Fixation probability favors increased fecundity over reduced generation time.

The cornerstone of population genetics is a probabilistic understanding of the ultimate fate--survival or extinction--of rare mutations. If a mutation is beneficial, it enables its carrier to reproduce faster than native wild-type individuals. In classic derivations and in the considerable body of research that has followed, "faster" has been defined mathematically to mean "able to produce more surviving offspring per generation." Many organisms, however, may increase their reproductive rate by producing the same number of offspring in a shorter generation time: a mutant bacterium, for example, may complete the cell cycle and produce two offspring more quickly than the wild type. We find that the ultimate fixation probability of a mutation conferring a shorter generation time differs from that of a mutation conferring more offspring by a factor of 2 ln(2)-nearly 40%. This predicts a reduction in the overall substitution rate for any mutation that decreases the generation time: fixation probability is biased toward increased offspring number.

A rapid assay for mitochondrial DNA damage and respiratory chain inhibition in the yeast Saccharomyces cerevisiae.

There is a need for a rapid assay to identify agents that damage mitochondria because the mitochondrion may be an important target for numerous environmental mitotoxins. Certainly at least one chemotherapeutic regimen (CHOP therapy) that includes doxorubicin can induce cardiomyopathy through mitochondrial genotoxicity in cardiac muscle cells. Yeast cells (1.5 x 10(6)-10(7)) in water are spread on a YEPD plate, and, when the suspension of cells has dried, a small well (12 mm diameter) is cut into the agar; 200-400 microl of a solution of the presumptive mitochondrial genotoxin is placed in the well, and the plates are incubated for 2 days. The genotoxin forms a concentration gradient through the agar and affects the growing cells. An overlay containing tetrazolium chloride is added, and the plates are incubated for 6-24 hr. Respiring cells turn red, and nonrespiring cells, with damaged DNA or inhibited respiratory chains, that are adjacent to the well, are white. A white ring, or a more lightly colored red ring, around the well indicates the presence of cells with lowered respiratory activity which may be fully reversible when the mitochondrial genotoxin is removed. In preliminary experiments, doxorubicin (= adriamycin) shows strong activity with this assay; cyclophosphamide is negative, and 4-hydroxycyclophosphamide, a metabolite of cyclophosphamide, is weakly positive. Ethidium bromide, methotrexate, 5-fluorouracil, and 5-fluorocytosine also are mitochondrial genotoxins. Antifungal agents similar to 5-fluorocytosine and anthelmintic compounds such as pyrvinium iodide can be powerful mitochondrial genotoxins.

Retrospective review of 50 canine intracranial tumors evaluated by magnetic resonance imaging.

Magnetic resonance imaging (MRI) was performed on 50 dogs with intracranial neoplasia. The following tumor features were assessed: axial origin, location, shape, growth pattern, MRI signal intensity, evidence for edema, and paramagnetic contrast enhancement. Histologic diagnosis included 5 intracranially invading nasal tumors, 7 pituitary tumors, 22 meningiomas, 6 choroid plexus tumors, 7 astrocytomas, 1 ependymoma, and 2 oligodendrogliomas. Axial origin, site, shape, and growth pattern were important diagnostic characteristics for tumor type. Signal intensity and contrast enhancement pattern allowed further differentiation. Characteristic MRI features that facilitate diagnosis and prognosis were identified. Accurate diagnosis of tumor type based on these features was not always possible because of similarities in MRI appearance for some tumors. Tissue biopsy remains necessary for definitive diagnosis of intracranial tumors.

Quantitative 123I IMP and 99mTc HMPAO imaging in the dog following cocaine administration.

