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Background Although Degenerative Spondylolisthesis (DS) is a common osseous dysfunction, very few studies have examined the bony morphology of lumbar the neural arch in the population afflicted with DS. Therefore, this study aimed to characterize the neural arch (NA) morphology along the entire lumbar spine in individuals with degenerative spondylolisthesis (DS) and compare them to healthy controls. Methods One hundred CTs from a database of 500 lumbar CTs of spondylolisthesis were selected. We excluded vertebral fractures, non-L4-L5 slips, previous surgeries, vertebral spondyloarthropathies, and scoliosis. Scans were divided into a study group of 50 individuals with single-level DS (grades 1–2) at L4–5 (25 males and 25 females), and an age-sex matched control group of 50 individuals. Linear and angular measurements from all lumbar segments included: vertebral canals, intervertebral foramens, pedicles, and articular facets. Results Compared with the controls, all individuals with DS had greater pedicle dimensions in the lower lumbar segments (∆ = 1 mm–2.14 mm) and shorter intervertebral foramens in all the lumbar segments (∆range:1.85 mm–3.94 mm). In DS females, the lower lumbar facets were mostly wider (∆ = 1.73–2.86 mm) and more sagittally-oriented (∆10°) than the controls. Greater prevalence of grade-3 facet arthrosis was found only in the DS population (DS = 40–90%,controls = 16.7–66.7%). In DS males, degenerated facets were observed along the entire lumbar spine (L1-S1), whereas, in DS females, the facets were observed mainly in the lower lumbar segments (L4-S1). Individuals with DS have shorter intervertebral foramens and greater pedicle dimensions compared with controls. Conclusions Females with DS have wider articular facets, more sagittally-oriented facets, and excessively degenerated facets than the controls. This unique NA shape may further clarify DS’s pathophysiology and explain its greater prevalence in females compared to males.

Abstract Nullomers and nullpeptides are short DNA or amino acid sequences that are absent from a genome or proteome, respectively. One potential cause for their absence could be their having a detrimental impact on an organism. Results Here, we identify all possible nullomers and nullpeptides in the genomes and proteomes of thirty eukaryotes and demonstrate that a significant proportion of these sequences are under negative selection. We also identify nullomers that are unique to specific functional categories: coding sequences, exons, introns, 5′UTR, 3′UTR, promoters, and show that coding sequence and promoter nullomers are most likely to be selected against. By analyzing all protein sequences across the tree of life, we further identify 36,081 peptides up to six amino acids in length that do not exist in any known organism, termed primes. We next characterize all possible single base pair mutations that can lead to the appearance of a nullomer in the human genome, observing a significantly higher number of mutations than expected by chance for specific nullomer sequences in transposable elements, likely due to their suppression. We also annotate nullomers that appear due to naturally occurring variants and show that a subset of them can be used to distinguish between different human populations. Analysis of nullomers and nullpeptides across vertebrate evolution shows they can also be used as phylogenetic classifiers. Conclusions We provide a catalog of nullomers and nullpeptides in distinct functional categories, develop methods to systematically study them, and highlight the use of variability in these sequences in other analyses

Perceptual learning can facilitate the recognition of hard-to-perceive (e.g., time-compressed or spectrally-degraded) speech. Although the learning induced by training with time-compressed speech is robust, previous findings suggest that intensive training yields learning that is partially specific to the items encountered during practice. Here, we asked whether three parameters of the training procedure - the overall number of training trials (training intensity), how these trials are distributed across sessions, and the number of semantically different items encountered during training (set size) - influence learning and transfer. Different groups of participants (69 normal-hearing young adults; nine to 11 participants/group) completed different training protocols (or served as an untrained control group) and tested on the recognition of time-compressed sentences taken from the training set (learning), new time-compressed sentences presented by the trained talker (semantic transfer), and time-compressed sentences taken from the training set but presented by a different talker (acoustic transfer). Compared to untrained listeners, all training protocols yielded both learning and transfer. More intense training resulted in greater item-specific learning and greater acoustic transfer than less intense training with the same number of training sessions. Training on a smaller set size (i.e., greater token repetition during training) also resulted in greater acoustic transfer, whereas distributing practice over a number of sessions improved semantic transfer. Together, these data suggest that whereas practice on a small set that results in stimulus repetition during training is not harmful for learning, distributed training can support transfer to new stimuli, perhaps because it provides multiple opportunities to consolidate learning.

Perceiving the spatial location and physical dimensions of touched objects is crucial for goal-directed actions. To achieve this, our brain transforms skin-based coordinates into a reference frame by integrating visual and posture information. In the current study, we examine the role of posture in mapping tactile sensations to a visual image. We developed a new visual-to-touch sensory substitution device that transforms images into a sequence of vibrations on the arm. 52 blindfolded participants performed spatial recognition tasks in three different arm postures and had to switch postures between trial blocks. As participants were not told which side of the device is down and which is up, they could choose how to map its vertical axis in their responses. Contrary to previous findings, we show that new proprioceptive inputs can be overridden in mapping tactile sensations. We discuss the results within the context of the spatial task and the various sensory contributions to the process.

Study design Retrospective, comparative, multicenter. Introduction Growth modulating spinal implants are used in the management of scoliosis such as anterior vertebral body tethering. A motion-sparing posterior device (PDDC) was recently approved for the treatment of moderate AIS. The purpose of this study was to determine if the PDDC can modulate growth in skeletally immature patients with AIS. Methods From a database of patients treated with the PDDC over 4 years, we identified those who had a minimum of 2 years follow-up. Pre-operative and post-operative Cobb angles and coronal plane wedging of the apical vertebra were evaluated on standing full length radiographs. Independent sample t test and one-way ANOVA with post-hoc Tukey HSD analysis was used to compare three groups in varying skeletal maturity: Risser 0–1, Risser 2–3, and Risser 4–5. Results 45 patients (14.2-years old, 11–17) were evaluated with a mean pre-op curve of 46° (35°-66°). The average preoperative major curve magnitude, of either Lenke 1 or 5 curve type, was similar among the three groups 47.6°, 46° and 41.5°. Deformity correction was similar in the three groups, with reduction to 26.4°, 20.4° and 26.2°, respectively, at final follow-up [p ]. Pre-op wedging 7.4° (3.8°–15°) was reduced after surgery to 5.7° (1°–15°) (p n = 16) had preoperative wedging of 9.5° (6°–14.5°) that was reduced to 5.4° (1°–8°) postoperatively (p n = 15) had pre-op 7.7° (4°–15°) vs. post-op 7.0° (3°–15°); Risser 4–5 (n = 14) had pre-op 4.8° (3.8°–6.5°) vs. post-op 4.7° (3.7°–6.5°). Delta Wedging in Risser 0–1 stage was significantly different than for Risser 2–3 and for Risser 4–5. Conclusion The posterior dynamic deformity correction device was able to modulate vertebral body wedging in skeletally immature patients with AIS. This was most evident in patients who were Risser 0–1. In contrast, curve correction was similar among the three groups. This finding lends support to the device’s ability to modulate growth.

The inner ear is a complex structure responsible for hearing and balance, and organ pathology is associated with deafness and balance disorders. To evaluate the role of epigenomic dynamics, we performed whole genome bisulfite sequencing at key time points during the development and maturation of the mouse inner ear sensory epithelium (SE). Our single-nucleotide resolution maps revealed variations in both general characteristics and dynamics of DNA methylation over time. This allowed us to predict the location of non-coding regulatory regions and to identify several novel candidate regulatory factors, such as Bach2, that connect stage-specific regulatory elements to molecular features that drive the development and maturation of the SE. Constructing in silico regulatory networks around sites of differential methylation enabled us to link key inner ear regulators, such as Atoh1 and Stat3, to pathways responsible for cell lineage determination and maturation, such as the Notch pathway. We also discovered that a putative enhancer, defined as a low methylated region (LMR), can upregulate the GJB6 gene and a neighboring non-coding RNA. The study of inner ear SE methylomes revealed novel regulatory regions in the hearing organ, which may improve diagnostic capabilities, and has the potential to guide the development of therapeutics for hearing loss by providing multiple intervention points for manipulation of the auditory system.

