Biomedical subjects
Publications and source records attributed to R J Schulz.
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Radiation-sensitive polymer gels have been adapted for making test objects that can be used to assess the imaging characteristics of magnetic resonance imaging (MRI) systems. The polymer gels contain acrylic monomers within a gel matrix, and when irradiated with x rays the constituents polymerize to produce highly cross-linked microparticles that dramatically affect water NMR relaxation rates where they form. The size of these effects depends on the radiation dose and composition of the mixture irradiated, while the spatial pattern of relaxation time changes can be precisely controlled by spatial modulation of the x-ray exposure. This permits the manufacture of complex test patterns free of susceptibility or edge effects, and overall image performance can be assessed by constructing contrast-detail diagrams using a singly irradiated gel containing areas of different sizes and contrasts. Polymer gels are stable and a variety of different tests objects can be constructed inexpensively. Such materials and test phantoms may find widespread application in diagnostic MRI quality assurance and testing programs.
Development of CD4-CD8- double negative (DN) alpha beta TCR+ cells were examined by cell transfer experiments using an Ly-5 congenic mouse system. Purified DN alpha beta TCR+ thymocytes injected intrathymically emigrated from the thymus to the spleen. The same cells did not return to the thymus when injected i.v. Similarly, peripheral DN alpha beta TCR+ cells from spleen and liver did not go to the thymus when injected i.v. but migrated to the spleen. These results indicate that DN alpha beta TCR+ thymocytes develop within the thymus and emigrate to peripheral organs. It is thus likely that peripheral DN alpha beta TCR+ cells are at least partly of thymic origin. DN alpha beta TCR+ thymocytes are unique in that they express a natural killer cell marker, NK1.1, which is not found on conventional T cells. We further examined the thymic selection of DN alpha beta TCR+NK1.1+ thymocytes by using an anti-HY TCR-transgenic (tg)/Rag-2(-/-) mouse system with H-2 backgrounds that were negative, positive, or nonselecting for conventional T cells. The number of DNtg TCR alpha beta+NK1.1+ cells was m prominent in male H-2b animals in which conventional T cells are deleted by HY/H-2Db recognition. Fewer DNtg TCR alpha beta+NK1.1+ cells were found in H-2b females (positive selecting background), and almost no DNtg TCR alpha beta+NK1.1+ cells were detected in H-2d animals (nonselecting background). Unlike conventional T cells, DNtg TCR alpha beta+NK1.1+ cells from anti-HY/Rag-2(-/-) H-2b mice express Fc(epsilon)RI(gamma) and CD3zeta as DN alpha beta TCR+NK1.1+ cells from normal C57BL/6 mice. Our results indicate that DNtg TCR alpha beta+NK1.1+ cells are positively selected by self Ag/MHC and emigrate to the peripheral organs.
During fetal development, early thymocyte progenitors transiently express low affinity Fc receptors for IgG (Fc gamma R) of both Fc gamma RII and III isoforms. Only the Fc gamma RIII isoform requires association of an Fc gamma RIII (CD16) alpha subunit with an Fc epsilon RI gamma homodimer for surface expression. To address the role of Fc gamma R in ontogeny, we studied thymic development in Fc epsilon RI gamma-/- mice. We fine that day 14.5 CD4-CD8- double-negative (DN) fetal thymocytes of Fc epsilon RI gamma-/- mice express mRNA of both Fc gamma RIIb1 and Fc gamma RIII. Surface expression of Fc gamma RII/III is readily detected on these cells. It appears that Fc gamma RIIb1, whose surface expression is Fc epsilon RI gamma independent, replaces Fc gamma RIII during thymic development in these animals. Moreover, subsequent development into CD4+CD8+ double-positive and CD4+CD8- and CD4-CD8+ single-positive subsets appears normal even in the absence of Fc epsilon RI gamma. However, alterations were noted in adult animals among the DN alpha beta TCR+ thymocytes and peripheral splenic DN T cells as well as CD8 alpha alpha + intestinal intraepithelial lymphocytes (iIEL). In contrast to conventional T lymphocytes, which do not express either Fc gamma RIII or Fc epsilon RI gamma, DN alpha beta TCR+ thymocytes and extrathymically derived alpha beta TCR+ and gamma delta TCR+ CD8 alpha alpha + beta- iIEL express TCR which incorporate Fc epsilon RI gamma as one of their subunits. Consistent with this, the TCR levels of these cells are lower than the TCR levels on cells from wild-type C57BL/6 mice. Despite the reduction in the level of surface TCR, the development of these cells was unaltered by the absence of Fc epsilon RI gamma. Thus, we observed alterations in adult DN alpha beta TCR+ thymocytes, splenic DN alpha beta TCR+ and DN gamma delta TCR+ large granular lymphocytes (LGL), and alpha beta TCR+ and gamma delta TCR+ CD8 alpha alpha+beta- iIEL, but no detectable changes in their major fetal thymic developmental pathways. Cultivation of peripheral DN alpha beta TCR+ and DN gamma delta TCR+ cells from Fc epsilon RI gamma-/- mice with interleukin-2 generates LGL which mediate natural killer activity. Unlike LGL from wild-type C57BL/6 mice, LGL from Fc epsilon RI gamma-/- mice lack Fc gamma RIII expression and could not mediate antibody-dependent cellular cytotoxicity through Fc gamma RIII.
