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Objective: The current study examines the prevalence of binge eating and its association with adiposity and psychosocial functioning in a large, diverse sample of youth with type 2 diabetes.Research Design and Methods: In the TODAY study, 678 (mean age 14.0 years; 64.9% girls) of the 704 youth randomized to the study completed a self-report measure of eating disorder symptoms and were categorized as nonovereaters, overeaters, subclinical binge eaters, or clinical binge eaters.Results: Youth with clinical (6%) and subclinical (20%) levels of binge eating had significantly higher levels and rates of extreme obesity, global eating disorder and depressive symptoms, and impaired quality of life.Conclusions: These findings highlight the importance of evaluating youth with type 2 diabetes for the presence of binge eating. Future research is needed to determine the cumulative effects of disordered eating, obesity, and psychosocial distress on adherence to lifestyle change recommendations and longitudinal response to treatment. [ABSTRACT FROM AUTHOR]

The Mst1 and 2 cytosolic serine/threonine protein kinases are the mammalian orthologs of the Drosophila Hippo protein. Mst1 has been shown previously to participate in T-cell and B-cell trafficking and the migration of lymphocytes into secondary lymphoid organs in a cell intrinsic manner. We show here that the absence of Mst1 alone only modestly impacts B cell homing to lymph nodes. The absence of both Mst1 and 2 in hematopoietic cells results in relatively normal B cell development in the bone marrow and does not impact migration of immature B cells to the spleen. However, follicular B cells lacking both Mst1 and Mst2 mature in the splenic white pulp but are unable to recirculate to lymph nodes or to the bone marrow. These cells also cannot traffic efficiently to the splenic red pulp. The inability of late transitional and follicular B cells lacking Mst 1 and 2 to migrate to the red pulp explains their failure to differentiate into marginal zone B cell precursors and marginal zone B cells. Mst1 and Mst2 are therefore required for follicular B cells to acquire the ability to recirculate and also to migrate to the splenic red pulp in order to generate marginal zone B cells. In addition B-1 a B cell development is defective in the absence of Mst1.

Background: The Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) clinical trial documented that metformin plus rosiglitazone, but not metformin plus lifestyle intervention, provided superior durability of glycemic control relative to metformin monotherapy., Objectives: We examined weight changes among TODAY participants that completed at least 6 months of treatment, evaluated predictors of lifestyle outcome, and examined whether weight changes were related to cardiometabolic outcomes across treatment arms., Methods: The 595 youth with type 2 diabetes, (85.1% of randomized participants aged 11-17 years) completed assessments of weight-related and cardiometabolic measures at months 0, 6, 12 and 24. Repeated measures models were used to investigate associations over time., Results: Lifestyle intervention did not enhance outcome relative to metformin alone and no predictors of response to lifestyle treatment were identified. However, changes in percent overweight across treatment arms were associated with changes in multiple cardiometabolic risk factors, and decreases of ≥ 7% in overweight were associated with significant benefits over 24 months., Conclusions: Although adjunctive intensive lifestyle intervention did not improve weight-related outcomes, weight changes in the full TODAY sample were associated with small, but significant improvements in cardiometabolic status, highlighting the importance of optimizing weight management in youth with T2DM., (© 2016 World Obesity Federation.)

The radiocephalic fistula dates back to the 1960s with good long-term survival and a low incidence of complications. The standard practice of creating an end cephalic vein to side radial artery fistula (ETS) has a high incidence of early thrombosis and failure to mature, which limits its efficacy. The hypothesis is that a 1.3- to 1.5-cm side-to-side with distal vein ligation anastomosis (STS) is associated with a lower early thrombosis rate and higher primary patency rate. We retrospectively evaluated all radiocephalic fistulas created at our hospital from January 1, 2012, to December 31, 2012, comparing a 1.3- to 1.5-cm STS anastomosis to the ETS anastomosis. Primary endpoints were patency at three and six months and the secondary outcome was suitability for cannulation. An ETS anastomosis resulted in an early thrombosis rate, 3-month cannulation rate, and 6-month primary patency rate of 14, 30, and 48 per cent, respectively. Outcomes from the STS technique were significantly improved with no early thrombosis (P < 0.05), 3-month cannulation rate of 67 per cent (P < 0.03), and a primary patency of 75 per cent (P = 0.03). A STS radiocephalic fistula with distal vein ligation is superior to the ETS radiocephalic fistula. Early thrombosis, 6-month primary patency, and cannulation rates were significantly improved.

