PubMed Health⌕ Search

Biomedical subjects

Howard J Halpern

Publications and source records attributed to Howard J Halpern.

15 recordsLinked to original sources

Spatially uniform sampling in 4-D EPR spectral-spatial imaging.

Four-dimensional EPR imaging involves a computationally intensive inversion of the sampled Radon transform. Conventionally, N-dimensional reconstructions have been carried out with N-1 stages of 2-D backprojection to exploit a dimension-dependent reduction in execution time. The huge data size of 4-D EPR imaging demands the use of a 3-stage reconstruction each consisting of 2-D backprojections. This gives three orders of magnitude reduction in computation relative to a single stage 4-D filtered backprojection. The multi-stage reconstruction, however, requires a uniform angular sampling that yields an inefficient distribution of gradient directions. We introduce a solution that involves acquisition of projections uniformly distributed in solid angle and reconstructs in three 2-D stages with the spatial uniform solid angle data set converted to uniform linear angular projections using 2-D interpolation. Images were taken from the two sampling schemes to compare the spatial resolution and the line width resolution. The degradation in the image quality due to the additional interpolation was small, and we achieved approximately 30% reduction in data acquisition time.

Algorithms↗

Electron paramagnetic resonance oxygen images correlate spatially and quantitatively with Oxylite oxygen measurements.

Tumor oxygenation predicts cancer therapy response and malignant phenotype. This has spawned a number of oxymetries. Comparison of different oxymetries is crucial for the validation and understanding of these techniques. Electron paramagnetic resonance (EPR) imaging is a novel technique for providing quantitative high-resolution images of tumor and tissue oxygenation. This work compares sequences of tumor pO2 values from EPR oxygen images with sequences of oxygen measurements made along a track with an Oxylite oxygen probe. Four-dimensional (three spatial and one spectral) EPR oxygen images used spectroscopic imaging techniques to measure the width of a spectral line in each image voxel from a trityl spin probe (OX063, Amersham Health R&D) in the tissues and tumor of mice after spin probe injection. A simple calibration allows direct, quantitative translation of each line width to an oxygen concentration. These four-dimensional EPR images, obtained in 45 minutes from FSa fibrosarcomas grown in the legs of C3H mice, have a spatial resolution of approximately 1 mm and oxygen resolution of approximately 3 Torr. The position of the Oxylite track was measured within a 2-mm accuracy using a custom stereotactic positioning device. A total of nine images that involve 17 tracks were obtained. Of these, most showed good correlation between the Oxylite measured pO2 and a track located in the tumor within the uncertainties of the Oxylite localizability. The correlation was good both in terms of spatial distribution pattern and pO2 magnitude. The strong correlation of the two modalities corroborates EPR imaging as a useful tool for the study of tumor oxygenation.

Animals↗

Spin echo spectroscopic electron paramagnetic resonance imaging.

The use of spin echoes to obtain spectroscopic EPR images (spectral-spatial images) at 250 MHz is described. The advantages of spin echoes-larger signals than the free induction decay, better phase characteristics for Fourier transformation, and decay shapes undistorted by instrumental dead time-are clearly shown. An advantage is gained from using a crossed loop resonator that isolates the 250-W pump power by greater than 50 dB from the observer arm preamplifiers. The echo decay rates can be used to determine the oxygen content in solutions containing 1 mM trityl concentrations. Two- and three-dimensional images of oxygen concentration are presented.

Electron Spin Resonance Spectroscopy↗

Reduction of image artifacts in mice by bladder flushing with a novel double-lumen urethral catheter.

In electron paramagnetic resonance imaging (EPRI), the accumulation of contrast agent in the bladder can create a very large source of signal, often far greater than that of the organ of interest. Mouse model images have become increasingly important in preclinical testing. To minimize bladder accumulation on mouse images, we developed a novel, minimally invasive, MRI/EPRI-friendly procedure for flushing a female mouse bladder. It is also applicable to other imaging techniques, for example, PET, SPECT, etc., where contrast agent accumulation in the bladder is also undesirable. A double-lumen urethral catheter was developed, using a standard IV catheter with a silicone tube extension, having a polyethylene tube threaded into the IV catheter. Flushing of the bladder provides a substantial reduction in artifacts, as shown in images of tumors in mice.

