The impact of input fluctuations on the frequency-current relationships of layer 5 pyramidal neurons in the rat medial prefrontal cortex

The role of irregular cortical firing in neuronal computation is still debated, and it is unclear how signals carried by fluctuating synaptic potentials are decoded by downstream neurons. We examined in vitro frequency versus current (f-I) relationships of layer 5 (L5) pyramidal cells of the rat medial prefrontal cortex (mPFC) using fluctuating stimuli. Studies in the somatosensory cortex show that L5 neurons become insensitive to input fluctuations as input mean increases and that their f-I response becomes linear. In contrast, our results show that mPFC L5 pyramidal neurons retain an increased sensitivity to input fluctuations, whereas their sensitivity to the input mean diminishes to near zero. This implies that the discharge properties of L5 mPFC neurons are well suited to encode input fluctuations rather than input mean in their firing rates, with important consequences for information processing and stability of persistent activity at the network level.

Exposure modeling of high-frequency electromagnetic fields

We developed a geospatial model that calculates ambient high-frequency electromagnetic field (HF-EMF) strengths of stationary transmission installations such as mobile phone base stations and broadcast transmitters with high spatial resolution in the order of 1 m. The model considers the location and transmission patterns of the transmitters, the three-dimensional topography, and shielding effects by buildings. The aim of the present study was to assess the suitability of the model for exposure monitoring and for epidemiological research. We modeled time-averaged HF-EMF strengths for an urban area in the city of Basel as well as for a rural area (Bubendorf). To compare modeling with measurements, we selected 20 outdoor measurement sites in Basel and 18 sites in Bubendorf. We calculated Pearson's correlation coefficients between modeling and measurements. Chance-corrected agreement was evaluated by weighted Cohen's kappa statistics for three exposure categories. Correlation between measurements and modeling of the total HF-EMF strength was 0.67 (95% confidence interval (CI): 0.33-0.86) in the city of Basel and 0.77 (95% CI: 0.46-0.91) in the rural area. In both regions, kappa coefficients between measurements and modeling were 0.63 and 0.77 for the total HF-EMF strengths and for all mobile phone frequency bands. First evaluation of our geospatial model yielded substantial agreement between modeling and measurements. However, before the model can be applied for future epidemiologic research, additional validation studies focusing on indoor values are needed to improve model validity.Journal of Exposure Science and Environmental Epidemiology (2008) 18, 183-191; doi:10.1038/sj.jes.7500575; published online 4 April 2007.

Influence of growth hormone (GH) receptor deletion of exon 3 and full-length isoforms on GH response and final height in patients with severe GH deficiency

CONTEXT: A polymorphism of the GH receptor (GHR) gene resulting in genomic deletion of exon 3 (GHR-d3) has been associated with responsiveness to GH therapy. However, the data reported so far do vary according to the underlying condition, replacement dose, and duration of the treatment. OBJECTIVE, DESIGN: The aim of this study was to analyze the impact of the GHR genotypes in terms of the initial height velocity (HV) resulting from treatment and the impact upon adult height in patients suffering from severe isolated GH deficiency. CONTROLS, PATIENTS, SETTING: A total of 181 subjects (peak stimulated GH

Measurement of the 1s-2s energy interval in muonium

The 1s-2s interval has been measured in the muonium (;mgr;(+)e(-)) atom by Doppler-free two-photon pulsed laser spectroscopy. The frequency separation of the states was determined to be 2 455 528 941.0(9.8) MHz, in good agreement with quantum electrodynamics. The result may be interpreted as a measurement of the muon-electron charge ratio as -1-1.1(2.1)x10(-9). We expect significantly higher accuracy at future high flux muon sources and from cw laser technology.

