Sustained Effects of Interleukin-1 Receptor Antagonist Treatment in Type 2 Diabetes

Objective: Interleukin (IL)-1 impairs insulin secretion and induces beta-cell apoptosis. Pancreatic beta-cell IL-1 expression is increased and interleukin-1-receptor antagonist (IL-1Ra) expression reduced in patients with type 2 diabetes mellitus. Treatment with recombinant IL-1Ra improves glycemia and beta-cell function and reduces inflammatory markers in patients with type 2 diabetes mellitus. Here we investigated the durability of these responses. Research Design and Methods: Among 70 ambulatory patients with type 2 diabetes and A1C and body mass index higher than 7.5% and 27, respectively, randomly assigned to receive 13 weeks of anakinra, a recombinant human IL-1Ra, or placebo, 67 completed treatment and were included in this double-blinded 39 week follow-up study. Primary outcome was change in betacell function following anakinra withdrawal. Analysis was done by intention-to-treat. Results: Thirty-nine weeks following anakinra withdrawal the proinsulin to insulin (PI/I) ratio but not stimulated C-peptide remained improved by -0.07 (95% CI -0.14 to -0.02, P=0.011) compared to placebo treated patients. Interestingly, a subgroup characterized by genetically determined low baseline IL-1Ra serum levels, maintained the improved stimulated C-peptide obtained by 13 weeks of IL-1Ra treatment. Reductions of C-reactive protein (-3.2 mg/l [95% CI -6.2 to -1.1, P=0.014]) and of IL-6 (-1.4 ng/l [95% CI -2.6 to -0.3, P=0.036]) were maintained until end of study. Conclusions: IL-1 blockade with anakinra induces improvement of the PI/I ratio and in markers of systemic inflammation lasting 39 weeks following treatment withdrawal

Stratification of asthma phenotypes by airway proteomic signatures

© 2019 Background: Stratification by eosinophil and neutrophil counts increases our understanding of asthma and helps target therapy, but there is room for improvement in our accuracy in prediction of treatment responses and a need for better understanding of the underlying mechanisms. Objective: We sought to identify molecular subphenotypes of asthma defined by proteomic signatures for improved stratification. Methods: Unbiased label-free quantitative mass spectrometry and topological data analysis were used to analyze the proteomes of sputum supernatants from 246 participants (206 asthmatic patients) as a novel means of asthma stratification. Microarray analysis of sputum cells provided transcriptomics data additionally to inform on underlying mechanisms. Results: Analysis of the sputum proteome resulted in 10 clusters (ie, proteotypes) based on similarity in proteomic features, representing discrete molecular subphenotypes of asthma. Overlaying granulocyte counts onto the 10 clusters as metadata further defined 3 of these as highly eosinophilic, 3 as highly neutrophilic, and 2 as highly atopic with relatively low granulocytic inflammation. For each of these 3 phenotypes, logistic regression analysis identified candidate protein biomarkers, and matched transcriptomic data pointed to differentially activated underlying mechanisms. Conclusion: This study provides further stratification of asthma currently classified based on quantification of granulocytic inflammation and provided additional insight into their underlying mechanisms, which could become targets for novel therapies

Evaluation der Knochenarchitektur mittels mikro-CT im Tiermodell der Ratte

Simple and reliable, high-throughput techniques to detect the zygosity of transgenic events in plants are valuable for biotechnology and plant breeding companies seeking robust genotyping data for the assessment of new lines and the monitoring of breeding programs. We show that next-generation sequencing (NGS) applied to short PCR products spanning the transgene integration site provides accurate zygosity data that are more robust and reliable than those generated by PCR-based methods. The NGS reads covered the 5' border of the transgenic events (incorporating part of the transgene and the flanking genomic DNA), or the genomic sequences flanking the unfilled transgene integration site at the wild-type locus. We compared the NGS method to competitive real-time PCR with transgene-specific and wild-type-specific primer/probe pairs, one pair matching the 5' genomic flanking sequence and 5' part of the transgene and the other matching the unfilled transgene integration site. Although both NGS and real-time PCR provided useful zygosity data, the NGS technique was favorable because it needed fewer optimization steps. It also provided statistically more-reliable evidence for the presence of each allele because each product was often covered by more than 100 reads. The NGS method is also more suitable for the genotyping of large panels of plants because up to 80 million reads can be produced in one sequencing run. Our novel method is therefore ideal for the rapid and accurate genotyping of large numbers of samples

Effect of psychological stress on glucose control in patients with Type 2 diabetes

AIM: To investigate the effect of acute psychological stress on glucose concentrations in patients with Type 2 diabetes, in the fasting state as well as in the postprandial state. METHODS: Thirty patients (12 female) with Type 2 diabetes were included. Mean ± SD age was 60 ± 12 years, BMI 28.8 ± 4.2 kg/m(2), diabetes duration 8.9 ± 6.7 years and HbA(1c) 51 ± 9 mmol/mol (6.8 ± 0.8%). Using a non-randomized approach, all participants were exposed to moderate psychological stress by means of the Trier Social Stress Test: 10 participants in the fasting state and 20 participants 75 min after intake of a standard meal. Blood pressure, heart rate and salivary cortisol were monitored on the control day and the stress-test day. Glucose concentrations were assessed using a continuous glucose monitoring system. RESULTS: On the stress-test day, blood pressure rose from 117/73 ± 13/12 to 155/92 ± 22/14 mmHg, heart rate from 77 ± 11 to 91 ± 25 b min(-1) and salivary cortisol concentrations from 8.5 ± 3.7 to 26.4 ± 12.1 nmol/l (P < 0.001); these measurements remained unchanged on the control day. On the stress-test day, when the Trier Social Stress Test was applied 75 min after the intake of a standard meal, the glucose concentrations were significantly higher compared with the control day (mean difference 1.5 mmol/l, 95% CI 0.5-2.4, P = 0.003). In the fasting state, glucose concentrations slightly decreased during the control day but remained stable on the stress-test day (mean difference compared with the control day 0.7 mmol/l, 95% CI -0.7 to 2.0, P = 0.31). CONCLUSIONS: When stress is experienced in the postprandial period, acute psychological stress significantly increases glucose concentrations in patients with Type 2 diabetes