Polycyclic aromatic hydrocarbons (PAHs) and estrogenic compounds in experimental flue gas streams

The importance of combustion processes as a source of substances with estrogenic activity in the environment was investigated. Wood (nontreated and treated with wood preservatives), barbecue charcoal, meat, and kitchen waste were combusted in a laboratory-scale incinerator. Flue gas emissions (particulates and gaseous pollutants) were trapped in polyurethane foam cartridges. The cartridges were subjected to Soxhlet extraction and part of the extracts redissolved in dimethylsulfoxide (DMSO) for analyses of estrogenic activity by means of the yeast-based human estrogen receptor (hER) bioassay. A synthetic estrogen, 17-alpha-ethinylestradiol (EE2), was used as the reference estrogenic compound. Part of the extracts was analyzed for the 16 USEPA priority polycyclic aromatic hydrocarbons (PAHs). Estrogenic compounds in the flue gas (wood) were as high as 234 +/- 25 ng m(-3) EE2 equivalent compared with 27 to 81 ng m(-3) EE2 equivalent in flue gas from combustion of barbecue charcoal. Concentrations of polycyclic aromatic hydrocarbons in both flue gas streams were in the range of 21000 +/- 2000 and 240 +/- 110 ng m(-3), respectively. In general, the concentrations of EE2 equivalent in the flue gas samples were at least a factor of 1000 lower than total PAH concentration. The EE2 levels were not related to the concentration of PAHs in any flue gas sample

Astrocyte calcium dysfunction causes early network hyperactivity in Alzheimer's disease

Dysfunctions of network activity and functional connectivity (FC) represent early events in Alzheimer's disease (AD), but the underlying mechanisms remain unclear. Astrocytes regulate local neuronal activity in the healthy brain, but their involvement in early network hyperactivity in AD is unknown. We show increased FC in the human cingulate cortex several years before amyloid deposition. We find the same early cingulate FC disruption and neuronal hyperactivity in AppNL-F mice. Crucially, these network disruptions are accompanied by decreased astrocyte calcium signaling. Recovery of astrocytic calcium activity normalizes neuronal hyperactivity and FC, as well as seizure susceptibility and day/night behavioral disruptions. In conclusion, we show that astrocytes mediate initial features of AD and drive clinically relevant phenotypes

Progressive leukoencephalopathy impairs neurobehavioral development in sialin-deficient mice

Slc17a5−/− mice represent an animal model for the infantile form of sialic acid storage disease (SASD). We analyzed genetic and histological time-course expression of myelin and oligodendrocyte (OL) lineage markers in different parts of the CNS, and related this to postnatal neurobehavioral development in these mice. Sialin-deficient mice display a distinct spatiotemporal pattern of sialic acid storage, CNS hypomyelination and leukoencephalopathy. Whereas few genes are differentially expressed in the perinatal stage (p0), microarray analysis revealed increased differential gene expression in later postnatal stages (p10–p18). This included progressive upregulation of neuroinflammatory genes, as well as continuous down-regulation of genes that encode myelin constituents and typical OL lineage markers. Age-related histopathological analysis indicates that initial myelination occurs normally in hindbrain regions, but progression to more frontal areas is affected in Slc17a5−/− mice. This course of progressive leukoencephalopathy and CNS hypomyelination delays neurobehavioral development in sialin-deficient mice. Slc17a5−/− mice successfully achieve early neurobehavioral milestones, but exhibit progressive delay of later-stage sensory and motor milestones. The present findings may contribute to further understanding of the processes of CNS myelination as well as help to develop therapeutic strategies for SASD and other myelination disorders

Deletion of PEA-15 in mice is associated with specific impairments of spatial learning abilities

