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PURPOSE: The purpose of this study was to develop a spiral-based combined spin- and gradient-echo (spiral-SAGE) method for simultaneous dynamic contrast-enhanced (DCE-MRI) and dynamic susceptibility contrast MRI (DSC-MRI). METHODS: Using this sequence, we obtained gradient-echo TEs of 1.69 and 26 ms, a SE TE of 87.72 ms, with a TR of 1663 ms. Using an iterative SENSE reconstruction followed by deblurring, spiral-induced image artifacts were minimized. Healthy volunteer images are shown to demonstrate image quality using the optimized reconstruction, as well as for comparison with EPI-based SAGE. A bioreactor phantom was used to compare dynamic-contrast time courses with both spiral-SAGE and EPI-SAGE. A proof-of-concept cohort of patients with brain tumors shows the range of hemodynamic maps available using spiral-SAGE. RESULTS: Comparison of spiral-SAGE images with conventional EPI-SAGE images illustrates substantial reductions of image distortion and artifactual image intensity variations. Bioreactor phantom data show similar dynamic contrast time courses between standard EPI-SAGE and spiral-SAGE for the second and third echoes, whereas first-echo data show improvements in quantifying T(1) changes with shorter echo times. In a cohort of patients with brain tumors, spiral-SAGE-based perfusion and permeability maps are shown with comparison with the standard single-echo EPI perfusion map. CONCLUSION: Spiral-SAGE provides a substantial improvement for the assessment of perfusion and permeability by mitigating artifacts typically encountered with EPI and by providing a shorter echo time for improved characterization of permeability. Spiral-SAGE enables quantification of perfusion, permeability, and vessel architectural parameters, as demonstrated in brain tumors.

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., Cardiac morbidity and mortality increase with age in both mice and humans. Here, we demonstrate that 8‐week treatment with rapamycin is sufficient to persistently improve diastolic function, decrease age‐related cardiac hypertrophy and passive stiffness, and modulate the cardiac proteome, even a further 8 weeks after cessation of treatment. These observations suggest that an optimal translational regimen for rapamycin therapy that promotes enhancement of healthspan may involve intermittent short‐term treatments.

Cystic or cavitating lung nodules may reflect an additional diagnostic challenge in benign metastasizing leiomyoma. Our case underlines the importance of combining clinical and radiological findings with specific pulmonary pathology consultation.

The complexity of modern in vivo magnetic resonance imaging (MRI) methods in oncology has dramatically changed in the last 10 years. The field has long since moved passed its (unparalleled) ability to form images with exquisite soft-tissue contrast and morphology, allowing for the enhanced identification of primary tumors and metastatic disease. Currently, it is not uncommon to acquire images related to blood flow, cellularity, and macromolecular content in the clinical setting. The acquisition of images related to metabolism, hypoxia, pH, and tissue stiffness are also becoming common. All of these techniques have had some component of their invention, development, refinement, validation, and initial applications in the preclinical setting using in vivo animal models of cancer. In this review, we discuss the genesis of quantitative MRI methods that have been successfully translated from preclinical research and developed into clinical applications. These include methods that interrogate perfusion, diffusion, pH, hypoxia, macromolecular content, and tissue mechanical properties for improving detection, staging, and response monitoring of cancer. For each of these techniques, we summarize the 1) underlying biological mechanism(s); 2) preclinical applications; 3) available repeatability and reproducibility data; 4) clinical applications; and 5) limitations of the technique. We conclude with a discussion of lessons learned from translating MRI methods from the preclinical to clinical setting, and a presentation of four fundamental problems in cancer imaging that, if solved, would result in a profound improvement in the lives of oncology patients. Level of Evidence: 5 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2019;50:1377-1392.

