Minimization of metabolic cost of transport predicts changes in gait mechanics over a range of ankle-foot orthosis stiffnesses in individuals with bilateral plantar flexor weakness

Neuromuscular disorders often lead to ankle plantar flexor muscle weakness, which impairs ankle push-off power and forward propulsion during gait. To improve walking speed and reduce metabolic cost of transport (mCoT), patients with plantar flexor weakness are provided dorsal-leaf spring ankle-foot orthoses (AFOs). It is widely believed that mCoT during gait depends on the AFO stiffness and an optimal AFO stiffness that minimizes mCoT exists. The biomechanics behind why and how an optimal stiffness exists and benefits individuals with plantar flexor weakness are not well understood. We hypothesized that the AFO would reduce the required support moment and, hence, metabolic cost contributions of the ankle plantar flexor and knee extensor muscles during stance, and reduce hip flexor metabolic cost to initiate swing. To test these hypotheses, we generated neuromusculoskeletal simulations to represent gait of an individual with bilateral plantar flexor weakness wearing an AFO with varying stiffness. Predictions were based on the objective of minimizing mCoT, loading rates at impact and head accelerations at each stiffness level, and the motor patterns were determined via dynamic optimization. The predictive gait simulation results were compared to experimental data from subjects with bilateral plantar flexor weakness walking with varying AFO stiffness. Our simulations demonstrated that reductions in mCoT with increasing stiffness were attributed to reductions in quadriceps metabolic cost during midstance. Increases in mCoT above optimum stiffness were attributed to the increasing metabolic cost of both hip flexor and hamstrings muscles. The insights gained from our predictive gait simulations could inform clinicians on the prescription of personalized AFOs. With further model individualization, simulations based on mCoT minimization may sufficiently predict adaptations to an AFO in individuals with plantar flexor weakness

Amino Acid Homeostasis and Fatigue in Chronic Hemodialysis Patients

Patients dependent on chronic hemodialysis treatment are prone to malnutrition, at least in part due to insufficient nutrient intake, metabolic derangements, and chronic inflammation. Losses of amino acids during hemodialysis may be an important additional contributor. In this study, we assessed changes in plasma amino acid concentrations during hemodialysis, quantified intradialytic amino acid losses, and investigated whether plasma amino acid concentrations and amino acid losses by hemodialysis and urinary excretion are associated with fatigue. The study included a total of 59 hemodialysis patients (65 +/- 15 years, 63% male) and 33 healthy kidney donors as controls (54 +/- 10 years, 45% male). Total plasma essential amino acid concentration before hemodialysis was lower in hemodialysis patients compared with controls (p = 0.006), while total non-essential amino acid concentration did not differ. Daily amino acid losses were 4.0 +/- 1.3 g/24 h for hemodialysis patients and 0.6 +/- 0.3 g/24 h for controls. Expressed as proportion of protein intake, daily amino acid losses of hemodialysis patients were 6.7 +/- 2.4% of the total protein intake, compared to 0.7 +/- 0.3% for controls (p < 0.001). Multivariable regression analyses demonstrated that hemodialysis efficacy (Kt/V) was the primary determinant of amino acid losses (Std. beta = 0.51; p < 0.001). In logistic regression analyses, higher plasma proline concentrations were associated with higher odds of severe fatigue (OR (95% CI) per SD increment: 3.0 (1.3; 9.3); p = 0.03), while higher taurine concentrations were associated with lower odds of severe fatigue (OR (95% CI) per log2 increment: 0.3 (0.1; 0.7); p = 0.01). Similarly, higher daily taurine losses were also associated with lower odds of severe fatigue (OR (95% CI) per log2 increment: 0.64 (0.42; 0.93); p = 0.03). Lastly, a higher protein intake was associated with lower odds of severe fatigue (OR (95% CI) per SD increment: 0.2 (0.04; 0.5); p = 0.007). Future studies are warranted to investigate the mechanisms underlying these associations and investigate the potential of taurine supplementation

Regional sediment deficits in the Dutch lowlands:Implications for long-term land-use options

