Evaluation and Treatment of Foot Drop Using Nerve Transfer Techniques.

Foot drop represents a complex pathologic condition, requiring a multidisciplinary approach for appropriate evaluation and treatment. Multiple etiologic factors require recognition before considering invasive/operative intervention. When considering surgical management for the treatment of foot drop, it is first and foremost imperative to establish the cause of the condition. Not all causes resulting in clinical foot drop have surgical options. Establishing a cause allows the provider to more appropriately curtail a multidisciplinary approach to working-up, and ultimately, treating the patient. The authors offer an algorithm for evaluating and treating foot drop conditions associated with lumbar spine radiculopathy and peripheral nerve lesions.

Interleukin-4 induces senescence in human renal carcinoma cell lines through STAT6 and p38 MAPK.

Interleukin (IL)-4, originally identified as a lymphocyte growth factor, can directly inhibit growth of certain tumor cell types. We reported previously that IL-4 induced cell cycle arrest in G1 phase through an increase in p21(WAF1/CIP1) expression in human renal cell carcinoma (RCC) cell lines. In the present study, we investigated the underlying mechanism of IL-4-induced growth inhibition. In four of six human RCC cell lines, including Caki-1, A498, SNU482, and SNU228, IL-4 induced cellular senescence as demonstrated by enlarged and flattened morphology, increased granularity, and senescence-associated-ß-galactosidase (SA-ß-gal) staining. Signal tranducer and activator of transcription 6 (STAT6) and p38 MAPK were found to mediate IL-4-induced growth inhibition and cellular senescence. Both of these molecules were activated by 10 min after IL-4 treatment, and inhibition of their activity or expression prevented growth suppression and cellular senescence induced by IL-4. Inhibiting or silencing either STAT6 or p38 MAPK alone partially reduced the effect of IL-4, whereas inhibiting or silencing both molecules exerted an additive effect and almost completely abrogated the effect of IL-4. Thus STAT6 and p38 MAPK appeared to independently mediate IL-4-induced growth inhibition and cellular senescence. The p21(WAF1/CIP1) up-regulation that accompanied growth inhibition and cellular senescence by IL-4 was also attenuated additively when p38 MAPK and STAT6 were silenced. Taken together, these results show that IL-4 induces cellular senescence through independent signaling pathways involving STAT6 and p38 MAPK in some human RCC cell lines.

Panaxydol induces apoptosis through an increased intracellular calcium level, activation of JNK and p38 MAPK and NADPH oxidase-dependent generation of reactive oxygen species.

Panaxydol, a polyacetylenic compound derived from Panax ginseng roots, has been shown to inhibit the growth of cancer cells. In this study, we demonstrated that panaxydol induced apoptosis preferentially in transformed cells with a minimal effect on non-transformed cells. Furthermore, panaxydol was shown to induce apoptosis through an increase in intracellular Ca(2+) concentration ([Ca(2+)](i)), activation of JNK and p38 MAPK, and generation of reactive oxygen species (ROS) initially by NADPH oxidase and then by mitochondria. Panaxydol-induced apoptosis was caspase-dependent and occurred through a mitochondrial pathway. ROS generation by NADPH oxidase was critical for panaxydol-induced apoptosis. Mitochondrial ROS production was also required, however, it appeared to be secondary to the ROS generation by NADPH oxidase. Activation of NADPH oxidase was demonstrated by the membrane translocation of regulatory p47(phox) and p67(phox) subunits and shown to be necessary for ROS generation by panaxydol treatment. Panaxydol triggered a rapid and sustained increase of [Ca(2+)](i), which resulted in activation of JNK and p38 MAPK. JNK and p38 MAPK play a key role in activation of NADPH oxidase, since inhibition of their expression or activity abrogated membrane translocation of p47(phox) and p67(phox) subunits and ROS generation. In summary, these data indicate that panaxydol induces apoptosis preferentially in cancer cells, and the signaling mechanisms involve a [Ca(2+)](i) increase, JNK and p38 MAPK activation, and ROS generation through NADPH oxidase and mitochondria.

IL-4 inhibits proliferation of renal carcinoma cells by increasing the expression of p21WAF1 and IRF-1.

Interleukin (IL)-4 inhibits proliferation of several human cancer cell lines in vitro. Although IL-4 is known to regulate proliferation of lymphocytes by modulating p27KIP1 expression, the mechanism involved in the IL-4-induced growth inhibition of nonhematopoietic cancer cells has not been fully elucidated. Previously, we reported that IL-4 suppressed proliferation of human renal cell carcinoma (RCC) cell lines in vitro. Here, we show that IL-4 inhibits cell cycle progression at the G1 phase in Caki-1 cells by increasing the expression of p21WAF1 and interferon regulatory factor (IRF)-1, and decreasing the cyclin dependent kinase (CDK) 2 activity. Up-regulation of p21WAF1 and IRF-1 expression is transcriptional, but independent of p53. The levels of p21WAF1 and IRF-1 proteins were enhanced as early as 1 h after IL-4 treatment. CDK2 activity started to decline at 4 h after IL-4 treatment, and by 24 h, was approximately 50% of the control. Neither the protein expressions of p27KIP1 and p16INK4a, nor the phosphorylation level of pRb was changed. The importance of p21WAF1 and IRF-1 in the growth inhibition induced by IL-4 was confirmed by antisense oligonucleotide transfection. Both of p21WAF1 and IRF-1 antisense oligonucleotides prevented IL-4-mediated growth inhibition by approximately 30% compared to the respective sense oligonucleotides. In summary, our study indicated that p21WAF1 and IRF-1 mediate the growth inhibitory effect of IL-4 in human RCC cells.