Human interleukin-6 (hIL-6) is a multifunctional cytokine that regulates immune and inflammatory responses in addition to metabolic and regenerative processes and cancer. hIL-6 binding to the IL-6 receptor (IL-6Rα) induces homodimerization and recruitment of the glycoprotein (gp130) to form a hexameric signaling complex. Anti-IL-6 and IL-6R antibodies are clinically approved inhibitors of IL-6 signaling pathway for treating rheumatoid arthritis and Castleman's disease, respectively. There is a potential to develop novel small molecule IL-6 antagonists derived from understanding the structural basis for IL-6/IL-6Rα interactions. Here, we combine homology modeling with extensive molecular dynamics (MD) simulations to examine the association of hIL-6 with IL-6Rα. A comparison with MD of apo hIL-6 reveals that the binding of hIL-6 to IL-6Rα induces structural and dynamic rearrangements in the AB loop region of hIL-6, disrupting intraprotein contacts and increasing the flexibility of residues 48 to 58 of the AB loop. In contrast, due to the involvement of residues 59 to 78 in forming contacts with the receptor, these residues of the AB loop are observed to rigidify in the presence of the receptor. The binary complex is primarily stabilized by two pairs of salt bridges, Arg181 (hIL-6)- Glu182 (IL-6Rα) and Arg184 (hIL-6)- Glu183 (IL-6Rα) as well as hydrophobic and aromatic stacking interactions mediated essentially by Phe residues in both proteins. An interplay of electrostatic, hydrophobic, hydrogen bonding, and aromatic stacking interactions facilitates the formation of the hIL-6/IL-6Rα complex.

Purpose Renal fibrosis is a hallmark of progressive renal disease; however, current clinical tests are insufficient for assessing renal fibrosis. Here we evaluated the utility of quantitative magnetization transfer MRI in detecting renal fibrosis in a murine model of progressive diabetic nephropathy (DN). Methods The db/db eNOS-/- mice, a well-recognized model of progressive DN, and normal wild-type mice were imaged at 7T. The quantitative magnetization transfer data were collected in coronal plane using a 2D magnetization transfer prepared spoiled gradient echo sequence with a Gaussian-shaped presaturation pulse. Parameters were derived using a two-pool fitting model. A normal range of cortical pool size ratio (PSR) was defined as Mean±2SD of wild-type kidneys (N = 20). The cortical regions whose PSR values exceeded this threshold (threshold PSR) were assessed. The correlations between the PSR-based and histological (collagen IV or picrosirius red stain) fibrosis measurements were evaluated. Results Compared with wild-type mice, moderate increases in mean PSR values and scattered clusters of high PSR region were observed in cortex of DN mouse kidneys. Abnormally high PSR regions (% area) that were detected by the threshold PSR were significantly increased in renal cortexes of DN mice. These regions progressively increased on aging and highly correlated with histological fibrosis measures, while the mean PSR values correlated much less. Conclusion Renal fibrosis in DN can be assessed by the quantitative magnetization transfer MRI and threshold analysis. This technique may be used as a novel imaging biomarker for DN and other renal diseases.

Purpose Quantitative evaluation of dynamic contrast enhanced MRI (DCE-MRI) allows for estimating perfusion, vessel permeability, and tissue volume fractions by fitting signal intensity curves to pharmacokinetic models. These compart mental models assume rapid equilibration of contrast agent within each voxel. However, there is increasing evidence that this assumption is violated for small molecular weight gadolinium chelates. To evaluate the error introduced by this invalid assumption, we simulated DCE-MRI experiments with volume fractions computed from entire histological tumor cross-sections obtained from murine studies. Methods A 2D finite element model of a diffusion-compensated Tofts-Kety model was developed to simulate dynamic T1 signal intensity data. Digitized histology slices were segmented into vascular (vp ), cellular and extravascular extracellular (ve ) volume fractions. Within this domain, Ktrans (the volume transfer constant) was assigned values from 0 to 0.5 min-1 . A representative signal enhancement curve was then calculated for each imaging voxel and the resulting simulated DCE-MRI data analyzed by the extended Tofts-Kety model. Results Results indicated parameterization errors of -19.1% ± 10.6% in Ktrans , -4.92% ± 3.86% in ve , and 79.5% ± 16.8% in vp for use of Gd-DTPA over 4 tumor domains. Conclusion These results indicate a need for revising the standard model of DCE-MRI to incorporate a correction for slow diffusion of contrast agent. Magn Reson Med 80:330-340, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Our understanding of the genetic control of bone has relied almost exclusively on estimates of bone mineral density. In contrast, here we have used high-resolution x-ray tomography (8 μm isotropic voxels) to measure femoral and tibial components across a set of ~600 mice belonging to 60 diverse BXD strains of mice. We computed heritabilities of 25 cortical and trabecular compartments. Males and females have well matched trait heritabilities, ranging from 0.25 to 0.75. We mapped 16 QTLs that collectively cover ~8% of all protein-coding genes in mouse. A majority of loci are detected only in females, and there is also a bias in favor of QTLs for cortical traits. To efficiently evaluate candidate genes we developed a method that couples gene ontologies with expression data to compute bone-enrichment scores for almost all protein-coding genes. We carefully collated and aligned murine candidates with recent human BMD genome-wide association results. We highlight a subset of 50 strong candidates that fall into three categories: 1. those linked to bone function that have already been experimentally validated (Adamts4, Ddr2, Darc, Adam12, Fkbp10, E2f6, Adam17, Grem2, Ifi204); 2. candidates with putative bone function but not yet tested (e.g., Greb1, Ifi202b) but several of which have been linked to phenotypes in humans; and 3. candidates that have high bone-enrichment scores but for which there is not yet any specific link to bone biology or skeletal disease, including Ifi202b, Ly9, Ifi205, Mgmt, F2rl1, Iqgap2. Our results highlight contrasting genetic architecture between the sexes and among major bone compartments. The joint use and alignment of murine and human data should greatly facilitate function analysis and preclinical testing.DisclosureThe authors declare that no competing interests exist.

