Objective Although postoperative cognitive dysfunction (POCD) often complicates recovery from major surgery, the pathogenic mechanisms remain unknown. We explored whether systemic inflammation, in response to surgical trauma, triggers hippocampal inflammation and subsequent memory impairment, in a mouse model of orthopedic surgery. Methods C57BL/6J, knock out (lacking interleukin [IL]-1 receptor, IL-1R−/−) and wild type mice underwent surgery of the tibia under general anesthesia. Separate cohorts of animals were tested for memory function with fear conditioning tests, or euthanized at different times to assess levels of systemic and hippocampal cytokines and microglial activation; the effects of interventions, designed to interrupt inflammation (specifically and nonspecifically), were also assessed. Results Surgery caused hippocampal-dependent memory impairment that was associated with increased plasma cytokines, as well as reactive microgliosis and IL-1β transcription and expression in the hippocampus. Nonspecific attenuation of innate immunity with minocycline prevented surgery-induced changes. Functional inhibition of IL-1β, both in mice pretreated with IL-1 receptor antagonist and in IL-1R−/− mice, mitigated the neuroinflammatory effects of surgery and memory dysfunction. Interpretation A peripheral surgery-induced innate immune response triggers an IL-1β-mediated inflammatory process in the hippocampus that underlies memory impairment. This may represent a viable target to interrupt the pathogenesis of postoperative cognitive dysfunction.

Dexmedetomidine attenuates isoflurane-induced injury in the developing brain, providing neurocognitive protection. Isoflurane-induced injury in vitro appears to be independent of activation of the gamma-amino-butyric-acid type A receptor. If isoflurane-induced neuroapoptosis proves to be a clinical problem, administration of dexmedetomidine may be an important adjunct to prevent isoflurane-induced neurotoxicity.

IntroductionThe impact of pro-inflammatory cytokines on neuroinflammation and cognitive function after lipopolysaccharide (LPS) challenge remains elusive. Herein we provide evidence that there is a temporal correlation between high-mobility group box 1 (HMGB-1), microglial activation, and cognitive dysfunction. Disabling the interleukin (IL)-1 signaling pathway is sufficient to reduce inflammation and ameliorate the disability.MethodsEndotoxemia was induced in wild-type and IL-1R-/- mice by intra peritoneal injection of E. Coli LPS (1 mg/kg). Markers of inflammation were assessed both peripherally and centrally, and correlated to behavioral outcome using trace fear conditioning.ResultsIncrease in plasma tumor necrosis factor-α (TNFα) peaked at 30 minutes after LPS challenge. Up-regulation of IL-1β, IL-6 and HMGB-1 was more persistent, with detectable levels up to day three. A 15-fold increase in IL-6 and a 6.5-fold increase in IL-1β mRNA at 6 hours post intervention (P < 0.001 respectively) was found in the hippocampus. Reactive microgliosis was observed both at days one and three, and was associated with elevated HMGB-1 and impaired memory retention (P < 0.005). Preemptive administration of IL-1 receptor antagonist (IL-1Ra) significantly reduced plasma cytokines and hippocampal microgliosis and ameliorated cognitive dysfunction without affecting HMGB-1 levels. Similar results were observed in LPS-challenged mice lacking the IL-1 receptor to those seen in LPS-challenged wild type mice treated with IL-1Ra.ConclusionsThese data suggest that by blocking IL-1 signaling, the inflammatory cascade to LPS is attenuated, thereby reducing microglial activation and preventing the behavioral abnormality.

Abstract:OBJECTIVE: Xenon provides neuroprotection in multiple animal models however little is known about the other noble gases. The aim of the current study was to compare xenon, argon and helium neuroprotection in a neonatal asphyxia model in MEASUREMENTS AND MAIN RESULTS: Control animals undergoing moderatehypoxic-ischemia endured reduced neuronal survival at 7 days with impaired neurological function at the juvenile age compared with naïve animals. Severe hypoxic-ischemic damage produced a large cerebral infarction in controls. Following moderate hypoxic-ischemia, all three noble gases improved cell survival, brain structural integrity and neurological function on post-natal day 40 compared to nitrogen. Interestingly argon improved cell survival to naïve levels while xenon and helium did not. When tested against more severe hypoxic-ischemic injury only, argon and xenon reduced infarct volume. Furthermore post-injury body weight in moderate insult was lower in the helium treated group compared to the naïve, control and other noble gas treatment groups while in severe injurious setting it is lower in both control and helium treated group than other groups. In the non-directly injured hemisphere argon, helium and xenon increased the expression of Bcl-2 while helium 4 and xenon increased Bcl-xL. In addition, Bax expression was enhanced in the control and helium groups.CONCLUSIONS: These studies indicate that argon and xenon provide neuroprotection against both moderate and severe hypoxia-ischemic brain injury likely via prosurvival proteins synthesis.

Physical activity is important for improving quality of life in people with chronic pain. However, actual or anticipated pain exacerbation, and lack of confidence when doing physical activity, make it difficult to maintain and build towards long-term activity goals. Research guiding the design of interactive technology to motivate and support physical activity in people with chronic pain is lacking. We conducted studies with: (1) people with chronic pain, to understand how they maintained and increased physical activity in daily life and what factors deterred them; and (2) pain-specialist physiotherapists, to understand how they supported people with chronic pain. Building on this understanding, we investigated the use of auditory feedback to address some of the psychological barriers and needs identified and to increase self-efficacy, motivation and confidence in physical activity. We conclude by discussing further design opportunities based on the overall findings.

No abstract

Although xenon pretreatment protects against nitrous oxide- and isoflurane-induced neuroapoptosis, hypoxic pretreatment exacerbates anesthetic-induced neonatal neurodegeneration.

Anesthesia induces apoptosis in the neonatal rat spinal cord; however, the functional consequences of this injury, if any, remain obscure. Neither motor nor nociceptive responses were affected by anesthetic treatment. Nonetheless, further investigation is required as regional anesthetic techniques may also trigger neuroapoptosis in the spinal cord with unknown potency.