Citations

Adipose tissue lipolysis is at least in part stimulated by the sympathetic nervous system (SNS). Although there is a generalized decrease in SNS activity with fasting, the rate of lipolysis during fasting increases. The aim of this study was to determine whether there is an association between activation of sympathetic nerves innervating adipose tissue and the increase in lipolysis seen during fasting in humans. We used the isotope dilution technique to measure regional norepinephrine spillover from abdominal sc adipose tissue from seven healthy subjects before and after a 72-h fast. Our results showed a significant increase in adipose tissue spillover of norepinephrine (mean ± sem, 0.40 ± 0.09 vs. 1.08 ± 0.18 pmol·100 g−1·min−1, P < 0.05) and arterial norepinephrine concentrations (0.92 ± 0.10 vs. 1.23 ± 0.08 nmol·liter−1, P < 0.05) after the fast with no significant change in total body norepinephrine spillover, forearm norepinephrine spillover, epinephrine concentrations, or energy expenditure. We show for the first time, in humans, a selective regional increase in adipose tissue norepinephrine spillover in response to a 72-h fast and suggest that the SNS may play a greater role in the regulation of lipid metabolism during fasting than previously thought.

Abstract Osteoporosis is a serious complication of systemic glucocorticoid use. However, while glucocorticoids increase bone resorption in vitro and in vivo, the mechanism(s) of this effect are at present unclear. Recent studies have identified the osteoprotegerin (OPG) ligand (OPG-L) as the final effector of osteoclastogenesis, an action that is opposed by the soluble neutralizing receptor, OPG. Thus, we assessed glucocorticoid regulation of OPG and OPG-L in various human osteoblastic lineage cells using Northern analysis, RT-PCR, and ELISA. Dexamethasone inhibited constitutive OPG messenger RNA (mRNA) steady-state levels by 70–90% in primary (MS) and immortalized stromal cells (hMS), primary trabecular osteoblasts (hOB), immortalized fetal osteoblasts (hFOB), and osteosarcoma cells (MG-63). In hFOB cells, dexamethasone inhibited constitutive OPG mRNA steady-state levels in a dose- and time-dependent fashion by 90%, and also suppressed cytokine-stimulated OPG mRNA steady-state levels. Dexamethasone-induced inhibition of OPG mRNA levels was not affected by the protein synthesis inhibitor, cycloheximide, and was shown to be due to inhibition of OPG gene transcription using a nuclear run-on assay. Moreover, dexamethasone also dose dependently (10−10m–10−7m) inhibited constitutive OPG protein concentrations in the conditioned medium of hFOB cells from 2.59 ± 0.02 ng/ml (control) to 0.30 ± 0.01 ng/ml (88% inhibition; P < 0.001 by ANOVA). Concurrently, dexamethasone stimulated OPG-L mRNA steady-state levels in MS and hFOB cells by 2- and 4-fold, respectively. Treatment of murine marrow cultures with conditioned medium harvested from dexamethasone-treated MG-63 cells increased tartrate-resistant acid phosphatase (TRAP) activity by 54% (P < 0.005) compared with medium harvested from control-treated cells (in the presence of OPG-L and macrophage colony-stimulating factor). Moreover, dexamethasone (10−8m) promoted osteoclast formation in vitro, as assessed by a 2.5-fold increase of TRAP activity in cell lysates (P < 0.001) and the appearance of TRAP-positive multinucleated cells. Our data are thus consistent with the hypothesis that glucocorticoids promote osteoclastogenesis by inhibiting OPG and concurrently stimulating OPG-L production by osteoblastic lineage cells, thereby enhancing bone resorption.

Objective Multiple-valve (MUV) procedures currently exhibit higher operative mortality than do single-valve procedures, but a paucity of scientific information exists to explain the observation. This topic was examined using The Society of Thoracic Surgeons Database. Methods All patients in the The Society of Thoracic Surgeons data set undergoing valve surgery (except pulmonary valve and aortic root operations) from 1993 through 2007 were identified (N = 623,039). Baseline characteristics and postoperative outcomes were contrasted between all seven combinations of single-valve and MUV procedures involving aortic, mitral, and tricuspid valves. Seven independent logistic regression analyses were performed, based on the seven procedures, and multivariable risk factors for mortality were compared, with emphasis on single-valve versus MUV procedures. Results Baseline characteristics for MUV procedures (n = 67,926) shared many similarities to those for single-valve procedures (n = 555,113), including age, ejection fraction, and comorbidities. Preoperative renal failure, New York Heart Association class III to IV, nonelective presentation, and reoperation were slightly more common in MUV subsets, and coronary bypass was less frequent. Operative mortality was almost double for MUV as compared with single-valve procedures (10.7% vs 5.7%, P = 0.0001). Categorical predictors with the largest odds ratios for mortality were emergency status, renal failure, and second reoperation. However, predictors for mortality were generally consistent in order and magnitude between the single-valve and MUV subgroups. Conclusions Despite similarities in preoperative profiles of the patients undergoing single-valve and MUV procedures, mortality for MUV surgery remains considerably higher. Determinants of operative mortality and morbidity differ little across the procedural groups, and these findings serve as a benchmark for future studies, as well as suggest a continued search for explanations of poorer MUV outcomes.