The effect of computer-based cognitive flexibility training on recovery of executive function after stroke: rationale, design and methods of the TAPASS study

Background: Stroke survivors frequently suffer from executive impairments even in the chronic phase after stroke, and there is a need for improved rehabilitation of these functions. One way of improving current rehabilitation treatment may be by online cognitive training. Based on a review of the effectiveness of computer-based cognitive training in healthy elderly, we concluded that cognitive flexibility may be a key element for an effective training, which results in improvements not merely on trained tasks but also in untrained tasks (i.e., far transfer). The aim of the current study was to track the behavioral and neural effects of computer-based cognitive flexibility training after stroke. We expected that executive functioning would improve after the cognitive flexibility training, and that neural activity and connectivity would normalize towards what is seen in healthy elderly. Methods/design: The design was a multicenter, double blind, randomized controlled trial (RCT) with three groups: an experimental intervention group, an active control group who did a mock training, and a waiting list control group. Stroke patients (3 months to 5 years post-stroke) with cognitive complaints were included. Training consisted of 58 half-hour sessions spread over 12 weeks. The primary study outcome was objective executive function. Secondary measures were improvement on training tasks, cognitive flexibility, objective cognitive functioning in other domains than the executive domain, subjective cognitive and everyday life functioning, and neural correlates assessed by both structural and resting-state functional Magnetic Resonance Imaging. The three groups were compared at baseline, after six and twelve weeks of training, and four weeks after the end of the training. Furthermore, they were compared to healthy elderly who received the same training. Discussion: The cognitive flexibility training consisted of several factors deemed important for effects that go beyond improvement on merely the training task themselves. Due to the presence of two control groups, the effects of the training could be compared with spontaneous recovery and with the effects of a mock training. This study provides insight into the potential of online cognitive flexibility training after stroke. We also compared its results with the effectiveness of the same training in healthy elderly

Frequent cases of RAS-mutated Down syndrome acute lymphoblastic leukaemia lack JAK2 mutations

The final published article can be found here: http://dx.doi.org/10.1038/ncomms5654This work was supported by KKL632 grant from the Kay Kendall Leukaemia Fund, Jerome Lejeune Foundation project grant 2011B-960, the Wellcome Trust Strategic Award WT 098330/Z/12/Z (The LonDownS Consortium) and the Lee Kong Chian School of Medicine, Nanyang Technological University-Singapore start-up funding grant M4230024 to D.N.; Swiss Cancer League (LSCC 2939-02-2012) and Dinu Lipatti 2014 grants to S.I.N.; SNF 144082, ERC 249968 and Foundation ‘ChildCare’ grants to S.E.A.; and by Cariparo bando ricerca pediatrica and by European commission (FP7 ENCCA, 261474, Trancan PER-2011-2353841) to G.B

An additional human chromosome 21 causes suppression of neural fate of pluripotent mouse embryonic stem cells in a teratoma model

Background: Down syndrome (DS), caused by trisomy of human chromosome 21 (HSA21), is the most common genetic cause of mental retardation in humans. Among complex phenotypes, it displays a number of neural pathologies including smaller brain size, reduced numbers of neurons, reduced dendritic spine density and plasticity, and early Alzheimer-like neurodegeneration. Mouse models for DS show behavioural and cognitive defects, synaptic plasticity defects, and reduced hippocampal and cerebellar neuron numbers. Early postnatal development of both human and mouse-model DS shows the reduced capability of neuronal precursor cells to generate neurons. The exact molecular cause of this reduction, and the role played by increased dosage of individual HSA21 genes, remain unknown.Results: We have subcutaneously injected mouse pluripotent ES cells containing a single freely segregating supernumerary human chromosome 21 (HSA21) into syngeneic mice, to generate transchromosomic teratomas. Transchromosomic cells and parental control cells were injected into opposite flanks of thirty mice in three independent experiments. Tumours were grown for 30 days, a time-span equivalent to combined intra-uterine, and early post-natal mouse development. When paired teratomas from the same animals were compared, transchromosomic tumours showed a three-fold lower percentage of neuroectodermal tissue, as well as significantly reduced mRNA levels for neuron specific (Tubb3) and glia specific (Gfap) genes, relative to euploid controls. Two thirds of transchromosomic tumours also showed a lack of PCR amplification with multiple primers specific for HSA21, which were present in the ES cells at the point of injection, thus restricting a commonly retained trisomy to less than a third of HSA21 genes.Conclusion: We demonstrate that a supernumerary chromosome 21 causes Inhibition of Neuroectodermal Differentiation (INDI) of pluripotent ES cells. The data suggest that trisomy of less than a third of HSA21 genes, in two chromosomal regions, might be sufficient to cause this effect

