Circulating adiponectin levels, body composition and obesity-related variables in Prader-Willi syndrome: comparison with obese subjects

BACKGROUND: People with obesity and/or the metabolic syndrome have an increased risk for developing diabetes and cardiovascular disease and may have low adiponectin levels. The obesity associated with Prader-Willi syndrome (PWS) would be expected to have similar complications. However, it was recently reported that, despite their adiposity, people with PWS have reduced visceral fat and are less likely to develop diabetes mellitus or the metabolic syndrome compared with people with simple obesity. OBJECTIVE: To determine if plasma adiponectin levels and other variables relevant to diabetes and cardiovascular risk are different in a cohort of PWS subjects with known genetic subtypes compared with age-, sex- and weight-matched control subjects. RESULTS: Fasting plasma glucose, C-peptide, triglycerides, leptin and cholesterol levels were similar in PWS and obese subjects. Our 20 PWS subjects (mean age = 27.7 years) had higher percent body fat (54.1 vs 48.5%) determined by DEXA measurements and lower percent lean mass (45.9 vs 51.5%) compared with 14 obese controls (mean age = 26.9 year). Plasma adiponectin levels were significantly higher in PWS (15.5 +/- 8.2 microg/ml) than in obese controls (7.5 +/- 2.7 microg/ml). A significant positive correlation was found with insulin sensitivity in PWS subjects (r = 0.75, P = 0.0003) but not in obese controls (r = 0.36, P = 0.20). DISCUSSION: Our study confirmed an earlier observation of higher adiponectin levels in PWS subjects and less insulin resistance proportionate to their obesity status than found in subjects with simple obesity. Furthermore, no differences were seen in PWS subjects with the chromosome 15 deletion or maternal disomy 15. The reported excessive visceral adiposity in subjects with simple obesity compared with PWS may be associated with decreased production and lower circulating levels of adiponectin.     

Clobazam in refractory childhood epilepsy

Objective  

To evaluate the efficacy of clobazam in childhood refractory epilepsy and to characterize the adverse drug reaction profile in the Indian population.     

Efficacy of anti-insulin-like growth factor I receptor monoclonal antibody cixutumumab in mesothelioma is highly correlated with insulin growth factor-I receptor sites/cell

Insulin growth factor-I receptor (IGF-IR) is expressed in mesothelioma and therefore an attractive target for therapy. The antitumor activity of cixutumumab, a humanized monoclonal antibody to IGF-IR, in mesothelioma and relationship to IGF-IR expression was investigated using eight early passage tumor cells obtained from patients, nine established cell lines and an in vivo human mesothelioma tumor xenograft model. Although IGF-IR expression at the mRNA and protein level was present in all mesothelioma cells, using a quantitative ELISA immunoassay, there was considerable variability of IGF-IR expression ranging from 1 to 14 ng/mg of lysate. Using flow cytometry, the number of IGF-IR surface receptors varied from ≈2,000 to 50,000 sites/cell. Cells expressing >10,000 sites/cell had greater than 10% growth inhibition when treated with cixutumumab (100 μg/ml). Cixutumumab also induced antibody-dependent cell-mediated toxicity (>10% specific lysis) in cell lines, which had >20,000 IGF-IR sites/cell. Treatment with cixutumumab decreased phosphorylation of IGF-IR, Akt and Erk in cell lines, H226 and H28 having 24,000 and 51,000 IGF-IR sites/cell, respectively, but not in the cell line H2052 with 3,000 IGF-IR sites/cell. In vivo, cixutumumab treatment delayed growth of H226 mesothelioma tumor xenografts in mice and improved the overall survival of these mice compared to mice treated with saline (p < 0.004). Our results demonstrate that the antitumor efficacy of cixutumumab including inhibition of IGF-IR downstream signaling is highly correlated with IGF-IR sites/cell. A phase II clinical trial of cixutumumab is currently ongoing for the treatment of patients with mesothelioma.     

Myocardial Apelin Production is Reduced in Humans With Left Ventricular Systolic Dysfunction

BackgroundApelin is a novel endogenous peptide with inotropic and vasodilatory properties that is the ligand for the APJ receptor. Apelin and APJ are widely distributed in the vasculature of a number of organs and peripheral venous apelin is reduced in heart failure (HF). The location of apelin production in humans with and without HF was investigated.Methods and ResultsPlasma apelin and brain natriuretic peptide (BNP) concentrations in coronary sinus (CS), aorta (Ao), and renal vein (RV) of individuals with HF (n = 9) were compared to subjects with normal structural hearts (n = 8). In HF the concentration of CS apelin was reduced compared with controls (310 pg/mL [interquartile range 290-390] vs. 470 pg/mL [340-570], P < .035) but Ao apelin (330 pg/mL [275-375] vs. 340 pg/mL [230-455], P = .76) and RV apelin (290 pg/mL [280-360] vs. 370 pg/mL [273-410], P = .56) were unchanged. Plasma BNP was increased at all sampling sites in patients with HF as compared with controls. A step down from CS to Ao to RV in all subjects was observed. The step down in apelin from CS to Ao (470 pg/mL [310-595] vs. 320 pg/mL [225-482], P < .04) in control subjects was not apparent in patients with HF.ConclusionsThese novel data show that apelin is produced in the human heart and that production is reduced in individuals with HF. In contrast to BNP, apelin production is not exclusive to the heart.