Role of neuronal IGF-1R signaling for the pathogenesis of Alzheimer's disease

Post mortem investigations of brains from patients with AD revealed a markedly down regulated expression IGF-1R, and insulin receptor substrate (IRS) proteins, and these changes progress with severity of neurodegeneration. A common feature in neurons from AD patients is a downregulation of IGF-1R. To investigate the role of neuronal IGF-1R signaling in AD neuron-specific IGF-1R (nIGF-1R-/-) deficient mice were generated. These mice were crossed with mice expressing the Swedish mutation of human APP695 harbouring the double mutation Lys670→; Asn, Met671→; Leu which was found in a Swedish family with early-onset AD (APPsw, Tg2576 mice). nIGF-1R-/- mice were generated using the cre-loxP-system under the control of the neuron-specific synapsin-1 promoter and crossed them into the Tg2576 background. The offsprings of these mice (WT, Tg2576, nIGF-1R-/-, nIGF-1R-/-Tg2576) were analysed at two different time points. Kaplan-Meier analysis, amyloid accumulation as well as metabolic and somatic factors of the offspring were investigated during an observation period of 60 weeks. Western blot analysis of isolated hippocampi displayed a 40% reduced IGF-1R expression in nIGF-1R-/- and nIGF-1R-/-Tg2576 compared to WT and Tg2576 animals, whereas other brain regions e.g. cortex or cerebellum did not show significant IGF-1R deletion. Thus, conditional IGF-1R deletion using Cre recombinase expression under the control of the synapsin-1 promoter leads to a hippocampus-specific downregulation of IGF-1R. Further analysis of Cre recombinase expression in a lacZ reporter mouse strain revealed a Cre recombinase activity driven by the synapsin-1 promoter in the dentus gyrus and the CA3 region of the hippocampus. Kaplan-Meier-analysis revealed a 60% mortality of Tg2576 mice after 60 weeks of observation. In contrast nIGF-1R-/-Tg2576 were protected against premature mortality of Tg2576 mice (p&≤0.02; Tg2576 vs. nIGF-1R-/-Tg2576). Isolated hippocampi of 28 and 60 weeks old nIGF-1R-/-Tg2576 animals showed a 50% reduced Aβ1-40 and Aβ1-42 accumulation compared to Tg2576. Additionally, APP α- and β-C-terminal fragments were reduced in hippocampi of nIGF-1R-/-Tg2576 compared Tg2576 mice due to a modification of α- and β-secretases activity. In addition Aβ plaque burden was reduced in Tg2576 animals with neuronal IGF-1R deletion. Taken together the results of the present thesis demonstrate that decreased neuronal IGF-1R signaling predominantly in the hippocampus protects against APPsw induced mortality. Moreover IGF-1R mediated signals influence APP processing due to a modification of α- and β-secretases leading to reduced Aβ accumulation and amyloid plaque burden. Thus, downregulation of IGF-1R observed in neurons of patients suffering from Alzheimer's disease is most likely a compensatory phenomenon to decrease amyloid accumulation and prolong survival

Lifetimes of Confined Acoustic Phonons in Ultra-Thin Silicon Membranes

We study the relaxation of coherent acoustic phonon modes with frequencies up to 500 GHz in ultra-thin free-standing silicon membranes. Using an ultrafast pump-probe technique of asynchronous optical sampling, we observe that the decay time of the first-order dilatational mode decreases significantly from \sim 4.7 ns to 5 ps with decreasing membrane thickness from \sim 194 to 8 nm. The experimental results are compared with theories considering both intrinsic phonon-phonon interactions and extrinsic surface roughness scattering including a wavelength-dependent specularity. Our results provide insight to understand some of the limits of nanomechanical resonators and thermal transport in nanostructures

Breakdown of the few-level approximation in collective systems

The validity of the few-level approximation in dipole-dipole interacting collective systems is discussed. As example system, we study the archetype case of two dipole-dipole interacting atoms, each modelled by two complete sets of angular momentum multiplets. We establish the breakdown of the few-level approximation by first proving the intuitive result that the dipole-dipole induced energy shifts between collective two-atom states depend on the length of the vector connecting the atoms, but not on its orientation, if complete and degenerate multiplets are considered. A careful analysis of our findings reveals that the simplification of the atomic level scheme by artificially omitting Zeeman sublevels in a few-level approximation generally leads to incorrect predictions. We find that this breakdown can be traced back to the dipole-dipole coupling of transitions with orthogonal dipole moments. Our interpretation enables us to identify special geometries in which partial few-level approximations to two- or three-level systems are valid

Impact of the indexed effective orifice area on mid-term cardiac-related mortality after aortic valve replacement

Background There has been ongoing controversy as to whether prosthesis-patient mismatch (PPM, defined as indexed effective orifice area (EOAI) <0.85 m(2)/cm(2)) influences mortality after aortic valve replacement (AVR). In most studies, PPM is anticipated by reference tables based on mean EOAs as opposed to individual assessment. These reference values may not reflect the actual in vivo EOAI and hence, the presence or absence of PPM may be based on false assumptions. Objective To assess the impact of small prosthesis EOA on survival after aortic valve replacement AVR. Methods 645 patients had undergone an AVR between 2000 and 2007 entered the study. All patients underwent transthoracic echocardiography for determination of the actual EOAI within 6 months postoperatively. In order to predict time from surgery to death a proportional hazards model for competing risks (cardiac death vs death from other causes) was used. EOAI was entered as a continuous variable. Results PPM occurred in 40% of the patients. After a median follow-up of 2.35 years, 92.1% of the patients were alive. The final Cox regression model showed a significantly increased risk for cardiac death among patients with a smaller EOAI (HR=0.32, p=0.022). The effect of EOAI on the 2-5 year mortality risk was demonstrated by risk plots. Conclusions In contrast to previous studies these EOAI values were obtained through postoperative echocardiography, substantially improving the accuracy of measurement, and the EOAI was modelled as a continuous variable. There was a significantly improved survival for larger EOAIs following AVR. Strategies to avoid PPM should become paramount during AVR