Motor neuron–specific microRNA-218 (miR-218) has recently received attention because of its roles in mouse development. However, miR-218 relevance to human motor neuron disease was not yet explored. Here, we demonstrate by neuropathology that miR-218 is abundant in healthy human motor neurons. However, in amyotrophic lateral sclerosis (ALS) motor neurons, miR-218 is down-regulated and its mRNA targets are reciprocally up-regulated (derepressed). We further identify the potassium channel Kv10.1 as a new miR-218 direct target that controls neuronal activity. In addition, we screened thousands of ALS genomes and identified six rare variants in the human miR-218-2 sequence. miR-218 gene variants fail to regulate neuron activity, suggesting the importance of this small endogenous RNA for neuronal robustness. The underlying mechanisms involve inhibition of miR-218 biogenesis and reduced processing by DICER. Therefore, miR-218 activity in motor neurons may be susceptible to failure in human ALS, suggesting that miR-218 may be a potential therapeutic target in motor neuron disease., Target ALS; European Union (European Union); Horizon 2020; European Research Council (ERC), European Union's Seventh Framework Programme (FP7/2007-2013); AFM Telethon; NIH; National Institute of Neurological Disorders and Stroke; NIH/NINDS; United Kingdom, Medical Research Council; Suna and İnan Kıraç Foundation; Legacy Heritage Fund; Bruno and Ilse Frick Foundation for Research on ALS; Teva Pharmaceutical Industries Ltd. as part of the Israeli National Network of Excellence in Neuroscience (NNE); Minna-James-Heineman Stiftung through Minerva; Israel Science Foundation; ALS-Therapy Alliance; Motor Neuron Disease Association (United Kingdom); Thierry Latran Foundation for ALS research; ERA-Net for Research Programmes on Rare Diseases (FP7); IsrALS, Yeda-Sela, Yeda-CEO, Israel Ministry of Trade and Industry; Y. Leon Benoziyo Institute for Molecular Medicine; Kekst Family Institute for Medical Genetics; David and Fela Shapell Family Center for Genetic Disorders Research; Crown Human Genome Center; Nathan, Shirley, Philip and Charlene Vener New Scientist Fund; Julius and Ray Charlestein Foundation; Fraida Foundation; Wolfson Family Charitable Trust; Adelis Foundation; Merck (United Kingdom); ALS Canada Tim E. Noel Postdoctoral Fellowship; Project5 for ALS; Robert Packard Center for ALS Research; University of Missouri Spinal Cord Injury/Disease Research Program; Hope Center for Neurological Disorders; ALS Association ; Biogen; ALS Finding a Cure; Angel Fund; ALS-One; Cellucci Fund; Motor Neurone Disease Association; National Institute for Health Research (NIHR) Biomedical Research Centre

Background The quantitative relations between RNA and protein are fundamental to biology and are still not fully understood. Across taxa, it was demonstrated that the protein-to-mRNA ratio in steady state varies in a direction that lessens the change in protein levels as a result of changes in the transcript abundance. Evidence for this behavior in tissues is sparse. We tested this phenomenon in new data that we produced for the mouse auditory system, and in previously published tissue datasets. A joint analysis of the transcriptome and proteome was performed across four datasets: inner-ear mouse tissues, mouse organ tissues, lymphoblastoid primate samples and human cancer cell lines. Results We show that the protein levels are more conserved than the mRNA levels in all datasets, and that changes in transcription are associated with translational changes that exert opposite effects on the final protein level, in all tissues except cancer. Finally, we observe that some functions are enriched in the inner ear on the mRNA level but not in protein. Conclusions We suggest that partial buffering between transcription and translation ensures that proteins can be made rapidly in response to a stimulus. Accounting for the buffering can improve the prediction of protein levels from mRNA levels. Electronic supplementary material The online version of this article (doi:10.1186/s12864-017-3683-9) contains supplementary material, which is available to authorized users.

INTRODUCTION Balance and fall risk before and after lumbar surgery was assessed to determine whether balance at baseline predicts long-term postsurgical outcomes. METHODS Forty-three patients in the United States and Israel performed the single-leg stance (SLS) test, four square step test (FSST), and 8-foot up-and-go (8FUG) test before and 2 to 4 months after lumbar spine surgery. They completed the Oswestry Disability Index (ODI) and pain rating before and 12 months after lumbar surgery. RESULTS From baseline to follow-up, the SLS time was 3.74 seconds longer (P = 0.01), the FSST time was 1.94 seconds faster (P < 0.001), and the 8FUG time was 1.55 seconds faster (P = 0.02). Before surgery, 26% of the patients were considered high fall risk according to the FSST and 51% according to the 8FUG. Postsurgery, all patients could complete the physical tests, but 26% remained at high fall risk according to the 8FUG and 7.5% according to the FSST. The three physical measures together explained 30% of the variance in postsurgical ODI scores (P = 0.02). Age was not correlated with performance. DISCUSSION Risk of falling is higher than surgeons suspect. Balance tests (ie, SLS, FSST, and 8FUG) are quick and easy to administer. The findings support the importance of screening for balance and fall risk in adults undergoing lumbar spine surgery.

Chemogenetics enables noninvasive chemical control over cell populations in behaving animals. However, existing small-molecule agonists show insufficient potency or selectivity. There is also a need for chemogenetic systems compatible with both research and human therapeutic applications. We developed a new ion channel-based platform for cell activation and silencing that is controlled by low doses of the smoking cessation drug varenicline. We then synthesized subnanomolar-potency agonists, called uPSEMs, with high selectivity for the chemogenetic receptors. uPSEMs and their receptors were characterized in brains of mice and a rhesus monkey by in vivo electrophysiology, calcium imaging, positron emission tomography, behavioral efficacy testing, and receptor counterscreening. This platform of receptors and selective ultrapotent agonists enables potential research and clinical applications of chemogenetics.

Brace treatment is the most common nonoperative treatment for the prevention of curve progression in adolescent idiopathic scoliosis. The success reported in level 1 and 2 clinical trials is approximately 75%. The aim of this review was to identify the main risk factors that significantly reduce success rate of brace treatment. A literature search using the MEDLINE and Embase databases was conducted. Studies were included if they identified specific risk factor(s) for curve progression. Studies that looked at nighttime braces, superiority of one type of brace over another, the effect of physical therapy on brace performance, cadaver or nonhuman studies were excluded. A total of 1,022 articles were identified of which 25 met all of the inclusion criteria. Seven risk factors were identified: Poor brace compliance (eight studies), lack of skeletal maturity (six studies), Cobb angle over a certain threshold (six studies), poor in-brace correction (three studies), vertebral rotation (four studies), osteopenia (two studies), and thoracic curve type (two studies). Three risk factors were highly repeated in the literature which identified specific subgroups of patients who have a much higher risk to fail brace treatment and to progress to fusion. This data demonstrates that 60% to 70% of the patients referred to bracing are Risser 0 and 30% to 70% of this group will not wear the brace enough to ensure treatment efficacy. Furthermore, Risser 0 patients who reach the accelerated growth phase with a curve ≥40° are at 70% to 100% risk of curve progression to the fusion surgical threshold despite proper brace wear. Skeletally immature patients with relatively large magnitude scoliosis who are noncompliant are at a higher risk of failing brace treatment.

