Magnetic relaxation contrast agents in magnetization transfer imaging

RATIONALE AND OBJECTIVES: The effects of magnetic relaxation agents are explored in the context of magnetization transfer pulse sequences using cross-linked protein gels as modeled tissue systems. METHODS: Magnetization transfer pulse sequences were used to study contrast agents that are designed to bind to rotationally immobilized protein targets. RESULTS: The dynamic range available from contrast agents, used in conjunction with magnetization transfer pulse sequences, is comparable with or better than that based on spin-echo imaging sequences with short repetition times. Furthermore, useful changes in the intensity of water resonances may be achieved by using this combined approach even though the paramagnetic metal center may not have a free coordination position in the chelate complex for water molecule exchange. CONCLUSIONS: The inclusion of magnetization transfer acquisition protocols in the context of magnetic imaging with contrast agents presents new opportunities for control of the information content of the image and for new classes of contrast agent structure and delivery.     

A cross-polarization magic-angle spinning 13C NMR characterization of the stable solid-state forms of cimetidine

Proton decoupled, cross-polarization magic-angle spinning 13C NMR spectra of four polymorphic forms (A, B, C, and D) and a monohydrate form (M1) of the histamine H2 antagonist cimetidine were obtained, and the chemical shifts of the various forms were tabulated. A modified polarization inversion pulse sequence was used to distinguish quaternary, methine, methylene, and methyl carbon resonances and thereby assist spectral assignment. It is also shown that the solid-state form of cimetidine in a commercial formulation can be reliably ascertained by NMR, despite the presence in the spectrum of signals from organic excipients that are much more intense than those from the compound.     

Expansion of transplanted hepatocytes during liver regeneration

A method for volume selective proton spectroscopy is presented based on a multiecho sequence with short refocusing interval tcp. It is demonstrated, that by appropriate choice of tcp on the order of 4-6 ms, signals from overlapping multiplets like the glutamine and glutamate (Glu/Gln) resonances in spectra of the human brain are considerably increased compared with a conventional PRESS volume selection scheme. Thus proton spectra from J-coupled multiplet signals can be acquired with TE on the order of 20-30 ms avoiding the baseline problems arising at shorter echo times due to broad resonances. This allows to selectively acquire spectra from substances with longer T2 without the confounding effects from J-coupling occurring in conventional volume selection techniques.     

Comparison of inversion recovery asymmetrical spin-echo EPI and gradient-echo EPI for brain motor activation study

An inversion recovery asymmetric spin-echo (IR-ASE) echo-planar imaging (EPI) sequence has been developed for functional studies of the brain. This technique uses an 180 degrees inversion pulse with a long inversion time (TI) to suppress the pulsatile cerebrospinal fluid and an asymmetric spin-echo readout to obtain activation signals from brain capillaries. Because gradient-echo sequences are most sensitive to large vessels, motor cortex activation studies using a gradient-echo technique also were conducted for comparison with the IR-ASE method. The results suggest that the IR-ASE pulse sequence may be a useful complement to the gradient-echo technique for the study of neuronal activity of the human brain.     

Comparison of conventional single echo and multi-echo sequences with a fast spin-echo sequence for quantitative T2 mapping: application to the prostate

The accuracy of water T2 maps generated from a fast spin-echo (FSE) sequence was compared with data obtained by conventional single and multi-echo spin-echo pulse sequences using a commercial gel phantom. Spatially localized stimulated echo acquisition mode (STEAM) proton spectroscopy was also used to confirm the reported water T2 values of the gels contained in the phantom. The FSE sequence was shown to be superior in accuracy to both the single and multi-echo spin echo sequences and comparable to STEAM, producing results that were within 10% of known values. The effectiveness of the FSE sequence was further demonstrated by generating T2 maps of the normal and diseased prostate in clinically acceptable imaging times, resulting in comparable T2 values to those obtained using STEAM. Accurate quantitative T2 maps can be produced with the FSE sequence.     

