Effects of growth hormone (GH) replacement therapy on very low density lipoprotein apolipoprotein B100 kinetics in patients with adult GH deficiency: a stable isotope study

Patients with adult GH deficiency are often dyslipidemic and may have an increased risk of cardiovascular disease. The secretion and clearance of very low density lipoprotein apolipoprotein B 100 (VLDL apoB) are important determinants of plasma lipid concentrations. This study examined the effect of GH replacement therapy on VLDL apoB metabolism using a stable isotope turnover technique. VLDL apoB kinetics were determined in 14 adult patients with GH deficiency before and after 3 months GH or placebo treatment in a randomized double blind, placebo-controlled study using a primed constant [1-(13)C]leucine infusion. VLDL apoB enrichment was determined by gas chromatography-mass spectrometry. GH replacement therapy increased plasma insulin-like growth factor I concentrations 2.9 +/- 0.5-fold (P < 0.001), fasting insulin concentrations 1.8 +/- 0.6-fold (P < 0.04), and hemoglobin A1C from 5.0 +/- 0.2% to 5.3 +/- 0.2% (mean +/- SEM; P < 0.001). It decreased fat mass by 3.4 +/- 1.3 kg (P < 0.05) and increased lean body mass by 3.5 +/- 0.8 kg (P < 0.01). The total cholesterol concentration (P < 0.02), the low density lipoprotein cholesterol concentration (P < 0.02), and the VLDL cholesterol/VLDL apoB ratio (P < 0.005) decreased. GH therapy did not significantly change the VLDL apoB pool size, but increased the VLDL apoB secretion rate from 9.2 +/- 2.0 to 25.9 +/- 10.3 mg/kg x day (P < 0.01) and the MCR from 11.5 +/- 2.7 to 20.3 +/- 3.2 mL/min (P < 0.03). No significant changes were observed in the placebo group. This study suggests that GH replacement therapy improves lipid profile by increasing the removal of VLDL apoB. Although GH therapy stimulates VLDL apoB secretion, this is offset by the increase in the VLDL apoB clearance rate, which we postulate is due to its effects in up-regulating low density lipoprotein receptors and modifying VLDL composition.

Who has really paid for the Reconstruction of East Germany? Expected and Realized Returns on Real Estate Investments in East and West Germany in the 1990s

We evaluate the profitability of investments in residential property in Germany after unification with a focus on the comparison of East and West Germany. Calculations are carried out for (1) the after-tax return an investor might have expected at the beginning of the 1990s, and (2) the after-tax return that has been realized ten years after. We compare a set of statistical data for investments in fifty major cities by using complete financial budgeting. The results show that tax subsidies could not always protect investors from losing money, but they have boosted realized returns after tax considerably. Therefore, it was indeed the taxpayers, not the investors, who have borne the cost of reconstructing East Germany.

Application of Time-Delay Estimation to Mixed Reality Multisensor Tracking

Spatial tracking is one of the most challenging and important parts of Mixed Reality environments. Many applications, especially in the domain of Augmented Reality, rely on the fusion of several tracking systems in order to optimize the overall performance. While the topic of spatial tracking sensor fusion has already seen considerable interest, most results only deal with the integration of carefully arranged setups as opposed to dynamic sensor fusion setups. A crucial prerequisite for correct sensor fusion is the temporal alignment of the tracking data from several sensors. Tracking sensors are typically encountered in Mixed Reality applications, are generally not synchronized. We present a general method to calibrate the temporal offset between different sensors by the Time Delay Estimation method which can be used to perform on-line temporal calibration. By applying Time Delay Estimation on the tracking data, we show that the temporal offset between generic Mixed Reality spatial tracking sensors can be calibrated. To show the correctness and the feasibility of this approach, we have examined different variations of our method and evaluated various combinations of tracking sensors. We furthermore integrated this time synchronization method into our UBITRACK Mixed Reality tracking framework to provide facilities for calibration and real-time data alignment.