HIGHLIGHTS: eOPN3 is a mosquito-derived rhodopsin that inhibits neurotransmission in neurons. Activation of eOPN3 activates the G(i/o) pathway and reduces Ca(2+) channel activity; eOPN3 can suppress neurotransmission in a variety of cell types in vitro and in vivo. Activation of eOPN3 in nigrostriatal dopamine axons modulates locomotor behavior. SUMMARY: Information is carried between brain regions through neurotransmitter release from axonal presynaptic terminals. Understanding the functional roles of defined neuronal projection pathways requires temporally precise manipulation of their activity. However, existing inhibitory optogenetic tools have low efficacy and off-target effects when applied to presynaptic terminals, while chemogenetic tools are difficult to control in space and time. Here, we show that a targeting-enhanced mosquito homolog of the vertebrate encephalopsin (eOPN3) can effectively suppress synaptic transmission through the G(i/o) signaling pathway. Brief illumination of presynaptic terminals expressing eOPN3 triggers a lasting suppression of synaptic output that recovers spontaneously within minutes in vitro and in vivo. In freely moving mice, eOPN3-mediated suppression of dopaminergic nigrostriatal afferents induces a reversible ipsiversive rotational bias. We conclude that eOPN3 can be used to selectively suppress neurotransmitter release at presynaptic terminals with high spatiotemporal precision, opening new avenues for functional interrogation of long-range neuronal circuits in vivo.

Animals constantly evaluate their environment in order to avoid potential threats and obtain reward in the form of food, shelter and social interactions. In order to appropriately respond to sensory cues from the environment, the brain needs to form and store multiple cue-outcome associations. These can then be used to form predictions of the valence of sounds, smells and other sensory inputs arising from the surroundings. However, these associations must be subject to constant update, as the environment can rapidly change. Failing to adapt to such change can be detrimental to survival. Several systems in the mammalian brain have evolved to perform these important behavioral functions. Among these systems, the amygdala and prefrontal cortex are prominent players. Although the amygdala has been shown to form strong cue-outcome associations, the prefrontal cortex is essential for modifying these associations through extinction and reversal learning, and synaptic plasticity occurring in the strong reciprocal connections between these structures is thought to underlie both adaptive and maladaptive learning. Here we review the synaptic organization of the amygdala-prefrontal circuit, and summarize the physiological and behavioral evidence for its involvement in appetitive and aversive learning.

Study Design Biomechanical test. Objective To summarize the preclinical tests performed to assess the durability of a novel fusionless dynamic device for the treatment of adolescent idiopathic scoliosis (AIS). Summary of Background Data The minimal invasive deformity correction (MID-C) system is a distractible posterior dynamic deformity correction device designed to reduce scoliosis for AIS patients, to maintain curve correction, and to preserve spinal motion. To overcome the challenges of wear and fatigue of this procedure, the system has two unique features: polyaxial joints at the rod-screw interface and a ceramic coating of the moving parts. Methods Five biomechanical tests were performed: Static compression to failure, fatigue loading per ASTM F 1717 with 5.5-mm screws for 10 million cycles (MC) at 5 Hz, wear assessment, wear test of the polyaxial joint under 100 N load for 10 MC, and wear particle implantation in rabbits. Results The system failed through buckling of the rod with loads over 3000 N (400% of human body weight). Dynamically, the system maintained 700 N for 10 MC with 5.5 mm screws. The maximum total steady-state wear rate was 0.074 mg/MC (0.03 per polyaxial joint and 0.014 mg/MC for the ratchet mechanism). Histologic evaluation of the particle injection sites indicated no difference in the local tissue response between the control and test articles. At 3 and 6 months postinjection, there were neither adverse local effects nor systemic effects observed. Conclusions The unique design features of the MID-C system, based on polyaxial joints and ceramic coating, resulted in favorable static, fatigue, and wear resistance properties. Wear properties were superior to those published for artificial spinal discs. Long-term outcomes from clinical use will be required to correlate these bench tests to the in vivo reality of clinical use. Level of Evidence Level V.

We investigated the efficacy of optogenetic inhibition at presynaptic terminals using halorhodopsin, archaerhodopsin and chloride-conducting channelrhodopsins. Precisely timed activation of both archaerhodopsin and halorhodpsin at presynaptic terminals attenuated evoked release. However, sustained archaerhodopsin activation was paradoxically associated with increased spontaneous release. Activation of chloride-conducting channelrhodopsins triggered neurotransmitter release upon light onset. Our results indicate that the biophysical properties of presynaptic terminals dictate unique boundary conditions for optogenetic manipulation.

Optogenetic silencing allows time-resolved functional interrogation of defined neuronal populations. However, the limitations of inhibitory optogenetic tools impose stringent constraints on experimental paradigms. The high light power requirement of light-driven ion pumps and their effects on intracellular ion homeostasis pose unique challenges, particularly in experiments that demand inhibition of a widespread neuronal population in vivo. Guillardia theta anion-conducting channelrhodopsins (GtACRs) are promising in this regard, due to their high single-channel conductance and favorable photon-ion stoichiometry. However, GtACRs show poor membrane targeting in mammalian cells, and the activity of such channels can cause transient excitation in the axon due to an excitatory chloride reversal potential in this compartment. Here, we address these problems by enhancing membrane targeting and subcellular compartmentalization of GtACRs. The resulting soma-targeted GtACRs show improved photocurrents, reduced axonal excitation and high light sensitivity, allowing highly efficient inhibition of neuronal activity in the mammalian brain., Current optogenetic inhibition methods like light-controlled ion pumps require high-intensity light and disrupt physiological ion gradients. Here, the authors somatically target the anion-conducting opsin GtACR to eliminate spiking in distal axons and improve photocurrents, thus enhancing its utility.

Reversible silencing of neuronal activity is a powerful approach for isolating the roles of specific neuronal populations in circuit dynamics and behavior. In contrast with neuronal excitation, for which the majority of studies have used a limited number of optogenetic and chemogenetic tools, the number of genetically encoded tools used for inhibition of neuronal activity has vastly expanded. Silencing strategies vary widely in their mechanism of action and in their spatial and temporal scales. Although such manipulations are commonly applied, the design and interpretation of neuronal silencing experiments present unique challenges, both technically and conceptually. Here, we review the most commonly used tools for silencing neuronal activity and provide an in-depth analysis of their mechanism of action and utility for particular experimental applications. We further discuss the considerations that need to be given to experimental design, analysis, and interpretation of collected data. Finally, we discuss future directions for the development of new silencing approaches in neuroscience.

The inner ear is composed of a complex mixture of cells, which together allow organisms to hear and maintain balance. The cells in the inner ear, which undergo an extraordinary process of development, have only recently begun to be studied on an individual level. As it has recently become clear that individual cells, previously considered to be of uniform character, may differ dramatically from each other, the need to study cell-to-cell variation, along with distinct transcriptional and regulatory signatures, has taken hold in the scientific community. In conjunction with high-throughput technologies, attempts are underway to dissect the inter- and intra-cellular variability of different cell types and developmental states of the inner ear from a novel perspective. Single cell analysis of the inner ear sensory organs holds the promise of providing a significant boost in building an omics network that translates into a comprehensive understanding of the mechanisms of hearing and balance. These networks may uncover critical elements for trans-differentiation, regeneration and/or reprogramming, providing entry points for therapeutics of deafness and vestibular pathologies.

Mitochondrial functions depend on the steep H+ electrochemical gradient (ΔμH+) across their inner membrane. The available tools for controlling this gradient are essentially limited to inhibitors of the respiratory chain or of the H+ ATPase or to uncouplers, poisons plagued by important side effects and that lack both cell and spatial specificity. We show here that, by transfecting cells with the cDNA encoding channelrhodopsins specifically targeted to the inner mitochondrial membrane, we can obtain an accurate and spatially confined, light-dependent control of mitochondrial membrane potential and, as a consequence, of a series of mitochondrial activities ranging from electron transport to ATP synthesis and Ca2+ signaling.

WOS: 000415310800007 PubMed ID: 29144972 Science is ideally suited to connect people from different cultures and thereby foster mutual understanding. To promote international life science collaboration, we have launched "The Science Bridge'' initiative. Our current project focuses on partnership between Western and Middle Eastern neuroscience communities. Medical Research Council [MC_UP_1202/5]

This study examined the association between spontaneous finger tapping and cognitive function, with a detailed analysis of the two main phases of finger tapping, the touch-phase and the off-phase. 170 elderly patients (83 men, 87 women; M age = 82.1yr., SD = 6.2) underwent cognitive assessment including the Mini-Mental State Examination, a forward digit span test, and 15sec. of finger tapping. Results indicated a significant increase in the length and variability of the finger-touch phase among participants with mild cognitive impairment or dementia compared to participants with no cognitive impairment, suggesting a relationship between finger tapping and attention, short-term memory, and cognitive diagnosis. Pattern classification analyses on the finger tapping parameters indicated a specificity of 0.91 and sensitivity of 0.52 for ruling out cognitive impairment.

