Magnetic Resonance Signal Intensity Research Articles

Correlation between pulp sensibility and magnetic resonance signal intensity following regenerative endodontic procedures in mature necrotic teeth- a retrospective cohort study

BackgroundWith increasing studies being published on regenerative endodontic procedures (REPs) as a treatment modality for mature necrotic teeth, the assessment of outcomes following regenerative endodontic procedures has become more challenging and the demand for a better understanding of the regenerated tissues following this treatment is rising. The study aimed to correlate cold, electric pulp testing (EPT), and magnetic resonance imaging (MRI) signal intensity (SI) in mature necrotic teeth treated with regenerative endodontic procedures.MethodologyThis retrospective cohort study included eighteen adult patients who experienced tooth necrosis in mature maxillary anterior teeth recruited from the outpatient clinic, Conservative Dentistry Department, Faculty of Dentistry, Alexandria University, Alexandria, Egypt from July 2017 until December 2018 with 12 months of follow-up. regenerative endodontic procedures via blood clot were performed. The canals were instrumented by ProTaper Next (PTN) files until final sizes X3 or X5. Biodentine was used as cervical plug material. Pre and post-operative clinical follow-up was done where the patients’ responses to cold and electric pulp testing were given a scoring system and were compared to the normal contralateral tooth. Pre and post-operative magnetic resonance imaging signal intensity of both the involved tooth and its contralateral at the middle and the apical thirds of the root canals were assessed after 3, 6, and 12 months. Data was analyzed using the ANOVA, Friedman and Bonferroni tests. Significance was set at a p-value < 0.05.ResultsAll 18 teeth scored a baseline score of “2” for cold and electric pulp testing. There was a significant difference between scores of the cold test at baseline and 12-month follow-up (p < 0.001). There was a significant difference between scores of the electric pulp testing of baseline and 12-month follow-up (p < 0.001). There was a moderately significant indirect (inverse) correlation between magnetic resonance imaging signal intensity and cold test in both the middle and apical thirds at 12 months. No significant correlations were detected between magnetic resonance imaging signal intensity and electric pulp testingat any of the time intervals (p > 0.05).ConclusionMagnetic resonance imaging is a successful non-invasive method to assess outcomes of regenerative endodontic procedures and correlating it with another reliable method of assessing pulpal responses, cold test, could validate these outcomes.Clinical trial registrationThe study was registered with ClinicalTrials.gov (ID: NCT03804450).

ADSCs labeled with SPIONs tracked in corpus cavernosum of rat and miniature pig by MR imaging and histological examination

Adipose tissue-derived stem cells (ADSCs) have been shown to improve erectile function in animal models of erectile dysfunction. However, few studies have been carried out using a reliable in vivo imaging method to trace transplanted cells in real time, which is necessary for systematic investigation of cell therapy. The study aims to explore the feasibility of non-invasively monitoring intracavernous injection of ADSCs in rat and miniature pig corpus cavernosum using in vivo magnetic resonance (MR) imaging. Thirty-six male Sprague Dawley rats (10 weeks old) and six healthy, sexually mature male miniature pigs (20 kg weight) were obtained. ADSCs were isolated from paratesticular fat of donor rats and cultured. Then ADSCs were labeled with superparamagnetic iron oxide nanoparticles (SPIONs), a type of MR imaging contrast agent, before transplantation into rats and pigs. After intracavernous injection, all rats and pigs underwent and were analyzed by MR imaging at the day of ADSC transplantation and follow-up at 1, 2 and 4 weeks after transplantation. In addition, penile histological examination was performed on all rats and pigs before (n = 6) and at 1 day (n = 6), 1 week (n = 6), 2 weeks (n = 6) or 4 weeks (n = 12) after ADSC transplantation. SPION-labeled ADSCs demonstrated a strong decreased signal intensity compared with distilled water, unlabeled ADSCs or agarose gel. SPION-labeled ADSCs showed a hypointense signal at all concentrations, and the greatest hypointense signal was observed at the concentration of 1 × 106. MR images of the corpus cavernosum showed a hypointense signal located at the injection site. T2*-weighted signal intensity increased over the course of 1 week after ADSCs transplantation, and demonstrated a similar MR signal with that before ADSCs transplantation. After SPION-labeled ADSC injection, T2*-weighted MR imaging clearly demonstrated a marked hypointense signal in pig corpus cavernosum. The T2*-weighted signal faded over time, similar to the MR imaging results in rats. Obvious acute inflammatory exudation was induced by intracavernous injection, and the T2*-weighted signal intensity of these exudation was higher than that of the injection site. The presence of iron was detected by Prussian blue staining, which demonstrated ADSC retention in rat corpus cavernosum. Lack of cellular infiltrations were demonstrated by H&E staining before and 4 weeks after transplantation, which indicated no negative immune response by rats. Prussian blue staining was positive for iron oxide nanoparticles at 2 weeks after transplantation. SPION-labeled ADSCs showed a clear hypointense signal on T2-weight MRI in vitro and in vivo. The MR signal intensity in the corpus cavernosum of the rats and miniature pigs faded and disappeared over time after ADSC transplantation. These findings suggested that MR imaging could trace transplanted ADSCs in the short term in the corpus cavernosum of animals.

