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International audience; Among a plethora of drug nanocarriers, biocompatible nanoscale metal-organic frameworks (nanoMOFs) with a large surface area and an amphiphilic internal microenvironment have emerged as promising drug delivery platforms, mainly for cancer therapy. However, their application in biomedicine still suffers from shortcomings such as a limited chemical and/or colloidal stability and/or toxicity. Here, we report the design of a hierarchically porous nano-object (denoted as USPIO@MIL) combining a benchmark nanoMOF (that is, MIL-100(Fe)) and ultra-small superparamagnetic iron oxide (USPIO) nanoparticles (that is, maghemite) that is synthesized through a one-pot, cost-effective and environmentally friendly protocol. The synergistic coupling of the physico-chemical and functional properties of both nanoparticles confers to these nano-objects valuable features such as high colloidal stability, high biodegradability, low toxicity, high drug loading capacity as well as stimuli-responsive drug release and superparamagnetic properties. This bimodal MIL-100(Fe)/maghemite nanocarrier once loaded with anti-tumoral and anti-inflammatory drugs (doxorubicin and methotrexate) shows high anti-inflammatory and anti-tumoral activities. In addition, the USPIO@MIL nano-object exhibits excellent relaxometric properties and its applicability as an efficient contrast agent for magnetic resonance imaging is herein demonstrated. This highlights the high potential of the maghemite@MOF composite integrating the functions of imaging and therapy as a theranostic anti-inflammatory formulation.

Une description des méthodes qui permettent de réaliser des angiographies, des cartes de perfusion tissulaire (débit, volume sanguin) ou des cartes de perméabilité vasculaire, avec ou sans agent de contraste (effets de relaxivité, de susceptibilité magnétique, marquage de spin artériel), dans différents organes comme le cerveau ou le cœur.

Les séquences d’imagerie rapides, cartésiennes et non-cartésiennes ainsi que les méthodes standards d’accélération et reconstruction sont décrites. Les champs d’application requérant ces techniques sont également présentés.

Lungs are the most frequent site of metastases growth. The amount and size of pulmonary metastases acquired from MRI imaging data are the important criteria to assess the efficacy of new drugs in preclinical models. While efficient solutions both for MR imaging and the downstream automatic segmentation have been proposed for human patients, both MRI lung imaging and segmentation in preclinical animal models remains challenging due to the physiological motion (respiratory and cardiac movements), to the low amount of protons in this organ and to the particular challenge of precise segmentation of metastases. As a consequence post-mortem analysis is currently required to obtain information on metastatic volume. In this work, we have developed a complete methodological pipeline for automated analysis of lungs and metastases in mice, consisting of an MR sequence for image acquisition and a deep learning method for automatic segmentation of both lungs and metastases. On one hand, we optimized an MR sequence for mouse lung imaging with high contrast for high detection sensitivity. On the other hand we developed DeepMeta, a multiclass U-Net 3+ deep learning model to automatically segment the images. To assess if the proposed deep learning pipeline is able to provide an accurate segmentation of both lungs and pulmonary metastases, we have longitudinally imaged mice with fast- and slow-growing metastasis. Fifty-five balb/c mice were injected with two different derivatives of renal carcinoma cells. Mice were imaged with a SG-bSSFP (self-gated balanced steady state free precession) sequence at different time points after the injection of cancer cells. Both lung and metastases segmentations were manually performed by experts. DeepMeta was trained to perform lung and metastases segmentation based on the resulting ground truth annotations. Volumes of lungs and of pulmonary metastases as well as the number of metastases per mouse were measured on a separate test dataset of MR images. Thanks to the SG method, the 3D bSSFP images of lungs were artifact-free, enabling the downstream detection and serial follow-up of metastases. Moreover, both lungs and metastases segmentation was accurately performed by DeepMeta as soon as they reached the volume of ∼0.02mm3. Thus we were able to distinguish two groups of mice in terms of number and volume of pulmonary metastases as well as in terms of the slow versus fast patterns of growth of metastases. We have shown that our methodology combining SG-bSSFP with deep learning, enables processing of the whole animal lungs and is thus a viable alternative to histology alone.

The magnetization-prepared 2 rapid acquisition gradient echo (MP2RAGE) sequence provides quantitative T1 maps in addition to high-contrast morphological images. Advanced acceleration techniques such as compressed sensing (CS) allow its acquisition time to be compatible with clinical applications. To consider its routine use in future neuroimaging protocols, the repeatability of the segmented brain structures was evaluated and compared with the standard morphological sequence (magnetization-prepared rapid gradient echo [MPRAGE]). The repeatability of the T1 measurements was also assessed.Thirteen healthy volunteers were scanned either 3 or 4 times at several days of interval, on a 3 T clinical scanner, with the 2 sequences (CS-MP2RAGE and MPRAGE), set with the same spatial resolution (0.8-mm isotropic) and scan duration (6 minutes 21 seconds). The reconstruction time of the CS-MP2RAGE outputs (including the 2 echo images, the MP2RAGE image, and the T1 map) was 3 minutes 33 seconds, using an open-source in-house algorithm implemented in the Gadgetron framework.Both precision and variability of volume measurements obtained from CAT12 and VolBrain were assessed. The T1 accuracy and repeatability were measured on phantoms and on humans and were compared with literature.Volumes obtained from the CS-MP2RAGE and the MPRAGE images were compared using Student t tests (P0.05 was considered significant).The CS-MP2RAGE acquisition provided morphological images of the same quality and higher contrasts than the standard MPRAGE images. Similar intravolunteer variabilities were obtained with the CS-MP2RAGE and the MPRAGE segmentations. In addition, high-resolution T1 maps were obtained from the CS-MP2RAGE. T1 times of white and gray matters and several deep gray nuclei are consistent with the literature and show very low variability (1%).The CS-MP2RAGE can be used in future protocols to rapidly obtain morphological images and quantitative T1 maps in 3-dimensions while maintaining high repeatability in volumetry and relaxation times.

Renal cell carcinoma (RCC) still lacks prognostic and predictive biomarkers to monitor the disease and the response to therapy. The usual strategy in translational research is to start from human samples, to identify molecular markers and gene networks and then to functionally validate themin vitroand in animal models. We devised herein a completely opposite strategy from “mouse to man” by performing an aggressiveness screen and used functional genomics, imaging, clinical data and computational approaches in order to discover molecular pathways and players in renal cancer development and metastasis. Multiple cell lines for primary tumor growth, survival in the blood circulation and lung metastasis or metastatic spread from the primary tumor were generated and analyzed using a multi-layered approach which includes large-scale transcriptome, genome and methylome analyses. Transcriptome and methylome analyses demonstrated distinct clustering in three different groups. Remarkably, DNA sequencing did not show significant genomic variations in the different groups which indicates absence of clonal selection during thein vivoamplification process. Transcriptome analysis revealed distinct signatures of tumor aggressiveness which were validated in patient cohorts. Methylome analysis of full-length DNA allowed clustering of the same groups and revealed clinically relevant signatures. Furthermore, we identified SAA2 and CFB as soluble prognostic and predictive biomarkers of the therapeutic response. We also uncovered IL34 as another soluble prognostic biomarker and key regulator of renal cell carcinoma (RCC) progression. This was also functionally validatedin vivo,and a mathematical model of IL34-dependent primary tumor growth and metastasis development was provided. These results indicate that such multilayered analysis in a RCC animal model leads to meaningful results that are of translational significance.One Sentence SummaryAn aggressiveness screen with multilayer systems analysis to identify signatures and biomarkers for renal cell carcinoma aggressiveness.