To evaluate the frequency of loss of neurophysiological potentials during head positioning, the usefulness of head repositioning to restore the potentials, and the effect on neurological outcome.We retrospectively reviewed consecutive cervical spine surgeries performed at the Israel Spine Center, Assuta Medical Center, during 2006 to 2013. Surgeries performed with neuromonitoring (transcranial-electric motor evoked potentials, somatosensory evoked potentials, electromyographic recordings) were included. Demographic data, medical history, findings at neurological examination and imaging, electrophysiological data recorded during surgery, and neurological outcomes were collected and analyzed.Three hundred eighty-one patients met inclusion criteria. Loss of potentials detected in nine patients during patient positioning and repositioning was undertaken with the aim of restoring electrophysiological signals. In 5/9 patients, repositioning resulted in immediate reappearance of potentials; in 1/5, potentials were affected again during decompression. In 4/9, repositioning did not immediately restore electrophysiological signals; in ¼, potentials reappeared later during the decompression and in ¾, potentials had not recovered till the conclusion of surgery. There were new neurological deficits in 2/9, including one patient with loss of potential that was not restored with repositioning and the one in whom potential was restored but lost again during decompression.Intraoperative neuro monitoring is an efficient tool to alert the surgical team to potential neurological damage. Head reposition often restores the electrophysiological signals with possible prevention of impending sequelae.

Interferon Regulatory Factor-8 (IRF-8) serves as a key factor in the hierarchical differentiation towards monocyte/dendritic cell lineages. While much insight has been accumulated into the mechanisms essential for its hematopoietic specific expression, the mode of restricting IRF-8 expression in non-hematopoietic cells is still unknown. Here we show that the repression of IRF-8 expression in restrictive cells is mediated by its 3rd intron. Removal of this intron alleviates the repression of Bacterial Artificial Chromosome (BAC) IRF-8 reporter gene in these cells. Fine deletion analysis points to conserved regions within this intron mediating its restricted expression. Further, the intron alone selectively initiates gene silencing only in expression-restrictive cells. Characterization of this intron's properties points to its role as an initiator of sustainable gene silencing inducing chromatin condensation with suppressive histone modifications. This intronic element cannot silence episomal transgene expression underlining a strict chromatin-dependent silencing mechanism. We validated this chromatin-state specificity of IRF-8 intron upon in-vitro differentiation of induced pluripotent stem cells (iPSCs) into cardiomyocytes. Taken together, the IRF-8 3rd intron is sufficient and necessary to initiate gene silencing in non-hematopoietic cells, highlighting its role as a nucleation core for repressed chromatin during differentiation.

Background In-shoe center of pressure (COP) measurement is essential in biomechanics. COP can be measured directly utilizing pressure-sensitive insoles, or calculated indirectly via force plate-generated data. While the latter does not require the use of additional measurement hardware (shoe insoles), its precision at calculating in-shoe COP has not been determined. Our purpose was to ascertain the precision of force plate in-shoe COP calculations and enhance their accuracy through a mathematical algorithm. Methods Twelve male students participated in the study. In-shoe COP was measured synchronously via the Pedar-X insole system and AMTI force plates, comparing the measurements of both systems. A mathematical algorithm was created to improve agreement between the systems and comparisons were recalculated. Results The two methods showed different measurements of in-shoe COP. The medio-lateral (ML) and anterior-posterior (AP) Pearson correlation coefficients between systems were 0.44±0.35 and 0.99±0.01, and the ML and AP RMS errors were 6.3±3.0mm and 43.0±12.5mm, respectively. Using a mathematical algorithm, the differences between the measurements of each system could be reduced significantly (all P Conclusions Without adjustment, force plates give an approximate location of the COP. Using an adjustment model greatly improves the accuracy of the COP trajectory during stance.

Cognitive and social deficits lie at the core of many neuropsychiatric diseases and are among the many behavioral symptoms not amenable to pharmacological intervention. Despite significant advances in identifying genes potentially involved in the pathogenesis of complex psychiatric conditions such as autism and schizophrenia, knowledge of the physiological functions that are affected (and are therefore potential targets for clinical intervention) is scarce. In psychiatric disorders with a strong genetic component, animal models have provided important links between disease-related genes and behavioral impairment. Social dysfunction, for instance, is commonly observed in transgenic rodent disease models. However, the causal relationships between the behavioral and physiological abnormalities in these models are not well-understood. Optogenetic techniques have evolved to provide a wide range of experimental paradigms in which neural circuit activity can be perturbed with high spatial and temporal precision, enabling causal investigation of the function of defined physiological events in neuronal subgroups. With optogenetics, researchers have begun to elucidate the basic neural mechanisms of social behaviors and of disease-relevant social and cognitive dysfunction. The synthesis of optogenetic technology with genetic animal models will allow forward- and reverse-engineering approaches to investigating the neural correlates of psychiatric disease. This review outlines the neural systems known to be involved in social behavior, illustrates how optogenetic technology has been applied to analyze this circuitry, and imagines how it might be further developed in future studies to elucidate these complex circuits both from a basic science perspective and in the context of psychiatric disease.

The capture and utilization of light is an exquisitely evolved process. The single-component microbial opsins, although more limited than multicomponent cascades in processing, display unparalleled compactness and speed. Recent advances in understanding microbial opsins have been driven by molecular engineering for optogenetics and by comparative genomics. Here we provide a Primer on these light-activated ion channels and pumps, describe a group of opsins bridging prior categories, and explore the convergence of molecular engineering and genomic discovery for the utilization and understanding of these remarkable molecular machines.

Severe behavioural deficits in psychiatric diseases such as autism and schizophrenia have been hypothesized to arise from elevations in the cellular balance of excitation and inhibition (E/I balance) within neural microcircuitry. This hypothesis could unify diverse streams of pathophysiological and genetic evidence, but has not been susceptible to direct testing. Here we design and use several novel optogenetic tools to causally investigate the cellular E/I balance hypothesis in freely moving mammals, and explore the associated circuit physiology. Elevation, but not reduction, of cellular E/I balance within the mouse medial prefrontal cortex was found to elicit a profound impairment in cellular information processing, associated with specific behavioural impairments and increased high-frequency power in the 30–80 Hz range, which have both been observed in clinical conditions in humans. Consistent with the E/I balance hypothesis, compensatory elevation of inhibitory cell excitability partially rescued social deficits caused by E/I balance elevation. These results provide support for the elevated cellular E/I balance hypothesis of severe neuropsychiatric disease-related symptoms. One model for the cellular disturbances underlying social and emotional deficits in disorders such as autism and schizophrenia is an imbalance in excitatory and inhibitory activity in certain neural systems. This idea has not been directly testable so far, but testability comes a little closer with the development of two optogenetic tools that have different spectral and temporal characteristics, thereby allowing selective control of two intermingled populations of neurons. Use of these new opsins shows that increasing relative excitation in mouse prefrontal cortex impairs social and learning behaviours. This provides support for the elevated cellular excitatory/inhibitory balance hypothesis of certain neuropsychiatric symptoms.

Genetically encoded, single-component optogenetic tools have made a significant impact on neuroscience, enabling specific modulation of selected cells within complex neural tissues. As the optogenetic toolbox contents grow and diversify, the opportunities for neuroscience continue to grow. In this review, we outline the development of currently available single-component optogenetic tools and summarize the application of various optogenetic tools in diverse model organisms.

