Enhanced radiosensitivity of malignant glioma cells after adenoviral p53 transduction.

OBJECT: The goal of this study was to determine whether adenoviral vector-mediated expression of human wildtype p53 can enhance the radiosensitivity of malignant glioma cells that express native wild-type p53. The p53 gene is thought to function abnormally in the majority of malignant gliomas, although it has been demonstrated to be mutated in only approximately 30%. This has led to studies in which adenoviral transduction with wild-type human p53 has been investigated in an attempt to slow tumor cell growth. Recent studies suggest that reconstitution of wild-type p53 can render cells more susceptible to radiation-mediated death, primarily by p53-mediated apoptosis. METHODS: Rat RT2 glioma cells were analyzed for native p53 status by reverse transcriptase-polymerase chain reaction and sequence analysis and for p53 expression by Western blot analysis. Clonogenic survival and the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling assay were used to characterize RT2 cell radiosensitivity and apoptosis, respectively, with and without prior transduction with p53-containing and control adenoviral vectors. Animal survival length was monitored after intracerebral implantation with transduced and nontransduced RT2 cells, with and without cranial radiation. The RT2 cells were demonstrated to express native rat wild-type p53 and to markedly overexpress human p53 following adenoviral p53 transduction. The combination of p53 transduction followed by radiation resulted in marked decreases in RT2 cell survival and increases in apoptosis at radiation doses from 2 to 6 Gy. Animals receiving cranial radiation after intracerebral implantation with RT2 cells previously transduced with p53 survived significantly longer than control animals (p<0.01). CONCLUSIONS: The ability to enhance the radiosensitivity of malignant glioma cells that express wild-type p53 by using adenoviral transduction to induce overexpression of p53 offers hope for this approach as a therapeutic strategy, not only in human gliomas that express mutant p53, but also in those that express wild-type p53.

Occupational factors and reproductive outcomes among a cohort of female veterinarians.

OBJECTIVE: To estimate absolute and relative risks of preterm delivery (PTD) and small-for-gestational-age (SGA) births among a cohort of female veterinarians in relation to selected occupational factors, including clinical practice type (CPT). DESIGN: Retrospective cohort survey. SAMPLE POPULATION: 2,997 female graduates from US veterinary colleges between 1970 and 1980. PROCEDURE: Relevant health and occupational data were collected through a self-administered mail questionnaire with telephone follow-up of nonrespondents. Absolute and relative risks of PTD and SGA births were estimated in relation to maternal CPT at the time of conception and exposure to 13 occupational factors. Attempts were made to control confounding by use of multiple logistic regression analyses. RESULTS: Absolute and relative risks of PTD were highest for veterinarians employed in exclusively equine clinical practice. Although several increased, none of the CPT-specific relative risk estimates were significantly different from the null value of 1. Exposure-specific analyses indicated that occupational involvement with solvents among exclusively small animal practitioners was associated with the highest relative risk of PTD. A small number of SGA births limited information that could be obtained from these analyses. Overall absolute risks of PTD and SGA births among cohort members were much lower in comparison with the general female population. CLINICAL IMPLICATIONS: Given the large number of women currently practicing and entering the profession of veterinary medicine, clinical tasks associated with potential reproductive hazards should be approached with heightened awareness and increased caution, especially activities that may involve exposure to solvents.

Mixed-mode survey of female veterinarians yields high response rate.

In a recent study of female veterinarians, a subgroup of health professionals growing rapidly in number, the authors employed a mixed-mode survey design in targeting the cohort of women graduating from all US veterinary colleges during the 11-year period 1970-80 (n = 2,997). The questionnaire elicited information on a variety of health and occupational factors and required 35 minutes on average to complete. In the first stage, a modified version of Dillman's Total Design Method for mailed, self-administered questionnaires was employed, yielding a response rate of 82.9%. In the second stage, a telephone interview of all mail non-respondents was attempted, yielding a response rate here of only 30.1%, but increasing the overall response rate among those contacted to 90.2%. Non-respondents differed little from mail (early) or telephone (late) respondents with respect to year of graduation and geographic region of veterinary college attendance. Gentle probing of telephone non-respondents suggested the personal nature of some questions and the amount of time required to answer all questions were the main reasons they chose not to participate. It therefore appears that conventional survey techniques may be successfully employed in health studies of health professionals, particularly if issues of great concern to the target population are addressed.

