Search

To assess the effects of PR-fampridine on cognitive functioning, fatigue and depression in patients with multiple sclerosis (PwMS). Thirty-two PwMS were included in this trial. Cognitive performance was assessed in an open-label and randomized double-blind, placebo-controlled study design using a comprehensive neuropsychological test battery as well as questionnaires examining depression and fatigue. We found significant improvements in cognitive measures assessing alertness (tonic alertness, p = 0.0244 and phasic alertness, p = 0.0428), psychomotor speed (p = 0.0140) as well as verbal fluency (p = 0.0002) during open-label treatment with PR-fampridine. These effects of performance were paralleled by patients’ perception of reduced fatigue (physical, p = 0.0131; cognitive, p = 0.0225; total, p = 0.0126). Fampridine-induced improvements in phasic alertness (p = 0.0010) and measures of fatigue (physical, p = 0.0014; cognitive, p = 0.0003; total, p = 0.0005) were confirmed during randomized, double-blind, placebo-controlled assessment in the second year. In addition, we found positive effects of PR-fampridine on depressive symptoms (p = 0.0049). We demonstrated persisting beneficial effects of PR-fampridine on fatigue in PwMS over a period of more than 2 years. Drug responsiveness regarding cognitive performance and fatigue was not limited to walking responders. Our data demonstrate significant positive effects of treatment with PR-fampridine over 2 years on different cognitive domains as well as fatigue and depression in a cohort of PwMS. These findings imply that PR-fampridine should be considered as symptomatic treatment improving aspects of cognition, fatigue and depression in PwMS.

Study Design This is a focused review article. Objectives To identify important concepts in lower extremity (LE) assessment with a focus on locomotor outcomes and provide guidance on how existing outcome measurement tools may be best used to assess experimental therapies in spinal cord injury (SCI). The emphasis lies on LE outcomes in individuals with complete and incomplete SCI in Phase II-III trials. Methods This review includes a summary of topics discussed during a workshop focusing on LE function in SCI, conceptual discussion of corresponding outcome measures and additional focused literature review. Results There are a number of sensitive, accurate, and responsive outcome tools measuring both quantitative and qualitative aspects of LE function. However, in trials with individuals with very acute injuries, a baseline assessment of the primary (or secondary) LE outcome measure is often not feasible. Conclusion There is no single outcome measure to assess all individuals with SCI that can be used to monitor changes in LE function regardless of severity and level of injury. Surrogate markers have to be used to assess LE function in individuals with severe SCI. However, it is generally agreed that a direct measurement of the performance for an appropriate functional activity supersedes any surrogate marker. LE assessments have to be refined so they can be used across all time points after SCI, regardless of the level or severity of spinal injury. Sponsors Craig H. Neilsen Foundation, Spinal Cord Outcomes Partnership Endeavor.

Three unexpected products derived from the unsymmetrically substituted amidinate anion [MeC(NEt)(NtBu)]− are reported. Treatment of 1-tert-butyl-3-ethyl-carbodiimide, tBu-N C N–Et, with 1 equiv. of methyllithium in diethyl ether afforded colorless crystals of the unusual octanuclear lithium amidinate derivative {[LiN(Et)C(Me)N(tBu)]2⋅LiN(Et)C(CH2Li)N(tBu) Et2O}2 (1) in 57% yield instead of the expected lithium amidinate Li[MeC(NEt)(NtBu)]. In the molecule of 1, one central methyl group in a trimer of Li[MeC(NEt)(NtBu)] is deprotoned and two of these partially deprotonated trimers are linked through a central eight-membered [C–N–Li–CH2]2 ring to afford the octanuclear product 1. The same reaction carried out in 1,2-dimethoxyethane (DME) solution produced the oxygen-centered, heptanuclear lithium amidinate cluster {Li[MeC(NEt)(NtBu)]}5⋅Li2O (2) (21% yield). Treatment of anhydrous praseodymium trichloride with in situ-prepared Li[MeC(NEt)(NtBu)] in Et2O/THF afforded green (THF)Li[Pr{MeC(NEt)(NtBu)}4] (3) as the first anionic tetrakis(amidinato)lanthanide(III) complex in 55% isolated yield. The molecular and crystal structures of all three new compounds have been elucidated by X-ray diffraction.