Biological activity and brain actions of recombinant rat interleukin-1alpha and interleukin-1beta

An HMQC experiment is proposed, dubbed FHMQC, where water flip-back is achieved by a single water-selective pulse preceding the basic HMQC pulse sequence. The scheme is demonstrated with a 15N,1H-HMQC spectrum of uniformly 15N/2H-labelled S. aureus DNA gyrase B with a molecular weight of 45 kDa for the unlabelled protein. The sensitivity of the experiment is improved compared to that of an FHSQC spectrum. It is further shown that the original FHSQC experiment can be shortened by the use of bipolar gradients. Relaxation times of different 15N magnetizations and coherences were measured. The new FHMQC scheme is implemented in 3D NOESY-15N-HMQC and 3D 15N-HMQC-NOESY-15N-HMQC pulse sequences which are demonstrated with a 24 kDa fragment of uniformly 15N/13C/2H-labelled S. aureus DNA gyrase B.     

Phase-modulated binomial RF pulses for fast spectrally-selective musculoskeletal imaging

Two fat-suppressed three-dimensional gradient echo pulse sequences, FLASH and DESS (Double Echo in Steady-State), that have significantly reduced scan time compared with conventional chemical shift fat-suppression sequences are presented. This fat-suppression technique is based on selectively exciting water spins using a time-optimized binomial RF pulse pair at the water resonance frequency with a null in the excitation profile at the fat frequency. To minimize the total pulse length, the delay between the binomial components of the RF pulse is decreased from a standard jump-return implementation. To maintain the proper null frequency, the phase of the second RF pulse is shifted such that it returns the fat resonance back to its initial z position while further tipping the water spins. Nonselective phase-modulated RF pulse pairs can be implemented in 1.20 ms at 1.0 T, significantly reducing the minimum TR.     

MR imaging of the brain: comparison of gradient-echo and spin-echo pulse sequences

OBJECTIVE: Gradient-echo pulse sequences can reduce imaging time and decrease motion artifacts. If gradient-echo pulse sequences are shown to be comparable to spin-echo sequences in MR imaging of the brain, then gradient-echo imaging can be valuable for examining critically ill, anxious, or uncooperative patients and can increase patient throughput. The purpose of this study was to prospectively compare one fast multiplanar spoiled gradient-recalled acquisition in the steady state (GRASS) (FMPSPGR) sequence with one conventional T1-weighted spin-echo sequence to determine the reliability of the FMPSPGR sequence for detecting cerebral lesions. SUBJECTS AND METHODS: Fifty-one patients with 142 cranial lesions, including brain tumors, infarction, infection, and noninflammatory lesions, were examined. Forty-two unenhanced and 39 contrast-enhanced FMPSPGR (113-240/2.6-3.6/90 degrees/4 [TR/TE/flip angle/acquisitions]) and spin-echo T1-weighted (400-579/11-12/90 degrees/2) MR images of the head were obtained with a 1.5-T system. The visibility, margination, and extent of the lesions; image quality; contrast; and artifacts were qualitatively and quantitatively compared. RESULTS: Supratentorial lesions were more conspicuous on the unenhanced FMPSPGR images because of the higher signal-to-noise ratio of the normal brain resulting in higher lesion contrast. The higher contrast-to-noise ratio of neoplasms on the contrast-enhanced spin-echo images was not found to be significant in the independent qualitative analysis. The conspicuity and extent of other lesions evaluated with the two pulse sequences were not significantly different for either the unenhanced or the contrast-enhanced studies. Vascular pulsation artifacts were significantly reduced on the contrast-enhanced FMPSPGR images. Susceptibility and chemical-shift phase-cancellation artifacts were more pronounced on the FMPSPGR images. CONCLUSION: The FMPSPGR sequence provides high-quality images with fewer vascular pulsation artifacts three to four times faster than the spin-echo sequence. The FMPSPGR sequence can reliably show intracranial lesions and can substitute for the T1-weighted spin-echo sequence in routine brain imaging.     