A new method of dosimetry of ionizing radiations has been developed that makes use of tissue-equivalent polymer gels which are capable of recording three-dimensional dose distributions. The dosimetric data stored within the gels are measured using optical tomographic densitometry. The dose-response mechanism relies on the production of light scattering microparticles which result from the polymerization of acrylic comonomers dispersed in the gel. The attenuation of a collimated light beam caused by scattering in the irradiated optically turbid medium is directly related to the radiation dose over the range 0-10 Gy. An optical scanner has been developed which incorporates an He-Ne laser, photodiode detectors, and a rotating gel platform. Using mirrors mounted on a translating stage, the laser beam scans across the gel between each incremental rotation of the platform. Using the set of optical density projections obtained, a cross sectional image of the radiation field is then reconstructed. Doses in the range 0-10 Gy can be measured to better than 5% accuracy with a spatial resolution approximately 2 mm using the current prototype scanner. This method can be used for the determination of three-dimensional dose distributions in irradiated gels, including measurements of the complex distributions produced by multi-leaf collimators, dynamic wedge and stereotactic treatments, and for quality assurance procedures.
Further progress in the development of polymer gel dosimetry using MRI is reported, together with examples of its application to verify treatment plans for stereotactic radiosurgery and high dose rate brachytherapy. The dose distribution image produced in the tissue-equivalent gel by radiation-induced polymerization, and encoded in the spatial distribution of the NMR transverse relaxation rates (R2) of the water protons in the gel, is permanent. Maps of R2 are constructed from magnetic resonance imaging data and serve as a template for dose maps, which can be used to verify complex dose distributions from external sources or brachytherapy applicators. The integrating, three-dimensional, tissue-equivalent characteristics of polymer gels make it possible to obtain dose distributions not readily measured by conventional methods. An improved gel formulation (BANG-2) has a linear dose response that is independent of energy and dose rate for the situations studied to date. There is excellent agreement between the dose distributions predicted using treatment planning calculations and those measured using the gel method, and the clinical practical utility of MRI-based polymer gel dosimetry is thereby demonstrated.
A new formulation of a tissue-equivalent polymer-gel dosimeter for the measurement of three-dimensional dose distributions of ionizing radiation has been developed. It is composed of aqueous gelatin infused with acrylamide and N, N'-methylene-bisacrylamide monomers, and made hypoxic by nitrogen saturation. Irradiation of the gel, referred to as BANG, causes localized polymerization of the monomers, which, in turn, reduces the transverse NMR relaxation times of water protons. The dose dependence of the NMR transverse relaxation rate, R2, is reproducible (less than 2% variation) and is linear up to about 8 Gy, with a slope of 0.25 s(-1)Gy(-1) at 1.5 T. Magnetic resonance imaging may be used to obtain accurate three-dimensional dose distributions with high spatial resolution. Since the radiation-induced polymers do not diffuse through the gelatin matrix, the dose distributions recorded by BANG gels are stable for long periods of time, and may be used to measure low-activity radioactive sources. Since the light-scattering properties of the polymerized regions are different from those of the clear, non-irradiated regions, the dose distributions are visible, and their optical densities are dependent on dose.
