Pharmacological Stimulation of the Cholinergic Antiinflammatory Pathway

Efferent activity in the vagus nerve can prevent endotoxin-induced shock by attenuating tumor necrosis factor (TNF) synthesis. Termed the “cholinergic antiinflammatory pathway,” inhibition of TNF synthesis is dependent on nicotinic α-bungarotoxin-sensitive acetylcholine receptors on macrophages. Vagus nerve firing is also stimulated by CNI-1493, a tetravalent guanylhydrazone molecule that inhibits systemic inflammation. Here, we studied the effects of pharmacological and electrical stimulation of the intact vagus nerve in adult male Lewis rats subjected to endotoxin-induced shock to determine whether intact vagus nerve signaling is required for the antiinflammatory action of CNI-1493. CNI-1493 administered via the intracerebroventricular route was 100,000-fold more effective in suppressing endotoxin-induced TNF release and shock as compared with intravenous dosing. Surgical or chemical vagotomy rendered animals sensitive to TNF release and shock, despite treatment with CNI-1493, indicating that an intact cholinergic antiinflammatory pathway is required for antiinflammatory efficacy in vivo. Electrical stimulation of either the right or left intact vagus nerve conferred significant protection against endotoxin-induced shock, and specifically attenuated serum and myocardial TNF, but not pulmonary TNF synthesis, as compared with sham-operated animals. Together, these results indicate that stimulation of the cholinergic antiinflammatory pathway by either pharmacological or electrical methods can attenuate the systemic inflammatory response to endotoxin-induced shock

Diophantine Approximation and applications in Interference Alignment

This paper is motivated by recent applications of Diophantine approximation in electronics, in particular, in the rapidly developing area of Interference Alignment. Some remarkable advances in this area give substantial credit to the fundamental Khintchine-Groshev Theorem and, in particular, to its far reaching generalisation for submanifolds of a Euclidean space. With a view towards the aforementioned applications, here we introduce and prove quantitative explicit generalisations of the Khintchine-Groshev Theorem for non-degenerate submanifolds of R n. The importance of such quantitative statements is explicitly discussed in Jafar's monograph [12, §4.7.1]

Information security: Listening to the perspective of organisational insiders

Aligned with the strategy-as-practice research tradition, this article investigates how organisational insiders understand and perceive their surrounding information security practices, how they interpret them, and how they turn such interpretations into strategic actions. The study takes a qualitative case study approach, and participants are employees at the Research & Development department of a multinational original brand manufacturer. The article makes an important contribution to organisational information security management. It addresses the behaviour of organisational insiders – a group whose role in the prevention, response and mitigation of information security incidents is critical. The article identifies a set of organisational insiders’ perceived components of effective information security practices (organisational mission statement; common understanding of information security; awareness of threats; knowledge of information security incidents, routines and policy; relationships between employees; circulation of stories; role of punishment provisions; and training), based on which more successful information security strategies can be developed

Protection of early phase hepatic ischemia-reperfusion injury by cholinergic agonists

BACKGROUND: Cytokine production is critical in ischemia/reperfusion (IR) injury. Acetylcholine binds to macrophages and inhibits cytokine synthesis, through the cholinergic anti-inflammatory pathway. This study examined the role of the cholinergic pathway in cytokine production and hepatic IR- injury. METHODS: Adult male mice underwent 90-min of partial liver ischemia followed by reperfusion. The AChR agonists (1,1-dimethyl-4-phenyl-L-pioperazinium-iodide [DMPP], and nicotine) or saline-vehicle were administered i.p. before ischemia. Plasma cytokine tumor necrosis factor (TNF)-α, macrophage inflammatory protein-2, and Interleukin-6 were measured. Liver injury was assessed by plasma alanine transaminase (ALT) and liver histopathology. RESULTS: A reperfusion time-dependent hepatocellular injury occurred as was indicated by increased plasma-ALT and histopathology. The injury was associated with marked elevation of plasma cytokines/chemokines. Pre-ischemic treatment of mice with DMPP or nicotine significantly decreased plasma-ALT and cytokines after 3 h of reperfusion. After 6 h of reperfusion, the protective effect of DMPP decreased and reached a negligible level by 24 h of reperfusion, despite significantly low levels of plasma cytokines. Histopathology showed markedly diminished hepatocellular injury in DMPP- and nicotine-pretreated mice during the early-phase of hepatic-IR, which reached a level comparable to saline-treated mice at late-phase of IR. CONCLUSION: Pharmacological modulation of the cholinergic pathway provides a means to modulate cytokine production and to delay IR-induced heaptocellular injury