ABSTRACT
Axons in the adult CNS have poor ability to grow after injury, impeding functional recovery in patients of spinal cord injury. This has been attributed to both a developmental decline in neuron-intrinsic growth ability and the presence of extrinsic growth inhibitors. We previously showed that genetic deletion of Nogo, an extrinsic inhibitor, promoted axonal sprouting from uninjured corticospinal tract (CST) neurons but not regeneration from injured CST neurons, whereas genetic deletion of PTEN, an intrinsic inhibitor, promoted both CST sprouting and regeneration. Here we test the hypothesis that combining an elevation of neuron-intrinsic growth ability and a reduction of extrinsic growth inhibition by genetic codeletion of PTEN and Nogo may further improve injury-induced axonal growth. In an apparent paradox, additionally deleting Nogo further enhanced CST regeneration but not sprouting in PTEN-deleted mice. Enhanced CST regeneration and sprouting in PTEN and PTEN/Nogo-deleted mice were associated with no or only temporary improvement in functional recovery. Our data illustrate that neuron-intrinsic and -extrinsic factors regulate axon regeneration and sprouting in complex ways and provide proof-of-principle evidence that targeting both can further improve regeneration. Neuron-intrinsic growth ability is an important determinant of neuronal responsiveness to changes in extrinsic growth inhibition, such that an elevated intrinsic growth state is a prerequisite for reducing extrinsic inhibition to take effect on CST regeneration. Meanwhile, additional strategies are required to unleash the full potential for functional recovery with enhanced axon regeneration and/or sprouting.
Subject(s)
Axons/physiology , Myelin Proteins/deficiency , Nerve Regeneration/physiology , PTEN Phosphohydrolase/deficiency , Pyramidal Tracts/physiology , Animals , Behavior, Animal/physiology , Mice , Mice, Mutant Strains , Myelin Proteins/genetics , Myelin Proteins/physiology , Nerve Regeneration/genetics , Nogo Proteins , PTEN Phosphohydrolase/genetics , PTEN Phosphohydrolase/physiology , Recovery of Function/genetics , Recovery of Function/physiology , Spinal Cord Injuries/physiopathologyABSTRACT
OBJECTIVES: Determine the relative impact of chronic hepatitis C (CHC) and co-morbid illnesses on health-related quality of life (HRQoL) in 3023 randomly selected veterans with known hepatitis C virus antibody (anti-HCV) status who previously completed a veteran-specific HRQoL questionnaire (SF-36V). METHODS: Multiple regression analyses were performed to measure the relative contribution of anti-HCV status, four demographic variables, and ten common medical and six psychiatric co-morbidities to HRQoL between 303 anti-HCV(+) and 2720 anti-HCV(-) patients. RESULTS: Anti-HCV(+) veterans were younger, reported a lower HRQoL on seven of eight 36-Item Short Form Health Survey for Veterans (SF-36V) subscales (P < or = 0.001) and the mental component summary (MCS) scale (P < 0.001). The ten medical and six psychiatric co-morbidities had variable impact on predicting lower HRQoL in both groups. After adjusting for demographic variables and co-morbid illnesses, we found that anti-HCV(+) patients reported a significantly lower MCS score (P < 0.001) and a trend toward a lower physical component summary (PCS) score (P < 0.07) compared to anti-HCV(-) veterans. Among the anti-HCV(+) veterans, co-morbid medical illnesses contributed to impaired PCS but not to MCS. CONCLUSIONS: Veterans with CHC were younger than HCV(-) veterans and hence less likely to have other co-morbid medical illnesses. Medical co-morbidities seen in those veterans with CHC contribute to impaired PCS but not MCS. Anti-HCV(+) status negatively affects HRQoL, particularly MCS, independently of medical and psychiatric co-morbidities.
