Magnetic resonance imaging of graded skeletal muscle injury in live rats.

INTRODUCTION: Increasing number of stretch-shortening contractions (SSCs) results in increased muscle injury. METHODS: Fischer Hybrid rats were acutely exposed to an increasing number of SSCs in vivo using a custom-designed dynamometer. Magnetic resonance imaging (MRI) imaging was conducted 72 hours after exposure when rats were infused with Prohance and imaged using a 7T rodent MRI system (GE Epic 12.0). Images were acquired in the transverse plane with typically 60 total slices acquired covering the entire length of the hind legs. Rats were euthanized after MRI, the lower limbs removed, and tibialis anterior muscles were prepared for histology and quantified stereology. RESULTS: Stereological analyses showed myofiber degeneration, and cellular infiltrates significantly increased following 70 and 150 SSC exposure compared to controls. MRI images revealed that the percent affected area significantly increased with exposure in all SSC groups in a graded fashion. Signal intensity also significantly increased with increasing SSC repetitions. DISCUSSION: These results suggest that contrast-enhanced MRI has the sensitivity to differentiate specific degrees of skeletal muscle strain injury, and imaging data are specifically representative of cellular histopathology quantified via stereological analyses.

Quantitative mapping of trimethyltin injury in the rat brain using magnetic resonance histology.

The growing exposure to chemicals in our environment and the increasing concern over their impact on health have elevated the need for new methods for surveying the detrimental effects of these compounds. Today's gold standard for assessing the effects of toxicants on the brain is based on hematoxylin and eosin (H&E)-stained histology, sometimes accompanied by special stains or immunohistochemistry for neural processes and myelin. This approach is time-consuming and is usually limited to a fraction of the total brain volume. We demonstrate that magnetic resonance histology (MRH) can be used for quantitatively assessing the effects of central nervous system toxicants in rat models. We show that subtle and sparse changes to brain structure can be detected using magnetic resonance histology, and correspond to some of the locations in which lesions are found by traditional pathological examination. We report for the first time diffusion tensor image-based detection of changes in white matter regions, including fimbria and corpus callosum, in the brains of rats exposed to 8 mg/kg and 12 mg/kg trimethyltin. Besides detecting brain-wide changes, magnetic resonance histology provides a quantitative assessment of dose-dependent effects. These effects can be found in different magnetic resonance contrast mechanisms, providing multivariate biomarkers for the same spatial location. In this study, deformation-based morphometry detected areas where previous studies have detected cell loss, while voxel-wise analyses of diffusion tensor parameters revealed microstructural changes due to such things as cellular swelling, apoptosis, and inflammation. Magnetic resonance histology brings a valuable addition to pathology with the ability to generate brain-wide quantitative parametric maps for markers of toxic insults in the rodent brain.

Intermolecular Multiple Quantum Coherences Enable Accurate Thermal Imaging of Red Bone Marrow During Thermal Therapy of Bone Metastases

Prostate and breast cancers are two of the most common types of cancer in the United States, and those cancers metastasize to bone in more than two thirds of patients. Recent evidence suggests that thermal therapy is effective at treating metastatic bone cancer. For example, thermal therapy enables targeted drug delivery to bone, ablation of cancer cells in bone marrow, and palliation of bone pain. Thermal therapy of bone metastases would be greatly improved if it were possible to image the temperature of the tissue surrounding the disease, which is usually red bone marrow (RBM). Unfortunately, current thermal imaging techniques are inaccurate in RBM.

This dissertation shows that many of the difficulties with thermal imaging of RBM can be overcome using a magnetic resonance phenomenon called an intermolecular multiple quantum coherence (iMQC). Herein, iMQCs are detected with a magnetic resonance imaging (MRI) pulse sequence called multi-spin-echo HOMOGENIZED with off resonance transfer (MSE-HOT). Compared to traditional methods, MSE-HOT provided ten-fold more accurate images of temperature change. Furthermore, MSE-HOT was translated to a human MRI scanner, which enabled imaging of RBM temperature during heating with a clinical focused ultrasound applicator. In summary, this dissertation develops a MRI technique that enables thermal imaging of RBM during thermal therapy of bone metastases.