Metal-Mediated Catalytic Polarization Transfer from para Hydrogen to 3,5-Dihalogenated Pyridines.

The neutral catalysts [IrCl(H)2(NHC)(substrate)2] or [IrCl(H)2(NHC)(substrate)(sulfoxide)] are used to transfer polarization from para hydrogen (pH2) to 3,5-dichloropyridine and 3,5-dibromopyridine substrates. This is achieved in a rapid, reversible, and low-cost process that relies on ligand exchange within the active catalyst. Notably, the sulfoxide-containing catalyst systems produced NMR signal enhancements between 1 and 2 orders of magnitude larger than its unmodified counterpart. Consequently, this signal amplification by reversible exchange hyperpolarization method can boost the 1H, 13C, and 15N nuclear magnetic resonance (NMR) signal intensities by factors up to 4350, 1550, and 46,600, respectively (14.0, 1.3, and 15.4% polarization). In this paper, NMR and X-ray crystallography are used to map the evolution of catalytically important species and provide mechanistic rational for catalytic efficiency. Furthermore, applications in spontaneous radiofrequency amplification by stimulated emission and NMR reaction monitoring are also shown.

Pediatric craniopharyngiomas: magnetic resonance imaging assessment for hypothalamus-pituitary axis dysfunction and outcome prediction.

In adamantinomatous craniopharyngiomas, tumor topographical categories, cystic component volume, and magnetic resonance signal intensity may impact prognosis. To identify magnetic resonance imaging (MRI) variables associated with pituitary-hypothalamic axis dysfunction and predictive of outcome in children with cystic adamantinomatous craniopharyngiomas. We evaluated 40 preoperative MRIs of adamantinomatous craniopharyngiomas to classify tumor topography, volume, and signal intensity of the cystic components and peritumoral edema. Volumes and normalized signal intensity minimum values were extracted from coronal T2-weighted images (nT2min). Radiological variables were compared to pituitary-hypothalamic axis dysfunction-related clinical data and surgical outcomes. Adamantinomatous craniopharyngiomas were categorized into five topographic classes (12 patients, sellar-suprasellar; seven patients, pseudo-intraventricular; six patients, strict intraventricular; 14 patients, secondary intraventricular; one patient, not strict intraventricular). All cases exhibited a predominant (30 patients, 80%) or total (10 patients, 20%) cystic tumor component and displayed low nT2min percentage values compared to cerebrospinal fluid (42.3% [interquartile range 28.4-54.6%]). Significant associations between tumor topographic classes and pituitary dysfunction (P<0.001), andbetween peritumoral edema and hypothalamic dysfunction (P<0.001) were found. Considering extent of surgical removal and tumor relapse, volume of the cystic tumor component displayed a positive correlation (P=0.002; r=0.48; P=0.02; r=0.36), while nT2min intensity values exhibited a negative correlation (P=0.01; r= - 0.40; P=0.028; r= - 0.34). Severe hypothalamic-pituitary axis dysfunction is associated with tumors along the pituitary stalk and peritumoral edema. Tumor invasion of the third ventricle, tight adherence to the hypothalamus, larger volumes, and lower nT2min intensity of the tumor cystic component are independent predictors of extent ofadamantinomatous craniopharyngioma excision and recurrence.

