CNI-1493 inhibits Aβ production, plaque formation, and cognitive deterioration in an animal model of Alzheimer's disease

Alzheimer's disease (AD) is characterized by neuronal atrophy caused by soluble amyloid β protein (Aβ) peptide “oligomers” and a microglial-mediated inflammatory response elicited by extensive amyloid deposition in the brain. We show that CNI-1493, a tetravalent guanylhydrazone with established antiinflammatory properties, interferes with Aβ assembly and protects neuronal cells from the toxic effect of soluble Aβ oligomers. Administration of CNI-1493 to TgCRND8 mice overexpressing human amyloid precursor protein (APP) for a treatment period of 8 wk significantly reduced Aβ deposition. CNI-1493 treatment resulted in 70% reduction of amyloid plaque area in the cortex and 87% reduction in the hippocampus of these animals. Administration of CNI-1493 significantly improved memory performance in a cognition task compared with vehicle-treated mice. In vitro analysis of CNI-1493 on APP processing in an APP-overexpressing cell line revealed a significant dose-dependent decrease of total Aβ accumulation. This study indicates that the antiinflammatory agent CNI-1493 can ameliorate the pathophysiology and cognitive defects in a murine model of AD

Contribution of the macrophage migration inhibitory factor superfamily of cytokines in the pathogenesis of preclinical and human multiple sclerosis: In silico and in vivo evidences.

Abstract Macrophage migration inhibitory factor (MIF) is a cytokine with pleiotropic actions involved in the pathogenesis of autoimmune disorders, including Multiple Sclerosis (MS). We have first evaluated in silico the involvement of MIF, its homologue D-DT, and the receptors CD74, CD44, CXCR2 and CXCR4 in encephalitogenic T cells from a mouse model of MS, the Experimental Allergic Encephalomyelitis (EAE), as well as in circulating T helper cells from MS patients. We show an upregulation of the receptors involved in MIF signaling both in the animal model and in patients. Also, a significant increase in MIF receptors is found in the CNS lesions associated to MS. Finally, the specific inhibitor of MIF, ISO-1, improved both ex vivo and in vivo the features of EAE. Overall, our data indicate that there is a significant involvement of the MIF pathway in MS ethiopathogenesis and that interventions specifically blocking MIF receptors may represent useful therapeutic approaches in the clinical setting

Multi-organ point-of-care ultrasound for COVID-19 (PoCUS4COVID): international expert consensus

COVID-19 has caused great devastation in the past year. Multi-organ point-of-care ultrasound (PoCUS) including lung ultrasound (LUS) and focused cardiac ultrasound (FoCUS) as a clinical adjunct has played a significant role in triaging, diagnosis and medical management of COVID-19 patients. The expert panel from 27 countries and 6 continents with considerable experience of direct application of PoCUS on COVID-19 patients presents evidence-based consensus using GRADE methodology for the quality of evidence and an expedited, modified-Delphi process for the strength of expert consensus. The use of ultrasound is suggested in many clinical situations related to respiratory, cardiovascular and thromboembolic aspects of COVID-19, comparing well with other imaging modalities. The limitations due to insufficient data are highlighted as opportunities for future research

Nurses' perceptions of aids and obstacles to the provision of optimal end of life care in ICU

Contains fulltext : 172380.pdf (publisher's version ) (Open Access

A two-level decision making approach for optimal integrated urban water and energy management

A spatial-temporal model is proposed for optimal integrated water and energy resource management in urban areas, considering daily surplus output from residential grid-connected rooftop photovoltaics as an energy source for sustainable supply. The model addresses optimal investment and operational decisions of a desalination-based water supply system driven by surplus photovoltaic output and grid electricity. The two-level mixed integer linear programming model considers demands, systems configuration, resources capacity and electricity tariffs and gives the solution such that the highest compatibility with available renewable energy is achieved. The model is then applied to Perth, Australia and solved for three operational scenarios. The results show, for a given year, hourly (flexible) basis scenario leads to $9 521 425 and$18 673 545 economic benefits over seasonal (semi-flexible) and yearly (fixed) basis scenarios, respectively. They also indicate 19.9% better economic performance in terms of annualised unit cost of water production over existing Southern seawater desalination plant in Perth. Additionally, it is shown that the seasonal change on the optimal solutions mainly corresponds to the share of each energy resource to meet water-related energy demand. Finally, the results indicate higher sensitivity to the variation of the photovoltaic installation density compared to financial rate

60 μg protein were separated by precast NuPAGE Novex 4–12% Bis-Tris gels and transferred onto nitrocellulose membranes using the XCell II blot system

The activation of glial cells was assessed by staining for the macrophage activation with antibodies against the F4/80 antigen. Immunoblot analysis revealed a decline of F4/80 in all CNI-1493 animals. Equal protein loading was assessed by reprobing the membrane with monoclonal antibodies against GAPDH.<p><b>Copyright information:</b></p><p>Taken from "CNI-1493 inhibits Aβ production, plaque formation, and cognitive deterioration in an animal model of Alzheimer's disease"</p><p></p><p>The Journal of Experimental Medicine 2008;205(7):1593-1599.</p><p>Published online 7 Jul 2008</p><p>PMCID:PMC2442637.</p><p></p