Summary We report here the design of nano-objects (i.e., denoted as MIL/USPIO-cit) that consist of nanoparticles of mesoporous iron trimesate metal-organic framework MIL-100(Fe), whose surface is decorated by maghemite nanoparticles. Not only is this bimodal nanovector produced through a cost-effective and reliable green approach, but it also exhibits excellent colloidal stability under simulated intravenous conditions, and its ability to encapsulate and progressively release drugs (doxorubicin here) is preserved. According to vibrating sample magnetometry and 57 Fe Mossbauer spectrometry, MIL-USPIO-cit presents a superparamagnetic behavior characterized by a high saturation magnetization at room temperature. More importantly, it combines low toxicity with high anti-tumoral activity and can be used in vivo as an efficient MRI contrast agent because of its excellent relaxivity properties. All these properties make this nano-object a potential candidate as a bimodal therapeutic nanovector coupling drug-delivery and MRI properties.

To develop a 2D radial multislice MP2RAGE sequence for fast and reliable TThe 2D-MP2RAGE sequence was performed with the following parameters: TIA three-lobe cardinal sine excitation pulse, combined with an inversion slice thickness and an interslice gap of respectively 150% and 50% of the imaging slice thickness, led to a SD and bias of the TThe multislice MP2RAGE sequence could be used for fast whole-body T

Purpose To develop and assess a 3D-cine self-gated method for cardiac imaging of murine models. Materials and Methods A 3D stack-of-stars (SOS) short echo time (STE) sequence with a navigator echo was performed at 7T on healthy mice (n = 4) and mice with acute myocardial infarction (MI) (n = 4) injected with ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles. In all, 402 spokes were acquired per stack with the incremental or the golden angle method using an angle increment of (360/402)° or 222.48°, respectively. A cylindrical k-space was filled and repeated with a maximum number of repetitions (NR) of 10. 3D cine cardiac images at 156 μm resolution were reconstructed retrospectively and compared for the two methods in terms of contrast-to-noise ratio (CNR). The golden angle images were also reconstructed with NR = 10, 6, and 3, to assess cardiac functional parameters (ejection fraction, EF) on both animal models. Results The combination of 3D SOS-STE and USPIO injection allowed us to optimize the identification of cardiac peaks on navigator signal and generate high CNR between blood and myocardium (15.3 ± 1.0). The golden angle method resulted in a more homogeneous distribution of the spokes inside a stack (P < 0.05), enabling reducing the acquisition time to 15 minutes. EF was significantly different between healthy and MI mice (P < 0.05). Conclusion The method proposed here showed that 3D-cine images could be obtained without electrocardiogram or respiratory gating in mice. It allows precise measurement of cardiac functional parameters even on MI mice. J. Magn. Reson. Imaging 2016;44:355–365.

International audience; 4D-MRI is a promising tool for organ exploration, target delineation and treatment planning. Intra-scan motion artifacts may be greatly reduced by increasing the imaging frame rate. However, poor signal-to-noise ratios (SNR) are observed when increasing spatial and/or frame number per physiological cycle, in particular in the abdomen. In the current work, the proposed 4D-MRI method favored spatial resolution, frame number, isotropic voxels and large field-of-view (FOV) during MR-acquisition. The consequential SNR penalty in the reconstructed data is addressed retrospectively using an iterative back-projection (IBP) algorithm. Practically, after computing individual spatial 3D deformations present in the images using a deformable image registration (DIR) algorithm, each 3D image is individually enhanced by fusing several successive frames in its local temporal neighborood, these latter being likely to cover common independent informations. A tuning parameter allows one to freely readjust the balance between temporal resolution and precision of the 4D-MRI. The benefit of the method was quantitatively evaluated on the thorax of 6 mice under free breathing using a clinically acceptable duration. Improved 4D cardiac imaging was also shown in the heart of 1 mice. Obtained results are compared to theoretical expectations and discussed. The proposed implementation is easily parallelizable and optimized 4D-MRI could thereby be obtained with a clinically acceptable duration.

The TA 3D radial encoding scheme was developed using a golden angle distribution for the k-space trajectories. As in that case, each projection contributes to the image contrast, the signal equations had to be modified. Phantoms containing increasing gadoteridol concentrations were used to determine the accuracy of the sequence in vitro. Healthy mice were repetitively scanned to assess the reproducibility of the TThe accuracy of the TThe radial MP2RAGE sequence could be used for fast 3D T• The Cartesian encoding of the MP2RAGE sequence was modified to a radial encoding. The modified sequence enabled accurate T

Mapping longitudinal relaxation times in 3D is a promising quantitative and non-invasive imaging tool to assess cardiac remodeling. Few methods are proposed in the literature allowing us to perform 3D T1 mapping. These methods often require long scan times and use a low number of 3D images to calculate T1. In this project, a fast 3D T1 mapping method using a stack-of-spirals sampling scheme and regular RF pulse excitation at 7 T is presented. This sequence, combined with a newly developed fitting procedure, allowed us to quantify T1 of the whole mouse heart with a high spatial resolution of 208 × 208 × 315 µm3 in 10–12 min acquisition time. The sensitivity of this method for measuring T1 variations was demonstrated on mouse hearts after several injections of manganese chloride (doses from 25 to 150 µmol kg−1). T1 values were measured in vivo in both pre- and post-contrast experiments. This protocol was also validated on ischemic mice to demonstrate its efficiency to visualize tissue damage induced by a myocardial infarction. This study showed that combining spiral gradient shape and steady RF excitation enabled fast and robust 3D T1 mapping of the entire heart with a high spatial resolution. Copyright © 2015 John Wiley & Sons, Ltd.