Validation of a Commercial Enzyme-Linked Immunosorbent Assay for Allopregnanolone in the Saliva of Healthy Pregnant Women

Enzyme-linked immunosorbent assays (ELISAs) for saliva are simple, non-invasive methods for hormone detection. Allopregnanolone (ALLO) is a neuroactive steroid hormone that plays a crucial role in the aetiology of reproductive mood disorders. To better understand the relationship between ALLO and mood, a validated method to measure peripheral hormone levels is required. Currently, there is no commercially available ELISA with which to measure ALLO in saliva. We validated two ELISAs, developed for use with blood, with the saliva samples of 25 pregnant women, examining the range and sensitivity, intra- and inter-assay precision, parallelism, linearity of dilution, and recovery. The samples were simultaneously analysed using the liquid-chromatography–mass-spectrometry (LC-MS) method. The kits differed in range (31.2–2000 pg/mL vs. 1.6–100 ng/mL) and sensitivity (<9.5 pg/mL vs. 0.9 ng/mL), with the latter showing significant matrix effects and the former fulfilling the acceptance criteria of all the parameters. The concentrations measured with LC–MS were below the lower limit of quantification (<1.0 ng/mL) and no signal was detected. One of the tested ELISAs is a valid method for detecting ALLO in the saliva of pregnant women. It has a suitable measurement range and higher sensitivity than the conventional LC–MS method

Coherent control in a decoherence-free subspace of a collective multi-level system

Decoherence-free subspaces (DFS) in systems of dipole-dipole interacting multi-level atoms are investigated theoretically. It is shown that the collective state space of two dipole-dipole interacting four-level atoms contains a four-dimensional DFS. We describe a method that allows to populate the antisymmetric states of the DFS by means of a laser field, without the need of a field gradient between the two atoms. We identify these antisymmetric states as long-lived entangled states. Further, we show that any single-qubit operation between two states of the DFS can be induced by means of a microwave field. Typical operation times of these qubit rotations can be significantly shorter than for a nuclear spin system.Comment: 15 pages, 11 figure

Primary stability of a press-fit cup in combination with impaction grafting in an acetabular defect model

The objectives of this study were to (a) assess primary stability of a press-fit cup in a simplified acetabular defect model, filled with compacted cancellous bone chips, and (b) to compare the results with primary stability of a press-fit cup combined with two different types of bone graft substitute in the same defect model. A previously developed acetabular test model made of polyurethane foam was used, in which a mainly medial contained defect was implemented. Three test groups (N = 6 each) were prepared: Cancellous bone chips (bone chips), tricalciumphosphate tetrapods + collagen matrix (tetrapods + coll), bioactive glass S53P4 + polyethylene glycol-glycerol matrix (b.a.glass + PEG). Each material was compacted into the acetabulum and a press-fit cup was implanted. The specimens were loaded dynamically in the direction of the maximum resultant force during level walking. Relative motion between cup and test model was assessed with an optical measurement system. At the last load step (3000 N), inducible displacement was highest for bone chips with median [25th percentile; 75th percentile] value of 113 [110; 114] µm and lowest for b.a.glass + PEG with 91 [89; 93] µm. Migration at this load step was highest for b.a.glass + PEG with 868 [845; 936] µm and lowest for tetrapods + coll with 491 [487; 497] µm. The results show a comparable behavior under load of tetrapods + coll and bone chips and suggest that tetrapods + coll could be an attractive alternative to bone chips. However, so far, this was found for one specific defect type and primary stability should be further investigated in additional/more severe defects

Synthesis and Ambiphilic Reactivity of Metalated Diorgano-Phosphonite Boranes

Unprecedented metalated phosphonite boranes were prepared from PH-substituted precursors and silyl amides. Although potassium derivatives were thermally stable and could even be isolated and structurally characterised, lithiated analogues proved to be unstable towards self-condensation under cleavage of LiOR at ambient temperature. Reaction studies revealed that the metalated phosphonite boranes exhibit ambiphilic character. Their synthetic potential as nucleophilic building blocks was demonstrated in the synthesis of the first stannylated phosphonite representing a new structural motif in phosphine chemistry.Peer reviewe

A method to assess primary stability of acetabular components in association with bone defects

The objectives of this study were to develop a simplified acetabular bone defect model based on a representative clinical case, derive four bone defect increments from the simplified defect to establish a step‐wise testing procedure, and analyze the impact of bone defect and bone defect filling on primary stability of a press‐fit cup in the smallest defined bone defect increment. The original bone defect was approximated with nine reaming procedures and by exclusion of specific procedures, four defect increments were derived. The smallest increment was used in an artificial acetabular test model to test primary stability of a press‐fit cup in combination with bone graft substitute (BGS). A primary acetabular test model and a defect model without filling were used as reference. Load was applied in direction of level walking in sinusoidal waveform with an incrementally increasing maximum load (300 N/1000 cycles from 600 to 3000 N). Relative motions (inducible displacement, migration, and total motion) between cup and test model were assessed with an optical measurement system. Original and simplified bone defect volume showed a conformity of 99%. Maximum total motion in the primary setup at 600 N (45.7 ± 5.6 µm) was in a range comparable to tests in human donor specimens (36.0 ± 16.8 µm). Primary stability was reduced by the bone defect, but could mostly be reestablished by BGS‐filling. The presented method could be used as platform to test and compare different treatment strategies for increasing bone defect severity in a standardized way