We present a race-specific model of propofol-induced loss of consciousness that is based on pharmacodynamic data collected and adapted from the peer-reviewed literature. In the proposed race-specific model that includes EC05 and EC95 concentrations, the median (EC50) (and where available 95%CI) propofol concentrations at the effect site compartment for propofol-induced loss of consciousness for whites, Chinese, blacks, and Indians are 2.8 (2.7-2.9), 2.2 (2.2-2.3), 2.0, and 1.9 μg/mL, respectively.

The effects of different processing steps and processing conditions for the fabrication of Y2O3 and Lu2O3 ceramics were investigated, particularly the effects of calcination, and sintering temperature on the content of open-volume and electronic defects. Ceramic bodies were prepared from calcined powders by sintering from 1400°C to 1700°C for 20 h. Density was determined by the Archimedes method and showed pellets reached about 99% of Y2O3 density for temperatures ≥1450°C, and reached 98% for sintering at 1700°C for Lu2O3. The content of open-volume defects was followed by positron annihilation lifetime (PAL) measurements. For both materials, two lifetimes were obtained. The faster lifetime, 211 ps for Y2O3 and 204 ps for Lu2O3, was assigned to bulk annihilation with possible contribution of grain boundaries. The longer lifetime was assigned to positronium annihilation in open-volume defects with radii of 2–4 A. Doppler broadening analysis revealed the same type of defect in Lu2O3 ceramics for all sintering temperatures. PAL analysis results showed that densification was achieved through the elimination and agglomeration of open-volume defects. Thermoluminescence (TL) measurements of Y2O3 showed that sintering is beneficial in eliminating traps and/or recombination centers, and that higher sintering temperatures increase TL signal.

Mechanisms underlying the association between fibroblastic growth factor 23 (FGF-23) and inflammation are uncertain. We found that FGF-23 was markedly up-regulated in LPS/INF-γ-induced proinflammatory M1 macrophages and Hyp mouse-derived peritoneal macrophages, but not in IL-4-induced M2 anti-inflammatory macrophages. NF-КB and JAK/STAT1 pathways mediated the increased transcription of FGF-23 in response to M1 polarization. FGF-23 stimulated TNF-α, but not IL-6, expression in M0 macrophages and suppressed Arginase-1 expression in M2 macrophages through FGFR-mediated mechanisms. 1,25(OH)2 D stimulated Arginase-1 expression and inhibited FGF-23 stimulation of TNF-α. FGF-23 has proinflammatory paracrine functions and counter-regulatory actions to 1,25(OH)2 D on innate immune responses.

