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...

A determination of the initial mass function (IMF) of the current, incomplete census of the 10 Myrold TW Hya association (TWA) is presented. This census is built from a literature compilation supplemented with new spectra and 17 new radial velocities from on-going membership surveys, as well as a re-analysis of Hipparcos data that confirmed HR 4334 (A2 Vn) as a member. Though the dominant uncertainty in the IMF remains census incompleteness, a detailed statistical treatment is carried out to make the IMF determination independent of binning, while accounting for small number statistics. The currently known high-likelihood members are fitted by a log-normal distribution with a central mass of 0.21−0.06 M and a characteristic width of 0.8 +0.2 −0.1 dex in the 12 M Jup -2 M range, whereas a Salpeter power law with α = 2.2 +1.1 −0.5 best describes the IMF slope in the 0.1-2 M range. This characteristic width is higher than other young associations, which may be due to incompleteness in the current census of low-mass TWA stars. A tentative overpopulation of isolated planetary-mass members similar to 2MASS J11472421-2040204 and 2MASS J11193254-1137466 is identified: this indicates that there might be as many as 10 +13 −5 similar members of TWA with hot-start modeldependent masses estimated at ∼ 5-7 M Jup , most of which would be too faint to be detected in 2MASS . Our new radial velocity measurements corroborate the membership of 2MASS J11472421-2040204, and secure TWA 28 (M8.5 γ), TWA 29 (M9.5 γ) and TWA 33 (M4.5 e) as members. The discovery of 2MASS J09553336-0208403, a young L7-type interloper unrelated to TWA, is also presented.

Soluble leptin receptor (SLR) represents the major leptin binding activity in plasma. It is generated by alternative splicing of OB-R mRNA (OB-Re) and/or ectodomain shedding of membrane-spanning receptors. To determine the role of SLR in leptin activation of its long-form receptor, OB-Rb, we established in vitro assays using a cell line stably expressing OB-Rb. Human embryonic kidney 293 cell lines stably overexpressing OB-Rb show a dose-dependent leptin-induced signal transducer and activator of transcription 3 (STAT3) tyrosine phosphorylation and STAT3-responsive luciferase (STAT3-luc) activity. We demonstrate that when SLR is incubated with free leptin, binding of leptin to OB-Rb is reduced, with corresponding decrease of leptin-induced STAT3 tyrosine phosphorylation and STAT3-luc activity. However, by preparing leptin/SLR mixtures containing the same amount of free leptin but increasing amounts of leptin-SLR complex, we show that leptin-SLR complex does not inhibit OB-Rb activation by free leptin. These results suggest that in settings in which leptin and SLR coexist, SLR may sequester leptin from productive interactions with OB-Rb. Because plasma SLR levels are independently regulated by many different physiological and pathophysiological conditions, SLR may modulate the actions of leptin in tissues in which direct action of leptin has been demonstrated.

The present-day envelope of gaseous planets is a relic of how these giant planets originated and evolved. Measuring their elemental composition therefore presents a powerful opportunity to answer long-standing questions regarding planet formation. Obtaining precise observational constraints on the elemental inventory of giant exoplanets has, however, remained challenging owing to the limited simultaneous wavelength coverage of current space-based instruments. Here, we present thermal emission observations of the nontransiting hot Jupiter τ Boo b using the new wide wavelength coverage (0.95–2.50 μm) and high spectral resolution (R = 70,000) CFHT/SPIRou spectrograph. By combining a total of 20 hr of SPIRou data obtained over five nights in a full atmospheric retrieval framework designed for high-resolution data, we constrain the abundances of all the major oxygen- and carbon-bearing molecules and recover a noninverted temperature structure using a new free-shape, nonparametric temperature–pressure profile retrieval approach. We find a volume mixing ratio of log(CO) = − 2.46 − 0.29 + 0.25 and a highly depleted water abundance of less than 0.0072 times the expected value for a solar composition envelope. Combined with upper limits on the abundances of CH4, CO2, HCN, TiO, and C2H2, this results in a gas-phase C/H ratio of 5.85 − 2.82 + 4.44 × solar, consistent with the value of Jupiter, and an envelope C/O ratio robustly greater than 0.60, even when taking into account the oxygen that may be sequestered out of the gas phase. Combined, the inferred supersolar C/H, O/H, and C/O ratios on τ Boo b support a formation scenario beyond the water snowline in a disk enriched in CO owing to pebble drift.

Indirect immunoperoxidase analysis using monoclonal antibodies (Mo Ab) was performed in 33 renal biopsies with interstitial cellular infiltration obtained from non-transplanted patients. We reviewed four acute interstitial nephritis (IN), three chronic IN, four granulomatous IN, four acute tubular necrosis, four vasculitis, seven primary glomerulonephritis and seven active lupus nephritis (LN). We used Mo Ab recognizing T and B cell markers [OKT3, OKT8, T4, B1, IOT14 (IL2 receptor)], HLA-DR related antigen (I2) and monocytes/macrophages (LeuM3). In all cases the interstitial cellular infiltrates were predominantly T cells, whereas the B cell population accounted for less than 20% of the infiltrate. LeuM3+ cells were present in 28 of 32 cases, usually in a lesser proportion than T cells. IOT14+ cells were exceptional. T4+/T8+ cells were clearly greater than one in three acute IN, three granulomatous IN, two LN and two vasculitis. The T8+ cell population predominated in one case of chronic IN related to a non-steroidal anti-inflammatory drug. In all the remaining cases T4+ and T8+ cells were equally present. Aberrant strong HLA-DR expression within tubular cells was noted in nine cases (4 LN) irrespective of the presence of tubular lesions. On the basis of the phenotypic analysis, our data do not support a specific pattern of the infiltrate in regard to a given etiology and thus cannot be used as a diagnostic tool. However, such analysis may aid in understanding the mechanisms of tissue injury.

MeCsA appears to be a safe and effective therapy in stable renal transplant patients and provides superior and more consistent absorption of cyclosporine when compared with ConCsA. Transient toxicity after conversion to MeCsA occurs in some patients, and may reflect the increased exposure to cyclosporine. Use of a limited sampling approach combining trough and 2-hr postdose concentrations may provide an effective way to monitor this exposure.