SPECT and associated imaging procedures were used in beagle dogs to (1) evaluate the uptake, distribution, and clearance properties of i.v.-injected 123I IMP (IMP) and 99mTc HMPAO (HMPAO) in the brain, lungs, liver, and kidneys; (2) quantify the acute effects (after 15 sec) of very low doses (0.5 or 1.0 mg/kg) cocaine on the kinetics and localization properties of IMP and HMPAO; and (3) evaluate comparative imaging properties of IMP and HMPAO for measuring regional cerebral blood flow (rCBF). Regional and global uptake and localization of IMP or HMPAO were evaluated in control studies using dynamic planar (0-30 min) and SPECT imaging (at 35 min). The regional distribution properties of IMP and HMPAO in the brain were estimated from regions of interest (ROIs) drawn around anatomic structures on MR slices and manually registered with corresponding SPECT slices. Cocaine significantly reduced the 30-min IMP uptake in the brain and lungs by approximately 15%, but only slightly changed HMPAO uptake in the brain and other organs. In the control studies, the respective uptakes of IMP in the brain and lungs were 9 and 39% greater (p < 0.01) than those of HMPAO. In control SPECT studies, the highest uptake of IMP was observed in the thalamus and progressively less activity was observed in the parietal lobe, frontal lobe, cerebellum, occipital lobe, and entire brain; activity in the olfactory bulb was lower than in all other regions. Cocaine reduced IMP uptake in the cerebellum (p < 0.01), occipital lobe (p < 0.01), and entire brain (p < 0.05). IMP uptake (cpm/pixel-mCi) in the different brain regions was 1.3 to 2.1 times greater than that of HMPAO (p < 0.001). HMPAO uptake was more homogeneous throughout the gray matter of the brain; no significant uptake differences were observed among flagged regions. Results indicate that single, acute doses of cocaine, 0.5 and 1.0 mg/kg, significantly altered the uptake and localization properties of IMP in the dog's brain, lungs, liver, and kidneys. Variations in regional uptake of IMP in the parietal, frontal, and occipital lobes, cerebellum, and thalamus were greater than with HMPAO.

Biodistribution of boron in dogs with spontaneous intracranial tumors following borocaptate sodium administration.

Borocaptate sodium (Na2B12H11SH) is a potentially useful compound for boron neutron capture therapy of intracranial tumors. Tumor and normal tissue boron concentrations were evaluated in 30 dogs with naturally occurring intracranial tumors after i.v. borocaptate sodium infusion (55 mg boron/kg). Postmortem tissue boron concentrations were measured for three postinfusion time periods (2, 6, and 12 h) by inductively coupled plasma atomic emission spectroscopy. Mean boron concentrations for extracerebral tumors were 40.6 +/- 16.9 (2 h; n = 8), 25.9 +/- 11.7 (6 h; n = 5), and 8.6 +/- 4.5 micrograms boron/g (12 h; n = 6). Mean boron concentrations for intracerebral tumors were 30.6 +/- 17.5 (2 h; n = 7) and 2.9 +/- 1.8 micrograms boron/g (6 h; n = 4). Mean tumor boron concentrations were lower at longer postinfusion times. The tumor:normal brain boron concentration ranged from 0.8 to 19.8. Tumor:blood boron concentrations were less than one for all but three dogs and ranged from 0.04 to 1.4. Mean peritumor boron concentrations were highly variable but exceeded that of normal brain in 10 of 20 dogs. In some dogs, the mean peritumor boron concentration was similar to or exceeded the tumor boron concentration. Distant or contralateral normal brain had consistently low boron concentrations. Some cranial and systemic tissues had high boron concentrations, indicating substantial extravascular boron. The spontaneous animal tumors provided a realistic spectrum of data and enabled extensive sampling of diseased and normal tissues. The biodistribution of boron from borocaptate sodium administration was partially favorable because of high tumor boron concentrations. Empirical radiation dose tolerance studies should be used to determine the impact of the unfavorably high boron concentration of blood and some cranial tissues.

Large animal normal tissue tolerance with boron neutron capture.

