Force platform feedback for standing balance training after stroke.

BACKGROUND: Standing balance deficits are common in individuals after stroke. One way to address these deficits is to provide the individual with feedback from a force platform while balance activities are performed. The feedback can take visual and/or auditory form. OBJECTIVES: To determine if visual or auditory force platform feedback improves the clinical and force platform standing balance outcomes in clients with stroke. SEARCH STRATEGY: We searched the Cochrane Stroke Group trials register (last searched December 2003), and the following electronic bibliographic databases: the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 3, 2003), MEDLINE (1966 to May 2003), EMBASE (1974 to May 2003), CINAHL (1982 to May 2003), PEDro (May 2003), CIRRIE (May 2003) and REHABDATA (May 2003). Reference lists of articles were reviewed and manufacturers of equipment were contacted. SELECTION CRITERIA: Randomized controlled trials comparing force platform with visual feedback and/or auditory feedback to other balance treatments. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trials for inclusion, methodological quality, and data extraction. Trials were combined for meta-analysis according to outcome and type of feedback. MAIN RESULTS: We included seven trials (246 participants). Force platform feedback did not improve clinical measures of balance when moving or walking (Berg Balance Scale and Timed Up and Go). Significant improvements in laboratory force platform indicators of stance symmetry were found for regimens using visual feedback (standardised mean difference (SMD) -0.68, 95% confidence interval (CI) -1.31 to -0.04, p = 0.04) and the concurrent visual and auditory feedback (weighted mean difference (WMD) -4.02, 95% CI -5.99 to -2.04, p = 0.00007). There were no significant effects on laboratory postural sway indicators, clinical outcomes or measures of function at follow-up assessment. REVIEWERS' CONCLUSIONS: Force platform feedback (visual or auditory) improved stance symmetry but not sway in standing, clinical balance outcomes or measures of independence.

Cell-cycle arrest in TrkA-expressing NIH3T3 cells involves nitric oxide synthase.

We have examined nerve growth factor (NGF)-triggered signaling in two NIH3T3 cell lines exogenously expressing the NGF receptor, TrkA. TRK1 cells cease to proliferate and extend long processes in response to NGF, while E25 cells continue to proliferate in the presence of NGF. These two cell lines express similar levels of TrkA and respond to NGF with rapid elevation of mitogen-activated protein kinase (MAPK) activity. MAPK activation is slightly more sustained for E25 cells than for TRK1 cells, although sustained activation of MAPK has been suggested to cause cell-cycle arrest. As judged by NADPH-diaphorase staining, nitric oxide synthase (NOS) activity is increased in TRK1 cells upon exposure to NGF. In contrast, diaphorase staining in E25 cells is unaffected by NGF treatment. Immunocytochemistry shows that levels of the brain NOS (bNOS) isoform are increased in TRK1, but not E25, cells exposed to NGF. Furthermore, Western blots show that NGF elevated cyclin-dependent kinase inhibitor, p21(WAF1), in TRK1 cells only. NGF-induced p21(WAF1) expression, cell-cycle arrest and process extension are abolished by N-nitro-L-arginine methyl ester (L-NAME), a competitive inhibitor of NOS. The inactive enantiomer, D-NAME, did not inhibit these responses. Furthermore, even though E25 cells do not respond to NGF or nitric oxide donors, they do undergo a morphological change in response to NGF plus a nitric oxide donor. Therefore, NOS and p21(WAF1) are induced only in the TrkA-expressing NIH3T3 cell line that undergoes cell-cycle arrest and morphological changes in response to NGF. These results demonstrate that sustained activation of MAPK is not the sole determining factor for NGF-induced cell-cycle arrest and implicate NO in the cascade of events leading to NGF-induced morphological changes and cell-cycle arrest.

A role for nuclear PTEN in neuronal differentiation.

Mutations of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a protein and lipid phosphatase, have been associated with gliomas, macrocephaly, and mental deficiencies. We have assessed PTEN's role in the nervous system and find that PTEN is expressed in mouse brain late in development, starting at approximately postnatal day 0. In adult brain, PTEN is preferentially expressed in neurons and is especially evident in Purkinje neurons, olfactory mitral neurons, and large pyramidal neurons. To analyze the function of PTEN in neuronal differentiation, we used two well established model systems-pheochromocytoma cells and cultured CNS stem cells. PTEN is expressed during neurotrophin-induced differentiation and is detected in both the nucleus and cytoplasm. Suppression of PTEN levels with antisense oligonucleotides does not block initiation of neuronal differentiation. Instead, PTEN antisense leads to death of the resulting, immature neurons, probably during neurite extension. In contrast, PTEN is not required for astrocytic differentiation. These observations indicate that PTEN acts at multiple sites in the cell, regulating the transition of differentiating neuroblasts to postmitotic neurons.

A novel, nerve growth factor-activated pathway involving nitric oxide, p53, and p21WAF1 regulates neuronal differentiation of PC12 cells.

