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Aims/hypothesisGlucagon-like peptide 1 (GLP-1) reduces appetite and energy intake in humans, whereas the other incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), seems to have no effect on eating behaviour. Interestingly, studies in rodents have shown that concomitant activation of GIP and GLP-1 receptors may potentiate the satiety-promoting effect of GLP-1, and a novel dual GLP-1/GIP receptor agonist was recently shown to trigger greater weight losses compared with a GLP-1 receptor agonist in individuals with type 2 diabetes. The aim of this study was to delineate the effects of combined GIP and GLP-1 receptor activation on energy intake, appetite and resting energy expenditure in humans.MethodsWe examined 17 overweight/obese men in a crossover design with 5 study days. On day 1, a 50 g OGTT was performed; on the following 4 study days, the men received an isoglycaemic i.v. glucose infusion (IIGI) plus saline (154 mmol/l NaCl; placebo), GIP (4 pmol kg−1 min−1), GLP-1 (1 pmol kg−1 min−1) or GIP+GLP-1 (4 and 1 pmol kg−1 min−1, respectively). All IIGIs were performed in a randomised order blinded for the participant and the investigators. The primary endpoint was energy intake as measured by an ad libitum meal after 240 min. Secondary endpoints included appetite ratings and resting energy expenditure, as well as insulin, C-peptide and glucagon responses.ResultsEnergy intake was significantly reduced during IIGI+GLP-1 compared with IIGI+saline infusion (2715 ± 409 vs 4483 ± 568 kJ [mean ± SEM, n = 17], p = 0.014), whereas there were no significant differences in energy intake during IIGI+GIP (4062 ± 520 kJ) or IIGI+GIP+GLP-1 (3875 ± 451 kJ) infusion compared with IIGI+saline (p = 0.590 and p = 0.364, respectively). Energy intake was higher during IIGI+GIP+GLP-1 compared with IIGI+GLP-1 infusion (p = 0.039).Conclusions/interpretationWhile GLP-1 infusion lowered energy intake in overweight/obese men, simultaneous GIP infusion did not potentiate this GLP-1-mediated effect.Trial registrationClinicalTrials.gov NCT02598791FundingThis study was supported by grants from the Innovation Fund Denmark and the Vissing Foundation.

Retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) are major causes of blindness. They result from mutations in many genes which has long hampered comprehensive genetic analysis. Recently, targeted next-generation sequencing (NGS) has proven useful to overcome this limitation. To uncover \"hidden mutations\" such as copy number variations (CNVs) and mutations in non-coding regions, we extended the use of NGS data by quantitative readout for the exons of 55 RP and LCA genes in 126 patients, and by including non-coding 5' exons. We detected several causative CNVs which were key to the diagnosis in hitherto unsolved constellations, e.g. hemizygous point mutations in consanguineous families, and CNVs complemented apparently monoallelic recessive alleles. Mutations of non-coding exon 1 of EYS revealed its contribution to disease. In view of the high carrier frequency for retinal disease gene mutations in the general population, we considered the overall variant load in each patient to assess if a mutation was causative or reflected accidental carriership in patients with mutations in several genes or with single recessive alleles. For example, truncating mutations in RP1, a gene implicated in both recessive and dominant RP, were causative in biallelic constellations, unrelated to disease when heterozygous on a biallelic mutation background of another gene, or even non-pathogenic if close to the C-terminus. Patients with mutations in several loci were common, but without evidence for di- or oligogenic inheritance. Although the number of targeted genes was low compared to previous studies, the mutation detection rate was highest (70%) which likely results from completeness and depth of coverage, and quantitative data analysis. CNV analysis should routinely be applied in targeted NGS, and mutations in non-coding exons give reason to systematically include 5'-UTRs in disease gene or exome panels. Consideration of all variants is indispensable because even truncating mutations may be misleading.

ObjectivesTo compare the effect of liberal versus restrictive transfusion strategies on the proportion of time (%time) spent with intermittent hypoxaemia (IH, ie, arterial haemoglobin oxygen saturation measured by pulse oximetry (SpO2) <80% lasting ≥60 s) in the ‘Effects of Transfusion Thresholds on Neurocognitive Outcome’ (ETTNO) population, and to investigate whether infants with above-median exposure to IH might benefit more from liberal transfusion strategies than those with lower exposure.Design, setting, patientsSecondary analysis in all 554/1013 infants of <1000 g birth weight recruited into the ETTNO trial (mean gestational age 26.2 weeks) with >80% completeness of SpO2 recordings during postnatal days 8–49.InterventionRandomly assigned liberal (n=268) or restrictive (n=286) transfusion strategies, defining transfusion triggers based on postnatal age and health status.Main outcome measures%time with IH, rate and mean duration of IH episodes during postnatal days 8–49. Interaction between exposure to IH and transfusion strategies with respect to ETTNO’s composite primary outcome, death or disability at 24 months corrected age.ResultsThe median (quartile 1–quartile 3) %time with IH was similar between treatment groups (0.91% (0.13%–2.83%) with liberal vs 0.79% (0.16%–2.44%) with restrictive transfusions). There was no interaction between exposure to IH and transfusion strategies on outcome at 24 months.ConclusionsIn infants <1000 g birth weight, a liberal transfusion strategy did not reduce IH. Blood transfusions should not be administered ‘liberally’ to reduce IH or to improve neurocognitive outcome in infants with above-average exposure to IH.Trial registration numberNCT01393496.

In the roots of pea plants (Pisum sativum L.) cultivated with 20 micromolar CdCl2 for 3 d, synthesis of phytochelatins [PCs or (gamma EC)nG, where gamma EC is gamma glutamylcysteine and G is glycine] and homophytochelatins [h-PCs, (gamma EC)n beta-alanine] is accompanied by a drastic decrease in glutathione (GSH) content, but an increase in homoglutathione (h-GSH) content. In contrast, the in vitro activity of GSH synthetase increases 5-fold, whereas h-GSH synthetase activity increases regardless of Cd exposure. The constitutive enzyme PC synthase, which catalyzes the transfer of the gamma-EC moiety of GSH to an acceptor GSH molecule thus producing (gamma EC)2G, is activated by heavy metals, with Cd and Cu being strong activators and Zn being a very poor activator. Using h-GSH or hm-GSH for substrate, the synthesis rate of (gamma EC)2 beta-alanine and (gamma EC)2-serine is only 2.4 and 0.3%, respectively, of the synthesis rate of (gamma EC)2G with GSH as substrate. However, in the presence of a constant GSH level, increasing the concentration of h-GSH or hm-GSH results in increased synthesis of (gamma EC)2 beta-alanine or (gamma EC)2-serine, respectively; simultaneously, the synthesis of (gamma EC)2G is inhibited. gamma EC is not a substrate of PC synthase. These results are best explained by assuming that PC synthase has a gamma EC donor binding site, which is very specific for GSH, and a gamma EC acceptor binding site, which is less specific and accepts several tripeptides, namely GSH, h-GSH, and hm-GSH