Does Glucose Variability Influence the Relationship Between Mean Plasma Glucose and HbA1cHbA_{1c} Levels in Type 1 and Type 2 Diabetic Patients?

Objective: The A1C-Derived Average Glucose (ADAG) study demonstrated a linear relationship between $HbA_{1c}$ and mean plasma glucose (MPG). As glucose variability (GV) may contribute to glycation, we examined the association of several glucose variability indices and the MPG-$HbA_{1c}$ relationship. Research Design and Methods: Analyses included 268 patients with type 1 diabetes and 159 with type 2 diabetes. MPG during 3 months was calculated from 7-point self-monitored plasma glucose and continuous glucose monitoring. We calculated three different measures of GV and used a multiple-step regression model to determine the contribution of the respective GV measures to the MPG-$HbA_{1c}$ relationship. Results: GV, as reflected by SD and continuous overlapping net glycemic action, had a significant effect on the MPG-$HbA_{1c}$ relationship in type 1 diabetic patients so that high GV led to a higher $HbA_{1c}$ level for the same MPG. In type 1 diabetes, the impact of confounding and effect modification of a low versus high SD at an MPG level of 160 mg/dL on the $HbA_{1c}$ level is 7.02 vs. 7.43 and 6.96 vs. 7.41. All GV measures showed the same tendency. Conclusions: In only type 1 diabetic patients, GV shows a significant interaction with MPG in the association with $HbA_{1c}$. This effect is more pronounced at higher $HbA_{1c}$ levels. However, the impact of GV on the $HbA_{1c}$ level in type 1 diabetes is modest, particularly when $HbA_{1c}$ is close to the treatment target of 7%

A case of recurrent epilepsy-associated rosette-forming glioneuronal tumor with anaplastic transformation in the absence of therapy.

Rosette-forming glioneuronal tumor (RGNT) most commonly occurs adjacent to the fourth ventricle and therefore rarely presents with epilepsy. Recent reports describe RGNT occurrence in other anatomical locations with considerable morphologic and genetic overlap with the epilepsy-associated dysembryoplastic neuroepithelial tumor (DNET). Examples of RGNT or DNET with anaplastic change are rare, and typically occur in the setting of radiation treatment. We present the case of a 5-year-old girl with seizures, who underwent near total resection of a cystic temporal lobe lesion. Pathology showed morphologic and immunohistochemical features of RGNT, albeit with focally overlapping DNET-like patterns. Resections of residual or recurrent tumor were performed 1 year and 5 years after the initial resection, but no adjuvant radiation or chemotherapy was given. Ten years after the initial resection, surveillance imaging identified new and enhancing nodules, leading to another gross total resection. This specimen showed areas similar to the original tumor, but also high-grade foci with oligodendroglial morphology, increased cellularity, palisading necrosis, microvascular proliferation, and up to 13 mitotic figures per 10 high power fields. Ancillary studies the status by sequencing showed wild-type of the isocitrate dehydrogenase 1 (IDH1), IDH2, and human histone 3.3 (H3F3A) genes, and BRAF studies were negative for mutation or rearrangement. Fluorescence in situ hybridization (FISH) showed codeletion of 1p and 19q limited to the high-grade regions. By immunohistochemistry there was loss of nuclear alpha-thalassemia mental retardation syndrome, X-linked (ATRX) expression only in the high-grade region. Next-generation sequencing showed an fibroblast growth factor receptor receptor 1 (FGFR1) kinase domain internal tandem duplication in three resection specimens. ATRX mutation in the high-grade tumor was confirmed by sequencing which showed a frameshift mutation (p.R1427fs), while the apparent 1p/19q-codeletion by FISH was due to loss of chromosome arm 1p and only partial loss of 19q. Exceptional features of this case include the temporal lobe location, 1p/19q loss by FISH without true whole-arm codeletion, and anaplastic transformation associated with ATRX mutation without radiation or chemotherapy

Exploring General Gauge Mediation

We explore various aspects of General Gauge Mediation(GGM). We present a reformulation of the correlation functions used in GGM, and further elucidate their IR and UV properties. Additionally we clarify the issue of UV sensitivity in the calculation of the soft masses in the MSSM, highlighting the role of the supertrace over the messenger spectrum. Finally, we present weakly coupled messenger models which fully cover the parameter space of GGM. These examples demonstrate that the full parameter space of GGM is physical and realizable. Thus it should be considered a valid basis for future phenomenological explorations of gauge mediation.Comment: 27 pages, minor changes, typos fixed in appendix

Plasma 25-Hydroxyvitamin D and Progression to Diabetes in Patients at Risk for Diabetes

OBJECTIVE To investigate the association between vitamin D status, assessed by plasma 25-hydroxyvitamin D, and risk of incident diabetes. RESEARCH DESIGN AND METHODS Prospective observational study with a mean follow-up of 2.7 years in the Diabetes Prevention Program (DPP), a multicenter trial comparing different strategies for prevention of diabetes in patients with prediabetes. We assessed the association between plasma 25-hydroxyvitamin D, measured repeatedly during follow-up, and incident diabetes in the combined placebo (n = 1,022) and intensive lifestyle (n = 1,017) randomized arms of the DPP. Variables measured at multiple study time points (25-hydroxyvitamin D, BMI, and physical activity) entered the analyses as time-varying “lagged” covariates, as the mean of the previous and current visits at which diabetes status was assessed. RESULTS After multivariate adjustment, including for the DPP intervention, participants in the highest tertile of 25-hydroxyvitamin D (median concentration, 30.1 ng/mL) had a hazard ratio of 0.72 (95% CI 0.56–0.90) for developing diabetes compared with participants in the lowest tertile (median concentration, 12.8 ng/mL). The association was in the same direction in placebo (0.70; 0.52–0.94) versus lifestyle arm (0.80; 0.54–1.17). CONCLUSIONS Higher plasma 25-hydroxyvitamin D, assessed repeatedly, was associated with lower risk of incident diabetes in high-risk patients, after adjusting for lifestyle interventions (dietary changes, increased physical activity, and weight loss) known to decrease diabetes risk. Because of the observational nature of the study, the potential association between vitamin D and diabetes needs to be confirmed in intervention studies