New pulse sequences for T1- and T1/T2-contrast enhancing in NMR imaging

Improved pulse sequences DIFN (abbreviation of the words: DIFferentiation by N pulses), 90 degrees - tau1 - 180 degrees tau1 - . . . 180 degrees - tau1 with optimised time intervals tau1- for T1 measurement and contrast enhancing in NMR imaging are presented. The pulse sequences DIFN have a better sensitivity to T1 than the well-known pulse sequence SR. In contrast to the IR pulse sequence, the information given by the DIFN pulse sequence is more reliable, because the NMR signal does not change its sign. For a given time interval tau0 < or = (0.1 - 0.3) T(1) the DIFN pulse sequences serve as T1-filters. They pass the signal components with relatively short T1 < T(1) and suppress the components with relatively long T1 < T(1). The effects of the radiofrequency field inhomogeneity and inaccurate adjusting of pulse lengths are also considered. It is also proposed in this work to use the joint T1T2-contrast in NMR imaging obtained as a result of applying the DIFN pulse sequences in combination with the well-known Carr-Purcell-Meiboom-Gill (CPMG) pulse sequence. The region of interest, where the contrast should be especially enhanced, is specified by the two times at which measurements are performed, which allow the amplitudes of pixels to reach some defined levels by spin-lattice and spin-spin relaxation.     

Quantitative diffusion coefficient maps using fast spin-echo MRI

In this work, we have evaluated the performance of a diffusion-sensitive fast spin-echo (FSE) pulse sequence. The proposed pulse sequence utilises velocity-compensating diffusion-encoding gradients and includes the collection of navigator echoes. Spoiler gradients were inserted in the slice-selecting direction to minimise effects from stimulated echoes. Calculations of the b values showed that cross-terms between imaging gradients and diffusion gradients only led to a marginal increase of b values. Pixel-wise calculation of apparent diffusion coefficient (ADC) maps was performed numerically, considering cross-terms between diffusion-encoding and imaging gradients. The sequences investigated used echo train lengths of 16, 8 and 4 echoes and were encoded in either the slice-, frequency- or phase-encoding direction. In order to allow for higher b values a pulse-sequence version using non-motion compensating diffusion-encoding gradients was written. Phantom measurements were performed and the diffusion coefficients of water and acetone were reasonable. Seven healthy volunteers (age 28-50 years) were examined and apparent diffusion coefficient values agreed well with expected values. Diffusion-weighted images, apparent diffusion coefficient maps and images corresponding to the trace of the diffusion tensor of good quality were retrieved in vivo.     

High-resolution mono- and multidimensional magic angle spinning 1H nuclear magnetic resonance of membrane peptides in nondeuterated lipid membranes and H2O

High-speed (14 kHz) solid-state magic angle spinning (MAS) 1H NMR has been applied to several membrane peptides incorporated into nondeuterated dilauroyl or dimyristoylphosphatidylcholine membranes suspended in H2O. It is shown that solvent suppression methods derived from solution NMR, such as presaturation or jump-return, can be used to reduce water resonance, even at relatively high water content. In addition, regioselective excitation of 1H peptide resonances promotes an efficient suppression of lipid resonances, even in cases where these are initially two orders of magnitude more intense. As a consequence, 1H MAS spectra of the peptide low-field region are obtained without interference from water and lipid signals. These display resonances from amide and other exchangeable 1H as well as from aromatic nonexchangeable 1H. The spectral resolution depends on the specific types of resonance and membrane peptide. For small amphiphilic or hydrophobic oligopeptides, resolution of most individual amide resonance is achieved, whereas for the transmembrane peptide gramicidin A, an unresolved amide spectrum is obtained. Partial resolution of aromatic 1H occurs in all cases. Multidimensional 1H-MAS spectra of membrane peptides can also be obtained by using water suppression and regioselective excitation. For gramicidin A, F2-regioselective 2D nuclear Overhauser effect spectroscopy (NOESY) spectra are dominated by intermolecular through-space connectivities between peptide aromatic or formyl 1H and lipid 1H. These appear to be compatible with the known structure and topography of the gramicidin pore. On the other hand, for the amphiphilic peptide leucine-enkephalin, F2-regioselective NOESY spectra mostly display cross-peaks originating from though-space proximities of amide or aromatic 1H with themselves and with aliphatic 1H. F3-regioselective 3D NOESY-NOESY spectra can be used to obtain through-space correlations within aliphatic 1H. Such intrapeptide proximities should allow determination of the conformation of the peptide in membranes. It is suggested that high-speed MAS multidimensional 1H NMR of peptides in nondeuterated membranes and in H2O can be used for studies of both peptide structure and lipid-peptide interactions.     

