Testosterone use was associated with increased hemoglobin and hematocrit, increased BMI, and lowered high-density lipoprotein levels; estrogen was associated with lower testosterone and alanine aminotransferase levels. Otherwise, cross-sex hormone administration in adolescents was not associated with significant differences in the selected metabolic parameters over time.

Given a growing emphasis on early intervention for children with autism, valid quantitative tools for measuring treatment response are needed. The Social Responsiveness Scale (SRS) is a brief (15-20 minute) quantitative measure of autistic traits in 4-to 18-year-olds, for which a version for 3-year-olds was recently developed. We obtained serial SRS measurements on 73 preschool children with (n = 51) and without (n = 22) autism spectrum conditions. Inter-rater reliability (mothers and teachers) and test-retest reliability were of the order of 0.75 (Pearson's r). There was substantial agreement between SRS scores and (1) the Vineland Adaptive Behavior Composite (Pearson's r = -0.86) and (2) scores for social impairment on the Autism Diagnostic Interview-Revised (r = 0.63). Overall, quantitative autistic trait scores tended to improve over time in preschoolers, irrespective of treatment conditions. We conclude that it is possible to obtain reliable quantitative measurements of autistic social impairment in preschoolers, suitable for assessing treatment response.

Nitric oxide (NO) is a multifunctional mediator that has been implicated in the short-term hemodynamic alterations that occur in acute streptozocin (STZ)-induced diabetes. We investigated the role of NO produced by inducible nitric oxide synthase (iNOS) in chronic STZ diabetic nephropathy. Diabetes was induced in C57BL/6 and iNOS knockout (KO) mice with two intraperitoneal injections of STZ, 100 mg/kg. Animals were maintained without insulin treatment for 40 weeks. There were no significant differences between the strains in blood urea nitrogen (BUN), serum creatinine or glucose concentration, or urinary protein excretion during the entire observation period. Urinary nitrite + nitrate excretion was significantly lower in iNOS KO mice compared to control animals at all time points; in C57 mice, urinary nitrite declined progressively with more prolonged duration of diabetes. Renal hypertrophy (kidney weight/body weight) was noted in both strains of mice. However, histopathological assessment of renal tissue specimens at 16 and 40 weeks demonstrated increased mesangial hypercellularity and expansion as well as more prominent tubulointerstitial fibrosis in iNOS KO versus C57 mice. These changes were accompanied by increased interstitial deposition of type I collagen at 16 and 40 weeks in iNOS KO mice. Glomerular basement membrane staining for type IV collagen was also increased at 40 weeks in diabetic iNOS KO mice. While iNOS protein was undetectable in any of the kidney specimens obtained from either strain, eNOS was present throughout the course of chronic STZ diabetes. Moreover, eNOS expression was significantly increased by approximately 40% at 16 and 40 weeks of observation in iNOS KO versus C57 mice. There was no difference in renal cortical malondialdehyde content between the strains early or late in the disease course. In time control animals, there was no evidence of renal histopathological damage in iNOS KO or C57 mice after 40 weeks. We conclude that iNOS-derived NO modulates glomerulosclerosis and tubulointerstitial fibrosis in chronic STZ nephropathy. This action is probably a result of the direct actions of NO on the synthesis and degradation of extracellular matrix proteins.

Circulating insulin-like growth factor 1 (IGF-1) has been shown to act as a negative feedback regulator of growth hormone (GH) gene expression; however, the mechanism of this negative feedback is poorly understood. Activation and regulation of GH gene expression require the binding of the transcription factor POU1F1 to the GH promoter along with cyclic AMP (cAMP) response element binding protein (CREB) binding protein (CBP). We investigate the role of CBP as a target of IGF-1 somatotroph regulation using the MtT/S somatotroph cell line. IGF-1 significantly inhibits basal GH mRNA levels but not POU1F1 levels. Chromatin immunoprecipitation assays demonstrate inhibition of CBP binding to the GH promoter after IGF-1 treatment. We hypothesized that IGF-1 receptor (IGF-1R) signaling disrupts the POU1F1/CBP complex to inhibit gene expression. In support, the use of a mutant CBP (S436A) construct, which lacks a critical phosphorylation site, leads to the loss of IGF-1 inhibition. The studies of CBP (S436A) knock-in mice show elevated serum GH levels, a greater response to GH releasing hormone (GHRH) stimulation along with lower weight gain, and decreased body fat. Our data confirm the inhibitory effects of IGF-1 on GH expression at the level of the promoter and provide evidence of CBP's role as a target of IGF-1R signaling.T he regulation of growth hormone (GH) is primarily influenced by the antagonistic actions of the hypothalamic hormones growth hormone releasing hormone (GHRH) and somatostatin (SRIF); however, it also well documented that the release of GH may be influenced by other factors and proteins produced both centrally and peripherally (2,5,8,14,45,47). Insulin-like growth factor 1 (IGF-1), which is produced primarily in the liver under the direct influence of GH, has an important role in not only somatic growth and metabolism but also negative feedback of GH release by targeting both the hypothalamus and pituitary (7,22,39,43). Several in vitro studies have demonstrated the ability of IGF-1 to decrease GH gene expression and hormone release (33,40,(52)(53)(54). Furthermore, transgenic animals with perturbations in the GH axis also demonstrate IGF-1's direct and indirect roles in regulation of the somatotroph (27,30,35,49,51). IGF-1R is a heterotetrameric glycoprotein comprised of two extracellular alpha subunits, which bind IGF-1, and two transmembrane beta subunits, which contain tyrosine kinase activity (13,22). Upon ligand binding to the receptor, two major pathways, the Ras/Raf/ mitogen-activated protein (MAP) kinase and the phosphatidylinositol 3-kinase (PI3 kinase) pathway, have been shown to play a role in mediating IGF-1 responses (16,17,24,26).Although in vitro and in vivo studies of IGF-1 negative feedback have proposed specific targets that ultimately affect GH expression and release, a mechanism of regulation at the cellular level remains unclear. We chose to first study IGF-1 regulation using an in vitro approach with the MtT/S cell line, which is an established rat tumor somatotroph cell line t...