Application of Distributed Parameter Model to Assessment of Glioma IDH Mutation Status by Dynamic Contrast-Enhanced Magnetic Resonance Imaging.

Previous studies using contrast-enhanced imaging for glioma isocitrate dehydrogenase (IDH) mutation assessment showed promising yet inconsistent results, and this study attempts to explore this problem by using an advanced tracer kinetic model, the distributed parameter model (DP). Fifty-five patients with glioma examined using dynamic contrast-enhanced imaging sequence at a 3.0 T scanner were retrospectively reviewed. The imaging data were processed using DP, yielding the following parameters: blood flow F, permeability-surface area product PS, fractional volume of interstitial space Ve, fractional volume of intravascular space Vp, and extraction ratio E. The results were compared with the Tofts model. The Wilcoxon test and boxplot were utilized for assessment of differences of model parameters between IDH-mutant and IDH-wildtype gliomas. Spearman correlation r was employed to investigate the relationship between DP and Tofts parameters. Diagnostic performance was evaluated using receiver operating characteristic (ROC) curve analysis and quantified using the area under the ROC curve (AUC). Results showed that IDH-mutant gliomas were significantly lower in F (P = 0.018), PS (P < 0.001), Vp (P < 0.001), E (P < 0.001), and Ve (P = 0.002) than IDH-wildtype gliomas. In differentiating IDH-mutant and IDH-wildtype gliomas, Vp had the best performance (AUC = 0.92), and the AUCs of PS and E were 0.82 and 0.80, respectively. In comparison, Tofts parameters were lower in K trans (P = 0.013) and Ve (P < 0.001) for IDH-mutant gliomas. No significant difference was observed in Kep (P = 0.525). The AUCs of K trans, Ve, and Kep were 0.69, 0.79, and 0.55, respectively. Tofts-derived Ve showed a strong correlation with DP-derived Ve (r > 0.9, P < 0.001). K trans showed a weak correlation with F (r < 0.3, P > 0.16) and a very weak correlation with PS (r < 0.06, P > 0.8), both of which were not statistically significant. The findings by DP revealed a tissue environment with lower vascularity, lower vessel permeability, and lower blood flow in IDH-mutant than in IDH-wildtype gliomas, being hostile to cellular differentiation of oncogenic effects in IDH-mutated gliomas, which might help to explain the better outcomes in IDH-mutated glioma patients than in glioma patients of IDH-wildtype. The advantage of DP over Tofts in glioma DCE data analysis was demonstrated in terms of clearer elucidation of tissue microenvironment and better performance in IDH mutation assessment.

Magnetic nanowires in biomedical applications.

Magnetic nanostructures and nanomaterials play essential roles in modern bio medicine and technology. Proper surface functionalization of nanoparticles (NPs) allows the selective bonding thus application of magnetic forces to a vast range of cellular structures and biomolecules. However, the spherical geometry of NPs poises a series of limitations in various potential applications. Mostly, typical spherical core shell structure consists of magnetic and non-magnetic layers have little tunability in terms of magnetic responses, and their single surface functionality also limits chemical activity and selectivity. In comparison to spherical NPs, nanowires (NWs) possess more degrees of freedom in achieving magnetic and surface chemical tenability. In addition to adjustment of magnetic anisotropy and inter-layer interactions, another important feature of NWs is their ability to combine different components along their length, which can result in diverse bio-magnetic applications. Magnetic NWs have become the candidate material for biomedical applications owing to their high magnetization, cheapness and cost effective synthesis. With large magnetic moment, anisotropy, biocompatibility and low toxicity, magnetic NWs have been recently used in living cell manipulation, magnetic cell separation and magnetic hyperthermia. In this review, the basic concepts of magnetic characteristics of nanoscale objects and the influences of aspect ratio, composition and diameter on magnetic properties of NWs are addressed. Some underpinning physical principles of magnetic hyperthermia (MH), magnetic resonance imaging (MRI) and magnetic separation (MS) have been discussed. Finally, recent studies on magnetic NWs for the applications in MH, MRI and MS were discussed in detail.

