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PubMed1987

Simultaneous double-isotope autoradiographic measurement of local cerebral glucose metabolic rate and acid-base status in rat brain.

We developed a double-isotope autoradiographic method for the simultaneous measurement of the local cerebral metabolic rate for glucose (1CMRG) and index of regional acid-base status (rABI) in single brain slices using [2-14C]deoxy-D-glucose (DG) and 5,5-dimethyl-[2-14C]oxazolidine-2,4,dione (DMO). After iv isotope administration, paper chromatography separates plasma DMO from DG activity using a methanol-methylene chloride solvent system. Initial tissue autoradiograms depict regional DMO plus DG and DG metabolite distribution. After 14 days in a well-ventilated hood, 97.5 +/- 0.5% of all DMO is lost from tissue sections by sublimation, and a second autoradiogram depicts DG plus DG metabolite distribution. Retention of brain lipids does not alter beta-particle self-absorption, avoiding problems associated with isotope extraction with solvents. Autoradiograms are digitized and converted to isotope-content images. The second autoradiogram is used for 1CMRG computation. After subtracting the second regional isotope-content value from the first, the DMO content is obtained and used to compute rABI. Application of this method to normal animals yields expected values for 1CMRG and rABI. This method is amenable to whole-slice digitization and creation of functional images of 1CMRG and ABI followed by pixel-by-pixel correlations of the two variables, making this a potentially valuable tool for the investigation of the relationships between glucose metabolism and brain acid-base balance.

Acid-Base Equilibrium↗
PubMed1985

Limits on asymmetric orthopositronium formation in high Z optically active molecules.

The proposed connection between the parity violating handedness of beta particles in radioactive decay and the sign (L) of biological chirality (the Vester-Ulbricht [V-U] hypothesis) is experimentally tested. The theoretically predicted asymmetry in triplet positronium formation (Aps) is measured in several high Z optically active molecules using low energy positrons with a net helicity. We find Aps less than 3 X 10(-4) in selenocystine (Z = 34) and thyroxine (Z = 53), excluding part of the theoretically predicted range of 4 X 10(-3) greater than Aps greater than 2 X 10(-6) in these molecules. The connection between these limits and limits on asymmetric radiolysis (AR) is made, with a new limit of AR greater than 10(-9) being placed. This limit on AR, which is thirty times lower than a previous measurement in the amino acid leucine (Z = 6), is still not small enough to rule out the V-U hypothesis. rule out the V-U hypothesis.

Cystine↗
PubMedDate not supplied

Optimum combination of targeted 131I therapy and total-body irradiation for treatment of disseminated tumors of differing radiosensitivity.

131I is the radionuclide most commonly used in biologically targeted radiotherapy at the present time. Microdosimetric analysis has shown that microtumors whose diameters are less than the beta-particle maximum range absorb radiation energy inefficiently from targeted radionuclides. Micrometastases of diameters < 1 mm are likely to be spared if targeted 131I is used as a single modality. Because of this, combined modality therapy incorporating targeted 131I, external beam total-body irradiation (TBI), and bone marrow rescue has been proposed. In this study, the minimum necessary TBI component is shown to depend on the radiosensitivity of the tumor cells. The analysis shows that the TBI component, to achieve radiocurability, increases directly with tumor radioresistance. For the most radiosensitive tumors, a whole-body TBI treatment dose 2 x 2 Gy is calculated to be obligatory, whereas practical arguments exist in favor of higher doses. For more radioresistant tumors, the analysis implies that a TBI treatment delivery of 5 x 2 Gy is obligatory. In all situations, external beam TBI appears to be an essential factor in providing reasonable probability of cure of disseminated malignant disease. Reasonable prospects of tumor cure by combination strategies incorporating 131I exist for the more radiosensitive tumor types (e.g., neuroblastoma, lymphoma, leukemia, myeloma, seminoma), but more resistant tumors are unlikely to be curable at present. Superior targeting agents, and the possible use of panels of different radionuclides, may be necessary to achieve high cure probabilities for less radiosensitive tumor types.