Background: Prolonged-release fampridine (PR-fampridine, 4-aminopyridine) increases walking speed in the timed 25-foot walk test (T25FW) in some patients (timed-walk responders) with multiple sclerosis (MS). Objective: To explore the effects of PR-fampridine on different aspects of walking function and to identify associated gait modifications in subjects with MS. Methods: In this prospective, randomized, placebo-controlled, double-blind, phase II study (FAMPKIN; clinicaltrials.gov , NCT01576354), subjects received a 6-week course of oral placebo or PR-fampridine treatment (10 mg, twice daily) before crossing over. Using 3D-motion-analysis, kinematic and kinetic parameters were assessed during treadmill walking (primary endpoint). Clinical outcome measures included T25FW, 6-minute walk test (6MWT), and balance scales. Physical activity in everyday life was measured with an accelerometer device. Results: Data from 55 patients were suitable for analysis. Seventeen subjects were timed-walk responders under PR-fampridine. For the total study population and for responders, a significant increase in walking speed (T25FW) and distance (6MWT) was observed. Gait pattern changes were found at the single-subject level and correlated with improvements in the T25FW and 6MWT. Physical activity was increased in responders. Conclusion: PR-fampridine improves walking speed, endurance, and everyday physical activity in a subset of subjects with MS and leads to individual modifications of the gait pattern.

Uncontrolled muscle spasms often develop after spinal cord injury. Structural and functional maladaptive changes in spinal neuronal circuits below the lesion site were postulated as an underlying mechanism but remain to be demonstrated in detail. To further explore the background of such secondary phenomena, rats received a complete sacral spinal cord transection at S(2) spinal level. Animals progressively developed signs of tail spasms starting 1 week after injury. Immunohistochemistry was performed on S(3/4) spinal cord sections from intact rats and animals were sacrificed 1, 4 and 12 weeks after injury. We found a progressive decrease of cholinergic input onto motoneuron somata starting 1 week post-lesion succeeded by shrinkage of the cholinergic interneuron cell bodies located around the central canal. The number of inhibitory GABAergic boutons in close contact with Ia afferent fibers was greatly reduced at 1 week after injury, potentially leading to a loss of inhibitory control of the Ia stretch reflex pathways. In addition, a gradual loss and shrinkage of GAD65 positive GABAergic cell bodies was detected in the medial portion of the spinal cord gray matter. These results show that major structural changes occur in the connectivity of the sacral spinal cord interneuronal circuits below the level of transection. They may contribute in an important way to the development of spastic symptoms after spinal cord injury, while reduced cholinergic input on motoneurons is assumed to result in the rapid exhaustion of the central drive required for the performance of locomotor movements in animals and humans.

Rodents are frequently used to model damage and diseases of the central nervous system (CNS) that lead to functional deficits. Impaired locomotor function is currently evaluated by using scoring systems or biomechanical measures. These methods often suffer from limitations such as subjectivity, nonlinearity and low sensitivity, or focus on a few very restricted aspects of movement. Thus, full quantitative profiles of motor deficits after CNS damage are lacking. Here we report the detailed characterization of locomotor impairments after applying common forms of CNS damage in rodents. We obtained many objective and quantitative readouts from rats with either spinal cord injuries or strokes and from transgenic mice (Epha4−/−) during skilled walking, overground walking, wading and swimming, resulting in model-specific locomotor profiles. Our testing and analysis method enables comprehensive assessment of locomotor function in rodents and has broad application in various fields of life science research.

We augment a model of endogenous credit cycles by Matsuyama et al.(2016) with human capital to study the impact of human capital on the stability of central economic aggregates. Thus we offer a linkage between human capital formation and credit market instability on a macrolevel combined with an analysis of functional income distribution. Human capital is modelled as pure external effect of production following a learning-by-producing approach. Agents have access to two different investment projects, which differ substantially in their next generations spillover effects. Some generate pecuniary externalities and technological spillovers through human capital formation whereas others fail to do so and are subject to financial frictions. Due to this endogenous credit cycles occur and a pattern of boom and bust cycles can be observed. We explore the impact of human capital on the stability of the system by numerical simulations which indicate that human capital has an ambiguous effect on the evolution of the output. Depending on the strength of the financial friction and the output share of human capital it either amplifies or mitigates output fluctuations. This analysis shows that human capital is an essential factor for economic stability and sustainable growth as a high human capital share tends to make the system's stability robust against shocks., Series: Department of Economics Working Paper Series