Arm swing in human walking is an active natural motion involving the upper extremities. Earlier studies have described the interrelationship between arms and legs during walking, but the effect of arm swing on energy expenditure and dynamic parameters during normal gait, is inconclusive. The aim of this study was to investigate the effect of restricted arm swing during walking on energy expenditure and spatio-temporal parameters. Fifteen healthy men (aged 19–29 years, height 158–192 cm, weight 50–80 kg) volunteered to walk on a Woodway (Hamburg, Germany) treadmill for 10 min at four different, random velocities, customary walking speed (CWS=100%), slow walking speed (80% CWS), fast walking speed (120% CWS) and very fast walking speed (140% CWS). Participants walked twice at each velocity: once with a natural arm swing and once with restricted arms. Sensor Medics Vmax29 (California, USA), a metabolic system machine measured oxygen consumption. Heart rate was also recorded. Concurrently, selected spatial-temporal parameters were taken. Walking with restricted arms resulted in a significant increase in VO2 consumption (VO2C) (8–34%), heart rate (8–17%) and O2 cost (8–20%). A significant increase in cadence (F=674.71; P Armbewegungen beim menschlichen Gang sind aktive naturliche Bewegungen unter Beteiligung der oberen Extremitaten. Fruhere Studien haben zwar den Zusammenhang von Armen und Beinen beim Gehen beschrieben, die Wirkung der Armbewegung auf den Energieaufwand und die dynamischen Parameter beim normalen Gang aber nicht beweiskraftig genug aufzeigen konnen. Ziel der vorliegenden Studie war die Untersuchung der Wirkung von eingeschrankten Armbewegungen beim Gehen auf den Energieaufwand und raumlich-zeitliche Parameter. Im Rahmen der Hamburger Studie gingen 15 gesunde mannliche Probanden (im Alter von 19–29 Jahren, Korpergrose: 158–192 cm, Gewicht: 50–80 kg) zehn Minuten lang auf einem Woodway-Laufband bei vier verschiedenen, randomisiert eingestellten Geschwindigkeiten: ubliche Gehgeschwindigkeit (CWS=100%), langsame Gehgeschwindigkeit (SWS=80% CWS), schnelle Gehgeschwindigkeit (FWS=120% CWS) und sehr schnelle Gehgeschwindigkeit (VFWS=140% CWS). Die Probanden gingen bei jeder Geschwindigkeit zweimal: einmal mit naturlicher Armbewegung und einmal mit eingeschrankter Armbewegung. Mit Sensor Medics Vmax29 (California, USA), einem Gerat zur Stoffwechselmessung, wurde der Sauerstoffverbrauch gemessen. Die Herzfrequenz wurde ebenso aufgezeichnet. Gleichzeitig wurden ausgewahlte raumlich-zeitliche Parameter gemessen. Gehen mit eingeschrankter Armbewegung hatte eine signifikante Steigerung des VO2-Verbrauchs (VO2C) (8–34%), der Herzfrequenz (8–17%) und der O2-Kosten (8–20%) zur Folge. Eine signifikante Steigerung der Kadenz (F=674.71; P La oscilacion de los miembros superiores de los humanos al andar es un movimiento natural activo. Estudios anteriores han descrito la interrelacion entre los miembros superiores y los inferiores durante la marcha; sin embargo, no se ha logrado precisar aun los efectos de la oscilacion de los miembros superiores en el gasto de energia y en los patrones dinamicos de la marcha normal. El objetivo de este estudio fue investigar los efectos de la restriccion de la oscilacion de los miembros superiores durante la marcha en el gasto de energia y en los aspectos espaciales y temporales de la marcha. Quince varones sanos (edad: 19–29 anos, estatura: 158–192 cm, peso: 50–80 kg) se ofrecieron como voluntarios para caminar en una rueda de andar de marca Woodway (Hamburgo, Alemania) durante 10 minutos a cuatro velocidades diferentes seleccionadas al azar: velocidad normal (VN=100%), velocidad lenta (VL=80% de la VN), velocidad acelerada (VA=120% de la VN) y velocidad muy acelerada (VMA=140% de la VN). Cada sujeto anduvo dos veces a cada una de estas velocidades: una vez haciendo uso de la oscilacion natural de los miembros superiores y otra vez con restriccion de los movimientos oscilatorios de los miembros superiores. Se utilizo un dispositivo de valoracion de parametros metabolicos, de marca Medics Vmax29 (California, EE.UU.) para medir el consumo de oxigeno (CO). Ademas, se midio la frecuencia cardiaca y se valoraron los aspectos espaciales y temporales de la marcha seleccionados para este estudio. Andar mientras estan restringidos los movimientos de oscilacion de los miembros superiores dio lugar a un aumento importante del consumo de oxigeno (VCO2) (8–34%), de la frecuencia cardiaca (8–17%) y del gasto de oxigeno (8–20%). Se produjo un aumento importante, ademas, en la cadencia de la marcha (F=674.71; P Chez l'homme, le balancement des bras lors de la marche est un mouvement naturel actif des membres superieurs. Des etudes precedentes ont decrit le rapport entre les bras et les jambes pendant la marche ; cependant les resultats concernant l'effet du balancement des bras sur la depense d'energie et les parametres dynamiques pendant la marche normale sont peu concluants. Cette etude avait pour objet d'etudier les effets d'un balancement de bras limite pendant la marche sur la depense d'energie et les parametres spatio-temporels. Quinze sujets masculins en bonne sante (âge : 19–29 ans, taille : 158–192 cm, poids : 50–80 kg) se sont portes volontaires pour marcher sur un marcheur Woodway (Hambourg, Allemagne) pendant 10 minutes a quatre vitesses differentes : marche ordinaire (CWS=100), marche lente (SWS=80 CWS), marche rapide (FWS=120 CWS) et marche tres rapide (VFWS=140 CWS). Les sujets ont marche deux fois a chaque vitesse : une fois avec un balancement naturel des bras, l'autre avec les bras restreints. Un capteur Medics Vmax29 (California, USA), appareil d'etude du systeme metabolique, a mesure de la consommation d'oxygene (CO). Le rythme cardiaque a egalement ete enregistre. Certains parametres spatiaux temporels ont ete simultanement enregistres. La marche bras restreints resulte dans une augmentation significative de la consommation VO2 (VO2C) (8–34%), du rythme cardiaque (8–17%) et de la consommation d'O2 (8–20). Une augmentation significative dans la cadence (F=674.71; P

Priming is the process by which vesicles become available for fusion at nerve terminals and it is modulated by numerous proteins and second messengers. One of the prominent members of this diverse family is Tomosyn. Tomosyn has been identified as a Syntaxin-binding protein; it inhibits vesicle priming, but its mode of action is not fully understood. Tomosyn's inhibitory activity depends on its N-terminal WD40-repeat domain and is regulated by the binding of its SNARE-motif to Syntaxin. The present review describes new physiological information on Tomosyn's function and addresses possible interpretations of these results in the framework of the recently described crystal structure of the yeast Tomosyn homolog Sro7. We also present possible molecular scenarios for vesicle priming and the involvement of Tomosyn in these processes.

