Key pointsr Exercise acutely increases the concentrations of metabolites and hormones such as growth hormone (GH) and, to a lesser extent, insulin-like growth factor 1 (IGF-1); however, the biological function of this response is unclear.r Pharmacological administration of these hormones stimulates collagen synthesis in muscle and tendon; however, whether the post-exercise biochemical milieu has a similar action is unknown.r Treating engineered ligaments with serum obtained from young healthy men after exercise resulted in more collagen and improved tensile strength over those treated with serum from resting men.r Further, we show that the increase in collagen induced by post-exercise serum (i) is not reproduced by treatment with recombinant GH or IGF-1, and (ii) is associated with the activation of PI3 kinase/mTORC1 and ERK1/2 signalling.Abstract Exercise stimulates a dramatic change in the concentration of circulating hormones, such as growth hormone (GH), but the biological functions of this response are unclear. Pharmacological GH administration stimulates collagen synthesis; however, whether the post-exercise systemic milieu has a similar action is unknown. We aimed to determine whether the collagen content and tensile strength of tissue-engineered ligaments is enhanced by serum obtained post-exercise. Primary cells from a human anterior cruciate ligament (ACL) were used to engineer ligament constructs in vitro. Blood obtained from 12 healthy young men 15 min after resistance exercise contained GH concentrations that were ß7-fold greater than resting serum (P < 0.001), whereas IGF-1 was not elevated at this time point (P = 0.21 vs. rest). Ligament constructs were treated for 7 days with medium supplemented with serum obtained at rest (RestTx) or 15 min post-exercise (ExTx), before tensile testing and collagen content analysis. Compared with RestTx, ExTx enhanced collagen content (+19%; 181 ± 33 vs. 215 ± 40 μg per construct P = 0.001) and ligament mechanical properties -maximal tensile load (+17%, P = 0.03 vs. RestTx) and ultimate tensile strength (+10%, P = 0.15 vs. RestTx). In a separate set of engineered ligaments, recombinant IGF-1, but not GH, enhanced collagen content and mechanics. Bioassays in 2D culture revealed that acute treatment with post-exercise serum activated mTORC1 and ERK1/2. In conclusion, the post-exercise biochemical milieu, but not recombinant GH, enhances collagen content and tensile strength of engineered ligaments, in association with mTORC1 and ERK1/2 activation.

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Morphine administered as a subcutaneous implant inhibits the initial increase in cytoplasmic free-calcium [Ca2+]i induced by mitogens in mouse splenocytes. This effect was not reproduced by incubation of splenocytes with morphine (10(-8)-10(-4) M). Analysis of splenocyte subpopulations demonstrates that this effect was manifest in both B and T cells. However, within T cell subpopulations, CD4+ but not CD8+ cells were affected. Adrenalectomy abolished this effect of morphine in CD4+ T but not CD4-, CD8- spleen cells (most likely Thy 1.2- B cells). Moreover, simultaneous administration of the opiate antagonist naltrexone blocked the effect of morphine in CD4-, CD8- spleen cells, but not in CD4+ T cells. These data indicate that the effects of morphine on mitogen-stimulated increase in [Ca2+]i may be mediated through distinct glucocorticoid-dependent and -independent mechanisms. The morphine-induced inhibition of an increase in [Ca2+]i in immune cells reported here may be an early event mediating opiate-induced immunosuppression.

Since 1992 many changes have occurred in the regulations, guidelines, and processes governing the FDA, the biomedical industry, other stakeholders, and their interactions. Of particular importance, the FDA Amendments Act of 2007 made public advisory committee meetings mandatory for new molecular entities and devices requiring clinical trials, unless the necessity of convening such a meeting has been waived by the FDA commissioner. For effective preparation, product teams must now assume that such a public review will be necessary, even if not initially specified by the FDA's review team. To understand what advisory committee members actually want from sponsors to enable their informed participation, the authors surveyed 101 current or former members of one of the FDA's public biomedical advisory committees within the Center for Biologics Evaluation and Research, the Center for Drug Evaluation and Research, and the Center for Devices and Radiological Health. Their goal was to understand more fully their preparatory practices and preferences regarding materials provided by the sponsor and the FDA, advisory committee presentations, and Q&A sessions. The findings suggest that sponsors need to be clear, concise, and scientifically credible, and that some advisory committee members need to be more uniformly prepared.