Bone Marrow Transplantation↗
PubMed2001

Proposal for a gamma-emitting stent for the prevention and treatment of coronary artery restenosis.

Radioactive stents have failed to prevent restenosis despite the demonstrated success of other radionuclide therapies using beta- or gamma-emitting radionuclides in the coronary arteries. This may be due to the rapid dose reduction at the end of the stent that occurs with a stent coated with 32P, which is a pure beta-emitter. A gamma-emitter will give a greater dose beyond the end of the stent and would therefore be expected to produce better results. However, it is essential that the gamma-emitter is not contaminated with beta particles of either sign nor with conversion electrons. This requirement generally demands the use of a high energy gamma-emitter, preferably with an energy greater than 500 keV. High energy gammas have other advantages, including a high radiation dose delivered per decay which reduces the total activity required and reduced dose near to the source due to electron disequilibrium. The ideal dose distribution is one that provides a uniform dose to the proliferating tissues and a reduced dose elsewhere. Although the target tissues are not well defined it is believed that the adventitia is the source of the proliferating cells. Hence the target tissue is between 0.5 and 2 mm depth into the artery. It is shown that 96Tc is a very suitable radionuclide for the production of radioactive stents giving a significantly greater dose compared with 32P both at depth and beyond the end of the stent for the same dose at the surface of the stent. Furthermore, 96Tc should be able to be made with a standard medical cyclotron and may be coated on to a stainless steel stent by a simple process that takes approximately 30 minutes to perform. Its half-life of 4.3 days will allow radioactive stents to be transported over significant distances and will result in a treatment time with a mean value of approximately 1 week. This will allow the rapid reestablishment of the endothelial layer which may be a further advantage of this radioactive stent.

Angioplasty, Balloon, Coronary↗
PubMed2002

Local injection of the 90Y-labelled peptidic vector DOTATOC to control gliomas of WHO grades II and III: an extended pilot study.

We have previously presented preliminary observations on targeting somatostatin receptor-positive malignant gliomas of all grades by local injection of the radiolabelled peptidic vector 90Y-DOTATOC. We now report on our more thorough clinical experience with this novel compound, focussing on low-grade and anaplastic gliomas. Small peptidic vectors have the potential to target invisible infiltrative disease within normal surrounding brain tissue, thereby opening a window of opportunity for early intervention. Five progressive gliomas of WHO grades II and III and five extensively debulked low-grade gliomas were treated with varying fractions of 90Y-DOTATOC. The vectors were locally injected into the resection cavity or into solid tumour. The activity per single injection ranged from 555 to 1,875 MBq, and the cumulative activity from 555 to 7,030 MBq, according to tumour volumes and eloquence of the affected brain area, yielding dose estimates from 76+/-15 to 312+/-62 Gy. Response was assessed by the clinical status, by steroid dependence and, every 4-6 months, by magnetic resonance imaging and fluorine-18 fluorodeoxyglucose positron emission tomography. In the five progressive gliomas, lasting responses were obtained for at least 13-45 months without the need for steroids. Radiopeptide brachytherapy had been the only modality applied to counter tumour progression. Interestingly, we observed the slow transformation of a solid, primarily inoperable anaplastic astrocytoma into a resectable multi-cystic lesion 2 years after radiopeptide brachytherapy. Based on these observations, we also assessed the feasibility of local radiotherapy following extensive debulking, which was well tolerated. Targeted beta-particle irradiation based on diffusible small peptidic vectors appears to be a promising modality for the treatment of malignant gliomas.

Adult↗
PubMed2002

Quantitation in PET using isotopes emitting prompt single gammas: application to yttrium-86.