Background, Aim and Scope. Coastal and river plains are the surfaces of depositional systems, to which sediment input is a parameter of key-importance. Their habitation and economic development usually requires protection with dikes, quays, etc., which are effective in retaining floods but have the side effect of impeding sedimentation in their hinterlands. The flood-protected Dutch lowlands (so-called dike-ring areas) have been sediment-starved for up to about a millennium. In addition to this, peat decomposition and soil compaction, brought about by land drainage, have caused significant land subsidence. Sediment deficiency, defined as the combined effect of sediment-starvation and drainage-induced volume losses, has already been substantial in this area, and it is expected to become urgent in view of the forecasted effects of climate change (sea-level rise, intensified precipitation and run-off). We therefore explore this deficiency, compare it with natural (Holocene) and current human sediment inputs, and discuss it in terms of long-term land-use options. Materials and Methods. We use available 3D geological models to define natural sediment inputs to our study area. Recent progress in large-scale modelling of peat oxidation and compaction enables us to address volume loss associated with these processes. Human sediment inputs are based on published minerals statistics. All results are given as first-order approximations. Results. The current sediment deficit in the diked lowlands of the Netherlands is estimated at 136 ± 67 million m3/a. About 85% of this volume is the hypothetical amount of sediment required to keep up with sea-level rise, and 15% is the effect of land drainage (peat decomposition and compaction). The average Holocene sediment input to our study area (based on a total of 145 km3) is -14 million m3/a, and the maximum (millennium-averaged) input ∼26 million m3/a. Historical sediment deficiency has resulted in an unused sediment accommodation space of about 13.3 km3. Net human input of sediment material currently amounts to ∼23 million m3/a. Discussion. As sedimentary processes in the Dutch lowlands have been retarded, the depositional system's natural resilience to sea-level rise is low, and all that is left to cope is human counter-measure. Preserving some sort of status quo with water management solutions may reach its limits in the foreseeable future. The most viable long-term option therefore seems a combination of allowing for more water in open country (anything from flood-buffer zones to open water) and raising lands that are to be built up (enabling their lasting protection). As to the latter, doubling or tripling the use of filling sand in a planned and sustained effort may resolve up to one half of the Dutch sediment deficiency problems in about a century. Conclusions, Recommendations and Perspectives. We conclude that sediment deficiency - past, present and future - challenges the sustainable habitation of the Dutch lowlands. In order to explore possible solutions, we recommend the development of long-term scenarios for the changing lowland physiography, that include the effects of Global Change, compensation measures, costs and benefits, and the implications for long-term land-use options. © 2007 ecomed publishers (Verlagsgruppe Hüthig Jehle Rehm GmbH)

Definitiestudie afwegingskader : naar een klimaatbestendig Nederland : definitiestudie Fase 1, kaders voor afweging

Onzekerheid over (omvang en tempo van) de gevolgen van klimaatverandering vormt een essentieel punt bij beslissingen over de ruimtelijke inrichting. De mate waarin en de snelheid waarmee veranderingen optreden zijn niet precies bekend. Een afwegingskader geeft de overheid en de planontwikkelaar instrumenten in handen om de risico’s, de kansen, de kosten en de baten van klimaatadaptatie op verschillende onderscheiden thema’s inzichtelijk te maken. Afwegen: hoe doe je dat. Daarvoor wordt in drie stappen een kader voor gegeven

A novel patient-derived tumorgraft model with TRAF1-ALK anaplastic large-cell lymphoma translocation.

Although anaplastic large-cell lymphomas (ALCL) carrying anaplastic lymphoma kinase (ALK) have a relatively good prognosis, aggressive forms exist. We have identified a novel translocation, causing the fusion of the TRAF1 and ALK genes, in one patient who presented with a leukemic ALK+ ALCL (ALCL-11). To uncover the mechanisms leading to high-grade ALCL, we developed a human patient-derived tumorgraft (hPDT) line. Molecular characterization of primary and PDT cells demonstrated the activation of ALK and nuclear factor kB (NFkB) pathways. Genomic studies of ALCL-11 showed the TP53 loss and the in vivo subclonal expansion of lymphoma cells, lacking PRDM1/Blimp1 and carrying c-MYC gene amplification. The treatment with proteasome inhibitors of TRAF1-ALK cells led to the downregulation of p50/p52 and lymphoma growth inhibition. Moreover, a NFkB gene set classifier stratified ALCL in distinct subsets with different clinical outcome. Although a selective ALK inhibitor (CEP28122) resulted in a significant clinical response of hPDT mice, nevertheless the disease could not be eradicated. These data indicate that the activation of NFkB signaling contributes to the neoplastic phenotype of TRAF1-ALK ALCL. ALCL hPDTs are invaluable tools to validate the role of druggable molecules, predict therapeutic responses and implement patient specific therapies

The Frenchness of Marcel Lefebvre and the Society of St Pius X:a new reading

The case of Marcel Lefebvre and the Society of St Pius X (SSPX) deserves fresh perspectives. The current historiography is too franco-centric, focused on selective aspects of Lefebvre’s biography and the actions of isolated individuals, rather than with the life of the SSPX itself. After evaluating the current state of the historiography, this article proposes a new analysis of the SSPX’s political discourses in France and internationally and undertakes to reframe the relationship between Lefebvre’s life and his congregation by re-examining his African missionary experiences. Such new perspectives will be helpful as the SSPX moves towards regularisation under the pontificate of Pope Francis

VASP, zyxin and TES are tension-dependent members of Focal Adherens Junctions independent of the α-catenin-vinculin module