The effect of sleep restriction, with or without high-intensity interval exercise, on myofibrillar protein synthesis in healthy young men

© 2020 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society. Key points: Sleep restriction has previously been associated with the loss of muscle mass in both human and animal models. The rate of myofibrillar protein synthesis (MyoPS) is a key variable in regulating skeletal muscle mass and can be increased by performing high-intensity interval exercise (HIIE), although the effect of sleep restriction on MyoPS is unknown. In the present study, we demonstrate that participants undergoing a sleep restriction protocol (five nights, with 4 h in bed each night) had lower rates of skeletal muscle MyoPS; however, rates of MyoPS were maintained at control levels by performing HIIE during this period. Our data suggest that the lower rates of MyoPS in the sleep restriction group may contribute to the detrimental effects of sleep loss on muscle mass and that HIIE may be used as an intervention to counteract these effects. Abstract: The present study aimed to investigate the effect of sleep restriction, with or without high-intensity interval exercise (HIIE), on the potential mechanisms underpinning previously-reported sleep-loss-induced reductions to muscle mass. Twenty-four healthy, young men underwent a protocol consisting of two nights of controlled baseline sleep and a five-night intervention period. Participants were allocated into one of three parallel groups, matched for age, (Formula presented.), body mass index and habitual sleep duration; a normal sleep (NS) group [8 h time in bed (TIB) each night], a sleep restriction (SR) group (4 h TIB each night), and a sleep restriction and exercise group (SR+EX, 4 h TIB each night, with three sessions of HIIE). Deuterium oxide was ingested prior to commencing the study and muscle biopsies obtained pre- and post-intervention were used to assess myofibrillar protein synthesis (MyoPS) and molecular markers of protein synthesis and degradation signalling pathways. MyoPS was lower in the SR group [fractional synthetic rate (% day–1), mean ± SD, 1.24 ± 0.21] compared to both the NS (1.53 ± 0.09) and SR+EX groups (1.61 ± 0.14) (P < 0.05). However, there were no changes in the purported regulators of protein synthesis (i.e. p-AKTser473 and p-mTORser2448) and degradation (i.e. Foxo1/3 mRNA and LC3 protein) in any group. These data suggest that MyoPS is acutely reduced by sleep restriction, although MyoPS can be maintained by performing HIIE. These findings may explain the sleep-loss-induced reductions in muscle mass previously reported and also highlight the potential therapeutic benefit of HIIE to maintain myofibrillar remodelling in this context

Proof-of-Concept, Randomized, Controlled Clinical Trial of Bacillus-Calmette-Guerin for Treatment of Long-Term Type 1 Diabetes

Background: No targeted immunotherapies reverse type 1 diabetes in humans. However, in a rodent model of type 1 diabetes, Bacillus Calmette-Guerin (BCG) reverses disease by restoring insulin secretion. Specifically, it stimulates innate immunity by inducing the host to produce tumor necrosis factor (TNF), which, in turn, kills disease-causing autoimmune cells and restores pancreatic beta-cell function through regeneration. Methodology/Principal Findings Translating these findings to humans, we administered BCG, a generic vaccine, in a proof-of-principle, double-blind, placebo-controlled trial of adults with long-term type 1 diabetes (mean: 15.3 years) at one clinical center in North America. Six subjects were randomly assigned to BCG or placebo and compared to self, healthy paired controls (n = 6) or reference subjects with (n = 57) or without (n = 16) type 1 diabetes, depending upon the outcome measure. We monitored weekly blood samples for 20 weeks for insulin-autoreactive T cells, regulatory T cells (Tregs), glutamic acid decarboxylase (GAD) and other autoantibodies, and C-peptide, a marker of insulin secretion. BCG-treated patients and one placebo-treated patient who, after enrollment, unexpectedly developed acute Epstein-Barr virus infection, a known TNF inducer, exclusively showed increases in dead insulin-autoreactive T cells and induction of Tregs. C-peptide levels (pmol/L) significantly rose transiently in two BCG-treated subjects (means: 3.49 pmol/L [95% CI 2.95–3.8], 2.57 [95% CI 1.65–3.49]) and the EBV-infected subject (3.16 [95% CI 2.54–3.69]) vs.1.65 [95% CI 1.55–3.2] in reference diabetic subjects. BCG-treated subjects each had more than 50% of their C-peptide values above the 95th percentile of the reference subjects. The EBV-infected subject had 18% of C-peptide values above this level. Conclusions/Significance: We conclude that BCG treatment or EBV infection transiently modified the autoimmunity that underlies type 1 diabetes by stimulating the host innate immune response. This suggests that BCG or other stimulators of host innate immunity may have value in the treatment of long-term diabetes. Trial Registration ClinicalTrials.gov NCT0060723