURPOSE OF REVIEW: Septic encephalopathy is a frequent complication in severe sepsis, the pathogenesis and mechanisms of which are not fully understood. Here, we review recent advances in our understanding of septic encephalopathy, from molecular mechanisms to behavioral alterations, from diagnostic tools to potential therapeutic agents. RECENT FINDINGS: Recent insights into septic encephalopathy include: microcirculatory failure precedes changes in evoked potential responses; blood-brain barrier alteration is prevented by reducing intercellular adhesion molecule expression and pericyte detachment; reducing infiltration of CD68 macrophages and inhibiting complement activation alleviates neuroinflammation in septic encephalopathy; and reducing mitochondrial dysfunction and inducible nitric oxide synthase expression can restore altered brain function. In addition, other factors such as the circulating levels of growth hormone are independent predictors for mortality and correlate with the severity of sepsis. Similar to humans, septic rats present recognition memory impairment and depressive-like symptoms but not anxiety-like behavior and will serve as efficient models to study the underlying mechanisms of septic encephalopathy. SUMMARY: Septic encephalopathy is a dynamic disease caused by a complex network of systems and pathways going awry. More insights into the pathogenesis of septic encephalopathy are expected to lead to new cellular and molecular targets, which in turn will permit design of specific septic encephalopathy-alleviating drugs and prevent its negative influence on survival. AD - Department of Pathology, University of Chicago, Chicago, Illinois 60637, USA. AN - 19387342 AU - Pytel, P AU - Alexander, JJ DA - Jun DO - 10.1097/WCO.0b013e32832b3101 KW - Animals Biological Markers Blood-Brain Barrier Central Nervous System Bacterial Infections Complement Activation Disease Models, Animal Humans Hypoxia-Ischemia, Brain Microcirculation Sepsis L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19387342 LA - eng IS - 3 PY - 2009 SN - 1473-6551 SP - 283-7 ST - Pathogenesis of septic encephalopathy. T2 - Curr Opin Neurol TI - Pathogenesis of septic encephalopathy. UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19387342 VL - 22 ID - 17 ER - TY - JOUR AB - Inflammation is implicated in the progressive nature of neurodegenerative diseases, such as Parkinson's disease, but the mechanisms are poorly understood. A single systemic lipopolysaccharide (LPS, 5 mg/kg, i.p.) or tumor necrosis factor alpha (TNFalpha, 0.25 mg/kg, i.p.) injection was administered in adult wild-type mice and in mice lacking TNFalpha receptors (TNF R1/R2(-/-)) to discern the mechanisms of inflammation transfer from the periphery to the brain and the neurodegenerative consequences. Systemic LPS administration resulted in rapid brain TNFalpha increase that remained elevated for 10 months, while peripheral TNFalpha (serum and liver) had subsided by 9 h (serum) and 1 week (liver). Systemic TNFalpha and LPS administration activated microglia and increased expression of brain pro-inflammatory factors (i.e., TNFalpha, MCP-1, IL-1beta, and NF-kappaB p65) in wild-type mice, but not in TNF R1/R2(-/-) mice. Further, LPS reduced the number of tyrosine hydroxylase-immunoreactive neurons in the substantia nigra (SN) by 23% at 7-months post-treatment, which progressed to 47% at 10 months. Together, these data demonstrate that through TNFalpha, peripheral inflammation in adult animals can: (1) activate brain microglia to produce chronically elevated pro-inflammatory factors; (2) induce delayed and progressive loss of DA neurons in the SN. These findings provide valuable insight into the potential pathogenesis and self-propelling nature of Parkinson's disease. AD - Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. AN - 17203472 AU - Qin, L. AU - Wu, X. AU - Block, M. L. AU - Liu, Y. AU - Breese, G. R. AU - Hong, J. S. AU - Knapp, D. J. AU - Crews, F. T. C2 - 2871685 DA - Apr 1 DO - 10.1002/glia.20467 DP - NLM ET - 2007/01/05 KW - Animals Brain/cytology/ immunology/metabolism Cell Death/immunology Disease Models, Animal Dopamine/metabolism Inflammation/chemically induced/complications Inflammation Mediators/immunology/metabolism Injections, Intraperitoneal Lipopolysaccharides/administration & dosage/ immunology Liver/metabolism Male Mice Mice, Inbred C57BL Mice, Inbred Strains Mice, Knockout Microglia/ immunology Neurodegenerative Diseases/etiology/ immunology/metabolism Neurons/ cytology/metabolism Parkinson Disease/immunology/metabolism RNA, Messenger/analysis Substantia Nigra/cytology/immunology/metabolism Time Factors Tumor Necrosis Factor-alpha/genetics/ metabolism LA - eng IS - 5 N1 - Qin, Liya Wu, Xuefei Block, Michelle L Liu, Yuxin Breese, George R Hong, Jau-Shyong Knapp, Darin J Crews, Fulton T P60 AA011605-070005/AA/NIAAA NIH HHS/United States Comparative Study Research Support, N.I.H., Extramural United States Glia Nihms197950 Glia. 2007 Apr 1;55(5):453-62. PY - 2007 SN - 0894-1491 (Print) 0894-1491 (Linking) SP - 453-62 ST - Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration T2 - Glia TI - Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration VL - 55 ID - 113 ER - TY - JOUR AB - INTRODUCTION: Outcome after cardiac arrest is mostly determined by the degree of hypoxic brain damage. Patients recovering from cardiopulmonary resuscitation are at great risk of subsequent death or severe neurological damage, including persistent vegetative state. The early definition of prognosis for these patients has ethical and economic implications. The main purpose of this study was to investigate the prognostic value of serum neuron-specific enolase (NSE) in predicting outcomes in patients early after in-hospital cardiac arrest. METHODS: Forty-five patients resuscitated from in-hospital cardiac arrest were prospectively studied from June 2003 to January 2005. Blood samples were collected, at any time between 12 and 36 hours after the arrest, for NSE measurement. Outcome was evaluated 6 months later with the Glasgow outcome scale (GOS). Patients were divided into two groups: group 1 (unfavorable outcome) included GOS 1 and 2 patients; group 2 (favorable outcome) included GOS 3, 4 and 5 patients. The Mann-Whitney U test, Student's t test and Fisher's exact test were used to compare the groups. RESULTS: The Glasgow coma scale scores were 6.1 +/- 3 in group 1 and 12.1 +/- 3 in group 2 (means +/- SD; p < 0.001). The mean time to NSE sampling was 20.2 +/- 8.3 hours in group 1 and 28.4 +/- 8.7 hours in group 2 (p = 0.013). Two patients were excluded from the analysis because of sample hemolysis. At 6 months, favorable outcome was observed in nine patients (19.6%). Thirty patients (69.8%) died and four (9.3%) remained in a persistent vegetative state. The 34 patients (81.4%) in group 1 had significantly higher NSE levels (median 44.24 ng/ml, range 8.1 to 370) than those in group 2 (25.26 ng/ml, range 9.28 to 55.41; p = 0.034). CONCLUSION: Early determination of serum NSE levels is a valuable ancillary method for assessing outcome after in-hospital cardiac arrest. AD - Servico de Medicina Intensiva, Hospital de Clinicas de Porto Alegre, Rua Ramiro Barcelos, 2350, Largo Eduardo Z, Faraco, Porto Alegre, RS, 90035-903, Brazil. tatianarech@terra.com.br AN - 16978415 AU - Rech, T. H. AU - Vieira, S. R. AU - Nagel, F. AU - Brauner, J. S. AU - Scalco, R. C2 - 1751053 DO - cc5046 [pii] 10.1186/cc5046 DP - NLM ET - 2006/09/19 KW - Aged Biological Markers/blood Cardiopulmonary Resuscitation Cohort Studies Female Heart Arrest/ enzymology/ epidemiology/therapy Hospitalization Humans Male Middle Aged Phosphopyruvate Hydratase/ blood Predictive Value of Tests Prognosis Prospective Studies Time Factors Treatment Outcome LA - eng IS - 5 N1 - Rech, Tatiana H Vieira, Silvia Regina Rios Nagel, Fabiano Brauner, Janete Salles Scalco, Rosana Comparative Study Multicenter Study Research Support, Non-U.S. Gov't England Critical care (London, England) Crit Care. 2006;10(5):R133. PY - 2006 SN - 1466-609X (Electronic) 1364-8535 (Linking) SP - R133 ST - Serum neuron-specific enolase as early predictor of outcome after in-hospital cardiac arrest: a cohort study T2 - Crit Care TI - Serum neuron-specific enolase as early predictor of outcome after in-hospital cardiac arrest: a cohort study VL - 10 ID - 120 ER - TY - JOUR AB - BACKGROUND: Clinical examination may be less sensitive than electrophysiological methods in the diagnosis of sepsis-associated encephalopathy. The aim of this study was to evaluate the changes in A-line Autoregression Index (AAI) induced by postsurgical sepsis. METHODS: The study involved patients admitted to the University High Dependency Unit (HDU) after major abdominal surgery. Patients that later developed sepsis entered the septic group (SG), and the other patients formed the control group (CG). The SG underwent measurements of AAI and tests for bedside mental status, consciousness abnormalities, heart rate, blood pressure, respiratory rate, tympanic temperature and white blood cell concentration at HDU admission (T1) and within 6 hours after the diagnosis of sepsis was confirmed (T2). The CG was evaluated at T1 and at day 4 of the HDU stay. All measured variables were compared between CG and SG at T1 and T2 using the Mann Whitney test with a significance cut-off of P<0.001. RESULTS: The CG and SG included 30 and 24 patients, respectively. There was no difference between the CG and SG at T1. At T2, the median AAI was significantly higher in the CG than in the SG. Significant differences were found also for reactive protein C and body temperature. CONCLUSION: The occurrence of sepsis significantly reduces AAI. Measurement of AAI thus has the potential to be a reliable diagnostic test to identify subclinical sepsis-associated encephalopathy. AD - Department of Critical Care, Section of Anesthesiology and Intensive Care, Careggi University Hospital, Florence, Italy. AN - 18438333 AU - Rinaldi, S AU - Consales, G AU - De Gaudio, AR DA - Jun DO - R02085131 [pii] KW - Aged Evoked Potentials, Auditory Humans Middle Aged Postoperative Complications Sepsis L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18438333 LA - eng IS - 6 PY - 2008 SN - 1827-1596 SP - 245-50 ST - Changes in auditory evoked potentials induced by postsurgical sepsis. T2 - Minerva Anestesiol TI - Changes in auditory evoked potentials induced by postsurgical sepsis. UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18438333 VL - 74 ID - 27 ER - TY - JOUR AB - OBJECTIVE AND DESIGN: Early microcirculatory failure is assumed as a key factor in the development of a septic encephalopathy. However, brain edema is also a common finding in sepsis syndromes possibly interfering with the vasoregulative mechanisms of the brain. We assessed the occurrence of brain edema in a rat model