Background To develop and evaluate three-dimensional (3D) self-gated balanced steady state free precession (bSSFP) imaging at high magnetic fields to track iron-labeled cells and metastases in murine abdomens. Methods Mice were injected intravenously with iron-labeled melanoma cells and imaged at 7 Tesla (T). Respiration peaks were identified using Free Induction Decay acquired immediately after the radiofrequency pulse. Respiration-corrupted k-space lines were deleted. Four images were acquired to reconstruct final images using the Sum-Of-Square technique. Image sharpness, metastasis contrast and iron-labeled cell detection with SG-bSSFP sequence (acquired with echo time [TE] = 3 ms or TE = 6 ms) were compared with standard methods (gradient echo (GRE) and RARE). Results After reconstruction, the 3D SG-bSSFP images were 75–80% sharper, free from banding (75% liver signal-to-noise ratio recovery) and respiratory motion (26–42% improvement in signal homogeneity) artifacts. Metastasis contrast was twice higher on SG-bSSFP with TE = 3 ms than on RARE images. Iron-labeled cells and metastases were simultaneously detected on SG-bSSFP images with TE = 6 ms, with similar void intensity and tumor contrast to GRE and RARE, respectively. Halving acquisition time preserved iron sensitivity and metastasis contrast, allowing for 3D abdomen imaging in 13 min (TE = 3 ms) or 26 min (TE = 6 ms). Conclusion Combining a self-gating technique with bSSFP sequences at 7T provides high-resolution 3D artifact-free abdominal images of small animals. J. Magn. Reson. Imaging 2015;41:1413–1421. © 2014 Wiley Periodicals, Inc.

Purpose To develop an undersampled anatomical, three-dimensional (3-D) time-resolved magnetic resonance angiography (MRA) method for small animals based on time-of-flight (TOF) effect and radial sampling. Methods Mouse carotid arteries and Circle of Willis images were acquired on a 7T scanner with an electrocardiogram (ECG)-triggered sequence. Preliminary experiments were used to generate an approximately uniform distribution of radial projections with a first golden angle and to produce anatomical TOF images. A second golden angle ratio between consecutive projections of cine acquisitions was added to make it possible to use a temporal filter during reconstruction of time-resolved angiography. A decreasing number of projections were tested, and their impact on signal-to-noise ratio (SNR) and spatial resolution was assessed. Results In anatomical MRA, the undersampled radial approach efficiently allows fast acquisition of mouse angiogram in 3D (22 sec). It was also only slightly sensitive to motion and flow artifacts. The time-resolved sequence can be performed with only 2,500 projections per cine and a temporal resolution under 4 ms in a relatively short acquisition time (less than 5 min). Conclusion This technique simultaneously provided high 3D isotropic spatial resolution and excellent temporal resolution with a good SNR level, allowing blood flow to be visualized in a restricted acquisition time. Magn Reson Med 73:984–994, 2015. © 2014 Wiley Periodicals, Inc.

Purpose To develop a fast three-dimensional (3D) k-space encoding method based on spiral projection imaging (SPI) with an interleaved golden-angle approach and to validate this novel sequence on small animal models. Methods A disk-like trajectory, in which each disk contained spirals, was developed. The 3D encoding was performed by tilting the disks with a golden angle. The sharpness was first calculated at different T2* values. Then, the sharpness was measured on phantom using variable undersampling ratios. Finally, the sampling method was validated by whole brain time-of-flight angiography and ultrasmall superparamagnetic iron oxide (USPIO) enhanced free-breathing liver angiography on mouse. Results The in vitro results demonstrated the robustness of the method for short T2* and high undersampling ratios. In vivo experiments showed the ability to properly detect small vessels in the brain with an acquisition time shorter than 1 min. Free-breathing mice liver angiography showed the insensitivity of this protocol toward motions and flow artifacts, and enabled the visualization of liver motion during breathing. Conclusions The method implemented here allowed fast 3D k-space sampling with a high undersampling ratio. Combining the advantages of center-out spirals with the flexibility of the golden angle approach could have major implications for real-time imaging. Magn Reson Med 77:1831-1840, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Bupivacaine is a widely used anaesthetic injected locally in clinical practice for short-term neurotransmission blockade. However, persistent side effects on mitochondrial integrity have been demonstrated in muscle parts surrounding the injection site. We use the precise language of metabolic control analysis in the present study to describe in vivo consequences of bupivacaine injection on muscle energetics during contraction. We define a model system of muscle energy metabolism in rats with a sciatic nerve catheter that consists of two modules of reactions, ATP/PCr (phosphocreatine) supply and ATP/PCr demand, linked by the common intermediate PCr detected in vivo by 31P-MRS (magnetic resonance spectroscopy). Measured system variables were \[PCr\] (intermediate) and contraction (flux). We first applied regulation analysis to quantify acute effects of bupivacaine. After bupivacaine injection, contraction decreased by 15.7% and, concomitantly, [PCr] increased by 11.2%. The regulation analysis quantified that demand was in fact directly inhibited by bupivacaine (−21.3%), causing an increase in PCr. This increase in PCr indirectly reduced mitochondrial activity (−22.4%). Globally, the decrease in contractions was almost fully explained by inhibition of demand (−17.0%) without significant effect through energy supply. Finally we applied elasticity analysis to quantify chronic effects of bupivacaine iterative injections. The absence of a difference in elasticities obtained in treated rats when compared with healthy control rats clearly shows the absence of dysfunction in energetic control of muscle contraction energetics. The present study constitutes the first and direct evidence that bupivacaine myotoxicity is compromised by other factors during contraction in vivo , and illustrates the interest of modular approaches to appreciate simple rules governing bioenergetic systems when affected by drugs. Abbreviations: Cr, creatine; MoCA, modular control analysis; MRS, magnetic resonance spectroscopy; PCr, phosphocreatine; TCA, tricarboxylic acid

Magnetoliposomes are liposomes surrounding an iron oxide core, which are used as contrast enhancing agents in magnetic resonance imaging (MRI). One method for producing magnetoliposomes consists of hydration of a lipid film with citrate-coated iron oxide particles followed by extrusion. Two parameters are of major importance for in vivo applications of magnetoliposomes, namely their size, which must be small, optimally around 100 nm diameter, in order to ensure their prolonged circulation in the bloodstream, and their iron content, which must be maximal for generating high MRI effect. We studied the formation of magnetoliposomes by passive encapsulation of maghemite (γ-Fe2O3) particle suspensions of varying concentrations, with the objective of producing magnetoliposomes of small size and high iron content. The iron to lipid ratio was used to determine the iron content of the magnetoliposomes after the successive purification steps and cryo-TEM was used to characterize their size, their homogeneity and the efficiency of purification. The size of citrate-coated maghemite clusters was found to be of critical importance for obtaining magnetoliposomes smaller than 200 nm. We were able to reproducibly synthesize magnetoliposomes of 100 nm diameter with high iron content –up to 77 particles per liposome (5.6 moles iron per mole lipid) – and high r2 MRI relaxivity – up to 320 m m−1 . s−1. The magnetoliposomes present improved characteristics compared with previous reports. Future research will focus on using these magnetoliposomes as drug delivery systems for in vivo diagnostics or therapeutics applications. Copyright © 2011 John Wiley & Sons, Ltd.

