CXCR4-targeted and MMP-responsive iron oxide nanoparticles for enhanced magnetic resonance imaging

MRI offers high spatial resolution with excellent tissue penetration but it has limited sensitivity and the commonly administered contrast agents lack specificity. In this study, two sets of iron oxide nanoparticles (IONPs) were synthesized that were designed to selectively undergo copper-free click conjugation upon sensing of matrix metalloproteinase (MMP) enzymes, thereby leading to a self-assembled superparamagnetic nanocluster network with T2 signal enhancement properties. For this purpose, IONPs with bioorthogonal azide and alkyne surfaces masked by polyethylene glycol (PEG) layers tethered to CXCR4-targeted peptide ligands were synthesized and characterized. The IONPs were tested in vitro and T2 signal enhancements of around 160 % were measured when the IONPs were incubated with cells expressing MMP2/9 and CXCR4. Simultaneous systemic administration of the bioorthogonal IONPs in tumor-bearing mice demonstrated the signal-enhancing ability of these ‘smart’ self-assembling nanomaterials

Comparison of Cartesian and Non-Cartesian Real-Time MRI Sequences at 1.5T to Assess Velar Motion and Velopharyngeal Closure during Speech

This project is funded by CLEFT (CLEFT-2013-1) and an Institute of Physics and Engineering in Medicine (IPEM) Innovation and Research Award for computer equipment. MEM is partly (20%) funded by the National Institute for Health Research Cardiovascular Biomedical Research Unit at Barts. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript

Lactate, N-acetylaspartate, choline and creatine concentrations, and spin-spin relaxation in thalamic and occipito-parietal regions of developing human brain

Previous studies of the brains of normal infants demonstrated lower lactate (Lac)/choline (Cho), Lac/creatine (Cr), and Lac/ N-acetylaspartate (Naa) peak-area ratios in the thalamic region (predominantly gray matter) compared with occipitoparietal (mainly unmyelinated white matter) values. In the present study, thalamic Cho, Cr, and Naa concentrations between 32-42 weeks\u27 gestational plus postnatal age were greater than occipito-parietal: 4.6 +/- 0.8 (mean +/- SE), 10.5 +/- 2.0, and 9.0 +/- 0.7 versus 1.8 +/- 0.6, 5.8 +/- 1.5, and 3.4 +/- 1.1 mmol/kg wet weight, respectively: Lac concentrations were similar, 2.7 +/- 0.6 and 3.3 +/- 1.3 mmol/kg wet weight, respectively. In the thalamic region, Cho and Naa T2s increased, and Cho and Lac concentrations decreased, during development. Lower thalamic Lac peak-area ratios are principally due to higher thalamic concentrations of Cho, Cr, and Naa rather than less Lac. The high thalamic Cho concentration may relate to active myelination; the high thalamic Naa concentration may be due to advanced gray-matter development including active myelination. Lac concentration is higher in neonatal than in adult brain

Frequency offset corrected inversion (FOCI) pulses for use in localized spectroscopy

Gradient localized spectroscopy techniques suffer from a well documented spatial localization error caused by the difference in chemical shifts between resonances. This results in the acquisition of spectra from partially overlapping spatial regions of the sample, with each resonance representing a different region. The image-selected in vivo spectroscopy technique uses hyperbolic secant inversion pulses, where the main limitation in reducing this error is in the RF power available for application of the selective RF pulse. This spatial localization error may be dramatically reduced by increasing, and temporally shaping, the gradient pulse during slice-selective spin inversion. The performance of these RF pulses have been experimentally verified

In vivo fluorescence lifetime tomography of a FRET probe expressed in mouse

Förster resonance energy transfer (FRET) is a powerful biological tool for reading out cell signaling processes. In vivo use of FRET is challenging because of the scattering properties of bulk tissue. By combining diffuse fluorescence tomography with fluorescence lifetime imaging (FLIM), implemented using wide-field time-gated detection of fluorescence excited by ultrashort laser pulses in a tomographic imaging system and applying inverse scattering algorithms, we can reconstruct the three dimensional spatial localization of fluorescence quantum efficiency and lifetime. We demonstrate in vivo spatial mapping of FRET between genetically expressed fluorescent proteins in live mice read out using FLIM. Following transfection by electroporation, mouse hind leg muscles were imaged in vivo and the emission of free donor (eGFP) in the presence of free acceptor (mCherry) could be clearly distinguished from the fluorescence of the donor when directly linked to the acceptor in a tandem (eGFP-mCherry) FRET construct

Low GABA concentrations in occipital cortex and anterior cingulate cortex in medication-free, recovered depressed patients

Studies using proton magnetic resonance spectroscopy (1H-MRS) indicate that unmedicated, acutely depressed patients have decreased levels of γ-aminobutyric acid (GABA) in the occipital cortex. The aim of this study was to use 1H-MRS to determine if changes in occipital and frontal cortical GABA levels were present in patients with a history of depression who had recovered and were no longer taking medication. We used 1H-MRS to measure levels of GABA in both occipital cortex and anterior cingulate cortex/prefrontal cortex in medication-free, fully recovered subjects with a history of recurrent unipolar depression. Levels of GABA in both occipital and anterior cingulate cortex were significantly lower in recovered depressed subjects than healthy controls. Our data provide preliminary evidence that a history of recurrent depression is associated with decreased GABA levels in anterior cingulate cortex and occipital cortex. These changes could represent part of the neurobiological vulnerability to recurrent depressive episodes