The Mst1 kinase is an important regulator of murine T cell adhesion, migration, proliferation, and apoptosis. In this study, we analyze mice lacking both Mst1 and Mst2 in hematopoietic cells. Compared with wild-type mice, these double knockout (DKO) mice exhibit a severe reduction in the number of mature T cells in the circulation and in secondary lymphoid organs (SLOs). CD4(+)CD8(-) and CD4(-)CD8(+) single-positive (SP) thymocytes in DKO mice resemble mature T cells of wild-type mice but undergo excessive apoptosis, and their egress from the thymus is reduced by >90%. Even when placed directly in the circulation, DKO SP thymocytes failed to enter SLOs. In SP thymocytes, deficiency of Mst1 and Mst2 abolished sphingosine-1 phosphate- and CCL21-induced Mob1 phosphorylation, Rac1 and RhoA GTP charging, and subsequent cell migration. When phosphorylated by Mst1 or Mst2, Mob1 binds and activates the Rac1 guanyl nucleotide exchanger Dock8, which is abundant in the thymus. Thus, the Mst1 and Mst2 kinases control Rho GTPase activation and the migratory responses of SP thymocytes.

L3MBTL1, a paralogue of Drosophila tumor suppressor lethal(3)malignant brain tumor (l(3)mbt), binds histones in a methylation state-dependent manner and contributes to higher order chromatin structure and transcriptional repression. It is the founding member of a family of MBT domain-containing proteins that has three members in Drosophila and nine in mice and humans. Knockdown experiments in cell lines suggested that L3MBTL1 has non-redundant roles in the suppression of oncogene expression. We generated a mutant mouse strain that lacks exons 13-20 of L3mbtl1. Markedly reduced levels of a mutant mRNA with an out-of-frame fusion of exons 12 and 21 were expressed, but a mutant protein was undetectable by Western blot analysis. L3MBTL1(-/-) mice developed and reproduced normally. The highest expression of L3MBTL1 was detected in the brain, but its disruption did not affect brain development, spontaneous movement, and motor coordination. Despite previous implications of L3mbtl1 in the biology of hematopoietic transcriptional regulators, lack of L3MBTL1 did not result in deficiencies in lymphopoiesis or hematopoiesis. In contrast with its demonstrated biochemical activities, embryonic stem (ES) cells lacking L3MBTL1 displayed no abnormalities in H4 lysine 20 (H4K20) mono-, di-, or trimethylation; had normal global chromatin density as assessed by micrococcal nuclease digests; and expressed normal levels of c-myc. Embryonic fibroblasts lacking L3MBTL1 displayed unaltered cell cycle arrest and down-regulation of cyclin E expression after irradiation. In cohorts of mice followed for more than 2 years, lack of L3MBTL1 did not alter normal lifespan or survival with or without sublethal irradiation.

The initial steps in the pathogenesis of acute leukemia remain incompletely understood. The TEL-AML1 gene fusion, the hallmark translocation in Childhood Acute Lymphoblastic Leukemia and the first hit, occurs years before the clinical disease, most often in utero. We have generated mice in which TEL-AML1 expression is driven from the endogenous promoter and can be targeted to specific populations. TEL-AML1 renders mice prone to malignancy after chemical mutagenesis when expressed in hematopoietic stem cells (HSCs), but not in early lymphoid progenitors. We reveal that TEL-AML1 markedly increases the number of HSCs and predominantly maintains them in the quiescent (G(0)) stage of the cell cycle. TEL-AML1(+) HSCs retain self-renewal properties and contribute to hematopoiesis, but fail to out-compete normal HSCs. Our work shows that stem cells are susceptible to subversion by weak oncogenes that can subtly alter their molecular program to provide a latent reservoir for the accumulation of further mutations.