Устройство советских мотоциклов

0|7|Введение [c. 7]0|11|Схема современного мотоцикла [c. 11]0|13|Принцип работы двигателя внутреннего сгорания [c. 13]0|28|Устройство деталей двигателей [c. 28]0|59|Охлаждение двигателя [c. 59]0|66|Смазка двигателя [c. 66]0|83|Карбюрация [c. 83]0|110|Электрооборудование мотоцикла [c. 110]0|150|Силовая передача [c. 150]0|172|Экипажная часть мотоцикла [c. 172]0|191|Органы управления мотоциклом [c. 191]0|198|Дополнительное оборудование мотоцикла [c. 198]0|199|Боковая прицепка [c. 199]0|202|Приспособления к мотоциклу для езды в условиях скользкого пути [c. 202]0|205|Управление мотоциклом [c. 205]0|212|Содержание [c. 212

Trisomic dose of several chromosome 21 genes perturbs haematopoietic stem and progenitor cell differentiation in Down's syndrome

Children with Down's syndrome (DS) have 20–50-fold higher incidence of all leukaemias (lymphoid and myeloid), for reasons not understood. As incidence of many solid tumours is much lower in DS, we speculated that disturbed early haematopoietic differentiation could be the cause of increased leukaemia risk. If a common mechanism is behind the risk of both major leukaemia types, it would have to arise before the bifurcation to myeloid and lymphoid lineages. Using the transchromosomic system (mouse embryonic stem cells (ESCs)) bearing an extra human chromosome 21 (HSA21)) we analyzed the early stages of haematopoietic commitment (mesodermal colony formation) in vitro. We observed that trisomy 21 (T21) causes increased production of haemogenic endothelial cells, haematopoietic stem cell precursors and increased colony forming potential, with significantly increased immature progenitors. Transchromosomic colonies showed increased expression of Gata-2, c-Kit and Tie-2. A panel of partial T21 ESCs allowed us to assign these effects to HSA21 sub-regions, mapped by 3.5 kbp-resolution tiling arrays. The Gata-2 increase on one side, and c-Kit and Tie-2 increases on the other, could be attributed to two different, non-overlapping HSA21 regions. Using human-specific small interfering RNA silencing, we could demonstrate that an extra copy of RUNX1, but not ETS-2 or ERG, causes an increase in Tie-2/c-Kit levels. Finally, we detected significantly increased levels of RUNX1, C-KIT and PU.1 in human foetal livers with T21. We conclude that overdose of more than one HSA21 gene contributes to the disturbance of early haematopoiesis in DS, and that one of the contributors is RUNX1. As the observed T21-driven hyperproduction of multipotential immature precursors precedes the bifurcation to lymphoid and myeloid lineages, we speculate that this could create conditions of increased chance for acquisition of pre-leukaemogenic rearrangements/mutations in both lymphoid and myeloid lineages during foetal haematopoiesis, contributing to the increased risk of both leukaemia types in DS

Down syndrome-recent progress and future prospects

Down syndrome (DS) is caused by trisomy of chromosome 21 (Hsa21) and is associated with a number of deleterious phenotypes, including learning disability, heart defects, early-onset Alzheimer's disease and childhood leukaemia. Individuals with DS are affected by these phenotypes to a variable extent; understanding the cause of this variation is a key challenge. Here, we review recent research progress in DS, both in patients and relevant animal models. In particular, we highlight exciting advances in therapy to improve cognitive function in people with DS and the significant developments in understanding the gene content of Hsa21. Moreover, we discuss future research directions in light of new technologies. In particular, the use of chromosome engineering to generate new trisomic mouse models and large-scale studies of genotype-phenotype relationships in patients are likely to significantly contribute to the future understanding of DS