High-throughput magnetic resonance imaging (MRI) tools are required for the longitudinal investigation of vascular diseases in mouse models. Angiographic data from various anatomic regions may be needed in a single experiment. This study involves a three-dimensional (3D) time-of-flight (TOF) magnetic resonance angiography (MRA) method using sequential acquisitions of four data sets corresponding to the head, the thorax, the abdomen, and the hind limbs of a mouse. After repositioning the animal, each anatomic region was acquired in 2 min, and the TOF effect was provided by the spatial selectivity of the radio frequency (RF) resonator. No slab selection was needed and whole-body MRA was performed in a total experiment time of 10 min. The voxel size was equal to or greater than 131 × 195 × 188 μm(3). To suppress the signal arising from stationary tissues, both inversion recovery and interspersed saturation, used as magnetization preparations, were compared from a theoretical and an experimental perspective. The arterial tree (carotid, aortic, iliac, renal, and smaller arteries) was well visualized by this method, both in control healthy mice and in mice with common carotid artery ligation. The potential interest of this method for evaluating arterial diseases is discussed.

Free Article on the editor website; International audience; For bone tissue engineering, human Adipose Derived Stem Cells (hADSCs) are proposed to be associated with a scaffold for promoting bone regeneration. After implantation, cellularised scaffolds require a non-invasive method for monitoring their fate in vivo. The purpose of this study was to use Magnetic Resonance Imaging (MRI)-based tracking of these cells, labelled with magnetic agents for in vivo longitudinal assessment. hADSCs were isolated from adipose tissue and labelled with USPIO-rhodamine (Ultrasmall SuperParamagnetic Iron Oxide). USPIO internalisation, absence of toxicity towards hADSCs, and osteogenic differentiation of the labelled cells were evaluated in standard culture conditions. Labelled cells were then seeded within a 3D porous polysaccharide-based scaffold and imaged in vitro using fluorescence microscopy and MRI. Cellularised scaffolds were implanted subcutaneously in nude mice and MRI analyses were performed from 1 to 28 d after implantation. In vitro, no effect of USPIO labelling on cell viability and osteogenic differentiation was found. USPIO were efficiently internalised by hADSCs and generated a high T2* contrast. In vivo MRI revealed that hADSCs remain detectable until 28 d after implantation and could migrate from the scaffold and colonise the area around it. These data suggested that this scaffold might behave as a cell carrier capable of both holding a cell fraction and delivering cells to the site of implantation. In addition, the present findings evidenced that MRI is a reliable technique to validate cell-seeding procedures in 3D porous scaffolds, and to assess the fate of hADSCs transplanted in vivo.

A knowledge of the spatial localization of cell vehicles used in gene therapy against glioma is necessary before launching therapy. For this purpose, MRI cell tracking is performed by labeling the cell vehicles with contrast agents. In this context, the goal of this study was to follow noninvasively the chemoattraction of therapeutic microglial cells to a human glioma model before triggering therapy. Silica nanoparticles grafted with gadolinium were used to label microglia. These vehicles, expressing constitutively the thymidine kinase suicide gene fused to the green fluorescent protein gene, were injected intravenously into human glioma-bearing nude mice. MRI was performed at 4.7 T to track noninvasively microglial accumulation in the tumor. This was followed by microscopy on brain slices to assess the presence in the glioma of the contrast agents, microglia and fusion gene through the detection of silica nanoparticles grafted with tetramethyl rhodamine iso-thiocyanate, 3,3'-dioctadecyloxacarbocyanine perchlorate and green fluorescent protein fluorescence, respectively. Finally, gancyclovir was administered systemically to mice. Human microglia were detectable in living mice, with strong negative contrast on T(2) *-weighted MR images, at the periphery of the glioma only 24 h after systemic injection. The location of the dark dots was identical in MR microscopy images of the extracted brains at 9.4 T. Fluorescence microscopy confirmed the presence of the contrast agents, exogenous microglia and suicide gene in the intracranial tumor. In addition, gancyclovir treatment allowed an increase in mice survival time. This study validates the MR tracking of microglia to a glioma after systemic injection and their use in a therapeutic strategy against glioma. Copyright © 2011 John Wiley & Sons, Ltd.

The noninvasive imaging of atherosclerotic plaques at an early stage of atherogenesis remains a major challenge for the evaluation of the pathologic state of patients at high risk of acute coronary syndromes. Recent studies have emphasized the importance of platelet–endothelial cell interactions in atherosclerosis-prone arteries at early stages, and the prominent role of P-selectin in the initial loose contact between platelets and diseased vessel walls. A specific MR contrast agent was developed here for the targeting, with high affinity, of P-selectin expressed in large amounts on activated platelets and endothelial cells. For this purpose, PEGylated dextran/iron oxide nanoparticles [PEG, poly(ethylene glycol)], named versatile ultrasmall superparamagnetic iron oxide (VUSPIO) particles, labeled with rhodamine were coupled to an anti-human P-selectin antibody (VH10). Flow cytometry and microscopy experiments on human activated platelets were highly correlated with MRI (performed at 4.7 and 0.2 T), with a 50% signal decrease in T2 and T1 values corresponding to the strong labeling of activated vs resting platelets. The number of 1000 VH10–VUSPIO nanoparticles attained per activated platelet appeared to be optimal for the detection of hypo- and hyper-signals in the platelet pellet on T2- and T1-weighted MRI. Furthermore, in vivo imaging of atherosclerotic plaques in ApoE mice at 4.7 T showed a spatial resolution adapted to the imaging of intimal thickening and a hypo-signal at 4.7 T, as a result of the accumulation of VH10–VUSPIO nanoparticles in the plaque. Our work provides support for the further assessment of the use of VH10–VUSPIO nanoparticles as a promising imaging modality able to identify the early stages of atherosclerosis with regard to the pertinence of both the target and the antibody-conjugated contrast agent used. Copyright © 2010 John Wiley & Sons, Ltd.

The increasing number of mouse models of cardiac diseases requires improvements in the current MRI tools. Anatomic and functional cardiac phenotyping by MRI calls for both time and space resolution in three dimensions. Black-blood contrast is often needed for the accurate delineation of myocardium and chambers, and is consistent with manganese contrast enhancement. In this article, we propose a fast, three-dimensional, time-resolved (four-dimensional), black-blood MRI sequence that allows mouse heart imaging at 10 periods of the cardiac cycle within 30 min at an isotropic resolution of 200 µm. Two-dimensional imaging was possible within 80 s. Blood cancellation was achieved by employing bipolar gradients without the use of a double inversion recovery preparation scheme. Saturation slices were added in two-dimensional experiments for better blood nulling. The rapidity of the two-dimensional acquisition protocol allowed the measurement of the time course of contrast enhancement on manganese infusion. Owing to the very high contrast-to-noise ratio, manganese-enhanced MRI in four dimensions made possible the accurate assessment of regional cardiac volumes in healthy animals. In experimentally infarcted mice, the size of the ischemic zone could be measured easily with this method. The technique might be valuable in evaluating mouse heart diseases and their follow-up in longitudinal studies. Copyright © 2010 John Wiley & Sons, Ltd.

