Impact of concentration and dilution of three macrocyclic gadolinium-based contrast agents on MRI signal intensity at 1.5T and 3T and different pulse sequences: results of a phantom study in human plasma.

BACKGROUND: Many factors influence the increase in signal intensity (SI) provided by magnetic resonance imaging (MRI) contrast media. PURPOSE: To assess the impact of different gadolinium concentrations and dilutions of three macrocyclic gadolinium-based contrast agents (GBCA) on SI. MATERIAL AND METHODS: This phantom study investigated gadobutrol, gadoteridol, and gadoterate in human plasma of a healthy donor pool at 37 °C. Different molar concentrations served to mimic conditions typically relevant for steady-state imaging; different dilutions served to mimic influence on first-pass bolus imaging. For SI measurement at 1.5T and 3T, we used two Magnetom Scanners (Siemens), applying the T1-weighted sequences Flash 2D/3D and VIBE. Regions of interest were placed on the central slice of the test vials. RESULTS: In the concentration series, gadobutrol showed the highest SI of all three GBCAs up to 2 mM, followed by gadoteridol and gadoterate. No major differences were seen between 1.5T and 3T. In the dilution series, gadobutrol showed the highest SI of all three GBCAs up to 10 mL/L. The highest effect was recorded with Flash 3D and VIBE at 3T. CONCLUSION: SIs measured in phantoms using three macrocyclic GBCAs strongly depend on their relaxivity and on the local concentration. The latter can be influenced-when comparing dilutions-by their initial concentration in their formulation. Furthermore, the pulse sequences and the chosen parameters have essential influence. At steady-state concentrations (≤2 mM) and first-pass bolus dilutions (up to 10 ml/L), gadobutrol showed highest SIs, followed by gadoterate and gadoteridol.

A non-linear mixed effect modelling approach for metabolite correction of the arterial input function in PET studies.

Quantitative PET studies with arterial blood sampling usually require the correction of the measured total plasma activity for the presence of metabolites. In particular, if labelled metabolites are found in the plasma in significant amounts their presence has to be accounted for, because it is the concentration of the parent tracer which is required for data quantification. This is achieved by fitting a Parent Plasma fraction (PPf) model to discrete metabolite measurements. The commonly used method is based on an individual approach, i.e. for each subject the PPf model parameters are estimated from its own metabolite samples, which are, in general, sparse and noisy. This fact can compromise the quality of the reconstructed arterial input functions, and, consequently, affect the quantification of tissue kinetic parameters. In this study, we proposed a Non-Linear Mixed Effect Modelling (NLMEM) approach to describe metabolite kinetics. Since NLMEM has been developed to provide robust parameter estimates in the case of sparse and/or noisy data, it has the potential to be a reliable method for plasma metabolite correction. Three different PET datasets were considered: [11C]-(+)-PHNO (54 scans), [11C]-PIB (22 scans) and [11C]-DASB (30 scans). For each tracer both simulated and measured data were considered and NLMEM performance was compared with that provided by individual analysis. Results showed that NLMEM provided improved estimates of the plasma parent input function over the individual approach when the metabolite data were sparse or contained outliers.

Automated Fiber Diameter and Porosity Measurements of Plasma Clots in Scanning Electron Microscopy Images.

Scanning Electron Microscopy (SEM) is a powerful, high-resolution imaging technique widely used to analyze the structure of fibrin networks. Currently, structural features, such as fiber diameter, length, density, and porosity, are mostly analyzed manually, which is tedious and may introduce user bias. A reliable, automated structural image analysis method would mitigate these drawbacks. We evaluated the performance of DiameterJ (an ImageJ plug-in) for analyzing fibrin fiber diameter by comparing automated DiameterJ outputs with manual diameter measurements in four SEM data sets with different imaging parameters. We also investigated correlations between biophysical fibrin clot properties and diameter, and between clot permeability and DiameterJ-determined clot porosity. Several of the 24 DiameterJ algorithms returned diameter values that highly correlated with and closely matched the values of the manual measurements. However, optimal performance was dependent on the pixel size of the images-best results were obtained for images with a pixel size of 8-10 nm (13-16 pixels/fiber). Larger or smaller pixels resulted in an over- or underestimation of diameter values, respectively. The correlation between clot permeability and DiameterJ-determined clot porosity was modest, likely because it is difficult to establish the correct image depth of field in this analysis. In conclusion, several DiameterJ algorithms (M6, M5, T3) perform well for diameter determination from SEM images, given the appropriate imaging conditions (13-16 pixels/fiber). Determining fibrin clot porosity via DiameterJ is challenging.

Emerging Advanced Technologies Developed by IPR for Bio Medical Applications ­.A Review.

