Hereditary hemochromatosis disrupts uric acid homeostasis and causes hyperuricemia via altered expression/activity of xanthine oxidase and ABCG2.

Hereditary hemochromatosis (HH) is mostly caused by mutations in the iron-regulatory gene HFE. The disease is associated with iron overload, resulting in liver cirrhosis/cancer, cardiomegaly, kidney dysfunction, diabetes, and arthritis. Fe2+-induced oxidative damage is suspected in the etiology of these symptoms. Here we examined, using Hfe-/- mice, whether disruption of uric acid (UA) homeostasis plays any role in HH-associated arthritis. We detected elevated levels of UA in serum and intestine in Hfe-/- mice compared with controls. Though the expression of xanthine oxidase, which generates UA, was not different in liver and intestine between wild type and Hfe-/- mice, the enzymatic activity was higher in Hfe-/- mice. We then examined various transporters involved in UA absorption/excretion. Glut9 expression did not change; however, there was an increase in Mrp4 and a decrease in Abcg2 in Hfe-/- mice. As ABCG2 mediates intestinal excretion of UA and mutations in ABCG2 cause hyperuricemia, we examined the potential connection between iron and ABCG2. We found p53-responsive elements in hABCG2 promoter and confirmed with chromatin immunoprecipitation that p53 binds to this promoter. p53 protein was reduced in Hfe-/- mouse intestine. p53 is a heme-binding protein and p53-heme complex is subjected to proteasomal degradation. We conclude that iron/heme overload in HH increases xanthine oxidase activity and also promotes p53 degradation resulting in decreased ABCG2 expression. As a result, systemic UA production is increased and intestinal excretion of UA via ABCG2 is decreased, causing serum and tissue accumulation of UA, a potential factor in the etiology of HH-associated arthritis.

PROTOCOL: The effectiveness of wilderness therapy and adventure learning in reducing anti-social and offending behaviour in children and young people at risk of offending.

This is the protocol for a Campbell systematic review. The objectives are as follows. The review will address the following research questions: (1) What are the long- and short-term effects of wilderness therapy and adventure learning on anti-social behaviour and violent and other offending behaviour? What factors explain any heterogeneity (i.e., moderate) these effects. What are the long- and short-term effects of wilderness therapy and adventure learning on intermediate mental health and behaviour outcomes such as social skills and self-regulation? What factors explain any heterogeneity (i.e., moderate) these effects? Factors such as setting (indoor/outdoor), quality of relationship with counsellors and the degree of the challenge element involved are important moderators of these effects, and help explain any observed heterogeneity across studies (2) What are the barriers and facilitators affecting the successful implementation of wilderness therapy and adventure learning programmes? (3) Are wilderness therapy and adventure learning interventions cost effective?

Complete resolution of arrhythmia-induced hydrops fetalis in utero.

A 21-year-old G3P2011 Caucasian woman at 27 weeks' gestation presented with fetal tachyarrhythmia between 240 and 270 beats per minute. Fetal supraventricular tachycardia, abdominal ascites, pleural effusion and pericardial effusion indicated hydrops fetalis. Management with digoxin and flecainide converted the fetus to sinus rhythm and resolved the ascites and pleural effusion within 4 days of treatment. Flecainide was discontinued at 31 weeks' gestation due to elevated liver enzymes. Intrahepatic cholestasis was treated with ursodiol. Caesarean section was performed at 37 weeks' gestation. Neonatal echocardiogram revealed a bicuspid aortic valve with mild regurgitation and a patent foramen ovale, and the infant showed no subsequent evidence of tachyarrhythmia or hydrops after delivery. Treatment of hydrops fetalis in the antenatal period is complex, and early diagnosis and treatment can quickly resolve supraventricular tachycardia-induced hydrops fetalis.