We conducted a randomized, multicenter study to determine whether treatment of subclinical rejection with increased corticosteroids resulted in beneficial outcomes in renal transplant patients receiving tacrolimus (TAC), mycophenolate mofetil (MMF) and prednisone. One hundred and twenty-one patients were randomized to biopsies at 0,1,2,3 and 6 months (Biopsy arm), and 119 to biopsies at 0 and 6 months only (Control arm). The primary endpoint of the study was the prevalence of the sum of the interstitial and tubular scores (ci + ct) > 2 (Banff) at 6 months. Secondary endpoints included clinical and subclinical rejection and renal function. At 6 months, 34.8% of the Biopsy and 20.5% of the Control arm patients had a ci + ct score ≥ 2 (p = 0.07). Between months 0 and 6, clinical rejection episodes were 12 in 10 Biopsy arm patients and 8 in 8 Control arm patients (p = 0.44). Overall prevalence of subclinical rejection in the Biopsy arm was 4.6%. Creatinine clearance at 6 months was 72.9 ± 21.7 in the Biopsy and 68.90 mL/min ± 18.35 mL/min in the Control arm patients (p = 0.18). In conclusion, we found no benefit to the procurement of early protocol biopsies in renal transplant patients receiving TAC, MMF and prednisone, at least in the short term. This is likely due to their low prevalence of subclinical rejection.

We present the discovery of a co-moving planetary-mass companion ∼ 42 ′′ (∼ 2000 AU) from a young M3 star, GU Psc, likely member of the young AB Doradus Moving Group (ABDMG). The companion was first identified via its distinctively red i-z color (> 3.5) through a survey made with Gemini-S/GMOS. Follow-up Canada-France-Hawaii Telescope/WIRCam near-infrared (NIR) imaging, Gemini-N/GNIRS NIR spectroscopy and Wide-field Infrared Survey Explorer photometry indicate a spectral type of T3.5 ± 1 and reveal signs of low gravity which we attribute to youth. Keck/Adaptive Optics NIR observations did not resolve the companion as a binary. A comparison with atmosphere models indicates T eff = 1000-1100 K and log g = 4.5-5.0. Based on evolution models, this temperature corresponds to a mass of 9-13 M Jup for the age of ABDMG (70-130 Myr). The relatively well-constrained age of this companion and its very large angular separation to its host star will allow its thorough characterization and will make it a valuable comparison for planetary-mass companions that will be uncovered by forthcoming planet-finder instruments such as Gemini Planet Imager and SPHERE.

Hyperlipidemia appears to play an integral role in loss of glucose-stimulated insulin secretion (GSIS) in type 2 diabetes. This impairment can be simulated in vitro by chronic culture of 832/13 insulinoma cells with high concentrations of free fatty acids, or by study of lipid-laden islets from Zucker diabetic fatty rats. Here we show that impaired GSIS is not a simple result of saturation of lipid storage pathways, as adenovirus-mediated overexpression of a cytosolically localized variant of malonylCoA decarboxylase in either cellular model results in dramatic lowering of cellular triglyceride stores but no improvement in GSIS. Instead, the glucose-induced increment in "pyruvate cycling" activity (pyruvate exchange with tricarboxylic acid cycle intermediates measured by 13 C NMR), previously shown to play an important role in GSIS, is completely ablated in concert with profound suppression of GSIS in lipid-cultured 832/13 cells, whereas glucose oxidation is unaffected. Moreover, GSIS is partially restored in both lipid-cultured 832/13 cells and islets from Zucker diabetic fatty rats by addition of a membrane permeant ester of a pyruvate cycling intermediate (dimethyl malate). We conclude that chronic exposure of islet ␤-cells to fatty acids grossly alters a mitochondrial pathway of pyruvate metabolism that is important for normal GSIS.A major contributing factor to the development of type 2 diabetes is inadequate insulin secretion to compensate for insulin resistance. A hallmark of this ␤-cell dysfunction is the impairment and eventual complete loss of glucose-stimulated insulin secretion (GSIS).1 Hyperlipidemia, and the consequent accumulation of triglycerides (TG) and other lipid-derived intermediates in ␤-cells, is now well recognized as a variable that correlates with development of impaired insulin secretion (1-6). Furthermore, culture of pancreatic islets (3,7,8) or insulinoma cell lines (9) with elevated levels of free fatty acids in vitro results in loss of GSIS, and glucose sensing is also dramatically impaired in fat-laden islets from Zucker diabetic fatty (ZDF) rats (2, 3). However, a biochemical mechanism linking chronic exposure of islet cells to high levels of free fatty acids and impairment of GSIS has not emerged.To gain more insight into this important issue, two independent model systems were exploited. First, we have described recently (10) stable subclones of the rat insulinoma INS-1 cell line with robust GSIS, such as cell line 832/13. As shown here, chronic culture of these cells in 1 mM oleate/palmitate (2:1) causes profound impairment of GSIS. Second, islets from ZDF rats are both lipid-laden and poorly glucose-responsive (3). By using these model systems, two hypotheses about the mechanism of lipid-induced impairment of GSIS were tested. The first is that accumulation of lipid-derived metabolites caused by chronic exposure of ␤-cells to fatty acids plays a direct role in the functional impairment. To test this idea, we have employed a recombinant adenovirus encoding a variant, cytosolic...