Long after a cut peripheral nerve reinnervates muscle and restores force production in adult cats, the muscle does not respond reflexively to stretch. Motivated by the likelihood that stretch areflexia is related to problems with sensing and controlling limb position after peripheral neuropathies, we sought to determine the underlying mechanism. Electrophysiological and morphological measurements were made in anesthetized rats having one of the nerves to the triceps surae muscles either untreated or cut and immediately rejoined surgically many months earlier. First, it was established that reinnervated muscles failed to generate stretch reflexes, extending observations of areflexia to a second species. Next, multiple elements in the sensorimotor circuit of the stretch reflex were examined in both the PNS and CNS. Encoding of muscle stretch by regenerated proprioceptive afferents was remarkably similar to normal, although we observed some expected abnormalities, e.g., increased length threshold. However, the robust stretch-evoked sensory response that arrived concurrently at the CNS in multiple proprioceptive afferents produced synaptic responses that were either smaller than normal or undetectable. Muscle stretch failed to evoke detectable synaptic responses in 13 of 22 motoneurons, although electrical stimulation generated monosynaptic excitatory postsynaptic potentials that were indistinguishable from normal. The ineffectiveness of muscle stretch was not attributable therefore to dysfunction at synapses made between regenerated Ia afferents and motoneurons. Among multiple candidate mechanisms, we suggest that centrally controlled neural circuits may actively suppress the sensory information encoded by regenerated proprioceptive afferents to prevent recovery of the stretch reflex.

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Bullinger KL, Nardelli P, Wang Q, Rich MM, Cope TC. Oxaliplatin neurotoxicity of sensory transduction in rat proprioceptors. J Neurophysiol 106: 704 -709, 2011. First published May 18, 2011 doi:10.1152/jn.00083.2011.-Neurotoxic effects of oxaliplatin chemotherapy, including proprioceptive impairments, are debilitating and dose limiting. Here, we sought to determine whether oxaliplatin interrupts normal proprioceptive feedback by impairing sensory transduction of muscle length and force by neurons that are not damaged by dying-back neuropathy. Oxaliplatin was administered over 4 wk to rats in doses that produced systemic changes, e.g., decreased platelets and stunted weight gain, but no significant abnormality in the terminal ends of primary muscle spindle sensory neurons. The absence of neuropathy enabled the determination of whether oxaliplatin caused functional deficits in sensory encoding without the confounding issue of axon death. Rats were anesthetized, and action potentials encoding muscle stretch and contraction were recorded intra-axonally from dorsal roots. In striking contrast with normal proprioceptors, those from oxaliplatin-treated rats typically failed to sustain firing during static muscle stretch. The ability of spindle afferents to sustain and centrally conduct trains of action potentials in response to rapidly repeated transient stimuli, i.e., vibration, demonstrated functional competence of the parent axons. These data provide the first evidence that oxaliplatin causes persistent and selective deficits in sensory transduction that are not due to axon degeneration. Our findings raise the possibility that even those axons that do not degenerate after oxaliplatin treatment may have functional deficits that worsen outcome. chemotherapy; neuropathy; muscle spindle; electrophysiology; afferent PERIPHERAL NEUROPATHY is the most common dose-limiting factor of oxaliplatin chemotherapy (for reviews, see Argyriou et al. 2008;Krishnan et al. 2005;Pasetto et al. 2006). Acute neurotoxicity, predominantly sensory in nature, is seen in nearly all patients and is characterized by cold intolerance, dysthesias, and, less commonly, laryngeal spasms (Wilson et al. 2002). With continued treatment, a cumulative sensory neuropathy can develop similar to that seen in patients treated with other platinum compounds. The onset of the neuropathy is gradual, and the severity worsens with an increase in cumulative dose. Chronic neuropathy is thought to primarily affect large-diameter sensory fibers (for evidence and earlier citations, see Jamieson et al. 2005), which include muscle afferents that provide the central nervous system with proprioceptive information. Consistent with this notion, patients often lose deep tendon reflexes, mediated by muscle spindle afferents, and develop proprioceptive loss seen as problems with coordinating movement, e.g., loss of dexterity and sensory ataxia.Sensory contributions to behavior and experience depend on conduction and central transmission of signals that are encoded by specialize...

Detection of circulating tumor cells remains a significant challenge due to their vast physical and biological heterogeneity. We developed a cell-surface-marker-independent technology based on telomerase-specific, replication-selective oncolytic herpes-simplex-virus-1 that targets telomerase-reverse-transcriptase-positive cancer cells and expresses green-fluorescent-protein that identifies viable CTCs from a broad spectrum of malignancies. Our method recovered 75.5–87.2% of tumor cells spiked into healthy donor blood, as validated by different methods, including single cell sequencing. CTCs were detected in 59–100% of 326 blood samples from patients with 6 different solid organ carcinomas and lymphomas. Significantly, CTC-positive rates increased remarkably with tumor progression from N0M0, N+M0 to M1 in each of 5 tested cancers (lung, colon, liver, gastric and pancreatic cancer, and glioma). Among 21 non-small cell lung cancer cases in which CTC values were consecutively monitored, 81% showed treatment-related decreases, which was also found after treatments in the other solid tumors. Moreover, monitoring CTC values provided an efficient treatment response indicator in hematological malignancies. Compared to CellSearch, our method detected significantly higher positive rates in 40 NSCLC in all stages, including N0M0, N+M0 and M1, and was less affected by chemotherapy. This simple, robust and clinically-applicable technology detects viable CTCs from solid and hematopoietic malignancies in early to late stages, and significantly improves clinical detection and treatment prognostication.

There is a long-standing debate concerning the localization of the primary insult that results in distal axonal degeneration, or 'dying back' neuropathy. To address this question, we created an in vitro model of vincristine neuropathy in rat dorsal root ganglia (DRG). DRGs were grown in compartmentalized chambers, allowing for isolated exposure of the cell body or the axon to vincristine. Initial dose-finding studies identified a dose of vincristine that showed differential effects on cell death when delivered to either the cell body or the axonal compartment. At this dose of 0.05 microM, exposure of the cell bodies had no effect on the growth of axons, whereas addition of vincristine to the axonal compartment caused axonal shortening without affecting the growth of unexposed 'sister' axons. Toxicity was seen only with exposure of the growing axonal tips. These data support localized axonal toxicity as a cause of distal axonal degeneration due to vincristine.