Treatment of dementia with neurotransmission modulation

The prevalence of dementia is growing in developed countries where elderly patients are increasing in numbers. Neurotransmission modulation is one approach to the treatment of dementia. Cholinergic precursors, anticholinesterases, nicotine receptor agonists and muscarinic M-2 receptor antagonists are agents that enhance cholinergic neurotransmission and that depend on having some intact cholinergic innervation to be effective in the treatment of dementia. The cholinergic precursor choline alfoscerate may be emerging as a potential useful drug in the treatment of dementia, with few adverse effects. Of the anticholinesterases, donepezil, in addition to having a similar efficacy to tacrine in mild-to-moderate Alzheimer's disease (AD), appears to have major advantages; its use is associated with lower drop-out rates in clinical trials, a lower incidence of cholinergic-like side effects and no liver toxicity. Rivastigmine is efficacious in the treatment in dementia with Lewy bodies, a condition in which the other anticholinesterases have not been tested extensively to date. Galantamine is an anticholinesterase and also acts as an allosteric potentiating modulator at nicotinic receptors to increase the release of acetylcholine. Pooled data from clinical trials of patients with mild-to-moderate AD suggest that the benefits and safety profile of galantamine are similar to those of the anticholinesterases. Selective nicotine receptor agonists are being developed that enhance cognitive performance without influencing autonomic and skeletal muscle function, but these have not yet entered clinical trial for dementia. Unlike the cholinergic enhancers, the M, receptor agonists do not depend upon intact cholinergic nerves but on intact M, receptors for their action, which are mainly preserved in AD and dementia with Lewy bodies. The M, receptor-selective agonists developed to date have shown limited efficacy in clinical trials and have a high incidence of side effects. A major recent advancement in the treatment of dementia is memantine, a non-competitive antagonist at NMDA receptors. Memantine is beneficial in the treatment of severe and moderate to-severe AD and may also be of some benefit in the treatment of mild-to-moderate vascular dementia. Drugs that modulate 5-HT, somatostatin and noradrenergic neurotransmission are also being considered for the treatment of dementia.

Integration of autonomic and local mechanisms in regulating cardiovascular responses to heating and cooling in a reptile (Crocodylus porosus)

Reptiles change heart rate and blood flow patterns in response to heating and cooling, thereby decreasing the behavioural cost of thermoregulation. We tested the hypothesis that locally produced vasoactive substances, nitric oxide and prostaglandins, mediate the cardiovascular response of reptiles to heat. Heart rate and blood pressure were measured in eight crocodiles (Crocodylus porosus) during heating and cooling and while sequentially inhibiting nitric-oxide synthase and cyclooxygenase enzymes. Heart rate and blood pressure were significantly higher during heating than during cooling in all treatments. Power spectral density of heart rate and blood pressure increased significantly during heating and cooling compared to the preceding period of thermal equilibrium. Spectral density of heart rate in the high frequency band (0.19-0.70 Hz) was significantly greater during cooling in the saline treatment compared to when nitric-oxide synthase and cyclooxygenase enzymes were inhibited. Cross spectral analysis showed that changes in blood pressure preceded heart rate changes at low frequencies (

Diabetic cardiomyopathy: Evidence, mechanisms, and therapeutic implications

The presence of a diabetic cardiomyopathy, independent of hypertension and coronary artery disease, is still controversial. This systematic review seeks to evaluate the evidence for the existence of this condition, to clarify the possible mechanisms responsible, and to consider possible therapeutic implications. The existence of a diabetic cardiomyopathy is supported by epidemiological findings showing the association of diabetes with heart failure; clinical studies confirming the association of diabetes with left ventricular dysfunction independent of hypertension, coronary artery disease, and other heart disease; and experimental evidence of myocardial structural and functional changes. The most important mechanisms of diabetic cardiomyopathy are metabolic disturbances (depletion of glucose transporter 4, increased free fatty acids, carnitine deficiency, changes in calcium homeostasis), myocardial fibrosis (association with increases in angiotensin II, IGF-I, and inflammatory cytokines), small vessel disease (microangiopathy, impaired coronary flow reserve, and endothelial dysfunction), cardiac autonomic neuropathy (denervation and alterations in myocardial catecholamine levels), and insulin resistance (hyperinsulinemia and reduced insulin sensitivity). This review presents evidence that diabetes is associated with a cardiomyopathy, independent of comorbid conditions, and that metabolic disturbances, myocardial fibrosis, small vessel disease, cardiac autonomic neuropathy, and insulin resistance may all contribute to the development of diabetic heart disease.

