Strong-meter and weak-meter rhythm identification in spina bifida meningomyelocele and volumetric parcellation of rhythm-relevant cerebellar regions.

Children with spina bifida meningomyelocele (SBM) are impaired relative to controls in terms of discriminating strong-meter and weak-meter rhythms, so congenital cerebellar dysmorphologies that affect rhythmic movements also disrupt rhythm perception. Cerebellar parcellations in children with SBM showed an abnormal configuration of volume fractions in cerebellar regions important for rhythm function: a smaller inferior-posterior lobe, and larger anterior and superior-posterior lobes

Shape driven confluent rigidity transition in curved biological tissues

Collective cell motions underlie structure formation during embryonic development. Tissues exhibit emergent multicellular characteristics such as jamming, rigidity transitions, and glassy dynamics, but there remain questions about how those tissue scale dynamics derive from local cell level properties. Specifically, there has been little consideration of the interplay between local tissue geometry and cellular properties influencing larger scale tissue behaviours. Here we consider a simple two dimensional computational vertex model for confluent tissue monolayers, which exhibits a rigidity phase transition controlled by the shape index (ratio of perimeter to square root area) of cells, on a spherical surface. We show that the critical point for the rigidity transition is a function of curvature such that more highly curved systems are more likely to be in a less rigid, more fluid, phase. A phase diagram we generate for the curvature and shape index constitutes a testable prediction from the model. The curvature dependence is interesting because it suggests a natural explanation for more dynamic tissue remodelling and facile growth in regions of higher surface curvature, without invoking the need for biochemical or other physical differences. This has potential ramifications for our understanding of morphogenesis of budding and branching structures

The Bt-DUX: Development of a subjective measure of health-related quality of life in patients who underwent surgery for lower extremity malignant bone tumor

Background. To examine the practical applicability, internal consistency, and validity of the Bt-DUX, a disease-specific Health Related Quality of Life (HRQoL) instrument. The Bt-Dux was developed to examine patients' individual values of their life after a malignant bone tumor of the lower extremity at four domains (cosmetic, social, emotional, and functional). Procedure. Patients were eligible for this cross-sectional, multicenter study if they underwent surgery for a malignant tumor of the leg in a period ranging between 12 and 60 months before the recruitment. Assessments included: Bt-DUX, Toronto Extremity Salvage Score (TESS) Short Form (SF)-36, TNO-AZL Questionnaire for Adult's Quality of Life (TAAQOL), and TNO-AZL Children's Quality of Life Questionnaire (TACQOL). Results. Seventy-two patients (35 male, 37 female), mean age 17 (SD 4) years were included. Limb sparing surgery took place in 32 patients and ablative surgery in 40 patients. The Bt-DUX was completed in less than 5 min and easy to comprehend. The mean Bt-DUX score was 69.8 (SD 15.5), with Cronbach's alpha being 0.92. Domain-total correlations ranged between 0.84 and 0.88 (P<0.01). Correlations between Bt-DUX Total score and TESS, SF-36 Physical and Mental Component Summary scales a

Expansion of prosodic abilities at the transition from babble to words: a comparison between children with cochlear implants and normally hearing children

Objectives: This longitudinal study examined the impact of emerging vocabulary production on the ability to produce the phonetic cues to prosodic prominence in babbled and lexical disyllables of infants with Cochlear Implants (CI) and normally hearing infants (NH). Current research on typical language acquisition emphasizes the importance of vocabulary development for phonological and phonetic acquisition. Children with cochlear implants (CI) experience significant difficulties with the perception and production of prosody, and the role of possible top-down effects is therefore particularly relevant for this population. Design: Isolated disyllabic babble and first words were identified and segmented in longitudinal audio-video recordings and transcriptions for 9 NH infants and 9 infants with CI interacting with their parents. Monthly recordings were included from the onset of babbling until children had reached a cumulative vocabulary of 200 words. Three cues to prosodic prominence, F0, intensity and duration, were measured in the vocalic portions of stand-alone disyllables. In order to represent the degree of prosodic differentiation between two syllables in an utterance, the raw values for intensity and duration were transformed to ratios, and for f0 a measure of the perceptual distance in semitones was derived. The degree of prosodic differentiation for disyllabic babble and words for each cue was compared between groups. In addition, group and individual tendencies on the types of stress patterns for babble and words were also examined. Results: The CI group had overall smaller pitch and intensity distances than the NH group. For the NH group, words had greater pitch and intensity distances than babbled disyllables. Especially for pitch distance, this was accompanied by a shift towards a more clearly expressed stress pattern that reflected the influence of the ambient language. For the CI group, the same expansion in words did not take place for pitch. For intensity, the CI group gave evidence of some increase of prosodic differentiation. The results for the duration measure showed evidence of utterance-final lengthening in both groups. In words, the CI group significantly reduced durational differences between syllables so that a more even-timed, less differentiated pattern emerged. Conclusions: The onset of vocabulary production did not have the same facilitatory effect for the CI infants on the production of phonetic cues for prosody, especially for pitch. It was argued that the results for duration may reflect greater articulatory difficulties in words for the CI group than the NH group. It was suggested that the lack of clear top-down effects of the vocabulary in the CI group may be due to a lag in development caused by an initial lack of auditory stimulation, possibly compounded by the absence of auditory feedback during the babble phase

