Myocardial Integrated Backscatter in Obese Adolescents: Associations with Measures of Adiposity and Left Ventricular Deformation.

Myocardial fibrosis has been proposed to play an important pathogenetic role in left ventricular (LV) dysfunction in obesity. This study tested the hypothesis that calibrated integrated backscatter (cIB) as a marker of myocardial fibrosis is altered in obese adolescents and explored its associations with adiposity, LV myocardial deformation, and metabolic parameters.Fifty-two obese adolescents and 38 non-obese controls were studied with conventional and speckle tracking echocardiography. The average cIB of ventricular septum and LV posterior wall was measured. In obese subjects, insulin resistance as estimated by homeostasis model assessment (HOMA-IR) and glucose tolerance were determined. Compared with controls, obese subjects had significantly greater cIB of ventricular septum (-16.8±7.8 dB vs -23.2±7.8 dB, p<0.001), LV posterior wall (-20.5±5.6 dBvs -25.0±5.1 dB, p<0.001) and their average (-18.7±5.7 dB vs -24.1±5.0 dB, p<0.001). For myocardial deformation, obese subjects had significantly reduced LV longitudinal systolic strain rate (SR) (p = 0.045) and early diastolic SR (p = 0.015), and LV circumferential systolic strain (p = 0.008), but greater LV longitudinal late diastolic SR (p<0.001), and radial early (p = 0.037) and late (p = 0.002) diastolic SR than controls. For the entire cohort, myocardial cIB correlated positively with body mass index (r = 0.45, p<0.001) and waist circumference (r = 0.45, p<0.001), but negatively with LV circumferential systolic strain (r = -0.23, p = 0.03) and systolic SR (r = -0.25, p = 0.016). Among obese subjects, cIB tended to correlate with HOMA-IR (r = 0.26, p = 0.07).Obese adolescents already exhibit evidence of increased myocardial fibrosis, which is associated with measures of adiposity and impaired LV circumferential myocardial deformation

Insulin-like growth factor-I (IGF-I) enhanced proteolysis of IGF-binding protein-4 in conditioned medium from primary cultures of human decidua: Independence from IGF receptor binding

Previous studies demonstrated that human decidual cells release insulin- like growth factor-binding protein (IGFBP)-1, IGFBP-2, and a 21 kilodalton (kDa) IGFBP in culture. The accumulation of 24-kDa IGFBP, as assessed by ligand blot analysis, decreased when the cells were exposed to IGF-I, but the mechanism was not explored. In the present study, we observed that the IGF- I-mediated decrease in IGFBP-4 accumulation could be explained by increased IGFBP-4 proteolysis. Analysis by IGFBP-4 immunoblotting demonstrated a decline in 24-kDa IGFBP-4 accompanied by a marked increase in a 17- to 18.5- kDa IGFBP-4 fragment(s). In addition, when medium from IGF-I-treated cells was incubated with rat IGFBP-4, the decrease in IGFBP-4 was inhibited by chelators of divalent cations and inhibitors of serine proteases. IGF-I enhancement of IGFBP-4 proteolysis occurs independent of the type I IGF receptor. [Leu 24,1-62]IGF-I, an analog with reduced receptor affinity, mimicked the effect of native IGF-I in cell culture. Additionally, α-IR 3, a monoclonal antibody to the type IIGF receptor, did not block the effect of IGF-I. When IGF-I was incubated with medium from control cells, there was a marked decrease in 24-kDa IGFBP-4 levels and a concomitant increase in levels of a 17- to 18.5-kDa fragment(s), suggesting that IGFBP-4 complexed with IGF- I is more susceptible to proteolysis than IGFBP-4 alone. Together, these findings suggest a novel mechanism for regulation of IGF-I action in the decidua.link_to_subscribed_fulltex

Mechanisms of Sertoli cell insulin-like growth factor (IGF)-binding protein-3 regulation by IGF-I and adenosine 3',5'-monophosphate

FSH, which stimulates cAMP in the Sertoli cell, markedly lowers the concentration of insulin-like growth factor-binding protein-3 (IGFBP-3) in Sertoli cell-conditioned medium; in contrast, insulin-like growth factor-I (IGF-I) increases BP-3 expression. In this study, the mechanisms controlling the contrasting effects of cAMP and IGF-I were investigated. The abundance of BP-3 mRNA was dramatically lowered by (Bu) 2cAMP, but was unaffected by IGF- I. Analyzed by ligand blot of conditioned medium, coincubation of (Bu) 2cAMP and IGF-I largely eliminated the increase observed with IGF-I alone. Based on the following evidence, the effect of IGF-I appeared to be solely related to the capacity of IGF-I to interact directly with BP-3. 1) Insulin at micromolar concentrations failed to increase BP-3 abundance despite documentation by affinity cross-linking that insulin displaced [ 125I]IGF- I from the IGF-I receptor. 2) A synthetic IGF-I analog, (Leu 24,1-62]IGF-I, which has reduced binding affinity for rat IGF-I receptor but displays high affinity for rat Sertoli cell-conditioned medium BPs, increased BP-3 abundance. 3) A synthetic IGF-I analog, B-chain mutant, which has reduced affinity for rat Sertoli cell BPs but displays normal affinity for the rat IGF-I receptor, failed to increase BP-3 abundance. 4) Human recombinant glycosylated [ 125I]BP-3 when added to cultured Sertoli cells was preserved in the medium when IGF-I or analogs with BP-3 affinity were present. 5) IGF- I, in dose-responsive manner, both retarded the disappearance from the medium of exogenously added human recombinant nonglycosylated BP-3 and decreased the amount of membrane-associated BP-3. These results indicate that whereas cAMP lowers BP-3 abundance in medium, most likely by markedly decreasing synthesis, IGF-I increases BP-3 accumulation by retarding its clearance by the Sertoli cell.link_to_subscribed_fulltex

Perinatal hypoxia-/ischemia-induced endothelin-1 mRNA in astrocyte-like and endothelial cells

Under pathological conditions in the adult CNS, such as ischemia, subarachnoid hemorrhage and Alzheimer's disease, endothelin (ET)-1- and -3-like immunoreactivities are elevated in astrocytes of the injured adult brain. However, it is not clear whether this is due to increased synthesis or increased binding of ET-1. Further, it is not known whether ET-1 expression is altered in the perinatal brain after cerebral hypoxia/ischemia (H/I). Here, we determined the sites of ET-1 expression in perinatal mouse brain after H/I injury by in situ hybridization using a probe specific for the ET-1 gene. Astrocyte-like cells, which do not normally express ET-1 mRNA, showed high levels of ET-I mRNA expression. Endothelial cells of the capillaries and small vessels also showed an increased level of ET-1 mRNA. Our data suggest that ET-1 mRNA levels in the astrocyte-like cells and vascular endothelial cells are dynamically regulated by ischemia and may participate in perinatal ischemia-relatecl neural damage. © 2001 Lippincott Williams & Wilkins.link_to_subscribed_fulltex

Comparison of echocardiographic indices between obese and non-obese adolescents.

<p>Abbreviations: A, transmitral late diastolic velocity, a, mitral annular late diastolic tissue velocity, BSA, body surface area, E, transmitral early diastolic velocity, e, mitral annular early diastolic tissue velocity, EDD, end-diastolic dimension, ESD, end-systolic dimension, IVSd, interventricular septal thickness at diastole, IVA, myocardial acceleration during isovolumic contraction, LV, left ventricular, PWd, posterior wall thickness at diastole</p><p>*statistically significant</p><p>Comparison of echocardiographic indices between obese and non-obese adolescents.</p