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Biomedical subjects

B V Worgul

Publications and source records attributed to B V Worgul.

At least 37 records · Page 2Linked to original sources

Effect of accelerated iron ions on the retina.

The eyes of rats were exposed to doses of 0.1 and 2.5 Gy of 450-MeV/amu 56Fe particles (LET approximately 195 keV/microns). The beam axes were oriented perpendicular to the central retina of the animals. Retinas were harvested immediately (less than 10 min), 24 h, 15 days, 136 days, and 186 days after the experiment. The retinas of animals of equivalent ages were sampled at the same intervals. By Day 15, the spatial densities of the pigment epithelial, photoreceptor, and bipolar cells in retinas irradiated with 2.5 Gy were 15 to 20% lower than those of the controls. The cellular density of the pigment epithelium returned to the control level by Day 186 while photoreceptor and bipolar cell numbers remained depressed. One and fifteen days after irradiation, the choroidal vessels showed signs of radiation damage. Exposure to 0.1 Gy did not affect the cellular density within the retina at the interval examined (186 days). None of the retinas showed evidence of track-specific injury that could be interpreted as microlesions or tunnel lesions.

Animals↗

Microlesions: theory and reality.

Efforts to assess radiation risk in space have been complicated by the considerable unknowns regarding the biological effects of the heavy ion component (HZE particles) of the cosmic rays. The attention has focused primarily on the assignation of a quality factor (Q) which would take into account the greater effectiveness of heavy ions vis-a-vis other forms of ionizing radiation. If however, as the so-called "Microlesion Theory" allows, the passage of HZE particles through living tissue produces unique biological damage, the traditional use of Q becomes meaningless. Therefore, it is critical to determine if microlesions, in fact, do exist. While the concept does not necessarily require detectable morphological damage, "tunnel-lesions" or holes in ocular tissues have been cited as evidence of microlesions. These data, however, are open to reinterpretation. On-going light, scanning and transmission electron microscopic studies of the corneas, lenses and retinas of rat eyes exposed to 450 MeV/amu 56Fe ions thus far have not revealed tunnel-lesion damage. The morphological effects of the heavy ions have been found to be qualitatively similar to the changes following other kinds of ionizing radiation.

Animals↗

Stationary radiation cataracts: an animal model.

The restitution of normal fibergenesis that occurs in stationary radiation cataracts provides a unique opportunity to study the cytopathomechanism of radiocataractogenesis. Previous attempts at investigating this phenomenon have been limited by the lack of an appropriate animal model. This report describes the induction of stationary radiation cataracts in postmetamorphic bullfrogs following ocular irradiation with a 10 Gy (1 Gy = 100 rads) dose of X-rays. The eyes of non-irradiated animals and animals irradiated with 25 Gy (an established dose known to induce progressive cataracts in frogs) served as controls. Animals were followed biomicroscopically and histopathologically over 79 weeks. As previously described, the cataracts developed in a dose-dependent manner. The 25 Gy irradiated lenses rapidly progressed to complete opacification (4+) by 26 weeks, while lenses exposed to 10 Gy advanced to the 2.5+ stage by 35 weeks and progressed no further. In the lower dose lenses, transparent cortex began to appear anteriorly and posteriorly between the capsule and opaque fibers at 45 weeks. As the clear fibers accumulated, the disrupted region came to occupy increasingly deeper cortex. Histologically, opacities in both groups were preceded by disorganization of the bow cytoarchitecture, meridional row disorganization, and the appearance in the lens epithelium of nuclear polymorphism, fragmented nuclei, micronuclei, clusters of nuclei, and abnormal mitotic figures. In the lenses exposed to the 25 Gy dose, this damage continued to worsen, so that the 4+ stage was characterized by extensive epithelial cell death, absence of the lens bow, degenerated fiber masses, and liquefied substrata. In contrast, prior to the appearance of transparent cortex in the 10 Gy group, the lens epithelial aberrations, are of the bow, and meridional row disorganization were all observed to improve. Further, by 69 weeks, the lens epithelium appeared as a largely homogeneous population, and the meridional rows and the are of the bow had become reestablished. The details of these observations and their possible relationship to the cytopathomechanism of radiation cataract formation are discussed.

Animals↗

Cortical cataract development--an expression of primary damage to the lens epithelium.