Efficacy and safety of subcutaneous tocilizumab in rheumatoid arthritis over 1 year: a UK real-world, open-label study

Objective. The ACT-MOVE study assessed the real-world efficacy and safety of s.c. tocilizumab (TCZSC), provided as monotherapy or in combination with conventional synthetic DMARDs (csDMARDs) over 1 year, in patients with RA and an inadequate response to csDMARD therapy and/or first TNF inhibitor. Methods. In this UK multicentre, open-label phase IIIb study, patients received TCZ-SC 162 mg once weekly for 52 weeks as monotherapy or with csDMARDs. Efficacy and safety were evaluated at baseline, weeks 2 and 4 and every 4 weeks thereafter up to week 52. Results. Of 161 patients who received at least one dose of TCZ-SC, 21 (13.0%) received TCZ-SC alone and 140 (87.0%) TCZ-SC with a csDMARD(s). From baseline to week 52, there was a mean decrease in DAS28-ESR score among all patients (!3.68), and within monotherapy (!3.75) and combination therapy (!3.67) groups. The proportion of patients who achieved DAS28 clinical remission (DAS28-ESR <2.6) at week 52 was 75.4% (95% CI 66.8, 82.8). At the same time point, "80% of patients who remained on TCZ-SC achieved DAS28 clinical remission or had low disease activity (DAS28-ESR "2.6 and #3.2). Overall, 6.2% of patients had at least one serious adverse event (10.2/ 100 patient-years), and there was one death; 11.2% of patients discontinued owing to adverse events. Conclusion. TCZ-SC was effective and tolerated in a real-world setting over 1 year. The efficacy of TCZ-SC was similar whether given as monotherapy or with csDMARDs; its safety profile was consistent with that previously establishe

The inclination for conscious motor control after stroke: Validating the Movement-Specific Reinvestment Scale for use in inpatient stroke patients

PURPOSE: Stroke survivors are inclined to consciously control their movements, a phenomenon termed "reinvestment". Preliminary evidence suggests reinvestment to impair patients' motor recovery. To investigate this hypothesis, an instrument is needed that can reliably assess reinvestment post-stroke. Therefore, this study aimed to validate the Movement-Specific Reinvestment Scale (MSRS) within inpatient stroke patients. METHOD: One-hundred inpatient stroke patients (<1 year post-stroke) and 100 healthy peers completed the MSRS, which was translated to Dutch for the study purpose. To assess structural validity, confirmatory factor analysis determined whether the scale measures two latent constructs, as previously reported in healthy adults. Construct validity was determined by testing whether patients had higher reinvestment than controls. Reliability analyses entailed assessment of retest reliability (ICC), internal consistency (Cronbach's alpha), and minimal detectable change. RESULTS: Both structural and construct validity of the MSRS were supported. Retest reliability and internal consistency indices were acceptable to good. The minimal detectable change was adequate on group level, but considerable on individual level. CONCLUSIONS: The MSRS is a valid and reliable tool and suitable to assess the relationship between reinvestment and motor recovery in the first months post-stroke. Eventually, this may help therapists to individualize motor learning interventions based on patients' reinvestment preferences. IMPLICATIONS FOR REHABILITATION: This study showed that the Movement-Specific Reinvestment Scale (MSRS) is a valid and reliable tool to objectify stroke patients' inclination for conscious motor control. The MSRS may be used to identify stroke patients who are strongly inclined to consciously control their movements, as this disposition may hinder their motor recovery. Eventually, the MSRS may enable clinicians to tailor motor learning interventions to stroke patients' motor control preferences

Image-in-Image Search for Digital History

Abstract for the Global Digital Humanities Symposium 202