Efficacy of the TURBO-fluid attenuated inversion recovery spin echo sequence of MRI as a preoperative neuroradiological examination]

Whenever the extirpation of intracranial tumors is planned, neurosurgeons always keep their eyes on the cerebrospinal fluid (CSF) space around intracranial tumors. If enough space exists in the neighborhood of the tumors, the damage to adjacent parenchyma may be reduced by the procedure through the CSF space. A newly advanced MRI pulse sequence: the FLAIR (fluid attenuated inversion recovery) imaging, in which a long TE spin echo sequence is used with suppression of the CSF with an inversion pulse, displays the CSF space as a no-signal intensity area. There have been only a few reports, however, on the FLAIR pulse sequence of brain tumors as yet. We examined 34 cases of intracranial tumors by FLAIR images and analyzed the advantages and disadvantages of the FLAIR pulse sequence for decision making on tumor removal. Making use of the FLAIR pulse sequence, the CSF space is depicted as a no-signal intensity area and much more information about perifocal edema and the invasion area around the tumors can be provided than that provided by the other ordinary pulse sequences (T1 weighted images, T2 weighted images and Proton weighted images). Therefore, operative strategies can be more easily worked out on the FLAIR images. Furthermore, the difference between arachnoid and epidermoid is able to be detected on the FLAIR images. Nevertheless, on FLAIR images, the tumors without perifocal edema or invasion to adjacent parenchyma were not apparent and the difference between tumoral dissemination into multi-ventricular space and the periventricular artifact of FLAIR images could not be distinguished. The FLAIR pulse sequence has other artifacts like intraventricular flow related enhancement and so on. If the images are carefully checked up on the above-mentioned points, the FLAIR pulse sequence of MRI can not fail to be useful in making plans for operations on intracranial neoplasms.     

MAGE, BAGE and GAGE: tumour antigen expression in benign and malignant ovarian tissue

An iterative method for differentiating between known resonances and uncharacterized baseline contributions in MR spectra is described. The method alternates parametric modeling, using a priori knowledge of spectral parameters, with non-parametric characterization of remaining signal components, using wavelet shrinkage and denoising. Rapid convergence of the iterative method is demonstrated, and examples are shown for analysis of simulated data and an in vivo 1H spectrum from the brain. Results show good separation between metabolite signals and strong baseline contributions.     

Phase labeling of C-H and C-C spin-system topologies: application in PFG-HACANH and PFG-HACA(CO)NH triple-resonance experiments for determining backbone resonance assignments in proteins

Triple-resonance experiments can be designed to provide useful information on spin-system topologies. In this paper we demonstrate optimized proton and carbon versions of PFG-CT-HACANH and PFG-CT-HACA(CO)NH 'straight-through' triple-resonance experiments that allow rapid and almost complete assignments of backbone H(alpha), 13C(alpha), 15N and H(N) resonances in small proteins. This work provides a practical guide to using these experiments for determining resonance assignments in proteins, and for identifying both intraresidue and sequential connections involving glycine residues. Two types of delay tunings within these pulse sequences provide phase discrimination of backbone Gly C(alpha) and H(alpha) resonances: (i) C-H phase discrimination by tuning of the refocusing period tau(a_f); (ii) C-C phase discrimination by tuning of the 13C constant-time evolution period 2T(c). For small proteins, C-C phase tuning provides better S/N ratios in PFG-CT-HACANH experiments while C-H phase tuning provides better S/N ratios in PFG-CT-HACA(CO)NH. These same principles can also be applied to triple-resonance experiments utilizing 13C-13C COSY and TOCSY transfer from peripheral side-chain atoms with detection of backbone amide protons for classification of side-chain spin-system topologies. Such data are valuable in algorithms for automated analysis of resonance assignments in proteins.     