Increasing Cervical Kyphosis Correlates With Cervical Degenerative Disk Disease in Patients With Adolescent Idiopathic Scoliosis.

Retrospective review. Our goal was to investigate the incidence of cervical degenerative disk disease (DDD) in patients with adolescent idiopathic scoliosis (AIS), before surgical intervention. AIS is often associated with thoracic hypokyphosis and compensatory cervical kyphosis. In adults, cervical kyphosis is associated with DDD. Although cervical kyphosis has been reported in up to 60% AIS patients, the association with cervical DDD has not been reported. A retrospective review was conducted from January 2014 to December 2019 of all consecutive AIS patients. Inclusion criteria were AIS patients over 10 years of age with cervical magnetic resonance imaging and anterior-posterior and lateral spine radiographs within 1 year of each other. Magnetic resonance imaging were reviewed for evidence of cervical DDD. Severity of cervical changes were graded using the Pfirrmann classification and by a quantitative measure of disk degeneration, the magnetic resonance signal intensity ratio. Eighty consecutive patients were included (mean age: 14.1 years, SD=2.5 years). Increasing cervical kyphosis was significantly correlated to decreasing thoracic kyphosis ( r =0.49, P <0.01) and increasing major curve magnitude ( r =0.22, P =0.04). Forty-five patients (56%) had the presence of DDD (grades 2-4) with a mean cervical kyphosis of 11.1° (SD=9.5°, P <0.01). More cervical kyphosis was associated with more severe cervical DDD as graded by Pfirrmann classification level ( P <0.01). Increasing cervical kyphosis was also positively associated with increasing magnetic resonance signal intensity ratio ( P <0.01). Nine patients had ventral cord effacement secondary to DDD with a mean cervical kyphosis of 22.8° (SD=8.6°) compared with 2.6° (SD=11.2°) in those who did not ( P <0.01). Cervical kyphosis was significantly associated with increasing severity of cervical DDD in patients with AIS. Patients with evidence of ventral cord effacement had the largest degree of cervical kyphosis with a mean of 22.8±8.6°. This is the first study to evaluate the association between cervical kyphosis in AIS with cervical DDD.

Early in vivo Radiation Damage Quantification for Pediatric Craniospinal Irradiation Using Longitudinal MRI for Intensity Modulated Proton Therapy

Proton vertebral body sparing craniospinal irradiation (CSI) treats the thecal sac while avoiding the anterior vertebral bodies in an effort to reduce myelosuppression and growth inhibition. However, robust treatment planning needs to compensate for proton range uncertainty, which contributes unwanted doses within the vertebral bodies. This work aimed to develop an early in vivo radiation damage quantification method using longitudinal magnetic resonance (MR) scans to quantify the dose effect during fractionated CSI. Ten pediatric patients were enrolled in a prospective clinical trial of proton vertebral body sparing CSI, in which they received 23.4 to 36 Gy. Monte Carlo robust planning was used, with spinal clinical target volumes defined as the thecal sac and neural foramina. T1/T2-weighted MR scans were acquired before, during, and after treatments to detect a transition from hematopoietic to less metabolically active fatty marrow. MR signal intensity histograms at each time point were analyzed and fitted by multi-Gaussian models to quantify radiation damage. Fatty marrow filtration was observed in MR images as early as the fifth fraction of treatment. Maximum radiation-induced marrow damage occurred 40 to 50 days from the treatment start, followed by marrow regeneration. The mean damage ratios were 0.23, 0.41, 0.59, and 0.54, corresponding to 10, 20, 40, and 60 days from the treatment start. We demonstrated a noninvasive method for identifying early vertebral marrow damage based on radiation-induced fatty marrow replacement. The proposed method can be potentially used to quantify the quality of CSI vertebral sparing and preserve metabolically active hematopoietic bone marrow.

Can we distinguish conventional osteosarcoma subtypes (osteoblastic and chondroblastic) based on their magnetic resonance signal intensities?