During development, neuronal differentiation is closely coupled with cessation of proliferation. We use nerve growth factor (NGF)-induced differentiation of PC12 pheochromocytoma cells as a model and find a novel signal transduction pathway that blocks cell proliferation. Treatment of PC12 cells with NGF leads to induction of nitric oxide synthase (NOS) (Peunova, N., and Enikolopov, G. (1995) Nature 375, 68-73). The resulting nitric oxide (NO) acts as a second messenger, activating the p21(WAF1) promoter and inducing expression of p21(WAF1) cyclin-dependent kinase inhibitor. NO activates the p21(WAF1) promoter by p53-dependent and p53-independent mechanisms. Blocking production of NO with an inhibitor of NOS reduces accumulation of p53, activation of the p21(WAF1) promoter, expression of neuronal markers, and neurite extension. To determine whether p21(WAF1) is required for neurite extension, we prepared a PC12 line with an inducible p21(WAF1) expression vector. Blocking NOS with an inhibitor decreases neurite extension, but induction of p21(WAF1) with isopropyl-1-thio-beta-D-galactopyranoside restored this response. Levels of p21(WAF1) induced by isopropyl-1-thio-beta-D-galactopyranoside were similar to those induced by NGF. Therefore, we have identified a signal transduction pathway that is activated by NGF; proceeds through NOS, p53, and p21(WAF1) to block cell proliferation; and is required for neuronal differentiation by PC12 cells.

The cyclin-dependent kinase inhibitor p21 (WAF1) is required for survival of differentiating neuroblastoma cells.

We are employing recent advances in the understanding of the cell cycle to study the inverse relationship between proliferation and neuronal differentiation. Nerve growth factor and aphidicolin, an inhibitor of DNA polymerases, synergistically induce neuronal differentiation of SH-SY5Y neuroblastoma cells and the expression of p21WAF1, an inhibitor of cyclin-dependent kinases. The differentiated cells continue to express p21WAF1, even after removal of aphidicolin from the culture medium. The p21WAF1 protein coimmunoprecipitates with cyclin E and inhibits cyclin E-associated protein kinase activity. Each of three antisense oligonucleotides complementary to p21WAF1 mRNA partially blocks expression of p21WAF1 and promotes programmed cell death. These data indicate that p21WAF1 expression is required for survival of these differentiating neuroblastoma cells. Thus, the problem of neuronal differentiation can now be understood in the context of negative regulators of the cell cycle.

TrkA neurogenic receptor regulates differentiation of neuroblastoma cells.

We examined events associated with neuronal differentiation of neuroblastoma cell line SH-SY5Y. Treatment with nerve growth factor (NGF) and aphidicolin, an inhibitor of DNA polymerases alpha and delta, induces terminal differentiation of SH-SY5Y cells. Following 3-4 days of treatment with NGF + aphidicolin, the cells irreversibly ceased proliferation and differentiated. There was a succession of events preceding differentiation. Down-regulation of c-myc was an early event occurring after less than 1 day of treatment with NGF + aphidicolin. Upregulation of the trkA and low-affinity NGF receptors (LNGFR) occurred after 3 days of NGF + aphidicolin treatment and required treatment with both NGF and aphidicolin. To test the role of TrkA in neuroblastic differentiation, we transfected SH-SY5Y cells with a TrkA-expression plasmid. In response to NGF in the absence of aphidicolin, the TrkA-transformant line ceased proliferation and irreversibly differentiated. SH-SY5Y cells bearing a control plasmid displayed only modest, reversible differentiation and did not cease cell proliferation in response to NGF. Hence, expression of NGF receptors is upregulated during differentiation of SH-SY5Y cells, and overexpression of TrkA enhances NGF-induced differentiation.

Neuronal differentiation triggered by blocking cell proliferation.

Treatment of the neuroblastoma cell line SHSY5Y with nerve growth factor (NGF) resulted in limited neurite extension, but proliferation continued. However, SHSY5Y cells treated with NGF and a pulse of the DNA polymerase alpha and delta inhibitor aphidicolin showed dramatic neuronal differentiation. Few differentiated cells were observed immediately following the NGF-aphidicolin treatment; however, continued treatment of the cells with NGF in the ensuing week resulted in extension of long neurites (> 400 microns). Neurite extension was not observed for cells treated with aphidicolin alone. Hence, aphidicolin and NGF act synergistically to induce differentiation of SHSY5Y cells. If maintained in NGF, the differentiated cells were stable for at least 1 month and displayed many neuronal characteristics. They were mitotically inactive, and, in contrast to control or NGF-treated cells, the differentiated cells required NGF for survival. The cells expressed multiple microtubule-associated proteins (MAP), including MAP 1A, MAP 1B, and tau. There was expression of synaptic vesicle antigens synaptophysin and SV2, but not synapsin Ia/b or synapsin IIa/b. Both hydroxyurea and thymidine, which inhibit synthesis of nucleotides, act synergistically with NGF to induce differentiation of SHSY5Y cells. Since aphidicolin, hydroxyurea, and thymidine are chemically unrelated, we conclude that these drugs enhance NGF-induced differentiation by blocking cell proliferation and not through an unrelated side effect. The model suggested by these studies is that differentiation is triggered by two simultaneous signals: NGF and cessation of cell proliferation.