Biomechanical properties of the spinal cord: implications for tissue engineering and clinical translation

Spinal cord injury is a severely debilitating condition which can leave individuals paralyzed and suffering from autonomic dysfunction. Regenerative medicine may offer a promising solution to this problem. Previous research has focused primarily on exploring the cellular and biological aspects of the spinal cord, yet relatively little remains known about the biomechanical properties of spinal cord tissue. Given that a number of regenerative strategies aim to deliver cells and materials in the form of tissue-engineered therapies, understanding the biomechanical properties of host spinal cord tissue is important. We review the relevant biomechanical properties of spinal cord tissue and provide the baseline knowledge required to apply these important physical concepts to spinal cord tissue engineering

Two-Stage Change Detection for Synthetic Aperture Radar

Coherent change detection using paired synthetic aperture radar (SAR) images is often performed using a classical coherence estimator that is invariant to the true variances of the populations underlying each paired sample. While attractive, this estimator is biased and requires a significant number of samples to yield good performance. Increasing sample size often results in decreased image resolution. Thus, we propose the use of Berger's coherence estimate because, with the same number of pixels, the estimator effectively doubles the sample support without sacrificing resolution when the underlying population variances are equal or near equal. A potential drawback of this approach is that it is not invariant since its distribution depends on the pixel pair population variances. While Berger's estimator is inherently sensitive to the inequality of population variances, we propose a method of insulating the detector from this acuity. A two-stage change statistic is introduced to combine a noncoherent intensity change statistic given by the sample variance ratio, followed by the alternative Berger estimator, which assumes equal population variances. The first-stage detector identifies pixel pairs that have nonequal variances as changes caused by the displacement of sizeable object. The pixel pairs that are identified to have equal or near-equal variances in the first stage are used as an input to the second stage. The second-stage test uses the alternative Berger coherence estimator to detect subtle changes such as tire tracks and footprints. We show experimentally that the proposed method yields higher contrast SAR change detection images than the classical coherent change detector (state of the art), the alternative coherent change detector, and the intensity change detector. Experimental results are presented to show the effectiveness and robustness of the proposed algorithm for SAR change detection

Hydroxyurea Therapy in UK Children with Sickle Cell Anaemia – A Single Centre Experience

Despite the demonstrated efficacy of hydroxyurea therapy, children with sickle cell anaemia in the United Kingdom (UK) are preferentially managed with supportive care or transfusion. Hydroxyurea is reserved for children with severe disease phenotype. This is in contrast to North America and other countries where hydroxyurea is widely used for children of all clinical phenotypes. The conservative UK practice may in part be due to concerns about toxicity, in particular marrow suppression with high doses, and growth in children. We monitored 37 paediatric patients with sickle cell anaemia who were treated with hydroxyurea at a single UK treatment centre. Therapy was well tolerated and mild transient cytopenias were the only toxicity observed. Comparative analysis of patients receiving ≥26mg/kg/day versus <26 mg/kg/day demonstrates increasing dose has a significant positive effect on foetal haemoglobin (29.2% v 20.4%, p=0.0151), mean cell volume (94.4 v 86.5, p=0.0183) and reticulocyte count (99.66 x109/L v 164.3x109/L, p=0.0059). Marrow suppression was not a clinical problem with high dose treatment, haemoglobin 92.25 g/L v 91.81 g/L (ns), neutrophil count 3.3 x109/L v 4.8 x109/L (ns) and platelet count 232.4 x109/L v 302.2 x109/L (ns). Normal growth rates were maintained in all children. Good adherence to therapy was a significant factor in reducing hospitalisations This study demonstrates the effectiveness and safety in practice of high dose hydroxyurea as a disease modifying therapy which we advocate for all children with sickle cell anaemia

Cell Therapies for Spinal Cord Injury: Trends and Challenges of Current Clinical Trials

Cell therapies have the potential to revolutionize the treatment of spinal cord injury. Basic research has progressed significantly in recent years, with a plethora of cell types now reaching early-phase human clinical trials, offering new strategies to repair the spinal cord. However, despite initial enthusiasm for preclinical and early-phase clinical trials, there has been a notable hiatus in the translation of cell therapies to routine clinical practice. Here, we review cell therapies that have reached clinical trials for spinal cord injury, providing a snapshot of all registered human trials and a summary of all published studies. Of registered trials, the majority have used autologous cells and approximately a third have been government funded, a third industry sponsored, and a third funded by university or healthcare systems. A total of 37 cell therapy trials have been published, primarily using stem cells, although a smaller number have used Schwann cells or olfactory ensheathing cells. Significant challenges remain for cell therapy trials in this area, including achieving stringent regulatory standards, ensuring appropriately powered efficacy trials, and establishing sustainable long-term funding. However, cell therapies hold great promise for human spinal cord repair and future trials must continue to capitalize on the exciting developments emerging from preclinical studies

Can the Shape of Nanoparticles Enable the Targeting to Cancer Cells over Healthy Cells?

