Modeling growth in biological materials

The biomechanical modeling of growing tissues has recently become an area of intense interest. In particular, the interplay between growth patterns and mechanical stress is of great importance, with possible applications to arterial mechanics, embryo morphogenesis, tumor development, and bone remodeling. This review aims to give an overview of the theories that have been used to model these phenomena, categorized according to whether the tissue is considered as a continuum object or a collection of cells. Among the continuum models discussed is the deformation gradient decomposition method, which allows a residual stress field to develop from an incompatible growth field. The cell-based models are further subdivided into cellular automata, center-dynamics, and vertex-dynamics models. Of these the second two are considered in more detail, especially with regard to their treatment of cell-cell interactions and cell division. The review concludes by assessing the prospects for reconciliation between these two fundamentally different approaches to tissue growth, and by identifying possible avenues for further research. © 2012 Society for Industrial and Applied Mathematics

Modelling of neurodevelopmental disorders associated with 1q21.1 deletion and duplication using human iPSCs

Copy number variation at the 1q21.1 locus (both deletion and duplication) has been associated with a wide variety of neurological phenotypes including changes in brain size and increased risk for developing psychiatric disorders. Deletion of the 1q21.1 locus is primarily associated with an increased risk of schizophrenia whereas duplication of the same locus is primarily associated with an increased risk of autism. These mutations present an untapped opportunity to understand the cellular deficits which underly both common and specific risk for psychiatric disorders. Patient derived iPSCs were made from individuals carrying either 1q21.1 deletion or duplication and were then used to model both neuronal and oligodendrocyte development. The presence of 1q21.1 CNVs was associated with significant changes in neuronal and oligodendroglial development. Deletion of the 1q21.1 locus was associated with increased neuronal activity and a reduced production of mature oligodendrocytes. On the other hand, duplication of the 1q21.1 locus was associated with deficits in the production of neurons and specification of oligodendrocytes. Key findings from the iPSC models were also validated using a 1q21.1 microdeletion mouse model and human brain imaging data from 1q21.1 carriers. These results constitute the first examination of human cellular dysfunction associated with copy number variation at the 1q21.1 locus. Furthermore, this work clearly demonstrates the importance of examining the effect of mutations on both glial and neuronal cells. To develop a system which could provide further insight into the interactions between these two cell types this study also examined the feasibility of bioprinting, as a technique for 3D cell culture. Using iPSC derived astrocytes and neurons a novel alginate based bioink was developed which could support the short-term maintenance of both cell types. Therefore, demonstrating that 3D bioprinting is a viable technique for generating 3D culture systems for iPSC derived neuronal cells

Three coronary arteries arising from the right coronary cusp with a malignant sub-pulmonary course of the left anterior descending artery

AbstractWe describe a case of a 45-year-old man presenting with acute myocardial infarction investigated by computed tomography coronary angiography. Interestingly all three coronary arteries arose from the right coronary cusp. The left anterior descending artery (LAD) subtended an acute angle from the aortic root, associated with significant kinking and stenosis at the ostium, before passing anteriorly, taking a sub-pulmonic course and descending in the anterior interventricular groove. The distal vessel was small with an atrophic appearance. The circumflex artery followed a retro-aortic route, before trifurcating to supply the lateral and posterior walls of the left ventricle. The right coronary artery was normal. Given his unstable presentation and the potentially lethal course of the LAD, he was referred for grafting of the LAD vessel which successfully ameliorated his symptoms and has thus far prevented recurrent myocardial infarction.<Learning objective: Computed tomography coronary angiography is becoming increasingly accessible to physicians for the investigation of patients with suspected coronary disease and the planning of surgery. As such, coronary anomalies are likely to be encountered more frequently, and it is important to appreciate their clinical significance.

Inhibitory effects of aspirin-triggered resolvin D1 on spinal nociceptive processing in rat pain models