<p>Abstract</p> <p>Background</p> <p>PEA-15 is a phosphoprotein that binds and regulates ERK MAP kinase and RSK2 and is highly expressed throughout the brain. PEA-15 alters c-Fos and CREB-mediated transcription as a result of these interactions. To determine if PEA-15 contributes to the function of the nervous system we tested mice lacking PEA-15 in a series of experiments designed to measure learning, sensory/motor function, and stress reactivity.</p> <p>Results</p> <p>We report that PEA-15 null mice exhibited impaired learning in three distinct spatial tasks, while they exhibited normal fear conditioning, passive avoidance, egocentric navigation, and odor discrimination. PEA-15 null mice also had deficient forepaw strength and in limited instances, heightened stress reactivity and/or anxiety. However, these non-cognitive variables did not appear to account for the observed spatial learning impairments. The null mice maintained normal weight, pain sensitivity, and coordination when compared to wild type controls.</p> <p>Conclusion</p> <p>We found that PEA-15 null mice have spatial learning disabilities that are similar to those of mice where ERK or RSK2 function is impaired. We suggest PEA-15 may be an essential regulator of ERK-dependent spatial learning.</p

Lipids revert inert Aβ amyloid fibrils to neurotoxic protofibrils that affect learning in mice

Although soluble oligomeric and protofibrillar assemblies of Aβ-amyloid peptide cause synaptotoxicity and potentially contribute to Alzheimer's disease (AD), the role of mature Aβ-fibrils in the amyloid plaques remains controversial. A widely held view in the field suggests that the fibrillization reaction proceeds ‘forward' in a near-irreversible manner from the monomeric Aβ peptide through toxic protofibrillar intermediates, which subsequently mature into biologically inert amyloid fibrils that are found in plaques. Here, we show that natural lipids destabilize and rapidly resolubilize mature Aβ amyloid fibers. Interestingly, the equilibrium is not reversed toward monomeric Aβ but rather toward soluble amyloid protofibrils. We characterized these ‘backward' Aβ protofibrils generated from mature Aβ fibers and compared them with previously identified ‘forward' Aβ protofibrils obtained from the aggregation of fresh Aβ monomers. We find that backward protofibrils are biochemically and biophysically very similar to forward protofibrils: they consist of a wide range of molecular masses, are toxic to primary neurons and cause memory impairment and tau phosphorylation in mouse. In addition, they diffuse rapidly through the brain into areas relevant to AD. Our findings imply that amyloid plaques are potentially major sources of soluble toxic Aβ-aggregates that could readily be activated by exposure to biological lipids

Animal models of focal brain ischemia

Stroke is a leading cause of disability and death in many countries. Understanding the pathophysiology of ischemic injury and developing therapies is an important endeavor that requires much additional research. Animal stroke models provide an important mechanism for these activities. A large number of stroke models have been developed and are currently used in laboratories around the world. These models are overviewed as are approaches for measuring infarct size and functional outcome

Genetic-Background Modulation of Core and Variable Autistic-Like Symptoms in Fmr1 Knock-Out Mice

International audienc

Improved clinical investigation and evaluation of high-risk medical devices: the rationale and objectives of CORE-MD (Coordinating Research and Evidence for Medical Devices)

: In the European Union (EU) the delivery of health services is a national responsibility but there are concerted actions between member states to protect public health. Approval of pharmaceutical products is the responsibility of the European Medicines Agency, whereas authorizing the placing on the market of medical devices is decentralized to independent 'conformity assessment' organizations called notified bodies. The first legal basis for an EU system of evaluating medical devices and approving their market access was the medical device directives, from the 1990s. Uncertainties about clinical evidence requirements, among other reasons, led to the EU Medical Device Regulation (2017/745) that has applied since May 2021. It provides general principles for clinical investigations but few methodological details-which challenges responsible authorities to set appropriate balances between regulation and innovation, pre- and post-market studies, and clinical trials and real-world evidence. Scientific experts should advise on methods and standards for assessing and approving new high-risk devices, and safety, efficacy, and transparency of evidence should be paramount. The European Commission recently awarded a Horizon 2020 grant to a consortium led by the European Society of Cardiology and the European Federation of National Associations of Orthopaedics and Traumatology, that will review methodologies of clinical investigations, advise on study designs, and develop recommendations for aggregating clinical data from registries and other real-world sources. The CORE-MD project (Coordinating Research and Evidence for Medical Devices) will run until March 2024; here we describe how it may contribute to the development of regulatory science in Europe