of endotoxic shock. MATERIAL AND SUBJECTS: Eleven mechanically ventilated male CD-rats. TREATMENT: Intravenous application of 5 mg/kg LPS (n = 8) or vehicle (n = 3). METHODS: Apparent diffusion coefficient (ADC) and T2-relaxation time (T2RT) were quantified on cerebral MRI at baseline and repeatedly for up to 3.5 h after LPS-injection. Change in blood pressure was compensated with norepinephrine. Brain water content was quantified using the wet/dry method. RESULTS: All LPS-treated rats developed endotoxic shock. No significant difference in T2RT or ADC was detectable before and after LPS-injection (T2RT: baseline 60.33 +/- 1.21; after 3.5 h 60.15 +/- 0.59; ADC: baseline 6.86 +/- 0.51; after 3.5 h 6.75 +/- 0.33). Post-mortem analysis did not indicate a difference in brain water content between septic and non-septic animals. CONCLUSIONS: Reports of early microcirculatory failure seem not to be related to the occurrence of early (< or =3.5 h) brain edema. AD - Department of Neurology, Justus-Liebig University of Giessen, Giessen, Germany. AN - 18830562 AU - Rosengarten, B AU - Walberer, M AU - Allendoerfer, J AU - Mueller, C AU - Schwarz, N AU - Bachmann, G AU - Gerriets, T DA - Oct DO - 10.1007/s00011-008-8042-5 KW - Animals Body Water Brain Edema Cerebrovascular Circulation Diffusion Magnetic Resonance Imaging Disease Models, Animal Lipopolysaccharides Male Microcirculation Rats Shock, Septic L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18830562 LA - eng IS - 10 PY - 2008 SN - 1023-3830 SP - 479-83 ST - LPS-induced endotoxic shock does not cause early brain edema formation - an MRI study in rats. T2 - Inflamm Res TI - LPS-induced endotoxic shock does not cause early brain edema formation - an MRI study in rats. UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18830562 VL - 57 ID - 22 ER - TY - JOUR AN - 12825558 AU - Schraag, S. DA - May DP - NLM ET - 2003/06/27 KW - Apache Animals Bacterial Infections/ physiopathology Brain Diseases/classification/etiology/physiopathology Electroencephalography Humans Models, Animal Sepsis/ complications LA - eng IS - 5 N1 - Schraag, Stefan Comment Editorial United States Intensive care medicine Intensive Care Med. 2003 May;29(5):667-8. PY - 2003 SN - 0342-4642 (Print) 0342-4642 (Linking) SP - 667-8 ST - Studying septic encephalopathy: what animal models can predict T2 - Intensive Care Med TI - Studying septic encephalopathy: what animal models can predict VL - 29 ID - 93 ER - TY - JOUR AB - BACKGROUND: Septic encephalopathy is a severe brain dysfunction caused by systemic inflammation in the absence of direct brain infection. Changes in cerebral blood flow, release of inflammatory molecules and metabolic alterations contribute to neuronal dysfunction and cell death. METHODS: To investigate the relation of electrophysiological, metabolic and morphological changes caused by SE, we simultaneously assessed systemic circulation, regional cerebral blood flow and cortical electroencephalography in rats exposed to bacterial lipopolysaccharide. Additionally, cerebral glucose uptake, astro- and microglial activation as well as changes of inflammatory gene transcription were examined by small animal PET using [18F]FDG, immunohistochemistry, and real time PCR. RESULTS: While the systemic hemodynamic did not change significantly, regional cerebral blood flow was decreased in the cortex paralleled by a decrease of alpha activity of the electroencephalography. Cerebral glucose uptake was reduced in all analyzed neocortical areas, but preserved in the caudate nucleus, the hippocampus and the thalamus. Sepsis enhanced the transcription of several pro- and anti-inflammatory cytokines and chemokines including tumor necrosis factor alpha, interleukin-1 beta, transforming growth factor beta, and monocot chemoattractant protein 1 in the cerebrum. Regional analysis of different brain regions revealed an increase in ED1-positive microglia in the cortex, while total and neuronal cell counts decreased in the cortex and the hippocampus. CONCLUSION: Together, the present study highlights the complexity of sepsis induced early impairment of neuronal metabolism and activity. Since our model uses techniques that determine parameters relevant to the clinical setting, it might be a useful tool to develop brain specific therapeutic strategies for human septic encephalopathy. AD - Department of Neurology, University Bonn, Bonn, Germany. AN - 18793399 AU - Semmler, A. AU - Hermann, S. AU - Mormann, F. AU - Weberpals, M. AU - Paxian, S. A. AU - Okulla, T. AU - Schafers, M. AU - Kummer, M. P. AU - Klockgether, T. AU - Heneka, M. T. C2 - 2553764 DO - 1742-2094-5-38 [pii] 10.1186/1742-2094-5-38 DP - NLM ET - 2008/09/17 KW - Animals Brain/anatomy & histology/ immunology/ metabolism/pathology Cerebrovascular Circulation Electroencephalography Glucose/metabolism Hemodynamics Humans Inflammation/ immunology Lipopolysaccharides/immunology Male Microglia/metabolism Neurons/cytology/physiology Positron-Emission Tomography Random Allocation Rats Rats, Wistar Regional Blood Flow Sepsis/ immunology LA - eng N1 - Semmler, Alexander Hermann, Sven Mormann, Florian Weberpals, Marc Paxian, Stephan A Okulla, Thorsten Schafers, Michael Kummer, Markus P Klockgether, Thomas Heneka, Michael T Research Support, Non-U.S. Gov't England Journal of neuroinflammation J Neuroinflammation. 2008 Sep 15;5:38. PY - 2008 SN - 1742-2094 (Electronic) SP - 38 ST - Sepsis causes neuroinflammation and concomitant decrease of cerebral metabolism T2 - J Neuroinflammation TI - Sepsis causes neuroinflammation and concomitant decrease of cerebral metabolism VL - 5 ID - 74 ER - TY - JOUR AB - BACKGROUND: Septic encephalopathy is a severe brain dysfunction caused by systemic inflammation in the absence of direct brain infection. Changes in cerebral blood flow, release of inflammatory molecules and metabolic alterations contribute to neuronal dysfunction and cell death. METHODS: To investigate the relation of electrophysiological, metabolic and morphological changes caused by SE, we simultaneously assessed systemic circulation, regional cerebral blood flow and cortical electroencephalography in rats exposed to bacterial lipopolysaccharide. Additionally, cerebral glucose uptake, astro- and microglial activation as well as changes of inflammatory gene transcription were examined by small animal PET using [18F]FDG, immunohistochemistry, and real time PCR. RESULTS: While the systemic hemodynamic did not change significantly, regional cerebral blood flow was decreased in the cortex paralleled by a decrease of alpha activity of the electroencephalography. Cerebral glucose uptake was reduced in all analyzed neocortical areas, but preserved in the caudate nucleus, the hippocampus and the thalamus. Sepsis enhanced the transcription of several pro- and anti-inflammatory cytokines and chemokines including tumor necrosis factor alpha, interleukin-1 beta, transforming growth factor beta, and monocot chemoattractant protein 1 in the cerebrum. Regional analysis of different brain regions revealed an increase in ED1-positive microglia in the cortex, while total and neuronal cell counts decreased in the cortex and the hippocampus. CONCLUSION: Together, the present study highlights the complexity of sepsis induced early impairment of neuronal metabolism and activity. Since our model uses techniques that determine parameters relevant to the clinical setting, it might be a useful tool to develop brain specific therapeutic strategies for human septic encephalopathy. AD - Department of Neurology, University Bonn, Bonn, Germany. AN - 18793399 AU - Semmler, A AU - Hermann, S AU - Mormann, F AU - Weberpals, M AU - Paxian, SA AU - Okulla, T AU - Schäfers, M AU - Kummer, MP AU - Klockgether, T AU - Heneka, MT C2 - PMC2553764 DO - 1742-2094-5-38 [pii] 10.1186/1742-2094-5-38 KW - Animals Brain Cerebrovascular Circulation Electroencephalography Glucose Hemodynamics Humans Inflammation Lipopolysaccharides Male Microglia Neurons Positron-Emission Tomography Random Allocation Rats Rats, Wistar Regional Blood Flow Sepsis L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18793399 LA - eng PY - 2008 SN - 1742-2094 SP - 38 ST - Sepsis causes neuroinflammation and concomitant decrease of cerebral metabolism. T2 - J Neuroinflammation TI - Sepsis causes neuroinflammation and concomitant decrease of cerebral metabolism. UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18793399 VL - 5 ID - 23 ER - TY - JOUR AB - During severe sepsis several immunological defence mechanisms initiate a cascade of inflammatory events leading to multi-organ failure including septic encephalopathy and ultimately death. To assess the reaction and participation of parenchymal brain cells during endotoxaemia, the present study evaluates micro- and astroglial activation, expression of the inducible nitric oxide synthase (iNOS) pro- and antiapoptotic protein levels Bax and Bcl-2, and apoptosis. Male Wistar rats received 10 mg/kg lipopolysaccharide (LPS) or vehicle intraperitoneally and were sacrificed for brain collection at 4, 8 or 24 h after induction of experimental sepsis. One group of animals received 10 mg/kg of the NOS inhibitor N-monomethyl-L-arginine (L-NMMA) intraperitoneally 1 day before and during the experiment. Immunohistochemical evaluation revealed a sepsis-induced, time-dependent increase in the immunoreactivity of iNOS, glial fibrillary acidic protein (GFAP) and activated microglia (ED-1), paralleled by a time-dependent increase of apoptotic brain cells marked by terminal deoxynucleotidyl transferase-mediated dUTP-nick end labeling (TUNEL), an increase of Bax-positive cells and a decrease of Bcl-2-positive cells. Evaluation of different brain regions revealed that the hippocampus is the most vulnerable region during experimental sepsis. iNOS-inhibition with L-NMMA significantly reduced the number of apoptotic cells in hippocampus, midbrain and cerebellum. In addition, it reduced the increase of the proapoptotic protein Bax in all examined brain regions and reduced the decrease of Bcl-2-positive cells in the hippocampus. We therefore conclude, that peripheral inflammation leads to a profound glial activation, the generation of nitric oxide and changes of Bax and Bcl-2 protein regulation critical for apoptosis. AD - Department of Neurology, University of Bonn, Germany. AN - 16122904 AU - Semmler, A AU - Okulla, T AU - Sastre, M AU - Dumitrescu-Ozimek, L AU - Heneka, MT DA - Oct DO - S0891-0618(05)00082-7 [pii] 10.1016/j.jchemneu.2005.07.003 KW - Animals Apoptosis Astrocytes Biological Markers Brain Brain Mapping Disease Models, Animal Ectodysplasins Encephalitis Enzyme Inhibitors Glial Fibrillary Acidic Protein Gliosis Immunohistochemistry In Situ Nick-End Labeling Lipopolysaccharides Male Membrane Proteins Microglia Nerve Degeneration Nitric Oxide Nitric Oxide Synthase Type II