Nephrogenic Systemic Fibrosis Risk Assessment and Skin Biopsy Quantification in Patients with Renal Disease following Gadobenate Contrast Administration.

BACKGROUND AND PURPOSE: Nephrogenic systemic fibrosis following administration of intravenous gadobenate during MR imaging is rare. This study aimed to analyze any nephrogenic systemic fibrosis-related risks and quantify skin gadolinium levels in patients with impaired renal function but without nephrogenic systemic fibrosis who had received gadobenate. MATERIALS AND METHODS: In this retrospective study with a prospective skin biopsy phase, patients with estimated glomerular filtration rates of <60 mL/min/1.73 m2 undergoing contrast-enhanced MR imaging from July 2007 through June 2014 were screened for nephrogenic systemic fibrosis using a questionnaire. This was highly sensitive but not specific and reliably excluded nephrogenic systemic fibrosis if responses to at least 6 of the 8 questions were negative. If no nephrogenic systemic fibrosis was detected, a skin biopsy was requested. RESULTS: Of 2914 patients who met these criteria, 1988 were excluded for various reasons. Of the remaining 926 patients, 860 were screened negative for nephrogenic systemic fibrosis. Of these, 17 (2%) had estimated glomerular filtration rates of <15 mL/min/1.73 m2, 51 (6%) had levels of 15 < 30 mL/min/1.73 m2, 234 (27%) had levels of 30 < 45 mL/min/1.73 m2, and 534 (62%) had levels of 45 < 60 mL/min/1.73 m2. Of the 66 who were not cleared of nephrogenic systemic fibrosis by the questionnaire, 6 patients were evaluated by a dermatologist and confirmed not to have nephrogenic systemic fibrosis (no biopsy required). CONCLUSIONS: A diagnosis of nephrogenic systemic fibrosis was excluded in 860 patients with impaired renal function who were followed up and received gadobenate during MR imaging. In 14 such patients who underwent at least 1 gadobenate-enhanced MR imaging examination and did not have nephrogenic systemic fibrosis, gadolinium levels in the skin were exceedingly low.

Assessment of neovascularization during bone healing using contrast-enhanced ultrasonography in a canine tibial osteotomy model: a preliminary study.

Blood perfusion of skeletal muscle and callus was evaluated using contrast-enhanced ultrasonography (CEUS) in a canine osteotomy model to determine the applicability of CEUS in the assessment of neovascularization during fracture healing and to compare the vascular signals on CEUS between external skeletal fixation and cast-applied dogs. In 6 Beagle dogs, a simple transverse osteotomy was performed at the left tibial shaft and external skeletal fixation (n = 3) or a cast (n = 3) was applied. Radiography, power Doppler ultrasonography (power Doppler), and CEUS were performed until complete union was achieved. On CEUS, vascular changes were quantitatively evaluated by measuring peak intensity (PI) and time to PI in the soft tissue and callus and by counting the vascular signals. Vascular signals from the soft tissue were detected on power Doppler and CEUS on day 2. Significantly more vascular signals were detected by CEUS than by power Doppler. On CEUS, PI in the surrounding soft tissue was markedly increased after the fracture line appeared indistinctively changed on radiography in all dogs. In the cast-applied dogs, vascular signals from the periosteal and endosteal callus were detected on CEUS before mineralized callus was observed on radiography. CEUS was useful in assessing the vascularity of soft tissue and callus, particularly in indirect fracture healing, and provided indications of a normally healing fracture.

Preliminary Assessment of a Microwave System to Detect Contrast Enhancing Agents.