Glycinergic and GABAergic synaptic activity differentially regulate motoneuron survival and skeletal muscle innervation

GABAergic and glycinergic synaptic transmission is proposed to promote the maturation and refinement of the developing CNS. Here we provide morphological and functional evidence that glycinergic and GABAergic synapses control motoneuron development in a region-specific manner during programmed cell death. In gephyrin-deficient mice that lack all postsynaptic glycine receptor and some GABA(A) receptor clusters, there was increased spontaneous respiratory motor activity, reduced respiratory motoneuron survival, and decreased innervation of the diaphragm. In contrast, limb-innervating motoneurons showed decreased spontaneous activity, increased survival, and increased innervation of their target muscles. Both GABA and glycine increased limb-innervating motoneuron activity and decreased respiratory motoneuron activity in wild-type mice, but only glycine responses were abolished in gephyrin-deficient mice. Our results provide genetic evidence that the development of glycinergic and GABAergic synaptic inputs onto motoneurons plays an important role in the survival, axonal branching, and spontaneous activity of motoneurons in developing mammalian embryos.

Cholinergic and adrenergic innervation of lingual salt glands of the estuarine crocodile, Crocodylus porosus

Many marine reptiles and birds possess extrarenal salt glands that facilitate the excretion of excess sodium and chloride ions accumulated as a consequence of living in saline environments. Control of the secretory activity of avian salt glands is under neural control, but little information is available on the control of reptilian salt glands. Innervation of the lingual salt glands of the salt water crocodile, Crocodylus porosus, was examined in salt water-acclimated animals using histological methods. Extensive networks of both cholinergic and adrenergic nerve fibres were identified close to salt-secreting lobules and vasculature. The identification of both catecholamine-containing and cholinergic neurons in the salt gland epithelium and close to major blood vessels in the tissue suggests the action of the neurotransmitters on the salt-secreting epithelium itself and the rich vascular network of the lingual salt glands.

Calcium channels controlling acetylcholine release from preganglionic nerve terminals in rat autonomic ganglia

Little is known about the nature of the calcium channels controlling neurotransmitter release from preganglionic parasympathetic nerve fibres. In the present study, the effects of selective calcium channel antagonists and amiloride were investigated on ganglionic neurotransmission. Conventional intracellular recording and focal extracellular recording techniques were used in rat submandibular and pelvic ganglia, respectively. Excitatory postsynaptic potentials and excitatory postsynaptic currents preceded by nerve terminal impulses were recorded as a measure of acetylcholine release from parasympathetic and sympathetic preganglionic fibres following nerve stimulation. The calcium channel antagonists omega-conotoxin GVIA (N type), nifedipine and nimodipine (L type), omega-conotoxin MVIIC and omega-agatoxin IVA (P/Q type), and Ni2+ (R type) had no functional inhibitory effects on synaptic transmission in both submandibular and pelvic ganglia. The potassium-sparing diuretic, amiloride, and its analogue, dimethyl amiloride, produced a reversible and concentration-dependent inhibition of excitatory postsynaptic potential amplitude in the rat submandibular ganglion. The amplitude and frequency of spontaneous excitatory postsynaptic potentials and the sensitivity of the postsynaptic membrane to acetylcholine were unaffected by amiloride. In the rat pelvic ganglion, amiloride produced a concentration-dependent inhibition of excitatory postsynaptic currents without causing any detectable effects on the amplitude or configuration of the nerve terminal impulse. These results indicate that neurotransmitter release from preganglionic parasympathetic and sympathetic nerve terminals is resistant to inhibition by specific calcium channel antagonists of N-, L-, P/Q- and R-type calcium channels. Amiloride acts presynaptically to inhibit evoked transmitter release, but does not prevent action potential propagation in the nerve terminals, suggesting that amiloride may block the pharmacologically distinct calcium channel type(s) on rat preganglionic nerve terminals. (C) 1999 IBRO. Published by Elsevier Science Ltd.

Substance P preferentially inhibits large conductance nicotinic ACh receptor channels in rat intracardiac ganglion neurons

