p38 is a member of the mitogen-activated protein (MAP) kinase superfamily activated by stress signals and implicated in cellular processes involving inflammation and apoptosis. Unlike the extracellular signalregulated kinases (p42 and p44 MAP kinases), which are stimulated by insulin in many cell types, p38 activity is inhibited by insulin in postmitotic fetal neurons for which insulin is a potent survival factor (Heidenreich, K. A., and Kummer, J. L. (1996) J. Biol. Chem. 271, 9891-9894). These data suggested that insulin's effects on neuronal survival are mediated by inhibition of a p38-mediated apoptotic pathway. To better understand the relationship between p38 activity and cell survival, we induced apoptosis in two cell lines and examined the ability of insulin or a specific p38 inhibitor (a pyridinyl imidazole compound PD169316) to block p38 activity and cell death. In Rat-1 fibroblasts grown in the presence of serum, p38 activity was undetectable by immune complex assays, and the number of apoptotic cells was very low (<0.5%). After the removal of serum for 16 h, p38 activity was markedly elevated, and apoptosis increased by 14 -15-fold. Insulin (50 ng/ml) inhibited p38 activity by ϳ70% and blocked apoptosis by at least 80%. PD169316 also blocked p38 enzyme activity and apoptosis by approximately 80%. Similar results were obtained in differentiated PC12 cells that were deprived of nerve growth factor (NGF) for 16 h. In the presence of NGF, p38 activity and the number of apoptotic cells was very low (ϳ1.0%). After NGF withdrawal, p38 activity was selectively elevated and apoptosis increased to 15%. Both insulin and PD169316 markedly blocked the increase in p38 activity and apoptosis. The MAP kinase kinase inhibitor, PD98059, had no effect on apoptosis in Rat-1 fibroblasts and only partially blocked apoptosis in PC12 cells. PD98059 did not influence insulin's ability to block apoptosis, indicating that the extracellular signalregulated kinase pathway does not mediate insulin's survival effects. These data further support the role of p38 in cellular apoptosis and support the hypothesis that insulin promotes cell survival, at least in part, by inhibiting the p38 pathway. Mammalian MAP1 kinases are serine/threonine kinases that mediate intracellular signal transduction (for reviews, see Refs. 1-3). Members of the MAP kinase family share conserved structural domains and are activated by dual phosphorylation within a Thr-X-Tyr motif by specific upstream MAP kinase kinases. The mammalian MAP kinases can be subdivided into the extracellular signal-regulated kinases (ERKs), the Jun Nterminal kinases (JNKs), and the p38 MAP kinases. ERK1 and ERK2 are regulated by mitogens and growth factors via a Ras-dependent pathway involving sequential activation of a MAP kinase kinase kinase and a MAP kinase kinase (MEK) (4). The JNK and p38 kinases are activated by proinflammatory cytokines, hyperosmolarity, heat shock, endotoxin, and other cellular stresses (5-8). The activation cascades for JNK and p38 appear to be distinct. ...

Associate Editor Ash Tewari Editorial Board Ralph Clayman, USA Inderbir Gill, USA Roger Kirby, UK Mani Menon, USA OBJECTIVE To report the initial clinical cases of scarless, single port, transumbilical nephrectomy and pyeloplasty. PATIENTS AND METHODS One patient each underwent single port transumbilical nephrectomy and pyeloplasty using the R‐Port (Advanced Surgical Concepts), inserted through a transumbilical incision in both cases. Novel, specialized instruments, curved at the shaft, were used in addition to standard laparoscopic instrumentation. During pyeloplasty, a 2‐mm needle‐port (MiniSite, USSC, Norfolk, CT, USA) was also inserted, with no skin incision, to facilitate suturing. RESULTS Both procedures were technically successful with no extra‐umbilical skin incisions. The total operative duration was 3.4 and 2.7 h, the estimated blood loss 100 and 50 mL, and the hospital stay was 1 and 2 days for the nephrectomy and pyeloplasty, respectively. There were no complications during or after surgery. The total analgesia requirement was 100 and 150 mg of keterolac, and visual analogue pain scores were 8/10 and 2/10 at 1 and 2 days after surgery, respectively. CONCLUSIONS Transumbilical, single port nephrectomy and pyeloplasty are technically feasible. The first initial clinical experience of organ‐ablative and reconstructive renal surgery with this approach is reported.

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