This paper presents a preliminary study of the impact of potential contrast enhancing agents on a 2-port microwave imaging system. To this end, we have conducted microwave measurements inside a dual cylindrical tank, comprised of an outer and inner cylinder filled with high and low loss liquids, respectively. A third smaller cylinder inside the low loss filled tank represents a target. The target materials consisted of safflower oil, water, PEGylated zinc oxide nanoparticles dispersed in water, and saline with varying concentrations of salt. To benchmark our experimental results, we have also performed accurate numerical simulations of the system under three target scenarios: safflower oil, water, and PEGylated zinc oxide suspension. Our results show that the difference in received signal strength in scenarios with and without PEGylated zinc oxide nanoparticles in our 2-port system was comparable to measurement error. However, with the use of varying concentrations of saline solutions as a target, we have observed a significant difference in received signal strength.

Inferior vena cava assessment can predict contrast-induced nephropathy in patients undergoing cardiac catheterization: A single-center prospective study.

BACKGROUND: Contrast-induced nephropathy (CIN) following cardiac catheterization remains a considerable clinic challenge. Volume status is very important in the development of CIN. It can be assessed noninvasively by measuring inferior vena cava (IVC) diameters. The aim of this study was to assess whether IVC can be used for prediction of CIN in patient undergoing cardiac catheterization. METHODS: A total of 269 patients undergoing cardiac catheterization were prospectively enrolled in this study. IVC inspiratory and expiratory diameters were measured by transthoracic echocardiography. Caval index was calculated as the percentage decrease in the IVC diameter during respiration. CIN was defined as a ≥0.5 mg/dL and/or a ≥25% increase in serum creatinine within 72 hour post-procedure. RESULTS: Contrast-induced nephropathy developed in 46 (17.1%) patients after cardiac catheterization. Caval index was significantly higher in patients with CIN than in patients without CIN (47% [40-64] vs 35% [26-50], P < 0.001). In addition, the used contrast volume (145 [90-217] vs 70 [60-100], P < 0.001) and the frequency of percutaneous coronary intervention (50% vs 17.9%, P < 0.001) were significantly higher in patients with CIN than in patients without CIN. In receiver operating characteristic (ROC) curve analysis, caval index ≥ 41% predicted CIN with a specificity of 69% and sensitivity of 72%. Multivariate analysis indicated that caval index ≥ 41% was an independent predictor of post-procedural CIN development (OR: 3.367, 95% CI: 1.574-7.203, P = 0.002). CONCLUSIONS: Caval index, a simple and noninvasive echocardiographic marker, is an independent predictor of post-procedural CIN development in patients undergoing cardiac catheterization.

Different sample treatments for the determination of ICM-XR in fish samples followed by LC-HRMS.

Iodinated X-ray contrast media (ICM-XR) are a group of pharmaceuticals widely used in medicine. Due to their low biodegradation rate, which makes their removal at wastewater treatment plants difficult, and the high doses at which they are administered, they have been detected in aquatic environments. In the present paper, a method for the quantitative determination of a group of ICM-XR in different fish species was developed and validated for the first time. Two extraction techniques were compared: pressurised liquid extraction (PLE) and QuEChERS (Quick, Easy, Cheap, Effective, Rugged and Safe), with PLE being selected, followed by liquid chromatography-high resolution mass spectrometry. In addition, several clean-up strategies were evaluated. The optimised method provided PLE recoveries ranging from 60% to 88% and limits of detection ranging from 5ng/g to 25ng/g (dry weight). The method was applied in order to evaluate the presence of the selected ICM-XR in different fish species.

Effect of iodine contrast agent concentration on cerebrovascular dose for synchrotron radiation microangiography based on a simple mouse head model and a voxel mouse head phantom by Monte Carlo simulation.

