Glucose transporters in diabetic nephropathy

Changes in glucose transporter expression in glomerular cells occur early in diabetes. These changes, especially the GLUT1 increase in mesangial cells, appear to play a pathogenic role in the development of ECM expansion and perhaps other features of diabetic nephropathy. In addition, it appears that at least some diabetic patients may be predisposed to nephropathy because of polymorphisms in their GLUT1 genes. GLUT1 overexpression leads to increased glucose metabolic flux which in turn triggers the polyol pathway and activation of PKCα and Β1. Activation of these PKC isoforms can lead directly to AP-1 induced increases in fibronectin expression and ECM accumulation. Other, more novel effects of GLUT1 on cellular hypertrophy and injury could also promote changes of diabetic nephropathy. Strategies to prevent GLUT1 overexpression could ameliorate or prevent the progression of diabetic nephropathy.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47826/1/467_2004_Article_1748.pd

Genetic variation of Glucose Transporter-1 (GLUT1) and albuminuria in 10,278 European Americans and African Americans: a case-control study in the Atherosclerosis Risk in Communities (ARIC) Study

<p>Abstract</p> <p>Background</p> <p>Evidence suggests glucose transporter-1(<it>GLUT1</it>) genetic variation affects diabetic nephropathy and albuminuria. Our aim was to evaluate associations with albuminuria of six <it>GLUT1 </it>single nucleotide polymorphisms(SNPs), particularly <it>XbaI </it>and the previously associated <it>Enhancer-2(Enh2</it>) SNP.</p> <p>Methods</p> <p>A two-stage case-control study was nested in a prospective cohort study of 2156 African Americans and 8122 European Americans with urinary albumin-to-creatinine ratio(ACR). Cases comprised albuminuria(N = 825; ≥ 30 μg/mg) and macroalbuminuria(N = 173; ≥ 300 μg/mg). ACR < 30 μg/mg classified controls(n = 9453). Logistic regression and odds ratios(OR) assessed associations. The evaluation phase(stage 1, n = 2938) tested associations of albuminuria(n = 305) with six <it>GLUT1 </it>SNPs: rs841839, rs3768043, rs2297977, <it>Enh2</it>(rs841847) <it>Xba</it>I(rs841853), and rs841858. <it>Enh2 </it>was examined separately in the replication phase(stage 2, n = 7340) and the total combined sample (n = 10,278), with all analyses stratified by race and type 2 diabetes.</p> <p>Results</p> <p>In European Americans, after adjusting for diabetes and other <it>GLUT1 </it>SNPs in stage 1, <it>Enh2 </it>risk genotype(TT) was more common in albuminuric cases(OR = 3.37, P = 0.090) whereas <it>XbaI </it>(OR = 0.94, p = 0.931) and remaining SNPs were not. In stage 1, the <it>Enh2 </it>association with albuminuria was significant among diabetic European Americans(OR = 2.36, P = 0.025). In African Americans, <it>Enh2 </it>homozygosity was rare(0.3%); <it>XbaI </it>was common(18.0% AA) and not associated with albuminuria. In stage 2(n = 7,340), <it>Enh2 </it>risk genotype had increased but non-significant OR among diabetic European Americans(OR = 1.66, P = 0.192) and not non-diabetics(OR = 0.99, p = 0.953), not replicating stage 1. Combining stages 1 and 2, <it>Enh2 </it>was associated with albuminuria(OR 2.14 [1.20-3.80], P = 0.009) and macroalbuminuria(OR 2.69, [1.02-7.09], P = 0.045) in diabetic European Americans. The <it>Enh2 </it>association with macroalbuminuria among non-diabetic European Americans with fasting insulin(OR = 1.84, P = 0.210) was stronger at the highest insulin quartile(OR = 4.08, P = 0.040).</p> <p>Conclusions</p> <p>As demonstrated with type 1 diabetic nephropathy, the <it>GLUT1 Enh2 </it>risk genotype, instead of <it>Xba</it>I, may be associated with type 2 diabetic albuminuria among European Americans, though an association is not conclusive. The association among diabetic European Americans found in stage 1 was not replicated in stage 2; however, this risk association was evident after combining all diabetic European Americans from both stages. Additionally, our results suggest this association may extend to non-diabetics with high insulin concentrations. Rarity of the <it>Enh2 </it>risk genotype among African Americans precludes any definitive conclusions, although data suggest a risk-enhancing role.</p

Mulsemedia: State of the art, perspectives, and challenges

Mulsemedia-multiple sensorial media-captures a wide variety of research efforts and applications. This article presents a historic perspective on mulsemedia work and reviews current developments in the area. These take place across the traditional multimedia spectrum-from virtual reality applications to computer games-as well as efforts in the arts, gastronomy, and therapy, to mention a few. We also describe standardization efforts, via the MPEG-V standard, and identify future developments and exciting challenges the community needs to overcome

Potentiation of brain stimulation reward by morphine: effects of neurokinin-1 receptor antagonism

The abuse potential of opioids may be due to their reinforcing and rewarding effects, which may be attenuated by neurokinin-1 receptor (NK1R) antagonists

Xpert MTB/RIF Assay Shows Faster Clearance of Mycobacterium tuberculosis DNA with Higher Levels of Rifapentine Exposure.