Stability measurements of 1-stage implants in the edentulous mandible by means of resonance frequency analysis

OBJECTIVE: Resonance frequency analysis (RFA) is a method of measuring implant stability. However, little is known about RFA of implants with long loading periods. The objective of the present study was to determine standard implant stability quotients (ISQs) for clinical successfully osseointegrated 1-stage implants in the edentulous mandible. MATERIALS AND METHODS: Stability measurements by means of RFA were performed in regularly followed patients who had received 1- stage implants for overdenture support. The time interval between implant placement and measurement ranged from 1 year up to 10 years. The short-term group comprised patients who were followed up to 5 years, while the long-term group included patients with an observation time of > 5 years up to 10 years. For further comparison RFA measurements were performed in a matching group with unloaded implants at the end of the surgical procedure. For statistical analysis various parameters that might influence the ISQs of loaded implants were included, and a mixed-effects model applied (regression analysis, P <.0125). RESULTS: Ninety-four patients were available with a total of 205 loaded implants, and 16 patients with 36 implants immediately after the surgical procedure. The mean ISQ of all measured implants was 64.5 +/- 7.9 (range, 58 to 72). Statistical analysis did not reveal significant differences in the mean ISQ related to the observation time. The parameters with overall statistical significance were the diameter of the implants and changes in the attachment level. In the short-term group, the gender and the clinically measured attachment level had a significant effect. Implant diameter had a significant effect in the long-term group. CONCLUSIONS: A mean ISQ of 64.5 +/- 7.9 was found to be representative for stable asymptomatic interforaminal implants measured by the RFA instrument at any given time point. No significant differences in ISQ values were found between implants with different postsurgical time intervals. Implant diameter appears to influence the ISQ of interforaminal implants.

Different response to eccentric and concentric training in older men and women

Sarcopenia is the age-related loss of muscle mass and strength and has been associated with an increased risk of falling and the development of metabolic diseases. Various training protocols, nutritional and hormonal interventions have been proposed to prevent sarcopenia. This study explores the potential of continuous eccentric exercise to retard age-related loss of muscle mass and function. Elderly men and women (80.6 +/- 3.5 years) were randomized to one of three training interventions demanding a training effort of two sessions weekly for 12 weeks: cognitive training (CT; n = 16), conventional resistance training (RET; n = 23) and eccentric ergometer training (EET; n = 23). Subjects were tested for functional parameters and body composition. Biopsies were collected from M. vastus lateralis before and after the intervention for the assessment of fiber size and composition. Maximal isometric leg extension strength (MEL: +8.4 +/- 1.7%) and eccentric muscle coordination (COORD: -43 +/- 4%) were significantly improved with EET but not with RET (MEL: +2.3 +/- 2.0%; COORD: -13 +/- 3%) and CT (MEL: -2.3 +/- 2.5%; COORD: -12 +/- 5%), respectively. We observed a loss of body fat (-5.0 +/- 1.1%) and thigh fat (-6.9 +/- 1.5%) in EET subjects only. Relative thigh lean mass increased with EET (+2.5 +/- 0.6%) and RET (+2.0 +/- 0.3%) and correlated negatively with type IIX/type II muscle fiber ratios. It was concluded that both RET and EET are beneficial for the elderly with regard to muscle functional and structural improvements but differ in their spectrum of effects. A training frequency of only two sessions per week seems to be the lower limit for a training stimulus to reveal measurable benefits.