Inasmuch as cortical opacities constitute the majority of senile cataracts their pathogenesis has been a matter of investigative concern for over a century. Evidence has been accumulating indicating a primary role for the lens epithelium in the loss of transparency of the cortex. Data from experimental work and clinical experience are consistent with a primary damage to the genome of the lens epithelial cell. The damage is mediated by the aberrant differentiation of lens fiber cells which collectively express as a cataract. The present paper reviews some of that evidence and offers preliminary analysis of the contributing aspects of cellular parameters associated with the pathology. Also, the concept of the "cataractotoxic load" and its applicability to the development of human senile cortical cataracts is discussed.

Aging↗

Accelerated heavy ions and the lens. IV. Biomicroscopic and cytopathological analyses of the lenses of mice irradiated with 600 MeV/amu 56Fe ions.

The lenses of mice exposed to 600 MeV/amu iron ions were evaluated by slit-lamp biomicroscopy and cytopathological analyses. The doses ranged from 0.05 to 1.6 Gy, and the lenses were assessed at several intervals postirradiation. Cataract, the development of which is dependent on both time and dose, is significantly more advanced in all of the exposed mice when compared to the unirradiated controls. The great difference between the severity of the cataracts caused by 0.05 Gy (the lowest dose used) and those that developed spontaneously in the control animals is an indication that 0.05 Gy may far exceed the threshold dose for the production of cataracts by accelerated iron ions. Cytopathologically, a similar dose dependence was observed for a number of end points including micronucleation, interphase death, and meridional row disorganization. In addition the exposure to the 56Fe ions produced a long-term effect on the mitotic population and a pronounced "focal" loss of epithelial cytoarchitecture. The microscopic changes support the view that the mechanism of heavy-ion-induced cataractogenesis is the same as that for cataracts caused by low-LET radiation.

Animals↗

Accelerated heavy particles and the lens. III. Cataract enhancement by dose fractionation.

For a number of biological end points it has been shown that, in contrast to low linear energy transfer (LET) radiation, dose fractionation of high-LET radiation does not result in a reduction in overall effectiveness. Studies were conducted to determine the effect of fractionating the exposures to heavy ion doses on the development of cataracts. Rat eyes were exposed to single doses of 1, 5, and 25 cGy of 570 MeV/amu40Ar ions and to 2, 4, and 10 Gy of 250 kVp X rays. These were compared to unirradiated controls and eyes which were exposed to the same total dose delivered in four fractions over 12 h. While in all cases fractionation of the exposure to X rays produced significant reduction in cataractogenic potential, fractionating doses of 40Ar ions caused a dose- and stage-dependent enhancement in the development of cataracts.

Animals↗

Accelerated heavy particles and the lens. V. Theoretical basis of cataract enhancement by dose fractionation.

That accelerated heavy ions are highly cataractogenic is indisputable. The basis of heavy particle effectiveness and the augmentation by fractionation, as recently demonstrated, remains less clear. There is no question, however, that these are tied to the 'track structure' and densely ionizing nature of the radiation. The unique energy deposition characteristics relating to charge and track structure are now being explored to begin to dissect the cellular response of the lens epithelium to radiation exposure. The elucidation of the basis of the cataractogenic effect of accelerated heavy ions is important not only to risk assessment, but also in the consideration of theories of radiation action and the mechanism of cortical opacification arising from a myriad of cataractotoxic agents.

Animals↗

Micronucleation in the lens epithelium following in vivo exposure to physical and chemical mutagens.

Rats were exposed to cataractogenic doses of known physical and chemical genotoxic agents in order to study the efficacy of using micronuclei to monitor mutagenicity in the lens epithelium. The total numbers of micronuclei were counted in lens epithelia from rats exposed to graded doses of either 250 kVp X-rays or the anti-leukemic drug, 1,4 dimethanesulfonoxybutane (Myleran (R)). The results indicate a dose-dependent incidence of micronucleation in the lens epithelium following exposure. The findings are consistent with the hypothesis that the cataractogenicity of certain agents may be related to their effect on the genome of lens epithelial cells.

Alkylating Agents↗

The effect of accelerated argon ions on the retina.