This paper considers Bayesian estimation of the threshold vector error correction (TVECM) model in moderate to large dimensions. Using the lagged cointegrating error as a threshold variable gives rise to additional difficulties that are typically solved by relying on large sample approximations. Relying on Markov chain Monte Carlo methods we circumvent these issues by avoiding computationally prohibitive estimation strategies like the grid search. Due to the proliferation of parameters we use novel global-local shrinkage priors in the spirit of Griffin and Brown (2010). We illustrate the merits of our approach in an application to five exchange rates vis-á-vis the US dollar and assess whether a given currency is over or undervalued. Moreover, we perform a forecasting comparison to investigate whether it pays off to adopt a non-linear modeling approach relative to a set of simpler benchmark models., Series: Department of Economics Working Paper Series

Minimum toe clearance (MTC) occurs during a highly dynamic phase of the gait cycle and is associated with the highest risk of unintentional contact with obstacles or the ground. Age, cognitive function, attention and visual feedback affect foot clearance but how these factors interact to influence MTC control is not fully understood. We measured MTC in 121 healthy individuals aged 20–80 under four treadmill walking conditions; normal walking, lower visual field restriction and two Stroop colour/word naming tasks of two difficulty levels. Competition for cognitive and attentional resources from the Stroop task resulted in significantly lower mean MTC in older adults, with the difficult Stroop task associated with a higher frequency of extremely low MTC values and subsequently an increased modelled probability of tripping in this group. While older adults responded to visual restriction by markedly skewing MTC distributions towards higher values, this condition was also associated with frequent, extremely low MTC values. We reveal task-specific, age-dependent patterns of MTC control in healthy adults. Age-related differences are most pronounced during heavy, distracting cognitive load. Analysis of critically-low MTC values during dual-task walking may have utility in the evaluation of locomotor control and fall risk in older adults and patients with motor control deficits.

The first antimony(III) aziridinyl derivatives are reported. Treatment of anhydrous SbCl3 with N-lithioaziridine Li(Azn) (Azn = NC2H4) afforded the structurally unique heterobimetallic lithium/antimony(III) amide complex [Li3Sb(μ3-Cl)2(μ-Azn)4(THF)2]∞ (1). Homoleptic Sb2(Azn)6 (2) has become available for the first time through an amide group exchange reaction between Sb(NMe2)3 and 3 equiv of aziridine. The low-melting Sb2(Azn)6 exhibits a “weak dimer” structure in the crystal.

Objective:To expand upon the limited knowledge of the long-term effects of prolonged-release (PR) fampridine in patients with multiple sclerosis (PwMS) regarding safety, walking improvements, and changes in drug responsiveness.Methods:Fifty-three PwMS who completed the FAMPKIN core study were included in this extension trial. Drug efficacy was assessed in an open-label and randomized double-blind, placebo-controlled study design with regular baseline assessments over a period of 2 years using the Timed 25-Foot Walk (T25FW), 6-Minute Walk Test (6MWT), and 12-item MS Walking Scale (MSWS-12) as outcome measures.Results:The data showed good tolerability and persisting efficacy of PR fampridine during long-term treatment in PwMS. Significant improvements in walking speed, endurance, and self-perceived ambulatory function were observed during open-label (T25FW: +11.5%; 6MWT: 10.7%; MSWS-12: 6.1 points) and double-blind controlled treatment with PR fampridine (T25FW: +13.1%; 6MWT: 11.9%; MSWS-12: 7.4 points). Several patients showed changes in drug responsiveness over time, resulting in an increased proportion of patients exceeding 10% or 20% improvements in walking measures after long-term treatment.Conclusions:Efficacy and tolerability data confirmed PR fampridine as a valuable long-term treatment for improving ambulatory function in gait-impaired PwMS. Similar results in open-label and double-blind phases reveal that the walking tests used are objective and reliable. The considerable proportion of patients in whom responsiveness to PR fampridine changed over time emphasizes the importance of regular reassessment of drug efficacy in clinical practice to optimize treatment. Such reassessments seem to be particularly important in patients with poor initial drug responses, as this group demonstrated enhanced responsiveness after long-term treatment.Clinicaltrials.gov identifier:NCT01576354.Classification of evidence:This study provides Class II evidence that PR fampridine significantly improved gait compared to placebo in a 2-week study in PwMS who had been using PR fampridine for 2 years.

