Reversible insulin resistance in muscle and fat unrelated to the metabolic syndrome in patients with acromegaly

BACKGROUND: Patients with active acromegaly exhibit insulin resistance despite a lean phenotype whereas controlled disease improves insulin sensitivity and increases fat mass. The mechanisms underlying this paradox remain elusive, but growth hormone (GH)-induced lipolysis plays a central role. The aim of the study was to investigative the molecular mechanisms of insulin resistance dissociated from obesity in patients with acromegaly. METHODS: In a prospective study, twenty-one patients with newly diagnosed acromegaly were studied at diagnosis and after disease control obtained by either surgery alone (n=10) or somatostatin analogue (SA) treatment (n=11) with assessment of body composition (DXA scan), whole body and tissue-specific insulin sensitivity and GH and insulin signalling in adipose tissue and skeletal muscle. FINDINGS: Disease control of acromegaly significantly reduced lean body mass (p<0.001) and increased fat mass (p<0.001). At diagnosis, GH signalling (pSTAT5) was constitutively activated in fat and enhanced expression of GH-regulated genes (CISH and IGF-I) were detected in muscle and fat. Insulin sensitivity in skeletal muscle, liver and adipose tissue increased after disease control regardless of treatment modality. This was associated with enhanced insulin signalling in both muscle and fat including downregulation of phosphatase and tensin homolog (PTEN) together with reduced signalling of GH and lipolytic activators in fat. INTERPRETATION: In conclusion, the study support that uncontrolled lipolysis is a major feature of insulin resistance in active acromegaly, and is characterized by upregulation of PTEN and suppression of insulin signalling in both muscle and fat. FUNDING: This work was supported by a grant from the Independent Research Fund, Denmark (7016-00303A) and from the Alfred Benzon Foundation, Denmark

In Alzheimer's disease, 6-month treatment with GLP-1 analog prevents decline of brain glucose metabolism:Randomized, placebo-controlled, double-blind clinical trial

In animal models, the incretin hormone GLP-1 affects Alzheimer’s disease (AD). We hypothesized that treatment with GLP-1 or an analog of GLP-1 would prevent accumulation of Aβ and raise, or prevent decline of, glucose metabolism (CMR(glc)) in AD. In this 26-week trial, we randomized 38 patients with AD to treatment with the GLP-1 analog liraglutide (n = 18), or placebo (n = 20). We measured Aβ load in brain with tracer [(11)C]PIB (PIB), CMR(glc) with [(18)F]FDG (FDG), and cognition with the WMS-IV scale (ClinicalTrials.gov NCT01469351). The PIB binding increased significantly in temporal lobe in placebo and treatment patients (both P = 0.04), and in occipital lobe in treatment patients (P = 0.04). Regional and global increases of PIB retention did not differ between the groups (P ≥ 0.38). In placebo treated patients CMR(glc) declined in all regions, significantly so by the following means in precuneus (P = 0.009, 3.2 μmol/hg/min, 95% CI: 5.45; 0.92), and in parietal (P = 0.04, 2.1 μmol/hg/min, 95% CI: 4.21; 0.081), temporal (P = 0.046, 1.54 μmol/hg/min, 95% CI: 3.05; 0.030), and occipital (P = 0.009, 2.10 μmol/hg/min, 95% CI: 3.61; 0.59) lobes, and in cerebellum (P = 0.04, 1.54 μmol/hg/min, 95% CI: 3.01; 0.064). In contrast, the GLP-1 analog treatment caused a numerical but insignificant increase of CMR(glc) after 6 months. Cognitive scores did not change. We conclude that the GLP-1 analog treatment prevented the decline of CMR(glc) that signifies cognitive impairment, synaptic dysfunction, and disease evolution. We draw no firm conclusions from the Aβ load or cognition measures, for which the study was underpowered

The Influence of Radiation Damage on the Deflection of High-Energy Beams in Bent Silicon Crystals

Experimental results obtained for deflection of 450 GeV/c protons channeling along the {111} planes in a bent, strongly irradiated silicon crystal are presented. A comparison between the deflection efficiencies in irradiated areas and non-irradiated areas in the crystal shows that irradiation by 2.4 · 1020 protons/cm2 leads to a reduction of around 30 % in deflection efficiency. As a consequence, beam-splitting and extraction from an accelerator by means of a bent crystal are feasible solutions at high energies even for intense beams and during long periods

Forgotten Antibiotics: An Inventory in Europe, the United States, Canada, and Australia

In view of the alarming spread of antimicrobial resistance in the absence of new antibiotics, this study aimed at assessing the availability of potentially useful older antibiotics. A survey was performed in 38 countries among experts including hospital pharmacists, microbiologists, and infectious disease specialists in Europe, the United States, Canada, and Australia. An international expert panel selected systemic antibacterial drugs for their potential to treat infections caused by resistant bacteria or their unique value for specific criteria. Twenty-two of the 33 selected antibiotics were available in fewer than 20 of 38 countries. Economic motives were the major cause for discontinuation of marketing of these antibiotics. Fourteen of 33 antibiotics are potentially active against either resistant Gram-positive or Gram-negative bacteria. Urgent measures are then needed to ensure better availability of these antibiotics on a global scal