Introduction/Objectives. Osteosarcoma is the most common primary malignant bone tumor in adolescents and young adults, with a tendency to produce variable amounts of osteoid, cartilage, and fibrous matrices. The objective of this study is to differentiate between osteosarcoma subtypes: osteoblastic and chondroblastic according to their magnetic resonance imaging (MRI) signal intensities and X-ray findings. Methods. We performed a retrospective analysis for 21 pathologically proven osteosarcoma subtypes: osteoblastic (n = 14) and chondroblastic (n = 7). Conventional images of the bone of origin, periosteal reactions, lytic and sclerotic features, the presence of calcification, and pathological fractures were investigated with X-rays. We measured the mean region of interest values for each lesion with MRI sequences. Results. Among the osteosarcoma lesions, 57% were localized at the knee. X-ray evaluations of the osteoblastic osteosarcomas revealed pure lytic lesions in 35.7%, and pure sclerotic lesions in 42.9% cases. Chondroblastic osteosarcomas revealed pure lytic lesions in 14.3% and pure sclerotic lesions in 42.9% cases. Due to variable osteoblastic, chondroblastic, and fibroblastic areas and proportions of the ossified matrix, osteosarcoma lesions have a heterogeneous MRI signal. However, no statistically significant value was detected. Conclusion. According to our results, MRI signal characteristics and X-ray findings may not be able to distinguish osteosarcoma subtypes, so prospective studies with larger patient cohorts are needed.

Effect of urinary glucose concentration and pH on signal intensity in magnetic resonance images.

PurposeWith advances in anti-diabetes drugs, increasing numbers of patients have high urinary glucose concentrations, which may alter magnetic resonance (MR) signal intensity. We sought to elucidate the effect of urinary glucose concentration and pH on transverse relaxation and MR signal intensity.Materials and methodsThe transverse relaxation rate (R2) was measured in samples with different glucose concentrations (in vitro) and in the urinary bladder of seven patients with diabetes and nine healthy volunteers (in vivo). The glucose concentration and pH in the in vitro samples and urine were measured. The signal intensity ratio of the bladder to adjacent tissues was obtained on T2-weighted imaging (WI), T1WI, and MR urography (in vivo). To clarify the effect of pH further, the urine of two healthy subjects was adjusted with acid and/or base to obtain various pH values (ex vivo).ResultsR2 increased significantly with high glucose concentrations in the in vitro study. In the in vivo study, high glucose concentration (p < 0.001) and low pH (p = 0.005) were significantly associated with high R2. R2 was higher (p = 0.002) and the signal in maximum-intensity projection images of MR urography was lower (p = 0.005) in patients with diabetes than in healthy subjects. Ex vivo study revealed that a decrease in pH in acid portion resulted in increased R2.ConclusionHigh concentrations of urinary glucose and low pH both enhance transverse relaxation, which, in turn, causes low signal intensity in urinary bladder on long echo time (TE) images, such as MR urography. Radiologists should be aware of this phenomenon when interpreting abnormally low-intensity bladders on long TE images.

Proton density fat fraction: magnetic resonance imaging applications beyond the liver.

Magnetic resonance imaging-proton density fat fraction (MRI-PDFF) is an emerging quantitative imaging biomarker that accurately measures the fat fraction of tissue by correcting factors influencing magnetic resonance signal intensity. Beyond fat quantification, it also measures R2* which is a direct measure of iron concentration. The utilization of MRI-PDFF in liver diseases is well established. In the present review, we focused on applications of MRI-PDFF in different body areas including pancreas, bone, muscle, spleen, testis, visceral, and subcutaneous adipose tissue. Future studies can enable tracking of quantitative fat fraction changes in different organs simultaneously, which can be critical in understanding fat metabolism.

The effect of time delay for magnetic resonance contrast-enhanced scan on imaging for small-volume brain metastases