Evidence for past variations in methane availability in a Siberian thermokarst lake based on δ13C of chitinous invertebrate remains

Understanding past methane dynamics in arctic wetlands and lakes is crucial for estimating future methane release. Methane fluxes from lake ecosystems have increasingly been studied, yet only few reconstructions of past methane emissions from lakes are available. In this study, we develop an approach to assess changes in methane availability in lakes based on δ13C of chitinous invertebrate remains and apply this to a sediment record from a Siberian thermokarst lake. Diffusive methane fluxes from the surface of ten newly sampled Siberian lakes and seven previously studied Swedish lakes were compared to taxon-specific δ13C values of invertebrate remains from lake surface sediments to investigate whether these invertebrates assimilated 13C-depleted carbon typical for methane. Remains of chironomid larvae of the tribe Orthocladiinae that, in the study lakes, mainly assimilate plant-derived carbon had higher δ13C than other invertebrate groups. δ13C of other invertebrates such as several chironomid groups (Chironomus, Chironomini, Tanytarsini, and Tanypodinae), cladocerans (Daphnia), and ostracods were generally lower. δ13C of Chironomini and Daphnia, and to a lesser extent Tanytarsini was variable in the lakes and lower at sites with higher diffusive methane fluxes. δ13C of Chironomini, Tanytarsini, and Daphnia were correlated significantly with diffusive methane flux in the combined Siberian and Swedish dataset (r = −0.72, p = 0.001, r = −0.53, p = 0.03, and r = −0.81, p < 0.001, respectively), suggesting that δ13C in these invertebrates was affected by methane availability. In a second step, we measured δ13C of invertebrate remains from a sediment record of Lake S1, a shallow thermokarst lake in northeast Siberia. In this record, covering the past ca 1000 years, δ13C of taxa most sensitive to methane availability (Chironomini, Tanytarsini, and Daphnia) was lowest in sediments deposited from ca AD 1250 to ca AD 1500, and after AD 1970, coinciding with warmer climate as indicated by an independent local temperature record. As a consequence the offset in δ13C between methane-sensitive taxa and bulk organic matter was higher in these sections than in other parts of the core. In contrast, δ13C of other invertebrate taxa did not show this trend. Our results suggest higher methane availability in the study lake during warmer periods and that thermokarst lakes can respond dynamically in their methane output to changing environmental conditions.

A tutorial on data-driven methods for statistically assessing ERP topographies

Dynamic changes in ERP topographies can be conveniently analyzed by means of microstates, the so-called "atoms of thoughts", that represent brief periods of quasi-stable synchronized network activation. Comparing temporal microstate features such as on- and offset or duration between groups and conditions therefore allows a precise assessment of the timing of cognitive processes. So far, this has been achieved by assigning the individual time-varying ERP maps to spatially defined microstate templates obtained from clustering the grand mean data into predetermined numbers of topographies (microstate prototypes). Features obtained from these individual assignments were then statistically compared. This has the problem that the individual noise dilutes the match between individual topographies and templates leading to lower statistical power. We therefore propose a randomization-based procedure that works without assigning grand-mean microstate prototypes to individual data. In addition, we propose a new criterion to select the optimal number of microstate prototypes based on cross-validation across subjects. After a formal introduction, the method is applied to a sample data set of an N400 experiment and to simulated data with varying signal-to-noise ratios, and the results are compared to existing methods. In a first comparison with previously employed statistical procedures, the new method showed an increased robustness to noise, and a higher sensitivity for more subtle effects of microstate timing. We conclude that the proposed method is well-suited for the assessment of timing differences in cognitive processes. The increased statistical power allows identifying more subtle effects, which is particularly important in small and scarce patient populations.

Impingement adversely affects 10-year survivorship after periacetabular osteotomy for DDH

