Pharmacokinetics and biodistribution study of self-assembled Gd-micelles demonstrating blood-pool contrast enhancement for MRI.

Magnetic resonance angiography (MRA) requires the use of contrast agents (CAs) to enable accurate diagnosis. There are currently no CAs on the market with appropriate pharmacokinetic (PK) parameters, namely long persistence in the blood, that can be easily used for MRA. We have recently synthesized amphiphilic building blocks loaded with gadolinium (Gd), which self-assemble into Gd-micelles in aqueous media, and have evaluated their potential as a blood-pool contrast agent (BPCA) in vivo. To assess the short and long term PK of Gd-micelles, the blood and organs of the mice were analyzed at t = 30 min, 1, 2, 3 h, 7, 14 and 21 days. Gd-DOTA was used as a control because it is the gold-standard CA for MRA despite its rapid clearance from the blood compartment. Gd-micelles circulated in the blood for more than 3 h postinjection whereas Gd-DOTA was eliminated less than half an hour postinjection. No side effects were observed in the mice up to the end of the study at 21 days and no accumulation of Gd was observed in the brain or bones. The Magnetic Resonance Imaging (MRI) parameters and the results of this in vivo study indicate the true BCPA properties of Gd-micelles and warrant further development.

Intra-Abdominal Cooling System Limits Ischemia-Reperfusion Injury During Robot-Assisted Renal Transplantation.

Robot-assisted kidney transplantation is feasible; however, concerns have been raised about possible increases in warm ischemia times. We describe a novel intra-abdominal cooling system to continuously cool the kidney during the procedure. Porcine kidneys were procured by standard open technique. Groups were as follows: Robotic renal transplantation with (n = 11) and without (n = 6) continuous intra-abdominal cooling and conventional open technique with intermittent 4°C saline cooling (n = 6). Renal cortex temperature, magnetic resonance imaging, and histology were analyzed. Robotic renal transplantation required a longer anastomosis time, either with or without the cooling system, compared to the open approach (70.4 ± 17.7 min and 74.0 ± 21.5 min vs. 48.7 ± 11.2 min, p-values < 0.05). The temperature was lower in the robotic group with cooling system compared to the open approach group (6.5 ± 3.1°C vs. 22.5 ± 6.5°C; p = 0.001) or compared to the robotic group without the cooling system (28.7 ± 3.3°C; p < 0.001). Magnetic resonance imaging parenchymal heterogeneities and histologic ischemia-reperfusion lesions were more severe in the robotic group without cooling than in the cooled (open and robotic) groups. Robot-assisted kidney transplantation prolongs the warm ischemia time of the donor kidney. We developed a novel intra-abdominal cooling system that suppresses the noncontrolled rewarming of donor kidneys during the transplant procedure and prevents ischemia-reperfusion injuries.

New Magnetic Resonance Imaging Index for Renal Fibrosis Assessment: A Comparison between Diffusion-Weighted Imaging and T1 Mapping with Histological Validation.

A need exists to noninvasively assess renal interstitial fibrosis, a common process to all kidney diseases and predictive of renal prognosis. In this translational study, Magnetic Resonance Imaging (MRI) T1 mapping and a new segmented Diffusion-Weighted Imaging (DWI) technique, for Apparent Diffusion Coefficient (ADC), were first compared to renal fibrosis in two well-controlled animal models to assess detection limits. Validation against biopsy was then performed in 33 kidney allograft recipients (KARs). Predictive MRI indices, ΔT1 and ΔADC (defined as the cortico-medullary differences), were compared to histology. In rats, both T1 and ADC correlated well with fibrosis and inflammation showing a difference between normal and diseased kidneys. In KARs, MRI indices were not sensitive to interstitial inflammation. By contrast, ΔADC outperformed ΔT1 with a stronger negative correlation to fibrosis (R(2) = 0.64 against R(2) = 0.29 p < 0.001). ΔADC tends to negative values in KARs harboring cortical fibrosis of more than 40%. Using a discriminant analysis method, the ΔADC, as a marker to detect such level of fibrosis or higher, led to a specificity and sensitivity of 100% and 71%, respectively. This new index has potential for noninvasive assessment of fibrosis in the clinical setting.