The effects of substance P (SP) on nicotinic acetylcholine (ACh)-evoked currents were investigated in parasympathetic neurons dissociated from neonatal rat intracardiac ganglia using standard whole cell, perforated patch, and outside-out recording configurations of the patch-clamp technique. Focal application of SP onto the soma reversibly decreased the peak amplitude of the ACh-evoked current with half-maximal inhibition occurring at 45 mu M and complete block at 300 mu M SP. Whole cell current-voltage (I-V) relationships obtained in the absence and presence of SP indicate that the block of ACh-evoked currents by SP is voltage independent. The rate of decay of ACh-evoked currents was increased sixfold in the presence of SP (100 mu M), suggesting that SP may increase the rate of receptor desensitization. SP-induced inhibition of ACh-evoked currents was observed following cell dialysis and in the presence of either 1 mM 8-Br-cAMP, a membrane-permeant cAMP analogue, 5 mu M H-7, a protein kinase C inhibitor, or 2 mM intracellular AMP-PNP, a nonhydrolyzable ATP analogue. These data suggest that a diffusible cytosolic second messenger is unlikely to mediate SP inhibition of neuronal nicotinic ACh receptor (nAChR) channels. Activation of nAChR channels in outside-out membrane patches by either ACh (3 mu M) or cytisine (3 mu M) indicates the presence of at least three distinct conductances (20, 35, and 47 pS) in rat intracardiac neurons. In the presence of 3 mu M SP, the large conductance nAChR channels are preferentially inhibited. The open probabilities of the large conductance classes activated by either ACh or cytisine were reversibly decreased by 10- to 30-fold in the presence of SP. The single-channel conductances were unchanged, and mean apparent channel open times for the large conductance nAChR channels only were slightly decreased by SP. Given that individual parasympathetic neurons of rat intracardiac ganglia express a heterogeneous population of nAChR subunits represented by the different conductance levels, SP appears to preferentially inhibit those combinations of nAChR subunits that form the large conductance nAChR channels. Since ACh is the principal neurotransmitter of extrinsic (vagal) innervation of the mammalian heart, SP may play an important role in modulating autonomic control of the heart.

Towards a standards-based autonomic context management system

Pervasive computing applications must be sufficiently autonomous to adapt their behaviour to changes in computing resources and user requirements. This capability is known as context-awareness. In some cases, context-aware applications must be implemented as autonomic systems which are capable of dynamically discovering and replacing context sources (sensors) at run-time. Unlike other types of application autonomy, this kind of dynamic reconfiguration has not been sufficiently investigated yet by the research community. However, application-level context models are becoming common, in order to ease programming of context-aware applications and support evolution by decoupling applications from context sources. We can leverage these context models to develop general (i.e., application-independent) solutions for dynamic, run-time discovery of context sources (i.e., context management). This paper presents a model and architecture for a reconfigurable context management system that supports interoperability by building on emerging standards for sensor description and classification.

An Autonomic Framework for Mobile Cloud Computing

This thesis presents the formal definition of a novel Mobile Cloud Computing (MCC) extension of the Networked Autonomic Machine (NAM) framework, a general-purpose conceptual tool which describes large-scale distributed autonomic systems. The introduction of autonomic policies in the MCC paradigm has proved to be an effective technique to increase the robustness and flexibility of MCC systems. In particular, autonomic policies based on continuous resource and connectivity monitoring help automate context-aware decisions for computation offloading. We have also provided NAM with a formalization in terms of a transformational operational semantics in order to fill the gap between its existing Java implementation NAM4J and its conceptual definition. Moreover, we have extended NAM4J by adding several components with the purpose of managing large scale autonomic distributed environments. In particular, the middleware allows for the implementation of peer-to-peer (P2P) networks of NAM nodes. Moreover, NAM mobility actions have been implemented to enable the migration of code, execution state and data. Within NAM4J, we have designed and developed a component, denoted as context bus, which is particularly useful in collaborative applications in that, if replicated on each peer, it instantiates a virtual shared channel allowing nodes to notify and get notified about context events. Regarding the autonomic policies management, we have provided NAM4J with a rule engine, whose purpose is to allow a system to autonomously determine when offloading is convenient. We have also provided NAM4J with trust and reputation management mechanisms to make the middleware suitable for applications in which such aspects are of great interest. To this purpose, we have designed and implemented a distributed framework, denoted as DARTSense, where no central server is required, as reputation values are stored and updated by participants in a subjective fashion. We have also investigated the literature regarding MCC systems. The analysis pointed out that all MCC models focus on mobile devices, and consider the Cloud as a system with unlimited resources. To contribute in filling this gap, we defined a modeling and simulation framework for the design and analysis of MCC systems, encompassing both their sides. We have also implemented a modular and reusable simulator of the model. We have applied the NAM principles to two different application scenarios. First, we have defined a hybrid P2P/cloud approach where components and protocols are autonomically configured according to specific target goals, such as cost-effectiveness, reliability and availability. Merging P2P and cloud paradigms brings together the advantages of both: high availability, provided by the Cloud presence, and low cost, by exploiting inexpensive peers resources. As an example, we have shown how the proposed approach can be used to design NAM-based collaborative storage systems based on an autonomic policy to decide how to distribute data chunks among peers and Cloud, according to cost minimization and data availability goals. As a second application, we have defined an autonomic architecture for decentralized urban participatory sensing (UPS) which bridges sensor networks and mobile systems to improve effectiveness and efficiency. The developed application allows users to retrieve and publish different types of sensed information by using the features provided by NAM4J's context bus. Trust and reputation is managed through the application of DARTSense mechanisms. Also, the application includes an autonomic policy that detects areas characterized by few contributors, and tries to recruit new providers by migrating code necessary to sensing, through NAM mobility actions.