Proto-Oncogene Proteins c-bcl-2 Rats Rats, Wistar Systemic Inflammatory Response Syndrome Tumor Necrosis Factors bcl-2-Associated X Protein L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16122904 LA - eng IS - 2-3 PY - 2005 SN - 0891-0618 SP - 144-57 ST - Systemic inflammation induces apoptosis with variable vulnerability of different brain regions. T2 - J Chem Neuroanat TI - Systemic inflammation induces apoptosis with variable vulnerability of different brain regions. UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16122904 VL - 30 ID - 46 ER - TY - JOUR AB - Sepsis-associated encephalopathy (SAE) is a frequent but poorly understood neurological complication in sepsis that negatively influences survival. Here we present clinical and experimental evidence that this brain dysfunction may be related to altered neurotransmission produced by inflammatory mediators. Compared with septic patients, SAE patients had higher interleukin-1beta (IL-1beta) plasma levels; interestingly, these levels decreased once the encephalopathy was resolved. A putative IL-1beta effect on type A gamma-aminobutyric acid receptors (GABA(A)Rs), which mediate fast synaptic transmission in most cerebral inhibitory synapses in mammals, was investigated in cultured hippocampal neurons and in Xenopus oocytes expressing native or foreign rat brain GABA(A)Rs, respectively. Confocal images in both cell types revealed that IL-1beta increases recruitment of GABA(A)Rs to the cell surface. Moreover, brief applications of IL-1beta to voltage-clamped oocytes yielded a delayed potentiation of the GABA-elicited chloride currents (I(GABA)); this effect was suppressed by IL-1ra, the natural IL-1 receptor (IL-1RI) antagonist. Western blot analysis combined with I(GABA) recording and confocal images of GABA(A) Rs in oocytes showed that IL-1beta stimulates the IL-1RI-dependent phosphatidylinositol 3-kinase activation and the consequent facilitation of phospho-Akt-mediated insertion of GABA(A)Rs into the cell surface. The interruption of this signaling pathway by specific phosphatidylinositol 3-kinase or Akt inhibitors suppresses the cytokine-mediated effects on GABA(A)R, whereas activation of the conditionally active form of Akt1 (myr-Akt1.ER*) with 4-hydroxytamoxifen reproduces the effects. These findings point to a previously unrecognized signaling pathway that connects IL-1beta with increased "GABAergic tone." We propose that through this mechanism IL-1beta might alter synaptic strength at central GABAergic synapses and so contribute to the cognitive dysfunction observed in SAE. AD - Departamento de Medicina, Hospital Universitario La Paz, Paseo de la Castellana 261, 28046 Madrid, Spain. AN - 16567807 AU - Serantes, R. AU - Arnalich, F. AU - Figueroa, M. AU - Salinas, M. AU - Andres-Mateos, E. AU - Codoceo, R. AU - Renart, J. AU - Matute, C. AU - Cavada, C. AU - Cuadrado, A. AU - Montiel, C. DA - May 26 DO - M512489200 [pii] 10.1074/jbc.M512489200 DP - NLM ET - 2006/03/29 KW - 1-Phosphatidylinositol 3-Kinase/ metabolism Animals Brain/metabolism/pathology Brain Injuries/ metabolism Cell Membrane/ metabolism Interleukin-1/ metabolism Neurons/metabolism Oocytes/metabolism Proto-Oncogene Proteins c-akt/ metabolism Rats Rats, Sprague-Dawley Receptors, GABA-A/ metabolism Sepsis/ pathology Xenopus LA - eng IS - 21 N1 - Serantes, Rocio Arnalich, Francisco Figueroa, Maria Salinas, Marta Andres-Mateos, Eva Codoceo, Rosa Renart, Jaime Matute, Carlos Cavada, Carmen Cuadrado, Antonio Montiel, Carmen Research Support, Non-U.S. Gov't United States The Journal of biological chemistry J Biol Chem. 2006 May 26;281(21):14632-43. Epub 2006 Mar 27. PY - 2006 SN - 0021-9258 (Print) 0021-9258 (Linking) SP - 14632-43 ST - Interleukin-1beta enhances GABAA receptor cell-surface expression by a phosphatidylinositol 3-kinase/Akt pathway: relevance to sepsis-associated encephalopathy T2 - J Biol Chem TI - Interleukin-1beta enhances GABAA receptor cell-surface expression by a phosphatidylinositol 3-kinase/Akt pathway: relevance to sepsis-associated encephalopathy VL - 281 ID - 89 ER - TY - JOUR AB - Sepsis-associated encephalopathy (SAE) is a frequent but poorly understood neurological complication in sepsis that negatively influences survival. Here we present clinical and experimental evidence that this brain dysfunction may be related to altered neurotransmission produced by inflammatory mediators. Compared with septic patients, SAE patients had higher interleukin-1beta (IL-1beta) plasma levels; interestingly, these levels decreased once the encephalopathy was resolved. A putative IL-1beta effect on type A gamma-aminobutyric acid receptors (GABA(A)Rs), which mediate fast synaptic transmission in most cerebral inhibitory synapses in mammals, was investigated in cultured hippocampal neurons and in Xenopus oocytes expressing native or foreign rat brain GABA(A)Rs, respectively. Confocal images in both cell types revealed that IL-1beta increases recruitment of GABA(A)Rs to the cell surface. Moreover, brief applications of IL-1beta to voltage-clamped oocytes yielded a delayed potentiation of the GABA-elicited chloride currents (I(GABA)); this effect was suppressed by IL-1ra, the natural IL-1 receptor (IL-1RI) antagonist. Western blot analysis combined with I(GABA) recording and confocal images of GABA(A) Rs in oocytes showed that IL-1beta stimulates the IL-1RI-dependent phosphatidylinositol 3-kinase activation and the consequent facilitation of phospho-Akt-mediated insertion of GABA(A)Rs into the cell surface. The interruption of this signaling pathway by specific phosphatidylinositol 3-kinase or Akt inhibitors suppresses the cytokine-mediated effects on GABA(A)R, whereas activation of the conditionally active form of Akt1 (myr-Akt1.ER*) with 4-hydroxytamoxifen reproduces the effects. These findings point to a previously unrecognized signaling pathway that connects IL-1beta with increased "GABAergic tone." We propose that through this mechanism IL-1beta might alter synaptic strength at central GABAergic synapses and so contribute to the cognitive dysfunction observed in SAE. AD - Departamento de Medicina, Hospital Universitario La Paz, Paseo de la Castellana 261, 28046 Madrid, Spain. AN - 16567807 AU - Serantes, R AU - Arnalich, F AU - Figueroa, M AU - Salinas, M AU - Andrés-Mateos, E AU - Codoceo, R AU - Renart, J AU - Matute, C AU - Cavada, C AU - Cuadrado, A AU - Montiel, C DA - May DO - M512489200 [pii] 10.1074/jbc.M512489200 KW - 1-Phosphatidylinositol 3-Kinase Animals Brain Brain Injuries Cell Membrane Interleukin-1 Neurons Oocytes Proto-Oncogene Proteins c-akt Rats Rats, Sprague-Dawley Receptors, GABA-A Sepsis Xenopus L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16567807 LA - eng IS - 21 PY - 2006 SN - 0021-9258 SP - 14632-43 ST - Interleukin-1beta enhances GABAA receptor cell-surface expression by a phosphatidylinositol 3-kinase/Akt pathway: relevance to sepsis-associated encephalopathy. T2 - J Biol Chem TI - Interleukin-1beta enhances GABAA receptor cell-surface expression by a phosphatidylinositol 3-kinase/Akt pathway: relevance to sepsis-associated encephalopathy. UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16567807 VL - 281 ID - 44 ER - TY - JOUR AB - The neuropathological correlates of encephalopathy and autonomic dysfunction in septic shock are unclear. We performed post mortem analysis of 5 brain areas susceptible to ischemia and 5 autonomic nuclei (AN) in 23 patients who had died in our intensive care unit (ICU) from septic shock and 8 dying from non-septic shock as well as 5 controls who had died suddenly from extracranial injury. Proinflammatory cytokine (IL1-beta and TNF-alpha) and inducible nitric oxide synthase (iNOS) expression was assessed by immunocytochemistry. Abnormalities in septic shock were: hemorrhages (26%), hypercoagulability syndrome (9%), micro-abscesses (9%), multifocal necrotizing leukoencephalopathy (9%) and ischemia (100%). The incidence of cerebral hemorrhage or hypercoagulability syndrome was not related to clotting disturbances. The intensity of ischemia within susceptible areas was the same in both ICU groups, but more pronounced in the autonomic centers of septic patients (P < 0.0001). Neuronal apoptosis assessed using anti-caspase 3 immunocytochemistry and in situ end labeling was more pronounced in the autonomic nuclei of septic patients. (P < 0.0001). TNF-alpha expression did not differ between groups but vascular iNOS expression assessed by immunocytochemistry was higher in sepsis (P<0.0001) and correlated with autonomic center neuronal apoptosis (P < 0.02). We conclude that septic shock is associated with diffuse cerebral damage and specific autonomic neuronal apoptosis which may be due to circulating factors particularly iNOS. AD - Service de Reanimation Medicale, Hopital Raymond Poincare, Faculte de Medecine Paris-Ile de France Ouest, Garches, France. AN - 14997934 AU - Sharshar, T. AU - Annane, D. AU - de la Grandmaison, G. L. AU - Brouland, J. P. AU - Hopkinson, N. S. AU - Francoise, G. DA - Jan DP - NLM ET - 2004/03/05 KW - Adult Aged Apoptosis/physiology Autonomic Nervous System/pathology Brain/metabolism/ pathology Brain Ischemia/etiology/metabolism/pathology Caspase 3 Caspases/metabolism Cerebral Hemorrhage/etiology/metabolism/pathology Cytokines/metabolism Female Humans Immunohistochemistry Male Middle Aged Nitric Oxide Synthase/metabolism Nitric Oxide Synthase Type II Shock, Septic/complications/metabolism/ pathology LA - eng IS - 1 N1 - Sharshar, Tarek Annane, Djillali de la Grandmaison, Geoffroy Lorin Brouland, Jean Philippe Hopkinson, Nicholas S Francoise, Gray Comparative Study Research Support, Non-U.S. Gov't Switzerland Brain pathology (Zurich, Switzerland) Brain Pathol. 