4D-DSA: Development and Current Neurovascular Applications.

Originally described by Davis et al in 2013, 4D-Digital Subtraction Angiography (4D-DSA) has developed into a commercially available application of DSA in the angiography suite. 4D-DSA provides the user with 3D time-resolved images, allowing observation of a contrast bolus at any desired viewing angle through the vasculature and at any time point during the acquisition (any view at any time). 4D-DSA mitigates some limitations that are intrinsic to both 2D- and 3D-DSA images. The clinical applications for 4D-DSA include evaluations of AVMs and AVFs, intracranial aneurysms, and atherosclerotic occlusive disease. Recent advances in blood flow quantification using 4D-DSA indicate that these data provide both the velocity and geometric information necessary for the quantification of blood flow. In this review, we will discuss the development, acquisition, reconstruction, and current neurovascular applications of 4D-DSA volumes.

Optimizing the Quality of 4D-DSA Temporal Information.

BACKGROUND AND PURPOSE: Quantification of blood flow using a 4D-DSA would be useful in the diagnosis and treatment of cerebrovascular diseases. A protocol optimizing identification of density variations in the time-density curves of a 4D-DSA has not been defined. Our purpose was to determine the contrast injection protocol most likely to result in the optimal pulsatility signal strength. MATERIALS AND METHODS: Two 3D-printed patient-specific models were used and connected to a pulsatile pump and flow system, which delivered 250-260 mL/min to the model. Contrast medium (Isovue, 370 mg I/mL, 75% dilution) was injected through a 6F catheter positioned upstream from the inlet of the model. 4D-DSA acquisitions were performed for the following injection rates: 1.5, 2.0, 2.5, 3.0 and 3.5 mL/s for 8 seconds. To determine pulsatility, we analyzed the time-density curve at the inlets using the oscillation amplitude and a previously described numeric metric, the sideband ratio. Vascular geometry from 4D-DSA reconstructions was compared with ground truth and micro-CT measurements of the model. Dimensionless numbers that characterize hemodynamics, Reynolds and Craya-Curtet, were calculated for each injection rate. RESULTS: The strongest pulsatility signal occurred with the 2.5 mL/s injections. The largest oscillation amplitudes were found with 2.0- and 2.5-mL/s injections. Geometric accuracy was best preserved with injection rates of >1.5 mL/s. CONCLUSIONS: An injection rate of 2.5 mL/s provided the strongest pulsatility signal in the 4D-DSA time-density curve. Geometric accuracy was best preserved with injection rates above 1.5 mL/s. These results may be useful in future in vivo studies of blood flow quantification.

Quantification of Blood Velocity with 4D Digital Subtraction Angiography Using the Shifted Least-Squares Method.

BACKGROUND AND PURPOSE: 4D-DSA provides time-resolved 3D-DSA volumes with high temporal and spatial resolutions. The purpose of this study is to investigate a shifted least squares method to estimate the blood velocity from the 4D DSA images. Quantitative validation was performed using a flow phantom with an ultrasonic flow probe as ground truth. Quantification of blood velocity in human internal carotid arteries was compared with measurements generated from 3D phase-contrast MR imaging. MATERIALS AND METHODS: The centerlines of selected vascular segments and the time concentration curves of each voxel along the centerlines were determined from the 4D-DSA dataset. The temporal shift required to achieve a minimum difference between any point and other points along the centerline of a segment was calculated. The temporal shift as a function of centerline point position was fit to a straight line to generate the velocity. The proposed shifted least-squares method was first validated using a flow phantom study. Blood velocities were also estimated in the 14 ICAs of human subjects who had both 4D-DSA and phase-contrast MR imaging studies. Linear regression and correlation analysis were performed on both the phantom study and clinical study, respectively. RESULTS: Mean velocities of the flow phantom calculated from 4D-DSA matched very well with ultrasonic flow probe measurements with 11% relative root mean square error. Mean blood velocities of ICAs calculated from 4D-DSA correlated well with phase-contrast MR imaging measurements with Pearson correlation coefficient r = 0.835. CONCLUSIONS: The availability of 4D-DSA provides the opportunity to use the shifted least-squares method to estimate velocity in vessels within a 3D volume.

