Amelioration of collagen-induced arthritis by CD95 (Apo-1/Fas)-ligand gene transfer.

Both rheumatoid arthritis and animal models of autoimmune arthritis are characterized by hyperactivation of synovial cells and hyperplasia of the synovial membrane. The activated synovial cells produce inflammatory cytokines and degradative enzymes that lead to destruction of cartilage and bones. Effective treatment of arthritis may require elimination of most or all activated synovial cells. The death factor Fas/Apo-1 and its ligand (FasL) play pivotal roles in maintaining self-tolerance and immune privilege. Fas is expressed constitutively in most tissues, and is dramatically upregulated at the site of inflammation. In both rheumatoid arthritis and animal models of autoimmune arthritis, high levels of Fas are expressed on activated synovial cells and infiltrating leukocytes in the inflamed joints. Unlike Fas, however, the levels of FasL expressed in the arthritic joints are extremely low, and most activated synovial cells survive despite high levels of Fas expression. To upregulate FasL expression in the arthritic joints, we have generated a recombinant replication-defective adenovirus carrying FasL gene; injection of the FasL virus into inflamed joints conferred high levels of FasL expression, induced apoptosis of synovial cells, and ameliorated collagen-induced arthritis in DBA/1 mice. The Fas-ligand virus also inhibited production of interferon-gamma by collagen-specific T cells. Coadministration of Fas-immunoglobulin fusion protein with the Fas-ligand virus prevented these effects, demonstrating the specificity of the Fas-ligand virus. Thus, FasL gene transfer at the site of inflammation effectively ameliorates autoimmune disease.

CD40L blockade prevents autoimmune encephalomyelitis and hampers TH1 but not TH2 pathway of T cell differentiation.

Although it is well established that CD40 and its ligand (CD40L) play pivotal roles in the development of humoral immunity, their roles in cell-mediated immunity and cell-mediated autoimmune diseases are not well defined. We report here that CD40:CD40L interaction is crucial for the development of experimental autoimmune encephalomyelitis (EAE), a prototype TH1-cell mediated autoimmune disease. Specific blockade of CD40L at the time of immunization markedly suppressed the incidence, mortality, day of onset, and clinical scores of EAE in (PLJ x SJL) F1 mice. Importantly, the disease suppression was not associated with anergy or deletion of autoreactive T cells but was accompanied by a drastic alteration of their cytokine profiles. The production of interferon (IFN)-gamma was markedly suppressed while that of interleukin (IL)-4 enhanced. These results suggest that CD40:CD40L interaction plays important roles in the differentiation of autoreactive TH1 versus TH2 cells in vivo, and that CD40L blockade is effective in preventing autoimmune encephalomyelitis.

Dosimetry of the Siemens Mevatron 67 linear accelerator.

Measurements have been made on a Siemens Mevatron 67 linear accelerator. The change of beam quality has been measured as a function of position off-axis and compared to another Siemens 6 MV linear accelerator. Similarly, beam profiles are compared to a Siemens Mevatron VI. Additional measurements include entrance dose, inverse square applicability, central axis percent depth dose, tissue-maximum ratios, output factors, wedge factors and block transmission factors. Comparison is made with an Atomic Energy of Canada Limited Therac 6 and Varian Clinac 6-100.

Manpower needs for radiation oncology: a preliminary report of the ASTRO Human Resources Committee. American Society for Therapeutic Radiology and Oncology.

In summary, the ASTRO Committee on Human Resources believes that there is ample evidence for the existence of an oversupply of radiation oncologists in the United States at the present time. It believes that this oversupply has already affected the specialty in a variety of ways that are difficult to measure, for example, increased competition, conflicts between radiation oncology groups, conflicts between the private sector and academics, and increased costs, and that it is beginning to have a significant effect on the job market. This oversupply came about because of the rapid expansion in medical school enrollment in the 1970s. This led to an increased number of graduates available for enrollment into specialty residencies, one of which was radiation oncology. The actual number of radiation oncology residency positions offered has not changed significantly since 1972. However, only about half of the residency positions were filled in the early years. Since 1986, virtually all radiation oncology training positions in the United States have been filled, and this has led to a significantly greater number of radiation oncologists entering the field than have left the field through death or retirement. Preliminary data suggest that a shift to a managed care system would result in decreased demand for radiation oncology services, and that would increase the manpower problem for our specialty.