2004 Jan;14(1):21-33. PY - 2004 SN - 1015-6305 (Print) 1015-6305 (Linking) SP - 21-33 ST - The neuropathology of septic shock T2 - Brain Pathol TI - The neuropathology of septic shock VL - 14 ID - 92 ER - TY - JOUR AB - BACKGROUND: Understanding of sepsis-induced brain dysfunction remains poor, and relies mainly on data from animals or post-mortem studies in patients. The current study provided findings from magnetic resonance imaging of the brain in septic shock. METHODS: Nine patients with septic shock and brain dysfunction [7 women, median age 63 years (interquartile range 61-79 years), SAPS II: 48 (44-56), SOFA: 8 (6-10)] underwent brain magnetic resonance imaging including gradient echo T1-weighted, fluid-attenuated inversion recovery (FLAIR), T2-weighted and diffusion isotropic images, and mapping of apparent diffusion coefficient. RESULTS: Brain imaging was normal in two patients, showed multiple ischaemic strokes in two patients, and in the remaining patients showed white matter lesions at the level of the centrum semiovale, predominating around Virchow-Robin spaces, ranging from small multiple areas to diffuse lesions, and characterised by hyperintensity on FLAIR images. The main lesions were also characterised by reduced signal on diffusion isotropic images and increased apparent diffusion coefficient. The lesions of the white matter worsened with increasing duration of shock and were correlated with Glasgow Outcome Score. CONCLUSION: This preliminary study showed that sepsis-induced brain lesions can be documented by magnetic resonance imaging. These lesions predominated in the white matter, suggesting increased blood-brain barrier permeability, and were associated with poor outcome. AD - Service de Reanimation Medicale, Hopital Raymond Poincare (APHP), Faculte de Medecine Paris Ile de France Ouest (UVSQ), 104, Boulevard Raymond Poincare, 92380, Garches, France. AN - 17377766 AU - Sharshar, T. AU - Carlier, R. AU - Bernard, F. AU - Guidoux, C. AU - Brouland, J. P. AU - Nardi, O. AU - de la Grandmaison, G. L. AU - Aboab, J. AU - Gray, F. AU - Menon, D. AU - Annane, D. DA - May DO - 10.1007/s00134-007-0598-y DP - NLM ET - 2007/03/23 KW - Aged Blood Glucose Blood-Brain Barrier Brain Diseases/diagnosis/etiology/ pathology Female Glasgow Coma Scale Humans Magnetic Resonance Imaging Male Middle Aged Shock, Septic/complications/ physiopathology Sodium/blood LA - eng IS - 5 N1 - Sharshar, Tarek Carlier, Robert Bernard, Francis Guidoux, Celine Brouland, Jean-Philippe Nardi, Olivier de la Grandmaison, Geoffroy Lorin Aboab, Jerome Gray, Francoise Menon, David Annane, Djillali United States Intensive care medicine Intensive Care Med. 2007 May;33(5):798-806. Epub 2007 Mar 22. PY - 2007 SN - 0342-4642 (Print) 0342-4642 (Linking) SP - 798-806 ST - Brain lesions in septic shock: a magnetic resonance imaging study T2 - Intensive Care Med TI - Brain lesions in septic shock: a magnetic resonance imaging study VL - 33 ID - 110 ER - TY - JOUR AB - During severe sepsis, several immunological defense mechanisms initiate a cascade of inflammatory events leading to multiorgan failure, including septic encephalopathy and ultimately death. Endothelin-1 (ET-1) has recently been investigated in different cerebral pathologies. Some reports suggest the involvement of ET-1 in sepsis. However, no study to date has reported the alterations in expression of the genes encoding preproET-1 and ET receptors in the frontal cortex of the septic brain. Male Sprague-Dawley (SD) rats 8 weeks of age were administered either saline or 15 mg/kg lipopolysaccharide (LPS) at different time points (1, 3, 6, and 10 hrs). Rats that did not receive LPS were considered to be controls. The rats were sacrificed with ether, and the brain tissues were harvested. Systolic and diastolic blood pressure decreased 1 hr after LPS administration and then gradually returned to normal, without any change in the heart rate. We confirmed the induction of endotoxemia in the brains of SD rats by measuring the expression of nitric oxide synthase (NOS) mRNA induced in the cerebrum. The expression of inducible NOS (iNOS) mRNA in the brains of SD rat after LPS administration was 30-fold higher than that in the brains of control rats. mRNA expression of preproET-1 in the frontal cortex of SD rats after LPS administration was 2-fold higher than that in control rats. A time-dependent increase in the expression of the gene encoding the ET(A) receptor (vasoconstrictive property) after LPS administration was observed in SD rat brain, whereas expression of the gene encoding the ET(B) receptor (vasodilatatory property) showed an initial upregulation and then gradually decreased as sepsis progressed. In conclusion, we report for the first time that expressions of the genes encoding ET-1 and ET receptors are altered in the endotoxemic brain and that these alterations are time-dependent in SD rats. The alterations in the ET system in brain tissue observed in the present study may contribute to the understanding of the pathophysiological changes in the endotoxemic brain. AD - Cardiovascular Division, Department of Internal Medicine, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan. AN - 16741049 AU - Shimojo, N AU - Jesmin, S AU - Zaedi, S AU - Maeda, S AU - Gando, S AU - Yamaguchi, I AU - Goto, K AU - Miyauchi, T DA - Jun DO - 231/6/1058 [pii] KW - Animals Brain Endothelin-1 Endotoxemia Lipopolysaccharides Nitric Oxide Synthase Type II RNA, Messenger Rats Receptor, Endothelin A Receptor, Endothelin B Time Factors L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16741049 LA - eng IS - 6 PY - 2006 SN - 1535-3702 SP - 1058-63 ST - Alterations of gene expressions of preproET-1 and ET receptors in brains of endotoxemic Sprague-Dawley rats. T2 - Exp Biol Med (Maywood) TI - Alterations of gene expressions of preproET-1 and ET receptors in brains of endotoxemic Sprague-Dawley rats. UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16741049 VL - 231 ID - 41 ER - TY - JOUR AB - Almost all degenerative diseases of the CNS are associated with chronic inflammation. A central step in this process is the activation of brain mononuclear phagocyte cells, called microglia. While it is recognized that healthy neurons and astrocytes regulate the magnitude of microglia-mediated innate immune responses and limit excessive CNS inflammation, the endogenous signals governing this process are not fully understood. In the peripheral nervous system, recent studies suggest that an endogenous 'cholinergic anti-inflammatory pathway' regulates systemic inflammatory responses via alpha 7 nicotinic acetylcholinergic receptors (nAChR) found on blood-borne macrophages. These data led us to investigate whether a similar cholinergic pathway exists in the brain that could regulate microglial activation. Here we report for the first time that cultured microglial cells express alpha 7 nAChR subunit as determined by RT-PCR, western blot, immunofluorescent, and immunohistochemistry analyses. Acetylcholine and nicotine pre-treatment inhibit lipopolysaccharide (LPS)-induced TNF-alpha release in murine-derived microglial cells, an effect attenuated by alpha 7 selective nicotinic antagonist, alpha-bungarotoxin. Furthermore, this inhibition appears to be mediated by a reduction in phosphorylation of p44/42 and p38 mitogen-activated protein kinase (MAPK). Though preliminary, our findings suggest the existence of a brain cholinergic pathway that regulates microglial activation through alpha 7 nicotinic receptors. Negative regulation of microglia activation may also represent additional mechanism underlying nicotine's reported neuroprotective properties. AD - Child Development Center, Neuroimmunology Laboratory, Department of Psychiatry and Behavioral Medicine, University of South Florida College of Medciine, Tampa, Florida, USA. AN - 15056277 AU - Shytle, R. D. AU - Mori, T. AU - Townsend, K. AU - Vendrame, M. AU - Sun, N. AU - Zeng, J. AU - Ehrhart, J. AU - Silver, A. A. AU - Sanberg, P. R. AU - Tan, J. DA - Apr DO - 10.1046/j.1471-4159.2004.02347.x JNC2347 [pii] DP - NLM ET - 2004/04/02 KW - Acetylcholine/ pharmacology Animals Bungarotoxins/pharmacology Cells, Cultured Lipopolysaccharides/pharmacology Mice Mice, Inbred C57BL Microglia/cytology/ drug effects/ metabolism Mitogen-Activated Protein Kinases/metabolism Nicotine/pharmacology Nicotinic Antagonists/pharmacology Phosphorylation/drug effects Receptors, Nicotinic/drug effects/ metabolism Signal Transduction/drug effects Tumor Necrosis Factor-alpha/metabolism p38 Mitogen-Activated Protein Kinases LA - eng IS - 2 N1 - Shytle, R Douglas Mori, Takashi Townsend, Kirk Vendrame, Martina Sun, Nan Zeng, Jin Ehrhart, Jared Silver, Archie A Sanberg, Paul R Tan, Jun Research Support, Non-U.S. Gov't England Journal of neurochemistry J Neurochem. 2004 Apr;89(2):337-43. PY - 2004 SN - 0022-3042 (Print) 0022-3042 (Linking) SP - 337-43 ST - Cholinergic modulation of microglial activation by alpha 7 nicotinic receptors T2 - J Neurochem TI - Cholinergic modulation of microglial activation by alpha 7 nicotinic receptors VL - 89 ID - 117 ER - TY - JOUR AB - Almost all degenerative diseases of the CNS are associated with chronic inflammation. A central step in this process is the activation of brain mononuclear phagocyte cells, called microglia. While it is recognized that healthy neurons and astrocytes regulate the magnitude of microglia-mediated innate immune responses and limit excessive CNS inflammation, the endogenous signals governing this process are not fully understood. In the peripheral nervous system, recent studies suggest that an endogenous 'cholinergic anti-inflammatory pathway' regulates systemic inflammatory responses via alpha 7 nicotinic acetylcholinergic receptors (nAChR) found on blood-borne macrophages. These data led us to investigate whether a similar cholinergic pathway exists in the brain that could regulate microglial activation. Here we report for the first time that cultured microglial cells express alpha 7 nAChR subunit as determined by RT-PCR, western blot, immunofluorescent, and immunohistochemistry analyses. Acetylcholine and nicotine pre-treatment inhibit lipopolysaccharide (LPS)-induced TNF-alpha release in murine-derived microglial cells, an effect attenuated by alpha 7 selective nicotinic antagonist, alpha-bungarotoxin. Furthermore, this inhibition appears to be mediated by a reduction in phosphorylation of p44/42 and p38 mitogen-activated protein kinase (MAPK). Though preliminary, our findings suggest the existence of a brain cholinergic pathway that regulates microglial activation through alpha 7 nicotinic receptors. Negative regulation of microglia activation may also represent additional mechanism underlying nicotine's reported neuroprotective properties. AD - Child Development Center, Neuroimmunology Laboratory, Department of Psychiatry and Behavioral Medicine, University of South Florida College of Medciine, Tampa, Florida, USA. AN - 15056277 AU - Shytle, R. D. AU - Mori, T. AU - Townsend, K. AU - Vendrame, M. AU - Sun, N. AU - Zeng, J. AU - Ehrhart, J. AU - Silver, A. A. AU - Sanberg, P. R. AU - Tan, J. DA - Apr DO - 10.1046/j.1471-4159.2004.02347.x JNC2347 [pii] DP - NLM ET - 2004/04/02 KW - Acetylcholine/ pharmacology Animals Bungarotoxins/pharmacology Cells, Cultured Lipopolysaccharides/pharmacology Mice Mice, Inbred C57BL Microglia/cytology/ drug effects/ metabolism Mitogen-Activated Protein Kinases/metabolism Nicotine/pharmacology Nicotinic Antagonists/pharmacology Phosphorylation/drug effects Receptors, Nicotinic/drug effects/ metabolism Signal Transduction/drug effects Tumor Necrosis Factor-alpha/metabolism p38 Mitogen-Activated Protein Kinases LA - eng IS - 2 N1 - Shytle, R Douglas Mori, Takashi Townsend, Kirk Vendrame, Martina Sun, Nan Zeng, Jin Ehrhart, Jared Silver, Archie A Sanberg, Paul R Tan, Jun Research Support, Non-U.S. Gov't England Journal of neurochemistry J Neurochem. 