Human arm swing looks and feels highly automated, yet it is increasingly apparent that higher centres, including the cortex, are involved in many aspects of locomotor control. The addition of a cognitive task increases arm swing asymmetry during walking, but the characteristics and mechanism of this asymmetry are unclear. We hypothesized that this effect is lateralized and a Stroop word-colour naming task—primarily involving left hemisphere structures—would reduce right arm swing only. We recorded gait in 83 healthy subjects aged 18–80 walking normally on a treadmill and while performing a congruent and incongruent Stroop task. The primary measure of arm swing asymmetry—an index based on both three-dimensional wrist trajectories in which positive values indicate proportionally smaller movements on the right—increased significantly under dual-task conditions in those aged 40–59 and further still in the over-60s, driven by reduced right arm flexion. Right arm swing attenuation appears to be the norm in humans performing a locomotor-cognitive dual-task, confirming a prominent role of the brain in locomotor behaviour. Women under 60 are surprisingly resistant to this effect, revealing unexpected gender differences atop the hierarchical chain of locomotor control.

Effect of cognitive load on ASI for the entire cohort (n = 119), separated into three groups based on inclusion status. Only individuals exhibiting an ASI between -20 and 20 were included in the final analysis. Low baseline ASI; excluded group exhibiting a right-dominant ASI during normal walking of < -20 (n=8). High baseline ASI; excluded group exhibiting a left-dominant ASI during normal walking of > 20 (n=28). ASI is given as the mean value per gait cycle over a trial of 45 seconds (approximately 42 gait cycles at 4kmh-1). Error bars represent 95% confidence intervals. ASI; arm swing symmetry index.

Mean ± SEM of gait parameters under three walking conditions on a treadmill; normal walking (no additional cognitive load), walking while performing a congruent Stroop task and walking while performing an incongruent Stroop task. Step length is the distance in the progression axis from heel strike to ipsilateral heel strike. Step width is the distance in the lateral axis from heel strike to contralateral heel strike. Phase dispersion is calculated as the point in the time normalised gait cycle at which the coordinated event occurs during the cycle of the second limb expressed as a percentage of the latter, with maximal arm protraction taken as the index event for arm swing and toe-off taken as that for stepping. Foot clearance is reported as the distance in the vertical axis of the toe marker from the treadmill at the point of ipsilateral mid swing. * indicates significant change to baseline walking condition, † indicates significant change between incongruent and congruent Stroop task condition (linear mixed model, p=0.05). CoV; coefficient of variation.

Basic spatiotemporal parameters under increasing cognitive loads during treadmill walking in younger, middle-aged and older adults. Statistical significance was determined using a linear mixed model with post-hoc t-tests. P values are corrected for multiple comparisons within each age group using the Bonferroni method. Error bars indicate 1 standard error of the mean. CoV; coefficient of variation.

Changes in ASI in individuals under increasing cognitive load for the entire cohort (n = 119), including excluded groups. ASI is given as the mean value per gait cycle over a trial of 45 seconds (approximately 42 gait cycles at 4kmh-1). Individuals' ASI values in the three different trials are linked with a dotted line. Individuals with an ASI less than -20 or more than 20 during normal walking were excluded from the final analysis. The ASI of these individuals during the incongruent Stroop task are indicated by a + (ASI during normal walking > 20) or a - (ASI during normal walking < -20).

Anatomically incomplete spinal cord injuries are often followed by considerable functional recovery in patients and animal models, largely because of processes of neuronal plasticity. In contrast to the corticospinal system, where sprouting of fibers and rearrangements of circuits in response to lesions have been well studied, structural adaptations within descending brainstem pathways and intraspinal networks are poorly investigated, despite the recognized physiological significance of these systems across species. In the present study, spontaneous neuroanatomical plasticity of severed bulbospinal systems and propriospinal neurons was investigated following unilateral C4 spinal hemisection in adult rats. Injection of retrograde tracer into the ipsilesional segments C3-C4 revealed a specific increase in the projection from the ipsilesional gigantocellular reticular nucleus in response to the injury. Substantial regenerative fiber sprouting of reticulospinal axons above the injury site was demonstrated by anterograde tracing. Regrowing reticulospinal fibers exhibited excitatory, vGLUT2-positive varicosities, indicating their synaptic integration into spinal networks. Reticulospinal fibers formed close appositions onto descending, double-midline crossing C3-C4 propriospinal neurons, which crossed the lesion site in the intact half of the spinal cord and recrossed to the denervated cervical hemicord below the injury. These propriospinal projections around the lesion were significantly enhanced after injury. Our results suggest that severed reticulospinal fibers, which are part of the phylogenetically oldest motor command system, spontaneously arborize and form contacts onto a plastic propriospinal relay, thereby bypassing the lesion. These rearrangements were accompanied by substantial locomotor recovery, implying a potential physiological relevance of the detour in restoration of motor function after spinal injury.