Biological and clinical MRS at ultra-high field

The advantages of performing spectroscopic studies at higher field strengths include increased SNR, improved spectral resolution for J-coupled resonances, and improvements in the selectivity of spectral editing schemes. By using pulse sequences that minimize the required echo time, refocus J-evolution, employ low peak B1 requiring pulses and take advantage of spectroscopic imaging methods, these advantages can also be utilized in clinical applications of spectroscopy at high field. In addition to the static measurements measurements of N-acetyl aspartate (NAA), creatine (CR) and choline (CH) which can be performed at 1.5 T, high resolution measurements of glutamate, glutamine, GABA and the incorporation of 13C labeled glucose into glutamate are possible with improved spatial and spectral resolution. These methods have been utilized in patients with seizure disorders and multiple sclerosis to identify, characterize and map the metabolic changes associated with these diseases and their treatment.     

Clinical studies of oral antiemetic drugs on delayed emesis induced by cancer chemotherapy]

BACKGROUND AND PURPOSE: Our purpose was to develop a classification scheme and method of presentation of in vivo single-voxel proton spectroscopic data from astrocytomas that most closely match the classification scheme determined from biopsy specimens. Since in vivo proton spectroscopy is noninvasive, it may be an attractive alternative to intracranial biopsy. METHODS: Single-voxel spectra were acquired using the point-resolved spectroscopic pulse sequence as part of the Probe spectroscopy package on a G.E. 1.5-T Signa scanner. Subjects consisted of 27 patients with biopsy-confirmed brain tumors (13 with glioblastoma multiforme, six with anaplastic astrocytoma, and eight with low-grade astrocytoma). The patients were divided into groups based on the histologic subtype of their tumor for different treatment protocols. RESULTS: Metabolic peak areas were normalized for each metabolite (choline, creatine, N-acetylaspartate, lactate) to the area of the unsuppressed water peak and to the area of the creatine peak. Kruskal-Wallis nonparametric analysis of variance (ANOVA) tests showed statistically significant differences among the tumor groups for all the area ratios. The lactate/water ratio could be used to distinguished all three tumor groups, whereas the choline/water ratio distinguished low-grade astrocytomas from the two high-grade groups. Both the choline and lactate ratios could be used to separate the high-grade from the low-grade tumors. CONCLUSION: Specific relative metabolic peak area ratios acquired from regions of contrast-enhancing brain tumor can be used to classify astrocytomas as to histopathologic grade.     

Identification of exon sequences involved in splice site selection

The involvement of exon sequences in splice site selection was studied in vivo in HeLa cells transfected with a series of model three exon-two intron pre-mRNAs which differed only in the sequence of their internal exons. When the majority of the human globin-derived 175-nucleotide internal exon (DUP175) was replaced with a sequence from the yeast URA3 gene (DUP184), the splicing pathway changed from complete inclusion of the internal exon in DUP175 to its predominant skipping in the DUP184 construct. Skipping of the exon was reversed by increasing the strength of its flanking splicing elements indicating that exon sequences exert their effect only in the presence of relatively weak splicing signals. A series of block mutations in the internal exon of DUP184 showed that a stretch of 6 cytidine nucleotides increased the inclusion of the DUP184 internal exon about 7-fold. Mutations generating purine-rich sequences (AAG and GAAG) at the 3' end of the exon led to complete exon inclusion while stepwise insertion of sequences from the internal exon of DUP175 into the DUP184 background increased exon inclusion 5-fold. Combination of the stretch of cytidines with sequences derived from DUP175 exon resulted in complete exon inclusion indicating that diverse signals within exons may cooperate with each other in affecting splice site selection.