Effect of ischaemic preconditioning on recurrence of hepatocellular carcinoma in an experimental model of liver steatosis.

BACKGROUND: Livers with parenchymal abnormalities tolerate ischaemia-reperfusion (IR) injury poorly. IR injury is a risk factor for hepatocellular carcinoma (HCC) recurrence. This study assessed the link between liver parenchymal abnormalities and HCC recurrence, and evaluated the protective effect of ischaemic preconditioning. METHODS: C57BL/6 mice were fed a choline-deficient diet for 6 and 12 weeks, or standard chow. Hepatic IR and ischaemic preconditioning were achieved by clamping liver blood inflow. Hepa 1-6 HCC cells were inoculated through the spleen. Thereafter, tumour burden, serum α-fetoprotein and cancer cell aggressiveness were compared among groups. RESULTS: Hepatocellular damage and expression of inflammatory genes (encoding interleukin 6, tumour necrosis factor α, hypoxia inducible factor 1α and E-selectin) were exacerbated after IR injury in mice with severe steatosis. Compared with control livers or those with minimal steatosis, livers exposed to a prolonged choline-deficient diet developed larger tumour nodules and had higher serum α-fetoprotein levels. Non-ischaemic liver lobes from mice with steatosis were not protected from accelerated tumour growth mediated by IR injury. This remote effect was linked to promotion of the aggressiveness of HCC cells. Ischaemic preconditioning before IR injury reduced the tumour burden to the level of that in non-ischaemic steatotic controls. This protective effect was associated with decreased cancer cell motility. CONCLUSION: Livers with steatosis tolerated IR poorly, contributing to more severe HCC recurrence patterns in mice with increasingly severe steatosis. IR injury also had a remote effect on cancer cell aggressiveness. Ischaemic preconditioning before IR injury reduced tumour load and serum α-fetoprotein levels. SURGICAL RELEVANCE: Liver ischaemia-reperfusion (IR) injury is associated with organ dysfunction and surgical morbidity. Livers with steatosis tolerate IR injury poorly in the setting of both liver resection and liver transplantation. Ischaemic preconditioning is a simple method to mitigate IR injury. This study shows that ischaemic preconditioning of mouse livers with steatosis reduces ischaemia-mediated tumour growth acceleration. Liver parenchymal abnormalities such as warm IR injury and liver steatosis should be taken into account to predict accurately the risk of liver cancer recurrence after surgical management. Ischaemic preconditioning strategies may hold therapeutic potential not only to mitigate surgical morbidity but also to reduce postoperative recurrence of liver cancer.

Occupation-dependent loading increases bone strength in men.

SUMMARY: Ex vivo analyses of humeri and radii from an anthropological collection and in vivo analyses of the distal radius of retired men indicate that occupation-dependent loading positively influences bone strength by an increase of bone size when young followed by a slowdown of the age-related endocortical and trabecular bone alteration. INTRODUCTION: Skeleton responds to mechanical stimuli, but it is not established whether chronic loading in the context of occupational activities (OA) influences bone properties. We assessed the impact of occupation-dependent loading on upper limb bone strength. METHODS: Individuals were classified according to the intensity of physical loading associated with their OA in two models. Ex vivo, computed tomography scans of the humeri and radii of 219 male skeletons (age of death, 20-93 years) from an anthropological collection of the 20th century (Simon collection) were used to determine estimates of bone strength and cross-sectional geometry. In vivo, distal radius were analysed in 180 men enrolled in the Geneva Retirees Cohort study using high-resolution peripheral quantitative computed tomography and finite element analysis. RESULTS: Heavy-loading OA was associated with higher bone strength in both models. This benefit was associated with higher total area (Tt.Ar), medullary area (Me.Ar) and cortical area (Ct.Ar) in young adult skeletons, but the difference decreased in older age. In older men, the humerus supporting heavy loading had a lower Me.Ar. This effect resulted in greater asymmetries of the Me.Ar and the Ct.Ar/Tt.Ar ratio between the humeri of men with unilateral versus bilateral heavy-loading OA. In vivo, an additional benefit of heavy-loading OA was observed on the distal radius trabecular density and microstructure. CONCLUSION: Repeated occupation-dependent loading positively influences bone strength by an increase of bone size when young followed by a slowdown of the age-related endocortical and trabecular bone alteration. These data supports the necessity to promote bone health in the context of sedentary occupation.