Patients with a spinal cord injury (SCI) are susceptible to deep tissue injury (DTI), a necrosis in excessively deformed muscle tissue overlying bony prominences, which, in wheelchair users, typically occurs in the gluteus muscles under the ischial tuberosities. Recently, we developed a generic real-time, subject-specific finite element (FE) modeling method to provide monitoring of mechanical conditions in deep tissues deformed between bony prominences and external surfaces. We previously employed this method to study internal tissue loads in plantar tissues of the foot [Yarnitzky, G., Z. Yizhar, and A. Gefen. J. Biomech. 39:2673-2689, 2006] and in muscle flaps of residual limbs in patients who underwent transtibial amputation (Portnoy, S., G. Yarnitzky, Z. Yizhar, A. Kristal, U. Oppenheim, I. Siev-Ner, and A. Gefen. Ann. Biomed. Eng. 35:120-135, 2007). The goal of the present study was to adapt the method to study the time-dependent mechanical stresses in glutei of patients with SCI during wheelchair sitting, continuously in real-time, and to compare the trends of internal tissue load data with those of controls. Prior to human studies, the real-time FE model-adapted to study the buttocks during sitting-was validated by comparing its predictions to data from a physical phantom of a buttocks and to non-real-time, commercial FE software. Next, real-time, subject-specific, FE models were built for six participating subjects (3 patients with SCI, 3 controls) based on their individual anatomies from MRI scans. Subjects were asked to sit normally in a wheelchair, on a ROHO cushion, and to watch a 90 min movie. Continuous interface pressure measurements from a pressure mat were used as subject-specific boundary conditions for real-time FE analyses of deep muscle stresses. Highest peaks of compression, shear and von Mises stresses throughout the trial period, and averages of peaks of these stresses were recorded over the trial for each individual. These parameters generally had 3-times to 5-times greater values in patients with SCI compared with controls. Likewise, stress doses, defined as the integration of peak compression stress over time, were approximately 35-times and approximately 50-times greater in the subjects with SCI, the values referring to the highest of all peaks recorded throughout the trial, and to average of peaks over the trial, respectively. We believe that by allowing-for the first time-practical and continuous monitoring of internal tissue loads in patients with motosensory deficits, without any risk or interruption to their lifestyle, and either at the clinical setting or at home, the present method can make a substantial contribution to the prevention of severe pressure ulcers and DTI.

Most trans-tibial amputation (TTA) patients use a prosthesis to retain upright mobility capabilities. Unfortunately, interaction between the residual limb and the prosthetic socket causes elevated internal strains and stresses in the muscle and fat tissues in the residual limb, which may lead to deep tissue injury (DTI) and other complications. Presently, there is paucity of information on the mechanical conditions in the TTA residual limb during load-bearing. Accordingly, our aim was to characterize the mechanical conditions in the muscle flap of the residual limb of a TTA patient after donning the prosthetic socket and during load-bearing. Knowledge of internal mechanical conditions in the muscle flap can be used to identify the risk for DTI and improve the fitting of the prosthesis. We used a patient-specific modelling approach which involved an MRI scan, interface pressure measurements between the residual limb and the socket of the prosthesis and three-dimensional non-linear large-deformation finite-element (FE) modelling to quantify internal soft tissue strains and stresses in a female TTA patient during static load-bearing. Movement of the truncated tibia and fibula during load-bearing was measured by means of MRI and used as displacement boundary conditions for the FE model. Subsequently, we calculated the internal strains, strain energy density (SED) and stresses in the muscle flap under the truncated bones. Internal strains under the tibia peaked at 85%, 129% and 106% for compression, tension and shear strains, respectively. Internal strains under the fibula peaked at substantially lower values, that is, 19%, 22% and 19% for compression, tension and shear strains, respectively. Strain energy density peaked at the tibial end (104kJ/m(3)). The von Mises stresses peaked at 215kPa around the distal end of the tibia. Stresses under the fibula were at least one order of magnitude lower than the stresses under the tibia. We surmise that our present patient-specific modelling method is an important tool in understanding the etiology of DTI in the residual limbs of TTA patients.

Lumbar epidural varices either primary or secondary to outflow obstruction have been implicated in causing lumbar radiculopathy. We report a case of an adolescent male who presented with lumbar radiculopathy attributable to thrombosed lumbar epidural varix as a result of inferior vena cava thrombosis emanating from factor V Leiden mutation. This rare cause of radiculopathy was diagnosed on contrast-enhanced computerized tomography. All symptoms resolved shortly after initiation of intravenous heparin therapy. The relevant literature is reviewed.

Tomosyn, a soluble R-SNARE protein identified as a binding partner of the Q-SNARE syntaxin 1A, is thought to be critical in setting the level of fusion-competent SNARE complexes for neurosecretion. To date, there has been no direct evaluation of the dynamics in which tomosyn transits through tomosyn-SNARE complexes or of the extent to which tomosyn-SNARE complexes are regulated by secretory demand. Here, we employed biochemical and optical approaches to characterize the dynamic properties of tomosyn-syntaxin 1A complexes in live adrenal chromaffin cells. We demonstrate that secretagogue stimulation results in the rapid translocation of tomosyn from the cytosol to plasma membrane regions and that this translocation is associated with an increase in the tomosyn-syntaxin 1A interaction, including increased cycling of tomosyn into tomosyn-SNARE complexes. The secretagogue-induced interaction was strongly reduced by pharmacological inhibition of the Rho-associated coiled-coil forming kinase, a result consistent with findings demonstrating secretagogue-induced activation of RhoA. Stimulation of chromaffin cells with lysophosphatidic acid, a nonsecretory stimulus that strongly activates RhoA, resulted in effects on tomosyn similar to that of application of the secretagogue. In PC-12 cells overexpressing tomosyn, secretagogue stimulation in the presence of lysophosphatidic acid resulted in reduced evoked secretory responses, an effect that was eliminated upon inhibition of Rho-associated coiled-coil forming kinase. Moreover, this effect required an intact interaction between tomosyn and syntaxin 1A. Thus, modulation of the tomosyn-syntaxin 1A interaction in response to secretagogue activation is an important mechanism allowing for dynamic regulation of the secretory response.

Background Ipsilateral recurrent disc herniation after lumbar discectomy is a significant problem in the management of lumbar disc disease and may necessitate repeat surgical intervention. A population-based study in Finland found that about 14% of all primary lumbar discectomies required additional surgical interventions. Interspinous devices, which have been shown to unload the posterior anulus, may reduce the occurrence of recurrent herniations. We report our short-term experience with the use of the Wallis device in the management of patients with lumbar disc herniation undergoing primary disc excision. Patients and methods Thirty-seven consecutive patients (23 males and 14 females, average age 36 y) underwent primary lumbar disc excision followed by fixation of the segment with the Wallis implant during a period of 1 year. Indications for implanting the Wallis device were a voluminous disc herniation and preservation of at least 50% of disc space height. Surgery was performed at level L4-5 in most patients. Average follow-up after surgery was 16 months (range 12 to 24). The last 14 patients were also evaluated by the preoperative and postoperative Oswestry Disability Index (ODI) questionnaire, the SF-36 survey, and by a visual analog scale (VAS) for back and leg pain. Results The average ODI dropped from 43 to 12.7. The average VAS for back pain dropped from 6.6 to1.4 and the average Vas for leg pain dropped from 8.2 to 1.5. Five patients (4 males and 1 female) with relapsing leg pain were diagnosed by contrast-enhanced magnetic resonance imaging as suffering from recurrent herniation (5/37, 13%). All reherniations occurred at level L4-5 level between 1 and 9 months after the index surgery. Two of the 5 patients subsequently underwent additional discectomy and fusion. Summary The current Wallis implant is probably incapable of reducing the incidence of recurrent herniations, but it still may be useful in patients with discogenic back pain due to early degenerative disc disease.

The clinical practice for minimizing the risk of pressure sores (PS) is to relief pressures under bony prominences of immobilized patients by changing their postures frequently. The US Department of Health advises to relief sitting pressures at least every 1 hour, and every 15 minutes for individuals who are body-abled. Surprisingly, there is paucity of information in the literature concerning motion of healthy subjects during prolonged sitting, which can be compared with these recommendations. Considering that healthy individuals are able to sit for hours without suffering injuries, such information seems particularly important. Accordingly, our objective was to measure frequency of postural changes and extent of motion during postural changes among healthy subjects who sit in a wheelchair (N=10), in order to provide information that is missing in the literature of PS biomechanics. Subjects were asked to sit comfortably for 90 minutes, during which their trunk's frontal and sagittal motions and sitting pressures were measured. We found that normals change their posture every 9 +/- 6 minutes in the sagittal plane, and independently, every 6 +/- 2 minutes in the frontal plane. Shoulders, thoracic-spine and lumbar-spine frontal plane motions were 8 +/- 4 degrees , 14 +/- 7 degrees and 15 +/- 7 degrees , respectively, and sagittal trunk-thigh movement was 10.3 +/- 7 degrees . The frequency of postural changes in normals, measured herein, was higher than frequencies reported in the literature for patients who suffered PS. This small study population therefore supports the hypothesis that prolonged immobilization contributes to PS onset.