2004 Apr;89(2):337-43. PY - 2004 SN - 0022-3042 (Print) 0022-3042 (Linking) SP - 337-43 ST - Cholinergic modulation of microglial activation by alpha 7 nicotinic receptors T2 - J Neurochem TI - Cholinergic modulation of microglial activation by alpha 7 nicotinic receptors VL - 89 ID - 118 ER - TY - JOUR AB - Brain dysfunction is a severe complication of sepsis with an incidence ranging from 9% to 71% that is associated with increased morbidity and mortality. Its diagnosis relies mainly on neurologic examination with clinical manifestations ranging from confusion to coma. An electroencephalogram, somatosensory evoked potentials, and measurement of plasma S-100b protein and neuron-specific enolase can be useful for the detection of brain dysfunction. Brain MRI can identify brain lesions such as cerebral infarction, posterior reversible encephalopathy syndrome, and leukoencephalopathy. The mechanism of sepsis-associated encephalopathy involves inflammatory and non-inflammatory processes that affect endothelial cells, glial cells, and neurons and induce blood-brain barrier breakdown, derangements of intracellular metabolism, and cell death. Specific treatments for sepsis-associated encephalopathy need to be developed. Currently, treatment is mainly the management of sepsis. AD - General Intensive Care Unit, Raymond Poincare Teaching Hospital (AP-HP), University of Versailles Saint-Quentin en Yvelines, 104 Boulevard Raymond Poincare, 92380 Garches, France. AN - 18241779 AU - Siami, S. AU - Annane, D. AU - Sharshar, T. DA - Jan DO - S0749-0704(07)00083-8 [pii] 10.1016/j.ccc.2007.10.001 DP - NLM ET - 2008/02/05 KW - Apoptosis Blood-Brain Barrier/ metabolism Brain Diseases/diagnosis/metabolism/ physiopathology Delirium/blood/etiology/ physiopathology Humans Nerve Growth Factors/metabolism Oxidative Stress/immunology/ physiology S100 Proteins/metabolism Sepsis/complications/ physiopathology LA - eng IS - 1 N1 - Siami, Shidasp Annane, Djillali Sharshar, Tarek Review United States Critical care clinics Crit Care Clin. 2008 Jan;24(1):67-82, viii. PY - 2008 SN - 0749-0704 (Print) 0749-0704 (Linking) SP - 67-82, viii ST - The encephalopathy in sepsis T2 - Crit Care Clin TI - The encephalopathy in sepsis VL - 24 ID - 79 ER - TY - JOUR AB - INTRODUCTION: Sepsis-associated encephalopathy (SAE) is a diffuse cerebral dysfunction induced by the immuno-inflammatory response to infection. Elevated levels of the brain-specific S100B protein are present in many septic patients and reflect the severity of SAE. Adjunctive treatment with drotrecogin alfa (activated) (DrotAA), the human recombinant form of activated protein C, has been shown to improve mortality in patients with severe sepsis-induced organ failure. We studied the effect of DrotAA on S100B levels in patients with acute septic shock who presented with increased baseline values of this biomarker. METHODS: All patients received standard goal-directed resuscitation treatment. Patients with pre-existing or acute neurological disorders were excluded. Based on the Glasgow coma scale (GCS), patients were classified into two groups: GCS >or= 13 and GCS <13. DrotAA was given as a continuous infusion of 24 microg/kg/h for 96 h. S100B was measured before sedation and the start of DrotAA (0 h) and at 32 h, 64 h and 96 h and at corresponding time points in patients not treated with DrotAA. The lower limit of normal was < 0.5 microg/L. RESULTS: Fifty-four patients completed the study. S100B was increased in 29 (54%) patients. Twenty-four patients (9 with GCS >or= 13 and 15 with GCS <13) received DrotAA. S100B levels in DrotAA-treated patients with a GCS <13, though higher at baseline than in untreated subjects (1.21 +/- 0.22 microg/L vs. 0.95 +/- 0.12 microg/L; P = 0.07), progressively and significantly decreased during infusion (0.96 +/- 0.22 microg/L at 32 h, P = 0.3; 0.73 +/- 0.12 microg/L at 64 h, P < 0.05; and 0.70 +/- 0.13 microg/L at 96 h, P < 0.05 vs. baseline). This patient group had also significantly lower S100B values at 64 h and at 96 h than their untreated counterparts. In the patients with a GCS >or= 13, S100B levels were not influenced by DrotAA treatment. CONCLUSIONS: S100B-positivity is present in more than half of the patients with septic shock. When increased S100B levels are used as a surrogate for SAE, adjunctive DrotAA treatment seems to beneficially affect the evolution of severe SAE as discriminated by an admission GCS <13. AD - Intensive Care Department, University Hospital, Vrije Universiteit Brussel, Laarbeeklaan 101, Brussels, Belgium. herbert.spapen@uzbrussel.be AN - 20374626 AU - Spapen, H. AU - Nguyen, D. N. AU - Troubleyn, J. AU - Huyghens, L. AU - Schiettecatte, J. C2 - 2887172 DO - cc8947 [pii] 10.1186/cc8947 DP - NLM ET - 2010/04/09 LA - eng IS - 2 N1 - Spapen, Herbert Nguyen, Duc Nam Troubleyn, Joris Huyghens, Luc Schiettecatte, Johan England Critical care (London, England) Crit Care. 2010;14(2):R54. Epub 2010 Apr 7. PY - 2010 SN - 1466-609X (Electronic) 1364-8535 (Linking) SP - R54 ST - Drotrecogin alfa (activated) may attenuate severe sepsis-associated encephalopathy in clinical septic shock T2 - Crit Care TI - Drotrecogin alfa (activated) may attenuate severe sepsis-associated encephalopathy in clinical septic shock VL - 14 ID - 59 ER - TY - JOUR AB - INTRODUCTION: Sepsis-associated encephalopathy (SAE) is a diffuse cerebral dysfunction induced by the immuno-inflammatory response to infection. Elevated levels of the brain-specific S100B protein are present in many septic patients and reflect the severity of SAE. Adjunctive treatment with drotrecogin alfa (activated) (DrotAA), the human recombinant form of activated protein C, has been shown to improve mortality in patients with severe sepsis-induced organ failure. We studied the effect of DrotAA on S100B levels in patients with acute septic shock who presented with increased baseline values of this biomarker. METHODS: All patients received standard goal-directed resuscitation treatment. Patients with pre-existing or acute neurological disorders were excluded. Based on the Glasgow coma scale (GCS), patients were classified into two groups: GCS >or= 13 and GCS <13. DrotAA was given as a continuous infusion of 24 microg/kg/h for 96 h. S100B was measured before sedation and the start of DrotAA (0 h) and at 32 h, 64 h and 96 h and at corresponding time points in patients not treated with DrotAA. The lower limit of normal was < 0.5 microg/L. RESULTS: Fifty-four patients completed the study. S100B was increased in 29 (54%) patients. Twenty-four patients (9 with GCS >or= 13 and 15 with GCS <13) received DrotAA. S100B levels in DrotAA-treated patients with a GCS <13, though higher at baseline than in untreated subjects (1.21 +/- 0.22 microg/L vs. 0.95 +/- 0.12 microg/L; P = 0.07), progressively and significantly decreased during infusion (0.96 +/- 0.22 microg/L at 32 h, P = 0.3; 0.73 +/- 0.12 microg/L at 64 h, P < 0.05; and 0.70 +/- 0.13 microg/L at 96 h, P < 0.05 vs. baseline). This patient group had also significantly lower S100B values at 64 h and at 96 h than their untreated counterparts. In the patients with a GCS >or= 13, S100B levels were not influenced by DrotAA treatment. CONCLUSIONS: S100B-positivity is present in more than half of the patients with septic shock. When increased S100B levels are used as a surrogate for SAE, adjunctive DrotAA treatment seems to beneficially affect the evolution of severe SAE as discriminated by an admission GCS <13. AD - Intensive Care Department, University Hospital, Vrije Universiteit Brussel, Laarbeeklaan 101, Brussels, Belgium. herbert.spapen@uzbrussel.be AN - 20374626 AU - Spapen, H AU - Nguyen, DN AU - Troubleyn, J AU - Huyghens, L AU - Schiettecatte, J C2 - PMC2887172 DO - cc8947 [pii] 10.1186/cc8947 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=20374626 LA - eng IS - 2 PY - 2010 SN - 1466-609X SP - R54 ST - Drotrecogin alfa (activated) may attenuate severe sepsis-associated encephalopathy in clinical septic shock. T2 - Crit Care TI - Drotrecogin alfa (activated) may attenuate severe sepsis-associated encephalopathy in clinical septic shock. UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=20374626 VL - 14 ID - 7 ER - TY - JOUR AB - Sepsis is a major disease entity with important clinical implications. Sepsis-induced multiple organ failure is associated with a high mortality rate in humans and is clinically characterized by pulmonary, cardiovascular, renal and gastrointestinal dysfunction. Recently, several studies have demonstrated that sepsis survivors present long-term cognitive impairment, including alterations in memory, attention, concentration and/or global loss of cognitive function. However, the pathogenesis and natural history of septic encephalopathy and cognitive impairment are still poorly known and further understanding of these processes is necessary for the development of effective preventive and therapeutic interventions. This review discusses the clinical presentation and underlying pathophysiology of the encephalopathy and cognitive impairment associated with sepsis. AD - Laboratorio de Fisiopatologia Experimental, Programa de Pos-graduacao em Ciencias da Saude, Unidade Academica de Ciencias da Saude, Universidade do Extremo Sul Catarinense, 88806-000, Criciuma, SC, Brazil. AN - 18461451 AU - Streck, E. L. AU - Comim, C. M. AU - Barichello, T. AU - Quevedo, J. DA - Nov DO - 10.1007/s11064-008-9671-3 DP - NLM ET - 2008/05/08 KW - Anxiety/etiology Brain/ physiopathology Cognition Disorders/etiology Depression/etiology Humans Learning Sepsis/complications/ physiopathology/psychology LA - eng IS - 11 N1 - Streck, Emilio L Comim, Clarissa M Barichello, Tatiana Quevedo, Joao Research Support, Non-U.S. Gov't Review United States Neurochemical research Neurochem Res. 2008 Nov;33(11):2171-7. Epub 2008 May 7. PY - 2008 SN - 1573-6903 (Electronic) 0364-3190 (Linking) SP - 2171-7 ST - The septic brain T2 - Neurochem Res TI - The septic brain VL - 33 ID - 72 ER - TY - JOUR AB - Sepsis is a major disease entity with important clinical implications. Sepsis-induced multiple organ failure is associated with a high mortality rate in humans and is clinically characterized by pulmonary, cardiovascular, renal and gastrointestinal dysfunction. Recently, several studies have demonstrated that sepsis survivors present long-term cognitive impairment, including alterations in memory, attention, concentration and/or global loss of cognitive function. However, the pathogenesis and natural history of septic encephalopathy and cognitive impairment are still poorly known and further understanding of these processes is necessary for the development of effective preventive and therapeutic interventions. This review discusses the clinical presentation and underlying pathophysiology of the encephalopathy and cognitive impairment associated with sepsis. AD - Laboratório de Fisiopatologia Experimental, Programa de