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.

Outward currents in smooth muscle cells isolated from sheep mesenteric lymphatics.

1. The patch-clamp technique was used to measure membrane currents in isolated smooth muscle cells dispersed from sheep mesenteric lymphatics. Depolarizing steps positive to -30 mV evoked rapid inward currents followed by noisy outward currents. 2. Nifedipine (1 microM) markedly reduced the outward current, while Bay K 8644 (1 microM) enhanced it. Up to 90% of the outward current was also blocked by iberiotoxin (Kd = 36 nM). 3. Large conductance (304 +/- 15 pS, 7 cells), Ca(2+)- and voltage-sensitive channels were observed during single-channel recordings on inside-out patches using symmetrical 140 mM K+ solutions (at 37 degrees C). The voltage required for half-maximal activation of the channels (V1/2) shifted in the hyperpolarizing direction by 146 mV per 10-fold increase in [Ca2+]i. 4. In whole-cell experiments a voltage-dependent outward current remained when the Ca(2+)-activated current was blocked with penitrem A (100 nM). This current activated at potentials positive to -20 mV and demonstrated the phenomenon of voltage-dependent inactivation (V1/2 = -41 +/- 2 mV, slope factor = 18 +/- 2 mV, 5 cells). 6. Tetraethylammonium (TEA; 30 mM) reduced the voltage-dependent current by 75% (Kd = 3.3 mM, 5 cells) while a maximal concentration of 4-aminopyridine (4-AP; 10 mM) blocked only 40% of the current. TEA alone had as much effect as TEA and 4-AP together, suggesting that there are at least two components to the voltage-sensitive K+ current. 7. These results suggest that lymphatic smooth muscle cells generate a Ca(2+)-activated current, largely mediated by large conductance Ca(2+)-activated K+ channels, and several components of voltage-dependent outward current which resemble 'delayed rectifier' currents in other smooth muscle preparations.

Positronium scattering by atomic hydrogen with inclusion of target excitation channels

Calculations are reported for positronium (Ps) scattering by atomic hydrogen (H) in the energy range 0-6.5 eV in a coupled- pseudostate approximation in which excitation and ionization channels of both the Ps and the H are taken into account. The approximation contains an accurate representation of the van der Waals coefficient. Results are presented for phase shifts, scattering lengths, effective ranges, and various cross sections including partial wave, total, and ortho-para conversion cross sections. An analysis of the possible spin transitions is provided and the energy of the positronium hydride (PsH) bound state is determined. Substantial differences are found from earlier work within the frozen target approximation, now clearly confirming the importance of target excitation channels. Good agreement is obtained with recent calculations of S-wave phase shifts and scattering lengths using the stabilization method. Convergence to the exact binding energy for PsH appears to be slow. Resonances corresponding to unstable states of the positron orbiting H- are seen in the electronic spin singlet partial waves. The importance of the H- formation channel is discussed.

Quantum-information processing with noisy cluster states

We provide an analysis of basic quantum-information processing protocols under the effect of intrinsic nonidealities in cluster states. These nonidealities are based on the introduction of randomness in the entangling steps that create the cluster state and are motivated by the unavoidable imperfections faced in creating entanglement using condensed-matter systems. Aided by the use of an alternative and very efficient method to construct cluster-state configurations, which relies on the concatenation of fundamental cluster structures, we address quantum-state transfer and various fundamental gate simulations through noisy cluster states. We find that a winning strategy to limit the effects of noise is the management of small clusters processed via just a few measurements. Our study also reinforces recent ideas related to the optical implementation of a one-way quantum computer.

Robust Speaker Recognition in Noisy Conditions

This paper investigates the problem of speaker identi-fication and verification in noisy conditions, assuming that speechsignals are corrupted by environmental noise, but knowledgeabout the noise characteristics is not available. This research ismotivated in part by the potential application of speaker recog-nition technologies on handheld devices or the Internet. Whilethe technologies promise an additional biometric layer of securityto protect the user, the practical implementation of such systemsfaces many challenges. One of these is environmental noise. Due tothe mobile nature of such systems, the noise sources can be highlytime-varying and potentially unknown. This raises the require-ment for noise robustness in the absence of information about thenoise. This paper describes a method that combines multicondi-tion model training and missing-feature theory to model noisewith unknown temporal-spectral characteristics. Multiconditiontraining is conducted using simulated noisy data with limitednoise variation, providing a “coarse” compensation for the noise,and missing-feature theory is applied to refine the compensationby ignoring noise variation outside the given training conditions,thereby reducing the training and testing mismatch. This paperis focused on several issues relating to the implementation of thenew model for real-world applications. These include the gener-ation of multicondition training data to model noisy speech, thecombination of different training data to optimize the recognitionperformance, and the reduction of the model’s complexity. Thenew algorithm was tested using two databases with simulated andrealistic noisy speech data. The first database is a redevelopmentof the TIMIT database by rerecording the data in the presence ofvarious noise types, used to test the model for speaker identifica-tion with a focus on the varieties of noise. The second database isa handheld-device database collected in realistic noisy conditions,used to further validate the model for real-world speaker verifica-tion. The new model is compared to baseline systems and is foundto achieve lower error rates.