Over the last decade, research has intensified worldwide on the use of low-temperature plasmas in medicine and healthcare. Researchers have discovered many methods of applying plasmas to living tissues to deactivate pathogens; to end the flow of blood without damaging healthy tissue; to sanitize wounds and accelerate its healing; and to selectively kill malignant cancer cells. This review paper presents the latest development of advanced and plasma-based technologies used for applications in neurology in particular. Institute for Plasma Research (IPR), an aided institute of the Department of Atomic Energy (DAE), has also developed various technologies in some of these areas. One of these is an Atmospheric Pressure Plasma Jet (APPJ). This device is being studied to treat skin diseases, for coagulation of blood at faster rates and its interaction with oral, lung, and brain cancer cells. In certain cases, in-vitro studies have yielded encouraging results and limited in-vivo studies have been initiated. Plasma activated water has been produced in the laboratory for microbial disinfection, with potential applications in the health sector. Recently, plasmonic nanoparticle arrays which allow detection of very low concentrations of chemicals is studied in detail to allow early-stage detection of diseases. IPR has also been developing AI-based software called DeepCXR and AIBacilli for automated, high-speed screening and detection of footprints of tuberculosis (TB) in Chest X-ray images and for recognizing single/multiple TB bacilli in sputum smear test images, respectively. Deep Learning systems are increasingly being used around the world for analyzing electroencephalogram (EEG) signals for emotion recognition, mental workload, and seizure detection.

Identification of positron emission tomography ligands for NPY Y5 receptors in the brain.

A series of trans-3-oxospiro[(aza)isobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide derivatives were synthesized and profiled for NPY Y5 binding affinity, brain and CSF penetrability in rats, and susceptibility to human and mouse P-glycoprotein transporters in order to develop a PET ligand. Compound 12b exhibited an acceptable profile for a PET ligand, and [(11)C]12b was successfully utilized in clinical settings as a Y5 PET ligand.

The effect of the Rochagan on radiolabeling with (99m)Tc.

Radionuclides are used in nuclear medicine by variety of diagnostic procedures. The labeling of red blood cells (RBC) with (99m)Tc is a current method applied in clinical nuclear medicine. Drugs can alter this labeling and modify the disposition of the radiopharmaceuticals. The influence of Rochagan on the labeling of blood constituents with (99m)Tc was reported. Samples of blood were incubated with different concentrations of Rochagan (0%; 6.25%; 12.5%; 25%; 50%; 100%). Stannous chloride and (99m)Tc (3.7MBq/mL) were added. Plasma (P) and (RBC) were isolated and precipitated with thricloroacetic acid 5%. The insoluble (IF) and soluble fractions (SF) were separated. The %ATI in RBC, IF-P and IF-RBC were calculated. The %ATI on RBC decreased significantly (p<0.05) from control to all concentrations of Rochagan, respectively: 90.15 + or - 0.14(control) to 70.80 + or - 4.21; to 64.36 + or - 0.33; to 57.30 + or - 1.56; to 50.28 + or - 2.71; to 42.41 + or - 2.24; on IF-RBC, respectively: 84.70 + or - 0.87(control) to 67.16 + or - 4.38; to 63.63 + or - 2.92; to 59.02 + or - 3.17; to 43.75 + or - 1.00; to 24.15 + or - 0.94 and also on IF-P, respectively: 83.46 + or - 1.09(control) to 50.90 + or - 3.36; to 35.46 + or - 4.13; to 35.78 + or - 2.31; to 28.74 + or - 3.09; to 19.66 + or - 1.34. The analyses were performed by T-Student and Mann Whitney tests, p<0.05. This effect was probably due to products present in Rochagan that may complex with ions or have a direct/indirect effect on intracellular stannous ion concentration.

Single-molecule 3D imaging of human plasma intermediate-density lipoproteins reveals a polyhedral structure.

Intermediate-density lipoproteins (IDLs), the remnants of very-low-density lipoproteins via lipolysis, are rich in cholesteryl ester and are associated with cardiovascular disease. Despite pharmacological interest in IDLs, their three-dimensional (3D) structure is still undetermined due to their variation in size, composition, and dynamic structure. To explore the 3D structure of IDLs, we reconstructed 3D density maps from individual IDL particles using cryo-electron microscopy (cryo-EM) and individual-particle electron tomography (IPET, without averaging from different molecules). 3D reconstructions of IDLs revealed an unexpected polyhedral structure that deviates from the generally assumed spherical shape model (Frias et al., 2007; Olson, 1998; Shen et al., 1977). The polyhedral-shaped IDL contains a high-density shell formed by flat surfaces that are similar to those of very-low-density lipoproteins but have sharper dihedral angles between nearby surfaces. These flat surfaces would be less hydrophobic than the curved surface of mature spherical high-density lipoprotein (HDL), leading to a lower binding affinity of IDL to hydrophobic proteins (such as cholesteryl ester transfer protein) than HDL. This is the first visualization of the IDL 3D structure, which could provide fundamental clues for delineating the role of IDL in lipid metabolism and cardiovascular disease.

Use of a column-switching high-performance liquid chromatography method to assess the presence of specific binding of (R)- and (S)-[(11)C]rolipram and their labeled metabolites to the phosphodiesterase-4 enzyme in rat plasma and tissues.

