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After central nervous system (CNS) injury, inhibitory factors in the lesion scar and poor axon growth potential prevent axon regeneration. Microtubule stabilization reduces scarring and promotes axon growth. However, the cellular mechanisms of this dual effect remain unclear. Here, delayed systemic administration of a blood-brain barrier-permeable microtubule-stabilizing drug, epothilone B (epoB), decreased scarring after rodent spinal cord injury (SCI) by abrogating polarization and directed migration of scar-forming fibroblasts. Conversely, epothilone B reactivated neuronal polarization by inducing concerted microtubule polymerization into the axon tip, which propelled axon growth through an inhibitory environment. Together, these drug-elicited effects promoted axon regeneration and improved motor function after SCI. With recent clinical approval, epothilones hold promise for clinical use after CNS injury.

High thoracic or cervical spinal cord injury (SCI) can lead to cardiovascular dysfunction. To monitor cardiovascular parameters, we implanted a catheter connected to a radio transmitter into the femoral artery of rats that underwent a T4 spinal cord transection with or without grafting of embryonic brainstem-derived neural stem cells expressing green fluorescent protein. Compared to other methods such as cannula insertion or tail-cuff, telemetry is advantageous to continuously monitor blood pressure and heart rate in freely moving animals. It is also capable of long term multiple data acquisitions. In spinal cord injured rats, basal cardiovascular data under unrestrained condition and autonomic dysreflexia in response to colorectal distension were successfully recorded. In addition, cardiovascular parameters before and after SCI can be compared in the same rat if a transmitter is implanted before a spinal cord transection. One limitation of the described telemetry procedure is that implantation in the femoral artery may influence the blood supply to the ipsilateral hindlimb.

Stage migration due to different methods of cancer staging can artifactually inflate cancer survival rates by shifting patients with a marginal prognosis out of a better prognosis group into a worse prognosis group. This bias can be avoided by ensuring that comparable staging methods are used when comparing survival across cancer cohorts. Keywords: prognosis; cohort; bias; survival; staging; Will Rogers effect

Replication of published studies is an important and respected aspect of the conduct of science. Most would argue that the interpretation of "negative" outcomes is still more challenging than the interpretation of "positive" findings, however, due to uncertainty in knowing precisely why a hypothesized outcome was not observed: in particular, are "negative" findings in replication studies a result of invalidity of the original experimental hypothesis, or due to a methodological failure, insensitivity of the applied instruments of analysis, or other factors? These points must be carefully considered. Steward and colleagues report findings of a study in which multipotent neural progenitor cells were grafted to sites of T3 complete transection. Unlike our study, cells failed to fill the lesion site, leaving collagenous rifts between rostral and caudal graft components. This "anatomical" failure precluded formation of neural relays across the lesion site, and was predictably associated with a failure to detect functional improvement. In summarizing outcomes of the study, Steward and colleagues did not clearly link the failure to achieve graft continuity in the lesion cavity with functional outcomes, despite the central role of this observation in cogently interpreting results of the replication study. In addition, the authors stated that they failed to replicate our report of "extensive" host axonal regeneration into grafts, but we did not report "extensive" host anatomical regeneration; moreover, underexposed images may have contributed to Steward's underestimation of host axonal penetration. The authors also stated that our original study excluded some animals from functional analysis, and this is incorrect. While replication studies are important and necessary, this particular report contained several errors, and the failure to form a continuous neural progenitor cell bridge across the lesion site limited the ability to conclude whether continuous grafts can restore function. In subsequent experiments we too have observed rift formation in animals grafted at long delays (>2weeks) after SCI, and we confirm that animals with rifts do not exhibit functional improvement; we are developing methods to remove or prevent rift formation. The replication study confirmed the cardinal finding of our original report: that early-stage neural precursors extend very large numbers of axons over remarkably long distances through the lesioned adult spinal cord.

Neurotrophic factors exert many effects on the intact and lesioned adult central nervous system (CNS). Among these effects are prevention of neuronal death (neurotrophism) and promotion of axonal growth (neurotropism) after injury. To date, however, it has not been established whether survival and axonal growth functions of neurotrophins can be independently modulated in injured adult neurons in vivo. To address this question, the ability of brain-derived neurotrophic factor (BDNF) to influence corticospinal motor neuronal survival and axonal growth was examined in two injury paradigms. In the first paradigm, a survival assay, adult Fischer 344 rats underwent subcortical lesions followed by grafts to the lesion cavity of syngenic fibroblasts genetically modified to secrete high amounts BDNF or, in control subjects, the reporter gene green fluorescent protein. In control subjects, only 36.2 +/- 7.0% of the retrogradely labeled corticospinal neurons survived the lesion, whereas 89.8 +/- 5.9% (P < 0.001) of the corticospinal neurons survived in animals that received BDNF-secreting grafts. However, in an axonal growth assay, BDNF-secreting cell grafts that were placed into either subcortical lesion sites or sites of thoracic spinal cord injury failed to elicit corticospinal axonal growth. Despite this lack of a neurotropic effect on lesioned corticospinal axons, BDNF-secreting cell grafts placed in the injured spinal cord significantly augmented the growth of other types of axons, including local motor, sensory, and coerulospinal axons. Immunolabeling for tyrosine kinase B (trkB) demonstrated that BDNF receptors were present on corticospinal neuronal somata and apical dendrites but were not detected on their projecting axons. Thus, single classes of neurons in the adult CNS appear to exhibit disparate survival and growth sensitivity to neurotrophic factors, potentially attributable at least in part to differential trafficking of neurotrophin receptors. The possibility of tropic/trophic divergence must be considered when designing strategies to promote CNS recovery from injury.