PPARs in Alzheimer's Disease

Peroxisome proliferator-activated receptors (PPARs) are well studied for their peripheral physiological and pathological impact, but they also play an important role for the pathogenesis of various disorders of the central nervous system (CNS) like multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's, and Parkinson's disease. The observation that PPARs are able to suppress the inflammatory response in peripheral macrophages and in several models of human autoimmune diseases lead to the idea that PPARs might be beneficial for CNS disorders possessing an inflammatory component. The neuroinflammatory response during the course of Alzheimer's disease (AD) is triggered by the neurodegeneration and the deposition of the β-amyloid peptide in extracellular plaques. Nonsteroidal anti-inflammatory drugs (NSAIDs) have been considered to delay the onset and reduce the risk to develop Alzheimer's disease, while they also directly activate PPARγ. This led to the hypothesis that NSAID protection in AD may be partly mediated by PPARγ. Several lines of evidence have supported this hypothesis, using AD-related transgenic cellular and animal models. Stimulation of PPARγ receptors by synthetic agonist (thiazolidinediones) inducing anti-inflammatory, anti-amyloidogenic, and insulin sensitising effects may account for the observed effects. Several clinical trials already revealed promising results using PPAR agonists, therefore PPARs represent an attractive therapeutic target for the treatment of AD

Winter storm risk of residential structures ? model development and application to the German state of Baden-Württemberg

International audienceThe derivation of probabilities of high wind speeds and the establishment of risk curves for storm damage is of prime importance in natural hazard risk analysis. Risk curves allow the assessment of damage being exceeded at a given level of probability. In this paper, a method for the assessment of winter storm damage risk is described in detail and applied to the German state of Baden-Württemberg. Based on meteorological observations of the years 1971?2000 and on damage information of 4 severe storm events, storm hazard and damage risk of residential buildings is calculated on the level of communities. For this purpose, highly resolved simulations of storm wind fields with the Karlsruher Atmospheric Mesoscale Model (KAMM) are performed and a storm damage model is developed. Risk curves including the quantification of the uncertainties are calculated for every community. Local differences of hazard and risk are presented in state-wide maps. An average annual winter storm damage to residential buildings of minimum 15 million Euro (reference year 2000) for Baden-Württemberg is expected

Impact and Therapeutic Potential of PPARs in Alzheimer's Disease

Peroxisome proliferator activated receptors (PPARs) are well studied for their role of peripheral metabolism, but they also may be involved in the pathogenesis of various disorders of the central nervous system (CNS) including multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's and, Parkinson's disease. The observation that PPARs are able to suppress the inflammatory response in peripheral macrophages and in several models of human autoimmune diseases, lead to the idea that PPARs might be beneficial for CNS disorders possessing an inflammatory component. The neuroinflammatory response during the course of Alzheimer's disease (AD) is triggered by the deposition of the β-amyloid peptide in extracellular plaques and ongoing neurodegeneration. Non-steroidal anti-inflammatory drugs (NSAIDs) have been considered to delay the onset and reduce the risk to develop Alzheimer’s disease, while they also directly activate PPARγ. This led to the hypothesis that NSAID protection in AD may be partly mediated by PPARγ. Several lines of evidence have supported this hypothesis, using AD related transgenic cellular and animal models. Stimulation of PPARγ by synthetic agonist (thiazolidinediones) inducing anti-inflammatory, anti-amyloidogenic and insulin sensitizing effects may account for the observed effects. Several clinical trials already revealed promising results using PPARγ agonists, therefore PPARγ represents an attractive therapeutic target for the treatment of AD

Distinct modulation of microglial amyloid β phagocytosis and migration by neuropeptidesi