INTRODUCTION: To complement recent studies using the high-affinity (11)C-labeled phosphodiesterase-4 (PDE4) inhibitor (R)-rolipram and the less active enantiomer (S)-[(11)C]rolipram for in vivo quantification of PDE4 levels, we evaluated the presence of radiolabeled metabolites and their potential binding to PDE4 in the rat plasma, brain, heart, pancreas, skeletal muscle and brown adipose tissue. METHODS: A reverse-phase capture and analytical HPLC column-switch method was used to detect (R)-[(11)C]rolipram, (S)-[(11)C]rolipram and their radiolabeled metabolites in rat plasma and tissue extracts. The relative proportion of PDE4-specific binding of the radiotracers and their labeled metabolites was analyzed following co-injections with a saturating dose of unlabeled (R)-rolipram at 45 min post-tracer injection in tissue extracts. RESULTS: Radiolabeled metabolites were found in the plasma (72-75% of total radioactive signal), and in the heart, skeletal muscle, pancreas and brown adipose tissue (44-52%), but not in the brain. In comparison to polar labeled metabolites, the proportion of unchanged (R)-[(11)C]rolipram was reduced in PDE4-rich organs by co-injection of unlabeled (R)-rolipram. Conversely, no changes were obtained in brown adipose tissue, or with (S)-[(11)C]rolipram, suggesting that radiolabeled metabolites of (R)-[(11)C]rolipram display no specific binding to PDE4. CONCLUSIONS: Radiolabeled hydrophilic metabolites are unlikely to compete with (R)-[(11)C]rolipram for PDE4-specific retention. However, due to the high proportion of the radioactive metabolites in the total radioactive signal, any kinetic modeling calculations in the peripheral tissues will need to take into account the presence of labeled metabolites.

Brain and whole-body imaging in nonhuman primates with [11C]MeS-IMPY, a candidate radioligand for beta-amyloid plaques.

[(11)C]MeS-IMPY ([S-methyl-(11)C]N,N-dimethyl-4-(6-(methylthio)imidazo[1,2-a]pyridine-2-yl)aniline) is a potential radioligand for imaging beta-amyloid plaques with positron emission tomography (PET). The aims of this study were to evaluate [(11)C]MeS-IMPY uptake in nonhuman primate brain and to estimate radiation exposure from serial whole-body images. Eight PET studies were performed in rhesus monkeys to measure the brain uptake and washout of [(11)C]MeS-IMPY. Time-activity data were analyzed with one-tissue and two-tissue compartmental models using radiometabolite-corrected plasma input function. In addition, two whole-body PET scans were acquired for 120 min to determine the biodistribution of [(11)C]MeS-IMPY. Tomographic PET images were compressed into a single planar image to identify organs with the highest radiation exposures. Estimates of the absorbed dose of radiation were calculated using OLINDA 1.0. Injection of [(11)C]MeS-IMPY caused little change in pulse rate, blood pressure, respiratory rate and temperature. [(11)C]MeS-IMPY showed high standardized brain uptake values of approximately 500% and 600% between 2 and 3 min in cortical regions and the cerebellum, respectively. The brain uptake of [(11)C]MeS-IMPY was widespread and quite uniform across all cortical regions. Activity rapidly washed out of the brain, with 20% of peak activity remaining at 40 min. Thus, all brain regions showed minimal retention of radioactivity, consistent with these healthy young animals having negligible amyloid plaques. Regional brain activity fitted well into a one-tissue compartment model. The average volume of distribution in all brain regions was 7.66+/-2.14 ml/cm(3) (n=4). The organs with the highest radiation exposure (muSv/MBq) were the gallbladder wall (33.4), urinary bladder (17) and lungs (12.9), with a resulting effective dose of 4.9 microSv/MBq (18 mrem/mCi). The high brain uptake, rapid washout and quantifiable volume of distribution in nonhuman primate brain further support the evaluation of [(11)C]MeS-IMPY. Calculated dosimetry results are comparable with those for other (11)C-labeled brain imaging radioligands.

Measurement of the ultrasonic attenuation coefficient of human blood plasma during clotting in the frequency range of 8 to 22 MHz.

The blood coagulation mechanism consists of a series of concatenated chemical reactions, governed by the coagulation factors present in the blood plasma, after the activation of the clot mechanism. The last reaction corresponds to the fibrinogen conversion into fibrin, followed by the fibrin polymerisation and production of a stable fibrin network. During the clotting process, there is a sol-gel transformation of the medium. The subject of the present paper is the measurement of the ultrasonic attenuation coefficient for human blood plasma during the coagulation process, in the frequency range of 8 to 22 MHz. The clot was obtained after the procedure to measure the prothrombin time (approximately 12 s): mixing 150 microL of reconstituted lyophilised normal plasma with 300 microL of reconstituted lyophilised thromboplastin immersed in a water bath with the temperature controlled at 36.5 degrees C. The attenuation coefficient for pure plasma remained constant within the measurement period of 10 s and at frequencies of 8, 9, 10, 15, 20, 21 and 22 MHz. On the other hand, there is a detectable time-decay of the attenuation coefficient for samples of plasma going through the coagulation process and at frequencies of 8, 9, 10 and 15 MHz. The time-decay becomes less and less detectable as the frequency increases and it becomes completely undetectable at 20, 21 and 22 MHz.