Heart rate reduction with ivabradine promotes shear stress-dependent anti-inflammatory mechanisms in arteries

Blood flow generates wall shear stress (WSS) which alters endothelial cell (EC) function. Low WSS promotes vascular inflammation and atherosclerosis whereas high uniform WSS is protective. Ivabradine decreases heart rate leading to altered haemodynamics. Besides its cardio-protective effects, ivabradine protects arteries from inflammation and atherosclerosis via unknown mechanisms. We hypothesised that ivabradine protects arteries by increasing WSS to reduce vascular inflammation. Hypercholesterolaemic mice were treated with ivabradine for seven weeks in drinking water or remained untreated as a control. En face immunostaining demonstrated that treatment with ivabradine reduced the expression of pro-inflammatory VCAM-1 (p<0.01) and enhanced the expression of anti-inflammatory eNOS (p<0.01) at the inner curvature of the aorta. We concluded that ivabradine alters EC physiology indirectly via modulation of flow because treatment with ivabradine had no effect in ligated carotid arteries in vivo, and did not influence the basal or TNFα-induced expression of inflammatory (VCAM-1, MCP-1) or protective (eNOS, HMOX1, KLF2, KLF4) genes in cultured EC. We therefore considered whether ivabradine can alter WSS which is a regulator of EC inflammatory activation. Computational fluid dynamics demonstrated that ivabradine treatment reduced heart rate by 20 % and enhanced WSS in the aorta. In conclusion, ivabradine treatment altered haemodynamics in the murine aorta by increasing the magnitude of shear stress. This was accompanied by induction of eNOS and suppression of VCAM-1, whereas ivabradine did not alter EC that could not respond to flow. Thus ivabradine protects arteries by altering local mechanical conditions to trigger an anti-inflammatory response

Age-dependent effects of chronic fluoxetine treatment on the serotonergic system one week following treatment

Abstract Rationale Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine are increasingly used for the treatment of depression in children. Limited data are, however, available on their effects on brain development and their efficacy remains debated. Moreover, previous experimental studies are seriously hampered in their clinical relevance. Objectives The aim of the present study was to investigate putative age-related effects of a chronic treatment with fluoxetine (5 mg/kg, either orally or i.p. for 3 weeks, 1 week washout) using conventional methods (behavioral testing and binding assay using [ 123 I]β-CIT) and a novel magnetic resonance imaging (MRI) approach. Methods Behavior was assessed, as well as serotonin transporter (SERT) availability and function through ex vivo binding assays and in vivo pharmacological MRI (phMRI) with an acute fluoxetine challenge (10 mg/kg oral or 5 mg/kg i.v.) in adolescent and adult rats. Results Fluoxetine caused an increase in anxiety-like behavior in treated adult, but not adolescent, rats. On the binding assays, we observed increased SERT densities in most cortical brain regions and hypothalamus in adolescent, but not adult, treated rats. Finally, reductions in brain activation were observed with phMRI following treatment, in both adult and adolescent treated animals. Conclusion Collectively, our data indicate that the shortterm effects of fluoxetine on the 5-HT system may be agedependent. These findings could reflect structural and functional rearrangements in the developing brain that do not occur in the matured rat brain. phMRI possibly will be well suited to study this important issue in the pediatric population

Evaluation of 3D T1-weighted imaging at 3T across scanner vendors and models

Volumetric analyses of 3D T1-weighted images has become an integral part of the clinical work-up and research studies. Variation between scanners, in both vendors and models, is a major confound in combining imaging-derived biomarkers across sites. In this work, we analyse test-retest data from di×erent days on six 3 T scanners from three vendors to quantify this inter-scanner variability compared to intra-scanner variability. Contrast-to-noise ratios as well as volumetric analyses are performed showing between-scanner variation in total brain volumes – indicating di×erent scanner calibrations – but also tissue-speciÒc di×erences – possibly arising from di×erent e×ective contrasts

Gray matter imaging in multiple sclerosis: what have we learned?

At the early onset of the 20th century, several studies already reported that the gray matter was implicated in the histopathology of multiple sclerosis (MS). However, as white matter pathology long received predominant attention in this disease, and histological staining techniques for detecting myelin in the gray matter were suboptimal, it was not until the beginning of the 21st century that the true extent and importance of gray matter pathology in MS was finally recognized. Gray matter damage was shown to be frequent and extensive, and more pronounced in the progressive disease phases. Several studies subsequently demonstrated that the histopathology of gray matter lesions differs from that of white matter lesions. Unfortunately, imaging of pathology in gray matter structures proved to be difficult, especially when using conventional magnetic resonance imaging (MRI) techniques. However, with the recent introduction of several more advanced MRI techniques, the detection of cortical and subcortical damage in MS has considerably improved. This has important consequences for studying the clinical correlates of gray matter damage. In this review, we provide an overview of what has been learned about imaging of gray matter damage in MS, and offer a brief perspective with regards to future developments in this field