Regulation of cell survival by sphingosine-1-phosphate receptor S1P1 via reciprocal ERK-dependent suppression of Bim and PI-3-kinase/protein kinase C-mediated upregulation of Mcl-1.

Although the ability of bioactive lipid sphingosine-1-phosphate (S1P) to positively regulate anti-apoptotic/pro-survival responses by binding to S1P1 is well known, the molecular mechanisms remain unclear. Here we demonstrate that expression of S1P1 renders CCL39 lung fibroblasts resistant to apoptosis following growth factor withdrawal. Resistance to apoptosis was associated with attenuated accumulation of pro-apoptotic BH3-only protein Bim. However, although blockade of extracellular signal-regulated kinase (ERK) activation could reverse S1P1-mediated suppression of Bim accumulation, inhibition of caspase-3 cleavage was unaffected. Instead S1P1-mediated inhibition of caspase-3 cleavage was reversed by inhibition of phosphatidylinositol-3-kinase (PI3K) and protein kinase C (PKC), which had no effect on S1P1 regulation of Bim. However, S1P1 suppression of caspase-3 was associated with increased expression of anti-apoptotic protein Mcl-1, the expression of which was also reduced by inhibition of PI3K and PKC. A role for the induction of Mcl-1 in regulating endogenous S1P receptor-dependent pro-survival responses in human umbilical vein endothelial cells was confirmed using S1P receptor agonist FTY720-phosphate (FTY720P). FTY720P induced a transient accumulation of Mcl-1 that was associated with a delayed onset of caspase-3 cleavage following growth factor withdrawal, whereas Mcl-1 knockdown was sufficient to enhance caspase-3 cleavage even in the presence of FTY720P. Consistent with a pro-survival role of S1P1 in disease, analysis of tissue microarrays from ER(+) breast cancer patients revealed a significant correlation between S1P1 expression and tumour cell survival. In these tumours, S1P1 expression and cancer cell survival were correlated with increased activation of ERK, but not the PI3K/PKB pathway. In summary, pro-survival/anti-apoptotic signalling from S1P1 is intimately linked to its ability to promote the accumulation of pro-survival protein Mcl-1 and downregulation of pro-apoptotic BH3-only protein Bim via distinct signalling pathways. However, the functional importance of each pathway is dependent on the specific cellular context.

Haemoperitoneum from benign ileal leiomyoma.

Intraluminal gastrointestinal haemorrhage is a common feature of benign leiomyoma of the small bowel. A case is reported of an ileal leiomyoma which caused free intraperitoneal haemorrhage. It is believed that such an occurrence has not been reported previously.

Comparative biliary excretion of cephalosporins in normal and partially hepatectomized rats.

The biliary excretion of six cephalosporins was examined in normal and partially hepatectomized rats. Cefamandole, cefazolin, cefuroxime, cefoxitin, and cephradine were excreted well in normal animals. In partially hepatectomized rats, the cumulative percentage of excretion reached only 11 to 36.8% of the control levels. Cephaloridine was excreted poorly in both groups.

The office retinal electrophysiology laboratory.

The "Visual Retinal Profile" can be obtained in the complete office evaluation of patients with night vision disorders, unexplained poor visual acuity, or undiagnosed retinal and/or choroidal diseases. This profile allows later follow-up evaluations and comparisons of previous tests to document improvement or progression of disease. The profile consists of the usual ophthalmologic evaluation plus color vision testing Amsler grid, stereoacuity, visual fields, electroretinogram (ERG), and electrooculogram (EOG). This entire set of tests, though time consuming, can be performed in the office by an ophthalmic assistant and greatly add to the ophthalmologists ability to evaluate and diagnose subtle retinal and/or choroidal diseases. A portable ERG/EOG and light source will be described that can be used in the office, clinic, nursing home, or operating room by trained office personnel.

Use of the ERG and EOG in evaluating the effect of sleep deprivation on visual function in flying personnel.

The electroretinogram (ERG) and electrooculogram (EOG) are electrophysiological tests employed in ophthalmology to diagnose degeneration or injury to the outer half of the retina, including the rods and cones of the visual system. This pilot study was undertaken to determine if sleep deprivation of more than 24 h in rated flying personnel may show an abnormality in retinal function as measured by the ERG and/or EOG. This may give insight to the visual function in flying personnel on deployment or other long missions where uninterrupted sleep may be a problem. The results of this study showed that some subjects deprived of sleep exhibited a statistically significant variance in their EOG ratios as compared to a nondeprived control group. No significant changes in ERG were detected. Principles and theory of electrophysiological testing in ophthalmology are presented.