Tissue identification with micro-magnetic resonance imaging in a caprine spinal fusion model

Nonunion is a major complication of spinal interbody fusion. Currently X-ray and computed tomography (CT) are used for evaluating the spinal fusion process. However, both imaging modalities have limitations in judgment of the early stages of this fusion process, as they only visualize mineralized bone. Magnetic resonance imaging (MRI) could be of great value as it is able to discriminate between different types of tissue. A feasibility study was performed in nine animals from a goat spinal fusion study, to evaluate the detection capacity of different tissues with micro-MRI. In this study bioresorbable polylactic acid cages were used. Six- and 12-months follow-up specimens were scanned in a 6.3 T micro-MRI scanner. After scanning, the specimens were processed for histology. Different types of tissue as well as the degradable cage material were identified in the fusion zone and designated as regions of interest (ROIs). Subsequently, the location of these ROIs was determined on the corresponding micro- MRI image, and average signal intensities of every individual ROI were measured. An excellent match was seen between the histological sections and micro-MRI images. The micro-MRI images showed quantifiable differences in signal intensity between bone with adipose marrow, bone with hematopoietic marrow, fibrocartilage, fibrous tissue, and degradable implant material. In time the signal intensity of bone with adipose marrow, bone with hematopoietic red marrow, and of fibrous tissue remained relatively constant. On the other hand, the signal intensity of the degradable implant material and the fibrocartilage changed significantly in time, indicating change of structure and composition. In conclusion, in our model using bioresorbable cages the MRI provides us with detailed information about the early fusion process and may therefore, allow early diagnosis of non-union

A CRISPR-based screen for Hedgehog signaling provides insights into ciliary function and ciliopathies.

Primary cilia organize Hedgehog signaling and shape embryonic development, and their dysregulation is the unifying cause of ciliopathies. We conducted a functional genomic screen for Hedgehog signaling by engineering antibiotic-based selection of Hedgehog-responsive cells and applying genome-wide CRISPR-mediated gene disruption. The screen can robustly identify factors required for ciliary signaling with few false positives or false negatives. Characterization of hit genes uncovered novel components of several ciliary structures, including a protein complex that contains δ-tubulin and ε-tubulin and is required for centriole maintenance. The screen also provides an unbiased tool for classifying ciliopathies and showed that many congenital heart disorders are caused by loss of ciliary signaling. Collectively, our study enables a systematic analysis of ciliary function and of ciliopathies, and also defines a versatile platform for dissecting signaling pathways through CRISPR-based screening

Calibrating Car-Following Models using Trajectory Data: Methodological Study

The car-following behavior of individual drivers in real city traffic is studied on the basis of (publicly available) trajectory datasets recorded by a vehicle equipped with an radar sensor. By means of a nonlinear optimization procedure based on a genetic algorithm, we calibrate the Intelligent Driver Model and the Velocity Difference Model by minimizing the deviations between the observed driving dynamics and the simulated trajectory when following the same leading vehicle. The reliability and robustness of the nonlinear fits are assessed by applying different optimization criteria, i.e., different measures for the deviations between two trajectories. The obtained errors are in the range between~11% and~29% which is consistent with typical error ranges obtained in previous studies. In addition, we found that the calibrated parameter values of the Velocity Difference Model strongly depend on the optimization criterion, while the Intelligent Driver Model is more robust in this respect. By applying an explicit delay to the model input, we investigated the influence of a reaction time. Remarkably, we found a negligible influence of the reaction time indicating that drivers compensate for their reaction time by anticipation. Furthermore, the parameter sets calibrated to a certain trajectory are applied to the other trajectories allowing for model validation. The results indicate that ``intra-driver variability'' rather than ``inter-driver variability'' accounts for a large part of the calibration errors. The results are used to suggest some criteria towards a benchmarking of car-following models

