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Increased sympathetic noradrenergic signaling is crucially involved in fear and anxiety as defensive states. MicroRNAs regulate dynamic gene expression during synaptic plasticity and genetic variation of microRNAs modulating noradrenaline transporter gene (SLC6A2) expression may thus lead to altered central and peripheral processing of fear and anxiety. In silico prediction of microRNA regulation of SLC6A2 was confirmed by luciferase reporter assays and identified hsa-miR-579-3p as a regulating microRNA. The minor (T)-allele of rs2910931 (MAFcases = 0.431, MAFcontrols = 0.368) upstream of MIR579 was associated with panic disorder in patients (pallelic = 0.004, ncases = 506, ncontrols = 506) and with higher trait anxiety in healthy individuals (pASI = 0.029, pACQ = 0.047, n = 3112). Compared to the major (A)-allele, increased promoter activity was observed in luciferase reporter assays in vitro suggesting more effective MIR579 expression and SLC6A2 repression in vivo (p = 0.041). Healthy individuals carrying at least one (T)-allele showed a brain activation pattern suggesting increased defensive responding and sympathetic noradrenergic activation in midbrain and limbic areas during the extinction of conditioned fear. Panic disorder patients carrying two (T)-alleles showed elevated heart rates in an anxiety-provoking behavioral avoidance test (F(2, 270) = 5.47, p = 0.005). Fine-tuning of noradrenaline homeostasis by a MIR579 genetic variation modulated central and peripheral sympathetic noradrenergic activation during fear processing and anxiety. This study opens new perspectives on the role of microRNAs in the etiopathogenesis of anxiety disorders, particularly their cardiovascular symptoms and comorbidities.
Background: The pro-inflammatory status of the elderly triggers most of the age-related diseases such as cancer and atherosclerosis. Atherosclerosis, the leading cause world wide of morbidity and death, is an inflammatory disease influenced by life-style and genetic host factors. Stimuli such as oxLDL or microbial ligands have been proposed to trigger inflammation leading to atherosclerosis. It has recently been shown that oxLDL activates immune cells via the Toll-like receptor (TLR) 4/6 complex. Several common single nucleotide polymorphisms (SNPs) of the TLR system have been associated with atherosclerosis. To investigate the role of TLR-6 we analyzed the association of the TLR-6 SNP Pro249Ser with atherogenesis.
Results: Genotyping of two independent groups with CAD, as well as of healthy controls revealed a significant association of the homozygous genotype with a reduced risk for atherosclerosis (odds ratio: 0.69, 95% CI 0.51-0.95, P = 0.02). In addition, we found a trend towards an association with the risk of restenosis after transluminal coronary angioplasty (odds ratio: 0.53, 95% CI 0.24-1.16, P = 0.12). In addition, first evidence is presented that the frequency of this protective genotype increases in a healthy population with age. Taken together, our results define a role for TLR-6 and its genetic variations in modulating the inflammatory response leading to atherosclerosis.
Conclusions: These results may lead to a better risk stratification, and potentially to an improved prophylactic treatment of high-risk populations. Furthermore, the protective effect of this polymorphism may lead to an increase of this genotype in the healthy elderly and may therefore be a novel genetic marker for the well-being during aging.
The HITRAP linear decelerator currently being set up at GSI will provide slow, few keV/u highly charged ions for atomic physics experiments. The expected beam intensity is up to 105 ions per shot. To optimize phase and amplitude of the RF systems intensity, bunch length and kinetic energy of the particles need to be monitored. The bunch length that we need to fit is about 2 ns, which is typically measured by capacitive pickups. However, they do not work for the low beam intensities that we face. We investigated the bunch length with a fast CVD diamond detector working in single particle counting mode. Averaging over 8 shots yields a clear, regular picture of the bunched beam. Energy measurements by capacitive pickups are limited by the presence of intense primary and partially decelerated beam and hence make tuning of the IH-structure impossible. The energy of the decelerated fraction of the beam behind the first deceleration cavity was determined to about 10 % accuracy with a permanent dipole magnet combined with a MCP. Better detector calibration should help reaching the required 1%. Design of the detectors as well as the results of the measurements will be presented.
Objectives: Investigate the effectiveness of a complex intervention aimed at improving the appropriateness of medication in older patients with multimorbidity in general practice.
Design: Pragmatic, cluster randomised controlled trial with general practice as unit of randomisation.
Setting: 72 general practices in Hesse, Germany.
Participants: 505 randomly sampled, cognitively intact patients (≥60 years, ≥3 chronic conditions under pharmacological treatment, ≥5 long-term drug prescriptions with systemic effects); 465 patients and 71 practices completed the study.
Interventions: Intervention group (IG): The healthcare assistant conducted a checklist-based interview with patients on medication-related problems and reconciled their medications. Assisted by a computerised decision support system, the general practitioner optimised medication, discussed it with patients and adjusted it accordingly. The control group (CG) continued with usual care.
Outcome measures: The primary outcome was a modified Medication Appropriateness Index (MAI, excluding item 10 on cost-effectiveness), assessed in blinded medication reviews and calculated as the difference between baseline and after 6 months; secondary outcomes after 6 and 9 months’ follow-up: quality of life, functioning, medication adherence, and so on.
Results: At baseline, a high proportion of patients had appropriate to mildly inappropriate prescriptions (MAI 0–5 points: n=350 patients). Randomisation revealed balanced groups (IG: 36 practices/252 patients; CG: 36/253). Intervention had no significant effect on primary outcome: mean MAI sum scores decreased by 0.3 points in IG and 0.8 points in CG, resulting in a non-significant adjusted mean difference of 0.7 (95% CI −0.2 to 1.6) points in favour of CG. Secondary outcomes showed non-significant changes (quality of life slightly improved in IG but continued to decline in CG) or remained stable (functioning, medication adherence).
Conclusions: The intervention had no significant effects. Many patients already received appropriate prescriptions and enjoyed good quality of life and functional status. We can therefore conclude that in our study, there was not enough scope for improvement.
Trial registration number: ISRCTN99526053. NCT01171339; Results.