PURPOSE Diabetic nephropathy (DN) is the leading cause of renal failure; however, current clinical tests are insufficient for assessing this disease. DN is associated with changes in renal metabolites, so we evaluated the utility of chemical exchange saturation transfer (CEST) imaging to detect changes characteristic of this disease. METHODS Sensitivity of CEST imaging at 7 Tesla to DN was evaluated by imaging diabetic mice [db/db, db/db endothelial nitric oxide synthase (eNOS)-/-] that show different levels of nephropathy as well as by longitudinal imaging (8 to 24 weeks). Nondiabetic (db/m) mice were used as controls. RESULTS Compared with nondiabetic mice, the CEST contrasts of hydroxyl metabolites that correspond to glucose and glycogen were significantly increased in papilla (P), inner medulla (IM), and outer medulla (OM) in db/db and db/db eNOS-/- kidneys at 16 weeks. The db/db eNOS-/- mice that showed advanced nephropathy exhibited greater CEST effects in OM and significant CEST contrasts were also observed in cortex. Longitudinally, db/db mice exhibited progressive increases in hydroxyl signals in IM+P and OM from 12 to 24 weeks and an increase was also observed in cortex at 24 weeks. CONCLUSION CEST MRI can be used to measure changes of hydroxyl metabolites in kidney during progression of DN. Magn Reson Med 76:1531-1541, 2016. © 2015 International Society for Magnetic Resonance in Medicine.

Purpose The goal of this study was to investigate the influence of water compartmentation and heterogeneous relaxation properties on quantitative magnetization transfer (qMT) imaging in tissues, and in particular whether a two-pool model is sufficient to describe qMT data in brain tumors. Methods Computer simulations and in vivo experiments with a series of qMT measurements before and after injection of Gd-DTPA were performed. Both off-resonance pulsed saturation (pulsed) and on-resonance selective inversion recovery (SIR) qMT methods were used, and all data were fit with a two-pool model only. Results Simulations indicated that a two-pool fitting of four-pool data yielded accurate measures of pool size ratio (PSR) of macromolecular versus free water protons when there were fast transcytolemmal exchange and slow R1 recovery. The fitted in vivo PSR of both pulsed and SIR qMT methods showed no dependence on R1 variations caused by different concentrations of Gd-DTPA during wash-out, whereas the fitted kex (magnetization transfer exchange rate) changed significantly with R1. Conclusion A two-pool model provides reproducible estimates of PSR in brain tumors independent of relaxation properties in the presence of relatively fast transcytolemmal exchange, whereas estimates of kex are biased by relaxation variations. In addition, estimates of PSR in brain tumors using the pulsed and SIR qMT methods agree well with one another. Magn Reson Med, 2015. © 2015 Wiley Periodicals, Inc.

Purpose A combined biophysical- and pharmacokinetic-based method is proposed to separate, quantify, and correct for both T1 and T2* leakage effects using dual-echo dynamic susceptibility contrast (DSC) acquisitions to provide more accurate hemodynamic measures, as validated by a reference intravascular contrast agent (CA). Theory and methods Dual-echo DSC-MRI data were acquired in two rodent glioma models. The T1 leakage effects were removed and also quantified to subsequently correct for the remaining T2* leakage effects. Pharmacokinetic, biophysical, and combined biophysical and pharmacokinetic models were used to obtain corrected cerebral blood volume (CBV) and cerebral blood flow (CBF), and these were compared with CBV and CBF from an intravascular CA. Results T1 -corrected CBV was significantly overestimated compared with MION CBV, while T1 + T2*-correction yielded CBV values closer to the reference values. The pharmacokinetic and simplified biophysical methods showed similar results and underestimated CBV in tumors exhibiting strong T2* leakage effects. The combined method was effective for correcting T1 and T2* leakage effects across tumor types. Conclusion Correcting for both T1 and T2* leakage effects yielded more accurate measures of CBV. The combined correction method yields more reliable CBV measures than either correction method alone, but for certain brain tumor types (e.g., gliomas), the simplified biophysical method may provide a robust and computationally efficient alternative. Magn Reson Med 76:613-625, 2016. © 2015 Wiley Periodicals, Inc.

The prevalence of double-stranded RNA (dsRNA) in eukaryotic cells has only recently been appreciated. Of interest here, RNA silencing begins with dsRNA substrates that are bound by the double-stranded RNA binding domains (dsRBDs) of their processing proteins. Specifically, processing of microRNA (miRNA) in the nucleus minimally requires the enzyme Drosha and its dsRBD-containing cofactor protein, DGCR8. The smallest recombinant construct of DGCR8 that is sufficient for in vitro dsRNA binding, referred to as DGCR8-Core, consists of its two dsRBDs and a C-terminal tail. Because dsRBDs rarely recognize the nucleotide sequence of dsRNA, it is reasonable to hypothesize that DGCR8 function is dependent on recognition of specific structural features in the miRNA precursor. Previously, we demonstrated that non-canonical structural elements that promote RNA flexibility within the stem of miRNA precursors are necessary for efficient in vitro cleavage by reconstituted Microprocessor complexes. Here we combine gel shift assays with in vitro processing assays to demonstrate that neither the N-terminal dsRBD of DGCR8 in isolation, nor the DGCR8-Core construct, are sensitive to the presence of non-canonical structural elements within the stem of miRNA precursors, or to single-stranded segments flanking the stem. Extending DGCR8-Core to include an N-terminal heme-binding region does not change our conclusions. Thus, our data suggest that while the DGCR8-Core region is necessary for dsRNA binding and recruitment to the Microprocessor, it is not sufficient to establish the previously observed connection between RNA flexibility and processing efficiency.