The planar cell polarity (PCP) pathway is responsible for polarizing and orienting cochlear hair cells during development through movement of a primary cilium, the kinocilium. GPSM2/LGN, a mitotic spindle-orienting protein associated with deafness in humans, is a PCP effector involved in kinocilium migration. Here, we link human and mouse truncating mutations in the GPSM2/LGN gene, both leading to hearing loss. The human variant, p.(Trp326*), was identified by targeted genomic enrichment of genes associated with deafness, followed by massively parallel sequencing. Lgn (ΔC) mice, with a targeted deletion truncating the C-terminal GoLoco motifs, are profoundly deaf and show misorientation of the hair bundle and severe malformations in stereocilia shape that deteriorates over time. Full-length protein levels are greatly reduced in mutant mice, with upregulated mRNA levels. The truncated Lgn (ΔC) allele is translated in vitro, suggesting that mutant mice may have partially functioning Lgn. Gαi and aPKC, known to function in the same pathway as Lgn, are dependent on Lgn for proper localization. The polarization of core PCP proteins is not affected in Lgn mutants; however, Lgn and Gαi are misoriented in a PCP mutant, supporting the role of Lgn as a PCP effector. The kinocilium, previously shown to be dependent on Lgn for robust localization, is essential for proper localization of Lgn, as well as Gαi and aPKC, suggesting that cilium function plays a role in positioning of apical proteins. Taken together, our data provide a mechanism for the loss of hearing found in human patients with GPSM2/LGN variants.

Most morphometric studies on lumbar degenerative spondylolisthesis (DS) have focused solely on the L4–L5 slipped level, neglecting the shape of the entire lumbar segments. The purpose of this study was to present a morphometric analysis of the entire lumbar IVDs and VBs in DS. Out of 500 lumbar CTs, the first 100 CTs, 50 with DS at L4 and 50 age- and sex-matched control CTs, were randomly selected. All lumbar IVD and VB heights, widths, lengths and sagittal wedging as well as lumbar lordosis (LL) and sacral inclination (SI) were measured and relevant ratios calculated. The prevalence of lumbar vertebral osteophyte was also measured. A total of 6700 measurements were taken. Age, height, weight and BMI had no effect on all parameters. Compared with controls, in females with DS, the majority of IVDs were flatter, with increased kyphotic wedging at L1–L2 (Δ1.3°) and L2–L3 (Δ1.8°), turning to lordotic wedging at L3–L4 (Δ5.9°), and decreased lordotic wedging at L4–L5 (Δ2.7°) and L5–S1 (Δ5.3°). The posterior IVD/VB ratio of all lumbar levels, middle IVD/VB ratio of L3–S1 and anterior IVD/VB ratio of L4–S1 were smaller. In males with DS, the L2–L3 IVD manifested more kyphotic wedging (Δ3.8°), the L4 VB wedging was more lordotic (Δ2.4°) and all L4–L5 IVD/VB ratios and L3–L4 middle and posterior IVD/VB ratios were smaller. Individuals with DS have a more generalized degenerative disc disease on all lumbar vertebral levels, characterized by decreased disc space heights and kyphotic posture of the upper lumbar segments, occurring more predominantly in females than in males with DS.

1. Ras signaling and oncogenesis depend on the dynamic interplay of Ras with distinctive plasma membrane (PM) microdomains and various intracellular compartments. Such interaction is dictated by individual elements in the carboxy-terminal domain of the Ras proteins, including a farnesyl isoprenoid group, sequences in the hypervariable region (hvr)-linker, and palmitoyl groups in H/N-Ras isoforms. 2. The farnesyl group acts as a specific recognition unit that interacts with prenyl-binding pockets in galectin-1 (Gal-1), galectin-3 (Gal-3), and cGMP phosphodiesterase delta. This interaction appears to contribute to the prolongation of Ras signals in the PM, the determination of Ras effector usage, and perhaps also the transport of cytoplasmic Ras. Gal-1 promotes H-Ras signaling to Raf at the expense of phosphoinositide 3-kinase (PI3-K) and Ral guanine nucleotide exchange factor (RalGEF), while galectin-3 promotes K-Ras signaling to both Raf and PI3-K. 3. The hvr-linker and the palmitates of H-Ras and N-Ras determine the micro- and macro-localizations of these proteins in the PM and in the Golgi, as well as in 'rasosomes', randomly moving nanoparticles that carry palmitoylated Ras proteins and their signal through the cytoplasm.4. The dynamic compartmentalization of Ras proteins contributes to the spatial organization of Ras signaling, promotes redistribution of Ras, and provides an additional level of selectivity to the signal output of this regulatory GTPase.

To determine the safety of pedicle screw fixation in thoracic spine deformity correction.One hundred twelve pedicle screws were surgically placed in 25 patients with degenerative, posttraumatic, and Scheuermann kyphosis and idiopathic and neuromuscular scoliosis. Screw position was evaluated using intraoperative and postoperative radiographs and thin-slice computed tomography.Of the total 112 thoracic pedicle screws that were inserted, 98 screws (87.5%) were fully contained within the cortical boundaries of the pedicle. When comparing proximal screws (T1-T8) with distal screws (T9-T12) and convex placed screws with concave ones, a statistically significant difference in screw placement was evident (P0.05). More misplaced screws were seen proximally and on the concave side. Of the 14 malpositioned screws, 2 (1.8%) demonstrated aortic abutment. There were no neurologic deficits, vascular injuries, or mechanical failures recorded.Placement of thoracic pedicle screws is both feasible and safe.

Object. The authors retrospectively evaluated the safety and efficacy of a decompression and fixation technique in the treatment of patients with multilevel cervical spondylotic myelopathy (CSM). Methods. The authors describe the “hybrid decompression fixation” technique, a procedure involving a combination of corpectomies and discectomies to preserve a vertebra intact within the area of the decompression, thus augmenting mechanical stability. The authors retrospectively reviewed outcomes in 25 patients with multilevel CSM in whom the hybrid technique was performed between 1999 and 2003. Twelve patients underwent a single-level corpectomy and three-level discectomies. In 13 patients a two-level corpectomy and adjacent four-level discectomies were conducted, leaving a vertebral bridge the middle. All patients underwent fusion involving placement of disc and vertebral body cages filled with autogenous local bone and supplemental anterior dynamic plate fixation. The mean preoperative Nurick grade was 3 and improvement in status was reflected by a postoperative decrease to 2.6 (p < 0.05). In one patient neurological deterioration was demonstrated. At the end of the follow-up period (mean 29 months) radiography revealed evidence of osseous fusion in 24 patients; fusion status could not be determined in one patient. No evidence of late-onset instrumentation-related failure was observed in any of the 25 patients. Conclusions. The authors found the hybrid technique to be safe and efficient for anterior decompression in patients with multilevel CSM. The use of this technique obviates the need for staged circumferential procedures.

Brief exposure to time-compressed speech yields both learning and generalization. Whether such learning continues over the course of multi-session training and if so whether it is more or less specific than exposure-induced learning is not clear, because the outcomes of intensive practice with time-compressed speech have rarely been reported. The goal here was to determine whether prolonged training on time-compressed speech yields additional learning and generalization beyond that induced by brief exposure. Listeners practiced the semantic verification of time-compressed sentences for one or three training sessions. Identification of trained and untrained tokens was subsequently compared between listeners who trained for one or three sessions, listeners who were briefly exposed to 20 time-compressed sentences and naive listeners. Trained listeners outperformed the other groups of listeners on the trained condition, but only the group that was trained for three sessions outperformed the other groups when tested with untrained tokens. These findings suggest that although learning of distorted speech can occur rapidly, more stable learning and generalization might be achieved with longer, multi-session practice. It is suggested that the findings are consistent with the framework proposed by the Reverse Hierarchy Theory of perceptual learning.