Postmortem magnetic resonance imaging of the heart ex situ: development of technical protocols.

Postmortem MRI (PMMR) examinations are seldom performed in legal medicine due to long examination times, unfamiliarity with the technique, and high costs. Furthermore, it is difficult to obtain access to an MRI device used for patients in clinical settings to image an entire human body. An alternative is available: ex situ organ examination. To our knowledge, there is no standardized protocol that includes ex situ organ preparation and scanning parameters for postmortem MRI. Thus, our objective was to develop a standard procedure for ex situ heart PMMR examinations. We also tested the oily contrast agent Angiofil® commonly used for PMCT angiography, for its applicability in MRI. We worked with a 3 Tesla MRI device and 32-channel head coils. Twelve porcine hearts were used to test different materials to find the best way to prepare and place organs in the device and to test scanning parameters. For coronary MR angiography, we tested different mixtures of Angiofil® and different injection materials. In a second step, 17 human hearts were examined to test the procedure and its applicability to human organs. We established two standardized protocols: one for preparation of the heart and another for scanning parameters based on experience in clinical practice. The established protocols enabled a standardized technical procedure with comparable radiological images, allowing for easy radiological reading. The performance of coronary MR angiography enabled detailed coronary assessment and revealed the utility of Angiofil® as a contrast agent for PMMR. Our simple, reproducible method for performing heart examinations ex situ yields high quality images and visualization of the coronary arteries.

Improved dynamic response assessment for intra-articular injected iron oxide nanoparticles.

The emerging importance of nanoparticle technology, including iron oxide nanoparticles for monitoring development, progression, and treatment of inflammatory diseases such as arthritis, drives development of imaging techniques. Studies require an imaging protocol that is sensitive and quantifiable for the detection of iron oxide over a wide range of concentrations. Conventional signal loss measurements of iron oxide nanoparticle containing tissues saturate at medium concentrations and show a nonlinear/nonproportional intensity to concentration profile due to the competing effects of T1 and T2 relaxation. A concentration calibration phantom and an in vivo study of intra-articular injection in a rat knee of known concentrations of iron oxide were assessed using the difference-ultrashort echo time sequence giving a positive, quantifiable, unambiguous iron signal and monotonic, increasing concentration response over a wide concentration range in the phantom with limited susceptibility artifacts and high contrast in vivo to all other tissues. This improved dynamic response to concentration opens possibilities for quantification due to its linear nature at physiologically relevant concentrations.

A novel method for quantitative monitoring of transplanted islets of langerhans by positive contrast magnetic resonance imaging.

The Automatic Quantitative Ultrashort Echo Time imaging (AQUTE) protocol for serial MRI allows quantitative in vivo monitoring of iron labeled pancreatic islets of Langerhans transplanted into the liver, quantifying graft implantation and persistence in a rodent model. Rats (n = 14), transplanted with iron oxide loaded cells (0-4000 islet equivalents, IEQ), were imaged using a 3D radial ultrashort echo time difference technique (dUTE) on a Siemens MAGNETOM 3T clinical scanner up to 5 months postsurgery. In vivo 3D dUTE images gave positive contrast from labeled cells, suppressing liver signal and small vessels, allowing automatic quantification. Position of labeled islet clusters was consistent over time and quantification of hyperintense pixels correlated with the number of injected IEQs (R² = 0.898, p < 0.0001), and showed persistence over time (5 months posttransplantation). Automatic quantification was superior to standard imaging and manual counting methods, due to the uniform suppressed background and high contrast, resulting in significant timesavings, reproducibility and ease of quantification. Three-dimensional coverage of the whole liver in the absence of cardiac/respiratory artifact provided further improvement over conventional imaging. This imaging protocol reliably quantifies transplanted islet mass and has high translational potential to clinical studies of transplanted pancreatic islets.