Physical characteristics of the M.D. Anderson Hospital clinical neutron beam.

The physical characteristics of the M.D. Anderson Hospital (MDAH) clinical neutron beam are presented. The central-axis percent depth-dose values are intermediate between a 4 and 6 MV X-ray beam. The build-up curves reach a depth of maximum dose at 1.2 cm and have surface dose values of approximately 30%. Teflon flattening filters are employed to flatten the beam at the depth of the 75% dose level. Two wedges are available for shaping the beam; they are made of Teflon and produce wedge angles of 31 degrees and 45 degrees as defined by the ICRU. Output factors ranged from 0.88 for a 4 x 4 cm field to 1.12 for a 20 x 20 cm field. Tungsten blocks reduced the dose received at Dmax to 25% of the unblocked value but only 52% of the unblocked value at a depth of 22.8 cm.

Dose in the buildup region outside the primary beam.

The dose received in the buildup region outside the primary beam has been measured for 60Co gamma rays and 6- and 18-MV X rays. The variation of this dose with field size and depth was evaluated. The effect of blocking trays and the importance of their design was determined.

Physical factors affecting absorbed dose to the skin from cobalt-60 gamma rays and 25-MV x rays.

When there is an absence of scattering material adjacent to the skin on the exit side of a megavoltage beam the dose to the skin is less than would be calculated using depth dose tables or isodose distributions measured in "semi-infinite" phantoms. Ionization measurements using a thin-window parallel-plate chamber show that the dose at 4 mg/cm2 from the exit surface is 14% to 16% less for cobalt-60 gamma rays and about 8% less for 25-MV x rays compared to the dose with full backscatter. As the angle of incidence increases the skin dose increases due to radiation scattered toward the surface. A method for the calculation of skin doses from tangential therapy beams is described.

Determination of the neutron and photon spectra of a clinical fast neutron beam.

A simple technique to determine the neutron and photon spectra of a clinical fast neutron beam is described. This technique involves making narrow beam attenuation measurements with a pair of ionization chambers and an iterative fitting program to analyze the data. A method is also described for determining the first-guess neutron spectrum for input into the iterative program. The results of the analysis yield spectra suitable for use in dose calculation algorithms and dosimetry protocols. Presented here is the first-known published photon spectrum from a clinical machine.

Measurement of the dose equivalent of leakage radiation through an isocentric gantry used for neutron therapy.

The leakage radiation through the shielding on an isocentric gantry of a neutron therapy machine was measured with a Rossi-type proportional counter. The dose equivalent of the leakage radiation was determined at two positions: (1) in the plane of the patient and (2) in the plane of the target. The dose equivalent of the leakage radiation is approximately the same as the leakage of a high-energy x-ray linac.

A method for verifying treatment times for simple high-dose-rate endobronchial brachytherapy procedures.

An empirical method for verifying the total treatment time for either a one- or a two-catheter high-dose-rate procedure has been developed. The method can be performed quickly and allows for easy verification of the accuracy of the treatment time arrived at by a computerized planning system. The method is designed to confirm the treatment time to within 10%.

Gadolinium neutron capture therapy for brain tumors: a computer study.

A Monte Carlo computer study of the total dose distribution from neutrons and prompt gamma emissions (but excluding the contribution from conversion and Auger electrons) for gadolinium neutron capture therapy of brain tumors has been carried out in order to test the theoretic feasibility of this modality using commercially available magnetic resonance contrast media. The three-dimensional dose distribution calculations were performed in a spherical head phantom with a spherical tumor at the center. Potentially achievable gadolinium concentrations of 150 micrograms/g of tissue in tumor and 3 micrograms/g in normal tissue were assumed with enrichment to 79.9% gadolinium-157, as supplied by Oak Ridge National Laboratory. Irradiation was assumed to be with a 2-keV monoenergetic cylindrical epithermal neutron beam having a radius of 4 cm. The three-dimensional thermal neutron fluence resulting from the 2-keV beam propagation through the tissue was modeled. For a single neutron beam, the maximum dose is delivered within the tumor but the dose is very inhomogeneous across the tumor volume due to rapid decrease of thermal neutron fluence with depth. Two parallel opposed neutron beams deliver to the interface of normal and malignant tissue 70%-80% of the maximum dose received at the center of the tumor. To deliver an average tumor dose of 500 cGy in 10 min would require a 2-keV source neutrons number of 8.0 x 10(11) per s within the geometry of the beam.