Effective setting strategies using Monte Carlo simulation are presented to mitigate the irradiation damage in synchrotron radiation microangiography (SRA). A one-dimensional mouse head model and a segmented voxel phantom mouse head were simulated using the EGSnrc/DOSXYZnrc code to investigate the dose enhancement effect of an iodine contrast agent irradiated by a monochromatic synchrotron radiation source. The influence of the iodine concentration, vessel width and depth, protection with and without the skull layer, and various incident X-ray energies were all simulated. The dose enhancement effect and the absolute dose based on the segmented voxel mouse head phantom were evaluated. The dose enhancement ratio depended little on the irradiation depth, but strongly and linearly increasing on iodine concentration. The protection given by the skull layer cannot be ignored in SRA because a 700 µm-thick skull can decrease the dose by 10%. The incident X-ray energy can affect the dose significantly. Compared with a dose of 33.2 keV for 50 mgI ml(-1), a dose of 32.7 keV decreased by 38%, whereas a dose of 33.7 keV increased by 69.2% and the variation strengthened more with enhanced iodine concentration. The segmented voxel mouse head phantom also showed that the average dose enhancement effect and the maximal voxel dose per photon depended little on the iodine voxel volume ratio but strongly on the iodine concentration. To decrease the damage caused by the dose in SRA, a high-Z contrast agent should be used as little as possible and irradiation of the injection site of the contrast agent should be avoided immediately after the injection. The fragile vessel containing iodine should avoid being closely irradiated. Avoiding irradiating through a thin (or no) skull region, or attaching a thin equivalent material on the outside for protection are better methods. An incident X-ray energy as low as possible should be used as long as the SRA image quality is ensured. The use of the synergetic and synchronous shuttering technique in SRA is also very critical in order to effectively shorten the accumulative irradiation time in in vivo animal irradiation experiments.

Low-Cost, Disposable, Flexible and Highly Reproducible Screen Printed SERS Substrates for the Detection of Various Chemicals.

Ideal SERS substrates for sensing applications should exhibit strong signal enhancement, generate a reproducible and uniform response, and should be able to fabricate in large-scale and low-cost. Herein, we demonstrate low-cost, highly sensitive, disposable and reproducible SERS substrates by means of screen printing Ag nanoparticles (NPs) on a plastic PET (Polyethylene terephthalate) substrates. While there are many complex methods for the fabrication of SERS substrates, screen printing is suitable for large-area fabrication and overcomes the uneven radial distribution. Using as-printed Ag substrates as the SERS platform, detection of various commonly known chemicals have been done. The SERS detection limit of Rhodamine 6G (R6G) is higher than the concentration of 1 × 10(-10) M. The relative standard deviation (RSD) value for 784 points on the detection of R6G and Malachite green (MG) is less than 20% revealing a homogeneous SERS distribution and high reproducibility. Moreover, melamine (MA) is detected in fresh liquid-milk without additional pretreatment, which may accelerate the application of rapid on-line detection of MA in liquid milk. Our screen printing method highlights the use of large-scale printing strategies for the fabrication of well-defined functional nanostructures with applications well beyond the field of SERS sensing.

Qualitative environmental risk assessment of photolytic transformation products of iodinated X-ray contrast agent diatrizoic acid.

Recent studies have confirmed that the aquatic ecosystem is being polluted with an unknown cocktail of pharmaceuticals, their metabolites and/or their transformation products (TPs). Although individual chemicals are typically present at low concentrations, they can interact with each other resulting in additive or potentially even synergistic mixture effects. Therefore it is necessary to assess the environmental risk caused by these chemicals. Data on exposure is required for quantitative risk assessment of TPs and/or metabolites. Such data are mostly missing because of the non-availability of TPs and very often metabolites for experimental testing. This study demonstrates the application of different in silico tools for qualitative risk assessment using the example of photodegradation TPs (photo-TPs) of diatrizoic acid (DIAT), which itself is not readily biodegradable. Its photolytic transformation was studied and the photodegradation pathway was established. The aerobic biodegradability of photo-TPs under the conditions of an aquatic environment was assessed using standardized OECD tests. The qualitative risk assessment of DIAT and selected photo-TPs was performed by the PBT approach (i.e. Persistence, Bioaccumulation and Toxicity), using experimental biodegradation test assays, applying different QSAR models with several different toxicological endpoints and in silico read-across approaches. The qualitative risk assessment pointed out that the photo-TPs were less persistent compared to DIAT and none of them possessed any bioaccumulation threat. However, a few photo-TPs were predicted to be active for mutagenicity and genotoxicity, which indicate the need for further testing to confirm these predictions. The present study demonstrates that in silico qualitative risk assessment analysis can increase the knowledge space about the environmental fate of TPs.