Signal Improvement and Contrast Enhancement in Magnetic Resonance Imaging

This thesis reports advances in magnetic resonance imaging (MRI), with the ultimate goal of improving signal and contrast in biomedical applications. More specifically, novel MRI pulse sequences have been designed to characterize microstructure, enhance signal and contrast in tissue, and image functional processes. In this thesis, rat brain and red bone marrow images are acquired using iMQCs (intermolecular multiple quantum coherences) between spins that are 10 μm to 500 μm apart. As an important application, iMQCs images in different directions can be used for anisotropy mapping. We investigate tissue microstructure by analyzing anisotropy mapping. At the same time, we simulated images expected from rat brain without microstructure. We compare those with experimental results to prove that the dipolar field from the overall shape only has small contributions to the experimental iMQC signal. Besides magnitude of iMQCs, phase of iMQCs should be studied as well. The phase anisotropy maps built by our method can clearly show susceptibility information in kidneys. It may provide meaningful diagnostic information. To deeply study susceptibility, the modified-crazed sequence is developed. Combining phase data of modified-crazed images and phase data of iMQCs images is very promising to construct microstructure maps. Obviously, the phase image in all above techniques needs to be highly-contrasted and clear. To achieve the goal, algorithm tools from Susceptibility-Weighted Imaging (SWI) and Susceptibility Tensor Imaging (STI) stands out superb useful and creative in our system.

Colchicine effectiveness in symptom and inflammation modification in knee osteoarthritis (COLKOA): study protocol for a randomized controlled trial.

BACKGROUND: Despite the high prevalence and global impact of knee osteoarthritis (KOA), current treatments are palliative. No disease modifying anti-osteoarthritic drug (DMOAD) has been approved. We recently demonstrated significant involvement of uric acid and activation of the innate immune response in osteoarthritis (OA) pathology and progression, suggesting that traditional gout therapy may be beneficial for OA. We therefore assess colchicine, an existing commercially available agent for gout, for a new therapeutic application in KOA. METHODS/DESIGN: COLKOA is a double-blind, placebo-controlled, randomized trial comparing a 16-week treatment with standard daily dose oral colchicine to placebo for KOA. A total of 120 participants with symptomatic KOA will be recruited from a single center in Singapore. The primary end point is 30% improvement in total Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score at week 16. Secondary end points include improvement in pain, physical function, and quality of life and change in serum, urine and synovial fluid biomarkers of cartilage metabolism and inflammation. A magnetic resonance imaging (MRI) substudy will be conducted in 20 participants to evaluate change in synovitis. Logistic regression will be used to compare changes between groups in an intention-to-treat analysis. DISCUSSION: The COLKOA trial is designed to evaluate whether commercially available colchicine is effective for improving signs and symptoms of KOA, and reducing synovial fluid, serum and urine inflammatory and biochemical joint degradation biomarkers. These biomarkers should provide insights into the underlying mechanism of therapeutic response. This trial will potentially provide data to support a new treatment option for KOA. TRIAL REGISTRATION: The trial has been registered at clinicaltrials.gov as NCT02176460 . Date of registration: 26 June 2014.

Effects of chronic mild traumatic brain injury on white matter integrity in iraq and afghanistan war veterans

Mild traumatic brain injury (TBI) is a common source of morbidity from the wars in Iraq and Afghanistan. With no overt lesions on structural MRI, diagnosis of chronic mild TBI in military veterans relies on obtaining an accurate history and assessment of behavioral symptoms that are also associated with frequent comorbid disorders, particularly posttraumatic stress disorder (PTSD) and depression. Military veterans from Iraq and Afghanistan with mild TBI (n = 30) with comorbid PTSD and depression and non-TBI participants from primary (n = 42) and confirmatory (n = 28) control groups were assessed with high angular resolution diffusion imaging (HARDI). White matter-specific registration followed by whole-brain voxelwise analysis of crossing fibers provided separate partial volume fractions reflecting the integrity of primary fibers and secondary (crossing) fibers. Loss of white matter integrity in primary fibers (P < 0.05; corrected) was associated with chronic mild TBI in a widely distributed pattern of major fiber bundles and smaller peripheral tracts including the corpus callosum (genu, body, and splenium), forceps minor, forceps major, superior and posterior corona radiata, internal capsule, superior longitudinal fasciculus, and others. Distributed loss of white matter integrity correlated with duration of loss of consciousness and most notably with "feeling dazed or confused," but not diagnosis of PTSD or depressive symptoms. This widespread spatial extent of white matter damage has typically been reported in moderate to severe TBI. The diffuse loss of white matter integrity appears consistent with systemic mechanisms of damage shared by blast- and impact-related mild TBI that involves a cascade of inflammatory and neurochemical events. © 2012 Wiley Periodicals, Inc.