PURPOSE: Normal tissue tolerance of boron neutron capture irradiation using borocaptate sodium (NA2B12H11SH) in an epithermal neutron beam was studied. METHODS AND MATERIALS: Large retriever-type dogs were used and the irradiations were performed by single dose, 5 x 10 dorsal portal. Fourteen dogs were irradiated with the epithermal neutron beam alone and 35 dogs were irradiated following intravenous administration of borocaptate sodium. RESULTS: Total body irradiation effect could be seen from the decreased leukocytes and platelets following irradiation. Most values returned to normal within 40 days postirradiation. Severe dermal necrosis occurred in animals given 15 Gy epithermal neutrons alone and in animals irradiated to a total peak physical dose greater than 64 Gy in animals following borocaptate sodium infusion. Lethal brain necrosis was seen in animals receiving between 27 and 39 Gy. Lethal brain necrosis occurred at 22-36 weeks postirradiation. A total peak physical dose of approximately 27 Gy and blood-boron concentrations of 25-50 ppm resulted in abnormal magnetic resonance imaging results in 6 months postexamination. Seven of eight of these animals remained normal and the lesions were not detected at the 12-month postirradiation examination. CONCLUSION: The bimodal therapy presents a complex challenge in attempting to achieve dose response assays. The resultant total radiation dose is a composite of low and high LET components. The short track length of the boron fission fragments and the geometric effect of the vessels causes much of the intravascular dose to miss the presumed critical target of the endothelial cells. The results indicate a large dose-sparing effect from the boron capture reactions within the blood.

Large animal normal tissue tolerance using an epithermal neutron beam and borocaptate sodium.

Irradiation of the canine head following intravenous Na2B12H11SH (BSH) administration has provided useful information concerning the tolerance of skin and brain to the resultant complex form of irradiation. The effect of the boron capture reaction in skin and brain has provided estimates of the influence of the microscopic dosimetry involved. Dogs irradiated with the epithermal beam alone provided valuable insight into the relative biological effectiveness (RBE) of the fast neutron component (> 10 keV) of the epithermal beam. When compared with literature values for X-rays for the occurrence of skin necrosis in dogs, an RBE of 4.5 was derived. Previous pharmacokinetic data concerning the distribution of Na2B12H11SH (BSH) to blood and brain has been used to obtain input parameters for computer models of the microvasculature of the brain. Monte Carlo computer models were used to simulate the microscopic distribution of BSH in the normal brain. The term compound factor describes the product of the microscopic boron fission fragment dose hitting the nucleus and the relative biologic effectiveness divided by the macroscopic equilibrium dose of the boron reaction in the tissue of interest. The computed compound factor for Na2B12H11SH (BSH) in normal brain was 0.37. This factor agreed very well with the value of 0.32 obtained for the brain necrosis with the dog irradiations. The compound factor for the dog's skin was experimentally derived from the dog experiments and was equal to 0.5.

Borocaptate sodium: a potential boron delivery compound for boron neutron capture therapy evaluated in dogs with spontaneous intracranial tumors.

Borocaptate sodium (Na2B12H11SH) is a boron-carrying compound under consideration for use in boron neutron capture therapy. The biodistribution of boron from borocaptate sodium administration will partly determine boron neutron capture therapy efficacy and normal tissue radiation tolerance. The biodistribution of boron was determined in 30 dogs with spontaneous intracranial tumors at 2, 6, or 12 hr after intravenous borocaptate sodium infusion. Blood and tissue boron concentrations were measured using inductively coupled plasma atomic emission spectroscopy. Mean tumor boron concentration (mean +/- standard error) was 35.9 +/- 4.6 (n = 15), 22.5 +/- 6.0 (n = 9), and 7.0 +/- 1.1 micrograms of boron per g (n = 6) at 2, 6, and 12 hr, respectively, after borocaptate sodium infusion. Peritumor boron concentrations were elevated above that of normal brain in half of the dogs. Normal brain boron concentration (mean +/- standard error) was 4.0 +/- 0.5, 2.0 +/- 0.4, and 2.0 +/- 0.3 micrograms of boron per g at 2, 6, and 12 hr after infusion, respectively. Some cranial and systemic tissues, and blood, had high boron concentration relative to tumor tissue. Geometric dose sparing should partly offset these relatively high normal tissue and blood concentrations. Borocaptate sodium biodistribution is favorable because tumor boron concentrations of recommended magnitude for boron neutron capture therapy were obtained and there was a high tumor-to-normal brain boron concentration ratio.