Two-way multi-lane traffic model for pedestrians in corridors

We extend the Aw-Rascle macroscopic model of car traffic into a two-way multi-lane model of pedestrian traffic. Within this model, we propose a technique for the handling of the congestion constraint, i.e. the fact that the pedestrian density cannot exceed a maximal density corresponding to contact between pedestrians. In a first step, we propose a singularly perturbed pressure relation which models the fact that the pedestrian velocity is considerably reduced, if not blocked, at congestion. In a second step, we carry over the singular limit into the model and show that abrupt transitions between compressible flow (in the uncongested regions) to incompressible flow (in congested regions) occur. We also investigate the hyperbolicity of the two-way models and show that they can lose their hyperbolicity in some cases. We study a diffusive correction of these models and discuss the characteristic time and length scales of the instability

Experimental study of pedestrian flow through a bottleneck

In this work the results of a bottleneck experiment with pedestrians are presented in the form of total times, fluxes, specific fluxes, and time gaps. A main aim was to find the dependence of these values from the bottleneck width. The results show a linear decline of the specific flux with increasing width as long as only one person at a time can pass, and a constant value for larger bottleneck widths. Differences between small (one person at a time) and wide bottlenecks (two persons at a time) were also found in the distribution of time gaps.Comment: accepted for publication in J. Stat. Mec

Criterion for traffic phases in single vehicle data and empirical test of a microscopic three-phase traffic theory

A microscopic criterion for distinguishing synchronized flow and wide moving jam phases in single vehicle data measured at a single freeway location is presented. Empirical local congested traffic states in single vehicle data measured on different days are classified into synchronized flow states and states consisting of synchronized flow and wide moving jam(s). Then empirical microscopic characteristics for these different local congested traffic states are studied. Using these characteristics and empirical spatiotemporal macroscopic traffic phenomena, an empirical test of a microscopic three-phase traffic flow theory is performed. Simulations show that the microscopic criterion and macroscopic spatiotemporal objective criteria lead to the same identification of the synchronized flow and wide moving jam phases in congested traffic. It is found that microscopic three-phase traffic models can explain both microscopic and macroscopic empirical congested pattern features. It is obtained that microscopic distributions for vehicle speed difference as well as fundamental diagrams and speed correlation functions can depend on the spatial co-ordinate considerably. It turns out that microscopic optimal velocity (OV) functions and time headway distributions are not necessarily qualitatively different, even if local congested traffic states are qualitatively different. The reason for this is that important spatiotemporal features of congested traffic patterns are it lost in these as well as in many other macroscopic and microscopic traffic characteristics, which are widely used as the empirical basis for a test of traffic flow models, specifically, cellular automata traffic flow models.Comment: 27 pages, 16 figure

Mouse Model of Alagille Syndrome and Mechanisms of Jagged1 Missense Mutations.

BACKGROUND & AIMS: Alagille syndrome is a genetic disorder characterized by cholestasis, ocular abnormalities, characteristic facial features, heart defects, and vertebral malformations. Most cases are associated with mutations in JAGGED1 (JAG1), which encodes a Notch ligand, although it is not clear how these contribute to disease development. We aimed to develop a mouse model of Alagille syndrome to elucidate these mechanisms. METHODS: Mice with a missense mutation (H268Q) in Jag1 (Jag1+/Ndr mice) were outbred to a C3H/C57bl6 background to generate a mouse model for Alagille syndrome (Jag1Ndr/Ndr mice). Liver tissues were collected at different timepoints during development, analyzed by histology, and liver organoids were cultured and analyzed. We performed transcriptome analysis of Jag1Ndr/Ndr livers and livers from patients with Alagille syndrome, cross-referenced to the Human Protein Atlas, to identify commonly dysregulated pathways and biliary markers. We used species-specific transcriptome separation and ligand-receptor interaction assays to measure Notch signaling and the ability of JAG1Ndr to bind or activate Notch receptors. We studied signaling of JAG1 and JAG1Ndr via NOTCH 1, NOTCH2, and NOTCH3 and resulting gene expression patterns in parental and NOTCH1-expressing C2C12 cell lines. RESULTS: Jag1Ndr/Ndr mice had many features of Alagille syndrome, including eye, heart, and liver defects. Bile duct differentiation, morphogenesis, and function were dysregulated in newborn Jag1Ndr/Ndr mice, with aberrations in cholangiocyte polarity, but these defects improved in adult mice. Jag1Ndr/Ndr liver organoids collapsed in culture, indicating structural instability. Whole-transcriptome sequence analyses of liver tissues from mice and patients with Alagille syndrome identified dysregulated genes encoding proteins enriched at the apical side of cholangiocytes, including CFTR and SLC5A1, as well as reduced expression of IGF1. Exposure of Notch-expressing cells to JAG1Ndr, compared with JAG1, led to hypomorphic Notch signaling, based on transcriptome analysis. JAG1-expressing cells, but not JAG1Ndr-expressing cells, bound soluble Notch1 extracellular domain, quantified by flow cytometry. However, JAG1 and JAG1Ndr cells each bound NOTCH2, and signaling from NOTCH2 signaling was reduced but not completely inhibited, in response to JAG1Ndr compared with JAG1. CONCLUSIONS: In mice, expression of a missense mutant of Jag1 (Jag1Ndr) disrupts bile duct development and recapitulates Alagille syndrome phenotypes in heart, eye, and craniofacial dysmorphology. JAG1Ndr does not bind NOTCH1, but binds NOTCH2, and elicits hypomorphic signaling. This mouse model can be used to study other features of Alagille syndrome and organ development