Record deflection efficiencies measured for high energy protons in a bent germanium crystal

New experimental results on the deflection of high energy protons in a bent germanium crystal are presented. At 450 GeV/c, the 50 mm long crystal gave record deflection efficiencies up to 60% for small angles (1 mrad), while at angles as large as 12 mrad, the efficiency is about 25 times larger than for a silicon crystal of the same size. The experimental results are in good agreement with a model for channeling and deflection developed by Ellison and give - together with a similar comparison for a 200 GeV/c beam - confidence in extrapolations to higher energies (e.g. to LHC), other crystal materials or different deflection angles

Uropathogenic Escherichia coli Metabolite-Dependent Quiescence and Persistence May Explain Antibiotic Tolerance during Urinary Tract Infection

In the present study, it is shown that although Escherichia coli CFT073, a human uropathogenic (UPEC) strain, grows in liquid glucose M9 minimal medium, it fails to grow on glucose M9 minimal medium agar plates seeded with ≤106 CFU. The cells on glucose plates appear to be in a “quiescent” state that can be prevented by various combinations of lysine, methionine, and tyrosine. Moreover, the quiescent state is characteristic of ~80% of E. coli phylogenetic group B2 multilocus sequence type 73 strains, as well as 22.5% of randomly selected UPEC strains isolated from community-acquired urinary tract infections in Denmark. In addition, E. coli CFT073 quiescence is not limited to glucose but occurs on agar plates containing a number of other sugars and acetate as sole carbon sources. It is also shown that a number of E. coliCFT073 mini-Tn5 metabolic mutants (gnd, gdhA, pykF, sdhA, and zwf) are nonquiescent on glucose M9 minimal agar plates and that quiescence requires a complete oxidative tricarboxylic acid (TCA) cycle. In addition, evidence is presented that, although E. coli CFT073 quiescence and persistence in the presence of ampicillin are alike in that both require a complete oxidative TCA cycle and each can be prevented by amino acids, E. coli CFT073 quiescence occurs in the presence or absence of a functional rpoS gene, whereas maximal persistence requires a nonfunctional rpoS. Our results suggest that interventions targeting specific central metabolic pathways may mitigate UPEC infections by interfering with quiescence and persistence

Systems analysis approach to the design of efficient water pricing policies under the EU Water Framework Directive

Economic theory suggests that water pricing can contribute to efficient management of water scarcity. The European Union (EU) Water Framework Directive (WFD) is a major legislative effort to introduce the use of economic instruments to encourage efficient water use and achieve environmental management objectives. However, the design and implementation of economic instruments for water management, including water pricing, has emerged as a challenging aspect of WFD implementation. This study demonstrates the use of a systems analysis approach to designing and comparing two economic approaches to efficient management of groundwater and surface water given EU WFD ecological flow requirements. Under the first approach, all wholesale water users in a river basin face the same volumetric price for water. This water price does not vary in space or in time, and surface water and groundwater are priced at the same rate. Under the second approach, surface water is priced using a volumetric price, while groundwater use is controlled through adjustments to the price of energy, which is assumed to control the cost of groundwater pumping. For both pricing policies, optimization is used to identify optimal prices, with the objective of maximizing welfare while reducing human water use in order to meet constraints associated with EU WFD ecological and groundwater sustainability objectives. The systems analysis approach demonstrates the successful integration of economic, hydrologic, and environmental components into an integrated framework for the design and testing of water pricing policies. In comparison to the first pricing policy, the second pricing policy, in which the energy price is used as a surrogate for a groundwater price, shifts a portion of costs imposed by higher water prices from low-value crops to high-value crops and from small urban/domestic locations to larger locations. Because growers of low-value crops will suffer the most from water price increases, the use of energy costs to control groundwater use offers the advantage of reducing this burden.The authors would like to thank the Danish Research School of Water Resources (FIVA) for financial support. Three anonymous reviewers made helpful suggestions that were incorporated into the revised version.Riegels, N.; Pulido-Velazquez, M.; Doulgeris, C.; Sturm, V.; Jensen, R.; Moller, F.; Bauer-Gottwein, P. (2013). Systems analysis approach to the design of efficient water pricing policies under the EU Water Framework Directive. Journal of Water Resources Planning and Management. 139(5):574-582. doi:10.1061/(ASCE)WR.1943-5452.0000284S574582139

Measurement of pair-production by high energy photons in an aligned tungsten crystal

A new measurement has been made of the rate of pair production in a 3.2 mm thick tungsten crystal, exposed to photons with energies in the range 10 to 150 GeV, for angles of incidence up to 10 mrad from the crystal axis. A strong enhancement of the pair-production rate is observed when the beam is aligned along the crystal axis, as compared to a random orientation. This effect can be exploited in the NA48 CP- violation experiment by using a thin crystal rather than an amorphous material to convert photons, thus minimising the scattering of kaons in the converter