The systemic angiogenic response during bone healing

INTRODUCTION: Angiogenesis is known to be a critical and closely regulated step during bone formation and fracture healing driven by a complex interaction of various cytokines. Delays in bone healing or even nonunion might therefore be associated with altered concentrations of specific angiogenic factors. These alterations might in turn be reflected by changes in serum concentrations. METHOD: To determine physiological time courses of angiogenic cytokines during fracture healing as well as possible changes associated with failed consolidation, we prospectively collected serum samples from patients who had sustained surgical treatment for a long bone fracture. Fifteen patients without fracture healing 4 months after surgery (nonunion group) were matched to a collective of 15 patients with successful healing (union group). Serum concentrations of angiogenin (ANG), angiopoietin 2 (Ang-2), basic fibroblast growth factor (bFGF), platelet derived growth factor AB (PDGF-AB), pleiotrophin (PTN) and vascular endothelial growth factor (VEGF) were measured using enzyme linked immunosorbent assays over a period of 24 weeks. RESULTS: Compared to reference values of healthy uninjured controls serum concentrations of VEGF, bFGF and PDGF were increased in both groups. Peak concentrations of these cytokines were reached during early fracture healing. Serum concentrations of bFGF and PDGF-AB were significantly higher in the union group at 2 and 4 weeks after the injury when compared to the nonunion group. Serum concentrations of ANG and Ang-2 declined steadily from the first measurement in normal healing fractures, while no significant changes over time could be detected for serum concentrations of these factures in nonunion patients. PTN serum levels increased asymptotically over the entire investigation in timely fracture healing while no such increase could be detected during delayed healing. CONCLUSION: We conclude that fracture healing in human subjects is accompanied by distinct changes in systemic levels of specific angiogenic factors. Significant alterations of these physiologic changes in patients developing a fracture nonunion over time could be detected as early as 2 (bFGF) and 4 weeks (PDGF-AB) after initial trauma surgery.

Noninvasive measurement of cardiac output during exercise by inert gas rebreathing technique

Reduced exercise tolerance and dyspnea during exercise are hallmarks of heart failure syndrome. Exercise capacity and various parameters of cardiopulmonary response to exercise are of important prognostic value. All the available parameters only indirectly reflect left ventricular dysfunction and hemodynamic adaptation to an increased demand. Noninvasive assessment of cardiac output, especially during an incremental exercise stress test, would allow the direct measure of cardiac reserve and may become the gold standard for prognostic evaluation in the future.

Quantifying the influence of bone density and thickness on resonance frequency analysis: an in vitro study of biomechanical test materials

PURPOSE: Resonance frequency analysis (RFA) offers the opportunity to monitor the osseointegration of an implant in a simple, noninvasive way. A better comprehension of the relationship between RFA and parameters related to bone quality would therefore help clinicians improve diagnoses. In this study, a bone analog made from polyurethane foam was used to isolate the influences of bone density and cortical thickness in RFA. MATERIALS AND METHODS: Straumann standard implants were inserted in polyurethane foam blocks, and primary implant stability was measured with RFA. The blocks were composed of two superimposed layers with different densities. The top layer was dense to mimic cortical bone, whereas the bottom layer had a lower density to represent trabecular bone. Different densities for both layers and different thicknesses for the simulated cortical layer were tested, resulting in eight different block combinations. RFA was compared with two other mechanical evaluations of primary stability: removal torque and axial loading response. RESULTS: The primary stability measured with RFA did not correlate with the two other methods, but there was a significant correlation between removal torque and the axial loading response (P < .005). Statistical analysis revealed that each method was sensitive to different aspects of bone quality. RFA was the only method able to detect changes in both bone density and cortical thickness. However, changes in trabecular bone density were easier to distinguish with removal torque and axial loading than with RFA. CONCLUSIONS: This study shows that RFA, removal torque, and axial loading are sensitive to different aspects of the bone-implant interface. This explains the absence of correlation among the methods and proves that no standard procedure exists for the evaluation of primary stability.