The effect of sulfur nutrition on plant glucosinolate content: physiology and molecular mechanisms.

Glucosinolates are sulfur-rich plant metabolites of the order Brassicales that function in the defense of plants against pests and pathogens. They are also important in human society as flavor components, cancer-prevention agents, and crop biofumigants. Since glucosinolates may represent up to 30 % of the total sulfur content of plant organs, their accumulation should depend intimately on the sulfur status of the entire plant. Here we review the literature on how sulfur supply affects glucosinolate content. In field and greenhouse experiments involving soil, hydroponic and tissue culture media, sulfur fertilisation usually led to an increase in glucosinolate content ranging from 25 % to more than 50-fold, depending on the plant species, amount of sulfur applied, and type of treatment. The effect was greater on glucosinolates derived from the sulfur amino acid, methionine, than on glucosinolates derived from tryptophan. These changes are regulated not by simple mass action effects, but by extensive changes in gene transcription. In sulfur-deficient plants, there is a general down-regulation of glucosinolate biosynthetic genes which accompanies an up-regulation of genes controlling sulfur uptake and assimilation. Glucosinolates may be considered a potential source of sulfur for other metabolic processes under low-sulfur conditions, since increased breakdown of glucosinolates has been reported under sulfur deficiency. However, the pathway for sulfur mobilisation from glucosinolates has not been determined. The breakdown of indolic glucosinolates to form auxin in roots under sulfur-deficient conditions may help stimulate root formation for sulfur uptake.

A gene controlling variation in Arabidopsis glucosinolate composition is part of the methionine chain elongation pathway.

Arabidopsis and other Brassicaceae produce an enormous diversity of aliphatic glucosinolates, a group of methionine (Met)-derived plant secondary compounds containing a beta-thio-glucose moiety, a sulfonated oxime, and a variable side chain. We fine-scale mapped GSL-ELONG, a locus controlling variation in the side-chain length of aliphatic glucosinolates. Within this locus, a polymorphic gene was identified that determines whether Met is extended predominantly by either one or by two methylene groups to produce aliphatic glucosinolates with either three- or four-carbon side chains. Two allelic mutants deficient in four-carbon side-chain glucosinolates were shown to contain independent missense mutations within this gene. In cell-free enzyme assays, a heterologously expressed cDNA from this locus was capable of condensing 2-oxo-4-methylthiobutanoic acid with acetyl-coenzyme A, the initial reaction in Met chain elongation. The gene methylthioalkylmalate synthase1 (MAM1) is a member of a gene family sharing approximately 60% amino acid sequence similarity with 2-isopropylmalate synthase, an enzyme of leucine biosynthesis that condenses 2-oxo-3-methylbutanoate with acetyl-coenzyme A.

A multicenter clinical trial of Gadolite Oral Suspension as a contrast agent for MRI.

The purpose of this study was to assess the effectiveness and safety of Gadolite Oral Suspension as a gastrointestinal (GI) contrast agent for MRI in a phase II and two phase III multicenter clinical trials. Gadolite was administered to 306 patients with known or suspected abdominal and/or pelvic disease. MRI with T1- and T2-weighted sequences was performed before and after ingestion. Efficacy was evaluated by having two masked readers rate the certainty of their MR diagnosis (0 = uncertain, 1 = probable, 2 = definite) on randomly presented pre- and post-Gadolite Oral Suspension enhanced images. Principal investigators also evaluated the images and established the final diagnosis. Vital signs, clinical chemistries, and adverse events were documented. Blood and urine samples were analyzed for gadolinium content to determine whether Gadolite Oral Suspension was absorbed systemically. Certainty in MR diagnosis increased significantly (P < .001) for both blinded readers between pre- and post-Gadolite images (.49-1.18 for reader 1: .46-1.53 for reader 2). Sensitivity, specificity, and accuracy also increased for both masked readers. No gadolinium was detected in blood or urine samples. There were no serious adverse events and no apparent drug-related trends in mean vital signs or laboratory values. Gadolite is a highly effective, safe, and well tolerated contrast agent for clinical use with MRI.