The role of imaging and molecular imaging in the early detection of metabolic and cardiovascular dysfunctions.

Despite intense effort, obesity is still rising throughout the world. Links between obesity and cardiovascular diseases are now well established. Most of the cardiovascular changes related to obesity can be followed by magnetic resonance imaging (MRI) or by magnetic resonance spectroscopy (MRS). In particular, we will see in this review that MRI/MRS is extremely well suited to depict (1) changes in cardiac mass and function, (2) changes in stroke volume, (3) accumulation of fat inside the mediastinum or even inside the cardiomyocytes, (4) cell viability and (5) molecular changes during early cardiovascular diseases.

Hyperpolarizing gases via dynamic nuclear polarization and sublimation.

A high throughput method was designed to produce hyperpolarized gases by combining low-temperature dynamic nuclear polarization with a sublimation procedure. It is illustrated by applications to 129Xe nuclear magnetic resonance in xenon gas, leading to a signal enhancement of 3 to 4 orders of magnitude compared to the room-temperature thermal equilibrium signal at 7.05 T.

Comparison of a guaiac and an immunochemical faecal occult blood test for the detection of colonic lesions according to lesion type and location.

We investigated variations in sensitivity of an immunochemical (I-FOBT) and a guaiac (G-FOBT) faecal occult blood test according to type and location of lesions in an average-risk 50- to 74-year-old population. Screening for colorectal cancer by both non-rehydrated Haemoccult II G-FOBT and Magstream I-FOBT was proposed to a sample of 20 322 subjects. Of the 1615 subjects with at least one positive test, colonoscopy results were available for 1277. A total of 43 invasive cancers and 270 high-risk adenomas were detected. The gain in sensitivity associated with the I-FOBT was calculated using the ratio of sensitivities (RSN) according to type and location of lesions, and amount of bleeding. The gain in sensitivity by using I-FOBT increased from invasive cancers (RSN=1.48 (1.16-4.59)) to high-risk adenomas (RSN=3.32 (2.70-4.07)), and was inversely related to the amount of bleeding. Among cancers, the gain in sensitivity was confined to rectal cancer (RSN=2.09 (1.36-3.20)) and concerned good prognosis cancers, because they involve less bleeding. Among high-risk adenomas, the gain in sensitivity was similar whatever the location. This study suggests that the gain in sensitivity by using an I-FOBT instead of a G-FOBT greatly depends on the location of lesions and the amount of bleeding. Concerning cancer, the gain seems to be confined to rectal cancer.

[The viability of kidneys tested by gadolinium-perfusion MRI during ex vivo perfusion]. / La viabilité des reins marginaux testée par perfusion de gadolinium sous IRM pendant leur réanimation.

INTRODUCTION: Marginal kidneys must be reanimated before their transplantation. Reanimation is conducted with hypothermic pulsatile perfusion. The tests used generally to demonstrate the viability is the vascular resistance which is not convenient for everybody. We have developed a magnetic resonance compatible perfusional technology allowing us to test the organs during the perfusion by Gd-perfusion MRI. METHODS AND RESULTS: We have used pigs' kidneys with no warm ischemic time to establish the basis in a normal kidney. After an eight-hour hypothermic pulsatile perfusion, kidneys are submitted to a Gd perfusion. First, we measure the anatomy of the vessels, then the distribution of Gd in the kidney. We obtain simultaneously a dynamic study of the organs where T0 represents the Gd bolus arrival in the cortex and TP the maximum saturation time of Gd. CONCLUSION: We have observed that a normal T0 is inferior to 30s and TP is inferior to one minute. We have compared these values with ATP resynthesis in these organs and found that they correlate. We hope for the future through that predictive use of Gd-MRI to avoid the clinical use of "too" marginal kidneys or the discard of good kidneys but not corresponding with the vascular resistance theory.