Use of simple quality assurance procedures in the analysis of beam asymmetries on cobalt-60 treatment units.

Recently, the mechanical failure of one of the upper collimator mechanical trimmers on a cobalt-60 unit resulted in large beam asymmetries and unacceptable flatness characteristics. This malfunction was not detected using currently accepted schedules for quality assurance tests. The incident suggests that the frequency of routine beam profile constancy checks should be increased to weekly for cobalt-60 units.

A microdosimetric characterization of a cyclotron-produced therapeutic neutron beam.

The therapeutic neutron beam of the Cyclotron Corporation's CP-42 negative-ion cyclotron is generated by protons of 42 MeV bombarding a thin beryllium target. Microdosimetric measurements were made for this neutron beam in a full-scatter water phantom at nine positions inside and outside the useful beam. The lineal energy distribution and the variations of dose-mean, frequency-mean, and saturated lineal energy are compared for these positions. The dose fraction due to gamma rays is also calculated at each of these positions, based upon previously published techniques. A theoretical relative biologic effectiveness, based upon the dual radiation action model of Kellerer and Rossi [Curr. Top. Radiat. Res. 8, 85 (1972)] is also shown for the positions of measurement.

Correlation of microdosimetric measurements with relative biological effectiveness from clinical experience for two neutron therapy beams.

Microdosimetric measurements were made for the neutron therapy beams at the University of Chicago and at the Cleveland Clinic with the same geometry and phantom material using the same tissue-equivalent spherical proportional counter and standard techniques. The energy deposition spectra (dose distributions in lineal energy) are compared for these beams and for their scattered components (direct beam blocked). The model of dual radiation action (DRA) of Kellerer and Rossi is employed to interpret these data in terms of biological effectiveness over this limited range of radiation qualities. The site-diameter parameter of the DRA theory is determined for the Cleveland beam by setting the biological effectiveness (relative to 60Co gamma radiation) equal to the relative biological effectiveness value deduced from radiobiology experiments and clinical experience. The resulting value of this site-diameter parameter is then used to predict the biological effectiveness of the Chicago beam. The prediction agrees with the value deduced from radiobiology and clinical experience. The biological effectiveness of the scattered components of both beams is also estimated using the model.

Use of routine quality assurance procedures to detect the loss of a linear accelerator primary scattering foil.

The effects of the mechanical loss of a stainless steel primary scattering foil on a 12-MeV electron beam from a dedicated intraoperative electron accelerator are discussed. Routine quality assurance tests, including dose output constancy, energy constancy, and beam uniformity (flatness and symmetry), were used to determine the nature of the malfunction when it occurred. It is concluded that these quality assurance checks, if done with the frequencies recommended by the AAPM Task Group 40 Report [Med. Phys. 21, 581-619 (1994)] and repeated at the time of occurrence, are sufficient to detect loss of an electron scattering foil.

Calibration frequency as determined by analysis of machine stability.

Simple statistical analysis is applied to the evaluation of the output measurements of equipment used in radiotherapy. The calibration frequency is calculated based on the stability of the equipment and the performance parameters required by the quality control criteria.

Photosynthetic responses of Microstegium vimineum (Trin.) A. Camus, a shade-tolerant, C4 grass, to variable light environments.