Class-switzched B cells display response to therapeutic B-cell depletion in rheumatoid arthritis

Introduction Reconstitution of peripheral blood (PB) B cells after therapeutic depletion with the chimeric anti-CD20 antibody rituximab (RTX) mimics lymphatic ontogeny. In this situation, the repletion kinetics and migratory properties of distinct developmental B-cell stages and their correlation to disease activity might facilitate our understanding of innate and adaptive B-cell functions in rheumatoid arthritis (RA). Methods Thirty-five 'RTX-naïve' RA patients with active arthritis were treated after failure of tumour necrosis factor blockade in an open-label study with two infusions of 1,000 mg RTX. Prednisone dose was tapered according to clinical improvement from a median of 10 mg at baseline to 5 mg at 9 and 12 months. Conventional disease-modifying antirheumatic drugs were kept stable. Subsets of CD19+ B cells were assessed by flow cytometry according to their IgD and CD27 surface expression. Their absolute number and relative frequency in PB were followed every 3 months and were determined in parallel in synovial tissue (n = 3) or synovial fluid (n = 3) in the case of florid arthritis. Results Six of 35 patients fulfilled the European League Against Rheumatism criteria for moderate clinical response, and 19 others for good clinical response. All PB B-cell fractions decreased significantly in number (P < 0.001) after the first infusion. Disease activity developed independently of the total B-cell number. B-cell repopulation was dominated in quantity by CD27-IgD+ 'naïve' B cells. The low number of CD27+IgD- class-switched memory B cells (MemB) in the blood, together with sustained reduction of rheumatoid factor serum concentrations, correlated with good clinical response. Class-switched MemB were found accumulated in flaring joints. Conclusions The present data support the hypothesis that control of adaptive immune processes involving germinal centre-derived, antigen, and T-cell-dependently matured B cells is essential for successful RTX treatment.

A Physiological Controller for Turbodynamic Ventricular Assist Devices Based on a Measurement of the Left Ventricular Volume

The current article presents a novel physiological control algorithm for ventricular assist devices (VADs), which is inspired by the preload recruitable stroke work. This controller adapts the hydraulic power output of the VAD to the end-diastolic volume of the left ventricle. We tested this controller on a hybrid mock circulation where the left ventricular volume (LVV) is known, i.e., the problem of measuring the LVV is not addressed in the current article. Experiments were conducted to compare the response of the controller with the physiological and with the pathological circulation, with and without VAD support. A sensitivity analysis was performed to analyze the influence of the controller parameters and the influence of the quality of the LVV signal on the performance of the control algorithm. The results show that the controller induces a response similar to the physiological circulation and effectively prevents over- and underpumping, i.e., ventricular suction and backflow from the aorta to the left ventricle, respectively. The same results are obtained in the case of a disturbed LVV signal. The results presented in the current article motivate the development of a robust, long-term stable sensor to measure the LVV.

Region Specific Response of Intervertebral Disc Cells to Complex Dynamic Loading: An Organ Culture Study Using a Dynamic Torsion-Compression Bioreactor

The spine is routinely subjected to repetitive complex loading consisting of axial compression, torsion, flexion and extension. Mechanical loading is one of the important causes of spinal diseases, including disc herniation and disc degeneration. It is known that static and dynamic compression can lead to progressive disc degeneration, but little is known about the mechanobiology of the disc subjected to combined dynamic compression and torsion. Therefore, the purpose of this study was to compare the mechanobiology of the intervertebral disc when subjected to combined dynamic compression and axial torsion or pure dynamic compression or axial torsion using organ culture. We applied four different loading modalities 1. control: no loading (NL), 2. cyclic compression (CC), 3. cyclic torsion (CT), and 4. combined cyclic compression and torsion (CCT) on bovine caudal disc explants using our custom made dynamic loading bioreactor for disc organ culture. Loads were applied for 8 h/day and continued for 14 days, all at a physiological magnitude and frequency. Our results provided strong evidence that complex loading induced a stronger degree of disc degeneration compared to one degree of freedom loading. In the CCT group, less than 10\% nucleus pulposus (NP) cells survived the 14 days of loading, while cell viabilities were maintained above 70\% in the NP of all the other three groups and in the annulus fibrosus (AF) of all the groups. Gene expression analysis revealed a strong up-regulation in matrix genes and matrix remodeling genes in the AF of the CCT group. Cell apoptotic activity and glycosaminoglycan content were also quantified but there were no statistically significant differences found. Cell morphology in the NP of the CCT was changed, as shown by histological evaluation. Our results stress the importance of complex loading on the initiation and progression of disc degeneration.