Functional recovery following central nervous system injuries is strongly influenced by rehabilitative training. In the clinical setting, the intensity of training and the level of motivation for a particular task are known to play important roles. With increasing neuroscience studies investigating the effects of training and rehabilitation, it is important to understand how the amount and type of training of individuals influences outcome. However, little is known about the influence of spontaneous “self-training” during daily life as it is often uncontrolled, not recorded, and mostly disregarded. Here, we investigated the effects of the intensity of self-training on motor skill acquisition in normal, intact rats and on the recovery of functional motor behavior following spinal cord injury in adult rats. We used a custom-designed small animal tracking system, “RatTrack,” to continuously record the activity of multiple rats, simultaneously in a complex Natural Habitat–enriched environment. Naïve, adult rats performed high-intensity, self-motivated motor training, which resulted in them out-performing rats that were conventionally housed and trained on skilled movement tasks, for example, skilled prehension (grasping) and ladder walking. Following spinal cord injury the amount of self-training was correlated with improved functional recovery. These data suggest that high-impact, self-motivated training leads to superior skill acquisition and functional recovery than conventional training paradigms. These findings have important implications for the design of animal studies investigating rehabilitation and for the planning of human rehabilitation programs.

The climate specific effectiveness of solar DEC-systems and relevant preferable adaptions of the system design have been so far predominantly analysed based on individual simulation for selected sites. In order to systematically deduce design-specific outline data for the application of the solar DEC-technology at climatically different sites a methodological zoning approach was further developed. A subsequent meteorological analysis for 17 sites mapping the world climate creates a transparent understanding on the activity of the specific system components. This results in a comprehension on the site-specific effectiveness of solar DEC-systems and provides insights on principally relevant and efficient system configurations.

The research project ‘Solar Heat in the Liquid Food Industry’ (part of the FORETA Research Network [1] ) focused on the development and optimisation of low-temperature heating systems for the liquid food industry. Its main objectives are in energy efficiency, waste heat recovery and the feasibility of a solar-thermal process heating system. Based on the particular simulation results the overall solar-thermal potentials for German breweries and dairies were determined. In this connection a literature review indicated that most of the potential studies on solar-thermal energy use in the industry or related to specific industrial sectors are based on the total use of low-temperature heat. In opposition to these results, the available and mainly limited roof area was found to be a more important aspect for the solar-thermal potential. Hence, the development of a methodology for a site- specific analysis was necessary. The interconnection of only a few defined evaluation criteria resulted in a more realistic estimation of the potential for a solar-thermal heat supply.

The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link. The increasing share of fluctuating energy generation causes new challenges in the power grids. The demand for flexible power plants is increasing. Solid biomass fueled combined heat and power (CHP) plants are able to get modified into dispatchable power plants. In this paper, boundaries for this operation mode are summarized and several measures to achieve a flexible power generation in biomass CHP plants are concluded. The integration of high temperature storage system for buffering the plants steam seems to be the most promising, however the least investigated option. The tasks and necessary features of such storage systems were investigated and a review of available technologies and systems for the storage of steam made.

Indigenous forests cover 24% of New Zealand and provide valuable ecosystem services. However, a national map of forest types, that is, physiognomic types, which would benefit conservation management, does not currently exist at an appropriate level of detail. While traditional forest classification approaches from remote sensing data are based on spectral information alone, the joint use of space-based optical imagery and structural information from synthetic aperture radar (SAR) and canopy metrics from air-borne Light Detection and Ranging (LiDAR) facilitates more detailed and accurate classifications of forest structure. We present a support vector machine (SVM) classification using data from the European Space Agency (ESA) Sentinel-1 and 2 missions, Advanced Land Orbiting Satellite (ALOS) PALSAR, and airborne LiDAR to produce a regional map of physiognomic types of indigenous forest. A five-fold cross-validation (repeated 100 times) of ground data showed that the highest classification accuracy of 80.5% is achieved for bands 2, 3, 4, 8, 11, and 12 from Sentinel-2, the ratio of bands VH (vertical transmit and horizontal receive) and VV (vertical transmit and vertical receive) from Sentinel-1, and mean canopy height and 97th percentile canopy height from LiDAR. The classification based on optical bands alone was 72.7% accurate and the addition of structural metrics from SAR and LiDAR increased accuracy by 7.4%. The classification accuracy is sufficient for many management applications for indigenous forest, including biodiversity management, carbon inventory, pest control, ungulate management, and disease management.