Downregulation of synapse-associated protein expression and loss of homeostatic microglial control in cerebrospinal fluid of infectious patients with delirium and patients with Alzheimer's disease

Delirium is a complex and multifactorial condition associated with long-term cognitive decline. Due to the strong links between systemic inflammation, delirium and dementia we hypothesized that responses within the brain in patients who develop delirium could show biochemical overlap with patients with Alzheimer's disease (AD). In this observational study we analyzed protein expression signatures in cerebrospinal fluid (CSF) from 15 patients with infectious delirium and compared these to 29 patients with AD, 30 infectious patients without delirium and 15 non-infectious controls free of neurological disease. A proximity extension assay was performed measuring a total of 184 inflammatory and neurology-related proteins. Eight inflammatory proteins (4%), including the key neuron-microglia communication marker CX3CL1 (fractalkine), were significantly upregulated in both delirium and AD, compared to infectious patients without delirium. Likewise, 23 proteins (13%) showed downregulation in both delirium and AD, relative to infectious patients without delirium, which interestingly included CD200R1, another neuron-microglia communication marker, as well as a cluster of proteins related to synapse formation and function. Synaptopathy is an early event in AD and correlates strongly with cognitive dysfunction. These results were partially mediated by aging, which is an important predisposing risk factor among many others for both conditions. Within this study we report the first in vivo human evidence suggesting that synapse pathology and loss of homeostatic microglial control is involved in the pathophysiology of both infectious delirium and AD and thus may provide a link for the association between infections, delirium and long-term cognitive decline

Establishing a health-based recommended occupational exposure limit for nitrous oxide using experimental animal data - A systematic review protocol

Item does not contain fulltextNitrous oxide (N2O) is widely used as inhalation analgesic and anaesthetic in medical, paramedical, and veterinary practice. Previous evaluations resulted in classification of N2O as a possible risk factor for adverse reproductive health outcomes based on evidence from animal data. Available human data were considered inadequate, partly due to the possibility that other risk factors, such as co-exposures to other inhalation anaesthetics may have contributed to the adverse outcomes. As no substantial new human evidence has emerged since previous evaluations, this protocol describes a planned systematic review of the evidence obtained from animal studies. The aim is to assess the available evidence on the effects of N2O on reproductive and developmental outcomes in animals to inform a health-based recommended occupational exposure limit (OEL) for N2O. Comprehensive search strategies were designed to retrieve animal studies addressing N2O exposure from PubMed, EMBASE, and Web of Science. Screening of the studies retrieved will be performed by at least two independent reviewers, while discrepancies will be resolved by reaching consensus through repeated review and discussions. Articles will be included according to criteria specified in this protocol. Outcome data relevant for reproduction and development will be extracted and risk of bias will be assessed by two independent reviewers using the SYRCLE's risk of bias tool. Primary reproductive and developmental outcomes of interest will be the number of resorptions, malformations, and birth weight. We will focus on dose-response studies that allow to derive an OEL with the benchmark dose (BMD) approach. Adverse outcomes occurring at doses that are equivalent to the exposures occurring in human occupational settings will be particularly relevant for dose-response modelling. The proposed review has not been performed before. We will follow the procedures specified in this protocol. We will adhere to guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), adapted for animal studies. Ethical approval will not be required, as the review will use existing data available in the public domain

Establishing a health-based recommended occupational exposure limit for nitrous oxide using experimental animal data - A systematic review protocol

Nitrous oxide (N2O) is widely used as inhalation analgesic and anaesthetic in medical, paramedical, and veterinary practice. Previous evaluations resulted in classification of N2O as a possible risk factor for adverse reproductive health outcomes based on evidence from animal data. Available human data were considered inadequate, partly due to the possibility that other risk factors, such as co-exposures to other inhalation anaesthetics may have contributed to the adverse outcomes. As no substantial new human evidence has emerged since previous evaluations, this protocol describes a planned systematic review of the evidence obtained from animal studies. The aim is to assess the available evidence on the effects of N2O on reproductive and developmental outcomes in animals to inform a health-based recommended occupational exposure limit (OEL) for N2O. Comprehensive search strategies were designed to retrieve animal studies addressing N2O exposure from PubMed, EMBASE, and Web of Science. Screening of the studies retrieved will be performed by at least two independent reviewers, while discrepancies will be resolved by reaching consensus through repeated review and discussions. Articles will be included according to criteria specified in this protocol. Outcome data relevant for reproduction and development will be extracted and risk of bias will be assessed by two independent reviewers using the SYRCLE's risk of bias tool. Primary reproductive and developmental outcomes of interest will be the number of resorptions, malformations, and birth weight. We will focus on dose-response studies that allow to derive an OEL with the benchmark dose (BMD) approach. Adverse outcomes occurring at doses that are equivalent to the exposures occurring in human occupational settings will be particularly relevant for dose-response modelling. The proposed review has not been performed before. We will follow the procedures specified in this protocol. We will adhere to guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), adapted for animal studies. Ethical approval will not be required, as the review will use existing data available in the public domain

Biosynthetic homeostasis and resilience of the complement system in health and infectious disease

Contains fulltext : 206044.pdf (publisher's version ) (Open Access