Scintigraphic evaluation of tissue viability after gunshot injury in a dog.

Triple-phase bone scintigraphy was used to evaluate tissue viability in the forelimb of a dog after gunshot injury. This technique was reliable, noninvasive, and easily performed. It was used to complement radiography by providing functional, rather than structural, assessment of tissues on the basis of regional vascular patterns. In this dog, vascular impairment caused by trauma appeared as photopenic or "cold" spots during immediate (vascular), soft tissue and bone phases of the scintigraphic study. On the basis of gross morphologic and scintigraphic findings, forelimb amputation was performed.

Quantitative electroencephalography in dogs anesthetized with 2.0% end-tidal concentration of isoflurane anesthesia.

Quantitative electroencephalography was assessed in dogs under controlled, 2% end-tidal isoflurane anesthetic conditions, and each variable at each electrode site was tested for normal distribution. With the quantitative electroencephalographic system used, 16 values for each of 21 electrode sites were evaluated. Absolute power ratios also were evaluated. The methods for quantitative electroencephalographic recording and analysis appear to be readily adaptable to the dog. Most of the data do not conform to a normal distribution. Therefore, distribution-free nonparametric statistics should be used when looking for differences under experimental or clinical conditions. Quantitative electroencephalography appears to be a sensitive noninvasive method that could be used to evaluate brain function under anesthetic, clinical, and experimental settings.

The social environment and the adaptation of mothers of physically handicapped children.

Evaluated relationships between social environmental characteristics and adaptation in 50 mothers of congenitally physically handicapped 6- to 11-year-old children. Mothers reported on utilitarian resources, child adjustment, psychosocial family resources, service utilization, and three dimensions of adaptation. Analyses of the concurrent correlational design indicated significant proportions of the variance in mental and social functioning were explained by features of the social environment. Mother's physical health could not be significantly predicted. Consistently strong contributions were made by psychosocial family resources in all adaptation domains.

Disability parameters, chronic strain, and adaptation of physically handicapped children and their mothers.

Investigated the contribution of disability parameters and chronic disability-related strain to the adaptation of 50 congenitally physically handicapped 6- to 11-year-old children and their mothers. Multiple dimensions of adaptation, disability status, and chronic disability-related strain were assessed with a variety of procedures. The mothers reported their children and themselves to display significantly worse adaptation than expected for a general sample. The adaptation of these children and their mothers, however, was not significantly related to the children's disability status nor the chronic strain thereto related. An exception was that the children's social functioning could be significantly explained by both of these factors. The inability to explain most dimensions of adaptation in the children and their mothers as it relates to the conceptual model guiding this research is discussed.

Self-concept, sexual knowledge and attitudes, and parental support in the sexual adjustment of women with early- and late-onset physical disability.

Three groups of college women were compared on the following dimensions: sexual experiences, sexual satisfaction, self-concept, sexual attitudes and knowledge, and parental support for sexual development. Groups were composed of women with late-onset physical disability, early-onset physical disability, and no disability. Measures utilized included an extension of the Sexual Interaction Inventory, the Tennessee Self-Concept Inventory, the Sexual Knowledge and Attitude Test, and questionnaires developed for this study. The early-onset group reported fewer current sexual experiences than did the nondisabled group. The early-onset group was dissatisfied with the frequency of sexual behavior to a greater degree than the nondisabled group. Also, both disabled groups believed that they could enjoy sexual experiences more than they did at present in contrast to the nondisabled group. There were no group differences for self-concept, though several aspects of self-concept contributed significantly to sexual adjustment for the disabled groups. No group differences were found for sexual knowledge and attitudes or parental support for sexual development, nor did these variables relate to sexual adjustment. Group differences in sexual adjustment are discussed in terms of functional, emotional, and social implications. Recommendations for further research include following the social development of women with late-onset conditions, comparing the social skills and cognitions of the two disabled groups, and assessing men who have established intimate relationships with disabled women.