Pós-graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, 88806-000, Criciuma, SC, Brazil. AN - 18461451 AU - Streck, EL AU - Comim, CM AU - Barichello, T AU - Quevedo, J DA - Nov DO - 10.1007/s11064-008-9671-3 KW - Anxiety Brain Cognition Disorders Depression Humans Learning Sepsis L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18461451 LA - eng IS - 11 PY - 2008 SN - 1573-6903 SP - 2171-7 ST - The septic brain. T2 - Neurochem Res TI - The septic brain. UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18461451 VL - 33 ID - 25 ER - TY - JOUR AB - INTRODUCTION: The pathophysiology of sepsis-associated encephalopathy (SAE) is not entirely clear. One of the possible underlying mechanisms is the alteration of the cerebral microvascular function induced by the systemic inflammation. The aim of the present work was to test whether cerebral vasomotor-reactivity is impaired in patients with SAE. METHODS: Patients fulfilling the criteria of clinical sepsis and showing disturbance of consciousness of any severity were included (n = 14). Non-septic persons without previous diseases affecting cerebral vasoreactivity served as controls (n = 20). Transcranial Doppler blood flow velocities were measured at rest and at 5, 10, 15 and 20 minutes after intravenous administration of 15 mg/kgBW acetazolamide. The time course of the acetazolamide effect on cerebral blood flow velocity (cerebrovascular reactivity, CVR) and the maximal vasodilatory effect of acetazolemide (cerebrovascular reserve capacity, CRC) were compared among the groups. RESULTS: Absolute blood flow velocities after administration of the vasodilator drug were higher among control subjects than in SAE. Assessment of the time-course of the vasomotor reaction showed that patients with SAE reacted slower to the vasodilatory stimulus than control persons. When assessing the maximal vasodilatory ability of the cerebral arterioles to acetazolamide during vasomotor testing, we found that patients with SAE reacted to a lesser extent to the drug than did control subjects (CRC controls:46.2 +/- 15.9%, CRC SAE: 31,5 +/- 15.8%, P < 0.01). CONCLUSIONS: We conclude that cerebrovascular reactivity is impaired in patients with SAE. The clinical significance of this pathophysiological finding has to be assessed in further studies. AD - Department of Anesthesiology and Intensive Care, University of Debrecen, Health and Medical Science Center, Debrecen, Nagyerdei krt, Hungary. szatmari@freemail.hu AN - 20356365 AU - Szatmari, S. AU - Vegh, T. AU - Csomos, A. AU - Hallay, J. AU - Takacs, I. AU - Molnar, C. AU - Fulesdi, B. C2 - 2887164 DO - cc8939 [pii] 10.1186/cc8939 DP - NLM ET - 2010/04/02 LA - eng IS - 2 N1 - Szatmari, Szilard Vegh, Tamas Csomos, Akos Hallay, Judit Takacs, Istvan Molnar, Csilla Fulesdi, Bela England Critical care (London, England) Crit Care. 2010;14(2):R50. Epub 2010 Mar 31. PY - 2010 SN - 1466-609X (Electronic) 1364-8535 (Linking) SP - R50 ST - Impaired cerebrovascular reactivity in sepsis-associated encephalopathy studied by acetazolamide test T2 - Crit Care TI - Impaired cerebrovascular reactivity in sepsis-associated encephalopathy studied by acetazolamide test VL - 14 ID - 60 ER - TY - JOUR AB - INTRODUCTION: The pathophysiology of sepsis-associated encephalopathy (SAE) is not entirely clear. One of the possible underlying mechanisms is the alteration of the cerebral microvascular function induced by the systemic inflammation. The aim of the present work was to test whether cerebral vasomotor-reactivity is impaired in patients with SAE. METHODS: Patients fulfilling the criteria of clinical sepsis and showing disturbance of consciousness of any severity were included (n = 14). Non-septic persons without previous diseases affecting cerebral vasoreactivity served as controls (n = 20). Transcranial Doppler blood flow velocities were measured at rest and at 5, 10, 15 and 20 minutes after intravenous administration of 15 mg/kgBW acetazolamide. The time course of the acetazolamide effect on cerebral blood flow velocity (cerebrovascular reactivity, CVR) and the maximal vasodilatory effect of acetazolemide (cerebrovascular reserve capacity, CRC) were compared among the groups. RESULTS: Absolute blood flow velocities after administration of the vasodilator drug were higher among control subjects than in SAE. Assessment of the time-course of the vasomotor reaction showed that patients with SAE reacted slower to the vasodilatory stimulus than control persons. When assessing the maximal vasodilatory ability of the cerebral arterioles to acetazolamide during vasomotor testing, we found that patients with SAE reacted to a lesser extent to the drug than did control subjects (CRC controls:46.2 +/- 15.9%, CRC SAE: 31,5 +/- 15.8%, P < 0.01). CONCLUSIONS: We conclude that cerebrovascular reactivity is impaired in patients with SAE. The clinical significance of this pathophysiological finding has to be assessed in further studies. AD - Department of Anesthesiology and Intensive Care, University of Debrecen, Health and Medical Science Center, Debrecen, Nagyerdei krt, Hungary. szatmari@freemail.hu AN - 20356365 AU - Szatmári, S AU - Végh, T AU - Csomós, A AU - Hallay, J AU - Takács, I AU - Molnár, C AU - Fülesdi, B C2 - PMC2887164 DO - cc8939 [pii] 10.1186/cc8939 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=20356365 LA - eng IS - 2 PY - 2010 SN - 1466-609X SP - R50 ST - Impaired cerebrovascular reactivity in sepsis-associated encephalopathy studied by acetazolamide test. T2 - Crit Care TI - Impaired cerebrovascular reactivity in sepsis-associated encephalopathy studied by acetazolamide test. UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=20356365 VL - 14 ID - 8 ER - TY - JOUR AB - INTRODUCTION: Pathophysiology of brain dysfunction due to sepsis remains poorly understood. Cerebral microcirculatory alterations may play a role; however, experimental data are scarce. This study sought to investigate whether the cerebral microcirculation is altered in a clinically relevant animal model of septic shock. METHODS: Fifteen anesthetized, invasively monitored, and mechanically ventilated female sheep were allocated to a sham procedure (n = 5) or sepsis (n = 10), in which peritonitis was induced by intra-abdominal injection of autologous faeces. Animals were observed until spontaneous death or for a maximum of 20 hours. In addition to global hemodynamic assessment, the microcirculation of the cerebral cortex was evaluated using Sidestream Dark-Field (SDF) videomicroscopy at baseline, 6 hours, 12 hours and at shock onset. At least five images of 20 seconds each from separate areas were recorded at each time point and stored under a random number to be analyzed, using a semi-quantitative method, by an investigator blinded to time and condition. RESULTS: All septic animals developed a hyperdynamic state associated with organ dysfunction and, ultimately, septic shock. In the septic animals, there was a progressive decrease in cerebral total perfused vessel density (from 5.9 ± 0.9 at baseline to 4.8 ± 0.7 n/mm at shock onset, P = 0.009), functional capillary density (from 2.8 ± 0.4 to 2.1 ± 0.7 n/mm, P = 0.049), the proportion of small perfused vessels (from 95 ± 3 to 85 ± 8%, P = 0.02), and the total number of perfused capillaries (from 22.7 ± 2.7 to 17.5 ± 5.2 n/mm, P = 0.04). There were no significant changes in microcirculatory flow index over time. In sham animals, the cerebral microcirculation was unaltered during the study period. CONCLUSIONS: In this model of peritonitis, the cerebral microcirculation was impaired during sepsis, with a significant reduction in perfused small vessels at the onset of septic shock. These alterations may play a role in the pathogenesis of septic encephalopathy. AD - Department of Intensive Care, Erasme Hospital, Université Libre de Bruxelles, Route de Lennik 808, 1070 Bruxelles, Belgium. ftaccone@ulb.ac.be AN - 20667108 AU - Taccone, FS AU - Su, F AU - Pierrakos, C AU - He, X AU - James, S AU - Dewitte, O AU - Vincent, JL AU - De Backer, D C2 - PMC2945121 DO - cc9205 [pii] 10.1186/cc9205 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=20667108 LA - eng IS - 4 PY - 2010 SN - 1466-609X SP - R140 ST - Cerebral microcirculation is impaired during sepsis: an experimental study. T2 - Crit Care TI - Cerebral microcirculation is impaired during sepsis: an experimental study. UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=20667108 VL - 14 ID - 2 ER - TY - JOUR AB - INTRODUCTION: Effects of systemic inflammation on cerebral function are not clear, as both inflammation-induced encephalopathy as well as stress-hormone mediated alertness have been described. METHODS: Experimental endotoxemia (2 ng/kg Escherichia coli lipopolysaccharide [LPS]) was induced in 15 subjects, whereas 10 served as controls. Cytokines (TNF-alpha, IL-6, IL1-RA and IL-10), cortisol, brain specific proteins (BSP), electroencephalography (EEG) and cognitive function tests (CFTs) were determined. RESULTS: Following LPS infusion, circulating pro- and anti-inflammatory cytokines, and cortisol increased (P < 0.0001). BSP changes stayed within the normal range, in which neuron specific enolase (NSE) and S100-beta changed significantly. Except in one subject with a mild encephalopathic episode, without cognitive dysfunction, endotoxemia induced no clinically relevant EEG changes. Quantitative EEG analysis showed a higher state of alertness detected by changes in the central region, and peak frequency in the occipital region. Improved CFTs during endotoxemia was found to be due to a practice effect as CFTs improved to the same extent in the reference group. Cortisol significantly correlated with a higher state of alertness detected on the EEG. Increased IL-10 and the decreased NSE both correlated with improvement of working memory and with psychomotor speed capacity. No other significant correlations between cytokines, cortisol, EEG, CFT and BSP were found. CONCLUSIONS: Short-term systemic inflammation does not provoke or explain the occurrence of septic encephalopathy, but primarily results in an inflammation-mediated increase in cortisol and alertness. TRIAL REGISTRATION: NCT00513110. AD - Department of Intensive Care Medicine, Radboud University Nijmegen Medical Centre, PO Box 9101, Nijmegen 6500HB, the Netherlands. m.vandenboogaard@ic.umcn.nl AN - 20444270 AU - van den Boogaard, M. AU - Ramakers, B. P. AU - van Alfen, N. AU - van der Werf, S. P. AU - Fick, W. F. AU - Hoedemaekers, C. W. AU - Verbeek, M. M. AU - Schoonhoven, L. AU - van der Hoeven, J. G. AU - Pickkers, P. C2 - 2911704 DO - cc9001 [pii] 10.1186/cc9001 DP - NLM ET - 2010/05/07 LA - eng IS - 3 N1 - van den Boogaard, Mark Ramakers, Bart P van Alfen, Nens van der Werf, Sieberen P Fick, Wilhelmina F Hoedemaekers, Cornelia W Verbeek, Marcel M Schoonhoven, Lisette van der Hoeven, Johannes G Pickkers, Peter