To demonstrate the feasibility of coronary magnetic resonance (MR) angiography in living mice and to evaluate a dynamic MR angiographic method for coronary flow measurement at 9.4-T field strength.This study was conducted according to European law and was in full compliance with National Institutes of Health recommendations for animal care and a local institutional animal care committee. Mice were anesthetized by using isoflurane. First, time-of-flight MR angiography was performed in 10 mice to measure coronary diameters at 80-mum isotropic resolution. Second, left coronary artery (LCA) velocity measurements were performed at seven cardiac phases in nine other mice to assess the velocity curve profile. Third, coronary velocities were measured at the middiastolic phase in 13 mice at rest and during adenosine-induced hyperemia to calculate coronary flow velocity reserve (CFVR). The Pearson coefficient compared the correlation between isoflurane dose and CFVR. Paired t tests compared R-R intervals and respiratory rates between rest and hyperemia.Proximal diameters were, respectively, 404 mum +/- 34 [standard deviation] and 259 mum +/- 22 for the LCAs and the right coronary arteries, which were in accordance with reported values. The velocity curve profile throughout the cardiac cycle was similar to values from the literature. Baseline and hyperemic velocities were, respectively, 19.0 cm/sec +/- 4.4 and 33.7 cm/sec +/- 4.7 (P.001), resulting in a CFVR of 1.77 +/- 0.19. CFVR did not correlate with isoflurane dose (r = 0.05, P = .88). R-R intervals shortened by 2.5% during hyperemia (P = .04). Respiratory rates showed no difference between rest and hyperemia (P = .39).High-spatial-resolution three-dimensional coronary MR angiography is feasible in living mice. Dynamic MR angiography depicts coronary velocity changes throughout the cardiac cycle and between rest and maximum hyperemia, providing a tool for CFVR assessment.

Matrix proteins of the SIBLING family interact with bone cells and with bone mineral and are thus in a key position to regulate bone development, remodeling and repair. Within this family, bone sialoprotein (BSP) is highly expressed by osteoblasts, hypertrophic chondrocytes and osteoclasts. We recently reported that mice lacking BSP (BSP−/−) have very low trabecular bone turnover. In the present study, we set up an experimental model of bone repair by drilling a 1 mm diameter hole in the cortical bone of femurs in both BSP−/− and +/+ mice. A non-invasive MRI imaging and bone quantification procedure was designed to follow bone regeneration, and these data were extended by μCT imaging and histomorphometry on undecalcified sections for analysis at cellular level. These combined approaches revealed that the repair process as reflected in defect-refilling in the cortical area was significantly delayed in BSP−/− mice compared to +/+ mice. Concomitantly, histomorphometry showed that formation, mineralization and remodeling of repair (primary) bone in the medulla were delayed in BSP−/− mice, with lower osteoid and osteoclast surfaces at day 15. In conclusion, the absence of BSP delays bone repair at least in part by impairing both new bone formation and osteoclast activity.

In gene therapy against glioma, targeting tumoral tissue is not an easy task. We used the tumor infiltrating property of microglia in this study. These cells are well adapted to this therapy since they can phagocyte nanoparticles and allow their visualization by MRI. Indeed, while many studies have used transfected microglia containing a suicide gene and other internalized nanoparticles to visualize microglia, none have combined both approaches during gene therapy. Microglia cells were transfected with the TK-GFP gene under the control of the HSP(70) promoter. First, the possible cellular stress induced by nanoparticle internalization was checked to avoid a non-specific activation of the suicide gene. Then, MR images were obtained on tubes containing microglia loaded with superparamagnetic nanoparticles (VUSPIO) to characterize their MR properties, as well as their potential to track cells in vivo. VUSPIO were efficiently internalized by microglia, were found non-toxic and their internalization did not induce any cellular stress. VUSPIO relaxivity r(2) was 224 mM(-1).s(-1). Such results could generate a very high contrast between loaded and unloaded cells on T(2)-weighted images. The intracellular presence of VUSPIO does not prevent suicide gene activity, since TK is expressed in vitro and functional in vivo. It allows MRI detection of gene modified macrophages during cell therapy strategies.

The purpose of this study was to demonstrate the feasibility of steady-state True fast imaging with steady precession (TrueFISP) four-dimensional imaging of mouse heart at high resolution and its efficiency for cardiac volumetry. Three-dimensional cine-imaging of control and hypoxic mice was carried out at 4.7 T without magnetization preparation or ECG-triggering. The k-space lines were acquired with the TrueFISP sequence (pulse repetition time/echo time = 4/2 ms) in a repeated sequential manner. Retrospective reordering of raw data allowed the reconstruction of 10 three-dimensional images per cardiac cycle. The acquisition scheme used an alternating radiofrequency phase and sum-of-square reconstruction method. Black-blood three-dimensional images at around 200 mum resolution were produced without banding artifact throughout the cardiac cycle. High contrast to noise made it possible to estimate cavity volumes during diastole and systole. Right and left ventricular stroke volume was significantly higher in hypoxic mice vs controls (20.2 +/- 2 vs 15.1 +/- 2; P < 0.05, 24.9 +/- 2 vs 20.4 +/- 2; P < 0.05, respectively). In conclusion, four-dimensional black-blood TrueFISP imaging in living mice is a method of choice to investigate cardiac abnormalities in mouse models.

Blood flow velocity is a functional parameter of fundamental importance in diagnosis and follow-up of various vascular diseases. Vascular pathologies can be efficiently studied in animal models, especially in small rodents. ECG-gated magnetic resonance imaging (MRI) assessment of blood velocity in small animals is a challenge because of limited spatial resolution and high-frequency physiological parameters. Here it is shown that a bright-blood cine-3D-MRI method can be used to measure blood velocity at specific times of the cardiac cycle in mouse pulmonary and carotid arteries. The method used a series of time-of-flight (TOF) acquisitions in a volume of interest at different times after signal cancellation in the same volume. This scheme was repeated at different periods of the cardiac cycle by varying the delay between the ECG R-wave peak and signal cancellation. Velocity values in mouse pulmonary artery varied from 35 cm/s in systole to 0–10 cm/s in diastole. A similar pattern was displayed in carotid arteries (18 and 2.5 cm/s, in systole and diastole, respectively). Results are discussed in terms of efficiency, limitation, and comparison with other methods. Copyright © 2009 John Wiley & Sons, Ltd.

Purpose To examine the ability of TrueFISP imaging for evaluating tumor size in mouse brain at high field. Materials and Methods Brains of healthy and glioma-implanted nude mice were imaged at 4.7T and 9.4T. 3D imaging was performed with TrueFISP and T2w-RARE. Radiofrequency pulses with alternating phase and the sum-of-squares reconstruction method were used in TrueFISP imaging. The contrast-to-noise ratio (CNR) was evaluated in healthy and in tumoral brain regions. Results Banding artifact was correctly suppressed in TrueFISP images thanks to the method used. The signal-to-noise ratio (SNR) and CNR were comparable in TrueFISP and T2w-RARE images at 4.7T, but acquisition was around 4 times shorter with TrueFISP. Tumor was well detected at 4.7T with TrueFISP, but CNR between tumor and healthy tissue was low at 9.4T. Conclusion TrueFISP is efficient and fast to perform brain imaging at 4.7T. Multiple TrueFISP acquisitions with phase-cycled radiofrequency (RF) pulses and sum-of-squares reconstruction allow suppression of banding artifact. Tumoral regions were well detected and the method allows longitudinal studies of tumor growth. J. Magn. Reson. Imaging 2008;28:497–503. © 2008 Wiley-Liss, Inc.