BACKGROUND Although periacetabular osteotomy (PAO) for developmental dysplasia of the hip (DDH) provides conceptual advantages compared with other osteotomies and reportedly is associated with joint survivorship of 60% at 20 years, the beneficial effect of proper acetabular reorientation with concomitant arthrotomy and creation of femoral head-neck offset on 10-year hip survivorship remains unclear. QUESTIONS/PURPOSES We asked the following questions: (1) Does the 10-year survivorship of the hip after PAO improve with proper acetabular reorientation and a spherical femoral head; (2) does the Merle d'Aubigné-Postel score improve; (3) can the progression of osteoarthritis (OA) be slowed; and (4) what factors predict conversion to THA, progression of OA, or a Merle d'Aubigné-Postel score less than 15 points? METHODS We retrospectively reviewed 147 patients who underwent 165 PAOs for DDH with two matched groups: Group I (proper reorientation and spherical femoral head) and Group II (improper reorientation and aspherical femoral head). We compared the Kaplan-Meier survivorship, Merle d'Aubigné-Postel scores, and progression of OA in both groups. A Cox regression analysis (end points: THA, OA progression, or Merle d'Aubigné-Postel score less than 15) was performed to detect factors predicting failure. The minimum followup was 10 years (median, 11 years; range, 10-14 years). RESULTS An increased survivorship was found in Group I. The Merle d'Aubigné-Postel score did not differ. Progression of OA in Group I was slower than in Group II. Factors predicting failure included greater age, lower preoperative Merle d'Aubigné-Postel score, and the presence of a Trendelenburg sign, aspherical head, OA, subluxation, postoperative acetabular retroversion, excessive acetabular anteversion, and undercoverage. CONCLUSIONS Proper acetabular reorientation and the creation of a spherical femoral head improve long-term survivorship and decelerate OA progression in patients with DDH.

The influence of muscle strength on the gait profile score (GPS) across different patients

BACKGROUND Muscle strength greatly influences gait kinematics. The question was whether this association is similar in different diseases. METHODS Data from instrumented gait analysis of 716 patients were retrospectively assessed. The effect of muscle strength on gait deviations, namely the gait profile score (GPS) was evaluated by means of generalised least square models. This was executed for seven different patient groups. The groups were formed according to the type of disease: orthopaedic/neurologic, uni-/bilateral affection, and flaccid/spastic muscles. RESULTS Muscle strength had a negative effect on GPS values, which did not significantly differ amongst the different patient groups. However, an offset of the GPS regression line was found, which was mostly dependent on the basic disease. Surprisingly, spastic patients, who have reduced strength and additionally spasticity in clinical examination, and flaccid neurologic patients showed the same offset. Patients with additional lack of trunk control (Tetraplegia) showed the largest offset. CONCLUSION Gait kinematics grossly depend on muscle strength. This was seen in patients with very different pathologies. Nevertheless, optimal correction of biomechanics and muscle strength may still not lead to a normal gait, especially in that of neurologic patients. The basic disease itself has an additional effect on gait deviations expressed as a GPS-offset of the linear regression line.

Deleterious effects of roving on learned tasks

In typical perceptual learning experiments, one stimulus type (e.g., a bisection stimulus offset either to the left or right) is presented per trial. In roving, two different stimulus types (e.g., a 30′ and a 20′ wide bisection stimulus) are randomly interleaved from trial to trial. Roving can impair both perceptual learning and task sensitivity. Here, we investigate the relationship between the two. Using a bisection task, we found no effect of roving before training. We next trained subjects and they improved. A roving condition applied after training impaired sensitivity.

Highly accurate evaluation of GPS synchronization for TDOA localization

Clock synchronization is critical for the operation of a distributed wireless network system. In this paper we investigate on a method able to evaluate in real time the synchronization offset between devices down to nanoseconds (as needed for positioning). The method is inspired by signal processing algorithms and relies on fine-grain time information obtained during the reconstruction of the signal at the receiver. Applying the method to a GPS-synchronized system show that GPS-based synchronization has high accuracy potential but still suffers from short-term clock drift, which limits the achievable localization error.

Metabolic divergence between sibling species of cichlids Pundamilia nyererei and Pundamilia pundamilia

This study compared Pundamilia nyererei and Pundamilia pundamilia males in routine metabolic rate (RR ) and in the metabolic costs males pay during territorial interactions (active metabolic rate, RA ). Pundamilia nyererei and P. pundamilia males housed in social isolation did not differ in RR . In contrast to expectation, however, P. nyererei males used less oxygen than P. pundamilia males, for a given mass and level of agonistic activity. This increased metabolic efficiency may be an adaptation to limit the metabolic cost that P. nyererei males pay for their higher rate of aggressiveness compared to P. pundamilia males. Thus, the divergence between the species in agonistic behaviour is correlated with metabolic differentiation. Such concerted divergence in physiology and behaviour might be widespread in the dramatically diverse cichlid radiations in East African lakes and may be an important factor in the remarkably rapid speciation of these fishes. The results did not support the hypothesis that higher metabolic rates caused a physiological cost to P. nyererei males that would offset their dominance advantage.