Mechanical forces are integrated at cadherin-based adhesion complexes to regulate morphology and strength of cell-cell junctions and organization of associated F-actin. A central mechanosensor at the cadherin complex is α-catenin, whose stretching recruits vinculin to regulate adhesion strength. The identity of the F-actin regulating signals that are also activated by mechanical forces at cadherin-based junctions has remained elusive. Here we identify the actin-regulators VASP, zyxin and TES as members of punctate, tensile cadherin-based junctions called Focal Adherens Junctions (FAJ) and show that they display mechanosensitive recruitment similar to that of vinculin. However, this recruitment is not altered by destroying or over-activating the α-catenin/vinculin module. Structured Illumination Microscopy (SIM) indicates that these tension sensitive proteins concentrate at locations within FAJs that are distinct from the core cadherin complex proteins. Furthermore, localization studies using mutated versions of VASP and zyxin indicate that these two proteins require binding to each other in order to localize to the FAJs. We conclude that there are multiple force sensitive modules present at the FAJ that are activated at distinct locations along the cadherin-F-actin axis and regulate specific aspects of junction dynamics

Measurement of inositol 1,4,5-trisphosphate in living cells using an improved set of resonance energy transfer-based biosensors

Improved versions of inositol-1,4,5-trisphosphate (InsP3) sensors were created to follow intracellular InsP3 changes in single living cells and in cell populations. Similar to previous InsP3 sensors the new sensors are based on the ligand binding domain of the human type-I InsP3 receptor (InsP3R-LBD), but contain a mutation of either R265K or R269K to lower their InsP3 binding affinity. Tagging the InsP3R-LBD with N-terminal Cerulean and C-terminal Venus allowed measurement of Ins P3 in single-cell FRET experiments. Replacing Cerulean with a Luciferase enzyme allowed experiments in multi-cell format by measuring the change in the BRET signal upon stimulation. These sensors faithfully followed the agonist-induced increase in InsP3 concentration in HEK 293T cells expressing the Gq-coupled AT1 angiotensin receptor detecting a response to agonist concentration as low as 10 pmol/L. Compared to the wild type InsP3 sensor, the mutant sensors showed an improved off-rate, enabling a more rapid and complete return of the signal to the resting value of InsP3 after termination of M3 muscarinic receptor stimulation by atropine. For parallel measurements of intracellular InsP3 and Ca2+ levels in BRET experiments, the Cameleon D3 Ca2+ sensor was modified by replacing its CFP with luciferase. In these experiments depletion of plasma membrane PtdIns(4,5)P2 resulted in the fall of InsP3 level, followed by the decrease of the Ca2+-signal evoked by the stimulation of the AT1 receptor. In contrast, when type-III PI 4-kinases were inhibited with a high concentration of wortmannin or a more specific inhibitor, A1, the decrease of the Ca2+-signal preceded the fall of InsP3 level indicating an InsP3-, independent, direct regulation of capacitative Ca2+ influx by plasma membrane inositol lipids. Taken together, our results indicate that the improved InsP3 sensor can be used to monitor both the increase and decrease of InsP3 levels in live cells suitable for high-throughput BRET applications. © 2015, Public Library of Science. All rights reserved

Effects of fatigue of plantarflexors on control and performance in vertical jumping

INTRODUCTION: We investigated the effects of a mismatch between control and musculoskeletal properties on performance in vertical jumping. METHODS: Six subjects performed maximum-effort vertical squat jumps before (REF) and after the plantarflexors of the right leg had been fatigued (FAT) while kinematic data, ground reaction forces, and EMG of leg muscles were collected. Inverse dynamics was used to calculate the net work at joints, and EMG was rectified and smoothed to obtain the smoothed rectified EMG (SREMG). The jumps of the subjects were also simulated with a musculoskeletal model comprising seven body segments and 12 Hill-type muscles, and having as only input muscle stimulation. RESULTS: Jump height was approximately 6 cm less in FAT jumps than in REF jumps. In FAT jumps, peak SREMG level was reduced by more than 35% in the right plantarflexors and by approximately 20% in the right hamstrings but not in any other muscles. In FAT jumps, the net joint work was reduced not only at the right ankle (by 70%) but also at the right hip (by 40%). Because the right hip was not spanned by fatigued muscles and the reduction in SREMG of the right hamstrings was relatively small, this indicated that the reduction in performance was partly due to a mismatch between control and musculoskeletal properties. The differences between REF and FAT jumps of the subjects were confirmed and explained by the simulation model. Reoptimization of control for the FAT model caused performance to be partly restored by approximately 2.5 cm. CONCLUSION: The reduction in performance in FAT jumps was partly due to a mismatch between control and musculoskeletal properties. © 2011 The American College of Sports Medicine