In vivo myocardial infarct area at risk assessment in the rat using manganese enhanced magnetic resonance imaging (MEMRI) at 1.5T.

The aim of this study was to measure the myocardial area at risk in rat, using MRI and manganese injection during a coronary occlusion/reperfusion model at 1.5T. A sequential protocol with occlusion and MnCl2 injection immediately followed by MRI was used with the assumption that MnCl2-induced contrast persistence is enough to accurately image the area at risk 90 min after occlusion. A total of 15 adult rats underwent a single 30-min episode of coronary occlusion followed by reperfusion. MnCl2 was injected (25 micromol/kg) at the beginning of the occlusion for 11 rats (group 1) and 6 h after reperfusion for four animals (group 2). A deficit of signal enhancement was observed in all rats. Hypoenhancement area in group 1 was correlated to the area at risk delineated by methylene blue (r=0.96, P<0.0001) whereas in group 2 it was correlated to the infarct area given by triphenyltetrazolium chloride (TTC) solution (r=0.98, P=0.003). The area at risk size was significantly correlated with left ventricle ejection fraction (LVEF), end-systolic volume and anterolateral wall thickening. This work demonstrates that hypoenhanced zone obtained after manganese injection during occlusion represents the area at risk and not only the infarct zone.

[Nephrogenic systemic fibrosis: another problem for patients with chronic renal failure]. / Nouveau problème pour les insuffisants rénaux chroniques: la fibrose systémique néphrogénique.

Nephrogenic systemic fibrosis, another problem for patients with chronic renal failure Nephrogenic systemic fibrosis is a rare but severe disease described in patients with kidney failure. High morbidity ant mortality are associated with this new condition. Epidemiological studies strongly suggest a link between nephrogenic systemic fibrosis and gadolinium administration for magnetic resonance imaging enhancement. The disease is primarily cutaneous, with oedema affecting the limbs, later evolving to fibrosis that leads to joints contractures. The lesions can spread to the trunk and involve systemic organs like the heart, lungs and muscles. Given the lack of proved efficient therapy, careful evaluation of the risks and benefits of gadolinium administration should be done in patients with kidney disease. If really needed, a highly stable contrast media should be used.

Clinical magnetic resonance imaging of pancreatic islet grafts after iron nanoparticle labeling.

There is a crucial need for noninvasive assessment tools after cell transplantation. This study investigates whether a magnetic resonance imaging (MRI) strategy could be clinically applied to islet transplantation. The purest fractions of seven human islet preparations were labeled with superparamagnetic iron oxide particles (SPIO, 280 microg/mL) and transplanted into four patients with type 1 diabetes. MRI studies (T2*) were performed prior to and at various time points after transplantation. Viability and in vitro and in vivo functions of labeled islets were similar to those of control islets. All patients could stop insulin after transplantation. The first patient had diffuse hypointense images on her baseline liver MRI, typical for spontaneous high iron content, and transplant-related modifications could not be observed. The other three patients had normal intensity on pretransplant images, and iron-loaded islets could be identified after transplantation as hypointense spots within the liver. In one of them, i.v. iron therapy prevented subsequent visualization of the spots because of diffuse hypointense liver background. Altogether, this study demonstrates the feasibility and safety of MRI-based islet graft monitoring in clinical practice. Iron overload (spontaneous or induced) represents the major obstacle to the technique.

Feasibility of complementary spatial modulation of magnetization tagging in the rat heart after manganese injection.

