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      Perioperative cerebrospinal fluid and plasma inflammatory markers after orthopedic surgery

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          Postoperative delirium is prevalent in older patients and associated with worse outcomes. Recent data in animal studies demonstrate increases in inflammatory markers in plasma and cerebrospinal fluid (CSF) even after aseptic surgery, suggesting that inflammation of the central nervous system may be part of the pathogenesis of postoperative cognitive changes. We investigated the hypothesis that neuroinflammation was an important cause for postoperative delirium and cognitive dysfunction after major non-cardiac surgery.


          After Institutional Review Board approval and informed consent, we recruited patients undergoing major knee surgery who received spinal anesthesia and femoral nerve block with intravenous sedation. All patients had an indwelling spinal catheter placed at the time of spinal anesthesia that was left in place for up to 24 h. Plasma and CSF samples were collected preoperatively and at 3, 6, and 18 h postoperatively. Cytokine levels were measured using ELISA and Luminex. Postoperative delirium was determined using the confusion assessment method, and cognitive dysfunction was measured using validated cognitive tests (word list, verbal fluency test, digit symbol test).


          Ten patients with complete datasets were included. One patient developed postoperative delirium, and six patients developed postoperative cognitive dysfunction. Postoperatively, at different time points, statistically significant changes compared to baseline were present in IL-5, IL-6, I-8, IL-10, monocyte chemotactic protein (MCP)-1, macrophage inflammatory protein (MIP)-1α, IL-6/IL-10, and receptor for advanced glycation end products in plasma and in IFN-γ, IL-6, IL-8, IL-10, MCP-1, MIP-1α, MIP-1β, IL-8/IL-10, and TNF-α in CSF.


          Substantial pro- and anti-inflammatory activity in the central neural system after surgery was found. If confirmed by larger studies, persistent changes in cytokine levels may serve as biomarkers for novel clinical trials.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s12974-016-0681-9) contains supplementary material, which is available to authorized users.

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          Most cited references 56

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          Small sample inference for fixed effects from restricted maximum likelihood.

          Restricted maximum likelihood (REML) is now well established as a method for estimating the parameters of the general Gaussian linear model with a structured covariance matrix, in particular for mixed linear models. Conventionally, estimates of precision and inference for fixed effects are based on their asymptotic distribution, which is known to be inadequate for some small-sample problems. In this paper, we present a scaled Wald statistic, together with an F approximation to its sampling distribution, that is shown to perform well in a range of small sample settings. The statistic uses an adjusted estimator of the covariance matrix that has reduced small sample bias. This approach has the advantage that it reproduces both the statistics and F distributions in those settings where the latter is exact, namely for Hotelling T2 type statistics and for analysis of variance F-ratios. The performance of the modified statistics is assessed through simulation studies of four different REML analyses and the methods are illustrated using three examples.
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            Predictors of cognitive dysfunction after major noncardiac surgery.

            The authors designed a prospective longitudinal study to investigate the hypothesis that advancing age is a risk factor for postoperative cognitive dysfunction (POCD) after major noncardiac surgery and the impact of POCD on mortality in the first year after surgery. One thousand sixty-four patients aged 18 yr or older completed neuropsychological tests before surgery, at hospital discharge, and 3 months after surgery. Patients were categorized as young (18-39 yr), middle-aged (40-59 yr), or elderly (60 yr or older). At 1 yr after surgery, patients were contacted to determine their survival status. At hospital discharge, POCD was present in 117 (36.6%) young, 112 (30.4%) middle-aged, and 138 (41.4%) elderly patients. There was a significant difference between all age groups and the age-matched control subjects (P < 0.001). At 3 months after surgery, POCD was present in 16 (5.7%) young, 19 (5.6%) middle-aged, and 39 (12.7%) elderly patients. At this time point, the prevalence of cognitive dysfunction was similar between age-matched controls and young and middle-aged patients but significantly higher in elderly patients compared to elderly control subjects (P < 0.001). The independent risk factors for POCD at 3 months after surgery were increasing age, lower educational level, a history of previous cerebral vascular accident with no residual impairment, and POCD at hospital discharge. Patients with POCD at hospital discharge were more likely to die in the first 3 months after surgery (P = 0.02). Likewise, patients who had POCD at both hospital discharge and 3 months after surgery were more likely to die in the first year after surgery (P = 0.02). Cognitive dysfunction is common in adult patients of all ages at hospital discharge after major noncardiac surgery, but only the elderly (aged 60 yr or older) are at significant risk for long-term cognitive problems. Patients with POCD are at an increased risk of death in the first year after surgery.
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              Activation of innate immunity in the CNS triggers neurodegeneration through a Toll-like receptor 4-dependent pathway.

              Innate immunity is an evolutionarily ancient system that provides organisms with immediately available defense mechanisms through recognition of pathogen-associated molecular patterns. We show that in the CNS, specific activation of innate immunity through a Toll-like receptor 4 (TLR4)-dependent pathway leads to neurodegeneration. We identify microglia as the major lipopolysaccharide (LPS)-responsive cell in the CNS. TLR4 activation leads to extensive neuronal death in vitro that depends on the presence of microglia. LPS leads to dramatic neuronal loss in cultures prepared from wild-type mice but does not induce neuronal injury in CNS cultures derived from tlr4 mutant mice. In an in vivo model of neurodegeneration, stimulating the innate immune response with LPS converts a subthreshold hypoxic-ischemic insult from no discernable neuronal injury to severe axonal and neuronal loss. In contrast, animals bearing a loss-of-function mutation in the tlr4 gene are resistant to neuronal injury in the same model. The present study demonstrates a mechanistic link among innate immunity, TLRs, and neurodegeneration.

                Author and article information

                415-750-2069 , jan.hirsch@ucsf.edu
                J Neuroinflammation
                J Neuroinflammation
                Journal of Neuroinflammation
                BioMed Central (London )
                30 August 2016
                30 August 2016
                : 13
                : 1
                [1 ]Department of Anesthesia and Perioperative Care, University of California San Francisco, 521 Parnassus Avenue, San Francisco, CA 94143-0648 USA
                [2 ]Anesthesia Service, San Francisco VA Medical Center, Mail 129, 4150 Clement Street, San Francisco, CA 94121 USA
                [3 ]Center of Gerontology, Virginia Tech University, 230 Grove Lane (0555), Blacksburg, VA 24061 USA
                [4 ]Department of Neurology, Memory and Aging Center, University of California San Francisco, 1500 Owens St. #320, San Francisco, CA 94158 USA
                [5 ]Department of Orthopedic Surgery, University of California San Francisco, 500 Parnassus Avenue, MU 320W, San Francisco, CA 94143-0728 USA
                © The Author(s). 2016

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: 1RO1AG031795-05
                Award ID: 1R01 GM104194
                Award Recipient :
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                © The Author(s) 2016


                blood-brain barrier, surgery, delirium, immune response


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