Musical training modulates the early but not the late stage of rhythmic syntactic processing

Syntactic processing is essential for musical understanding. Although the processing of harmonic syntax has been well studied, very little is known about the neural mechanisms underlying rhythmic syntactic processing. The present study investigated the neural processing of rhythmic syntax and whether and to what extent long-term musical training impacts such processing. Fourteen musicians and 14 nonmusicians listened to syntactic-regular or -irregular rhythmic sequences and judged the completeness of these sequences. Musicians, as well as nonmusicians, showed a P600 effect to syntactic-irregular endings, indicating that musical exposure and perceptual learning of music are sufficient to enable nonmusicians to process rhythmic syntax at the late stage. However, musicians, but not nonmusicians, also exhibited an ERAN response to syntactic-irregular endings, which suggests that musical training only modulates the early but not the late stage of rhythmic syntactic processing. These findings revealed for the first time the neural mechanisms underlying the processing of rhythmic syntax in music, which has important implications for theories of hierarchically-organized music cognition and comparative studies of syntactic processing in music and language

Transgenic force sensors and software to measure force transmission across the mammalian nuclear envelope in vivo

Nuclear mechanotransduction is a growing field with exciting implications for the regulation of gene expression and cellular function. Mechanical signals may be transduced to the nuclear interior biochemically or physically through connections between the cell surface and chromatin. To define mechanical stresses upon the nucleus in physiological settings, we generated transgenic mouse strains that harbour FRET-based tension sensors or control constructs in the outer and inner aspects of the nuclear envelope. We knocked-in a published esprin-2G sensor to measure tensions across the LINC complex and generated a new sensor that links the inner nuclear membrane to chromatin. To mitigate challenges inherent to fluorescence lifetime analysis in vivo, we developed software (FLIMvivo) that markedly improves the fitting of fluorescence decay curves. In the mouse embryo, the sensors responded to cytoskeletal relaxation and stretch applied by micro-aspiration. They reported organ-specific differences and a spatiotemporal tension gradient along the proximodistal axis of the limb bud, raising the possibility that mechanical mechanisms coregulate pattern formation. These mouse strains and software are potentially valuable tools for testing and refining mechanotransduction hypotheses in vivo

No Abuse Potential of Silexan in Healthy Recreational Drug Users: A Randomized Controlled Trial

BACKGROUND Silexan is a lavender essential oil with established anxiolytic and calming efficacy. Here we asked whether there is a potential for abuse in human patients. METHODS We carried out a phase I abuse liability single-center, double-blind, 5-way crossover study in healthy users of recreational central nervous system depressants. They received single oral doses of 80 mg (therapeutic dose) and 640 mg Silexan, 2 mg and 4 mg lorazepam (active control) and placebo in randomized order, with 4- to 14-day washout periods between treatments. Pharmacodynamic measures included validated visual analogue scales assessing positive, negative, and sedative drug effects and balance of effects; a short form of the Addiction Research Center Inventory; and a drug similarity assessment. The primary outcome measure was the individual maximum value on the drug liking visual analogue scale during 24 hours post-dose. RESULTS Forty participants were randomized and 34 were evaluable for pharmacodynamic outcomes. In intraindividual head-to-head comparisons of the drug liking visual analogue scale maximum value, both doses of Silexan were rated similar to placebo whereas differences were observed between Silexan and lorazepam and between placebo and lorazepam (P < .001). These data were supported by all secondary measures of positive drug effects and of balance of effects. Differences between placebo and both doses of Silexan were always negligible in magnitude. Moreover, Silexan showed no sedative effects and was not perceived to be similar to commonly used drugs that participants had used in the past. CONCLUSIONS Silexan did not exhibit any abuse potential in a standard abuse potential detection screen study and is unlikely to be recreationally abused