Higher frequency of genetic variants conferring increased risk for ADRs for commonly used drugs treating cancer, AIDS and tuberculosis in persons of African descent

There is established clinical evidence for differences in drug response, cure rates and survival outcomes between different ethnic populations, but the causes are poorly understood. Differences in frequencies of functional genetic variants in key drug response and metabolism genes may significantly influence drug response differences in different populations. To assess this, we genotyped 1330 individuals of African (n=372) and European (n=958) descent for 4535 single-nucleotide polymorphisms in 350 key drug absorption, distribution, metabolism, elimination and toxicity genes. Important and remarkable differences in the distribution of genetic variants were observed between Africans and Europeans and among the African populations. These could translate into significant differences in drug efficacy and safety profiles, and also in the required dose to achieve the desired therapeutic effect in different populations. Our data points to the need for population-specific genetic variation in personalizing medicine and care.

EVOLUTION OF DOMINANCE UNDER FREQUENCY-DEPENDENT INTRASPECIFIC COMPETITION IN AN ASSORTATIVELY MATING POPULATION

We study the evolution of higher levels of dominance as a response to negative frequency-dependent selection. In contrast to previous studies, we focus on the effect of assortative mating on the evolution of dominance under frequency-dependent intraspecific competition. We analyze a two-locus two-allele model, in which the primary locus has a major effect on a quantitative trait that is under a mixture of frequency-independent stabilizing selection, density-dependent selection, and frequency-dependent selection caused by intraspecific competition for a continuum of resources. The second (modifier) locus determines the degree of dominance at the trait level. Additionally, the population mates assortatively with respect to similarities in the ecological trait. Our analysis shows that the parameter region in which dominance can be established decreases if small levels of assortment are introduced. In addition, the degree of dominance that can be established also decreases. In contrast, if assortment is intermediate, sexual selection for extreme types can be established, which leads to evolution of higher levels of dominance than under random mating. For modifiers with large effects, intermediate levels of assortative mating are most favorable for the evolution of dominance. For large modifiers, the speed of fixation can even be higher for intermediate levels of assortative mating than for random mating.

Jet energy measurement with the ATLAS detector in proton-proton collisions at sqrt(s) = 7 TeV

The jet energy scale (JES) and its systematic uncertainty are determined for jets measured with the ATLAS detector at the LHC in proton-proton collision data at a centre-of-mass energy of sqrt(s) = 7 TeV corresponding to an integrated luminosity of 38 inverse pb. Jets are reconstructed with the anti-kt algorithm with distance parameters R=0.4 or R=0.6. Jet energy and angle corrections are determined from Monte Carlo simulations to calibrate jets with transverse momenta pt > 20 GeV and pseudorapidities eta<4.5. The JES systematic uncertainty is estimated using the single isolated hadron response measured in situ and in test-beams. The JES uncertainty is less than 2.5% in the central calorimeter region (eta<0.8) for jets with 60 < pt < 800 GeV, and is maximally 14% for pt < 30 GeV in the most forward region 3.2 50 GeV after a dedicated correction for this effect. The JES is validated for jet transverse momenta up to 1 TeV to the level of a few percent using several in situ techniques by comparing a well-known reference such as the recoiling photon pt, the sum of the transverse momenta of tracks associated to the jet, or a system of low-pt jets recoiling against a high-pt jet. More sophisticated jet calibration schemes are presented based on calorimeter cell energy density weighting or hadronic properties of jets, providing an improved jet energy resolution and a reduced flavour dependence of the jet response. The JES systematic uncertainty determined from a combination of in situ techniques are consistent with the one derived from single hadron response measurements over a wide kinematic range. The nominal corrections and uncertainties are derived for isolated jets in an inclusive sample of high-pt jets.