An efficient approach for glomerular filtration rate assessment in older adults.

AIMS: Assessment of glomerular filtration rate (GFR) is crucial because the GFR value defines the stage of chronic kidney disease and determines the adjustment of drug dosage. The aim was to investigate a new method for the accurate determination of GFR in older adults based on the combination of an exogenous filtration marker, iohexol, and an endogenous marker, serum creatinine or cystatin C. METHODS: We combined variables for the estimation of GFR with a reduced set of measurements of the marker iohexol. In a population-based sample of 570 subjects (≥70 years old) from the Berlin Initiative Study (BIS), we investigated the following: (i) the BIS1 and BIS2 equations based on age, gender and serum creatinine with or without serum cystatin C; (ii) equations based on one or two iohexol measurements; and (iii) equations based on the combination of variables from BIS1 or BIS2 with iohexol measurements. The reference standard was based on eight iohexol measurements. The cut-off value of 60 ml min(-1) (1.73 m)(-2) was chosen to assess accuracy. Equations were constructed using a learning sample (n = 285) and an independent validation sample (n = 285). RESULTS: Misclassification rates were 17.2% (BIS1), 11.6% (BIS2), 14.7% [iohexol measurement at 240 min (iohexol240 )], 7.0% (iohexol240 combined with variables included in BIS1) and 6.7% (iohexol240 combined with variables included in BIS2). Misclassification rates did not decrease significantly after inclusion of two or three iohexol measurements. CONCLUSIONS: Combined strategies for the determination of GFR lead to a relevant increase of diagnostic validity.

EPR assessment of protein sites for incorporation of Gd(III) MRI contrast labels.

We have engineered apolipoprotein A-I (apoA-I), a major protein constituent of high-density lipoprotein (HDL), to contain DOTA-chelated Gd(III) as an MRI contrast agent for the purpose of imaging reconstituted HDL (rHDL) biodistribution, metabolism and regulation in vivo. This protein contrast agent was obtained by attaching the thiol-reactive Gd[MTS-ADO3A] label at Cys residues replaced at four distinct positions (52, 55, 76 and 80) in apoA-I. MRI of infused mice previously showed that the Gd-labeled apoA-I migrates to both the liver and the kidney, the organs responsible for HDL catabolism; however, the contrast properties of apoA-I are superior when the ADO3A moiety is located at position 55, compared with the protein labeled at positions 52, 76 or 80. It is shown here that continuous wave X-band (9 GHz) electron paramagnetic resonance (EPR) spectroscopy is capable of detecting differences in the Gd(III) signal when comparing the labeled protein in the lipid-free with the rHDL state. Furthermore, the values of NMR relaxivity obtained for labeled variants in both the lipid-free and rHDL states correlate to the product of the X-band Gd(III) spectral width and the collision frequency between a nitroxide spin label and a polar relaxation agent. Consistent with its superior relaxivity measured by NMR, the rHDL-associated apoA-I containing the Gd[MTS-ADO3A] probe attached to position 55 displays favorable dynamic and water accessibility properties as determined by X-band EPR. While room temperature EPR requires >1 m m Gd(III)-labeled and only >10 µ m nitroxide-labeled protein to resolve the spectrum, the volume requirement is exceptionally low (~5 µl). Thus, X-band EPR provides a practical assessment for the suitability of imaging candidates containing the site-directed ADO3A contrast probe.

In vivo multispectral photoacoustic and photothermal flow cytometry with multicolor dyes: a potential for real-time assessment of circulation, dye-cell interaction, and blood volume.