It has been shown that manganese-enhanced MRI (MEMRI) can safely depict the myocardial area at risk in models of coronary occlusion-reperfusion for at least 2 h after reperfusion. To achieve this, a solution of MnCl(2) is injected during coronary occlusion. In this model, the regional function quantification deficit of the stunning phase cannot be assessed before contrast injection using MR tagging. The relaxation effects of manganese (which remains in normal cardiac myocytes for several hours) may alter the tags by increasing tag fading and hence the quality of strain measurement. Therefore, we evaluated the feasibility of cardiac MR tagging after manganese injection in normal rats. Six normal Sprague-Dawley rats were imaged in vivo using complementary spatial modulation of magnetization (C-SPAMM) at 1.5 T, before and 15 min after intraperitoneal injection of MnCl(2) solution (~17.5 micromol kg(-1)). The contrast-to-noise ratio of the tag pattern increased significantly (P < 0.001) after injection and remained comparable to the control scan in spite of the higher myocardial relaxation rate caused by the presence of manganese. The measurements of circumferential strain obtained from harmonic phase imaging analysis of the tagged images after MnCl(2) injection did not differ significantly from the measurements before injection in the endocardial, mid-wall, and epicardial regions. In particular, the transmural strain gradient was preserved. Thus, our study suggests that MR tagging could be used in combination with MEMRI to study the acute phase of coronary artery disease.

Myocardial perfusion assessment by use of system identification method in a one-compartment model.

Cardiovascular magnetic resonance has been shown to provide high data quality for myocardial perfusion assessment. However, to analyze the perfusion data, some signal processing and modeling is needed to correct for motion related artifacts and limited spatial resolution. This study describes a method based on system identification, allowing, after a first step of image registration, to integrate and correct the partial volume effect in the myocardium perfusion quantification. This method is then applied to patients with coronary artery disease or hypertrophic obstructive cardiomyopathy.

Comparison of a guaiac based and an immunochemical faecal occult blood test in screening for colorectal cancer in a general average risk population.

BACKGROUND: The guaiac faecal occult blood test (G-FOBT) is recommended as a screening test for colorectal cancer but its low sensitivity has prevented its use throughout the world. METHODS: We compared the performances of the reference G-FOBT (non-rehydrated Hemoccult II test) and the immunochemical faecal occult blood test (I-FOBT) using different positivity cut-off values in an average risk population sample of 10,673 patients who completed the two tests. Patients with at least one test positive were asked to undergo colonoscopy. RESULTS: Using the usual cut-off point of 20 ng/ml haemoglobin, the gain in sensitivity associated with the use of I-FOBT (50% increase for cancer and 256% increase for high risk adenoma) was balanced by a decrease in specificity. The number of extra false positive results associated with the detection of one extra advanced neoplasia (cancer or high risk adenoma) was 2.17 (95% confidence interval 1.65-2.85). With a threshold of 50 ng/ml, I-FOBT detected more than twice as many advanced neoplasias as the G-FOBT (ratio of sensitivity = 2.33) without any loss in specificity (ratio of false positive rate = 0.99). With a threshold of 75 ng/ml, associated with a similar positivity rate to G-FOBT (2.4%), the use of I-FOBT allowed a gain in sensitivity of 90% and a decrease in the false positive rate of 33% for advanced neoplasia. CONCLUSIONS: Evidence in favour of the substitution of G-FOBT by I-FOBT is increasing, the gain being more important for high risk adenomas than for cancers. The automated reading technology allows choice of the positivity rate associated with an ideal balance between sensitivity and specificity.

Analysis of contrast-enhanced MR images to assess renal function.

The image analysis and kinetic modeling methods used in dynamic contrast-enhanced magnetic resonance imaging of the kidney are reviewed. Image analysis includes various techniques of coregistration and segmentation. Few methods have been completely implemented. Nevertheless, the use of coregistration may become a standard to decrease the effect of motion on abdominal images and improve the quality of the renal signals. Kinetic models are classified into three categories: enhancement-based, external and internal representations. Enhancement-based representations are limited to a basic analysis of the tracer concentration curves in the kidneys. Their relationship to the underlying physiology is complex and undefined. However, they can be used to evaluate the split renal function. External representations assess the kidney input and output. An external representation based on the up-slope of the renal enhancement to calculate the renal perfusion is commonly used because of its simplicity. In contrast, external representation based on deconvolution or identification methods remain underexploited. For glomerular filtration, an internal representation based on a two-compartmental model is mostly used. Internal representations based on multi-compartmental models describe the renal function in a more realistic way. Because of their numerical complexity, these models remain rarely used.