PurposeTo study the effect of different enhancement timings of magnetic resonance (MR) on small-volume brain metastases (BM) visualisation and provide a basis for the contour of tumour targets. MethodWe prospectively enrolled 101 patients with BM who received radiotherapy. All patients underwent computed tomography (CT) and MR simulations. Contrast-enhanced MR scans at 1, 3, 5, 10, 18, and 20 min after injection of contrast medium were performed. The tumour target was determined on MR images at different enhancement times, and the differences of tumour target volume, maximum diameter, and MR signal intensity were compared. Results(1) Of the 453 metastatic lesions, 24 (5.2 %) were not detected at 1 min and 8 (1.8 %) were not detected at 3 min; however, all metastases were detected after 5 min. The volume and maximum diameter of the 28 (6.2 %) metastases were stable at any time. (2) The average volume of metastatic lesions at 1, 3, 5, 10, 18, and 20 min was 0.09 cm3, 0.10 cm3, 0.12 cm3, 0.12 cm3, 0.13 cm3, and 0.13 cm3, respectively. Compared to 1 min, BM volume at other times increased by 13.1 %, 21.5 %, 31.6 %, 39.6 %, and 41.7 %, and the difference between the maximum and minimum volumes was statistically significant (p < 0.05). (3) The distribution of the maximum ratio of tumours to white matter mean signal intensity at different times were 39.6 %, 20 %, 14.6 %, 8.0 %, 10.4 %, and 10 %, respectively. ConclusionThe visualisation of small-volume BM was significantly different at different enhancement times. Our results suggest that multi-timing enhancement scans for small-volume BM should be implemented and that scanning at >10 min is essential.

Following Molecular Mobility during Chemical Reactions: No Evidence for Active Propulsion.

The reported changes in self-diffusion of small molecules during reactions have been attributed to "boosted mobility". We demonstrate the critical role of changing concentrations of paramagnetic ions on nuclear magnetic resonance (NMR) signal intensities, which led to erroneous measurements of diffusion coefficients. We present simple methods to overcome this problem. The use of shuffled gradient amplitudes allows accurate diffusion NMR measurements, even with time-dependent relaxation rates caused by changing concentrations of paramagnetic ions. The addition of a paramagnetic relaxation agent allows accurate determination of both diffusion coefficients and reaction kinetics during a single experiment. We analyze a copper-catalyzed azide-alkyne cycloaddition "click" reaction, for which boosted mobility has been claimed. With our methods, we accurately measure the diffusive behavior of the solvent, starting materials, and product and find no global increase in diffusion coefficients during the reaction. We overcome NMR signal overlap using an alternative reducing agent to improve the accuracy of the diffusion measurements. The alkyne reactant diffuses slower as the reaction proceeds due to binding to the copper catalyst during the catalytic cycle. The formation of this intermediate was confirmed by complementary NMR techniques and density functional theory calculations. Our work calls into question recent claims that molecules actively propel or swim during reactions and establishes that time-resolved diffusion NMR measurements can provide valuable insight into reaction mechanisms.

Effect of Dihydropyridine Enrichment in the Microstructure of the Palisade Layer on the Stability of Fat Nano-emulsions.

Relationship between the stability of fat nano-emulsions and the incorporated drug at the molecular level are rarely known. Herein, fat nano-emulsions containing dihydropyridine drugs were prepared and the microstructure of their palisade layers were investigated.The prepared 1.0mg/mL nimodipine nano-emulsion was found to contain 65.50% drug in the palisade layer. The increasing drug concentration led to a decrease-increase-decrease trend in centrifugal stability constant, particle size and proton nuclear magnetic resonance (1H NMR) signal intensity of the lecithin trimethyl ammonium group in the nimodipine and felodipine nano-emulsions. The 1H NMR spectra of test solutions including nano-emulsions suggest that increasing drugs penetrated into the palisade layer, resulting in the lecithin arrangement from loose to tight, and then from monolayer to bilayer. Nimodipine and felodipine nano-emulsions showed two valley values at concentrations of 0.15 and 0.75mg/mL, and 0.30 and 0.90mg/mL respectively, which indicated that the nano-emulsion has two more stable states corresponding to the tightly arranged mono- and bi-palisade layer. These two concentrations are positively correlated with lipophilicity of nimodipine and felodipine. Further, nimodipine liposomes were prepared to validate the effect of drugs on the arrangement of lecithin in the palisade layer. 1H NMR characterizations of the liposomes showed a similar profile to that of nano-emulsions. These results demonstrated that the increasing drug concentration could cause a rearrangement of lecithin in the palisade layer, thus affecting emulsion stability.

Technical Note: Histological validation of anatomical imaging for breast modeling using a novel cryo-microtome.