Administration, Intravesical↗

EPR imaging: the relationship between CW spectra acquired from an extended sample subjected to fixed stepped gradients and the Radon transform of the resonance density.

EPR spectroscopy can be extended to a spectroscopic imaging modality by applying magnetic field gradients across the sample to encode spatial information in the measured spectra. In this work, we present a mathematical model of the EPR imaging process in terms of the Radon transform. We describe a model for electron paramagnetic resonance imaging, derive its explicit relationship to the Radon transform, and discuss several options for reconstructing the sample absorption and dispersion densities. An important extension to previous descriptions is the incorporation of large amplitude magnetic field modulation, which can be used to improve the signal-to-noise ratio for continuous wave signal acquisition. Magnetic field modulation is shown to cause well understood changes in the shapes of spectra in the reconstructed images, but does not affect the spatial resolution achieved in these images. Since many of the novel image reconstruction strategies and noise filtering algorithms that have been developed for other modalities start from this formalism, this work allows for their direct application to EPR imaging. This promises to lead to further improvements in EPR imaging techniques.

Algorithms↗

Influence of conformation on the EPR spectrum of 5,5-dimethyl-1-hydroperoxy-1-pyrrolidinyloxyl: a spin trapped adduct of superoxide.

Spin trapping, a technique used to characterize short-lived free radicals, consists of using a nitrone or nitroso compound to "trap" an unstable free radical as a long-lived aminoxyl that can be characterized by EPR spectroscopy. The resultant aminoxyl exhibits hyperfine splitting constants that are dependent on the spin trap and the free radical. Such is the case with 2,2-dimethyl-5-hydroxy-1-pyrrolidinyloxyl (DMPO-OH) and 2,2-dimethyl-5-hydroperoxy-1-pyrrodinyloxyl (DMPO-OOH) whose hyperfine splitting constants, A(N) = A(H) = 14.9 G and A(N) = 14.3 G, A(H)(beta) = 11.7 G, and A(H)(gamma) = 1.25 G, respectively, have been used to demonstrate the generation of HO(*) and O(2)(*)(-). However, to date, the source of the apparent A(H)(gamma) hyperfine splitting in DMPO-OOH is not known. We consider three possible explanations to account for the unique EPR spectrum of DMPO-OOH. The first is that the gamma-splitting arises from one of the hydrogen atoms at either carbon 3 or carbon 4 of DMPO-OOH. The second is that the gamma-splitting originates from the hydrogen atom of DMPO-OOH. The third is that the conformational properties of DMPO-R change upon going from DMPO-OH to DMPO-OOH. Experimental and theoretical chemical approaches as well as EPR spectral modeling were used to investigate which of these hypotheses may explain the asymmetric EPR spectrum of DMPO-OOH. From these studies it is shown that the 12-line EPR spectrum of DMPO-OOH results not from any proximal hydrogen, but from additional conformers of DMPO-OOH. Thus, the 1.25 G hyperfine splitting, which has been assigned as a gamma-splitting, is actually from two individual EPR spectra associated with different conformers of DMPO-OOH.

Electron Spin Resonance Spectroscopy↗

Nitroxide conjugate of a thermally responsive elastin-like polypeptide for noninvasive thermometry.