Microglial activation plays an integral role in the development and course of neurodegeneration. Although neuropeptides such as bradykinin (BK), somatostatin (SST), and endothelin (ET) are known to be important mediators of inflammation in the periphery, evidence of a similar function in brain is scarce. Using immunocytochemistry, we demonstrate the expression of receptors for BK (B1, B2 subtypes), ET (ETA, ETB subtypes) and SST (SST 2, 3, 4 subtypes) in primary microglia and microglial cell lines. Exposure of BV2 and N9, as well as primary microglial cells to BK or SST increased Aβ uptake in a concentration-dependent manner, whereas endothelin decreased Aβ uptake. This was caused by increased phagocytosis of Aβ since the rate of intracellular Aβ degradation remained unaffected. All neuropeptides increased chemotactic activity of microglia. In addition, BK reduced Aβ-induced expression of proinflammatory genes including iNOS and COX-2. ET decreased the Aβ-induced expression of monocyte chemoattractant protein 1 and interleukin-6. These results suggest that neuropeptides play an important role in chemotaxis and Aβ clearance and modulate the brain's response to neuroinflammatory processes

A phase III wait-listed randomised controlled trial of novel targeted inter-professional clinical education intervention to improve cancer patients' reported pain outcomes (The Cancer Pain Assessment (CPAS) Trial): Study protocol

© 2019 The Author(s). Background: Variations in care models contribute to cancer pain being under-recognised and under-treated in half of all patients with cancer. International and national cancer pain management guidelines are achievable with minimal investment but require practice changes. While much of the cancer pain research over the preceding decades has focused on management interventions, little attention has been given to achieving better adherence to recommended cancer pain guideline screening and assessment practices. This trial aims to reduce unrelieved cancer pain by improving cancer and palliative doctors' and nurses' ('clinicians') pain assessment capabilities through a targeted inter-professional clinical education intervention delivered to participants' mobile devices ('mHealth'). Methods: A wait-listed, randomised control trial design. Cancer and/or palliative care physicians and nurses employed at one of the six participating sites across Australia will be eligible to participate in this trial and, on enrolment, will be allocated to the active or wait-listed arm. Participants allocated to the active arm will be invited to complete the mHealth cancer pain assessment intervention. In this trial, mHealth is defined as medical or public health practice supported by mobile devices (i.e. phones, patient monitoring devices, personal digital assistants and other wireless devices). This mHealth intervention integrates three evidence-based elements, namely: the COM-B theoretical framework; spaced learning pedagogy; and audit and feedback. This intervention will be delivered via the QStream online platform to participants' mobile devices over four weeks. The trial will determine if a tailored mHealth intervention, targeting clinicians' cancer pain assessment capabilities, is effective in reducing self-reported cancer pain scores, as measured by a Numerical Rating Scale (NRS). Discussion: If this mHealth intervention is found to be effective, in addition to improving cancer pain assessment practices, it will provide a readily transferable evidence-based framework that could readily be applied to other evidence practice gaps and a scalable intervention that could be administered simultaneously to multiple clinicians across diverse geographical locations. Moreover, if found to be cost-effective, it will help transform clinical continuing professional development. In summary, this mHealth intervention will provide health services with an opportunity to offer an evidence-based, pedagogically robust, cost-effective, scalable training alternative. Trial registration: Australian New Zealand Clinical Trials Registry (ANZCTR), ACTRN12618001103257. Registered on 3 July 2018