Several yttrium-90 labelled somatostatin analogues are now available for cancer radiotherapy. After injection, a large amount of the compound is excreted via the urinary tract, while a variable part is trapped in the tumour(s), allowing the curative effect. Unfortunately, the compound may also be trapped in critical tissues such as kidney or bone marrow. As a consequence, a method for assessment of individual biodistribution and pharmacokinetics is required to predict the maximum dose that can be safely injected into patients. However, (90)Y, a pure beta(-)particle emitter, cannot be used for quantitative imaging. Yttrium-86 is a positron emitter that allows imaging of tissue uptake using a PET camera. In addition to the positron, (86)Y also emits a multitude of prompt single gamma-rays, leading to significant overestimation of uptake when using classical reconstruction methods. We propose a patient-dependent correction method based on sinogram tail fitting using an (86)Y point spread function library. When applied to abdominal phantom acquisition data, the proposed correction method significantly improved the accuracy of the quantification: the initial overestimation of background activity by 117% was reduced to 9%, while the initial error in respect of kidney uptake by 84% was reduced to 5%. In patient studies, the mean discrepancy between PET total body activity and the activity expected from urinary collections was reduced from 92% to 7%, showing the benefit of the proposed correction method.

Algorithms↗
PubMed2002

Therapy of ankylosing spondylitis with 224Ra-radium chloride: dosimetry and risk considerations.

Ankylosing spondylitis (AS) is a chronic inflammatory rheumatic disease which reduces the quality of life and leads to disability in approximately one-third of the patients. The spectrum of therapeutic modalities is limited. The renaissance of the use of (224)Ra-radium chloride for AS treatment, however, gives rise to concern which should result in the reconsideration of (224)Ra dosimetry and in the discussion of the risks associated with this treatment. The present study introduces new dosimetric calculations for alpha and beta/gamma rays performed according to the model proposed by the International Commission on Radiological Protection (ICRP). After a treatment schedule of 10 intravenous injections, each with 1 MBq of (224)Ra, the absorbed doses were calculated to be highest on the bone surface of the patient (4.4 Gy) with a resulting effective dose of 2.5 Sv.

Adult↗
PubMed1992

Telomere reduction in endometrial adenocarcinoma.

OBJECTIVE: Some of the genomic instability that is observed in solid tumors may be due to the loss of telomeric sequences. These experiments were designed to compare the number of telomeric repeat sequences in endometrial adenocarcinoma with that found in adjacent normal tissue. STUDY DESIGN: Deoxyribonucleic acid was extracted from normal and malignant uterine tissue of 11 patients undergoing hysterectomy for treatment of endometrial adenocarcinoma and also from five endometrial carcinoma cell lines. The relative number of telomeric repeat sequences in each sample was measured by hybridization of these deoxyribonucleic acids to a probe specific for the human telomeric repeat. Hybridization signals were quantified by autoradiography and a beta-particle detection system. RESULTS: A reduction of telomeric repeat sequences in tumor versus normal tissue was found in 10 of 11 cases. Telomere reduction was also seen in endometrial carcinoma cell lines. CONCLUSIONS: Telomere reduction is a genetic characteristic of many endometrial tumors. Telomere reduction may contribute to the genesis and progression of endometrial carcinoma, or it may be a secondary effect of the tumorigenesis process.

Adenocarcinoma↗
PubMed1992

Quantification of desferrioxamine and its iron chelating metabolites by high-performance liquid chromatography and simultaneous ultraviolet-visible/radioactive detection.

An HPLC-based method for quantification of desferrioxamine (DFO) and its iron chelating metabolites in plasma has been developed. This assay overcomes stability problems associated with DFO by the addition of radioactive iron to convert unbound drug and metabolites to radio-iron-bound species. A dual detection system utilizing uv-vis absorption and radioactive (beta-particle) detector was used to quantify total and radio-iron-bound species. The use of octadecyl silanol solid phase extraction cartridges permits concentration of samples and allows accurate quantification of drug and metabolites down to 0.1 nmol/ml.

Chromatography, High Pressure Liquid↗
PubMed1994

PCDOSE: an interactive software system to calculate internal radiation dose on a personal computer.

An interactive, menu directed, software system to calculate committed dose equivalents for individuals with different physiques after inhalation, ingestion or injection of radionuclides has been developed. The calculations are based on ICRP 26/30 methods. The programs are written in PASCAL and can be implemented on a personal computer with a MS-DOS operating system and a hard disk with a storage capacity of at least 20 Mb. This paper describes the development and features of the system.

Adult↗
PubMed1982

Quantification in macroscopic autoradiography with carbon-14--an evaluation of the method.