Precise correlation between three-dimensional (3D) imaging and histology can aid biomechanical modeling of the breast. We develop a framework to register ex vivo images to histology using a novel cryo-fluorescence tomography (CFT) device. A formalin-fixed cadaveric breast specimen, including chest wall, was subjected to high-resolution magnetic resonance (MR) imaging. The specimen was then frozen and embedded in an optimal cutting temperature (OCT) compound. The OCT block was placed in a CFT device with an overhead camera and 50μm thick slices were successively shaved off the block. After each shaving, the block-face was photographed. At select locations including connective/adipose tissue, muscle, skin, and fibroglandular tissue, 20μm sections were transferred onto cryogenic tape for manual hematoxylin and eosin staining, histological assessment, and image capture. A 3D white-light image was automatically reconstructed from the photographs by aligning fiducial markers embedded in the OCT block. The 3D MR image, 3D white-light image, and photomicrographs were rigidly registered. Target registration errors (TREs) were computed based on 10 pairs of points marked at fibroglandular intersections. The overall MR-histology registration was used to compare the MR intensities at tissue extraction sites with a one-way analysis of variance. The MR image to CFT-captured white-light image registration achieved a mean TRE of 0.73 ± 0.25mm (less than the 1 mm MR slice resolution). The block-face white-light image and block-face photomicrograph registration showed visually indistinguishable alignment of anatomical structures and tissue boundaries. The MR intensities at the four tissue sites identified from histology differed significantly (p<0.01). Each tissue pair, except the skin-connective/adipose tissue pair, also had significantly different MR intensities (p<0.01). Fine sectioning in a highly controlled imaging/sectioning environment enables accurate registration between the MR image and histology. Statistically significant differences in MR signal intensities between histological tissues are indicators for the specificity of correlation between MRI and histology.

In-vivo Evaluation of Bleomycin-induced Lung Fibrosis Model Mouse Using Ultra High-field 7 T-MRI and Micro-CT

This study aimed to perform longitudinal observation using 4D-computed tomography (CT) and compare images acquired by 3D-CT and 3D-ultrashort echo time (UTE) for evaluation of bleomycin-induced lung fibrosis model. The pulmonary fibrosis model was induced by instilling intratracheally with 50 μl of bleomycin. 4D-CT images were classified into four phases after acquisition and analyzed. To study the effects of respiratory gating, we aquired 3D-CT and 3D-UTE images with and without respiratory gating. For comparison between CT and UTE images, we performed no-triggerd 3D-CT and 3D-UTE under free-breathing. MR signal intensity ratio and CT values were measured in three regions of the upper, middle, and lower lung. At 4DCT, total lung volume at maximum inspiration (4th phase) decreased significantly compared with control mouse and the ratio of lung volume at inspiration to expiration also showed a significant decrease. In comparison of the images between with and without respiratory gating, clearer images were obtained by respiratory gating. However, there was no significant difference between both. In comparison between CT and UTE images, magnetic resonance (MR) signal intensity ratio and CT value were significantly correlated, but 3D-UTE images showed poor delineation of the lower lung and that near the diaphragm compared with 3D-CT images. 4D micro-CT and nontriggered 3D UTE-magnetic resonance imaging (MRI) under free breathing can be useful to evaluate bleomycininduced lung fibrosis model mouse.

Outcomes of arthroscopic repair using the all-inside inter-leaf vertical suture technique for horizontal meniscal tears sustained in sports.

The aim of the study was to evaluate the outcomes of arthroscopic repair using the all-inside inter-leaf vertical suture arthroscopic technique for sports-related horizontal meniscal tears.The inter-leaf vertical suture procedure was performed to repair sports-related horizontal tears in the middle and posterior segments of the medial (11 cases) and lateral (2 cases) menisci in 13 patients (mean age: 30 ± 14 years). Pre- and post-operative Barrett criteria, Lysholm scores, and patient ability to resume sports were assessed. Magnetic resonance imaging (MRI) grades and signal intensity changes near the joint capsule were evaluated in the 9 cases among which pre- and post-operative MRI images were available.All Barrett criteria items were negative following surgery; Lysholm scores increased from 70.2 ± 13.1 before surgery to 98.9 ± 2.64 after surgery (P < .01). All patients were able to resume their sport. Preoperative MRI grade of tears was 3 for all patients; postoperative MRI grades were 1 in 3 cases, 2 in 4 cases, and 3 in 2 cases (P < .05). Importantly, MRI signal intensity at the repaired menisci near the joint capsule was reduced in 8 of these 9 cases postoperatively.The inter-leaf vertical suture procedure is associated with good outcomes for horizontal tears in the middle and posterior segments of the medial and lateral menisci. The procedure is useful and convenient.