SummaryS6 kinase (S6K) deletion in metazoans causes small cell size, insulin hypersensitivity, and metabolic adaptations; however, the underlying molecular mechanisms are unclear. Here we show that S6K-deficient skeletal muscle cells have increased AMP and inorganic phosphate levels relative to ATP and phosphocreatine, causing AMP-activated protein kinase (AMPK) upregulation. Energy stress and muscle cell atrophy are specifically triggered by the S6K1 deletion, independent of S6K2 activity. Two known AMPK-dependent functions, mitochondrial biogenesis and fatty acid β-oxidation, are upregulated in S6K-deficient muscle cells, leading to a sharp depletion of lipid content, while glycogen stores are spared. Strikingly, AMPK inhibition in S6K-deficient cells restores cell growth and sensitivity to nutrient signals. These data indicate that S6K1 controls the energy state of the cell and the AMPK-dependent metabolic program, providing a mechanism for cell mass accumulation under high-calorie diet.

We report facile fabrication of advanced hybrid silica–spinel iron oxide (maghemite) composite microspheres built with both superparamagnetic nanoparticles for MR imaging, hyperthermia, and a hybrid mesoporous matrix enabling the transport of bioactive molecules for in vivo biomedical applications. Elaboration of such multifunctional platforms is performed by spray drying a sol of tunable composition that allows one to control the size and amount of magnetic particles embedded in the matrix, without aggregation, and to adjust the size and the surface chemical properties of the porous silica cavities. The resulting nanocomposites (γ-Fe2O3 8 nm particles in silica matrices from TEOS templated by CTAB or P123, without or with functionalisation with –Ph, –SH or –NH2) were characterised by chemical analysis, XRD, TEM, BET, FTIR and magnetisation measurements. Tests of the materials both as MRI T2-contrast agents and as heating sources of hyperthermia are presented in support of potential applications in diagnosis and therapy.

To develop and assess a 3D-cine self-gated method for cardiac imaging of murine models.A 3D stack-of-stars (SOS) short echo time (STE) sequence with a navigator echo was performed at 7T on healthy mice (n = 4) and mice with acute myocardial infarction (MI) (n = 4) injected with ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles. In all, 402 spokes were acquired per stack with the incremental or the golden angle method using an angle increment of (360/402)° or 222.48°, respectively. A cylindrical k-space was filled and repeated with a maximum number of repetitions (NR) of 10. 3D cine cardiac images at 156 μm resolution were reconstructed retrospectively and compared for the two methods in terms of contrast-to-noise ratio (CNR). The golden angle images were also reconstructed with NR = 10, 6, and 3, to assess cardiac functional parameters (ejection fraction, EF) on both animal models.The combination of 3D SOS-STE and USPIO injection allowed us to optimize the identification of cardiac peaks on navigator signal and generate high CNR between blood and myocardium (15.3 ± 1.0). The golden angle method resulted in a more homogeneous distribution of the spokes inside a stack (P0.05), enabling reducing the acquisition time to 15 minutes. EF was significantly different between healthy and MI mice (P0.05).The method proposed here showed that 3D-cine images could be obtained without electrocardiogram or respiratory gating in mice. It allows precise measurement of cardiac functional parameters even on MI mice. J. Magn. Reson. Imaging 2016;44:355-365.

Background To show that 3D sequences with ultra-short echo times (UTEs) can generate a positive contrast whatever the magnetic field (4.7, 7 or 9.4 T) and whatever Ultra Small Particles of Iron Oxide (USPIO) concentration injected and to use it for 3D time-resolved imaging of the murine cardiovascular system with high spatial and temporal resolutions. Methods Three different concentrations (50, 200 and 500 μmol Fe/kg) of USPIO were injected in mice and static images of the middle part of the animals were acquired at 4.7, 7 and 9.4 T pre and post-contrast with UTE (TE/TR = 0.05/4.5 ms) sequences. Signal-to-Noise Ratio (SNR) and Contrast-to-Noise Ratio (CNR) of blood and static tissus were evaluated before and after contrast agent injection. 3D-cine images (TE/TR = 0.05/3.5 ms, scan time

Our aim was to investigate by in vivo biopanning the lesions developed early in atherosclerosis and identify human antibodies that home to diseased regions. We have designed a two-step approach for a rapid isolation of human Monoclonal phage-display single-chain antibodies (MoPhabs) reactive with proteins found in lesions developed in an animal model of atherosclerosis. After a single round of in vivo biopanning, the MoPhabs were eluted from diseased sections of rabbit aorta identified by histology and NMR microscopy. MoPhabs expressed in situ were selected by subtractive colony filter screening for their capacity to recognize atherosclerotic but not normal aorta. MoPhabs selected by our method predominantly bind atherosclerotic lesions. Two of them, B3.3G and B3.GER, produced as scFv fragments, recognized an epitope present on the surface in early atherosclerotic lesions and within the intimal thickness in more complex plaques. These human MoPhabs homed to atherosclerotic lesions in ApoE(-/-) mice after in vivo injection. A protein of approximately 56 kDa recognized by B3.3G was affinity-purified and identified by mass spectrometry analysis as vitronectin. This is the first time that single round in vivo biopanning has been used to select human antibodies as candidates for diagnostic imaging and for obtaining insight into targets displayed in atherosclerotic plaques.

Mapping longitudinal relaxation times in 3D is a promising quantitative and non-invasive imaging tool to assess cardiac remodeling. Few methods are proposed in the literature allowing us to perform 3D T1 mapping. These methods often require long scan times and use a low number of 3D images to calculate T1 . In this project, a fast 3D T1 mapping method using a stack-of-spirals sampling scheme and regular RF pulse excitation at 7 T is presented. This sequence, combined with a newly developed fitting procedure, allowed us to quantify T1 of the whole mouse heart with a high spatial resolution of 208 × 208 × 315 µm(3) in 10-12 min acquisition time. The sensitivity of this method for measuring T1 variations was demonstrated on mouse hearts after several injections of manganese chloride (doses from 25 to 150 µmol kg(-1) ). T1 values were measured in vivo in both pre- and post-contrast experiments. This protocol was also validated on ischemic mice to demonstrate its efficiency to visualize tissue damage induced by a myocardial infarction. This study showed that combining spiral gradient shape and steady RF excitation enabled fast and robust 3D T1 mapping of the entire heart with a high spatial resolution.

