The effect of alendronate (Fosamax) and implant surface on bone integration and remodeling in a canine model.

Patients at high risk for osteoporosis and its associated morbidity, including postmenopausal women, are being pharmacologically managed to stabilize and improve bone mass. Alendronate sodium (Fosamax) is a commonly used antiresorptive agent effective in osteopenic women for reducing bone resorption, increasing bone density, and decreasing fracture incidence. With the increased incidence of alendronate-treated women who are undergoing hip replacement or fracture repair by prosthesis placement, data are needed to predict how alendronate affects host bone integration with uncemented surfaces. The aim of this study was to determine the effect of alendronate on new bone formation and attachment to implant surfaces in a normal and simulated estrogen-deficient, calcium-deficient canine model, using an implantable bone growth chamber. Alendronate did not affect host bone integration to surfaces commonly used in uncemented total joint arthroplasty, but there were significant differences dependent solely on the type of surface.

Relationship between structure and neutralizing activity of rabbit tetanus antibodies elicited by acellular and whole-cell pertussis DTP vaccines.

Symmetric and asymmetric IgGs having different neutralizing capacity are synthesized in variable proportions by the same clones during the course of immune response. The neutralizing activity of tetanus antibodies was studied in rabbits vaccinated with acellular (DTPa) or whole-cell pertussis (DTPw) vaccines. Symmetric and asymmetric F(ab)'2 fragments from the IgG fraction of the peak serum pools from each group of rabbits were purified by concanavalin A chromatography and measured by ELISA. After the third vaccine dose the asymmetric antibody percentage for DTPw (40%) was twice that for DTPa (20%). The neutralizing activity of asymmetric antibodies was roughly sixfold lower than symmetric ones. When antibody values titrated by ELISA approach minimal protective level, the proportion of symmetric antibodies with high toxin neutralizing activity acquires crucial importance.

Lymphocyte proliferation assays as potential biomarkers for toxicant exposures.

Recently there has been interest in developing assays that can be used as indicators (biomarkers) of exposure to toxic agents. We have been exploring the potential utility of three lymphocyte proliferation assays [the responses of B lymphocytes to the mitogen lipopolysaccharide (LPS), the responses of T lymphocytes to the mitogen concanavalin A (ConA), and the responses of T lymphocytes to antigenic stimuli in a mixed lymphocyte culture (MLC) assay] as biomarkers of toxicant exposure. Studies were initiated to assess the applicability and specificity of these assays and to investigate the mechanisms by which toxicants alter lymphocyte proliferation. All studies were performed using cells isolated from Fischer 344 rats. To assess applicability, mitogen assays were performed using in vitro exposures to eight different toxicants: hydroquinone, benzoquinone, Aroclor 1254, styrene oxide, and the salts of mercury, cadmium, chromate, and nickel. In vitro concentrations spanned five orders of magnitude (100 to 0.01 mg/l). At the lowest concentration tested, all eight compounds induced changes in at least one mitogen assay, indicating that these assays may be applicable to a wide range of toxicants. Variations of the ConA and MLC assays were used to test for specificity. In both assays, splenocytes taken from rats exposed in vivo to either chromate or to cadmium responded differently when the cells were cocultured with exogenously added chromate or cadmium ions, indicating that it may be possible to detect exposure to a specific toxicant by performing modified lymphocyte proliferation assays. In the mechanistic studies, splenocytes from cadmium and chromate-treated rats altered the ConA-induced proliferation of cocultured syngeneic cells. In addition, the antigenicity of splenocytes isolated from cadmium-treated rats was enhanced when these cells were used as stimulators for allogeneic splenocytes. The results of these studies indicate that lymphocyte proliferation assays may be useful for detecting exposure to a wide range of toxicants and that variations of these assays may be useful for implementing immunologically based tests for detecting exposures to specific chemicals.

Immune function assays as indicators of chromate exposure.

The potential immunomodulatory effects of chromium were investigated using a series of in vitro and in vivo studies. Chromium (as K2CrO4) in concentrations spanning five orders of magnitude was added in vitro to T-lymphocyte (concanavalin A) and B-lymphocyte (liposaccharide) mitogen cultures and was found to inhibit T-lymphocyte responses at all concentrations tested and to inhibit B-lymphocyte responses at all but the lowest concentration tested (0.01 mg/L). When the same concentrations of chromium were employed in mixed lymphocyte cultures, antigen-induced thymidine uptake was inhibited at the highest concentrations (100 mg/L-1 mg/L), enhanced at 0.1 mg/L, and equal to control values at lower concentrations. Splenocytes isolated from rats exposed to K2CrO4 in drinking water exhibited enhanced responses to T- and B-lymphocyte mitogens. The addition of 0.1 mg/L of chromium to a mixed lymphocyte culture containing splenocytes taken from chromium-exposed rats increased by 5-fold the uptake of thymidine by these cells. These increased responses of cells from chromium-exposed rats may indicate chromium-induced sensitization and may possibly be used as a biological marker for chromium exposure.