Short-term feed intake is regulated by macronutrient oxidation in lactating Holstein cows

In addition to plasma metabolites and hormones participating as humoral signals in the control of feed intake, oxidative metabolic processes in peripheral organs also generate signals to terminate feeding. Although the degree of oxidation over longer periods is relatively constant, recent work suggests that the periprandial pattern of fuel oxidation is involved in regulating feeding behavior in the bovine. However, the association between periprandial oxidative metabolism and feed intake of dairy cows has not yet been studied. Therefore, the aim of this study was to elucidate possible associations existing between single feed intake events and whole-body net fat and net carbohydrate oxidation as well as their relation to plasma metabolite concentrations. To this end, 4 late-lactating cows equipped with jugular catheters were kept in respiratory chambers with continuous and simultaneous recording of gas exchange and feed intake. Animals were fed ad libitum (AL) for 24h and then feed restricted (RE) to 50% of the previous AL intake for a further 24h. Blood samples were collected hourly to analyze β-hydroxybutyrate (BHBA), glucose, nonesterified fatty acids (NEFA), insulin, and acylated ghrelin concentrations. Cross-correlation analysis revealed an offset ranging between 30 and 42 min between the maximum of a feed intake event and the lowest level of postprandial net fat oxidation (FOX(net)) and the maximum level of postprandial net carbohydrate oxidation (COX(net)), respectively. During the AL period, FOX(net) did not increase above -0.2g/min, whereas COX(net) did not decrease below 6g/min before the start of the next feed intake event. A strong inverse cross-correlation was obtained between COX(net) and plasma glucose concentration. Direct cross-correlations were observed between COXnet and insulin, between heat production and BHBA, between insulin and glucose, and between BHBA and ghrelin. We found no cross-correlation between FOX(net) and NEFA. During RE, FOX(net) increased with an exponential slope, exceeded the threshold of -0.2g/min as indicated by increasing plasma NEFA concentrations, and approached a maximum rate of 0.1g/min, whereas COX(net) decayed in an exponential manner, approaching a minimal COX(net) rate of about 2.5 g/min in all cows. Our novel findings suggest that, in late-lactating cows, postprandial increases in metabolic oxidative processes seem to signal suppression of feed intake, whereas preprandially an accelerated FOX(net) rate and a decelerated COX(net) rate initiate feed intake.

Learner preferences regarding integrating, sequencing and aligning virtual patients with other activities in the undergraduate medical curriculum: A focus group study

CONTEXT: E-learning resources, such as virtual patients (VPs), can be more effective when they are integrated in the curriculum. To gain insights that can inform guidelines for the curricular integration of VPs, we explored students' perceptions of scenarios with integrated and non-integrated VPs aimed at promoting clinical reasoning skills. METHODS: During their paediatric clerkship, 116 fifth-year medical students were given at least ten VPs embedded in eight integrated scenarios and as non-integrated add-ons. The scenarios differed in the sequencing and alignment of VPs and related educational activities, tutor involvement, number of VPs, relevance to assessment and involvement of real patients. We sought students' perceptions on the VP scenarios in focus group interviews with eight groups of 4-7 randomly selected students (n = 39). The interviews were recorded, transcribed and analysed qualitatively. RESULTS: The analysis resulted in six themes reflecting students' perceptions of important features for effective curricular integration of VPs: (i) continuous and stable online access, (ii) increasing complexity, adapted to students' knowledge, (iii) VP-related workload offset by elimination of other activities, (iv) optimal sequencing (e.g.: lecture--1 to 2 VP(s)--tutor-led small group discussion--real patient) and (V) optimal alignment of VPs and educational activities, (vi) inclusion of VP topics in assessment. CONCLUSIONS: The themes appear to offer starting points for the development of a framework to guide the curricular integration of VPs. Their impact needs to be confirmed by studies using quantitative controlled designs.