Recently, photoacoustic (PA) flow cytometry (PAFC) has been developed for in vivo detection of circulating tumor cells and bacteria targeted by nanoparticles. Here, we propose multispectral PAFC with multiple dyes having distinctive absorption spectra as multicolor PA contrast agents. As a first step of our proof-of-concept, we characterized high-speed PAFC capability to monitor the clearance of three dyes (Indocyanine Green [ICG], Methylene Blue [MB], and Trypan Blue [TB]) in an animal model in vivo and in real time. We observed strong dynamic PA signal fluctuations, which can be associated with interactions of dyes with circulating blood cells and plasma proteins. PAFC demonstrated enumeration of circulating red and white blood cells labeled with ICG and MB, respectively, and detection of rare dead cells uptaking TB directly in bloodstream. The possibility for accurate measurements of various dye concentrations including Crystal Violet and Brilliant Green were verified in vitro using complementary to PAFC photothermal (PT) technique and spectrophotometry under batch and flow conditions. We further analyze the potential of integrated PAFC/PT spectroscopy with multiple dyes for rapid and accurate measurements of circulating blood volume without a priori information on hemoglobin content, which is impossible with existing optical techniques. This is important in many medical conditions including surgery and trauma with extensive blood loss, rapid fluid administration, and transfusion of red blood cells. The potential for developing a robust clinical PAFC prototype that is safe for human, and its applications for studying the liver function are further highlighted.

Whole blood reflectance for assessment of hematologic condition and detection of angiographic contrast media.

We present simple whole blood reflectance analyses in the range 500-900 nm, using intact whole blood to simultaneously quantify hematocrit and oxygen saturation from a single spectral reading. We applied these results for the development of an intravascular catheter-based reflectance sensing system to detect and remove contrast media injected during angiography so as to reduce the risk of complications associated with the injected contrast media. We further tested the practicality of the optical detection of angiographic contrast media in a pilot animal study in vivo. We successfully demonstrated the feasibility of real-time in vivo contrast detection and removal during angiography. Our simple method for the detection and removal of angiographic contrast media will facilitate the development of intravascular optical sensing systems.

Development and evaluation of a liquid chromatography-mass spectrometry assay and its application for the assessment of renal function.

In the present study we evaluated two commonly used iodinated contrast agents, iohexol and iodixanol, as potential markers of impaired renal function. A reversed phase LC-MS method has been developed in order to separate and quantify the two substances. The assay was linear between 0.02 and 9.7 micromol/L for iohexol and between 0.4 and 49.3 micromol/L for iodixanol (r(2) > 0.998). The recovery during sample preparation ranged from 89.1 to 112.4%. The intra- and inter-assay RSD values were 3.06-13.6% for iohexol and 4.32-12.7% for iodixanol. The validated method was subsequently applied to 17 patients scheduled for angiographic procedure displaying normal and impaired renal function. A mixture of iohexol and iodixanol was intra-arterially injected and their corresponding plasma levels were determined periodically over a 24h period following administration. The elimination of both contrast agents followed by the LC-MS approach allowed us to discriminate between patients with normal and impaired renal function at 4, 8 and 24h after administration. Our preliminary results support the predictive value of iohexol and/or iodixanol clearance in a clinical environment to screen and identify patients at risk of developing CIN.

Development and validation of an HPLC-UV method for determination of iohexol in human plasma.

An HPLC-UV analytical method for estimation of iohexol in human plasma was developed and validated. Protein precipitation and iohexol extraction from plasma (100 microl) was carried out by adding 800 microl perchloric acid (5%, v/v in water) containing iohexol related compound B as the internal standard followed by vortex mixing and centrifugation. The supernatant (90 microl) was then injected onto a microBondapak C(18) column (150 mm x 3.9 mm, 10 microm) maintained at 30 degrees C. The mobile phase comprised of various proportions of acetonitrile and water with a total run time of 12 min and the wavelength of the UV detector was set at 254 nm. The extraction recovery of iohexol from plasma was >95% and the calibration curve was linear (r(2)=0.99) over iohexol concentrations ranging from 10 to 750 microg/ml (n=8). The method had an accuracy of >92% and intra- and inter-day CV of <3.7% and <3.6%, respectively. The method reported is simple, reliable, precise, accurate and has the capability of being used for determination of iohexol in clinical settings.