Current MRI techniques for the assessment of renal disease.

PURPOSE OF REVIEW: Over the past decade, a variety of MRI methods have been developed and applied to many kidney diseases. These MRI techniques show great promise, enabling the noninvasive assessment of renal structure, function and injury in individuals. This review will highlight the current applications of functional MRI techniques for the assessment of renal disease and discuss future directions. RECENT FINDINGS: Many pathological (functional and structural) changes or factors in renal disease can be assessed by advanced MRI techniques. These include renal vascular structure and function (contrast-enhanced MRI, arterial spin labelling), tissue oxygenation (blood oxygen level dependent MRI), renal tissue injury and fibrosis (diffusion or magnetization transfer imaging, magnetic resonance elastography), renal metabolism (chemical exchange saturation transfer, spectroscopic imaging), nephron endowment (cationic-contrast imaging), sodium concentration (23Na-MRI) and molecular events (targeted-contrast imaging). SUMMARY: Current advances in MRI techniques have enabled the noninvasive investigation of renal disease. Further development, evaluation and application of the MRI techniques should facilitate better understanding and assessment of renal disease, and the development of new imaging biomarkers, enabling the intensified treatment of high-risk populations and a more rapid interrogation of novel therapeutic agents and protocols.

Nitrite induces the extravasation of iron oxide nanoparticles in hypoxic tumor tissue.

Nitrite undergoes reconversion to nitric oxide under conditions characteristic of the tumor microenvironment, such as hypoxia and low pH. This selective conversion of nitrite into nitric oxide in tumor tissue has led to the possibility of using nitrite to enhance drug delivery and the radiation response. In this work, we propose to serially characterize the vascular response of brain tumor-bearing rats to nitrite using contrast-enhanced R2 * mapping. Imaging is performed using a multi-echo gradient echo sequence at baseline, post iron oxide nanoparticle injection and post-nitrite injection, whilst the animal is breathing air. The results indicate that nitrite sufficiently increases the vascular permeability in C6 gliomas, such that the iron oxide nanoparticles accumulate within the tumor tissue. When animals breathed 100% oxygen, the contrast agent remained within the vasculature, indicating that the conversion of nitrite to nitric oxide occurs in the presence of hypoxia within the tumor. The hypoxia-dependent, nitrite-induced extravasation of iron oxide nanoparticles observed herein has implications for the enhancement of conventional and nanotherapeutic drug delivery.

Assessment of renal function in mice with unilateral ureteral obstruction using 99mTc-MAG3 dynamic scintigraphy.

BACKGROUND: Renal scintigraphy using 99mTc-mercaptoacetyltriglycine (99mTc-MAG3) is widely used for the assessment of renal function in humans. However, the application of this method to animal models of renal disease is currently limited, especially in rodents. Here, we have applied 99mTc-MAG3 renal scintigraphy to a mouse model of unilateral ureteral obstruction (UUO) and evaluated its utility in studying obstructive renal disease. METHODS: UUO mice were generated by complete ligation of the left ureter. Sham-operated mice were used as a control. Renal function was investigated on days 0, 1, 3, and 6 post-surgery using dynamic planar imaging of 99mTc-MAG3 activity following retro-orbital injection. Time-activity curves (TACs) were produced for individual kidneys and renal function was assessed by 1) the slope of initial 99mTc-MAG3 uptake (SIU), which is related to renal perfusion; 2) peak activity; and 3) the time-to-peak (TTP). The parameters of tubular excretion were not evaluated in this study as 99mTc-MAG3 is not excreted from UUO kidneys. RESULTS: Compared to sham-operated mice, SIU was remarkably (>60%) reduced in UUO kidneys at day 1 post surgery and the TACs plateaued, indicating that 99mTc-MAG3 is not excreted in these kidneys. The plateau activity in UUO kidneys was relatively low (~40% of sham kidney's peak activity) as early as day1 post surgery, demonstrating that uptake of 99mTc-MAG3 is rapidly reduced in UUO kidneys. The time to plateau in UUO kidneys exceeded 200 sec, suggesting that 99mTc-MAG3 is slowly up-taken in these kidneys. These changes advanced as the disease progressed. SIU, peak activity and TTPs were minimally changed in contra-lateral kidneys during the study period. CONCLUSIONS: Our data demonstrate that renal uptake of 99mTc-MAG3 is remarkably and rapidly reduced in UUO kidneys, while the changes are minimal in contra-lateral kidneys. The parametric analysis of TACs suggested that renal perfusion as well as tubular uptake is reduced in UUO kidneys. This imaging technique should allow non-invasive assessments of UUO renal injury and enable a more rapid interrogation of novel therapeutic agents and protocols.

How the term "white privilege" affects participation, polarization, and content in online communication.

