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.

The effect of type of hip protector and resident characteristics on adherence to use of hip protectors in nursing and residential homes - an exploratory study

Objectives: To investigate the factors influencing the acceptability of hip protectors to residents of nursing and residential homes, especially the effect of hip protector type, and resident characteristics. Design: A randomised controlled trial with 12 weeks follow-up. Participants were randomised to receive either Safehips or HipSaverTM hip protectors. Setting/Participants: 109 residents aged 61 to 98 years from seven residential homes and two nursing homes in Northern Ireland. Main outcome measures: Percentage day-time use of the hip protectors over 12 weeks and ongoing use at 12 weeks. Results: 42% (119/285) of residents invited to enter the studyagreed to take part, and 109 started to wear the hip protectors. 43.1% (47/109) were still using them at 12 weeks. Mean percentage day-time use for all residents during 12 weeks was 48.6%. There was no significant difference in percentage day-time use (p=0.40), or use at 12 weeks (p=0.56) between the residents wearing Safehips and HipSaverTM protectors. Greater percentage daytime use of hip protectors was associated with being resident in a home for the elderlymentallyinfirm (75.1%, pp0.0005), having a low (12 or less) Barthel score (61.1%, pp0.0005), and having been injured in a fall in the last 12 months (57.3%, p=0.012). Conclusions: The type of hip protector appeared to make no difference to their continued use by residents. Residents with a historyof a fall and those who are physicallyand mentallyincapacitated appear to be more likelyto wear hip protectors. These residents, who are at high risk of falling, are also highlydependent on nursing staff. Efforts to increase hip protector use in residential and nursing home should focus on staff, who are in the best position to advise and influence residents and their relatives.

Relative energetics and structural properties of zirconia using a self-consistent tight-binding model

We describe an empirical, self-consistent, orthogonal tight-binding model for zirconia, which allows for the polarizability of the anions at dipole and quadrupole levels and for crystal field splitting of the cation d orbitals, This is achieved by mixing the orbitals of different symmetry on a site with coupling coefficients driven by the Coulomb potentials up to octapole level. The additional forces on atoms due to the self-consistency and polarizabilities are exactly obtained by straightforward electrostatics, by analogy with the Hellmann-Feynman theorem as applied in first-principles calculations. The model correctly orders the zero temperature energies of all zirconia polymorphs. The Zr-O matrix elements of the Hamiltonian, which measure covalency, make a greater contribution than the polarizability to the energy differences between phases. Results for elastic constants of the cubic and tetragonal phases and phonon frequencies of the cubic phase are also presented and compared with some experimental data and first-principles calculations. We suggest that the model will be useful for studying finite temperature effects by means of molecular dynamics.

Magnetic tight binding and the iron-chromium enthalpy anomaly

We describe a self-consistent magnetic tight-binding theory based in an expansion of the Hohenberg-Kohn density functional to second order, about a non-spin-polarized reference density. We show how a first order expansion about a density having a trial input magnetic moment leads to a fixed moment model. We employ a simple set of tight-binding parameters that accurately describes electronic structure and energetics, and show these to be transferable between first row transition metals and their alloys. We make a number of calculations of the electronic structure of dilute Cr impurities in Fe, which we compare with results using the local spin density approximation. The fixed moment model provides a powerful means for interpreting complex magnetic configurations in alloys; using this approach, we are able to advance a simple and readily understood explanation for the observed anomaly in the enthalpy of mixing.

Electronic structure and total energy of interstitial hydrogen in iron: Tight-binding models

An application of the tight binding approximation is presented for the description of electronic structure and interatomic force in magnetic iron, both pure and containing hydrogen impurities. We assess the simple canonical d-band description in comparison to a non orthogonal model including s and d bands. The transferability of our models is tested against known properties including the segregation energies of hydrogen to vacancies and to surfaces of iron. In many cases agreement is remarkably good, opening up the way to quantum mechanical atomistic simulation of the effects of hydrogen on mechanical properties.