The IL-4Ralpha pathway in macrophages and its potential role in silica-induced pulmonary fibrosis

Crystalline silica exposure can result in pulmonary fibrosis, where the pulmonary macrophage is key as a result of its ability to react to silica particles. In the mouse silicosis model, there is initial Th1-type inflammation, characterized by TNF-alpha and IFN-gamma. Previous studies determined that Th2 mediators (i.e., IL-13) are vital to development of pulmonary fibrosis. The present study, using in vivo and in vitro techniques, compares silica exposures between Balb/c and Th2-deficient mice in an effort to determine the link between Th2 immunity and silicosis. In long-term experiments, a significant increase in fibrosis and activated interstitial macrophages was observed in Balb/c but not IL-4Ralpha(-/-) mice. Additionally, a significant increase in Ym1 mRNA levels, a promoter of Th2 immunity, was determined in the interstitial leukocyte population of silica-exposed Balb/c mice. To elucidate the effects of silica on macrophage function, bone marrow-derived macrophages (BMdM) were exposed to particles and assayed for T cell (TC) stimulation activity. As a control, Ym1 mRNA expression in Balb/c BMdM was determined using IL-4 stimulation. In the in vitro assay, a significant increase in TC activation, as defined by surface markers and cytokines, was observed in the cultures containing the silica-exposed macrophages in wild-type and IL-4Ralpha(-/-) mice, with one exception: IL-4Ralpha(-/-) BMdM were unable to induce an increase in IL-13. These results suggest that crystalline silica alters cellular functions of macrophages, including activation of TC, and that the increase in Th2 immunity associated with silicosis is via the IL-4Ralpha-Ym1 pathway.     

Expression of surface and secreted IgG22a by a murine B-lymphoma before and after hybridization to myeloma cells

A20 is a spontaneous Balb/c murine lymphoma which has been reported to express immunoglobulin, Fc receptors, and la antigens, but not complement receptors, on its cell surface. Approximately 0.1% of the protein synthesized by a subclone of A20 (A20-1.11) is IgG_2a,which is present on the cell surface as well as secreted by the cells. Biosynthetic labeling studies reveal that A20-1.11 cells synthesize a single κ light chain as well as two species of intracellular γ_2a heavy chain. The smaller γ_2a heavy chain, with a molecular weight of 62,000 daltons, is the intracellular precursor to a 64,000 dalton γ_2a heavy chain which is present in secreted IgG_2a. The larger intracellular γ_2a heavy chain, with a molecular weight of 68,000 daltons, is the intracellular precursor to a 70,000 dalton γ_2a heavy chain which is present in surface IgG_2a. Fusion of A20-1.11 lymphoma cells to murine myeloma cells results in hybrids expressing the more differentiated myeloma phenotype. That is, the expression of the secreted form of the lymphoma IgG_2a is amplified as much as 150 fold while the expression of the surface form of the lymphoma IgG_2a is abolished in the hybrid. The relationship of the γ_2a heavy chains expressed in these cells is discussed in relation to what has been reported for surface and secreted μ heavy chains.     

The building and sustaining of a health care partnership: the Meharry-Vanderbilt Alliance.

The ability of academic health centers (AHCs) to maintain their financial viability and mission in the face of revolutionary changes was broadly discussed during the last decade. Among the suggestions for protecting the future of AHCs was to form strategic alliances to further the missions of education, research, and service. Although the evidence indicates that 55% of strategic alliances fall apart after three years, the Meharry-Vanderbilt Alliance is now beginning its fifth year, and it appears to be growing stronger. This article presents a brief overview of the evolving historical relationship between Meharry Medical College and Vanderbilt University Medical Center-two institutions that share the same fundamental missions but have very different traditions, cultures, resources, and emphases for medical training-and their relationship with Metropolitan General Hospital at Meharry, a public hospital. The characteristics that have distinguished this strategic alliance are its organizational structure, clearly articulated and measurable objectives, an independent central office, and a shared responsibility for the management and provision of clinical services at Nashville General Hospital. The belief that the Meharry-Vanderbilt Alliance is the "right thing to do" has provided a foundation for cooperation at all levels of both AHCs.     

African American community breast health education: a pilot project.

This paper reports the results of a project designed to examine the effectiveness of a Train the Trainer breast health education and screening program for African American, elderly and underserved women residing in the greater Nashville area. The project aimed to identify a cadre of women from the community willing to serve as leaders advocated and peer breast health educators. Data collected from the community leaders and the women from the local community during the course of the project suggest that the Train the Trainer model was well suited to provide education, support and breast cancer resource referral to women residing within this rural Tennessee community.     

Kinetics of size changes of individual Bacillus thuringiensis spores in response to changes in relative humidity

Using an automated scanning microscope, we report the surprising result that individual dormant spores of Bacillus thuringiensis grow and shrink in response to increasing and decreasing relative humidity. We simultaneously monitored the size of inorganic calibration particles. We found that the spores consistently swell in response to increased relative humidity, and shrink to near their original size on reexposure to dry air. Although the dispersion of swelling amplitudes within an ensemble of spores is wide (approximately 30% of the average amplitude), amplitudes for individual spores are highly correlated between different swelling episodes, suggesting that individual spores respond consistently to changes in humidity. We find evidence for two distinct time scales for swelling: one with a time scale of no more than approximately 50 s, and another with a time scale of approximately 8 min. We speculate that these two mechanisms may be due to rapid diffusion of water into the spore coat + cortex, followed by slower diffusion of water into the spore core, respectively. Humidity-dependent swelling may account for the greater kill effectiveness of spores by gas-phase chlorine dioxide, formaldehyde, and ethylene oxide at very high relative humidity.     

Differential effects of enalapril and losartan on body composition and indices of muscle quality in aged male Fischer 344 �� Brown Norway rats

The primary purpose of the present set of studies was to provide a direct comparison of the effects of the angiotensin-converting enzyme inhibitor enalapril and the angiotensin receptor blocker losartan on body composition, physical performance, and muscle quality when administered late in life to aged rats. Overall, enalapril treatment consistently attenuated age-related increases in adiposity relative to both placebo and losartan. The maximal effect was achieved after 3 months of treatment (between 24 and 27 months of age), at a dose of 40 mg/kg and was observed in the absence of any changes in physical activity, body temperature, or food intake. In addition, the reduction in fat mass was not due to changes in pathology given that enalapril attenuated age-related increases in tumor development relative to placebo- and losartan-treated animals. Both enalapril and losartan attenuated age-related decreases in grip strength, suggesting that changes in body composition appear dissociated from improvements in physical function and may reflect a differential impact of enalapril and losartan on muscle quality. To link changes in adiposity to improvements in skeletal muscle quality, we performed gene array analyses to generate hypotheses regarding cell signaling pathways altered with enalapril treatment. Based on these results, our primary follow-up pathway was mitochondria-mediated apoptosis of myocytes. Relative to losartan- and placebo-treated rats, only enalapril decreased DNA fragmentation and caspase-dependent apoptotic signaling. These data suggest that attenuation of the severity of skeletal muscle apoptosis promoted by enalapril may represent a distinct mechanism through which this compound improves muscle strength/quality.