Chemotherapy-induced peripheral neuropathy in a dish: dorsal root ganglion cells treated in vitro with paclitaxel show biochemical and physiological responses parallel to that seen in vivo.

The mechanisms underlying chemotherapy-induced peripheral neuropathy have yet to be fully elucidated, but primary afferent neurons have emerged as an especially vulnerable initiating pathophysiological target. An important recent study has also shown that the initial toxicity produced by paclitaxel in patients was highly predictive of long-term outcome. In this study, we therefore focused on defining the mechanisms of acute toxicity produced by paclitaxel treatment on primary sensory neurons under in vitro conditions. In primary rat dorsal root ganglion (DRG) culture with paclitaxel, an increase of pERK and pp38 was observed at 2 hours, and this was accompanied by an increase in expression and release of C-C chemokine ligand 2 (CCL2). There was no change in pJNK. The increase in pERK was sustained at 48 hours of exposure when the expression of TLR4, MyD88, and IL-6 was also increased. IL-6 and CCL2 were colocalized to TLR4-positive cells, and all these responses were prevented by coincubation with a TLR4 antagonist (LPS-RS). Whole-cell patch-clamp recordings revealed that DRG neurons developed spontaneous depolarizing fluctuations (DSFs) in membrane potential and hyperexcitability to current injection but no ectopic action potential activity at 24 and 48 hours of paclitaxel incubation. However, CCL2 applied to cultured neurons not only induced DSFs but also evoked action potentials. Evidence of oxidative stress and mitotoxicity was observed at 48 hours of exposure. These results closely parallel the responses measured in the DRG with paclitaxel exposure in vivo and so indicate that acute toxicity of paclitaxel on the DRG can be modelled using an in vitro approach.

Cervical spine posteroanterior stiffness differs with neck position.

PURPOSE: Spinal stiffness is commonly considered when treating patients with neck pain, but there are few studies reporting the objective measurement of cervical spine stiffness or the possible kinesiological factors that may affect its quantification. The aim of this study was to determine if the position of the neck affects cervical spine stiffness. METHODS: An instrumented stiffness assessment device measured posteroanterior cervical spine stiffness at C4 of 25 prone-lying asymptomatic subjects in three neck positions in randomised order: maximal flexion, maximal extension, and neutral. The device applied five standardised mechanical oscillatory pressures while measuring the applied force and concurrent displacement, defining stiffness as the slope of the linear portion of the force-displacement curve. Repeated measures analysis of variance with Bonferroni-adjusted post hoc comparisons determined whether stiffness differed between neck positions. RESULTS: There was a significant difference in cervical spine stiffness between different neck positions (F((1.6,38.0)) = 16.6, P < 0.001). Stiffness was least in extension with a mean of 3.09 N/mm (95% CI 2.59, 3.58) followed by neutral (3.94, 95% CI 3.49, 4.39), and then flexion (4.32, 95% CI 3.96, 4.69). CONCLUSION: When assessing cervical spine stiffness, neck position should be standardised to ensure maximal reliability and utility of stiffness judgments.