BackgroundChronic 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]).MethodsHere, 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).ResultsInjection of LPS (100 μg/kg), at 12 weeks postinoculation (PI), resulted in heightened CNS interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α), and interferon-beta (IFN-β) transcription and microglial IL-1β 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 μg/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.ConclusionsThese 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.
Background: Drainage after routine thyroid and parathyroid surgery remains controversial. However, there is increasing evidence from a number of randomized clinical trials (RCTs) suggesting no benefit from the use of drains.Methods: A systematic review and meta-analysis was performed according to PRISMA guidelines. A literature search was carried out, and RCTs comparing the use of drains versus no drains in patients who underwent thyroid or parathyroid surgery were included. Trials including patients who underwent lateral neck dissection were excluded. Methodological quality was graded and data were extracted by independent reviewers. Risk ratio (RR) or mean difference (MD) with 95 per cent confidence interval (c.i.) was calculated and heterogeneity was assessed.Results: Twenty-five RCTs were included in the meta-analysis comprising 2939 patients. There was no significant difference between the two groups in rate of reoperation for neck haematoma (RR 1·90, 95 per cent c.i. 0·87 to 4·14), ultrasound-assessed fluid volume on day 1 after surgery (MD 2·30 (95 per cent c.i. -0·73 to 5·34) ml), wound collection requiring intervention (RR 0·64, 0·38 to 1·09) or not (RR 0·93, 0·66 to 1·30), transient voice change (RR 2·33, 0·91 to 5·96) and persistent recurrent laryngeal nerve palsy (RR 1·67, 0·22 to 12·51). Length of hospital stay was significantly greater in the drain group (MD 1·25 (0·83 to 1·68) days), as were wound infection rates (RR 2·53, 1·23 to 5·21) and pain score measure using a visual analogue scale from 1 to 10 on day 1 after surgery (MD 1·46 (0·67 to 2·26) units). Conclusion:The results indicate that drain use after routine thyroid surgery does not confer a benefit to patients.
The cell cycle of hypothesis of neural dysfunction in chronic neurodegenerative conditions such as Alzheimer's disease (AD) offers a unified approach to understanding both existing and novel strategies for drug development. At the present time, a ligand based approach is a pragmatic solution for identifying new chemical leads on which to base future discovery and optimisation. We have pursued a ligand based approach on the basis of public domain data to identify existing compounds capable of abrogating the cell cycle at the G0-G1 interface. Selected on this basis, irrespective of the tissue under study, we identified several classes of compounds as potential chemical leads. Of these compounds, at least ten have already been shown to be neuroprotective in animal models of acute neurodegeneration. Such compounds could form the basis of a screening exercise after development of suitable screening tools. Progressing of chemical leads through such an approach will be more efficient if future leads display relevant "drug-like" properties. Further, drug development in this arena should take account of the special concerns raised by targeting an elderly population. This will involve accounting for frequent polypharmacy in the aging population, and age-related alterations in physiology.
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