Low back pain around retirement age and physical occupational exposure during working life

<p>Abstract</p> <p>Background</p> <p>Physical occupational exposure is a risk factor for low back pain in workers but the long term effects of exposure remain unclear. As several countries consider increasing the retirement age, further information on this topic is relevant. This study aimed to describe the prevalence of low back pain among middle aged and aging individuals in the general French population according to physical occupational exposure and retirement status.</p> <p>Methods</p> <p>The study population originated from the French national survey 'Enquête décennale santé 2002'. Low back pain for more than 30 days within the previous twelve months (LBP) was assessed using a French version of the Nordic questionnaire. Occupational exposure was self assessed. Subjects were classified as "exposed" if they were currently or had previously been exposed to handling of heavy loads and/or to tiring postures. The weighted prevalence of LBP was computed separately for men and women, for active (aged 45-59) and retiree (aged 55-74), according to 5-year age group and past/present occupational exposure.</p> <p>Results</p> <p>For active men, the prevalence of LBP was significantly higher in those currently or previously exposed (n = 1051) compared with those never exposed (n = 1183), respectively over 20% versus less than 11%. Among retired men, the prevalence of LBP tended towards equivalence with increasing age among those previously exposed (n = 748) and those unexposed (n = 599).</p> <p>Patterns were quite similar for women with a higher prevalence in exposed active women (n = 741) compared to unexposed (n = 1260): around 25% versus 15%. Similarly, differences between previously exposed (n = 430) and unexposed (n = 489) retired women tended to reduce with age.</p> <p>Conclusion</p> <p>The prevalence of LBP in active workers was associated with occupational exposure. The link with past exposure among retirees decreased with age. These results should be considered for policies dealing with prevention at the workplace and retirement.</p

Evaluation of a multi-disciplinary back pain rehabilitation programme—individual and group perspectives

To evaluate the impact of a multi-disciplinary back pain rehabilitation programme using a combination of individual and group change data. A total of 261 consecutive patients attending an assessment session for the back pain rehabilitation programme completed the SF-36 health survey questionnaire. The patients were requested to complete the questionnaires again at programme completion and at the 6-month follow-up. The Reliable Change Index was used to define 'clinical significance' in terms of the assessment of individual change. Half of those patients considered to be suitable for the programme subsequently completed it. In group terms, non-completers scored lower than completers on all SF-36 scales. Statistically significant improvements were evident for those completing the programme (all scales at P < 0.000), with improvement maintained at follow-up. In individual terms, 'clinical significance' was exceeded most frequently in the Physical Functioning and Role Physical scales. Whilst some participants lost previous improvements between completion and follow-up, others improved over this same time period. The majority of those completing the programme showed improvement in at least one scale. Adding assessment of individual change to traditional group change measures provides greater insight into the impact a rehabilitation programme has upon participants' quality of life. Whilst the programme is clearly effective for those who complete it, work is required to limit post-programme deterioration and improve uptak