Background: Harnessing the actions of the resolvin pathways has the potential for the treatment of a wide range of conditions associated with overt inflammatory signalling. Aspirin-triggered resolvin D1 (AT-RvD1) has robust analgesic effects in behavioural models of pain; however, the potential underlying spinal neurophysiological mechanisms contributing to these inhibitory effects in vivo are yet to be determined. This study investigated the acute effects of spinal AT-RvD1 on evoked responses of spinal neurones in vivo in a model of acute inflammatory pain and chronic osteoarthritic (OA) pain and the relevance of alterations in spinal gene expression to these neurophysiological effects. Methods: Pain behaviour was assessed in rats with established carrageenan-induced inflammatory or monosodium iodoacetate (MIA)-induced OA pain, and changes in spinal gene expression of resolvin receptors and relevant enzymatic pathways were examined. At timepoints of established pain behaviour, responses of deep dorsal horn wide dynamic range (WDR) neurones to transcutaneous electrical stimulation of the hind paw were recorded pre- and post direct spinal administration of AT-RvD1 (15 and 150 ng/50 μl). Results: AT-RvD1 (15 ng/50 μl) significantly inhibited WDR neurone responses to electrical stimuli at C- (29 % inhibition) and Aδ-fibre (27 % inhibition) intensities. Both wind-up (53 %) and post-discharge (46 %) responses of WDR neurones in carrageenan-treated animals were significantly inhibited by AT-RvD1, compared to pre-drug response (p < 0.05). These effects were abolished by spinal pre-administration of a formyl peptide receptor 2 (FPR2/ALX) antagonist, butoxy carbonyl-Phe-Leu-Phe-Leu-Phe (BOC-2) (50 μg/50 μl). AT-RvD1 did not alter evoked WDR neurone responses in non-inflamed or MIA-treated rats. Electrophysiological effects in carrageenan-inflamed rats were accompanied by a significant increase in messenger RNA (mRNA) for chemerin (ChemR23) receptor and 5-lipoxygenase-activating protein (FLAP) and a decrease in 15-lipoxygenase (15-LOX) mRNA in the ipsilateral spinal cord of the carrageenan group, compared to controls. Conclusions: Our data suggest that peripheral inflammation-mediated changes in spinal FLAP expression may contribute to the novel inhibitory effects of spinal AT-RvD1 on WDR neuronal excitability, which are mediated by FPR2/ALX receptors. Inflammatory-driven changes in this pathway may offer novel targets for inflammatory pain treatment

Seismic anisotropy as a constraint on composition in the lower crust

Our current interpretation of the composition of the middle and lower crust comes mainly from seismic observations, yet it remains a challenge to link seismic observations directly to composition. This is because isotropic seismic properties are similar across a range of compositions. Taking anisotropy into account allows for further refinement of our interpretation of composition provided that anisotropy is characterized for candidate rock types. This study uses electron backscatter diffraction (EBSD) measurements of crystallographic preferred orientation of minerals to calculate seismic anisotropy in samples of the Pelona-Orocopia-Rand (POR) schist from the Mojave region of southern California. The goals of this work are to characterize the seismic anisotropy of the POR schist and its relationship to observed lower crustal anisotropy in the region, and to refine predictions of lower crustal composition based on seismic anisotropy

Building realistic potential patient queries for medical information retrieval evaluation

To evaluate and improve medical information retrieval, benchmarking data sets need to be created. Few benchmarks have been focusing on patients’ information needs. There is a need for additional benchmarks to enable research into effective retrieval methods. In this paper we describe the manual creation of patient queries and investigate their automatic generation. This work is conducted in the framework of a medical evaluation campaign, which aims to evaluate and improve technologies to help patients and laypeople access eHealth data. To this end, the campaign is composed of different tasks, including a medical information retrieval (IR) task. Within this IR task, a web crawl of medically related documents, as well as patient queries are provided to participants. The queries are built to represent the potential information needs patients may have while reading their medical report. We start by describing typical types of patients’ information needs. We then describe how these queries have been manually generated from medical reports for the first two years of the eHealth campaign. We then explore techniques that would enable us to automate the query generation process. This process is particularly challenging, as it requires an understanding of the patients’ information needs, and of the electronic health records. We describe various approaches to automatically generate potential patient queries from medical reports and describe our future development and evaluation phase

Acute Dosing and p53-Deficiency Promote Cellular Sensitivity to DNA Methylating Agents

Risk assessment of human exposure to chemicals is crucial for understanding whether such agents can cause cancer. The current emphasis on avoidance of animal testing has placed greater importance on in vitro tests for the identification of genotoxicants. Selection of an appropriate in vitro dosing regime is imperative in determining the genotoxic effects of test chemicals. Here, the issue of dosing approaches was addressed by comparing acute and chronic dosing, uniquely using low-dose experiments. Acute 24h exposures were compared with equivalent dosing every 24h over 5-day, fractionated treatment periods. The In Vitro Micronucleus Assay was used to measure clastogenicity induced by methyl methanesulphonate (MMS) and N-methyl-N-nitrosourea (MNU) in human lymphoblastoid cell line, TK6. Quantitative RT-PCR was used to measure mRNA level induction of DNA repair enzymes. Lowest observed genotoxic effect levels (LOGELs) for MMS were obtained at 0.7μg/ml for the acute study and 1.0μg/ml for the chronic study. For acute MNU dosing, a LOGEL was observed at 0.46μg/ml, yet genotoxicity was completely removed following the chronic study. Interestingly, acute MNU dosing demonstrated a statistically significant decrease at 0.009μg/ml. Levels of selected DNA repair enzymes did not change significantly following doses tested. However, p53-deficiency (using the TK6-isogenic cell line, NH32) increased sensitivity to MMS during chronic dosing, causing this LOGEL to equate to the acute treatment LOGEL. In the context of the present data for two alkylating agents, chronic dosing could be a valuable in vitro supplement to acute dosing and could contribute to reduction of unnecessary in vivo follow-up test