Detecting offsets in GPS time series: first results from the Detection of Offsets in GPS Experiment

The accuracy of Global Positioning System (GPS) time series is degraded by the presence of offsets. To assess the effectiveness of methods that detect and remove these offsets, we designed and managed the Detection of Offsets in GPS Experiment. We simulated time series that mimicked realistic GPS data consisting of a velocity component, offsets, white and flicker noises (1/f spectrum noises) composed in an additive model. The data set was made available to the GPS analysis community without revealing the offsets, and several groups conducted blind tests with a range of detection approaches. The results show that, at present, manual methods (where offsets are hand picked) almost always give better results than automated or semi‒automated methods (two automated methods give quite similar velocity bias as the best manual solutions). For instance, the fifth percentile range (5% to 95%) in velocity bias for automated approaches is equal to 4.2 mm/year (most commonly ±0.4 mm/yr from the truth), whereas it is equal to 1.8 mm/yr for the manual solutions (most commonly 0.2 mm/yr from the truth). The magnitude of offsets detectable by manual solutions is smaller than for automated solutions, with the smallest detectable offset for the best manual and automatic solutions equal to 5 mm and 8 mm, respectively. Assuming the simulated time series noise levels are representative of real GPS time series, robust geophysical interpretation of individual site velocities lower than 0.2–0.4 mm/yr is therefore certainly not robust, although a limit of nearer 1 mm/yr would be a more conservative choice. Further work to improve offset detection in GPS coordinates time series is required before we can routinely interpret sub‒mm/yr velocities for single GPS stations.

Practical use of dabigatran etexilate for stroke prevention in atrial fibrillation

Atrial fibrillation (AF) is associated with an increased risk of thromboembolism, and is the most prevalent factor for cardioembolic stroke. Vitamin K antagonists (VKAs) have been the standard of care for stroke prevention in patients with AF since the early 1990s. They are very effective for the prevention of cardioembolic stroke, but are limited by factors such as drug-drug interactions, food interactions, slow onset and offset of action, haemorrhage and need for routine anticoagulation monitoring to maintain a therapeutic international normalised ratio (INR). Multiple new oral anticoagulants have been developed as potential replacements for VKAs for stroke prevention in AF. Most are small synthetic molecules that target thrombin (e.g. dabigatran etexilate) or factor Xa (e.g. rivaroxaban, apixaban, edoxaban, betrixaban, YM150). These drugs have predictable pharmacokinetics that allow fixed dosing without routine laboratory monitoring. Dabigatran etexilate, the first of these new oral anticoagulants to be approved by the United States Food and Drug Administration and the European Medicines Agency for stroke prevention in patients with non-valvular AF, represents an effective and safe alternative to VKAs. Under the auspices of the Regional Anticoagulation Working Group, a multidisciplinary group of experts in thrombosis and haemostasis from Central and Eastern Europe, an expert panel with expertise in AF convened to discuss practical, clinically important issues related to the long-term use of dabigatran for stroke prevention in non-valvular AF. The practical information reviewed in this article will help clinicians make appropriate use of this new therapeutic option in daily clinical practice.

Glacial–interglacial dynamics of Antarctic firn columns: comparison between simulations and ice core air-δ15N measurements

Correct estimation of the firn lock-in depth is essential for correctly linking gas and ice chronologies in ice core studies. Here, two approaches to constrain the firn depth evolution in Antarctica are presented over the last deglaciation: outputs of a firn densification model, and measurements of δ15N of N2 in air trapped in ice core, assuming that δ15N is only affected by gravitational fractionation in the firn column. Since the firn densification process is largely governed by surface temperature and accumulation rate, we have investigated four ice cores drilled in coastal (Berkner Island, BI, and James Ross Island, JRI) and semi-coastal (TALDICE and EPICA Dronning Maud Land, EDML) Antarctic regions. Combined with available ice core air-δ15N measurements from the EPICA Dome C (EDC) site, the studied regions encompass a large range of surface accumulation rates and temperature conditions. Our δ15N profiles reveal a heterogeneous response of the firn structure to glacial–interglacial climatic changes. While firn densification simulations correctly predict TALDICE δ15N variations, they systematically fail to capture the large millennial-scale δ15N variations measured at BI and the δ15N glacial levels measured at JRI and EDML – a mismatch previously reported for central East Antarctic ice cores. New constraints of the EDML gas–ice depth offset during the Laschamp event (~41 ka) and the last deglaciation do not favour the hypothesis of a large convective zone within the firn as the explanation of the glacial firn model–δ15N data mismatch for this site. While we could not conduct an in-depth study of the influence of impurities in snow for firnification from the existing datasets, our detailed comparison between the δ15N profiles and firn model simulations under different temperature and accumulation rate scenarios suggests that the role of accumulation rate may have been underestimated in the current description of firnification models.