Role of ionotropic glutamate receptors in long-term potentiation in rat hippocampal CA1 oriens-lacunosum moleculare interneurons

Some interneurons of the hippocampus exhibit NMDA receptor-independent long-term potentiation (LTP) that is induced by presynaptic glutamate release when the postsynaptic membrane potential is hyperpolarized. This "anti-Hebbian" form of LTP is prevented by postsynaptic depolarization or by blocking AMPA and kainate receptors. Although both AMPA and kainate receptors are expressed in hippocampal interneurons, their relative roles in anti-Hebbian LTP are not known. Because interneuron diversity potentially conceals simple rules underlying different forms of plasticity, we focus on glutamatergic synapses onto a subset of interneurons with dendrites in stratum oriens and a main ascending axon that projects to stratum lacunosum moleculare, the oriens-lacunosum moleculare (O-LM) cells. We show that anti-Hebbian LTP in O-LM interneurons has consistent induction and expression properties, and is prevented by selective inhibition of AMPA receptors. The majority of the ionotropic glutamatergic synaptic current in these cells is mediated by inwardly rectifying Ca(2+)-permeable AMPA receptors. Although GluR5-containing kainate receptors contribute to synaptic currents at high stimulus frequency, they are not required for LTP induction. Glutamatergic synapses on O-LM cells thus behave in a homogeneous manner and exhibit LTP dependent on Ca(2+)-permeable AMPA receptors

Traveling Wave Magnetic Particle Imaging for determining the iron-distribution in rock: Traveling Wave Magnetic Particle Imaging for determining the iron-distribution in rock

Determining the composition of solid materials is of high interest in areas such as material research or quality assurance. There are several modalities at disposal with which various parameters of the material can be observed, but of those only magnetic resonance imaging (MRI) or computer tomography (CT) offer anon-destructive determination of material distribution in 3D. A novel non-destructive imaging method is Magnetic Particle Imaging (MPI), which uses dynamic magnetic fields for a direct determination of the distribution of magnetic materials in 3D. With this approach, it is possible to determine and differentiate magnetic and non-magnetic behaviour. In this paper, the first proof-of-principle measurements of magnetic properties in solid environments are presented using a home-built traveling wave magnetic particle imaging scanner

Interaction between the obesity-risk gene FTO and the dopamine D2 receptor gene ANKK1/TaqIA on insulin sensitivity

Variations in FTO are the strongest common genetic determinants of adiposity, and may partly act by influencing dopaminergic signalling in the brain leading to altered reward processing that promotes increased food intake. Therefore, we investigated the impact of such an interaction on body composition, and peripheral and brain insulin sensitivity. Participants from the Tubingen Family study (n = 2245) and the Malmo Diet and Cancer study (n = 2921) were genotyped for FTO SNP rs8050136 and ANKK1 SNP rs1800497. Insulin sensitivity in the caudate nucleus, an important reward area in the brain, was assessed by fMRI in 45 participants combined with intranasal insulin administration. We found evidence of an interaction between variations in FTO and an ANKK1 polymorphism that associates with dopamine (D2) receptor density. In cases of reduced D2 receptor availability, as indicated by the ANKK1 polymorphism, FTO variation was associated with increased body fat and waist circumference and reduced peripheral insulin sensitivity. Similarly, altered central insulin sensitivity was observed in the caudate nucleus in individuals with the FTO obesity-risk allele and diminished D2 receptors. The effects of variations in FTO are dependent on dopamine D2 receptor density (determined by the ANKK1 polymorphism). Carriers of both risk alleles might, therefore, be at increased risk of obesity and diabetes.Peer reviewe

a randomized, placebo-controlled phase II AIO trial with serum biomarker program

Background As a multi-targeted anti-angiogenic receptor tyrosine kinase (RTK) inhibitor sunitinib (SUN) has been established for renal cancer and gastrointestinal stromal tumors. In advanced refractory esophagogastric cancer patients, monotherapy with SUN was associated with good tolerability but limited tumor response. Methods This double-blind, placebo-controlled, multicenter, phase II clinical trial was conducted to evaluate the efficacy, safety and tolerability of SUN as an adjunct to second and third-line FOLFIRI (NCT01020630). Patients were randomized to receive 6-week cycles including FOLFIRI plus sodium folinate (Na-FOLFIRI) once every two weeks and SUN or placebo (PL) continuously for four weeks followed by a 2-week rest period. The primary study endpoint was progression-free survival (PFS). Preplanned serum analyses of VEGF-A, VEGF-D, VEGFR2 and SDF-1α were performed retrospectively. Results Overall, 91 patients were randomized, 45 in each group (one patient withdrew). The main grade ≥3 AEs were neutropenia and leucopenia, observed in 56 %/20 % and 27 %/16 % for FOLFIRI + SUN/FOLFIRI + PL, respectively. Median PFS was similar, 3.5 vs. 3.3 months (hazard ratio (HR) 1.11, 95 % CI 0.70–1.74, P = 0.66) for FOLFIRI + SUN vs. FOLFIRI + PL, respectively. For FOLFIRI + SUN, a trend towards longer median overall survival (OS) compared with placebo was observed (10.4 vs. 8.9 months, HR 0.82, 95 % CI 0.50–1.34, one-sided P = 0.21). In subgroup serum analyses, significant changes in VEGF-A (P = 0.017), VEGFR2 (P = 0.012) and VEGF-D (P < 0.001) serum levels were observed. Conclusions Although sunitinib combined with FOLFIRI did not improve PFS and response in chemotherapy-resistant gastric cancer, a trend towards better OS was observed. Further biomarker-driven studies with other anti- angiogenic RTK inhibitors are warranted. Trial registration This study was registered prospectively in the NCT Clinical Trials Registry (ClinicalTrials.gov) under NCT01020630 on November 23, 2009 after approval by the leading ethics committee of the Medical Association of Rhineland- Palatinate, Mainz, in coordination with the participating ethics committees (see Additional file 2) on September 16, 2009

Eating less or more – Mindset induced changes in neural correlates of pre-meal planning

Obesity develops due to an imbalance between energy intake and expenditure. Besides the decision about what to eat, daily energy intake might be even more dependent on the decision about the portion size to be consumed. For decisions between different foods, attentional focus is considered to play a key role in the choice selection. In the current study, we investigated the attentional modulation of portion size selection during pre-meal planning. We designed a functional magnetic resonance task in which healthy participants were directed to adopt different mindsets while selecting their portion size for lunch. Compared with a free choice condition, participants reduced their portion sizes when considering eating for health or pleasure, which was accompanied by increased activity in left prefrontal cortex and left orbitofrontal cortex, respectively. When planning to be full until dinner, participants selected larger portion sizes and showed a trend for increased activity in left insula. These results provide first evidence that also the cognitive process of pre-meal planning is influenced by the attentional focus at the time of choice, which could provide an opportunity for influencing the control of meal size selection by mindset manipulation