The epithelial Na ؉ channel (ENaC) plays a critical role in Na ؉ absorption in the kidney and other epithelia. Mutations in the C terminus of the ␤ or ␥ENaC subunits increase renal Na ؉ absorption, causing Liddle's syndrome, an inherited form of hypertension. These mutations delete or disrupt a PY motif that was recently shown to interact with Nedd4, a ubiquitin-protein ligase expressed in epithelia. We found that Nedd4 inhibited ENaC when they were coexpressed in Xenopus oocytes. Liddle's syndrome-associated mutations that prevent the interaction between Nedd4 and ENaC abolished inhibition, suggesting that a direct interaction is required for inhibition by Nedd4. Inhibition also required activity of a ubiquitin ligase domain within the C terminus of Nedd4. Nedd4 had no detectable effect on the single channel properties of ENaC. Rather, Nedd4 decreased cell surface expression of both ENaC and a chimeric protein containing the C terminus of the ␤ subunit. Decreased surface expression resulted from an increase in the rate of degradation of the channel complex. Thus, interaction of Nedd4 with the C terminus of ENaC inhibits Na ؉ absorption, and loss of this interaction may play a role in the pathogenesis of Liddle's syndrome and other forms of hypertension.

To estimate the limits of dose escalation for prostate cancer as a function of planning target volume (PTV) margins, the maximum achievable dose (MAD) was determined through iterative plan optimizations from data sets of 18 patients until the dose constraints for rectum, bladder and PTV could no longer be met. PTV margins of 10, 5 and 3 mm yielded a mean MAD of 83.0 Gy (range, 73.8-108.0 Gy), 113.1 Gy (range, 90.0-151.2 Gy) and 135.9 Gy (range, 102.6-189.0 Gy), respectively. All comparisons of MAD among margin groups were statistically significant (P < 0.001). Comparison of prostate volumes of 30-50 mL (n = 8) with volumes of 51-70 mL (n = 7) and 71-105 mL (n = 3) showed an inverse relationship with MAD. Decreases in PTV margin significantly decreased the PTV overlap of the rectum (P < 0.001 for all margin comparisons). With decreases in the PTV margin and maintenance of identical dose constraints, doses well above those currently prescribed for treatment of localized prostate cancer appear feasible. However, the dose escalation suggested by these findings is a theoretical estimate, and additional dose constraints will likely be necessary to limit toxicity to normal tissue.

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Purpose To examine specific prostate and urethra dimensions and prostate shape to facilitate the design of a transurethral ultrasonographic imaging device. Methods and Materials Computed tomographic (CT) data sets were retrospectively evaluated from 191 patients who underwent permanent prostate brachytherapy at our institution. The prostate, rectum, urethra, and bladder were each segmented with imaging software. Collected data and calculations included prostate volume at specific distances from the urethra and rectum, distances from seeds to urethra (SU), distances from seeds to rectum (SR), prostate length, and curvilinear prostatic urethra length. Results CT-based, postimplant mean prostate volume was 49 cm3 (range, 22–106 cm3). Mean prostate length was 4.5 cm (range, 3.1–6.0 cm). The mean curvilinear length of the prostatic urethra was 4.5 cm. The mean (standard deviation) prostatic urethra bend was 29.0° (12.2°). The mean surface distance from the prostate to the urethra was 2.9 cm and from the prostate to the rectum, 4.6 cm (p<.001, paired t test). The mean SU distance was 1.6 cm, and the mean SR distance was 2.3 cm (p<.001). In the largest prostate, the mean SU distance was 3.9 cm and the mean SR distance was 6.0 cm. Conclusions A urethral imaging device for prostate brachytherapy and other minimally invasive prostate therapies should ideally have a 6-cm imaging field of view to image all the prostates in this series in a single image. The mean distance from the urethra to seeds in PPB is less than 70% of the mean seed distance to the rectum.

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