Macroscopic autoradiograms can generally be quantified by exposing previously calibrated standard sources together with the labeled sections and measuring the silver grain density by photometric methods. Variation in section thickness is a real problem with isotopes like 14C, with beta-particles of higher energy than those of 3H. Differences in self-absorption between tissues may be neglected at low section thickness. A simple fitting procedure for non-linear relationship between radiation dose and optical density is described. The combined effect of the examined errors for the practical evaluation of autoradiograms is discussed.

Animals↗
PubMed1979

Glycogen accumulation in the central nervous system in the cerebro-hepato-renal syndrome. Report of a case with ultrastructural studies.

We found marked accumulation of glycogen in the brain in one case of the cerebro-hepato-renal syndrome (CHRS). Glycogen in the form of beta-particles was deposited freely within the nucleus, perikaryon and cell processes of neurons and glial cells. The changes involved the gray matter diffusely but were more prominent in the cerebral cortex. The patient died at the age of 4 months after a clinical course characterized by severe hypotonia, seizures, and apneic episodes. Other neuropathologic findings were developmental malformations of the central nervous systen (CNS) (pachygyria, polymicrogyria, and hypoplasia of the inferior olives), white matter abnormalities (deficiency in myelination and diffuse accumulation of sudanophilic droplets within glial cells), clusters of peculiar "globoid" histiocytes with pleomorphic lipid inclusions, and microglial nodules in gray and white matter. This unusual combination of findings is regarded as characteristic of the CHRS.

Brain↗
PubMed1979

Aspergillus nidulans as a test organism for assessing radio-induced chromosomal non-disjunction.

A genetically marked heterozygous diploid of Aspergillus nidulans was synthesized and the feasibility of using this system for the simultaneous estimation of radio-induced mitotic crossing-over and non-disjunction has been investigated. In the case of the latter, serious experimental problems have been encountered. Nevertheless, induction curves for non-disjunction with 15-MeV electrons, 50-kVp X-rays, beta-particles and alpha-particles are presented showing an increase in non-disjunction with increasing LET.

Aspergillus nidulans↗
PubMed1976

Evolution of the glycogen content and of glucose-6-phosphatase activity in the liver of Salmo gairdneri during development.

The evolution of the liver's glycogenic content, cytochemical characterization of the glycogen and glucose-6-phosphatase activity enable us to define three successive phases up to stage 36, just before the first feed. The grade which was low up to stage 24 is then due to beta-particles of ovule origin. Then, up to stage 27, there is a storage phase: alpha-particles appear and accumulate while the enzymatic activity remains non-existent. From the stage 28 to 36 the grade is progressively increasing, the enzymatic activity appears and increases. When the phase ends the liver is able to ensure glycemic regulation and to deal with exogenous nutritional contributions.

Animals↗
PubMed1989

Graphical and statistical approaches to data analysis for in situ hybridization.

Quantification of gene expression in a morphological context is an invaluable tool for neurobiological investigation. The ability to measure the quantity of specific mRNA molecules at the level of the single neuron permits one to monitor the modulation of complex cell synthetic activity of intact neuron populations. The cells of interest can be contiguous or dispersed in functionally significant patterns throughout a broad anatomical region of the brain. The application of quantitative in situ hybridization is technically difficult and labor intensive. Nevertheless, it has great utility for investigating gene expression from a structural perspective. (1) In situ hybridization permits one to ask questions concerning the anatomical pattern of neuronal gene expression. (2) It permits analyses concerning the initiation of expression, cell location, cell type, and alterations of level of expression within a spatial and temporal context. (3) In cases where blotting methods suggest a message exists at low copy, in situ hybridization permits queries at the single-cell level. For example, in situ hybridization can determine if very few cells are expressing the gene product or if many neurons dispersed throughout a brain region exhibit low mRNA copy number/cell. Quantitative analyses also allow detailed investigation of cell response to physiologically meaningful stimulation. Our application of statistical and numerical methods is a demonstration of the utility of probabilistic models; the mixture distribution accounted for data from both labeled and unlabeled sources. In agreement with many previous investigations, grain density over an unlabeled uniform source (oxytocinergic cells) was suitably described by the Poisson distribution. The population of labeled vasopressinergic cells, however, was best described by the negative binomial distribution. Previous investigations from different fields of biology show that the negative binomial can be used to describe many biological phenomena, and this distribution was considered in at least two previous investigations to evaluate autoradiographic data which did not fit the Poisson function. From a theoretical perspective, the probabilistic relationship between beta-particle decay (a Poisson function) and the distribution of message levels among individual neurons in a cell group (gamma distribution) prompts consideration of the negative binomial. For both data sets the observed variances were larger than the mean, and the labeled portion of the data sets exhibited positive skewness.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1987