ENIGMA and the individual: Predicting factors that affect the brain in 35 countries worldwide.

In this review, we discuss recent work by the ENIGMA Consortium (http://enigma.ini.usc.edu) - a global alliance of over 500 scientists spread across 200 institutions in 35 countries collectively analyzing brain imaging, clinical, and genetic data. Initially formed to detect genetic influences on brain measures, ENIGMA has grown to over 30 working groups studying 12 major brain diseases by pooling and comparing brain data. In some of the largest neuroimaging studies to date - of schizophrenia and major depression - ENIGMA has found replicable disease effects on the brain that are consistent worldwide, as well as factors that modulate disease effects. In partnership with other consortia including ADNI, CHARGE, IMAGEN and others(1), ENIGMA's genomic screens - now numbering over 30,000 MRI scans - have revealed at least 8 genetic loci that affect brain volumes. Downstream of gene findings, ENIGMA has revealed how these individual variants - and genetic variants in general - may affect both the brain and risk for a range of diseases. The ENIGMA consortium is discovering factors that consistently affect brain structure and function that will serve as future predictors linking individual brain scans and genomic data. It is generating vast pools of normative data on brain measures - from tens of thousands of people - that may help detect deviations from normal development or aging in specific groups of subjects. We discuss challenges and opportunities in applying these predictors to individual subjects and new cohorts, as well as lessons we have learned in ENIGMA's efforts so far.

A phase 1-2 clinical trial of gene therapy for recurrent glioblastoma multiforme by tumor transduction with the herpes simplex thymidine kinase gene followed by ganciclovir.

This study has investigated the effects of herpes simplex thymidine kinase gene (HSV-tk) transfer followed by ganciclovir treatment as adjuvant gene therapy to surgical resection in patients with recurrent glioblastoma multiforme (GBM). The study was open and single-arm, and aimed at assessing the feasibility and safety of the technique and indications of antitumor activity. In 48 patients a suspension of retroviral vector-producing cells (VPCs) was administered by intracerebral injection immediately after tumor resection. Intravenous ganciclovir was infused daily 14 to 27 days after surgery. Patients were monitored for adverse events and for life by regular biosafety assaying. Tumor changes were monitored by magnetic resonance imaging (MRI). Reflux during injection was a frequent occurrence but serious adverse events during the treatment period (days 1-27) were few and of a nature not unexpected in this population. One patient experienced transient neurological disorders associated with postganciclovir MRI enhancement. There was no evidence of replication-competent retrovirus in peripheral blood leukocytes or in tissue samples of reresection or autopsy. Vector DNA was shown in the leukocytes of some patients but not in autopsy gonadal samples. The median survival time was 8.6 months, and the 12-month survival rate was 13 of 48 (27%). On MRI studies, tumor recurrence was absent in seven patients for at least 6 months and for at least 12 months in two patients, one of whom remains recurrence free at more than 24 months. Treatment-characteristic images of injection tracks and intracavity hemoglobin were apparent. In conclusion, the gene therapy is feasible and appears to be satisfactorily safe as an adjuvant to the surgical resection of recurrent GBM, but any benefit appears to be marginal. Investigation of the precise effectiveness of this gene therapy requires prospective, controlled studies.

Report from an International Nutrient Workshop focusing on Phosphate Analysis

A practical analytical workshop at NIOZ (Royal Netherlands Institute for Sea Research), The Netherlands, was held on 12-15 November 2012. The aim of the workshop was to gain information from the global nutrient analytical community about general problems which arise when measuring nutrients, and then to attempt to investigate these problems in the laboratory, with a small select representative group of International nutrient analysts conducting the lab work. 18 experts were participated and worked simultaneously on four different PO4 gas segmented CFA systems. This report documents the finding of the workshop and describes recommendations based on group consensus which can hopefully assist the larger community of labs worldwide participating in the Inter-Laboratory Comparison RMNS 2012 studies organized by MRI in Japan.