Hyperthermia, as an adjuvant with radiation and chemotherapy, has shown promise in the treatment of cancer. The relevant biological effects of a hyperthermia treatment are both time and temperature-dependent, creating a need for accurate thermometry. We present a novel noninvasive thermometry modality that combines a temperature responsive biopolymer, the elastin-like polypeptide (ELP), and nitroxide to produce an ELP-nitroxide conjugate. When examined with electron paramagnetic resonance (EPR) spectroscopy, the ELP-nitroxide conjugate has temperature-dependent spectral line widths whose predictive accuracy is approximately 0.3 degrees C (80 microM). We believe that the temperature-dependent changes observed in the EPR spectrum are due to the combined effect of temperature, viscosity and effective radius on the rotational correlation time of the ELP-nitroxide conjugate.

Biocompatible Materials↗

Esters of 5-carboxyl-5-methyl-1-pyrroline N-oxide: a family of spin traps for superoxide.

Apparent rate constants, at acidic pH and neutral pH for the reaction of a family of ester-containing 5-carboxyl-5-methyl-1-pyrroline N-oxides with superoxide (O2*-) were estimated, using ferricytochrome c as a competitive inhibitor. It was of interest to note that the rate constants were similar among the different nitrones and not that significantly different from that found for 5-(diethoxyphosphoryl)-5-dimethyl-1-pyrroline N-oxide. At acidic pH, the rate constant for spin trapping O2*- was 3-fold greater than that at physiological pH. Subsequent experiments determined the half-life of aminoxyls, derived from the reaction of these nitrones with O2*-. The EPR spectra were modeled by using a global analysis method. The results clearly demonstrated that EPR spectra of all the aminoxyls were inconsistent with a model that included a single gamma-hydrogen splitting. A better interpretation modeled them as two diastereomers with identical nitrogen splittings and slightly different beta-hydrogen splittings. Detailed line width analyses slightly favored an equal line width-unequal population ratio for the two diastereomers.

Binding, Competitive↗

Oral administration is as effective as intraperitoneal administration of amifostine in decreasing nitroxide EPR signal decay in vivo.

A rapid method to determine the systemic incorporation of amifostine has been sought in order to determine the effectiveness of different administration routes without the delay inherent in awaiting therapeutic results. Consistent changes in animal measurements of nitroxide signal decay were monitored using in vivo EPR at frequencies low enough to ensure uniform sensitivity to organs deep in 20-g C3H mice. Conditions included both co-administration of the amifostine with the carbamoyl-proxyl spin probe (CP) via i.p. injection (n=6) and oral administration (n=8) of the amifostine. These decreased the first order rate of decay of the CP EPR signal after a dose of 13.5 Gy radiation, by 23% and 18%, respectively. These changes were significantly different from the rate of decay of the CP EPR signal without amifostine, but were statistically indistinguishable from each other. These data demonstrate: (1) condition-dependent exponential decay of CP EPR signal allowing its use to determine systemic availability of a drug, and (2) that oral administration and i.p. injection of amifostine are both effective in affecting the CP EPR signal decay rate in a mouse model. This is a strong indicator of similar bioavailability in mice from both routes of administration.

Administration, Oral↗

Quantitative tumor oxymetric images from 4D electron paramagnetic resonance imaging (EPRI): methodology and comparison with blood oxygen level-dependent (BOLD) MRI.

This work presents a methodology for obtaining quantitative oxygen concentration images in the tumor-bearing legs of living C3H mice. The method uses high-resolution electron paramagnetic resonance imaging (EPRI). Enabling aspects of the methodology include the use of injectable, narrow, single-line triaryl methyl spin probes and an accurate model of overmodulated spectra. Both of these increase the signal-to-noise ratio (SNR), resulting in high resolution in space (1 mm)(3) and oxygen concentrations (approximately 3 torr). Thresholding at 15% the maximum spectral amplitude gives leg/tumor shapes that reproduce those in photographs. The EPRI appears to give reasonable oxygen partial pressures, showing hypoxia (approximately 0-6 torr, 0-10(3) Pa) in many of the tumor voxels. EPRI was able to detect statistically significant changes in oxygen concentrations in the tumor with administration of carbogen, although the changes were not increased uniformly. As a demonstration of the method, EPRI was compared with nearly concurrent (same anesthesia) T(2)*/blood oxygen level-dependent (BOLD) MRI. There was a good spatial correlation between EPRI and MRI. Homogeneous and heterogeneous T(2)*/BOLD MRI correlated well with the quantitative EPRI. This work demonstrates the potential for EPRI to display, at high spatial resolution, quantitative oxygen tension changes in the physiologic response to environmental changes.