England Critical care (London, England) Crit Care. 2010;14(3):R81. Epub 2010 May 5. PY - 2010 SN - 1466-609X (Electronic) 1364-8535 (Linking) SP - R81 ST - Endotoxemia-induced inflammation and the effect on the human brain T2 - Crit Care TI - Endotoxemia-induced inflammation and the effect on the human brain VL - 14 ID - 58 ER - TY - JOUR AB - INTRODUCTION: Effects of systemic inflammation on cerebral function are not clear, as both inflammation-induced encephalopathy as well as stress-hormone mediated alertness have been described. METHODS: Experimental endotoxemia (2 ng/kg Escherichia coli lipopolysaccharide [LPS]) was induced in 15 subjects, whereas 10 served as controls. Cytokines (TNF-alpha, IL-6, IL1-RA and IL-10), cortisol, brain specific proteins (BSP), electroencephalography (EEG) and cognitive function tests (CFTs) were determined. RESULTS: Following LPS infusion, circulating pro- and anti-inflammatory cytokines, and cortisol increased (P < 0.0001). BSP changes stayed within the normal range, in which neuron specific enolase (NSE) and S100-beta changed significantly. Except in one subject with a mild encephalopathic episode, without cognitive dysfunction, endotoxemia induced no clinically relevant EEG changes. Quantitative EEG analysis showed a higher state of alertness detected by changes in the central region, and peak frequency in the occipital region. Improved CFTs during endotoxemia was found to be due to a practice effect as CFTs improved to the same extent in the reference group. Cortisol significantly correlated with a higher state of alertness detected on the EEG. Increased IL-10 and the decreased NSE both correlated with improvement of working memory and with psychomotor speed capacity. No other significant correlations between cytokines, cortisol, EEG, CFT and BSP were found. CONCLUSIONS: Short-term systemic inflammation does not provoke or explain the occurrence of septic encephalopathy, but primarily results in an inflammation-mediated increase in cortisol and alertness. TRIAL REGISTRATION: NCT00513110. AD - Department of Intensive Care Medicine, Radboud University Nijmegen Medical Centre, PO Box 9101, Nijmegen 6500HB, the Netherlands. m.vandenboogaard@ic.umcn.nl AN - 20444270 AU - van den Boogaard, M AU - Ramakers, BP AU - van Alfen, N AU - van der Werf, SP AU - Fick, WF AU - Hoedemaekers, CW AU - Verbeek, MM AU - Schoonhoven, L AU - van der Hoeven, JG AU - Pickkers, P C2 - PMC2911704 DO - cc9001 [pii] 10.1186/cc9001 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=20444270 LA - eng IS - 3 PY - 2010 SN - 1466-609X SP - R81 ST - Endotoxemia-induced inflammation and the effect on the human brain. T2 - Crit Care TI - Endotoxemia-induced inflammation and the effect on the human brain. UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=20444270 VL - 14 ID - 6 ER - TY - JOUR AB - Systemic infection and drugs with anticholinergic effects are well-recognised and prevalent risk factors for delirium in elderly people. Experimental findings and neuropathological observations suggest that activation of microglia is pivotal for mediation of the behavioural effects of systemic infections. The microglial response is usually regulated tightly, but defensive features could turn neurotoxic once microglial cells escape from cholinergic inhibition. A self-propelling neuroinflammatory reaction might follow, and this cascade could account for the strong association between delirium and long-term cognitive impairment and even dementia. Here, we propose a hypothetical model, suggesting that poor outcome after delirium can be averted in vulnerable elderly people by use of readily available drugs. Agents that either restore cholinergic control of microglia or directly inhibit neuroinflammation warrant testing in clinical trials. AD - Department of Neurology, Academic Medical Center, Amsterdam, Netherlands. w.a.vangool@amc.uva.nl AN - 20189029 AU - van Gool, W. A. AU - van de Beek, D. AU - Eikelenboom, P. DA - Feb 27 DO - S0140-6736(09)61158-2 [pii] 10.1016/s0140-6736(09)61158-2 DP - NLM ET - 2010/03/02 KW - Acetylcholine/ physiology Aged Cholinergic Agents/ pharmacology Cholinergic Antagonists/ adverse effects/pharmacology Cytokines/ physiology Delirium/chemically induced/ immunology/prevention & control Humans Inflammation/complications/ etiology Microglia/drug effects/ metabolism/pathology Middle Aged Reaction Time/drug effects Risk Factors Sepsis/drug therapy/immunology/ metabolism/ pathology Space Perception/drug effects Thinking/drug effects LA - eng IS - 9716 N1 - van Gool, Willem A van de Beek, Diederik Eikelenboom, Piet England Lancet Lancet. 2010 Feb 27;375(9716):773-5. PY - 2010 SN - 1474-547X (Electronic) 0140-6736 (Linking) SP - 773-5 ST - Systemic infection and delirium: when cytokines and acetylcholine collide T2 - Lancet TI - Systemic infection and delirium: when cytokines and acetylcholine collide VL - 375 ID - 112 ER - TY - JOUR AB - Encephalopathy due to hepatic or renal failure, electrolyte disturbances, or the administration of benzodiazepines and narcotics is commonly encountered, well reviewed in the literature, and, therefore, not usually missed. This article focuses on encephalopathies that were previously well described but may be overlooked by modern clinicians, as well as those that are still taught in the classroom but seldom thought of in practice. Due to the presumed relative rarity of these cases and emphasis on the well-memorized "classic" clinical presentations, these often treatable, and perhaps not so rare, encephalopathies due to systemic medical illness may go undiagnosed and untreated. Pancreatic encephalopathy, Wernicke's encephalopathy, and pellagra encephalopathy are reviewed in detail; cefepime and ifosfamide encephalopathies are discussed as examples of specific medication-induced encephalopathies. Septic encephalopathy, central pontine myelinolysis, and fat embolism syndrome are briefly reviewed. The encephalopathies reviewed have the potential for devastating neurological consequences if recognition and, therefore, treatment are delayed. Clinical improvement for many of these syndromes depends on prompt intervention. This article highlights some representative examples of less-commonly diagnosed metabolic and toxic encephalopathies. AD - Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois 60612, USA. AN - 19370494 AU - Weathers, A. L. AU - Lewis, S. L. DA - Apr DO - 10.1055/s-0029-1213734 DP - NLM ET - 2009/04/17 KW - Central Nervous System Diseases/ complications Hepatic Encephalopathy/ diagnosis Humans Pancreatic Diseases/complications/ diagnosis Pellagra/complications/ diagnosis Rare Diseases/diagnosis Uremia/complications/diagnosis Wernicke Encephalopathy/complications/ diagnosis LA - eng IS - 2 N1 - Weathers, Allison L Lewis, Steven L Review United States Seminars in neurology Semin Neurol. 2009 Apr;29(2):136-53. Epub 2009 Apr 15. PY - 2009 SN - 0271-8235 (Print) 0271-8235 (Linking) SP - 136-53 ST - Rare and unusual ... or are they? Less commonly diagnosed encephalopathies associated with systemic disease T2 - Semin Neurol TI - Rare and unusual ... or are they? Less commonly diagnosed encephalopathies associated with systemic disease VL - 29 ID - 68 ER - TY - JOUR AB - To date, long-term consequences of septic encephalopathy on cerebral metabolism, cognition, learning, and memory capabilities and factors involved are poorly understood. In this study, we used a murine sepsis model to demonstrate that bacterial lipopolysaccharide (LPS) causes long-term cognitive deficits in mice. Two months after LPS treatment, wild-type mice committed more working and reference memory errors than controls. The behavioral impairment was independent of the cerebral glucose uptake as evidenced by (18)F-Fluordeoxyglucose small animal positron emission tomography. In contrast, mice deficient for the inducible nitric oxide synthase gene (NOS2-/-) did not show any cognitive changes when challenged with LPS. Immunohistochemical analysis demonstrated that LPS did not lead to neuronal cell death but caused sustained microglial activation in wild-type as compared to NOS2-/- mice. Expression analysis showed that LPS-treated NOS2-/- mice had lower brain mRNA levels for proinflammatory factors compared with wild-type mice. Expression analysis demonstrated distinct changes in the content of synaptic proteins in wild-type mice, which were not observed in the NOS2-/- mice. Together, this data set outlines the importance of the NOS2 activation for long-term cerebral changes after severe sepsis. AD - Department of Neurology, University of Bonn, 53127 Bonn, Germany. AN - 19906966 AU - Weberpals, M AU - Hermes, M AU - Hermann, S AU - Kummer, MP AU - Terwel, D AU - Semmler, A AU - Berger, M AU - Schäfers, M AU - Heneka, MT DA - Nov DO - 29/45/14177 [pii] 10.1523/JNEUROSCI.3238-09.2009 KW - Animals Brain Cell Death Cognition Disorders Glucose Lipopolysaccharides Maze Learning Memory, Short-Term Mice Mice, Inbred C57BL Mice, Knockout Microglia Nitric Oxide Synthase Type II RNA, Messenger Sepsis Synapses L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19906966 LA - eng IS - 45 PY - 2009 SN - 1529-2401 SP - 14177-84 ST - NOS2 gene deficiency protects from sepsis-induced long-term cognitive deficits. T2 - J Neurosci TI - NOS2 gene deficiency protects from sepsis-induced long-term cognitive deficits. UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19906966 VL - 29 ID - 11 ER - TY - JOUR AB - BACKGROUND: Infective endocarditis is associated with serious neurological sequelae. OBJECTIVE: Here, we report a patient with Staphylococcus aureus endocarditis, secondary to congenital heart disease, with subacute onset of multiple neurological complications. RESULTS: Despite prompt antibiotic treatment with rapid sterilization of blood cultures, the patient died with brain herniation within 96 hours of admission. Neuropathological examination showed intraparenchymal hemorrhages, mycotic aneurysms, micro-abscesses and septic arteritis with accompanying infarction. Immunocytochemical studies revealed enhanced CD45 and GFAP immunoreactivity, together with adenosine A1 receptor detection on macrophages and microglia. CONCLUSIONS: Infective endocarditis is associated with multiple neuropathological lesions, which may contribute to its poor clinical outcome and activation of cells of monocyte-microglial lineage throughout the brain. AD - Department of Medicine, University of Calgary, AB, Canada. AN - 11513347 AU - Weeks, S. G. AU - Silva, C. AU - Auer, R. N. AU - Doig, C. J. AU - Gill, M. J. AU - Power, C. DA - Aug DP - NLM ET - 2001/08/22 KW - Adult Antigens, CD45/metabolism Brain/pathology Brain Diseases/ complications/pathology Endocarditis, Bacterial/ complications/pathology Fatal Outcome Glial Fibrillary Acidic Protein/metabolism Humans Immunohistochemistry Magnetic Resonance Imaging