The ups and downs of bone-marrow adipose tissue in space.

Knowledge is rapidly accumulating on basic roles and modulation of bone-marrow adipose tissue (BMAT). Among key modulators are physical forces on bones as exerted by gravity and exercise. Studying humans returning from space has revealed that, in addition to physical forces, local energetics within the bone marrow can play modulatory roles.

Bone marrow adiposity modulation after long duration spaceflight in astronauts.

Space travel requires metabolic adaptations from multiple systems. While vital to bone and blood production, human bone marrow adipose (BMA) tissue modulation in space is unknown. Here we show significant downregulation of the lumbar vertebrae BMA in 14 astronauts, 41 days after landing from six months' missions on the International Space Station. Spectral analyses indicated depletion of marrow adipose reserves. We then demonstrate enhanced erythropoiesis temporally related to low BMA. Next, we demonstrated systemic and then, local lumbar vertebrae bone anabolism temporally related to low BMA. These support the hypothesis that BMA is a preferential local energy source supplying the hypermetabolic bone marrow postflight, leading to its downregulation. A late postflight upregulation abolished the lower BMA of female astronauts and BMA modulation amplitude was higher in younger astronauts. The study design in the extreme environment of space can limit these conclusions. BMA modulation in astronauts can help explain observations on Earth.

Bone Marrow Reconversion With Reambulation: A Prospective Clinical Trial.

METHODS: In a prospective clinical trial, 20 healthy men participated in a 60-day, 6-degree head-down tilt bed rest study. Serial 3-T magnetic resonance (MR) imaging measures of the lumbar spine were performed at baseline, after 57 days of bed rest, and at 30, 360, and 720 days of reambulation (100 MR imaging scans). Proton density with and without fat saturation, 2-point Dixon, and single-voxel MR spectroscopy techniques were used to assess bone marrow composition (300 measures). Erythropoiesis was measured using hematocrit, reticulocyte, and ferritin. Also, participants randomly received either a nutritional intervention composed of polyphenols, omega-3, vitamin E, and selenium or a normal diet. RESULTS: Thirty days of reambulation after 60 days of bed rest caused a marked decrease of the mean lumbar vertebral fat fraction (VFF) (-9.2 ± 1.6 percentage points, -8.0 ± 1.3 percentage points, and -12.7 ± 1.2 percentage points compared with baseline using proton density, Dixon, MR spectroscopy, respectively; all 3, P < 0.05). Reambulation also decreased the fat saturation index (-5.3 ± 1.1 percentage points compared with baseline; P < 0.05). These coincided with lower hematocrit and ferritin and with increased reticulocytes at reambulation day 13 compared with baseline (all 3, P < 0.05). After 57 days of bed rest, the VFF was unchanged from baseline (all 3 MR techniques, P > 0.05); reambulation for 2 years returned the lumbar VFF to baseline values. INTERPRETATION: This longitudinal trial established that 30 days of reambulation after 60 days of bed rest constituted a powerful stimulus for bone marrow reconversion. In this model, the enhanced erythropoiesis coupled with preferential consumption of fatty acids from regulated marrow adipose tissue to supply energy for erythropoiesis and bone anabolism may explain the lumbar vertebrae reconversion. These results will help interpreting bone marrow signal in ambulatory patients after long periods of bed rest.

The ß-blocker Nebivolol Is a GRK/ß-arrestin biased agonist.

Nebivolol, a third generation ß-adrenoceptor (ß-AR) antagonist (ß-blocker), causes vasodilation by inducing nitric oxide (NO) production. The mechanism via which nebivolol induces NO production remains unknown, resulting in the genesis of much of the controversy regarding the pharmacological action of nebivolol. Carvedilol is another ß-blocker that induces NO production. A prominent pharmacological mechanism of carvedilol is biased agonism that is independent of Gαs and involves G protein-coupled receptor kinase (GRK)/ß-arrestin signaling with downstream activation of the epidermal growth factor receptor (EGFR) and extracellular signal-regulated kinase (ERK). Due to the pharmacological similarities between nebivolol and carvedilol, we hypothesized that nebivolol is also a GRK/ß-arrestin biased agonist. We tested this hypothesis utilizing mouse embryonic fibroblasts (MEFs) that solely express ß2-ARs, and HL-1 cardiac myocytes that express ß1- and ß2-ARs and no detectable ß3-ARs. We confirmed previous reports that nebivolol does not significantly alter cAMP levels and thus is not a classical agonist. Moreover, in both cell types, nebivolol induced rapid internalization of ß-ARs indicating that nebivolol is also not a classical ß-blocker. Furthermore, nebivolol treatment resulted in a time-dependent phosphorylation of ERK that was indistinguishable from carvedilol and similar in duration, but not amplitude, to isoproterenol. Nebivolol-mediated phosphorylation of ERK was sensitive to propranolol (non-selective ß-AR-blocker), AG1478 (EGFR inhibitor), indicating that the signaling emanates from ß-ARs and involves the EGFR. Furthermore, in MEFs, nebivolol-mediated phosphorylation of ERK was sensitive to pharmacological inhibition of GRK2 as well as siRNA knockdown of ß-arrestin 1/2. Additionally, nebivolol induced redistribution of ß-arrestin 2 from a diffuse staining pattern into more intense punctate spots. We conclude that nebivolol is a ß2-AR, and likely ß1-AR, GRK/ß-arrestin biased agonist, which suggests that some of the unique clinically beneficial effects of nebivolol may be due to biased agonism at ß1- and/or ß2-ARs.

A taxonomy for user-healthcare robot interaction.

This paper evaluates existing taxonomies aimed at characterizing the interaction between robots and their users and modifies them for health care applications. The modifications are based on existing robot technologies and user acceptance of robotics. Characterization of the user, or in this case the patient, is a primary focus of the paper, as they present a unique new role as robot users. While therapeutic and monitoring-related applications for robots are still relatively uncommon, we believe they will begin to grow and thus it is important that the spurring relationship between robot and patient is well understood.