High resolution autoradiography at the regional topographic level with [14C]2-deoxyglucose and [3H]2-deoxyglucose.

After injection of 2-deoxyglucose (2-DG) labeled with tritium or carbon-14, autoradiograms were produced by thaw-mounting 4 micron frozen sections of rat brains on nuclear emulsion-coated slides. The results show that the distribution of radioactivity among different brain regions was similar and that the resolution at the regional topographical level was virtually identical for both compounds. The resolution obtained with the thaw-mounting of thin frozen sections onto nuclear emulsion was considerably greater than the resolution demonstrated in published results in the literature, when carbon-14 or tritium-labeled 2-deoxyglucose were used with 20 micron frozen sections and X-ray film or tritium-sensitive film. The results indicate that section thickness, detection medium and intimacy of contact between section and photographic emulsion influence resolution. At the regional level, the detection medium apparently influences resolution to a greater extent than the energy differences of the beta particles emitted from 14C or 3H. Although diffusion of radiolabeled 2-deoxyglucose and metabolites during the thaw-mounting process precludes single cell resolution of these autoradiograms, the improvement of visualizing regional topographic detail demonstrates that the described technique is a valuable approach with which to study regional 2-DG uptake.

Animals↗
PubMed1987

Radiation sensitivity of fibroblast strains from patients with Usher's syndrome, Duchenne muscular dystrophy, and Huntington's disease.

The colony-forming ability of 10 normal human fibroblast cell strains and of 10 strains representing 3 degenerative diseases of either nerve or muscle cells was determined after exposure of the cells to X-rays or beta-particles from tritiated water. Both methods of irradiation yielded similar comparative results. The fibroblast strains from the 5 Usher's syndrome patients and from 1 of the 2 Huntington's disease patients were hypersensitive to radiation, while those from the 3 Duchenne muscular dystrophy patients and the second Huntington's disease patient had normal sensitivity to radiation. These results indicate both disease-specific and strain-specific differences in the survival of fibroblasts after exposure to ionizing radiation.

Cell Survival↗
PubMed1995

In vitro positron emission tomography (PET): use of positron emission tracers in functional imaging in living brain slices.

Positron-emitting radionuclides have short half-lives and high radiation energies compared with radioisotopes generally used in biomedical research. We examined the possibility of applying positron emitter-labeled compounds to functional imaging in brain slices kept viable in an oxygenated buffer solution. Brain slices (300 microns thick) containing the striatum were incubated with positron emitter-labeled tracers for 30-45 min. The slices were then rinsed and placed on the bottom of a Plexiglas chamber filled with oxygenated Krebs-Ringer solution. The bottom of the chamber consisted of a thin polypropylene film to allow good penetration of beta+ particles from the brain slices. The chamber was placed on a storage phosphor screen, which has a higher sensitivity and a wider dynamic range than X-ray films. After an exposure period of 15-60 min, the screen was scanned by the analyzer and radioactivity images of brain slices were obtained within 20 min. We succeeded in obtaining quantitative images of (1) [18F]fluorodeoxyglucose uptake, (2) dopamine D2 receptor binding, (3) dopa-decarboxylase activity, and (4) release of [11C]dopamine preloaded as L-[11C]DOPA in the brain slice preparation. These results demonstrate that positron emitter-labeled tracers in combination with storage phosphor screens are useful for functional imaging of living brain slices as a novel neuroscience technique.

Animals↗