Biomedical subjects
B R Smith
Publications and source records attributed to B R Smith.
Effect of storage temperature and time on stability of cefmenoxime, ceftriaxone, and cefotetan in 5% dextrose injection.
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Cefuroxime: antimicrobial activity, Pharmacology, and clinical efficacy.
The antimicrobial activity, pharmacology, toxicity, and clinical efficacy of cefuroxime are reviewed. Cefuroxime has a second-generation cephalosporin spectrum of activity similar to cefamandole. Addition of a methoxyimino side chain has enhanced its beta-lactamase stability. Cefuroxime is active against certain cephalothin-, cefamandole-, and gentamicin-resistant bacteria. Cefuroxime has an extended half-life which allows dosing every 8 h. If penetrates into bodily tissues and fluids, including the cerebrospinal fluid, in therapeutic concentrations. Cefuroxime has been used successfully in the treatment of meningitis; sepsis; urinary tract, bone and joint, pulmonary, skin, and soft tissue infections; and gonorrhea. Competitive pricing of cefuroxime should provide a cost-effective substitute for cefamandole and, in certain situations, third-generation cephalosporins.
In Waldenstrom's macroglobulinemia the quantity of detectable circulating monoclonal B lymphocytes correlates with clinical course.
Using a sensitive flow-cytometer-based method of detecting small numbers of morphologically normal monoclonal B lymphocytes, we have investigated the presence and quantity of these cells in the blood of 12 patients with Waldenstrom's macroglobulinemia. All 12 patients, including 6 at the time of asymptomatic presentation, had such circulating monoclonal cells. By comparison, 2 of 7 patients with multiple myeloma had such cells, and prior studies have shown that 80% of patients with non-Hodgkin's lymphoma exhibit blood involvement by these criteria. Enzymatic removal of surface immunoglobulin (lg) with subsequent regeneration by the cells after overnight culture established that the monoclonal surface lg being studied was of intrinsic cell membrane origin and not passively adsorbed serum lg. Serial studies were performed in 7 patients. In the 4 cases where a clinical response to therapy and a decrease in serum IgM level was seen, there was a corresponding decrease in the estimated number of abnormal cells. In the 3 cases where there was neither clinical nor serum M-component evidence of response, the estimated percent abnormal cells likewise increased or remained constant. We conclude that patients with Waldenstrom's macroglobulinemia have a significant number of peripheral blood monoclonal B lymphocytes, even early in their disease, and that for a given patient, serial determinations of the number of these cells as estimated by flow cytometry reflects the clinical activity of the disease.
Thyroid autoantibody synthesis by cultures of thyroid and peripheral blood lymphocytes. I. Lymphocyte markers and response to pokeweed mitogen.
Thyroid lymphocytes from Graves' and Hashimoto patients have been investigated and compared with lymphocytes from the peripheral blood. Considerably more lymphocytes (20-30 X 10(6)/g) could be isolated from Hashimoto thyroids than from Graves' tissue (1-5 X 10(6)/g) but the cell suspensions extracted from Hashimoto and Graves' glands were similar in terms of cell surface markers and the ability to synthesize immunoglobulin. Thyroid lymphocytes contained a lower proportion of T cells (OKT3+ cells) and in some cases more B cells than the peripheral blood but the ratio of helper to suppressor T cells (OKT4+:OKT8+ cells) was similar to the values obtained for blood lymphocytes. Further, thyroid lymphocytes (unlike blood lymphocytes) synthesized relatively large amounts of microsomal and/or thyroglobulin antibody when cultured in medium only and these levels were significantly decreased by the addition of pokeweed mitogen. The results of this study provide further evidence for the role of the thyroid as a major site of thyroid autoantibody synthesis and emphasize the importance of characterizing the cells infiltrating the gland in autoimmune thyroid disease.
Estimation of the styrene 7,8-oxide-detoxifying potential of epoxide hydrolase in glutathione-depleted, perfused rat livers.