The language used in online discussions affects who participates in them and how they respond, which can influence perceptions of public opinion. This study examines how the term white privilege affects these dimensions of online communication. In two lab experiments, US residents were given a chance to respond to a post asking their opinions about renaming college buildings. Using the term white privilege in the question decreased the percentage of whites who supported renaming. In addition, those whites who remained supportive when white privilege was mentioned were less likely to create an online post, while opposing whites and non-whites showed no significant difference. The term also led to more low-quality posts among both whites and non-whites. The relationship between question language and the way participants framed their responses was mediated by their support or opposition for renaming buildings. This suggests that the effects of the term white privilege on the content of people's responses is primarily affective. Overall, mention of white privilege seems to create internet discussions that are less constructive, more polarized, and less supportive of racially progressive policies. The findings have the potential to support meaningful online conversation and reduce online polarization.

The shape of educational inequality.

Hundreds of thousands of students drop out of school each year in the United States, despite billions of dollars of funding and myriad educational reforms. Existing research tends to look at the effect of easily measurable student characteristics. However, a vast number of harder-to-measure student traits, skills, and resources affect educational success. We present a conceptual framework for the cumulative effect of all factors, which we call student capital. We develop a method for estimating student capital in groups of students and find that student capital is distributed exponentially in each of 140 cohorts of community college students. Students' ability to be successful does not behave like standard tests of intelligence. Instead, it acts like a limited resource, distributed unequally. The results suggest that rather than removing barriers related to easily measured characteristics, interventions should be focused on building up the skills and resources needed to be successful in school.

A practical method for multimodal registration and assessment of whole-brain disease burden using PET, MRI, and optical imaging.

Many neurological diseases present with substantial genetic and phenotypic heterogeneity, making assessment of these diseases challenging. This has led to ineffective treatments, significant morbidity, and high mortality rates for patients with neurological diseases, including brain cancers and neurodegenerative disorders. Improved understanding of this heterogeneity is necessary if more effective treatments are to be developed. We describe a new method to measure phenotypic heterogeneity across the whole rodent brain at multiple spatial scales. The method involves co-registration and localized comparison of in vivo radiologic images (e.g. MRI, PET) with ex vivo optical reporter images (e.g. labeled cells, molecular targets, microvasculature) of optically cleared tissue slices. Ex vivo fluorescent images of optically cleared pathology slices are acquired with a preclinical in vivo optical imaging system across the entire rodent brain in under five minutes, making this methodology practical and feasible for most preclinical imaging labs. The methodology is applied in various examples demonstrating how it might be used to cross-validate and compare in vivo radiologic imaging with ex vivo optical imaging techniques for assessing hypoxia, microvasculature, and tumor growth.

Rapamycin persistently improves cardiac function in aged, male and female mice, even following cessation of treatment.

Even in healthy aging, cardiac morbidity and mortality increase with age in both mice and humans. These effects include a decline in diastolic function, left ventricular hypertrophy, metabolic substrate shifts, and alterations in the cardiac proteome. Previous work from our laboratory indicated that short-term (10-week) treatment with rapamycin, an mTORC1 inhibitor, improved measures of these age-related changes. In this report, we demonstrate that the rapamycin-dependent improvement of diastolic function is highly persistent, while decreases in both cardiac hypertrophy and passive stiffness are substantially persistent 8 weeks after cessation of an 8-week treatment of rapamycin in both male and female 22- to 24-month-old C57BL/6NIA mice. The proteomic and metabolomic abundance changes that occur after 8 weeks of rapamycin treatment have varying persistence after 8 further weeks without the drug. However, rapamycin did lead to a persistent increase in abundance of electron transport chain (ETC) complex components, most of which belonged to Complex I. Although ETC protein abundance and Complex I activity were each differentially affected in males and females, the ratio of Complex I activity to Complex I protein abundance was equally and persistently reduced after rapamycin treatment in both sexes. Thus, rapamycin treatment in the aged mice persistently improved diastolic function and myocardial stiffness, persistently altered the cardiac proteome in the absence of persistent metabolic changes, and led to persistent alterations in mitochondrial respiratory chain activity. These observations suggest that an optimal translational regimen for rapamycin therapy that promotes enhancement of healthspan may involve intermittent short-term treatments.

Evidence of multiexponential T2 in rat glioblastoma.

The aim of this study was to characterize multiexponential T(2) (MET(2)) relaxation in a rat C6 glioblastoma tumor model. To do this, rats (n = 11) were inoculated with the C6 cells via stereotaxic injection into the brain. Ten days later, MET(2) measurements were performed in vivo using a single-slice, multi-echo spin-echo sequence at 7.0 T. Tumor signal was biexponential in eight animals with a short-lived T(2) component (T(2) = 20.7 +/- 5.4 ms across samples) representing 6.8 +/- 6.2% of the total signal and a long-lived T(2) component (T(2) = 76.4 +/- 9.3 ms) representing the remaining signal fraction. In contrast, signal from contralateral grey matter was consistently monoexponential (T(2) = 48.8 +/- 2.3 ms). Additional ex vivo studies (n = 3) and Monte Carlo simulations showed that the in vivo results were not significantly corrupted by partial volume averaging or noise. The underlying physiological origin of the observed MET(2) components is unknown; however, MET(2) analysis may hold promise as a non-invasive tool for characterizing tumor microenvironment in vivo on a sub-voxel scale.