Microstegium vimineum (Trin.) A. Camus, a shade-tolerant C4 grass, has spread throughout the eastern United States since its introduction in 1919. This species invades disturbed understory habitats along streambanks and surrounding mesic forests, and has become a major pest in areas such as Great Smoky Mountains National Park. The focus of this study was to characterize the photosynthetic induction responses of M. vimineum, specifically its ability to utilize low light and sunflecks, two factors that may be critical to invasive abilities and survival in the understory. In addition, we were curious about the ability of a grass with the C4 photosynthetic pathway to respond to sunflecks. Plants were grown under 25% and 50% ambient sunlight, and photosynthetic responses to both steady-state and variable light were determined. Plants grown in both 25% and 50% ambient sun became 90% light saturated between 750-850 µmol m-2 s-1; however, plants grown in 50% ambient sun had significantly higher maximum steady-state photosynthetic rates (16.09 ± 1.37 µmol m-2 s-1 vs. 12.71 ± 1.18 µmol m-2 s-1). Both groups of plants induced to 50% of the steady-state rate in 3-5 min, while it took 10-13 min to reach 90% of maximum rates, under both flashing and steady-state light. For both groups of plants, stomatal conductance during induction reached maximum rates in 6-7 min, after which rates decreased slightly. Upon return to low light, rates of induction loss and stomatal closure were very rapid in both groups of plants, but were more rapid in those grown in high light. Rapid induction and the ability to induce under flashing light may enable this species to invade and dominate mesic understory habitats, while rapid induction loss due to stomatal closure may prevent excess water loss when low light constrains photosynthesis. The C4 pathway itself does not appear to present an insurmountable barrier to the ability of this grass species to respond to sunflecks in an understory environment.

Leaf gas exchange characteristics differ among Sonoran Desert riparian tree species.

We investigated leaf gas exchange responses to leaf temperature, leaf-to-air vapor pressure deficit (VPD), and predawn and midday shoot water potential (psipd and psimd, respectively) of two native Sonoran Desert riparian tree species, Fremont cottonwood (Populus fremontii S. Wats.) and Goodding willow (Salix gooddingii Ball), and one exotic riparian tree species, saltcedar (Tamarix chinensis Lour. and related species). Measurements were made at two sites over 2 years that differed climatically. Because multiple linear regression models explained less than 29% of the variation in stomatal conductance (gs) and less than 48% of the variation in net photosynthetic rate (Pn) of all species, we used boundary-line analysis to compare gas exchange responses among species. Gas exchange rates were high in all species. The hyperbolic relationship between Pn and gs suggested that initial reductions in gs at high gs did not inhibit Pn. Reductions in gs of cottonwood and willow occurred at psimd values at or below previously reported xylem cavitation thresholds (-1.6 and -1.4 MPa, respectively), indicating tight stomatal regulation of water loss and a narrow cavitation safety margin. In contrast, reductions in gs of saltcedar occurred at psimd values well above the cavitation threshold (-7.0 MPa), but at much lower psimd values than in cottonwood and willow, suggesting a wider cavitation safety margin and less tight regulation of water loss in saltcedar. High VPD had a smaller effect on leaf gas exchange in willow than in cottonwood. In contrast, willow had a less negative psipd threshold for stomatal closure than cottonwood. Compared with cottonwood and willow, leaf gas exchange of saltcedar was more tolerant of high VPD and low psipd. These physiological characteristics of saltcedar explain its widespread success as an invader of riparian ecosystems containing native Fremont cottonwood and Goodding willow in the Sonoran Desert.

Application of the "rule of 72" in medical physics and dosimetry.

The "rule of 72," commonly applied to financial questions, is discussed as to its applicability in medical physics and dosimetry.

A comparison of high-energy oblique lung irradiation techniques.

The lung cancer death rate in the U.S. rose 440% between 1957-59 and 1987-89, from 5.4 to 29.4 per 100,000. While surgical resection of small, localized carcinomas offers the best prognosis, only 15-20% of lung cancers fall into this category. The remaining 80-85% of patients are generally candidates for radiation therapy. Typically, the tumor volume (plus a 2 cm margin) and the mediastinum will be irradiated, using parallel opposed anterior and posterior ports, until the spinal cord has reached tolerance at 45 Gy. At this point, an off-cord lateral or oblique treatment technique will be used to complete the prescribed dose to the tumor. The depth to isocenter for oblique ports may easily be 15 cm. With this depth, a high-energy x-ray beam seems to be required; however, the beam may pass through a significant portion of lung tissue, reducing the equivalent depth. Another factor to consider is the build-up region beyond the lower density lung tissue. Two different energy beams, 6 MV and 18 MV, were compared for the oblique treatment ports. Plans were run using a thorax CT slice of an anthropomorphic phantom for parallel opposed oblique fields at these two energies, each with and without CT correction. Further data were collected for comparison by thermoluminescent dosimetry measurements. This paper describes the process and results obtained.