The importance of epoxide hydrolase in preventing styrene 7,8-oxide-induced hepatoxicity was studied in isolated perfused rat livers depleted of GSH. GSH depletion was accomplished by treating the rats with diethyl maleate 45 min before surgical removal of their livers. Diethyl maleate itself caused mild hepatotoxicity that was observed histologically and measured biochemically by the release of hepatic transaminase enzymes into the circulation. GSH transferase activity was decreased in perfused livers from diethyl maleate-treated rats as shown by the persistence of circulating styrene oxide compared with that seen in experiments with livers from control animals. In the absence of GSH transferase activity, the rate of styrene oxide biotransformation by epoxide hydrolase was sufficient to prevent measurable hepatotoxicity, up to epoxide concentrations tolerated by livers from control rats. The administration of 500 mumol of styrene oxide to perfused livers from diethyl maleate-treated rats caused periportal necrosis and extensive covalent binding of styrene oxide-derived radioactivity to tissue protein. These effects, however, were no more severe than those seen in perfused livers from control animals given 500 mumol of styrene oxide. Due to high GSH transferase activity in perfused livers from untreated rats, the capacity of epoxide hydrolase to detoxify styrene oxide is difficult to measure in this system. The detoxication potential of epoxide hydrolase was clearly demonstrated in this study with GSH-depleted liver preparations.
Thyroid autoantibody synthesis by cultures of thyroid and peripheral blood lymphocytes. II. Effect of thyroglobulin on thyroglobulin antibody synthesis.
The influence of antigen (thyroglobulin, Tg) on Tg antibody synthesis has been investigated using cultures of Hashimoto thyroid and peripheral blood lymphocytes. In cultures of thyroid lymphocytes, Tg antibody synthesis was stimulated by a 24h pulse of Tg (10-100 micrograms/ml) and similar results were obtained using spleen lymphocytes from BALB/c mice immunized with human Tg. In contrast, Tg antibody synthesis by Hashimoto peripheral blood lymphocytes was not affected by similar concentrations of Tg (1-240 micrograms/ml) in the presence or absence of pokeweed mitogen (PWM). However, peripheral blood lymphocytes from two out of nine patients produced increased levels of Tg antibody in the presence of very low concentrations of Tg (50 ng/ml). This increase in Tg antibody production was accompanied by a rise in total IgG synthesis indicating that the response to Tg was polyclonal. On the basis of other unusual features of the lymphocyte cultures from these two patients including a relatively small response to PWM and evidence of circulating plasma cells, it is suggested that sufficient numbers of lymphocytes responsive to Tg are only released into the circulation during active phases of the disease process.
Tuberculosis therapy.
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An enzyme-linked immunoassay for thyroid microsomal antibodies.
An enzyme-linked immunoassay (ELISA) for microsomal antibody is described. The method was found to be rapid, sensitive and precise and analysis of 115 serum samples showed good correlation between the ELISA and the conventional tanned red cell haemagglutination test. The presence of thyroglobulin antibody, rheumatoid factor, antinuclear factor or gastric parietal cell antibodies did not interfere in the microsomal antibody ELISA but some sera with mitochondrial antibody activity appeared to cause a non-specific effect. The ELISA was particularly useful for analysing microsomal antibody production by Hashimoto lymphocyte cultures and in some cases antibody synthesis could be studied in the absence of mitogen. The high capacity of the ELISA combined with its sensitivity suggest that it will be a valuable technique for studying microsomal autoantibody activity both in serum and in lymphocyte cultures.
Intraventricular self-administration of leucine-enkephalin by laboratory rats.
Naive laboratory rats, without pre-exposure to operant training procedures or to opioids, were shown to self-administer directly into their cerebral ventricles the endogenous opiate peptide, leucine-enkephalin. They were shown to self-administer the peptide consistently for six consecutive days with no indication of the development of tolerance. The results indicate that leucine-enkephalin may possess potent reinforcing properties and suggests that it may play a role as an endogenous reward transmitter.
Structure-function relations of the thyrotropin receptor.