It has been postulated that high energy heavy ions cause a unique form of damage in living tissue, which results from the high linear energy transfer of accelerated single particles. We have searched for these single-particle effects, so-called "microlesions," in composite electron micrographs of retinas of rats which had been irradiated with a dose of 1 Gy of 570 MeV/amu argon ions. The calculated rate of energy deposition of the radiation in the retina was about 100 keV/micron and the influence was four particles per 100 micron 2. Different areas of the irradiated retinas which combined would have been expected to be traversed by approximately 2400 particles were examined. We were unable to detect ultrastructural changes in the irradiated retinas distinct from those of controls. The spatial cellular densities of pigment epithelial and photoreceptor cells remained within the normal range when examined at 24 h and at 6 months after irradiation. These findings suggest that the retina is relatively resistant to heavy-ion irradiation and that under the experimental conditions the passage of high energy argon ions does not cause retinal microlesions that can be detected by ultrastructural analysis.

Animals↗

The lens and cataract: clastogenic responses in epithelial cells of the organ-cultured rat lens.

The epithelial cells of the vertebrate lens have an unique character and a probable involvement in cataract formation, which could be initiated by exogenous stimuli. Individual rat lenses were organ-cultured, and the effects of mitomycin C and gamma rays on sister chromatid exchanges (SCE), chromosomal aberrations, and cellular kinetics assessed in cells from the epithelial monolayer. SCE showed about a 5.5-fold increase over the mitomycin C dose range (0, 17, 83, 170 nM), while chromosomal aberrations increased 38-fold. In cells from untreated lenses, SCE were 1,600 times more frequent than aberrations and at a level consistent with in vivo assessments in other cell types. Gamma rays (up to 4 Gy) had a greater inhibiting effect on cellular progression, while 17 nM mitomycin C and 1 Gy induced similar clastogenic responses. This first demonstration of such changes in lens epithelial cells expands on the cell types available for monitoring potential mutagen-carcinogens. Additionally chromosomal changes resulting from lens cellular challenge could be the basis of later cytopathological changes in the lens, of which cataract is the primary concern to humans. Potential cataractogens warrant monitoring, and the study outlined may aid in this endeavor, as well as contributing to an understanding of cataract etiology.

Animals↗

Near-total glutathione depletion and age-specific cataracts induced by buthionine sulfoximine in mice.

The specific inhibitor of glutathione biosynthesis, L-buthionine sulfoximine (L-BSO), although relatively nontoxic in adult mice, induces severe glutathione depletion and age-specific pathological changes when repeatedly administered to male suckling mice. Dense cataracts developed when mice aged 9 to 12 days were given a series of injections of L-BSO, despite excellent survival and the absence of other significant long-term effects. By contrast, similar treatment of mice aged 14 to 17 days, although slightly less effective in reducing glutathione levels, resulted frequently in death, hind-leg paralysis, or impaired spermatogenesis, but did not produce cataracts. Administration of L-BSO to preweanling mice provides a novel model system for the induction of cataracts by depletion of lens glutathione and may enable the study of critical functions of glutathione in the lens and other growing tissues during early postnatal development.

Age Factors↗

The effects of nuclear magnetic resonance imaging on ocular tissues.

Nuclear magnetic resonance, an imaging technique with great promise for detecting cerebral abnormalities, was studied to determine its possible deleterious effects on the mammalian eye. Young (3.5-week-old) Columbia-Sherman rats were exposed simultaneously to a constant magnetic field of 2.7 tesla and radio frequency pulses of 29 MHz at 800-ms intervals for six hours at field strengths representing the maximum used in a clinical setting. The six-hour exposure is many times greater than the four to six minutes currently employed in most diagnostic protocols. The animals were examined by slit-lamp biomicroscopy and ophthalmoscopy at regular intervals. Autoradiograms of lenses from animals injected with tritiated thymidine prior to exposure did not reveal any disturbances in cell-cycle kinetics. Eyes from rats not previously injected with the isotope were processed for cytopathologic analysis at various intervals. A two-year follow-up has indicated that at both the slit-lamp biomicroscopic and the light microscopic levels, there were no discernable effects on the rat eye.

Animals↗

Cataract analysis and the assessment of radiation risk in space.