A new type of tissue-equivalent medium for magnetic resonance imaging of the dose distributions produced by ionizing radiation has been developed. Agarose gel is infused with acrylamide and N,N'-methylene-bis-acrylamide (Bis) comonomers, which are readily polymerized by free radical initiators in de-aerated aqueous solutions. Polymerization and cross-linking induced locally by free radical products of water radiolysis increase the rate of water proton spin relaxation gradually up to doses of about 15 Gy. The slopes of the dose-response curves at 64 MHz are 0.015 and 0.28 s-1 Gy-1 for R1 and R2, respectively. The agarose matrix as well as the high (50% by weight) relative concentration of the cross-linker (Bis) per total comonomer limit the spread of polymerization so that the spatial distribution of the radiation dose is faithfully represented in the resultant spatial distribution of relaxation rates. The gel can be imaged with conventional magnetic resonance imaging devices with high spatial resolution and accuracy. In addition, due to the well established effect of the precipitation of insoluble agglomerates of highly cross-linked acrylamide, the optical turbidity of the gel increases gradually with the absorbed dose. This may provide an additional means of visualizing the dose distribution in three dimensions. The major advantage of the acrylamide-Bis-agarose gels over those that depend on ionic chemical dosimeters, for example, Fricke-infused gels, lies in the lack of diffusion of radiation-induced chemical changes subsequent to or concurrent with irradiation.
The absorbed dose to water from a 160 MeV proton beam as determined by a flexible, temperature regulated, sealed glass core, water calorimeter was compared to that determined from ionization chambers used in accordance with AAPM Report 16. The ratios of these doses as obtained from two experiments done over four months apart, are 0.992 +/- 0.004 and 0.990 +/- 0.004. As there are no radiation dependent parameters required for the water calorimeter, these data add to the growing body of evidence which supports the use of the calorimeter as a reliable absorbed dose standard. They also support the use of 60Co-calibrated ionization chambers used in accordance with AAPM Report 16 for the dosimetry of proton beams.
The thermal defects of A-150 plastic and graphite referenced to aluminium were determined for 800 keV protons scattered by a 2 micron nickel foil (mean transmitted energy = 550 keV). Composite cores of Al/A-150, graphite/A-150 and Al/graphite which could be irradiated from one side or the other were employed. The temperature increase of a core caused by 30-100 s of irradiation (3-6 nA of proton beam current) was detected by two thermistors mounted in opposite legs of a Wheatstone bridge. The thermal defect of A-150 plastic was determined to be 0.0421 +/- 0.0036 (SE) referenced to aluminium and 0.0402 +/- 0.0034 referenced to graphite. The thermal defect of graphite referenced to aluminium is 0.0043 +/- 0.0034. No change in the thermal defect of A-150 plastic was detected for accumulated doses up to 8 x 10(5) Gy.
The radiation-response characteristics of agarose gels prepared with Fricke dosemeter solution have been studied. The response mechanism is an increase in the NMR longitudinal relaxation rate of protons caused by ferric ions. It has been observed that: (i) oxygen saturation assures consistent and maximum sensitivity; (ii) agarose concentrations in the range 1.0-2.0% have no effect upon sensitivity; (iii) the initial G value is 150 Fe3+/100 eV for gels containing 0.5 mM Fe2+ ions; (iv) increasing NMR frequencies only causes a moderate increase in sensitivity; (v) the gel dosemeters are dose rate independent in the range 4.7-24.2 Gy min-1; (vi) sensitivity is pH dependent, being zero at pH 7; (vii) freshly prepared gels are slightly more sensitive than those more than 24 h old; and (ix) the diffusion coefficient for ferric ions in a 1.0% agarose gel containing 0.0125 M H2SO4 is 1.83 x 10(-2) cm2 h-1, and this will require consideration for the NMR imaging of dose distributions.