Calorie restriction (CR) and rapamycin (RP) extend lifespan and improve health across model organisms. Both treatments inhibit mammalian target of rapamycin (mTOR) signaling, a conserved longevity pathway and a key regulator of protein homeostasis, yet their effects on proteome homeostasis are relatively unknown. To comprehensively study the effects of aging, CR, and RP on protein homeostasis, we performed the first simultaneous measurement of mRNA translation, protein turnover, and abundance in livers of young (3 month) and old (25 month) mice subjected to 10-week RP or 40% CR. Protein abundance and turnover were measured in vivo using (2) H3 -leucine heavy isotope labeling followed by LC-MS/MS, and translation was assessed by polysome profiling. We observed 35-60% increased protein half-lives after CR and 15% increased half-lives after RP compared to age-matched controls. Surprisingly, the effects of RP and CR on protein turnover and abundance differed greatly between canonical pathways, with opposite effects in mitochondrial (mt) dysfunction and eIF2 signaling pathways. CR most closely recapitulated the young phenotype in the top pathways. Polysome profiles indicated that CR reduced polysome loading while RP increased polysome loading in young and old mice, suggesting distinct mechanisms of reduced protein synthesis. CR and RP both attenuated protein oxidative damage. Our findings collectively suggest that CR and RP extend lifespan in part through the reduction of protein synthetic burden and damage and a concomitant increase in protein quality. However, these results challenge the notion that RP is a faithful CR mimetic and highlight mechanistic differences between the two interventions.

Purpose In this study, we propose a simplified acquisition and analysis approach for spin and gradient echo (SAGE)-based dynamic susceptibility-contrast MRI (DSC-MRI) data that is free of contrast agent T1 leakage effects. Methods A five-echo SAGE sequence was used to acquire DSC-MRI data in rat C6 tumors (n = 7). Nonlinear fitting of all echoes was performed to obtain T1-insensitive ΔR2* and ΔR2 time series. The simplified approach, which includes two gradient echoes and one spin echo, was also used to analytically compute T1-insensitive ΔR2* using the two gradient echoes and ΔR2 using all three echoes. The blood flow, blood volume, and vessel size values derived from each method were compared. Results In all cases, the five-echo and simplified SAGE ΔR2* and ΔR2 were in excellent agreement and demonstrated significant T1 leakage correction compared with the uncorrected single-echo data. The derived hemodynamic parameters for blood volume, blood flow, and vessel size were not significantly different between the two methods. Conclusions The proposed simplified SAGE technique enables the acquisition of gradient and spin echo DSC-MRI data corrected for T1 leakage effects yields parameters that are in agreement with the five-echo SAGE approach and does not require nonlinear fitting to extract ΔR2* and ΔR2 time series. Magn Reson Med, 2015. © 2015 Wiley Periodicals, Inc.

Virtual environments VEs have been shown to be beneficial in physical rehabilitation, increasing motivation and the range of exercises that can be safely performed. However, little is known about how disabilities may impact a user's responses to a VE, which could affect rehabilitation motivation. Thus, the primary objective of this research is to understand how VEs affect users with mobility impairments MI. Specifically, we investigate the influence of full body avatars that have canes. To begin investigating this, we designed a VE that included a range of multimodal feedback to induce a strong sense of presence and was novel to the participants. Using this VE, we conducted a study with two different populations: eight persons with MI and eight healthy persons as a control. The healthy participants were of similar demographics e.g., age, weight, height, and previous VE experience to the participants with MI who walked with a cane i.e., on the basis of strict selection criteria to maintain homogeneity. This is one of the first studies to investigate how a VE can affect the gait of the users with MI, physiological response, presence, behavior, and the influence of avatars. Results of the study suggest generalizable guidelines for the design of VEs for users with MI. Copyright © 2014 John Wiley & Sons, Ltd.

