Biomedical subjects
R deShazo
Publications and source records attributed to R deShazo.
Fitting in integrated delivery systems: advice for department chairs.
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Immunologic aspects of granulomatous and interstitial lung diseases.
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Immune abnormalities associated with HLA-B8: lymphocyte subsets and functional correlates.
Mononuclear cell populations were enumerated in healthy young adults with or without the histocompatibility antigen HLA-B8. Mononuclear cell counts were lower in subjects with HLA-B8, as was reflected in lower absolute numbers of the cell subsets. When cell populations were compared as percentages of total mononuclear cells, subjects with HLA-B8 had significantly more B lymphocytes bearing IgM than did subjects without HLA-B8. The T4/T8 ratio was significantly increased in subjects with HLA-B8. due both to increases in OKT4+ cells and to decrease in OKT8+ cells. B-Lymphocyte function was compared in subjects with and without HLA-B8 by measuring pokeweed mitogen driven differentiation of B cells to IgM bearing blasts, and was significantly greater in subjects with HLA-B8. Subjects with HLA-B8. Subjects with HLA-B8 were also found to have decreased Con A-induced suppression. Alterations in lymphocyte subsets and lymphocyte functions may underlie the predisposition to autoimmunity associated with HLA-B8.
A modified double antibody sandwich enzyme-linked immunosorbent assay for measurement of alpha-1-antitrypsin in biologic fluids.
Alpha-1-antitrypsin (alpha 1AT) is the major protease inhibitor in human serum, and plays an important role protecting tissues from potentially harmful enzymes released during inflammatory reactions. Proteolytic enzymes such as leukocyte elastase are usually released and inactivated locally at the site of inflammation, so there has been much recent interest in measuring local alpha 1AT concentrations in biologic fluids. In this study, we developed a modified double antibody sandwich enzyme-linked immunosorbent assay (ELISA) and used it to measure alpha 1AT concentrations in several biologic fluids. The assay was sensitive to as little as 20 ng/ml of alpha 1AT. Serum concentrations measured by the ELISA correlated well with levels determined by radial immunodiffusion (RID) and the ELISA was far more sensitive than RID. In synovial fluid, higher concentrations determined by the ELISA compared with RID probably reflect interference of diffusion of alpha 1AT in the RID gel by hyaluronic acid and protease-inhibitor complexes. Synovial fluid did not interfere with the detection of added alpha 1AT by ELISA, but it did reduce the amount detected by RID by about 30% in 2 fluids. In saliva, alpha 1AT concentrations of less than 1 microgram/ml were easily quantified. Bronchoalveolar lavage fluids have been extensively studied because of the important role of alpha 1AT in pulmonary inflammatory processes. We found concentrations of 1-3 micrograms/ml in most samples with our assay. These levels were comparable to those previously reported with assays that required up to 50-fold concentration of the fluid. Neither saliva nor bronchoalveolar fluid significantly interfered with detection by ELISA of added alpha 1AT. This modified double antibody sandwich ELISA may have broad applications for studies of the role of alpha 1AT in health and disease.
Immunologic aspects of granulomatous and interstitial lung diseases.
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Iodine treatment of iodine-induced thyrotoxicosis.
A 62-year-old female who had received prolonged iodine therapy for asthma presented with severe thyrotoxicosis and severe asthma. Her history, elevated serum thyroxine and triiodothyronine, low 131I uptake, and elevated intrathyroidal iodine content by fluorescent scan were most consistent wiht a diagnosis of iodine-induced thyrotoxicosis (IITT). The clinical course of her thyrotoxicosis was protracted, and in spite of its etiologic role in the precipitaton of thyrotoxicosos, iodine was therapeutically efficacious, although combined treatment with methimazole was required to ultimately restore euthyroidism. Therapy with lithium was also employed but appeared to be only transiently effective and combined no additional decrement in serum T4 than that seen with iodine alone. The case exemplifies the heterogeneity of what is considered "iodine-induced" thyrotoxicosis, the complexities inherent in establishing a diagnosis of IITT, and the use of other rapid acting pharmacologic agents in IITT when beta blockade is contraindicated by asthma.
Fire ant venom alkaloid, isosolenopsin A, a potent and selective inhibitor of neuronal nitric oxide synthase.
Massive, multiple fire ant, Solenopsis invicta, stings are often treated aggressively, particularly in the elderly, despite limited evidence of systemic toxicity due to the venom. Over 95% of the S. invicta venom is composed of piperidine alkaloid components, whose toxicity, if any, is unknown. To assess a possible pharmacological basis for systemic toxicity, an alkaloid-rich, protein-free methanol extract of the venom from whole ants was assayed for inhibitory activity on the following nitric oxide synthase (NOS) isoforms, rat cerebellar neuronal (nNOS), bovine recombinant endothelial (eNOS), and murine recombinant immunologic (iNOS). Cytosolic NOS activity was determined by measuring the conversion of [(3)H]arginine to [(3)H]citrulline in vitro. Rat nNOS activity was inhibited significantly and in a concentration-dependent manner by the alkaloid-rich venom extract. For nNOS, enzyme activity was inhibited by approximately 50% with 0.33 +/- 0.06 microg of this venom extract, and over 95% inhibition of the three isoforms, nNOS, eNOS, and iNOS, was found with doses of 60 microg in 60 microl reaction mixture. These results indicate that the alkaloid components of S. invicta venom can produce potent inhibition of all three major NOS isoforms. Isosolenopsin A (cis-2-methyl-6-undecylpiperidine), a naturally occurring fire ant piperidine alkaloid, was synthesized and tested for inhibitory activity against the three NOS isoforms. Enzyme activities for nNOS and eNOS were over 95% inhibited with 1000 microM of isosolenopsin A, whereas the activity of iNOS was inhibited by only about 20% at the same concentration. The IC(50) for each of three NOS isoforms was approximately 18 +/- 3.9 microM for nNOS, 156 +/- 10 microM for eNOS, and >1000 microM for iNOS, respectively. Kinetic studies showed isosolenopsin A inhibition to be noncompetitive with L-arginine (K(i) = 19 +/- 2 microM). The potency of isosolenopsin A as an inhibitor of nNOS compares favorably with the inhibitory potency of widely used nNOS inhibitors. Inhibition of NOS isoforms by isosolenopsin A and structurally similar compounds may have toxicological significance with respect to adverse reactions to fire ant stings.