Leptin Resistance in Vagal Afferent Neurons Inhibits Cholecystokinin Signaling and Satiation in Diet Induced Obese Rats

Background and Aims: The gastrointestinal hormone cholecystokinin (CCK) plays an important role in regulating meal size and duration by activating CCK1 receptors on vagal afferent neurons (VAN). Leptin enhances CCK signaling in VAN via an early growth response 1 (EGR1) dependent pathway thereby increasing their sensitivity to CCK. In response to a chronic ingestion of a high fat diet, VAN develop leptin resistance and the satiating effects of CCK are reduced. We tested the hypothesis that leptin resistance in VAN is responsible for reducing CCK signaling and satiation. Results: Lean Zucker rats sensitive to leptin signaling, significantly reduced their food intake following administration of CCK8S (0.22 nmol/kg, i.p.), while obese Zucker rats, insensitive to leptin, did not. CCK signaling in VAN of obese Zucker rats was reduced, preventing CCK-induced up-regulation of Y2 receptor and down-regulation of melanin concentrating hormone 1 receptor (MCH1R) and cannabinoid receptor (CB1). In VAN from diet-induced obese (DIO) Sprague Dawley rats, previously shown to become leptin resistant, we demonstrated that the reduction in EGR1 expression resulted in decreased sensitivity of VAN to CCK and reduced CCK-induced inhibition of food intake. The lowered sensitivity of VAN to CCK in DIO rats resulted in a decrease in Y2 expression and increased CB1 and MCH1R expression. These effects coincided with the onset of hyperphagia in DIO rats. Conclusions: Leptin signaling in VAN is required for appropriate CCK signaling and satiation. In response to high fat feeding

Rivastigmine Lowers Aβ and Increases sAPPα Levels, Which Parallel Elevated Synaptic Markers and Metabolic Activity in Degenerating Primary Rat Neurons

Overproduction of amyloid-β (Aβ) protein in the brain has been hypothesized as the primary toxic insult that, via numerous mechanisms, produces cognitive deficits in Alzheimer's disease (AD). Cholinesterase inhibition is a primary strategy for treatment of AD, and specific compounds of this class have previously been demonstrated to influence Aβ precursor protein (APP) processing and Aβ production. However, little information is available on the effects of rivastigmine, a dual acetylcholinesterase and butyrylcholinesterase inhibitor, on APP processing. As this drug is currently used to treat AD, characterization of its various activities is important to optimize its clinical utility. We have previously shown that rivastigmine can preserve or enhance neuronal and synaptic terminal markers in degenerating primary embryonic cerebrocortical cultures. Given previous reports on the effects of APP and Aβ on synapses, regulation of APP processing represents a plausible mechanism for the synaptic effects of rivastigmine. To test this hypothesis, we treated degenerating primary cultures with rivastigmine and measured secreted APP (sAPP) and Aβ. Rivastigmine treatment increased metabolic activity in these cultured cells, and elevated APP secretion. Analysis of the two major forms of APP secreted by these cultures, attributed to neurons or glia based on molecular weight showed that rivastigmine treatment significantly increased neuronal relative to glial secreted APP. Furthermore, rivastigmine treatment increased α-secretase cleaved sAPPα and decreased Aβ secretion, suggesting a therapeutic mechanism wherein rivastigmine alters the relative activities of the secretase pathways. Assessment of sAPP levels in rodent CSF following once daily rivastigmine administration for 21 days confirmed that elevated levels of APP in cell culture translated in vivo. Taken together, rivastigmine treatment enhances neuronal sAPP and shifts APP processing toward the α-secretase pathway in degenerating neuronal cultures, which mirrors the trend of synaptic proteins, and metabolic activity

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

PB-MII: replacing static RSUs with public buses-based mobile intermediary infrastructure in urban VANET-based clouds

The success of vehicular ad hoc network (VANET) among vehicle consumers is subject to the quality of comfort and realism of safety promised by this technology. Recently VANET evolved to a rather more application and services-rich paradigm referred to as VANET-based clouds. However, the initial deployment stage of VANET and its successor VANET-based cloud is going to be a daunting challenge due to less market penetration rate of the technology-enabled vehicles, and the deployment and cost of road-side infrastructure. To fill the gaps, in this paper, after arguing on the predictability of spatiotemporal characteristics of the public transport buses in urban areas, we propose a mechanism where these buses are used as mobile gateways (MGs) among vehicles on the road, VANET authorities, and the cloud infrastructure. MGs work as functional entities of the mobile intermediary infrastructure (MII) in VANET-based clouds. Our proposed scheme can serve as a feasible, cost-effective, and pre-established MII for standalone VANET and VANET-based clouds. We furthermore, carry out feasibility analysis through a communication scheme in VANET-based clouds. More precisely we consider the traffic information aggregation and dissemination in VANET-based clouds. In order to argue on the feasibility of buses as MGs, we consider real-time road network dynamics in Seoul, South Korea where the public buses provide perfect connectivity to other vehicular nodes in the neighborhood. In VANET-based clouds application, vehicles share coarse-grained information with clouds through MGs and receive fine-grained traffic information from cloud infrastructure through MGs in real-time. Our simulation results show that MGs provide almost 100% coverage in average traffic scenarios and about 98% coverage in worst traffic scenarios. These MGs also provide the vehicles with about 84% traffic information in worst case and over 90% traffic information in average traffic scenarios. Our proposed infrastructure can be a strong rationale for the initial deployment of these technologies and can possibly be a reasonable partial or full replacement for static RSUs in the urban scenarios.</p