Postmodification via Thiol-Click Chemistry Yields Hydrophilic Trityl-Nitroxide Biradicals for Biomolecular High-Field Dynamic Nuclear Polarization.

Dynamic nuclear polarization (DNP) is a powerful method to enhance nuclear magnetic resonance (NMR) signal intensities, enabling unprecedented applications in life and material science. An ultimate goal is to expand the use of DNP-enhanced solid-state NMR to ultrahigh magnetic fields where optimal spectral resolution and sensitivity are integrated. Trityl-nitroxide (TN) biradicals have attracted significant interest in high-field DNP, but their application to complex (bio)molecules has so far been limited. Here we report a novel postmodification strategy for synthesis of hydrophilic TN biradicals in order to improve their use in biomolecular applications. Initially, three TN biradicals (referred to as NATriPols 1-3) with amino-acid linkers were synthesized. EPR studies showed that the α-position of the amino-acid linkers is an ideal modification site for these biradicals since their electron-electron magnetic interactions are marginally affected by the substituents at this position. On the basis of this finding, we synthesized NATriPol-4 with pyridine disulfide appended at the α-position. Postmodification of NATriPol-4 via thiol-click chemistry resulted in various TN biradicals including hydrophilic NATriPol-5 in a quantitative manner. Interestingly, DNP enhancements at 18.8 T of NATriPols for 13C,15N-proline in a glycerol/water matrix are inversely correlated with their hydrophobicity. Importantly, applications of hydrophilic NATriPol-5 and NATriPol-3 to biomolecules including a globular soluble protein and a membrane targeting peptide reveal significantly improved performance compared to TEMTriPol-1 and AMUPol. Our work provides an efficient approach for one-step synthesis of new polarizing agents with tunable physicochemical properties, thus expediting optimization of new biradicals for biomolecular applications at ultrahigh magnetic fields.

Optimization of Parameters of RF Pulse Sequences for MRI Investigations in the Presence of Magnetic Nanoparticles

We consider the effect of various radio frequency (rf) pulse sequences on the contrast of magnetic resonance (MR) images. We have developed a program for simulating magnetic resonance tomograms and for determining optimal values of parameters of rf pulse sequences for obtaining the best contrast of MR images. This program has been tested for MRI experiments with negative contrast agents based on magnetic iron oxide nanoparticles and positive contrast agents based on gadolinium. Their effect on the MR signal intensity depending on concentration has been analyzed. Recommendations concerning the choice of optimal values of parameters of rf sequences for MRI diagnostics using contrast agents have been developed.

Feasibility of free-breathing quantitative myocardial perfusion using multi-echo Dixon magnetic resonance imaging

Dynamic contrast-enhanced quantitative first-pass perfusion using magnetic resonance imaging enables non-invasive objective assessment of myocardial ischemia without ionizing radiation. However, quantification of perfusion is challenging due to the non-linearity between the magnetic resonance signal intensity and contrast agent concentration. Furthermore, respiratory motion during data acquisition precludes quantification of perfusion. While motion correction techniques have been proposed, they have been hampered by the challenge of accounting for dramatic contrast changes during the bolus and long execution times. In this work we investigate the use of a novel free-breathing multi-echo Dixon technique for quantitative myocardial perfusion. The Dixon fat images, unaffected by the dynamic contrast-enhancement, are used to efficiently estimate rigid-body respiratory motion and the computed transformations are applied to the corresponding diagnostic water images. This is followed by a second non-linear correction step using the Dixon water images to remove residual motion. The proposed Dixon motion correction technique was compared to the state-of-the-art technique (spatiotemporal based registration). We demonstrate that the proposed method performs comparably to the state-of-the-art but is significantly faster to execute. Furthermore, the proposed technique can be used to correct for the decay of signal due to T2* effects to improve quantification and additionally, yields fat-free diagnostic images.

Ventilation-perfusion heterogeneity measured by the multiple inert gas elimination technique is minimally affected by intermittent breathing of 100% O2.