NMR microscopy is usually achieved at ultra-high-static magnetic field (9.4 Tesla) with the use of home-built coils adapted to the size of the sample. In that way, well-resolved images can be obtained with voxel size smaller than 50 m. The purpose of this article is to show that high-resolution imaging can be realized at lower field strength (4.7 Tesla) using 5- and 10-mm probes initially dedicated to vertical magnets. These coils are easily adaptable to horizontal imaging systems. Excellent quality and filling factors permitted isotro- pic resolutions (50 m) on a biomaterial and on mouse femoris. This study also demonstrates that spoiled-gradient echo sequence (FLASH) with low reception bandwidth or with the use of gadolinium are particularly effective for 3D MR microscopy. © 2005 Wiley Periodicals, Inc.

We have investigated growth and vascularization of malignant glioma in mice upon conditional inhibition of fibroblast growth factor (FGF) receptor activity. C6 rat glioma cells were transfected with a dominant-negative fibroblast growth factor receptor-2 (FGFR2-DN) cDNA under the control of a tetracycline-regulated expression promoter (tet off) and implanted in the brain of immunodeficient mice. Magnetic resonance imaging analysis showed a significant decrease in tumor growth 14 days after implantation when FGFR2-DN was expressed compared to control. This size difference disappeared after 20 days. However, after 20 days, tumor and endothelial cells apoptosis were higher in the FGFR2-DN group and consequently angiogenesis was decreased whereas tumor cells were similarly associated with blood vessels at the tumor periphery. Pericyte coverage was not different between the two groups but a higher amount of pericytes not associated with vessels was found in the FGFR2-DN expressing group. This demonstrates, that conditional expression of inhibitor of FGF receptor activity in gliomas implanted in the brain of immunodeficient mice can be achieved efficiently, and that FGFs are major players in glioma development and in glioma angiogenesis.

To develop and evaluate three-dimensional (3D) self-gated balanced steady state free precession (bSSFP) imaging at high magnetic fields to track iron-labeled cells and metastases in murine abdomens.Mice were injected intravenously with iron-labeled melanoma cells and imaged at 7 Tesla (T). Respiration peaks were identified using Free Induction Decay acquired immediately after the radiofrequency pulse. Respiration-corrupted k-space lines were deleted. Four images were acquired to reconstruct final images using the Sum-Of-Square technique. Image sharpness, metastasis contrast and iron-labeled cell detection with SG-bSSFP sequence (acquired with echo time [TE] = 3 ms or TE = 6 ms) were compared with standard methods (gradient echo (GRE) and RARE).After reconstruction, the 3D SG-bSSFP images were 75-80% sharper, free from banding (75% liver signal-to-noise ratio recovery) and respiratory motion (26-42% improvement in signal homogeneity) artifacts. Metastasis contrast was twice higher on SG-bSSFP with TE = 3 ms than on RARE images. Iron-labeled cells and metastases were simultaneously detected on SG-bSSFP images with TE = 6 ms, with similar void intensity and tumor contrast to GRE and RARE, respectively. Halving acquisition time preserved iron sensitivity and metastasis contrast, allowing for 3D abdomen imaging in 13 min (TE = 3 ms) or 26 min (TE = 6 ms).Combining a self-gating technique with bSSFP sequences at 7T provides high-resolution 3D artifact-free abdominal images of small animals.

To develop an undersampled anatomical, three-dimensional (3-D) time-resolved magnetic resonance angiography (MRA) method for small animals based on time-of-flight (TOF) effect and radial sampling.Mouse carotid arteries and Circle of Willis images were acquired on a 7T scanner with an electrocardiogram (ECG)-triggered sequence. Preliminary experiments were used to generate an approximately uniform distribution of radial projections with a first golden angle and to produce anatomical TOF images. A second golden angle ratio between consecutive projections of cine acquisitions was added to make it possible to use a temporal filter during reconstruction of time-resolved angiography. A decreasing number of projections were tested, and their impact on signal-to-noise ratio (SNR) and spatial resolution was assessed.In anatomical MRA, the undersampled radial approach efficiently allows fast acquisition of mouse angiogram in 3D (22 sec). It was also only slightly sensitive to motion and flow artifacts. The time-resolved sequence can be performed with only 2,500 projections per cine and a temporal resolution under 4 ms in a relatively short acquisition time (less than 5 min).This technique simultaneously provided high 3D isotropic spatial resolution and excellent temporal resolution with a good SNR level, allowing blood flow to be visualized in a restricted acquisition time.

Cellular density is a parameter measured for glioma grade and invasiveness diagnosis. The characterization of the cellular density can be performed, non invasively, by magnetic resonance imaging (MRI), since, this technique displays a good resolution. Nevertheless MRI sensitivity is critical. Development of smart contrast agents appears useful to increase MRI signal to noise ratio (SNR). Tumor invasiveness is correlated with high expression of integrins that can be targeted by RGD motif. In this study, MRI contrast agents or fluorescent probes linked to RGD-peptides were used, in a glioma model, to assess the relation between RGD uptake/signal improvement/cell density and consequently tumor invasiveness. Experiments were performed in vitro with U87-MG glioma cells. Flow cytometry and microscopy experiments with RGD and iRGD-alexa488 demonstrated that cell internalization was dependent on cell density. The internalization involved a clathrin-dependent endocytosis. Cytoskeleton and particularly the microtubules were concerned. Actin filaments played a minor role. The internalization was also dependent on the glycolysis and the oxidative phosphorylations. The cellular density modulated the importance of the endocytosis pathways and of the metabolism but not the cytoskeleton contribution. The internalization of the RGD-peptide associated to gadolinium chelate increased the SNR of U87 cells. Moreover, following the cell density augmentation, the SNR increased with a low amplitude but a trend was clearly determined. In conclusion, RGD-peptide internalization appeared, in vitro, as a marker of cellular density. In perspective, the combination of these peptides with contrast agents associated to more sensitive MRI techniques could improve the MRI signal allowing the characterization of cellular density for tumor diagnosis.

To characterise the effects of high-salt diet (HSD) on left ventricular (LV) mass, systolic function and coronary reserve in living mice using cardiac magnetic resonance imaging (MRI).Thirty C57BL/6 1-month-old female mice were fed either a control (n = 15) or an HSD (n = 15). After 3 months, LV volumes, ejection fraction and mass were assessed using time-resolved three-dimensional (3D) black-blood manganese-enhanced MRI, and coronary flow velocity reserve (CFVR) was assessed using dynamic MR angiography at rest and during adenosine-induced hyperaemia. Hearts were excised to assess LV wet mass and micro-vascular remodelling at histology.Micro-vascular remodelling was found at histology in all investigated hearts from the HSD group and none from the control group. No difference between the HSD and control groups was found in terms of heart weight, LV volumes and ejection fraction. Heart to body weight ratio was higher in the HSD group (4.39 ± 0.24 vs 4.02 ± 0.16 mg/g, P 0.001), because of lower body weight (22.3 ± 0.9 vs 24.0 ± 1.4 g, P 0.001). CFVR was lower in the HSD group (1.73 ± 0.11 vs 1.94 ± 0.12, P 0.001).Phenotyping of hypertensive heart disease is feasible in living mice using dynamic MR angiography and time-resolved 3D black-blood manganese-enhanced MRI. HSD is associated with early impairment of coronary reserve, before the onset of significant hypertrophy.