Clinical Features, Treatment, and Outcome in 102 Adult and Pediatric Patients with Localized High-Grade Synovial Sarcoma

Background. There remains controversy on the routine use of chemotherapy in localized SS. Methods. The records of 87 adult (AP) and 15 pediatric (PP) patients with localized SS diagnosed between 1986 and 2007 at 2 centres in Toronto were reviewed. Results. Median age for AP and PP was 37.6 (range 15–76) and 14 (range 0.4–18) years, respectively. 65 (64%) patients had large tumours (>5 cm). All patients underwent en bloc surgical resection resulting in 94 (92.2%) negative and 8 (7.8%) microscopically positive surgical margins. 72 (82.8%) AP and 8 (53%) PP received radiotherapy. Chemotherapy was administered to 12 (13.8%) AP and 13 (87%) PP. 10 AP and 5 PP were evaluable for response to neoadjuvant chemotherapy, with response rate of 10% and 40%, respectively. 5-year EFS and OS was 69.3 ± 4.8% and 80.3 ± 4.3%, respectively, and was similar for AP and PP, In patients with tumors >5 cm, in whom chemotherapy might be considered most appropriate, relapse occurred in 9/19 (47%) with chemotherapy, compared to 17/46 (37%) In those without. Conclusions. Patients with localized SS have a good chance of cure with surgery and RT. Evidence for a well-defined role of chemotherapy to improve survival In localized SS remains elusive

Oscillatory cortical forces promote three dimensional cell intercalations that shape the murine mandibular arch

Multiple vertebrate embryonic structures such as organ primordia are composed of confluent cells. Although mechanisms that shape tissue sheets are increasingly understood, those which shape a volume of cells remain obscure. Here we show that 3D mesenchymal cell intercalations are essential to shape the mandibular arch of the mouse embryo. Using a genetically encoded vinculin tension sensor that we knock-in to the mouse genome, we show that cortical force oscillations promote these intercalations. Genetic loss- and gain-of-function approaches show that Wnt5a functions as a spatial cue to coordinate cell polarity and cytoskeletal oscillation. These processes diminish tissue rigidity and help cells to overcome the energy barrier to intercalation. YAP/TAZ and PIEZO1 serve as downstream effectors of Wnt5a-mediated actomyosin polarity and cytosolic calcium transients that orient and drive mesenchymal cell intercalations. These findings advance our understanding of how developmental pathways regulate biophysical properties and forces to shape a solid organ primordium

The flipflop orphan genes are required for limb bud eversion in the Tribolium embryo

Abstract Background Unlike Drosophila but similar to other arthropod and vertebrate embryos, the flour beetle Tribolium castaneum develops everted limb buds during embryogenesis. However, the molecular processes directing the evagination of epithelia are only poorly understood. Results Here we show that the newly discovered genes Tc-flipflop1 and Tc-flipflop2 are involved in regulating the directional budding of appendages. RNAi-knockdown of Tc-flipflop results in a variety of phenotypic traits. Most prominently, embryonic limb buds frequently grow inwards rather than out, leading to the development of inverted appendages inside the larval body. Moreover, affected embryos display dorsal closure defects. The Tc-flipflop genes are evolutionarily non-conserved, and their molecular function is not evident. We further found that Tc-RhoGEF2, a highly-conserved gene known to be involved in actomyosin-dependent cell movement and cell shape changes, shows a Tc-flipflop-like RNAi-phenotype. Conclusions The similarity of the inverted appendage phenotype in both the flipflop- and the RhoGEF2 RNAi gene knockdown led us to conclude that the Tc-flipflop orphan genes act in a Rho-dependent pathway that is essential for the early morphogenesis of polarised epithelial movements. Our work describes one of the few examples of an orphan gene playing a crucial role in an important developmental process