The thyrotropin (thyroid-stimulating hormone or TSH) receptor is an amphiphilic membrane component with a relative molecular mass of about 200,000 as judged by gel filtration and an isoelectric point close to pH 5. Analyses with chemical, enzymic and affinity probes indicate that the receptor is a glycoprotein containing a disulphide bridge and that the integrity of the disulphide bond is essential for maintaining the structure of the TSH-binding site. Serum from patients with Graves' disease contains antibodies which inhibit the binding of TSH to its receptor and there is considerable evidence that this effect is due to a direct interaction between the antibodies and the receptor. The antibody-receptor interaction is probably responsible for the TSH agonist properties of Graves' serum and, similarly, the TSH antagonist properties of the sera from a small number of patients can be explained on the basis of antibody-receptor binding. Although TSH and IgG from Graves' disease patients appear to bind to the same receptor, the relationship between the sites for the two substances is not clearly understood. However, Fab fragments of Graves' IgG are as effective as intact IgG in competing with TSH for the receptor and gel filtration and immunoprecipitation studies indicate that the binding of hormone and antibody to the receptor is mutually exclusive. Current evidence suggests therefore that the binding sites for TSH and TSH receptor antibodies are very closely related and may well be identical.
The enhancement of immunoglobulin synthesis by human lymphocytes with lithium.
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Studies of thyroglobulin autoantibody synthesis using a micro-ELISA assay.
Thyroglobulin autoantibody synthesis by Hashimoto lymphocyte cultures has been studied using an ELISA, a plaque assay and tanned red cell haemagglutination. The ELISA system was found to be the most suitable and using this method IgG-class thyroglobulin antibody synthesis was detectable in cultures of mitogen-stimulated lymphocytes from all 10 Hashimoto patients studied, but not in cultures of lymphocytes from 4 normal donors. The ELISA was also sufficiently sensitive to detect thyroglobulin antibody synthesis in mitogen-free lymphocyte cultures from 4 out of the 10 Hashimoto patients and consequently it should be possible to use this system to study the effect of various pathophysiological factors on autoantibody synthesis which would otherwise be masked by mitogenic stimulation.
Evidence that the porcine thyrotropin (TSH) receptor contains an essential disulphide bridge.
The effects of reducing agents on membrane bound and detergent solubilised porcine TSH receptors have been investigated. Both 2-mercaptoethanol and dithiothreitol appeared to inhibit the TSH-binding activity by a direct effect on the TSH receptor itself and Scatchard analysis suggested that this was primarily due to an alteration in TSH-binding capacity. In addition, some binding activity could be recovered by reoxidation of reduced receptor preparations. These results suggest therefore that the porcine TSH receptor contains an essential disulphide bridge.
Comparative study of ceftizoxime and cefamandole in the treatment of bronchopulmonary infections.
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An improved radioreceptor assay for TSH receptor antibodies.
An improved receptor assay for TSH receptor antibodies is described in which detergent-solubilized TSH receptors and 125I-labelled TSH are used. Normal human serum and immunoglobulin concentrates from normal serum showed little effect on the interaction between labelled TSH and detergent-solubilized receptors whereas immunoglobulin concentrates from some Graves sera caused marked inhibition of TSH binding. Precipitation with polyethylene glycol was the most convenient way of preparing immunoglobulin concentrates and using this technique the assay could be completed in a few hours. The coefficient of inter assay variation at 51% inhibition of labelled TSH binding was 3.7% and analysis of serum samples from patients with Graves' disease (n = 42), Hashimoto's disease (n = 26), multinodular goitre (n = 9), rheumatoid arthritis (n = 10) and normal donors (n = 35) suggested that the assay could detect TSH receptor antibodies in about 80% of patients (treated and untreated) with Graves' disease.
Effect of radioiodine on stimulatory activity of Graves' immunoglobulins.
The effects of 131I therapy on the activity of thyroid stimulating antibody (TSAb) and thyrotrophin binding inhibiting immunoglobulin (TBII) in nineteen patients with Graves' disease have been studied. Prior to 131I administration TSAb was detected in 84%, and TBII in 68% of patients. Following 131I administration TSAb and TBII were detectable in 100% of patients. The elevation 3 months after treatment of the means of both the TSAb and TBII indices for the group of nineteen patients was highly significant compared with pre treatment values. All the patients went into remission during the course of the study and the TSAb index declined in all patients, becoming undetectable in eleven; TBII also declined in most patients but remained detectable in thirteen. The study furthermore afforded the opportunity for a direct comparison of binding with stimulatory activity. These results show that after 131I therapy for Graves' hyperthyroidism there is a transient increase in TSAb as well as TBII, followed by a decline, and that the measurement of binding and stimulatory activities are in good general agreement.
[Antibodies of the TSH receptor in Graves' disease (author's transl)].
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