Proton magnetic resonance (MR) imaging to quantify regional ventilation–perfusion ( V˙A/Q˙) ratios combines specific ventilation imaging (SVI) and separate proton density and perfusion measures into a composite map. Specific ventilation imaging exploits the paramagnetic properties of O2, which alters the local MR signal intensity, in an FIO2‐dependent manner. Specific ventilation imaging data are acquired during five wash‐in/wash‐out cycles of breathing 21% O2 alternating with 100% O2 over ~20 min. This technique assumes that alternating FIO2 does not affect V˙A/Q˙ heterogeneity, but this is unproven. We tested the hypothesis that alternating FIO2 exposure increases V˙A/Q˙ mismatch in nine patients with abnormal pulmonary gas exchange and increased V˙A/Q˙ mismatch using the multiple inert gas elimination technique (MIGET).The following data were acquired (a) breathing air (baseline), (b) breathing alternating air/100% O2 during an emulated‐SVI protocol (eSVI), and (c) 20 min after ambient air breathing (recovery). MIGET heterogeneity indices of shunt, deadspace, ventilation versus V˙A/Q˙ ratio, LogSD V˙, and perfusion versus V˙A/Q˙ ratio, LogSD Q˙ were calculated. LogSD V˙ was not different between eSVI and baseline (1.04 ± 0.39 baseline, 1.05 ± 0.38 eSVI, p = .84); but was reduced compared to baseline during recovery (0.97 ± 0.39, p = .04). There was no significant difference in LogSD Q˙ across conditions (0.81 ± 0.30 baseline, 0.79 ± 0.15 eSVI, 0.79 ± 0.20 recovery; p = .54); Deadspace was not significantly different (p = .54) but shunt showed a borderline increase during eSVI (1.0% ± 1.0 baseline, 2.6% ± 2.9 eSVI; p = .052) likely from altered hypoxic pulmonary vasoconstriction and/or absorption atelectasis. Intermittent breathing of 100% O2 does not substantially alter V˙A/Q˙ matching and if SVI measurements are made after perfusion measurements, any potential effects will be minimized.

Effects of multiple injections on the efficacy and cytotoxicity of folate-targeted magnetite nanoparticles as theranostic agents for MRI detection and magnetic hyperthermia therapy of tumor cells

Folate-targeted iron oxide nanoparticles (FA@Fe3O4 NPs) were prepared by a one-pot hydrothermal method and then used as cancer theranostic agents by combining magnetic resonance imaging (MRI) and magnetic hyperthermia therapy (MHT). Crystal structure, morphology, magnetic properties, surface functional group, and heating efficacy of the synthesized nanoparticles were characterized by XRD, TEM, VSM, FTIR, and hyperthermia analyses. The results indicated that the crystal structure, magnetic properties, and heating efficacy of the magnetite nanoparticles were improved by hydrothermal treatment. Toxicity of the prepared NPs was assessed in vitro and in vivo on the mammary cells and BALB/c mice, respectively. The results of the in vitro toxicity analysis showed that the FA@Fe3O4 NPs are relatively safe even at high concentrations of the NPs up to 1000 µg mL−1. Also, the targetability of the FA@Fe3O4 NPs for the detection of folate over-expressed cancer cells was evaluated in an animal model of breast tumor using MRI analysis. It was observed that T2-weighted magnetic resonance signal intensity was decreased with the three-time injection of the FA@Fe3O4 NPs with 24 h interval at a safe dose (50 mg kg−1), indicating the accumulation and retention of the NPs within the tumor tissues. Moreover, the therapeutic efficacy of the MHT using the FA@Fe3O4 NPs was evaluated in vivo in breast tumor-bearing mice. Hyperthermia treatment was carried out under a safe alternating magnetic field permissible for magnetic hyperthermia treatment (f = 150 kHz, H = 12.5 mT). The therapeutic effects of the MHT were evaluated by monitoring the tumor volume during the treatment period. The results showed that the mice in the control group experienced an almost 3.5-fold increase in the tumor volume during 15 days, while, the mice in the MHT group had a mild increase in the tumor volume (1.8-fold) within the same period (P < 0.05). These outcomes give promise that FA@Fe3O4 NPs can be used as theranostic agents for the MRI and MHT applications.