The Xpert MTB/RIF assay is both sensitive and specific as a diagnostic test. Xpert also reports quantitative output in cycle threshold (CT) values, which may provide a dynamic measure of sputum bacillary burden when used longitudinally. We evaluated the relationship between Xpert CT trajectory and drug exposure during tuberculosis (TB) treatment to assess the potential utility of Xpert CT for treatment monitoring. We obtained serial sputum samples from patients with smear-positive pulmonary TB who were consecutively enrolled at 10 international clinical trial sites participating in study 29X, a CDC-sponsored Tuberculosis Trials Consortium study evaluating the tolerability, safety, and antimicrobial activity of rifapentine at daily doses of up to 20 mg/kg of body weight. Xpert was performed at weeks 0, 2, 4, 6, 8, and 12. Longitudinal CT data were modeled using a nonlinear mixed effects model in relation to rifapentine exposure (area under the concentration-time curve [AUC]). The rate of change of CT was higher in subjects receiving rifapentine than in subjects receiving standard-dose rifampin. Moreover, rifapentine exposure, but not assigned dose, was significantly associated with rate of change in CT (P = 0.02). The estimated increase in CT slope for every additional 100 μg · h/ml of rifapentine drug exposure (as measured by AUC) was 0.11 CT/week (95% confidence interval [CI], 0.05 to 0.17). Increasing rifapentine exposure is associated with a higher rate of change of Xpert CT, indicating faster clearance of Mycobacterium tuberculosis DNA. These data suggest that the quantitative outputs of the Xpert MTB/RIF assay may be useful as a dynamic measure of TB treatment response

Time-Independent Gravitational Fields

This article reviews, from a global point of view, rigorous results on time independent spacetimes. Throughout attention is confined to isolated bodies at rest or in uniform rotation in an otherwise empty universe. The discussion starts from first principles and is, as much as possible, self-contained.Comment: 47 pages, LaTeX, uses Springer cl2emult styl

Isotope shift calculations for atoms with one valence electron

This work presents a method for the ab initio calculation of isotope shift in atoms and ions with one valence electron above closed shells. As a zero approximation we use relativistic Hartree-Fock and then calculate correlation corrections. The main motivation for developing the method comes from the need to analyse whether different isotope abundances in early universe can contribute to the observed anomalies in quasar absorption spectra. The current best explanation for these anomalies is the assumption that the fine structure constant, alpha, was smaller at early epoch. We test the isotope shift method by comparing the calculated and experimental isotope shift for the alkali and alkali-like atoms Na, MgII, K, CaII and BaII. The agreement is found to be good. We then calculate the isotope shift for some astronomically relevant transitions in SiII and SiIV, MgII, ZnII and GeII.Comment: 11 page

Right Scaling for Right Pricing: A Case Study on Total Cost of Ownership Measurement for Cloud Migration

Cloud computing promises traditional enterprises and independent software vendors a myriad of advantages over on-premise installations including cost, operational and organizational efficiencies. The decision to migrate software configured for on-premise delivery to the cloud requires careful technical consideration and planning. In this chapter, we discuss the impact of right-scaling on the cost modelling for migration decision making and price setting of software for commercial resale. An integrated process is presented for measuring total cost of ownership, taking in to account IaaS/PaaS resource consumption based on forecast SaaS usage levels. The process is illustrated with a real world case study

Rapid expansion of Greenland’s low-permeability ice slabs

In recent decades, meltwater runoff has accelerated to become the dominant mechanism for mass loss in the Greenland ice sheet1,2,3. In Greenland’s high- elevation interior, porous snow and firn accumulate; these can absorb surface meltwater and inhibit runoff4, but this buffering effect is limited if enough water refreezes near the surface to restrict percolation5,6. However, the influence of refreezing on runoff from Greenland remains largely unquantified. Here we use firn cores, radar observations and regional climate models to show that recent increases in meltwater have resulted in the formation of metres-thick, low-permeability ‘ice slabs’ that have expanded the Greenland ice sheet’s total runoff area by 26 ± 3 per cent since 2001. Although runoff from the top of ice slabs has added less than one millimetre to global sea-level rise so far, this contribution will grow substantially as ice slabs expand inland in a warming climate. Runoff over ice slabs is set to contribute 7 to 33 millimetres and 17 to 74 millimetres to global sea-level rise by 2100 under moderate- and high-emissions scenarios, respectively—approximately double the estimated runoff from Greenland’s high-elevation interior, as predicted by surface mass balance models without ice slabs. Ice slabs will have an important role in enhancing surface meltwater feedback processes, fundamentally altering the ice sheet’s present and future hydrology

Receptor Reserve Moderates Mesolimbic Responses to Opioids in a Humanized Mouse Model of the OPRM1 A118G Polymorphism

The OPRM1 A118G polymorphism is the most widely studied μ-opioid receptor (MOR) variant. Although its involvement in acute alcohol effects is well characterized, less is known about the extent to which it alters responses to opioids. Prior work has shown that both electrophysiological and analgesic responses to morphine but not to fentanyl are moderated by OPRM1 A118G variation, but the mechanism behind this dissociation is not known. Here we found that humanized mice carrying the 118GG allele (h/mOPRM1-118GG) were less sensitive than h/mOPRM1-118AA littermates to the rewarding effects of morphine and hydrocodone but not those of other opioids measured with intracranial self-stimulation. Reduced morphine reward in 118GG mice was associated with decreased dopamine release in the nucleus accumbens and reduced effects on GABA release in the ventral tegmental area that were not due to changes in drug potency or efficacy in vitro or receptor-binding affinity. Fewer MOR-binding sites were observed in h/mOPRM1-118GG mice, and pharmacological reduction of MOR availability unmasked genotypic differences in fentanyl sensitivity. These findings suggest that the OPRM1 A118G polymorphism decreases sensitivity to low-potency agonists by decreasing receptor reserve without significantly altering receptor function