The survival of Chinese hamster cells exposed to 59.5 keV 241Am gamma rays was compared with that obtained after exposure to 226Ra gamma rays. The Fricke dosimeter in conjunction with the calculational techniques of transition-zone dosimetry was employed to determine the dose rates to the cells at the petri dish/growth medium interface. The dose rates to the cells ranged from 11 to 133 cGy/h. In all cases, cell survival versus dose was best described by a simple exponential function of dose. For both radiations, graphs of D0 versus dose rate show complex but similar patterns of peaks and valleys. As the curve for 241Am is displaced toward lower dose rates compared with that for 226Ra, the relative biological effectiveness of 241Am vs 226Ra varies considerably with dose rate, ranging from 1.7 at 20 cGy/h to 1.1 at 40 cGy/h to 1.6 at 50 cGy/h. This phenomenon may be due to the LET-dependent accumulation of cells at the G2 + M interface in the cell cycle. The mean unrestricted track-average LET of 241Am (3.7 keV/microns) is 12 times higher than that for 226Ra (0.31 keV/microns) but only one-fifth that of carbon ions (18 keV/microns) for which G2 + M pile-up is observed. Application of the in vitro data derived from this study to the clinical situation, where the dose rate decreases rapidly with distance from the source, suggests that, dose for dose, 241Am will produce results little different from those obtained with 226Ra.
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A flexible, temperature-regulated water calorimeter has been constructed containing two pairs of thermistor sensors at depths of 6.23 and 10.0 cm. It may be irradiated by vertical or horizontal beams, and operated at temperatures in the range from 3 to 40 degrees C. When irradiated at 30 degrees C with a vertically downward 19 MeV electron beam, the responses of the proximal and midline thermistors were in accordance with the depth-dose curve. When irradiated horizontally, the initial patterns of temperature rise were the same, but after about 30 s (4 Gy) the rate of temperature rise decreased at the proximal thermistors and increased at the midline thermistors. Shortly after irradiation, the temperature curve and increased at the midline thermistors. Shortly after irradiation, the temperature curve of the midline thermistors crossed that for the proximal thermistors, a pattern that suggested the presence of convection currents. To test this hypothesis, the calorimeter was operated at 4 degrees C. The temperature patterns for horizontal irradiation became the same as those obtained with vertical beams, thus demonstrating the production of convection currents in water at a temperature of 30 degrees C for temperature gradients as small as 10(-3) degrees C cm-1.
A method is described for determining the spatial distribution of radiation dose in a tissue-equivalent phantom using nuclear magnetic resonance imaging. The conversion of ferrous ions to ferric by ionising radiation alters the magnetic moment and electron spin relaxation times of the metal ion. The spin relaxation times (T1 and T2) of the hydrogen nuclei in an aqueous solution of a ferrous salt are consequently reduced substantially. These changes in T1 and T2 can be measured using standard NMR techniques. The same conversion is used in conventional Fricke dosimetry, which can be used to calibrate the technique.
The antineoplastic effects of the glucose analog 5-thio-D-glucose (5TG) were tested using EMT6 mouse mammary tumors in vivo and EMT6 cells in cell culture. In vitro, 5TG selectively killed hypoxic EMT6 cells. However, administration of 5TG to mice bearing EMT6 tumors produced no significant toxicity to the cells of unirradiated tumors and did not alter the survival of cells in irradiated tumors. Fasting the mice to lower blood glucose concentrations before administration of 5TG increased the toxicity of the drug to the mice, but did not allow more efficacious treatment of the tumors. The data provided no evidence that 5-thio-D-glucose can be used effectively for the treatment of solid tumors, either as a cytotoxic agent or as a radiosensitizer.
The toxicity of 5-thio-D-glucose (5TG) to mammalian cells in culture has been studied with respect to oxygen tension, concentration, and temperature. At 37 degrees C and at 5 mM concentration of the drug in normal growth medium, survival is 10(-3) for 4-hr exposure to 5 ppm O2; this increases to 0.5 for 24-hr exposure to 200 ppm O2. The relationship between survival and oxygen tension is nonlinear with the greatest change occurring between 50 and 100 ppm. The drug is essentially nontoxic to aerated cells. Drug toxicity increases with concentration up to about 5 mM at which point a plateau is reached. The effect of elevated temperature is to reduce the time required to obtain a specific level of survival, but temperatures as high as 42 degrees C had only a slight effect on drug toxicity for oxygen tensions higher than 100 ppm. The effect of D-glucose on the toxicity of 5TG was studied, and an inverse relationship was established. At D-glucose concentrations greater than 20 mM the toxicity of 5TG was nullified regardless of oxygen tension or 5TG concentration.
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