Autonomic dysfunction in unselected and untreated primary open angle glaucoma patients:A pilot study

Purpose: To investigate the presence of silent cardiac ischaemic episodes and the status of autonomic function in consecutive, newly diagnosed and untreated primary open-angle glaucoma patients. Methods: Twenty-four consecutively diagnosed glaucoma patients and 22 age-matched controls were subjected to ambulatory 24-h blood pressure (BP) and electrocardiogram (ECG) monitoring by using Cardiotens-01 (Meditech Ltd). Based on the ECG recordings, heart rate variability (HRV) frequency domain parameters [low-frequency (LF), high-frequency (HF) and LF/HF ratio] were calculated and analysed in the two study groups. Results: Glaucoma patients demonstrated higher LF and LF/HF values than normal subjects for both the active period (p = 0.020 and 0.029) and the passive period (p = 0.044 and 0.049 respectively). HRV parameters were similar in patients and controls suffering from silent cardiac ischaemia (p > 0.05); however, glaucoma patients with normal ECG demonstrated higher LF and LF/HF values during the active period of the 24-h measurement period than control subjects characterized by the same cardiac activity (p = 0.010 and 0.021 respectively). Conclusion: Independent of a history and/or clinical signs of cardiovascular disease, glaucoma patients exhibit abnormal autonomic function. © 2007 The Authors.

Autonomic correlates of ocular accommodation and cardiovascular function

PURPOSE: To evaluate the hypothesis that objective measures of open- and closed-loop ocular accommodation are related to systemic cardiovascular function, and ipso facto autonomic nervous system activity. METHODS: Sixty subjects (29 male; 31 female) varying in age from 18 to 33 years (average: 20.3 +/- 2.9 years) with a range of refractive errors [mean spherical equivalent (MSE): -7.12 to +1.82 D] participated in the study. Five 20-s continuous objective recordings of the accommodative response, measured with an open-view IR autorefractor (Shin-Nippon SRW-5000), were obtained for a variety of open- and closed-loop accommodative demands while simultaneous continuous measurement of heart rate was recorded with a finger-mounted piezo-electric pulse transducer for 5 min. Fast Fourier Transformation of cardiovascular function allowed the absolute and relative power of the autonomic components to be assessed in the frequency-domain, whereas heart period gave an indication of the time-domain response. RESULTS: Increasing closed-loop accommodative demand led to a concurrent increase in heart rate of approximately 2 beats/min for a 4.0 D increase in accommodative demand. The increase was attributable to a reduction in the absolute (p < 0.05) and normalised (p < 0.001) input of the systemic parasympathetic nervous system, and was unaffected by refractive group. The interaction with refractive group failed to reach significance. CONCLUSIONS: For sustained accommodation effort, the data demonstrate covariation between the oculomotor and cardiovascular systems which implies that a near visual task can significantly influence cardiovascular behaviour. Accommodative effort alone, however, is not a sufficient stimulus to induce autonomic differences between refractive groups. The data suggest that both the oculomotor and cardiovascular systems are predominantly attributable to changes in the systemic parasympathetic nervous system.

Reconfigurable service-oriented architecture for autonomic computing

Almost a decade has passed since the objectives and benefits of autonomic computing were stated, yet even the latest system designs and deployments exhibit only limited and isolated elements of autonomic functionality. In previous work, we identified several of the key challenges behind this delay in the adoption of autonomic solutions, and proposed a generic framework for the development of autonomic computing systems that overcomes these challenges. In this article, we describe how existing technologies and standards can be used to realise our autonomic computing framework, and present its implementation as a service-oriented architecture. We show how this implementation employs a combination of automated code generation, model-based and object-oriented development techniques to ensure that the framework can be used to add autonomic capabilities to systems whose characteristics are unknown until runtime. We then use our framework to develop two autonomic solutions for the allocation of server capacity to services of different priorities and variable workloads, thus illustrating its application in the context of a typical data-centre resource management problem.

Using quantitative analysis to implement autonomic IT systems

The software underpinning today’s IT systems needs to adapt dynamically and predictably to rapid changes in system workload, environment and objectives. We describe a software framework that achieves such adaptiveness for IT systems whose components can be modelled as Markov chains. The framework comprises (i) an autonomic architecture that uses Markov-chain quantitative analysis to dynamically adjust the parameters of an IT system in line with its state, environment and objectives; and (ii) a method for developing instances of this architecture for real-world systems. Two case studies are presented that use the framework successfully for the dynamic power management of disk drives, and for the adaptive management of cluster availability within data centres, respectively.