The effect of gonadal and adrenal steroid therapy on skeletal health in adolescents and young women with anorexia nervosa

Anorexia nervosa (AN) is characterized by subnormal estrogen and dehydroepiandrosterone (DHEA) levels. We sought to determine whether the combination of DHEA + estrogen/progestin is superior to placebo in preserving skeletal health over 18 months in AN. Females with AN, aged 13 to 27 years, were recruited for participation in this double-blind, placebo-controlled, randomized trial. Ninety-four subjects were randomized, of whom 80 completed baseline assessments and received either study drug (oral micronized DHEA 50 mg + 20 μg ethinyl estradiol/0.1 mg levonorgestrel combined oral contraceptive pill [COC] daily; n = 43) or placebo (n = 37). Serial measurements of areal bone mineral density (aBMD), bone turnover markers, and serum hormone concentrations were obtained. Sixty subjects completed the 18-month trial. Spinal and whole-body aBMD z scores were preserved in the DHEA + COC group, but decreased in the placebo group (comparing trends, P = .008 and P = .001, respectively). Bone turnover markers initially declined in subjects receiving DHEA + COC and then returned to baseline. No differences in body composition, adverse effects of therapy, or alterations in biochemical safety parameters were observed. Combined therapy with DHEA + COC appears to be safe and effective for preventing bone loss in young women with AN, whereas placebo led to decreases in aBMD. Dehydroepiandrosterone + COC may be safely used to preserve bone mass as efforts to reverse the nutritional, psychological, and other hormonal components of AN are implemented.     

Molecular basis of Tank-binding kinase 1 activation by transautophosphorylation

Tank-binding kinase (TBK)1 plays a central role in innate immunity: it serves as an integrator of multiple signals induced by receptor-mediated pathogen detection and as a modulator of IFN levels. Efforts to better understand the biology of this key immunological factor have intensified recently as growing evidence implicates aberrant TBK1 activity in a variety of autoimmune diseases and cancers. Nevertheless, key molecular details of TBK1 regulation and substrate selection remain unanswered. Here, structures of phosphorylated and unphosphorylated human TBK1 kinase and ubiquitin-like domains, combined with biochemical studies, indicate a molecular mechanism of activation via transautophosphorylation. These TBK1 structures are consistent with the tripartite architecture observed recently for the related kinase IKKβ, but domain contributions toward target recognition appear to differ for the two enzymes. In particular, both TBK1 autoactivation and substrate specificity are likely driven by signal-dependent colocalization events.     

Anti‐gravity treadmills are effective in reducing knee forces

Lower body positive pressure (LBPP) treadmills permit significant unweighting of patients and have the potential to enhance recovery following lower limb surgery. We determined the efficacy of an LBPP treadmill in reducing knee forces in vivo. Subjects, implanted with custom electronic tibial prostheses to measure forces in the knee, were tested on a treadmill housed within a LBPP chamber. Tibiofemoral forces were monitored at treadmill speeds from 1.5 mph (0.67 m/s) to 4.5 mph (2.01 m/s), treadmill incline from ?10° to +10°, and four treadmill chamber pressure settings adjusted to decrease net treadmill reaction force from 100% to 25% of the subject's body weight (BW). The peak axial tibiofemoral force ranged from 5.1 times BW at a treadmill speed of 4.5 mph (2.01 m/s) and a pressure setting of 100% BW to 0.8 times BW at 1.5 mph (0.67 m/s) and a pressure setting of 25% BW. Peak knee forces were significantly correlated with walking speed and treadmill reaction force (R² = 0.77, p = 0.04). The LBPP treadmill might be an effective tool in the rehabilitation of patients following lower‐extremity surgery. The strong correlation between tibiofemoral force and walking speed and treadmill reaction forces allows for more precisely achieving the target knee forces desired during early rehabilitation. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31: 672–679, 2013