Macropinocytosis is a consequence of oncogenic alterations of cancer cells while most healthy cells are non-macropinocytic. It is currently unclear whether macropinocytic cancer cells can be targeted rather than healthy cells, by adjusting the shape and size of nanoparticles. Herein, the endocytosis of two differently shaped nanoparticles; nanorods and nanospheres are compared in cancer and healthy cells. The cells are breast epithelial cancer cells (MCF7) and breast epithelial healthy cells (MCF10A) and pancreas cancer cells (PANC-1 cells) and non-tumourogenic patient-derived cancer-associated fibroblasts (CAFs). The endocytosis pathway is quantified by a combination of pair correlation microscopy and endocytosis inhibitors. MCF7 cells use clathrin-mediated endocytosis and macropinocytosis to take up the nanorods while MCF10A cells use predominantly clathrin-mediated endocytosis. Based on the comparison of endocytic behavior of cancer and healthy cells, MCF7 cells can be induced to take up more nanorods and suppress the metabolism and endocytosis of nanorods in MCF10A cells. The nanorods allow targeting to breast cancer MCF7 cells and pancreas cancer cells over the healthy cells. This study opens exciting possibilities for shape to target the cancer cells over healthy cells, by adjusting nanoparticle shape

Individual participant data validation of the PICNICC prediction model for febrile neutropenia

BACKGROUND: Risk-stratified approaches to managing cancer therapies and their consequent complications rely on accurate predictions to work effectively. The risk-stratified management of fever with neutropenia is one such very common area of management in paediatric practice. Such rules are frequently produced and promoted without adequate confirmation of their accuracy. METHODS: An individual participant data meta-analytic validation of the 'Predicting Infectious ComplicatioNs In Children with Cancer' (PICNICC) prediction model for microbiologically documented infection in paediatric fever with neutropenia was undertaken. Pooled estimates were produced using random-effects meta-analysis of the area under the curve-receiver operating characteristic curve (AUC-ROC), calibration slope and ratios of expected versus observed cases (E/O). RESULTS: The PICNICC model was poorly predictive of microbiologically documented infection (MDI) in these validation cohorts. The pooled AUC-ROC was 0.59, 95% CI 0.41 to 0.78, tau2=0, compared with derivation value of 0.72, 95% CI 0.71 to 0.76. There was poor discrimination (pooled slope estimate 0.03, 95% CI -0.19 to 0.26) and calibration in the large (pooled E/O ratio 1.48, 95% CI 0.87 to 2.1). Three different simple recalibration approaches failed to improve performance meaningfully. CONCLUSION: This meta-analysis shows the PICNICC model should not be used at admission to predict MDI. Further work should focus on validating alternative prediction models. Validation across multiple cohorts from diverse locations is essential before widespread clinical adoption of such rules to avoid overtreating or undertreating children with fever with neutropenia

Exhaled volatile organic compounds in patients with non-small cell lung cancer: cross sectional and nested short-term follow-up study

BACKGROUND: Non-invasive diagnostic strategies aimed at identifying biomarkers of lung cancer are of great interest for early cancer detection. The aim of this study was to set up a new method for identifying and quantifying volatile organic compounds (VOCs) in exhaled air of patients with non-small cells lung cancer (NSCLC), by comparing the levels with those obtained from healthy smokers and non-smokers, and patients with chronic obstructive pulmonary disease. The VOC collection and analyses were repeated three weeks after the NSCLC patients underwent lung surgery. METHODS: The subjects' breath was collected in a Teflon(® )bulb that traps the last portion of single slow vital capacity. The 13 VOCs selected for this study were concentrated using a solid phase microextraction technique and subsequently analysed by means of gas cromatography/mass spectrometry. RESULTS: The levels of the selected VOCs ranged from 10(-12 )M for styrene to 10(-9 )M for isoprene. None of VOCs alone discriminated the study groups, and so it was not possible to identify one single chemical compound as a specific lung cancer biomarker. However, multinomial logistic regression analysis showed that VOC profile can correctly classify about 80 % of cases. Only isoprene and decane levels significantly decreased after surgery. CONCLUSION: As the combination of the 13 VOCs allowed the correct classification of the cases into groups, together with conventional diagnostic approaches, VOC analysis could be used as a complementary test for the early diagnosis of lung cancer. Its possible use in the follow-up of operated patients cannot be recommended on the basis of the results of our short-term nested study