Animals↗

Spectral fitting: the extraction of crucial information from a spectrum and a spectral image.

A highly accurate line-width simulation computer program is used that can account for both high amplitude and frequency of the Zeeman modulation in an electron paramagnetic resonance (EPR) experiment. This allows for the overmodulation of EPR lines to increase signal-to-noise ratio (SNR) in EPR spectra and spectroscopic images, without any sacrifice in the determination of the intrinsic line width (1/gamma. T(2e)). The technique was applied to continuous-wave EPR spectroscopic images of a narrow, single-line trityl spin probe wherein a full EPR spectrum was extracted from each 3D spatial voxel. Typical improvements are a three- to fivefold increase in SNR in the high-gradient projections in the image and a reduction in the standard deviation (SD), by a factor of 3, of the line widths in the low-gradient domain. This method is a general one that is also applicable to the analysis of conventional (14)N or (15)N nitroxide spin probes.

Computer Simulation↗

Using high spectral and spatial resolution bold MRI to choose the optimal oxygenating treatment for individual cancer patients.

We evaluate whether high spectral and spatial resolution (HiSS) BOLD MRI can correctly rank the effects of three tumor-oxygenating treatments on radiosensitivity in BA1112 rhabdomyosarcomas (n = 5). Significant decreases in spectral linewidth predict that treatment with carbogen gas combined with a perfluorocarbon emulsion will increase radiosensitivity more than either treatment alone, which agrees with the known effects of these treatments on hypoxic fraction. High-resolution maps show that tumor response to each treatment is spatially heterogeneous, and that there is a paradoxical response to the treatments in 7-12% of tumor pixels. Because HiSS MRI emphasizes changes in necrotic and/or hemorrhagic regions, it is more sensitive to oxygenation changes compared to conventional MRI. These results demonstrate that HiSS MRI is a practical, noninvasive method that could be used to choose the treatment that maximizes the size and extent of increases in tumor oxygenation for individual patients.

Animals↗

General synthesis of persistent trityl radicals for EPR imaging of biological systems.

In this paper we describe the syntheses of the tetraoxygenated triarylmethyl (trityl) radical 14 and the tetrathiatriarylmethyl (trityl) radicals 15 and 16. The syntheses include new and improved preparations of the key intermediate compounds 1 and 2. The new route to compound 2 is noteworthy for its efficiency and its avoidance of the highly toxic compound phosgene as well as the isolation of the air-sensitive 1,2,4,5-benzenetetrathiol.

Catalysis↗

Imaging spin probe distribution in the tumor of a living mouse with 250 MHz EPR: correlation with BOLD MRI.

Electron paramagnetic resonance imaging (EPRI) promises to provide new insights into the physiology of tissues in health and disease. Understanding the in vivo imaging capability of this new modality requires comparison with other physiologically responsive techniques. Here, an initial comparison between 2D EPR spatial imaging of a narrow single line injectable paramagnetic trityl spin probe and 2D slice-selected carbogen subtraction BOLD MRI is presented. The images were obtained from the same FSa fibrosarcoma grown in the leg of a C3H mouse. This tumor was unusual in comparison with others imaged with subtraction BOLD MRI because of its peripheral distribution of intensity. The spatial distribution of the EPR spin probe showed the same peripheral distribution. The pixel resolutions of these images are comparable. These images provide an early in vivo comparison of EPRI with a well-established imaging modality. The comparison validates the in vivo distribution of spin probe as imaged with EPRI, and provides a proof of principle for the comparison of BOLD and EPRI.

Animals↗