Magnetoliposomes are liposomes surrounding an iron oxide core, which are used as contrast enhancing agents in magnetic resonance imaging (MRI). One method for producing magnetoliposomes consists of hydration of a lipid film with citrate-coated iron oxide particles followed by extrusion. Two parameters are of major importance for in vivo applications of magnetoliposomes, namely their size, which must be small, optimally around 100 nm diameter, in order to ensure their prolonged circulation in the bloodstream, and their iron content, which must be maximal for generating high MRI effect. We studied the formation of magnetoliposomes by passive encapsulation of maghemite (γ-Fe(2)O(3)) particle suspensions of varying concentrations, with the objective of producing magnetoliposomes of small size and high iron content. The iron to lipid ratio was used to determine the iron content of the magnetoliposomes after the successive purification steps and cryo-TEM was used to characterize their size, their homogeneity and the efficiency of purification. The size of citrate-coated maghemite clusters was found to be of critical importance for obtaining magnetoliposomes smaller than 200 nm. We were able to reproducibly synthesize magnetoliposomes of 100 nm diameter with high iron content -up to 77 particles per liposome (5.6 moles iron per mole lipid) - and high r(2) MRI relaxivity - up to 320 m m(-1) . s(-1) . The magnetoliposomes present improved characteristics compared with previous reports. Future research will focus on using these magnetoliposomes as drug delivery systems for in vivo diagnostics or therapeutics applications.

A specific mouse whole body coil and a dedicated gradient system at 4.7 T were coupled with an ultra-fast 3D gradient echo MRI and keyhole reconstruction technique to obtain 3D whole-body dynamic T(1)-weighted or T(2)*-weighted imaging. The technique was used to visualize the real-time distribution of non-targeting T(1) and T(2)* contrast agent (CA) in a glioma-bearing mouse model. T(1) dynamic contrast-enhancement imaging was performed with a fast imaging with steady-state precession sequence [echo time/repetition time (TE/TR), 1.32/3.7 ms] before and after CA injection (Gd-DOTA and BSA-Gd-DOTA) for 21 min. The temporal resolution was 1 image/6.5 s. T(2)* imaging (TE/TR, 4/8 ms) was performed before and after iron-based (small and ultra-small particles of iron oxide) CA injection for 45 min. The temporal resolution was 1 image/14 s. Signal-to-noise ratio curves were determined in various mouse organs. The whole-body coil and gradient systems made it possible to acquire data with sufficient and homogeneous signal-to-noise ratio on the whole animal. The spatial resolution allowed adequate depiction of the major organs, blood vessels and brain glioma. The distribution and the time-course of T(1) and T(2)* contrasts upon contrast agent injection were also assessed. 3D whole-body mouse MRI is feasible at high spatial resolution in movie mode and can be applied successfully to visualize real-time contrast agent distribution. This method should be effective in future preclinical molecular imaging studies.

Parmi les differentes etapes d’elaboration et de validation d’un produit d’ingenierie tissulaire pour la reconstruction osseuse, l’experimentation in vivo est encore actuellement un temps necessaire qui permet une evaluation dans des conditions proches de la physiologie (Muschler 2009). Ces etudes ont longtemps ete realisees uniquement a travers des analyses histologiques post mortem, ce qui necessitait des cohortes importantes afin d’etudier les differents temps de cicatrisation. L’introduction de methodes d’imagerie in vivo non invasives dediees permet actuellement d’etudier plus finement les differentes etapes de l’integration du materiau et de la cicatrisation chez le petit animal (souris, rat), en utilisant un seul groupe etudie a plusieurs temps, sous anesthesie generale (isofluorane). L’objectif de cette note technique est d’exposer les progres technologiques recents dans le domaine de l’imagerie in vivo pour la recherche, a travers trois methodes utilisees dans le domaine de l’ingenierie tissulaire osseuse : le microscanner, la micro-IRM et la bio-luminescence. La principale application du micro-scanner (µCT) in vivo est l’etude de l’os et des tissus mineralises (Schambach 2009), meme si des applications recentes en imagerie cardiopulmonaire et tumorale ont ete decrites (Badea 2008). Concernant les applications osseuses, le µ-CT in vivo chez la souris (µCT General Electric © ) permet l’appreciation de la morphologie et la quantification de la densite osseuse, de facon longitudinale, sans sacrifice de l’animal. La limite de resolution in vivo de 50 µm est liee aux imperatifs de dosimetrie puisque les µCT ex-vivo permettent d’atteindre des resolutions de 8 µm. Il a prealablement ete demontre que les quantifications morphologiques obtenues sont significativement correlees avec

We used MoCA (Modular Control and Regulation Analysis) to demonstrate in intact beating rat heart that physiological activation of contraction by adrenaline involves the almost perfect parallel activation of both mitochondria and myofibrils by intracellular Ca2+. This explains the perfect homoeostasis of the energetic intermediate PCr (phosphocreatine) in heart. When using drugs specifically stimulating either supply or demand activities, MoCA helped reveal the very specific mode of regulation of heart contraction energetics. Only activation of myofibrils activity (demand), either by increasing intracellular Ca2+ concentration or myofibrils sensitivity to Ca2+, triggers activation of contractile activity. In contrast, the activation of mitochondrial activity (supply) has strictly no effect on contraction, either directly or through PCr changes (intermediate).

The purpose of this study was to demonstrate the feasibility of steady-state True fast imaging with steady precession (TrueFISP) four-dimensional imaging of mouse heart at high resolution and its efficiency for cardiac volumetry. Three-dimensional cine-imaging of control and hypoxic mice was carried out at 4.7 T without magnetization preparation or ECG-triggering. The k-space lines were acquired with the TrueFISP sequence (pulse repetition time/echo time = 4/2 ms) in a repeated sequential manner. Retrospective reordering of raw data allowed the reconstruction of 10 three-dimensional images per cardiac cycle. The acquisition scheme used an alternating radiofrequency phase and sum-of-square reconstruction method. Black-blood three-dimensional images at around 200 mum resolution were produced without banding artifact throughout the cardiac cycle. High contrast to noise made it possible to estimate cavity volumes during diastole and systole. Right and left ventricular stroke volume was significantly higher in hypoxic mice vs controls (20.2 +/- 2 vs 15.1 +/- 2; P0.05, 24.9 +/- 2 vs 20.4 +/- 2; P0.05, respectively). In conclusion, four-dimensional black-blood TrueFISP imaging in living mice is a method of choice to investigate cardiac abnormalities in mouse models.