Hematopoietic stem cells (HSCs) are thought to divide infrequently based on their resistance to cytotoxic injury targeted at rapidly cycling cells and have been presumed to retain labels such as the thymidine analog 5-bromodeoxyuridine (BrdU). However, BrdU retention is neither a sensitive nor specific marker for HSCs. Here we show that transient, transgenic expression of a histone 2B (H2B)-green fluorescent protein (GFP) fusion protein in mice has several advantages for label-retention studies over BrdU, including rapid induction of H2B-GFP in virtually all HSCs, higher labeling intensity and the ability to prospectively study label-retaining cells, which together permit a more precise analysis of division history. Mathematical modeling of H2B-GFP dilution in HSCs, identified with a stringent marker combination (L(-)K(+)S(+)CD48(-)CD150(+)), revealed unexpected heterogeneity in their proliferation rates and showed that approximately 20% of HSCs divide at an extremely low rate (< or =0.8-1.8% per day).

Background: The current study was undertaken to identify factors specific to kidney transplantation that are associated with posttransplant functional performance (FP) and health-related quality of life (HRQOL)., Methods: Karnofsky FP status was assessed longitudinally in 86 adult kidney transplant recipients. Patients reported HRQOL using the Short Form-36 (SF-36) health survey and the Psychosocial Adjustment to Illness Scale (PAIS)., Results: FP improved (P <0.001) after kidney transplantation (from 75 +/- 1 to 77 +/- 1, 81 +/- 1, and 82 +/- 1 at 0, 3, 6, and 12 months, respectively). Patients receiving organs from living donors showed continued improvement through posttransplant year 1 while those receiving cadaveric organs stabilized at month 6 (simple interaction contrast, year 1 versus pretransplant; P <0.05). Patients receiving dialysis therapy for 6 months or more prior to transplantation demonstrated lower SF-36 posttransplant physical component scores in comparison with patients who were transplanted preemptively (38 +/- 1 versus 45 +/- 2, P <0.05). Path analysis demonstrated the positive direct effect of time on FP with kidney transplantation (beta = 0.23, P <0.05), and the negative direct effects on FP of diabetes (beta = -0.22) and cadaveric organs (beta = -0.22, both P <0.05). In turn, FP had a positive direct effect on HRQOL (beta = 0.40, P <0.001)., Conclusions: Overall improvement in FP is attenuated 1 year after kidney transplantation in recipients of organs from cadaveric donors. The positive effect of time after transplantation, and the negative effects of cadaveric organs and diabetes on posttransplant HRQOL, are indirect and are mediated by the direct effects of these variables on posttransplant FP.

Previous studies of healthy volunteers and small numbers of transplant recipients have suggested that the oral solution formulation of Sandimmune (cyclosporine [CsA]; Sandoz Pharmaceuticals, East Hanover, NJ) is bioequivalent to the soft gelatin capsule (SGC) formulation. However, there is conflicting evidence as to whether the two formulations are bioequivalent in all patients; to date, there are no published studies that explicitly address their bioequivalence in patients. We conducted a randomized, open-label, two-sequence, two-period, crossover study. Of 20 maintenance renal transplant recipients shown by a screening pharmacokinetic (PK) profile to be poor absorbers of CsA, half were randomized to receive first the SGC formulation and half the oral solution formulation for a period of 7 days. Each patient then underwent a 12-hour PK profile on the last day of the assigned formulation before a crossover to receive the other formulation and repeat the 7-day treatment and PK profile cycle. The results showed that peak and total exposure to CsA was greater with the SGC formulation. The SGC-oral solution ratios indicated an average 38% greater peak and 11% greater total exposure for the SGC formulation (P < 0.01 and P = 0.09, respectively). Trough levels were more similar between formulations, with SGC showing an average of 5% greater troughs (P > 0.10). In our selected population of malabsorbers, the SGC formulation made a difference in drug exposure.