Urinary 2- to 16α-hydroxyestrone ratio did not change with cruciferous vegetable intake in premenopausal women.

The mass ratio of urinary 2-hydroxyestrone to 16-α-hydroxyestrone (2:16) is hypothesized as a biomarker of breast cancer risk in premenopausal women, with higher ratios being theoretically protective. Cruciferous vegetable intake has been associated with higher urinary 2:16 in some studies. We investigated whether a whole-food supplement made from dried Brussels sprouts and kale would increase urinary 2:16 in comparison with placebo or cruciferous vegetables in women. This randomized, parallel arm, placebo-controlled, partly blinded study included 78 healthy premenopausal women (38-50 y) with screening urinary 2:16 ≤3.0. Subjects received either six capsules containing 550 mg dried Brussels sprouts and kale per capsule, 40 g daily alternating broccoli or Brussels sprouts, or placebo for eight weeks. Urinary 2:16 and creatinine were measured at baseline, four, and eight weeks. Intent-to-treat repeated measures-ANOVA with multiple imputation (n=100) for missing values identified no treatment effect (P=0.9) or treatment-by-time interaction (P=0.6); however, a significant time effect was noted (P=0.02). Per-protocol analyses including complete cases found no treatment effect (P=1) or treatment-by-time interaction (P=0.6); however, the significant time effect remained (P=0.03). Restricting analysis to subjects with >80% compliance maintained the time effect (P=0.02). Using Pearson correlations, android-pattern and android:gynoid fat were predictive of change (P≤0.05). In conclusion, neither cruciferous supplements nor an added vegetable serving altered urinary 2:16 in premenopausal women with eight weeks treatment. This ratio did vary with time, which is important for designing future trials.

Selective Ablation of Dehydrodolichyl Diphosphate Synthase in Murine Retinal Pigment Epithelium (RPE) Causes RPE Atrophy and Retinal Degeneration.

Patients with certain defects in the dehydrodolichyl diphosphate synthase (DHDDS) gene (RP59; OMIM #613861) exhibit classic symptoms of retinitis pigmentosa, as well as macular changes, suggestive of retinal pigment epithelium (RPE) involvement. The DHDDS enzyme is ubiquitously required for several pathways of protein glycosylation. We wish to understand the basis for selective ocular pathology associated with certain DHDDS mutations and the contribution of specific ocular cell types to the pathology of mutant Dhdds-mediated retinal degeneration. To circumvent embryonic lethality associated with Dhdds knockout, we generated a Cre-dependent knockout allele of murine Dhdds (Dhddsflx/flx). We used targeted Cre expression to study the importance of the enzyme in the RPE. Structural alterations of the RPE and retina including reduction in outer retinal thickness, cell layer disruption, and increased RPE hyper-reflectivity were apparent at one postnatal month. At three months, RPE and photoreceptor disruption was observed non-uniformly across the retina as well as RPE transmigration into the photoreceptor layer, external limiting membrane descent towards the RPE, and patchy loss of photoreceptors. Functional loss measured by electroretinography was consistent with structural loss showing scotopic a- and b-wave reductions of 83% and 77%, respectively, at three months. These results indicate that RPE dysfunction contributes to DHDDS mutation-mediated pathology and suggests a more complicated disease mechanism than simply disruption of glycosylation.

Evaluation of Methadone-Induced QTc Prolongation in a Veteran Population.

Understanding the effects of methadone on the QTc interval in a veteran patient population using the drug at lower doses for pain may help clinicians develop strategies and protocols for safe use.