To evaluate the feasibility and clinical improvement of a total posterior arthroplasty system in the surgical management of lumbar degenerative spondylolisthesis and or spinal stenosis. During a 1-year period (June 2006 to July 2007), ten patients were enrolled in a non-randomized prospective clinical study. The primary indication was neurogenic claudication due to spinal stenosis with single-level degenerative spondylolisthesis. Patients were evaluated with X-rays and MRI scans, visual analog scale (VAS) for back and leg pain, the Oswestry disability questionnaire, and the SF-36 health survey preoperatively, at 6 weeks, 3 months and 6 months and at 1, 2, 3 and 7 years postoperatively. The VAS score for back pain dropped from 56.2 preoperatively to 12.5 at 6 weeks and 19 at 7 years follow-up. The VAS score for worse leg pain dropped from 83.5 before surgery to 13 at 6 weeks and 8.8 at 7 years follow-up. The ODI dropped from 49.1 preoperatively to 13.5 at 6 weeks and 7.8 at 7 years follow-up. MRI examination at 7 years after surgery did not demonstrate stenosis adjacent to the stabilized segment. Spondylolisthesis did not progress in any of the cases. One patient had a symptomatic L3–L4 far lateral disc herniation 5 years after surgery whose symptoms resolved with non-operative treatment. In one patient, conversion to posterolateral fusion was performed due to an early device malfunction. In patients with spinal stenosis and degenerative spondylolisthesis, decompression and posterior arthroplasty with the TOPS System can maintain clinical improvement and radiologic stability over time.

The brain is a large network of interconnected neurons where each cell functions as a nonlinear processing element. Unraveling the mysteries of information processing in the complex networks of the brain requires versatile neurostimulation and imaging techniques. Optogenetics is a new stimulation method which allows the activity of neurons to be modulated by light. For this purpose, the cell-types of interest are genetically targeted to produce light-sensitive proteins. Once these proteins are expressed, neural activity can be controlled by exposing the cells to light of appropriate wavelengths. Optogenetics provides a unique combination of features, including multimodal control over neural function and genetic targeting of specific cell-types. Together, these versatile features combine to a powerful experimental approach, suitable for the study of the circuitry of psychiatric and neurological disorders. The advent of optogenetics was followed by extensive research aimed to produce new lines of light-sensitive proteins and to develop new technologies: for example, to control the distribution of light inside the brain tissue or to combine optogenetics with other modalities including electrophysiology, electrocorticography, nonlinear microscopy, and functional magnetic resonance imaging. In this paper, the authors review some of the recent advances in the field of optogenetics and related technologies and provide their vision for the future of the field., United States. Defense Advanced Research Projects Agency (Space and Naval Warfare Systems Center, Pacific Grant/Contract No. N66001-12-C-4025), University of Wisconsin--Madison (Research growth initiative; grant 101X254), University of Wisconsin--Madison (Research growth initiative; grant 101X172), University of Wisconsin--Madison (Research growth initiative; grant 101X213), National Science Foundation (U.S.) (MRSEC DMR-0819762), National Science Foundation (U.S.) (NSF CAREER CBET-1253890), National Institutes of Health (U.S.) (NIH/NIBIB R00 Award (4R00EB008738), National Institutes of Health (U.S.) (NIH Director’s New Innovator award (1-DP2-OD002989)), Okawa Foundation (Research Grant Award), National Institutes of Health (U.S.) (NIH Director’s New Innovator Award (1DP2OD007265)), National Science Foundation (U.S.) (NSF CAREER Award (1056008), Alfred P. Sloan Foundation (Fellowship), Human Frontier Science Program (Strasbourg, France) (Grant No. 1351/12), Israeli Centers of Research Excellence (I-CORE grant, program 51/11), MINERVA Foundation (Germany)

Background: Familial dysautonomia is a hereditary multisystemic disease primarily affecting people of Ashkenazi Jewish descent. Musculoskeletal problems are related to gait disorders, spinal deformities, foot deformities, fractures, and arthropathies. Methods: The charts and radiographs of 136 patients who ranged in age from three months to forty-six years (mean, sixteen years) were reviewed. Sixty-four patients were available for follow-up examination. Results: Spinal deformity was the most common orthopaedic problem and was diagnosed in seventy-eight patients starting at the age of four years, with a prevalence of 86 percent (forty-eight of fifty-six) by the age of fifteen years. Forty-one (53 percent) of the seventy-eight patients had scoliosis only, thirty-four (44 percent) had kyphoscoliosis, and three (4 percent) had kyphosis only. Bracing was accompanied by emotional, pulmonary, and skin problems, leading to a high rate of noncompliance and progression of the curve. Twenty-four patients had an operation at a mean age of thirteen years (range, five to eighteen years): twenty patients had posterior spinal arthrodesis, and four had combined anterior and posterior arthrodesis. Fifteen patients had a total of nineteen complications, of which seven were systemic and twelve were related to the spinal fixation. Eight patients had revision surgery. At the time of the surgery, scoliosis was corrected from a mean of 55 degrees to a mean of 35 degrees and kyphosis was corrected from a mean of 69 degrees to a mean of 61 degrees. After a mean duration of follow-up of sixty-five months, scoliosis measured 49 degrees (range, 18 to 62 degrees) and kyphosis measured 67 degrees (range, 30 to 115 degrees). Postoperative progression of the deformity was caused by failure of the instrumentation or progression in unfused segments. Walking was delayed in 72 percent (ninety-four) of the 130 patients who were of walking age. All sixty-four of the patients who were examined had an ataxic gait. Foot deformities were found in sixteen patients, six of whom were treated surgically. Two patients had Charcot joints. Fifty-five patients sustained at least one fracture before skeletal maturity, with a mean of 1.5 fractures per patient. All but one of the fractures was treated nonoperatively, and fracture-healing was often accompanied by profuse callus formation. Conclusions: Spinal deformity is common in patients with familial dysautonomia. Bracing is of questionable benefit, and surgical intervention should be considered once curve progression is well documented. Arthrodesis should be extended as far proximally as possible to prevent junctional kyphosis. Swelling and warmth in a limb should raise suspicion of an undiagnosed fracture.

We report a patient who developed recurrent hepatic artery thrombosis and deep venous thrombosis following orthotopic liver transplantation. Investigations revealed the presence of activated protein C (APC) resistance due to a mutation in the factor V gene in the transplanted liver. The patient’s own peripheral blood cells did not carry the mutation. Although part of factor V is located in the platelets and may be endogenously synthesized by megakaryocytes, this case demonstrates the major clinical importance of hepatic-derived factor V. It may be reasonable to screen liver donors with a history of a thrombotic event for APC, and to consider anticoagulation in the recipients of livers positive for this defect.

The introduction of two microbial opsin-based tools, channelrhodopsin-2 (ChR2) and halorhodopsin (NpHR), to neuroscience has generated interest in fast, multimodal, cell type-specific neural circuit control. Here we describe a cation-conducting channelrhodopsin (VChR1) from Volvox carteri that can drive spiking at 589 nm, with excitation maximum red-shifted approximately 70 nm compared with ChR2. These results demonstrate fast photostimulation with yellow light, thereby defining a functionally distinct third category of microbial rhodopsin proteins.

Spondylolysis and spondylolisthesis are common causes of low back pain in children and adolescents. Disc space infection is less common, but is another cause of severe back pain in this population. The combination of both processes in the same segment is rare. This case report is of a 13-year-old patient with isthmic lumbosacral spondylolisthesis and disc space infection at the same level. A patient who presented with severe low back pain and a radiological picture of isthmic slip with end plate irregularities and anterior bridging osteophyte was diagnosed with disc space infection at the slip level. He was managed with intravenous antibiotics for 6 weeks, followed by oral medication for an additional 2 weeks. At follow-up 28 weeks later, a spontaneous radiological fusion at the slip level was noted with complete relief of his symptoms. The patient was able to resume sports activities. In conclusion, isthmic spondylolisthesis and disc space height infection might coexist. Nonoperative treatment will usually result in spontaneous fusion and the complete relief of symptoms.