Abnormal endothelial tight junctions in active lesions and normal-appearing white matter in multiple sclerosis

Blood-brain barrier (BBB) breakdown, demonstrable in vivo by enhanced MRI is characteristic of new and expanding inflammatory lesions in relapsing remitting and chronic progressive multiple sclerosis (MS). Subtle leakage may also occur in primary progressive MS. However, the anatomical route(s) of BBB leakage have not been demonstrated. We investigated the possible involvement of interendothelial tight junctions (TJ) by examining the expression of TJ proteins (occludin and ZO-1 ) in blood vessels in active MS lesions from 8 cases of MS and in normal-appearing white (NAWM) matter from 6 cases. Blood vessels (10-50 per frozen section) were scanned using confocal laser scanning microscopy to acquire datasets for analysis. TJ abnormalities manifested as beading, interruption, absence or diffuse cytoplasmic localization of fluorescence, or separation of junctions (putative opening) were frequent (affecting 40% of vessels) in oil red-O-positive active plaques but less frequent in NAWM (15%), and in normal (

Non-invasive in vivo imaging in small animal research

Non-invasive real time in vivo molecular imaging in small animal models has become the essential bridge between in vitro data and their translation into clinical applications. The tremendous development and technological progress, such as tumour modelling, monitoring of tumour growth and detection of metastasis, has facilitated translational drug development. This has added to our knowledge on carcinogenesis. The modalities that are commonly used include Magnetic Resonance Imaging (MRI), Computed Tomography (CT), Positron Emission Tomography (PET), bioluminescence imaging, fluorescence imaging and multi-modality imaging systems. The ability to obtain multiple images longitudinally provides reliable information whilst reducing animal numbers. As yet there is no one modality that is ideal for all experimental studies. This review outlines the instrumentation available together with corresponding applications reported in the literature with particular emphasis on cancer research. Advantages and limitations to current imaging technology are discussed and the issues concerning small animal care during imaging are highlighted.

Social networks and cooperative learning in a MOOC

MOOCs are changing the educational landscape and gaining a lot of attention in scientific literature. However, the pedagogical design of these proposals has been called into question. It is precisely MOOCs’ social aspect, i.e. the interaction between course participants and the support for learning processes that has become one of the main topics of interest. This article presents the results of a research project carried out at the University of the Basque Country, which focused in cooperative learning and the intensive use of social networks in a MOOC. Significant data was compiled through Likert-type surveys, revealing that the use of both external and internal social networks in a massive open online course is a factor that is evaluated positively by students. We argue that the use of social networks as a learning strategy in a MOOC has an influence on academic performance and on the students' success rate. Furthermore, the participants’ age also has a bearing on the social networks they use, and we have found that the younger members tend to work with external networks such as Twitter or personal blogs, whereas the older students are more inclined to use forums from the Chamilo or Ning platforms.

High-performance 3D median filter architecture for medical image despeckling

A high-sample rate 3D median filtering processor architecture is proposed, based on a novel 3D median filtering algorithm, that can reduce the computing complexity in comparison with the traditional bubble sorting algorithm. A 3 x 3 x 3 filter processor is implemented in VHDL, and the simulation verifies that the processor can process a 128 x 128 x 96 MRI image in 0.03 seconds while running at 50 MHz.

Robust Estimation of HDR in fMRI using H∞ Filters

Estimation and detection of the hemodynamic response (HDR) are of great importance in functional MRI (fMRI) data analysis. In this paper, we propose the use of three H 8 adaptive filters (finite memory, exponentially weighted, and time-varying) for accurate estimation and detection of the HDR. The H 8 approach is used because it safeguards against the worst case disturbances and makes no assumptions on the (statistical) nature of the signals [B. Hassibi and T. Kailath, in Proc. ICASSP, 1995, vol. 2, pp. 949-952; T. Ratnarajah and S. Puthusserypady, in Proc. 8th IEEE Workshop DSP, 1998, pp. 1483-1487]. Performances of the proposed techniques are compared to the conventional t-test method as well as the well-known LMSs and recursive least squares algorithms. Extensive numerical simulations show that the proposed methods result in better HDR estimations and activation detections.