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Abstract-Epidemiologic studies, animal models, and preliminary clinical trials in children implicate uric acid in the development of essential hypertension. Controversy remains as to whether the observations indicate a general mechanism or a surrogate phenomenon. We sought to determine whether uric acid is a causative mediator of increased blood pressure (BP) and impaired vascular compliance. We report a randomized, double-blinded, placebo-controlled trial comparing 2 mechanisms of urate reduction with placebo in prehypertensive, obese, adolescents, aged 11 to 17 years. Subjects were randomized to the xanthine oxidase inhibitor, allopurinol, uricosuric, probenecid, or placebo. Subjects treated with urate-lowering therapy experienced a highly significant reduction in BP. In clinic systolic BP fell 10.2 mm Hg and diastolic BP fell 9.0 mm Hg in treated patients compared with a rise of 1.7 mm Hg and 1.6 mm Hg systolic and diastolic BP, respectively in patients on placebo. Urate-lowering therapy also resulted in significant reduction in systemic vascular resistance. These data indicate that, at least in adolescents with prehypertension, uric acid causes increased BP that can be mitigated by urate lowering therapy. (Hypertension. 2012;60:1148-1156.)

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Obesity increases risk of endometrial cancer through dysregulation of estrogen and insulin signaling. The primary aim of this study was to evaluate the impact of metformin or lifestyle intervention on endometrial proliferation in postmenopausal obese women. Secondary aims included evaluating obesity-related biomarkers and adverse events experienced. Obese, postmenopausal women with prediabetes were randomized into four groups for a 16-week intervention using a 2 (metformin 1700 mg/day vs. placebo) × 2 (lifestyle intervention vs. no lifestyle intervention) factorial design. Pre- and postintervention endometrial proliferation, anthropometrics, body composition, and serum biomarkers (sex hormones, sex hormone binding globulin, IGF-I, adiponectin, omentin, insulin, glucose, and others) were assessed. Data were analyzed with linear regression models and false-discovery rate correction. Of 576 women approached for the study, 52 attended initial screening, 29 were eligible and randomized, and 26 completed the study. Lifestyle intervention resulted in significant loss of weight (-4.23 kg, = 0.006) and total fat mass (-3.23 kg, < 0.001). Participants receiving metformin lost 3.43 kg of weight ( = 0.023), but this was not statistically significant after multiple comparisons adjustment controlling false-discovery rate to 10%. Endometrial proliferation was low at baseline (mean 7.1%) and remained unchanged by 16 weeks, but included substantial variability. Metformin and lifestyle intervention produced minor changes to serum biomarkers. Lifestyle intervention produced the most significant changes in weight and body composition. While it is known that obese postmenopausal women are at increased risk for endometrial cancer, improved biomarkers are needed to stratify risk and test prevention strategies, particularly at the endometrial tissue level. .

Recent evidence from adult hemodialysis (HD) patient studies reveal improved biochemical control and reported health-related quality of life after transition from conventional thrice weekly to daily home maintenance HD treatment. Published pediatric frequent dialysis experiences demonstrate similar improvement but all used conventional HD machines, which employ a treated municipal water supply, thereby frequently exposing patients to proinflammatory components. We report our pediatric experience with six-times-weekly HD using the NxStage system, which uses sterile dialysis fluid to provide dialysis in the home or center setting. Four patients (weight range 38-61.4 kg) completed the 16-week study. Patients exhibited progressive reductions in casual pretreatment systolic and diastolic blood pressures, discontinuation of antihypertensive medications, and decreased blood pressure load by ambulatory blood pressure monitoring. Mean serum phosphorus improved without change in phosphorus binder medication, and all three patients with a normalized protein catabolic rate <1 g/kg per day at the beginning of the study improved to a normalized protein catabolic rate (nPCR) of >1.1 g/kg per day. Patients reported no adverse effects. Variable changes in proinflammatory cytokine levels were observed. We suggest that frequent HD with the NxStage system be considered for children who would benefit from home-based maintenance dialysis.

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1551 Background: Obesity significantly increases risk of endometrial cancer (EC) through systemic metabolic effects and local tissue action, driven by estrogen and dysregulated insulin signaling. EC is most commonly diagnosed in postmenopausal women. Metformin, an antidiabetes drug, and lifestyle intervention were evaluated for effects on endometrial proliferation and serum biomarkers, in parallel with weight loss. Methods: Obese postmenopausal women were randomized into 4 groups for a 16 week intervention using a 2 (metformin 1700 mg/day vs placebo) x 2 (lifestyle intervention vs no lifestyle intervention) factorial design based on the Diabetes Prevention Program. Pre- and post-intervention endometrial biopsies were assessed for proliferation (% Ki67+). Body weight and serum markers were measured pre- and post-intervention (estrone, FSH, DHEA-S, SHBG, IGF-1, adiponectin, omentin, insulin, glucose, A1C, ALT, triglycerides, and others). Results: Of 576 women approached for the study, 29 women were randomized and 26 completed the study. Similar adherence was seen for placebo and metformin, with 88% and 94% of doses taken, respectively. Adverse events were grade 1 or 2, most commonly flatulence, headache, and diarrhea. Metformin+lifestyle group lost the most weight (-7.4%), followed by lifestyle (-5.2%), metformin only (-3.1%), and placebo (+0.1%). Endometrial proliferation was not changed. Overall proliferation was low (7.1% at baseline) with substantial variability even in this postmenopausal cohort. Biopsies produced limited endometrium, precluding evaluation of other tissue markers. Metformin significantly increased serum DHEA (p = 0.002). SHBG increased (p = 0.031) and insulin decreased with lifestyle intervention (p = 0.035) but were not statistically significant after multiple comparisons correction. Conclusions: Metformin and lifestyle intervention produced positive changes in serum markers and weight loss. While it is known that obese postmenopausal women are at increased risk for EC, improved biomarkers are needed to stratify risk and test prevention strategies, particularly at the endometrial tissue level. Clinical trial information: NCT01697566.

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