Introduction The prevalence and characteristics of agrin and low-density lipoprotein-related receptor protein 4 (LRP4) antibody-positive amyotrophic lateral sclerosis (ALS) patients were studied. Methods We tested 82 ALS patients and 59 controls for agrin and LRP4 antibodies using enzyme-linked immunoassay (ELISA). Results We found that 13.8% of ALS patients had agrin antibodies, and 9.8% had LRP4 antibodies. Women with ALS are twice as likely as men to have antibodies. Agrin-positive ALS patients are younger than agrin-negative ALS patients. Conclusions Antibodies to agrin and LRP4 are found in ALS patients. It must be determined whether these antibodies are pathogenic. Because antibody-positive patients have upper as well as lower motor neuron findings, the antibodies' effects cannot be explained solely by their actions at the neuromuscular junction. A breakdown in interneuronal signaling may be the cause of ALS. Further research is needed to resolve this question. Muscle Nerve, 2016 Muscle Nerve 55: 430-432, 2017.

Purpose In brain tumor dynamic susceptibility contrast (DSC)-MRI studies, multiecho acquisition methods are used to quantify the dynamic changes in T1 and T2* that occur when contrast agent (CA) extravasates. Such methods also enable the estimation of the effective tissue CA transverse relaxivity. The goal of this study was to evaluate the sensitivity of the transverse relaxivity at tracer equilibrium (TRATE) to tumor cytoarchitecture. Methods Computational and in vitro studies were used to evaluate the biophysical basis of TRATE. In 9L, C6, and human brain tumors, TRATE, the apparent diffusion coefficient (ADC), the CA transfer constant (Ktrans), the extravascular extracellular volume fraction (ve), and histological data were compared. Results Simulations and in vitro results indicate that TRATE is highly sensitive to variations in cellular properties such as cell size and density. The histologic cell density and TRATE values were significantly higher in 9L tumors as compared to C6 tumors. In animal and human tumors, a voxel-wise comparison of TRATE with ADC, ve, and Ktrans maps showed low spatial correlation. Conclusion The assessment of TRATE is clinically feasible and its sensitivity to tissue cytoarchitectural features not present in other imaging methods indicate that it could potentially serve as a unique structural signature or “trait” of cancer. Magn Reson Med 74:772–784, 2015. © 2014 Wiley Periodicals, Inc.

Some plant extracts, have been demonstrated to interfere with the microbial metabolism of several pathogenic bacteria. Within this antimicrobial properties it has been described the potential to inhibit or destroy biofilms or to interfere in quorum-sensing (QS) systems. However, to our knowledge, no study exploring this potential of wheat-bran (WB) has been published. The purpose of the present study is to evaluate the anti-biofilm activity of WB against a cow mastitis strain of Staphylococcus aureus and also its possible interference with bacterial QS systems. The potential of inhibition and destruction of the biofilm was studied by different in vitro assays. Also, we tested the ability of WB to interfere in bacterial QS by degrading acyl-homoserine lactones (AHL) as one of the most studied QS signal molecules for Gram-negative bacteria. The soluble extract of WB at 0.5% showed anti-biofilm activity, inhibiting biofilm formation and also destroying it. Similarly, the > 300 kDa fraction from WB had significant anti-biofilm activity in both in vitro assays. The WB also showed a potential to interfere with bacterial QS systems, as it was demonstrated to contain certain lactonase activity able to reduce AHL concentration in the medium. The present study reveals two additional beneficial properties of WB extract never explored before, which may be related to the presence of defence compounds in the plant extract able to interfere with microbial biofilms and also QS systems.

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.

Purpose This study investigates amide proton transfer (APT) and nuclear overhauser enhancement (NOE) in phantoms and 9L tumors in rat brains at 9.4 Tesla, using a recently developed method that can isolate different contributions to exchange. Methods Chemical exchange rotation transfer (CERT) was used to quantify APT and NOEs through subtraction of signals acquired at two irradiation flip angles, but with the same average irradiation power. Results CERT separates and quantifies specific APT and NOE signals without contamination from other proton pools, and thus overcomes a key shortcoming of conventional CEST asymmetry approaches. CERT thus has increased specificity, though at the cost of decreased signal strength. In vivo experiments show that the APT effect acquired with CERT in 9L rat tumors (3.1%) is relatively greater than that in normal tissue (2.5%), which is consistent with previous CEST asymmetry analysis. The NOE effect centered at −1.6 ppm shows substantial image contrast within the tumor and between the tumor and the surrounding tissue, while the NOE effect centered at −3.5 ppm shows little contrast. Conclusion CERT provides an image contrast that is more specific to chemical exchange than conventional APT by means of asymmetric CEST Z-spectra analysis. Magn Reson Med 72:471–476, 2014. © 2013 Wiley Periodicals, Inc.