Male Mitral Valve/pathology Myocardium/pathology Neutrophil Infiltration/physiology Staphylococcal Infections/ complications/pathology Tomography, X-Ray Computed LA - eng IS - 3 N1 - Weeks, S G Silva, C Auer, R N Doig, C J Gill, M J Power, C Case Reports Canada The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques Can J Neurol Sci. 2001 Aug;28(3):260-4. PY - 2001 SN - 0317-1671 (Print) 0317-1671 (Linking) SP - 260-4 ST - Encephalopathy with staphylococcal endocarditis: multiple neuropathological findings T2 - Can J Neurol Sci TI - Encephalopathy with staphylococcal endocarditis: multiple neuropathological findings VL - 28 ID - 100 ER - TY - JOUR AB - Treatment of severe sepsis and septic shock often focuses on resolving immediate life-threatening problems related to infection (source control, antibiotics) and providing circulatory, ventilatory and other organ support. Neurologic complications, such as sepsis-associated encephalopathy, frequently occur in septic patients and are associated with higher mortality and long-term complications. As case fatalities and overall mortality continue to decline, long-term cognitive problems are becoming more common among survivors. Although the aetiology of septic encephalopathy has not been clearly established, systemic inflammation appears to play a key role in altering both the blood-brain barrier permeability and amplifying the inflammatory response. Several new therapies are now aimed at reducing systemic inflammation. These may eventually play a role in reducing neurologic complications related to the acute pathophysiology of sepsis and may be able to reduce early cerebral dysfunction with the goal of reducing long-term neurologic complications. Coupled plasma filtration adsorption is an extracorporeal therapy aimed at the non-specific removal of cytokines and mediators involved in systemic inflammation and immune suppression by the use of plasma filtration coupled to an adsorbent resin cartridge with high affinity for many cytokines and mediators. Several cytokines that are removed by coupled plasma filtration adsorption have also been implicated in blood-brain barrier permeability, leucocyte recruitment and amplification of the inflammatory response. Current studies are ongoing to determine whether treatments such as coupled plasma filtration adsorption may also be beneficial in reducing long-term neurologic complications. AD - Sorin Group, Acute Therapies, Mirandola, MO, Italy. marylou.wratten@sorin.com AN - 18289409 AU - Wratten, M. L. DO - S0265021507003444 [pii] 10.1017/s0265021507003444 DP - NLM ET - 2008/04/17 KW - Adsorption Animals Blood-Brain Barrier Cytokines/metabolism Equipment Design Hemofiltration Humans Infection Inflammation Nervous System Diseases/complications/ therapy Sepsis/complications/ therapy Signal Transduction LA - eng N1 - Wratten, M L Review England European journal of anaesthesiology. Supplement Eur J Anaesthesiol Suppl. 2008;42:1-7. PY - 2008 SN - 0952-1941 (Print) 0952-1941 (Linking) SP - 1-7 ST - Therapeutic approaches to reduce systemic inflammation in septic-associated neurologic complications T2 - Eur J Anaesthesiol Suppl TI - Therapeutic approaches to reduce systemic inflammation in septic-associated neurologic complications VL - 42 ID - 80 ER - TY - JOUR AB - Treatment of severe sepsis and septic shock often focuses on resolving immediate life-threatening problems related to infection (source control, antibiotics) and providing circulatory, ventilatory and other organ support. Neurologic complications, such as sepsis-associated encephalopathy, frequently occur in septic patients and are associated with higher mortality and long-term complications. As case fatalities and overall mortality continue to decline, long-term cognitive problems are becoming more common among survivors. Although the aetiology of septic encephalopathy has not been clearly established, systemic inflammation appears to play a key role in altering both the blood-brain barrier permeability and amplifying the inflammatory response. Several new therapies are now aimed at reducing systemic inflammation. These may eventually play a role in reducing neurologic complications related to the acute pathophysiology of sepsis and may be able to reduce early cerebral dysfunction with the goal of reducing long-term neurologic complications. Coupled plasma filtration adsorption is an extracorporeal therapy aimed at the non-specific removal of cytokines and mediators involved in systemic inflammation and immune suppression by the use of plasma filtration coupled to an adsorbent resin cartridge with high affinity for many cytokines and mediators. Several cytokines that are removed by coupled plasma filtration adsorption have also been implicated in blood-brain barrier permeability, leucocyte recruitment and amplification of the inflammatory response. Current studies are ongoing to determine whether treatments such as coupled plasma filtration adsorption may also be beneficial in reducing long-term neurologic complications. AD - Sorin Group, Acute Therapies, Mirandola, MO, Italy. marylou.wratten@sorin.com AN - 18289409 AU - Wratten, ML DO - S0265021507003444 [pii] 10.1017/S0265021507003444 KW - Adsorption Animals Blood-Brain Barrier Cytokines Equipment Design Hemofiltration Humans Infection Inflammation Nervous System Diseases Sepsis Signal Transduction L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18289409 LA - eng PY - 2008 SN - 0952-1941 SP - 1-7 ST - Therapeutic approaches to reduce systemic inflammation in septic-associated neurologic complications. T2 - Eur J Anaesthesiol Suppl TI - Therapeutic approaches to reduce systemic inflammation in septic-associated neurologic complications. UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18289409 VL - 42 ID - 28 ER - TY - JOUR AB - ABSTRACT : Sepsis-associated encephalopathy (SAE) resembles metabolic encephalopathies but with a difference: there is the potential for enduring brain damage/dysfunction. The pathogenesis of SAE is likely multifactorial. However, the severity of SAE parallels the severity of the septic illness and the brain's microcirculation is probably affected in a similar manner to that of other organs. Mild cases of SAE are often completely reversible, but there is increasing evidence that severe cases have neurological sequelae. A better understanding of the mechanisms may lead to brain-sparing, protective strategies. AD - Departments of Clinical Neurological Sciences and Medicine, The University of Western Ontario, London, Ontario, Canada. bryan.young@lhsc.on.ca AN - 20565836 AU - Young, G. B. C2 - 2911713 DO - cc9010 [pii] 10.1186/cc9010 DP - NLM ET - 2010/06/23 LA - eng IS - 3 N1 - Young, G Bryan Comment England Critical care (London, England) Crit Care. 2010;14(3):159. Epub 2010 May 21. PY - 2010 SN - 1466-609X (Electronic) 1364-8535 (Linking) SP - 159 ST - Sparing brain damage in severe sepsis: a beginning T2 - Crit Care TI - Sparing brain damage in severe sepsis: a beginning VL - 14 ID - 57 ER - TY - JOUR AB - ABSTRACT : Sepsis-associated encephalopathy (SAE) resembles metabolic encephalopathies but with a difference: there is the potential for enduring brain damage/dysfunction. The pathogenesis of SAE is likely multifactorial. However, the severity of SAE parallels the severity of the septic illness and the brain's microcirculation is probably affected in a similar manner to that of other organs. Mild cases of SAE are often completely reversible, but there is increasing evidence that severe cases have neurological sequelae. A better understanding of the mechanisms may lead to brain-sparing, protective strategies. AD - Departments of Clinical Neurological Sciences and Medicine, The University of Western Ontario, London, Ontario, Canada. bryan.young@lhsc.on.ca AN - 20565836 AU - Young, GB C2 - PMC2911713 DO - cc9010 [pii] 10.1186/cc9010 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=20565836 LA - eng IS - 3 PY - 2010 SN - 1466-609X SP - 159 ST - Sparing brain damage in severe sepsis: a beginning. T2 - Crit Care TI - Sparing brain damage in severe sepsis: a beginning. UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=20565836 VL - 14 ID - 4 ER - TY - JOUR AB - OBJECTIVE: Sensory evoked potential (SEP) peak latencies were recorded in order to evaluate the incidence and severity of septic encephalopathy, testing the hypothesis that the occurrence of septic encephalopathy is more frequent than generally assumed. DESIGN: Prospective cohort study. SETTING: Medical intensive care unit of a university hospital. PATIENTS: Sixty-eight critically ill patients were studied within 48 hrs after the development of severe sepsis (n = 41) or septic shock (n = 27). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Septic encephalopathy was defined as prolongation of SEP peak latencies beyond the upper limit of the reference range of subcortical (N13-N20 interpeak latency) and cortical SEP pathways (N20-N70 interpeak latency), as well as asymmetry of peak latencies marked by the presence of subclinical cerebral focal signs. Subcortical SEP pathways were impaired in 34% and cortical SEP pathways in 84% of all patients. The prolongation of the cortical SEP pathway correlated with the Acute Physiology and Chronic Health Evaluation III score (r = 0.23; p <.0001). SEP peak latencies did not differ in patients with severe sepsis compared with those with septic shock. Subclinical cerebral focal signs were present in 24% of the subcortical SEP pathways and in 6% of the cortical SEP pathways. CONCLUSIONS: Septic encephalopathy occurs more frequently than generally assumed, and its severity is associated with the severity of illness. The impairment of subcortical and cortical SEP pathways was not different between patients with severe sepsis and those with septic shock. AD - Department of Internal Medicine IV, Intensive Care Unit, University of Vienna, Vienna, Austria. Christian.Zauner@akh-wien.ac.at AN - 12006815 AU - Zauner, C. AU - Gendo, A. AU - Kramer, L. AU - Funk, G. C. AU - Bauer, E. AU - Schenk, P. AU - Ratheiser, K. AU - Madl, C. DA - May DP - NLM ET - 2002/05/15 KW - Brain Diseases Cerebral Cortex/physiology Evoked Potentials, Somatosensory/ physiology Female Humans Male Middle Aged Neural Pathways/physiology Reaction Time/physiology Sepsis/ physiopathology Shock, Septic/physiopathology LA - eng IS - 5 N1 - Zauner, Christian Gendo, Alexandra Kramer, Ludwig Funk, Georg C Bauer, Edith Schenk, Peter Ratheiser, Klaus Madl, Christian United States Critical care medicine Crit Care Med. 2002 May;30(5):1136-9. PY - 2002 SN - 0090-3493 (Print) 0090-3493 (Linking) SP - 1136-9 ST - Impaired subcortical and cortical sensory evoked potential pathways in septic patients T2 - Crit Care Med TI - Impaired subcortical and cortical sensory evoked potential pathways in septic patients VL - 30 ID - 98 ER -