Oxaliplatin induces hyperexcitability at motor and autonomic neuromuscular junctions through effects on voltage-gated sodium channels

Oxaliplatin, an effective cytotoxic treatment in combination with 5-fluorouracil for colorectal cancer, is associated with sensory, motor and autonomic neurotoxicity. Motor symptoms include hyperexcitability while autonomic effects include urinary retention, but the cause of these side-effects is unknown. We examined the effects on motor nerve function in the mouse hemidiaphragm and on the autonomic system in the vas deferens. In the mouse diaphragm, oxaliplatin (0.5 mM) induced multiple endplate potentials (EPPs) following a single stimulus, and was associated with an increase in spontaneous miniature EPP frequency. In the vas deferens, spontaneous excitatory junction potential frequency was increased after 30 min exposure to oxaliplatin; no changes in resting Ca(2+) concentration in nerve terminal varicosities were observed, and recovery after stimuli trains was unaffected.In both tissues, an oxaliplatin-induced increase in spontaneous activity was prevented by the voltage-gated Na(+) channel blocker tetrodotoxin (TTX). Carbamazepine (0.3 mM) also prevented multiple EPPs and the increase in spontaneous activity in both tissues. In diaphragm, beta-pompilidotoxin (100 microM), which slows Na(+) channel inactivation, induced multiple EPPs similar to oxaliplatin's effect. By contrast, blockers of K(+) channels (4-aminopyridine and apamin) did not replicate oxaliplatin-induced hyperexcitability in the diaphragm. The prevention of hyperexcitability by TTX blockade implies that oxaliplatin acts on nerve conduction rather than by effecting repolarisation. The similarity between beta-pompilidotoxin and oxaliplatin suggests that alteration of voltage-gated Na(+) channel kinetics is likely to underlie the acute neurotoxic actions of oxaliplatin.

Predisposition to arrhythmia and autonomic dysfunction in Nhlh1-deficient mice.

Nhlh1 is a basic helix-loop-helix transcription factor whose expression is restricted to the nervous system and which may play a role in neuronal differentiation. To directly study Nhlh1 function, we generated null mice. Homozygous mutant mice were predisposed to premature, adult-onset, unexpected death. Electrocardiograms revealed decreased total heart rate variability, stress-induced arrhythmia, and impaired baroreceptor sensitivity. This predisposition to arrhythmia is a likely cause of the observed death in the mutant mice. Heterozygosity for the closely related transcription factor Nhlh2 increased the severity of the Nhlh1-null phenotype. No signs of primary cardiac structural or conduction abnormalities could be detected upon necropsy of the null mice. The pattern of altered heart rhythm observed in basal and experimental conditions (stress and pharmacologically induced) suggests that a deficient parasympathetic tone may contribute to the arrhythmia in the Nhlh1-null mouse. The expression of Nhlh1 in the developing brain stem and in the vagal nuclei in the wild-type mouse further supports this hypothesis. The Nhlh1 mutant mouse may thus provide a model to investigate the contribution of the autonomic nervous system to arrhythmogenesis.

Co-design of Distributed Systems Using Skeleton and Autonomic Management Abstractions

We discuss how common problems arising with multi/many core distributed architectures can he effectively handled through co-design of parallel/distributed programming abstractions and of autonomic management of non-functional concerns. In particular, we demonstrate how restricted patterns (or skeletons) may be efficiently managed by rule-based autonomic managers. We discuss the basic principles underlying pattern+manager co-design, current implementations inspired by this approach and some result achieved with proof-or-concept, prototype.

Semi-formal Models to Support Program Development: Autonomic Management within Component Based Parallel and Distributed Programming

Functional and non-functional concerns require different programming effort, different techniques and different methodologies when attempting to program efficient parallel/distributed applications. In this work we present a "programmer oriented" methodology based on formal tools that permits reasoning about parallel/distributed program development and refinement. The proposed methodology is semi-formal in that it does not require the exploitation of highly formal tools and techniques, while providing a palatable and effective support to programmers developing parallel/distributed applications, in particular when handling non-functional concerns.

Towards hierarchical management of autonomic components: a case study

We address the issue of autonomic management in hierarchical component-based distributed systems. The long term aim is to provide a modelling framework for autonomic management in which QoS goals can be defined, plans for system adaptation described and proofs of achievement of goals by (sequences of) adaptations furnished. Here we present an early step on this path. We restrict our focus to skeleton-based systems in order to exploit their well-defined structure. The autonomic cycle is described using the Orc system orchestration language while the plans are presented as structural modifications together with associated costs and benefits. A case study is presented to illustrate the interaction of managers to maintain QoS goals for throughput under varying conditions of resource availability.

Autonomic management of non-functional concerns in distributed & parallel application programming

An approach to the management of non-functional concerns in massively parallel and/or distributed architectures that marries parallel programming patterns with autonomic computing is presented. The necessity and suitability of the adoption of autonomic techniques are evidenced. Issues arising in the implementation of autonomic managers taking care of multiple concerns and of coordination among hierarchies of such autonomic managers are discussed. Experimental results are presented that demonstrate the feasibility of the approach.

Behavioural skeletons in GCM: autonomic management of grid components

Autonomic management can be used to improve the QoS provided by parallel/distributed applications. We discuss behavioural skeletons introduced in earlier work: rather than relying on programmer ability to design “from scratch” efficient autonomic policies, we encapsulate general autonomic controller features into algorithmic skeletons. Then we leave to the programmer the duty of specifying the parameters needed to specialise the skeletons to the needs of the particular application at hand. This results in the programmer having the ability to fast prototype and tune distributed/parallel applications with non-trivial autonomic management capabilities. We discuss how behavioural skeletons have been implemented in the framework of GCM(the Grid ComponentModel developed within the CoreGRID NoE and currently being implemented within the GridCOMP STREP project). We present results evaluating the overhead introduced by autonomic management activities as well as the overall behaviour of the skeletons. We also present results achieved with a long running application subject to autonomic management and dynamically adapting to changing features of the target architecture.
Overall the results demonstrate both the feasibility of implementing autonomic control via behavioural skeletons and the effectiveness of our sample behavioural skeletons in managing the “functional replication” pattern(s).

Relations between behavioral and cardiac autonomic reactivity to acute pain in preterm neonates

The purpose of this study was to assess relations and concordance between behavioral and physiologic reactivity to pain in preterm neonates at 32 weeks postconceptional age as a function of gestational age at birth.