Two brothers with a leukodystrophy, progressive spastic diplegia, and peripheral neuropathy were found to have proteinaceous aggregates in the peripheral nerve myelin sheath. The patients' mother had only subclinical peripheral neuropathy, but the maternal grandmother had adult-onset leukodystrophy. Sequencing of the proteolipid protein (PLP) gene showed a point mutation IVS4 + 1 G-->A within the donor splice site of intron 4. We identified one transcript with a deletion of exon 4 (Deltaex4, 169bp) encoding for PLP and DM20 proteins and lacking two transmembrane domains, and a second transcript with exon 4 + 10bp encoding three transmembrane domains. Immunohistochemistry showed abnormal aggregation in the myelin sheath of MBP and P0. Myelin-associated glycoprotein was present in the Schmidt-Lanterman clefts but significantly reduced in the periaxonal region. Using immunogold electron microscopy, we demonstrated the presence of mutated PLP/DM20 and the absence of the intact protein in the patient peripheral myelin sheath. We conclude that insertion of mutant PLP/DM20 with resulting aberrant distribution of other myelin proteins in peripheral nerve may constitute an important mechanism of dysmyelination in disorders associated with PLP mutations.

Purpose To compare whole-body magnetic resonance imaging (MRI), including diffusion-weighted imaging (DWI), to computed tomography (CT) for staging newly diagnosed lymphoma. Materials and Methods In all, 108 patients with newly diagnosed lymphoma prospectively underwent whole-body MRI (T1-weighted and T2-weighted short inversion time inversion recovery [n = 108], and DWI [n = 104]) and CT. Ann Arbor stages were assigned according to whole-body MRI and CT findings. Staging disagreements were resolved using bone marrow biopsy, FDG-PET, and follow-up studies. The results were descriptively analyzed. Results Staging results of whole-body MRI without DWI were equal to those of CT in 66.6%, higher in 24.1%, and lower in 9.3%, with correct/incorrect/unresolved higher staging and incorrect/unresolved lower staging relative to CT in 15/7/4 and 9/1 patient(s), respectively. Staging results of whole-body MRI with DWI were equal to those of CT in 65.4%, higher in 27.9%, and lower in 6.7%, with correct/incorrect/unresolved higher staging and incorrect/unresolved lower staging relative to CT in 18/6/5 and 6/1 patient(s), respectively. Conclusion The results of this study suggest that whole-body MRI staging equals CT staging in the majority of patients with newly diagnosed lymphoma. No advantage of additional DWI was demonstrated. Whole-body MRI can be a good alternative to CT if radiation exposure should be avoided. J. Magn. Reson. Imaging 2014;40:26–36. © 2013 Wiley Periodicals, Inc.

Purpose To evaluate the repeatability of MRI-derived relative blood volume (RBV) measurements in mouse kidneys across subjects and days and to evaluate sensitivity of this approach to renal pathology. Materials and Methods A 7 Tesla MRI system and an intravascular iron-oxide contrast agent were used to acquire spin-echo–based renal RBV maps in 10 healthy mice on 2 consecutive days. Renal RBV maps were also acquired in the Alport and unilateral ureteral obstruction mouse models of renal disease. Results The average renal RBV measured on consecutive days was 19.97 ± 1.50 and 19.86 ± 1.62, yielding a concordance correlation coefficient of 0.94, indicating that this approach is highly repeatable. In the disease models, the RBV values were regionally dissimilar and substantially lower than those found in control mice. Conclusion In vivo renal iron-oxide–based RBV mapping in mice complements the physiological information obtained from conventional assays of kidney function and could shed new insights into the pathological mechanisms of kidney disease. J. Magn. Reson. Imaging 2014;39:866–871. © 2013 Wiley Periodicals, Inc.