Toward uniform implementation of parametric map Digital Imaging and Communication in Medicine standard in multisite quantitative diffusion imaging studies.

This paper reports on results of a multisite collaborative project launched by the MRI subgroup of Quantitative Imaging Network to assess current capability and provide future guidelines for generating a standard parametric diffusion map Digital Imaging and Communication in Medicine (DICOM) in clinical trials that utilize quantitative diffusion-weighted imaging (DWI). Participating sites used a multivendor DWI DICOM dataset of a single phantom to generate parametric maps (PMs) of the apparent diffusion coefficient (ADC) based on two models. The results were evaluated for numerical consistency among models and true phantom ADC values, as well as for consistency of metadata with attributes required by the DICOM standards. This analysis identified missing metadata descriptive of the sources for detected numerical discrepancies among ADC models. Instead of the DICOM PM object, all sites stored ADC maps as DICOM MR objects, generally lacking designated attributes and coded terms for quantitative DWI modeling. Source-image reference, model parameters, ADC units and scale, deemed important for numerical consistency, were either missing or stored using nonstandard conventions. Guided by the identified limitations, the DICOM PM standard has been amended to include coded terms for the relevant diffusion models. Open-source software has been developed to support conversion of site-specific formats into the standard representation.

Dexamethasone normalizes brain tumor hemodynamics as indicated by dynamic susceptibility contrast MRI perfusion parameters.

The purpose of this study is to demonstrate the utility of dynamic susceptibility contrast (DSC) MRI-derived perfusion parameters to characterize the hemodynamic effects of dexamethasone in a 9L gliosarcoma tumor model. Twenty-four rats underwent intracerebral inoculation with 9L tumor cells. Fifteen were treated with a total of 3mg/kg of dexamethasone on days 10-14 post-inoculation, while the remaining 9 rats served as controls. Fourteen days post-inoculation, MRI images, sensitive to total and micro-vascular cerebral blood flow (CBF), mean transit time (MTT), and intravoxel transit time distributions (TTD)s were obtained using a simultaneous gradient-echo(GE)/spin-echo(SE) DSC-MRI method. Dexamethasone-treated animals had a microvascular (SE) tumor CBF that was 45.9% higher (p = 0.0008) and a MTT that was 47.8% lower (p = 0.0005) than untreated animals. With treatment, there was a non-significant 91.3% increase in total (GE) vascular CBF (p = 0.35), and a significant decrease in MTT (49.1%, p = 0.02). The total vascular and microvascular TTDs from the treated tumors were similar to normal brain, unlike the TTDs in the untreated tumors. These findings demonstrate that DSC-MRI perfusion methods can be used to non-invasively detect the morphological and functional changes in tumor vasculature that occur in response to dexamethasone treatment.

Correlation between estimates of tumor perfusion from microbubble contrast-enhanced sonography and dynamic contrast-enhanced magnetic resonance imaging.

OBJECTIVE: We compared measurements of tumor perfusion from microbubble contrast-enhanced sonography (MCES) and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in an animal tumor model. METHODS: Seven mice were implanted with Lewis lung carcinoma cells on their hind limbs and imaged 14 days later with a Philips 5- to 7-MHz sonography system (Philips Medical Systems, Andover, MA) and a Varian 7.0-T MRI system (Varian, Inc, Palo Alto, CA). For sonographic imaging 100 microL of a perfluoropropane microbubble contrast agent (Definity; Bristol-Myers Squibb Medical Imaging, Billerica, MA) was injected and allowed to reach a pseudo steady state, after which a high-mechanical index pulse was delivered to destroy the microbubbles within the field of view, and the replenishment of the microbubbles was imaged for 30 to 60 seconds. The MRI included acquisition of a T(10) map and 35 serial T(1)-weighted images (repetition time, 100 milliseconds; echo time, 3.1 milliseconds; alpha, 30 degrees ) after the injection of 100 microL of 0.2-mmol/kg gadopentetate dimeglumine (Magnevist; Berlex, Wayne, NJ). Region-of-interest and voxel-by-voxel analyses of both data sets were performed; microbubble contrast-enhanced sonography returned estimates of microvessel cross-sectional area, microbubble velocity, and mean blood flow, whereas DCE-MRI returned estimates of a perfusion-permeability index and the extravascular extracellular volume fraction. RESULTS: Comparing similar regions of tumor tissue seen on sonography and MRI, region-of-interest analyses revealed a strong (r(2) = 0.57) and significant relationship (P < .002) between the estimates of perfusion obtained by the two modalities. CONCLUSIONS: Microbubble contrast-enhanced sonography can effectively depict intratumoral heterogeneity in preclinical xenograft models when voxel-by-voxel analysis is performed, and this analysis correlates with similar DCE-MRI measurements.