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In the present study we used human breast cancer cell lines to assess the influence of ceramide and glucosylceramide (GC) on expression of MDR1, the multidrug resistance gene that codes for P-glycoprotein (P-gp), because GC has been shown to be a substrate for P-gp. Acute exposure (72 h) to C8-ceramide (5 microg/ml culture medium), a cell-permeable ceramide, increased MDR1 mRNA levels by 3- and 5-fold in T47D and in MDA-MB-435 cells, respectively. Acute exposure of MCF-7 and MDA-MB-231 cells to C8-GC (10 microg/ml culture medium), a cell-permeable analog of GC, increased MDR1 expression by 2- and 4- fold, respectively. Chronic exposure of MDA-MB-231 cells to C8-ceramide for extended periods enhanced MDR1 mRNA levels 45- and 390-fold at passages 12 and 22, respectively, and also elicited expression of P-gp. High-passage C8-ceramide-grown MDA-MB-231 (MDA-MB-231/C8cer) cells were more resistant to doxorubicin and paclitaxel. Incubation with [1-(14)C]C6-ceramide showed that cells converted short-chain ceramide into GC, lactosylceramide, and sphingomyelin. When challenged with 5 mug/ml [1-(14)C]C6-ceramide, MDA-MB-231, MDA-MB-435, MCF-7, and T47D cells took up 31, 17, 21, and 13%, respectively, and converted 82, 58, 62, and 58% of that to short-chain GC. Exposing cells to the GCS inhibitor, ethylenedioxy-P4, a substituted analog of 1-phenyl-2-hexadecanoylamino-3-pyrrolidino-1-propanol, prevented ceramide's enhancement of MDR1 expression. These experiments show that high levels of ceramide and GC enhance expression of the multidrug resistance phenotype in cancer cells. Therefore, ceramide's role as a messenger of cytotoxic response might be linked to the multidrug resistance pathway.

Color-coded duplex sonography was accurate in diagnosing the disease location, wall thickness, and extraintestinal inflammatory findings associated with Crohn disease, potentially placing it as the first-line imaging modality for the diagnosis of Crohn disease relapse and complications.

We present a possible important association of tumor necrosis factor-alpha inhibition (TNFa-i) and erectile function in a male patient with rheumatoid arthritis (RA). Long-standing, untreated RA may result in significant physical limitation and disability, however often overlooked is the association between RA and erectile and sexual dysfunction. Ischemic priapism is currently unrecognized as an adverse reaction associated with TNFa-i use and there have been no reported cases with adalimumab. Our patient, a 58-year-old Hispanic man, with sero-positive, erosive RA developed persistent priapism (17 days) despite multiple urologic interventions after initial adalimumab 40 mg administration. TNFa has recently been implicated as a potential factor in erectile dysfunction through its role in vascular reactivity. Excess TNFa, from active RA, may perturb intracavernosal smooth muscle and endothelial cell function; theoretically, TNFa inhibition may then causes excess local nitric oxide production and subsequent priapism. The potential role of TNFa-i in ED and risk for priapism is an important area for future study.

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