Sepsis causes neuroinflammation and concomitant decrease of cerebral metabolism

<p>Abstract</p> <p>Background</p> <p>Septic encephalopathy is a severe brain dysfunction caused by systemic inflammation in the absence of direct brain infection. Changes in cerebral blood flow, release of inflammatory molecules and metabolic alterations contribute to neuronal dysfunction and cell death.</p> <p>Methods</p> <p>To investigate the relation of electrophysiological, metabolic and morphological changes caused by SE, we simultaneously assessed systemic circulation, regional cerebral blood flow and cortical electroencephalography in rats exposed to bacterial lipopolysaccharide. Additionally, cerebral glucose uptake, astro- and microglial activation as well as changes of inflammatory gene transcription were examined by small animal PET using [18F]FDG, immunohistochemistry, and real time PCR.</p> <p>Results</p> <p>While the systemic hemodynamic did not change significantly, regional cerebral blood flow was decreased in the cortex paralleled by a decrease of alpha activity of the electroencephalography. Cerebral glucose uptake was reduced in all analyzed neocortical areas, but preserved in the caudate nucleus, the hippocampus and the thalamus. Sepsis enhanced the transcription of several pro- and anti-inflammatory cytokines and chemokines including tumor necrosis factor alpha, interleukin-1 beta, transforming growth factor beta, and monocot chemoattractant protein 1 in the cerebrum. Regional analysis of different brain regions revealed an increase in ED1-positive microglia in the cortex, while total and neuronal cell counts decreased in the cortex and the hippocampus.</p> <p>Conclusion</p> <p>Together, the present study highlights the complexity of sepsis induced early impairment of neuronal metabolism and activity. Since our model uses techniques that determine parameters relevant to the clinical setting, it might be a useful tool to develop brain specific therapeutic strategies for human septic encephalopathy.</p

Neuroinflammation in Alzheimer's Disease

Increasing evidence suggests that Alzheimer's disease pathogenesis is not restricted to the neuronal compartment but strongly interacts with immunological mechanisms in the brain. Misfolded and aggregated proteins bind to pattern recognition receptors on micro- and astroglia and trigger an innate immune response, characterized by the release of inflammatory mediators, which contribute to disease progression and severity. Genome wide analysis suggests that several genes, which increase the risk for sporadic Alzheimer's disease en-code for factors that regulate glial clearance of misfolded proteins and the inflammatory reaction. External factors, including systemic inflammation and obesity are likely to interfere with the immunological processes of the brain and further promote disease progression. This re-view provides an overview on the current knowledge and focuses on the most recent and exciting findings. Modulation of risk factors and intervention with the described immune mechanisms are likely to lead to future preventive or therapeutic strategies for Alzheimer's disease

PPAR Gamma Activators: Off-Target Against Glioma Cell Migration and Brain Invasion

Today, there is increasing evidence that PPARγ agonists, including thiazolidinediones (TDZs) and nonthiazolidinediones, block the motility and invasiveness of glioma cells and other highly migratory tumor entities. However, the mechanism(s) by which PPARγ activators mediate their antimigratory and anti-invasive properties remains elusive. This letter gives a short review on the debate and adds to the current knowledge by applying a PPARγ inactive derivative of the TDZ troglitazone (Rezulin) which potently counteracts experimental glioma progression in a PPARγ independent manner

Cosmology from LOFAR Two-metre Sky Survey Data Release 2: Angular Clustering of Radio Sources

Covering ∼5600 deg2 to rms sensitivities of ∼70−100 μJy beam−1, the LOFAR Two-metre Sky Survey Data Release 2 (LoTSS-DR2) provides the largest low-frequency (∼150 MHz) radio catalogue to date, making it an excellent tool for large-area radio cosmology studies. In this work, we use LoTSS-DR2 sources to investigate the angular two-point correlation function of galaxies within the survey. We discuss systematics in the data and an improved methodology for generating random catalogues, compared to that used for LoTSS-DR1, before presenting the angular clustering for ∼900,000 sources ≥1.5 mJy and a peak signal-to-noise ≥7.5 across ∼80% of the observed area. Using the clustering we infer the bias assuming two evolutionary models. When fitting {angular scales of 0.5≤θ&lt;5°, using a linear bias model, we find LoTSS-DR2 sources are biased tracers of the underlying matter, with a bias of bC=2.14+0.22−0.20 (assuming constant bias) and bE(z=0)=1.79+0.15−0.14 (for an evolving model, inversely proportional to the growth factor), corresponding to bE=2.81+0.24−0.22 at the median redshift of our sample, assuming the LoTSS Deep Fields redshift distribution is representative of our data. This reduces to bC=2.02+0.17−0.16 and bE(z=0)=1.67+0.12−0.12 when allowing preferential redshift distributions from the Deep Fields to model our data. Whilst the clustering amplitude is slightly lower than LoTSS-DR1 (≥2 mJy), our study benefits from larger samples and improved redshift estimates