Stochastic Threshold Exponential (TE) Model for Hematopoietic Tissue Reconstitution Deficit after Radiation Damage.

Whole-body exposure to large radiation doses can cause severe loss of hematopoietic tissue cells and threaten life if the lost cells are not replaced in a timely manner through natural repopulation (a homeostatic mechanism). Repopulation to the baseline level N 0 is called reconstitution and a reconstitution deficit (repopulation shortfall) can occur in a dose-related and organ-specific manner. Scott et al. (2013) previously introduced a deterministic version of a threshold exponential (TE) model of tissue-reconstitution deficit at a given follow-up time that was applied to bone marrow and spleen cellularity (number of constituent cells) data obtained 6 weeks after whole-body gamma-ray exposure of female C.B-17 mice. In this paper a more realistic, stochastic version of the TE model is provided that allows radiation response to vary between different individuals. The Stochastic TE model is applied to post gamma-ray-exposure cellularity data previously reported and also to more limited X-ray cellularity data for whole-body irradiated female C.B-17 mice. Results indicate that the population average threshold for a tissue reconstitution deficit appears to be similar for bone marrow and spleen and for 320-kV-spectrum X-rays and Cs-137 gamma rays. This means that 320-kV spectrum X-rays could successfully be used in conducting such studies.

A Comparison of In Vivo Cellular Responses to Cs-137 Gamma Rays And 320-kV X Rays.

Research reported here relates to comparing the relative effectiveness of 320-kV X rays compared to Cs-137 gamma rays for two in vivo endpoints in C.B-17 mice after whole-body exposure: (1) cytotoxicity to bone marrow cells and splenocytes evaluated at 24-hours post exposure and (2) bone marrow and spleen reconstitution deficits (repopulation shortfalls) evaluated at 6 weeks post exposure. We show that cytotoxicity dose-response relationships for bone marrow cells and splenocytes are complex, involving negative curvature (decreasing slope as dose increases), presumably implicating a mixed cell population comprised of large numbers of hypersensitive, modestly radiosensitive, and resistant cells. The radiosensitive cells appear to respond with 50% being killed by a dose < 0.5 Gy. The X-ray relative biological effectiveness (RBE), relative to gamma rays, for destroying bone marrow cells in vivo is > 1, while for destroying splenocytes it is < 1. In contrast, dose-response relationships for reconstitution deficits in the bone marrow and spleen of C.B-17 mice at 6 weeks after radiation exposure were of the threshold type with gamma rays being more effective in causing reconstitution deficit.

Biological microdosimetry based on radiation cytotoxicity data.

Researchers in the field of radiation microdosimetry have attempted to explain the relative biological effectiveness (RBE) of different ionising photon radiation sources on the basis of the singly stochastic, microdose metric lineal energy y, which only addresses physical stochasticity related to energy (ε) deposition via single events in the critical targets (cell nuclei assumed here). Biological stochasticity related to variable nuclei geometries and cell orientations (relative to the incoming radiation) is usually not addressed. Here a doubly stochastic microdose metric, the single-event hit size q (=ε/T), is introduced which allows the track length T to be stochastic. The new metric is used in a plausible model of metabolic-activity-based in vitro cytotoxicity of low-dose ionising photon radiation. The cytotoxicity model has parameters E{q} (average single-event hit size with q assumed to be exponentially distributed) and E{α}, which is the average value of the cellular response parameter α. E{α} is referred to as the biological signature and it is independent of q. Only E{q} is needed for determination of RBE. The model is used to obtain biological-microdosimetry-based q spectra for 320-kV X-rays and (137)Cs gamma rays and the related RBE for cytotoxicity. The spectra are similar to published lineal energy y spectra for 200-kV X-rays and (60)Co gamma rays for 1-µm biological targets.

Neonatal giant pial arteriovenous malformation: genesis or rapid enlargement in the third trimester.

A neonate with congestive heart failure at birth due to a nearly holohemispheric pial arteriovenous malformation is described. This occurred despite a normal second trimester prenatal sonogram. Successful treatment of heart failure was achieved by embolization alone. This case demonstrates that hemodynamically significant lesions may arise later or enlarge more rapidly in utero than previously thought.

A defense in depth approach to radiation protection for 125I production activities.

Not all operational radiation protection situations lend themselves to simple solutions. Often a Radiation Protection Program must be developed and implemented for difficult situations. A defense in depth approach to radiation protection was developed for 125I production activities. Defense in depth relies on key radiation protection elements that tend to be mutually supportive and in combination provide reasonable assurance that the overall desired level of protection has been provided. For difficult situations, defense in depth can provide both a reasonable and appropriate approach to radiation protection.

A simple method for assessing exposure to internal emitters.

One of the most challenging aspects of regulatory compliance can be demonstrating compliance with internal dosimetry requirements. For long-lived alpha-emitting radionuclides in particular, the sensitivity and accuracy of bioassay analysis and whole body counting may not allow for adequate assessment of intakes. Simple and effective measures can be used to control the workplace for the internal hazards associated with long-lived radioactive material using methods that measure directly the air to which workers are exposed. This paper provides an easy assessment tool that uses direct measurement of the specific activity of dusts in breathing zone air to evaluate internal exposures. Using this method, sensitive assessments can be made to determine if intakes are likely to have occurred and, if so, at what magnitude. It is not a substitute for confirmatory bioassay or whole body counting but a simple method to evaluate expectations for internal exposures.

End-product control of enzymes of branched-chain amino acid biosynthesis in Streptomyces coelicolor.

In streptomycetes, the branched-chain amino acids leucine, isoleucine and valine may serve as precursors for commercially important polyketides, and it is of interest to investigate whether the availability of these amino acids affects the production of the secondary metabolites derived from them. This paper reports studies on end-product control in the model organism Streptomyces coelicolor of the enzymes acetohydroxy acid synthase (AHAS) and isopropylmalate synthase (IPMS), mediating steps in the pathways to isoleucine-valine and leucine respectively. Specific activities of both enzymes were similarly affected when minimal medium was supplemented with the amino acids singly or in combination. Isoleucine alone caused a 2- to 3-fold increase, while all three amino acids caused a 5- to 8-fold decrease. Growth of an ilv auxotroph in media with limiting isoleucine gave enzyme specific activities 4- to 6-fold higher than in unsupplemented minimal medium. Spontaneous mutants were obtained by growing S. coelicolor on minimal medium containing 4-azaleucine. At lease four patterns of end-product control were found among the mutants, one of which showed high constitutive levels of both enzymes (7- and 15-fold above unsupplemented minimal medium values for AHAS and IPMS respectively). It is concluded that the variation in specific activities of the two enzymes under different physiological and genetic conditions spans a range of around 50 to 100, and that S. coelicolor has molecular mechanisms capable of producing this response.