The signal transducer and activator of transcription, STAT5b, has been implicated in signal transduction pathways for a number of cytokines and growth factors, including growth hormone (GH). Pulsatile but not continuous GH exposure activates liver STAT5b by tyrosine phosphorylation, leading to dimerization, nuclear translocation, and transcriptional activation of the STAT, which is proposed to play a key role in regulating the sexual dimorphism of liver gene expression induced by pulsatile plasma GH. We have evaluated the importance of STAT5b for the physiological effects of GH pulses using a mouse gene knockout model. STAT5b gene disruption led to a major loss of multiple, sexually differentiated responses associated with the sexually dimorphic pattern of pituitar y GH secretion. Malecharacteristic body growth rates and male-specific liver gene expression were decreased to wild-type female levels in STAT5b ؊͞؊ males, while female-predominant liver gene products were increased to a level intermediate between wild-type male and female levels. Although these responses are similar to those observed in GH-deficient Little mice, STAT5b ؊͞؊ mice are not GH-deficient, suggesting that they may be GH pulseresistant. Indeed, the dwarfism, elevated plasma GH, low plasma insulin-like growth factor I, and development of obesity seen in STAT5b ؊͞؊ mice are all characteristics of Laron-type dwarfism, a human GH-resistance disease generally associated with a defective GH receptor. The requirement of STAT5b to maintain sexual dimorphism of body growth rates and liver gene expression suggests that STAT5b may be the major, if not the sole, STAT protein that mediates the sexually dimorphic effects of GH pulses in liver and perhaps other target tissues. STAT5b thus has unique physiological functions for which, surprisingly, the highly homologous STAT5a is unable to substitute.

Vasodilation after coronary artery bypass surgery is a common complication. Inflammatory mediators influence the expression of alpha1-adrenergic receptors. Do patients requiring high doses of postoperative inotropic support have down-regulated alpha-adrenergic receptors? Is there a characteristic pattern of preoperative inflammatory mediator expression that could predict a complicated course after the operation? Forty-four patients undergoing cardiac bypass surgery with extracorporeal circulation were prospectively investigated. Five perioperative blood samples were taken (preoperative, two hours, 12 hours, 36 hours and 72 hours postoperative). The leucocyte mRNA-expression of the three alpha1-adrenergic receptor subtypes (A, B and D) and 11 different pro-inflammatory mediators were investigated with the real-time reverse transcriptase polymerase chain reaction. The patients were divided into three groups (No-noradrenaline [No-NA]=0 μg/min, Low-noradrenaline [Low-NA]=0.1-7 μg/min, High-noradrenaline [High-NA] >7 μg/min), according to their postoperative noradrenaline requirements. Preoperatively, alpha1 A-receptor expression was 4.9-fold (High-NA) and 18.7-fold (Low-NA) higher than the No-NA group (P=0.005) and plasma noradrenaline levels were higher in the High-NA group (P=0.005). Across all groups at 12 hours after the operation, alpha1 A-receptor expression decreased to approximately one-fifth of preoperative levels (P=0.01); but with greater duration and magnitude of relative decrease in the High-NA group. Patients in the No-NA group had significant postoperative increases in leucocyte inflammatory mediator expression for IL-1ß, TLR4, TREM, MPO, MMP9 and TNF genes, whereas the changes in the Low-NA and High-NA groups were not significant. Low preoperative levels of noradrenaline and low expression of alpha1 A-adrenoreceptors in leucocytes was associated with less probability of requiring noradrenaline support after cardiac surgery.