Adhesiveness of human ligament fibroblasts to laminin.

The adhesiveness of fibroblasts from the human anterior cruciate and medial collateral ligaments to the laminin molecule was studied, with particular emphasis on the intrinsic differences between fibroblasts from the two ligaments. Cellular adhesion strength, adhesion area, laminin concentration, and seeding time were examined. Cell adhesion to laminin anchored with poly-D-lysine to a cleaned cover glass was measured with a micropipette micromanipulation system after seeding. The adhesion strength of fibroblasts from the anterior cruciate ligament to laminin was greater than and significantly different from that of fibroblasts from the medial collateral ligament, depending on the laminin concentration. Fibroblasts from the anterior cruciate ligament also exhibited an increase in adhesion strength, dependent on laminin concentration of as much as 30 micrograms/ml, at which the laminin receptors were thought to be saturated. Fibroblasts from the medial collateral ligament did not show such an increase except at laminin concentrations of 5-10 micrograms/ml. There was no significant difference in adhesion area between fibroblasts from the two ligaments except after 45 minutes at a laminin concentration of 40 micrograms/ml. For both, the adhesion to laminin showed little correlation to seeding time during periods of as long as 60 minutes. Measurements of adhesion area also failed to show a significant correlation to seeding time for fibroblasts from either ligament at laminin concentrations of 20 and 40 micrograms/ml. Adhesion strength normalized by adhesion area had no correlation to seeding time.(ABSTRACT TRUNCATED AT 250 WORDS)

The death surround: factors influencing the grief experience of survivors.

Factors surrounding the death of a loved one can have a profound impact on the grief experience of survivors. This study examined the relationship between participation in a hospice program of care, place of death, length of illness prior to death, and the grief experience of survivors of patients who have died of cancer. Sixty survivors responded to the Grief Experience Inventory (GEI). Survivors of terminally ill people who participated in a hospice program prior to the death showed decreased feelings of guilt, dependency, loss of control, despair, numbness, shock, and disbelief. Survivors of those who died in the home had fewer guilt feelings and decreased death anxiety, but showed greater social isolation tendencies and were more apt to dwell on thoughts of the deceased. Finally, survivors of those who were ill six months or less had a greater need for dependency on others, isolated themselves more, and had increased feelings of anger and hostility. Study findings have significant implications for providing a death surround that enables an appropriate death for the patient and adaptation of the family that can lead to a more successful bereavement for survivors.

Inhibition of cytotoxicity by sulfasalazine. I. Sulfasalazine inhibits spontaneous cell-mediated cytotoxicity by peripheral blood and intestinal mononuclear cells from control and inflammatory bowel disease patients.

We have studied the effects of sulfasalazine and its metabolites on cell-mediated cytotoxicity by peripheral blood and intestinal mononuclear cells from both control and inflammatory bowel disease (IBD) patients. Sulfasalazine and sulfapyridine, as well as hydrocortisone and nordihydroguaiaretic acid inhibited spontaneous cell-mediated cytotoxicity by control and IBD peripheral blood cells. Sulfasalazine and nordihydroguaiaretic acid inhibited spontaneous cell-mediated cytotoxicity by control and IBD intestinal mononuclear cells cultured for 72 h in media alone. In contrast, 5-aminosalicylate, indomethacin and benzylimidazole had no effect on cytotoxicity by any cell population. Lectin-induced, antibody-dependent and interleukin-2-induced cell-mediated cytotoxicity, as well as lymphokine-activated killing were not inhibited by the drugs: inhibitory effects in these assays were primarily upon the underlying spontaneous cell-mediated cytotoxicity. The inhibition induced by sulfasalazine, sulfapyridine and nordihydroguaiaretic acid could not be reversed by adding the lipoxygenase metabolites leukotriene B4 or 12-hydroxyeicosatetraenoic acid. These findings demonstrate that spontaneous cell-mediated cytotoxicity by control and IBD mononuclear cells can be inhibited by sulfasalazine.