Coenzyme A biosynthesis in plants: partial purification and characterization of pantothenate kinase from spinach.

A study of the biosynthesis of coenzyme A (CoA), a critical cofactor in the metabolism of lipids and other molecules in higher plants, was initiated. Pantothenate kinase was partially purified from spinach leaves. This enzyme was predominantly localized in the chloroplast with very little activity observed in the mitochondria or cytosol. DEAE-agarose chromatography resolved two pantothenate kinase activity peaks which differed in their requirement for reductant, stability upon boiling, and reactivity in the presence of spinach holo-acyl carrier protein (ACP) I. One active peak of this enzyme was further purified on Cibacron blue 3GA to yield a preparation containing pantothenate kinase enriched to 20% of the total protein within the fraction. Pantothenate kinase was inhibited by malonyl-CoA, but not by CoASH or acetyl-CoA, and the activity was stabilized by the phosphatase inhibitors sodium molybdate, sodium tungstate, and the phosphatase substrate glycerol 2-phosphate, but was inhibited by sodium fluoride. Further experiments demonstrated a linear increase in pantothenate kinase activity during spinach seed germination, consistent with a role for this enzyme in the developmental utilization of seed triacylglycerol.

Cardiovascular evaluation in Turner syndrome: utility of MR imaging.

Forty patients with karyotypically proven Turner syndrome were prospectively studied using magnetic resonance imaging (MRI) and echocardiography in order to determine the frequency of cardiovascular anomalies and to assess the utility of both imaging modalities as methods for cardiovascular evaluation in Turner syndrome. Cardiovascular anomalies were found in 45% of patients. A high absolute prevalence of bicuspid aortic valve (17.5%) and aortic coarctation (12.5%) were observed relative to comparable series. Of clinically significant abnormalities, three of five aortic coarctations and four of five ascending aortic dilatations were solely MRI detected and not evident at echocardiographic examination. MRI is thus seen as a valuable adjunct to echocardiography in the cardiovascular evaluation of Turner syndrome patients. The usefulness of MRI primarily relates to its ability to provide excellent visualisation of the entire thoracic aorta where a large proportion of clinically significant anomalies occur in Turner syndrome.

Metabolism of Monoterpenes in Cell Cultures of Common Sage (Salvia officinalis) : Biochemical Rationale for the Lack of Monoterpene Accumulation.

Leaves of common sage (Salvia officinalis) accumulate monoterpenes in glandular trichomes at levels exceeding 15 milligrams per gram fresh weight at maturity, whereas sage cells in suspension culture did not accumulate detectable levels of monoterpenes (<0.3 nanograms per gram fresh weight) at any stage of the growth cycle, even in the presence of a polystyrene resin trap. Monoterpene biosynthesis from [U-(14)C]sucrose was also virtually undetectable in this cell culture system. In vitro assay of each of the enzymes required for the sequential conversion of the ubiquitous isoprenoid precursor geranyl pyrophosphate to (+)-camphor (a major monoterpene product of sage) in soluble extracts of the cells revealed the presence of activity sufficient to produce (+)-camphor at a readily detectable level (>0.3 micrograms per gram fresh weight) at the late log phase of growth. Other monoterpene synthetic enzymes were present as well. In vivo measurement of the ability to catabolize (+)-camphor in these cells indicated that degradative capability exceeded biosynthetic capacity by at least 1000-fold. Therefore, the lack of monoterpene accumulation in undifferentiated sage cultures could be attributed to a low level of biosynthetic activity (relative to the intact plant) coupled to a pronounced capacity for monoterpene catabolism.