Radiation cataract, a non-stochastic effect on the lens, is readily amenable to non-invasive analysis. Thus, it provides the means to assess radiation risk in space and for long-term monitoring of those who frequent that environment. The importance of such evaluations are underscored by the uncertainties associated with the assignment of quality factors for the effects of heavy charged particles constituting cosmic and solar radiation. Experimental studies were conducted using albino rats to evaluate the cataractogenic potential of 570 MeV/amu Argon ions administered as both single and protracted doses. The cataract studies and investigations of quantitative cytopathological changes associated with them indicate that as the dose of heavy particles decreases, the relative biological effectiveness, compared to X rays, increases. Fractionating the exposures not only failed to reduce the cataractogenic effect but caused a dose-dependent enhancement in the time of onset of opacification. Cytopathologically, the damage caused by heavy particles, when compared to low-LET radiation was found to be quantitatively dissimilar but qualitatively identical. In addition, damage which might be consistent with microlesions was not evident. The data indicates that as regards the cataractogenic potential of heavy particles at low doses an assignment of a Quality Factor (QF) of at least 40 may be in order.

Animals↗

The effects of ionizing radiation on the dividing cells of the conjunctival epithelium.

The influence of an X-ray dose of 10 Gy (1000 rads) on mitosis in the rat conjunctival epithelium was assessed. A mitotic inhibition began 1 hour postirradiation and continued for 4 days. The mitotic index was depressed to 10% of control values. After 5 days postirradiation, the mitotic index surpassed the control values peaking at 7 days postirradiation. The spindle axes of cells in telophase of the perilimbal rat conjunctival epithelium assume a characteristic, three dimensional orientation relative to the limbus. Ionizing radiation did not disrupt this organization at any time postirradiation. In fact, the frequency of mitotic figures preferentially aligned in irradiated tissue was enhanced during the mitotic rebound.

Animals↗

Accelerated heavy particles and the lens II. Cytopathological changes.

To assess more fully the risk to normal tissue exposed to accelerated heavy particles in the space program and during radiotherapy on earth, the cytopathological effects of a variety of doses of accelerated (570 MeV/amu) Argon (40Ar) ions on the rat lens were investigated. Time-course analyses of lenses exposed to a 1 Gy (100 rad)-dose revealed that the effects of the particles on mitotic index, nuclear fragmentation, and meridional row (MR) cytoarchitecture were qualitatively similar to those caused by 185 kVp x-rays. The effects of dose on the lens epithelium was also examined at 67 wk post-irradiation. The mitotic index returned to normal levels by that time; however, the biological effectiveness (RBE) of 40Ar relative to x-rays, in causing MR disorganization, increased with decreasing dose and closely resembled the RBE for cataractogenesis. The RBE data are consonant with the view that radiation cataracts are the result of damage to the lens epithelial population, which is later expressed as aberrant differentiation during fibergenesis.

Animals↗

Lens epithelium and radiation cataract. V. Observations on acid phosphatase and meridional row nuclear fragmentation.

The influence of X-radiation on acid phosphatase activity in differentiating meridional row cells of rat lens epithelia was examined by ultrastructural cytochemistry. X-ray doses of 10-12 Gy (1000-1200 rads) produced clearly observable nuclear and cytoplasmic damage at 13-19 hr postirradiation. In those cells, acid phosphatase reaction product was associated with much of the electron dense material of fragmented nuclei and various parts of the cytoplasm. In addition, many irradiated cells without observable damage were positive for reaction product. The presence of acid phosphatase activity in these otherwise normal-appearing cells is suggestive of more subtle radiation damage than that observed in the more severely damaged cells.

Acid Phosphatase↗

Posterior capsule opacification: experimental analyses.

The lenses of New Zealand White and Flemish Giant rabbits were removed using five techniques representative of the different clinical approaches to extracapsular cataract extraction currently employed. Posterior capsule opacification developed in all experimental animals within 6 weeks of the operation. None of the techniques reduced the incidence of the capsular opacification. Histological analyses including immunofluorescent and tritiated thymidine labelling were used to determine the nature of the cellular constitutents of the secondary membrane. The evidence indicates that the opacity is due not only to lens cells remaining after the operation but also consists of cells of nonlenticular origin. The data strongly implicate the anterior uvea as the source of those cells. Furthermore, the findings suggest that posterior capsule opacification is the product of a migration and a proliferation of both cell populations.

Animals↗