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Biomedical subjects

B R Smith

Publications and source records attributed to B R Smith.

At least 253 records · Page 14Linked to original sources
PubMed1985

Origin of cell populations after bone marrow transplantation. Analysis using DNA sequence polymorphisms.

After successful bone marrow transplantation, patient hematopoietic and lymphoid cells are replaced by cells derived from the donor marrow. To document and characterize successful engraftment, host and donor cells must be distinguished from each other. We have used DNA sequence polymorphism analysis to determine reliably the host or donor origin of posttransplant cell populations. Using a selected panel of six cloned DNA probes and associated sequence polymorphisms, at least one marker capable of distinguishing between a patient and his sibling donor can be detected in over 95% of cases. Posttransplant patient peripheral leukocytes were examined by DNA restriction enzyme digestion and blot hybridization analysis. We have studied 18 patients at times varying from 13 to 1,365 d after marrow transplantation. Mixed lymphohematopoietic chimerism was detected in 3 patients, with full engraftment documented in 15. One patient with severe combined immunodeficiency syndrome was demonstrated to have T cells of purely donor origin, with granulocytes and B cells remaining of host origin. Posttransplant leukemic relapse was studied in one patient and shown to be of host origin. DNA analysis was of particular clinical value in three cases where failure of engraftment or graft loss was suspected. In two of the three cases, full engraftment was demonstrated and in the third mixed lymphohematopoietic chimerism was detected. DNA sequence polymorphism analysis provides a powerful tool for the documentation of engraftment after bone marrow transplantation, for the evaluation of posttransplant lymphoma or leukemic relapse, and for the comprehensive study of mixed hematopoietic and lymphoid chimeric states.

Adult↗
PubMed1985

Discordance between transferrin receptor expression and susceptibility to lysis by natural killer cells.

Expression of the transferrin receptor on target cell lines has recently been implicated as a determinant of susceptibility to cytolysis by natural killer (NK) lymphocytes. We have examined this proposed relationship in several ways. First, K562 (a cell line highly vulnerable to NK lysis) cells were grown for 24 h in the iron chelator desferrioxamine. Under these conditions, the cells doubled their surface transferrin receptor expression as determined both by radioligand binding and surface binding of the OK-T9 monoclonal anti-transferrin receptor antibody. In contrast, cells grown for the same period of time in hemin halved their receptor expression. This fourfold change in transferrin receptor expression between the desferrioxamine-treated and hemin-treated cells produced no change in susceptibility to NK cytolysis. Second, HeLa (a cell line which in its native state is very resistant to NK cytolysis) cells were compared with K562 cells with respect to surface transferrin receptor expression. The difference in NK susceptibility of the two cell lines was not reflected in differences in transferrin receptor expression: the K562 cells expressed approximately 1.5 X 10(5) receptors per cell while HeLa cells expressed 2.0 X 10(5) receptors/cell. Third, infection of HeLa cells by measles virus greatly increased their susceptibility to NK lysis but produced no change in surface transferrin receptor expression. Furthermore, when measles-infected HeLa cells were grown for 6 d in medium supplemented with iron-saturated human transferrin they underwent a 50% reduction in receptor expression but no change in NK susceptibility. Finally, possible alterations in the surface expression of NK target antigens on modified cells were further assayed by their ability to serve as cold-target inhibitors of cytolysis of NK-sensitive target cells. We examined two groups of cells in which transferrin receptor expression was reduced. These were the transferrin-treated, measles-infected HeLa cells with the 50% receptor reduction, and K562 cells grown in medium containing hemin and iron salts where the reduction was five- to sixfold relative to control. In neither case was there a change in the apparent expression of NK target antigen(s). We conclude that there is a discordance between transferrin receptor expression and susceptibility to NK cytolysis in the model systems examined. Therefore, it is unlikely that the transferrin receptor per se is the target recognition structure for human NK cells, although a role in concert with other, as yet undefined molecules, cannot be excluded.

Binding, Competitive↗
PubMed1985

Amoxicillin-potassium clavulanate: a novel beta-lactamase inhibitor.

Potassium clavulanate is a novel beta-lactamase inhibitor, which, in combination, expands the spectrum of amoxicillin to include many amoxicillin-resistant organisms. Potassium clavulanate is excreted 30-50 percent unchanged renally and its plasma time-course parallels that of amoxicillin. Several studies suggest that an increased incidence of gastrointestinal side effects may occur with this combination. In the current oral formulation, its greatest utility may be in pediatric infections due to beta-lactamase-producing Haemophilus influenzae and B. cattarhalis. In adults, the combination has not been adequately studied against other effective antibiotics.

Amoxicillin↗
PubMed1985

TSH crosslinks to the TSH receptor through the beta subunit.

TSH binds specifically to the TSH receptor present on the surface of thyroid follicular cells and consequently activates adenylate cyclase. It was not known, however, which of the two subunits of the TSH bound to the receptor. By covalently crosslinking TSH to its receptor and characterizing the product with antisera specific for either the alpha or beta subunit of TSH, we have shown that the TSH beta subunit but not the TSH alpha subunit crosslinks to the TSH receptor.

Animals↗
PubMed1985

The effect of carbimazole on thyroid autoantibody synthesis by thyroid lymphocytes.

Thyroid autoantibody synthesis was investigated in cultures of lymphocytes isolated from several sources, including thyroid and lymph nodes from patients with hyperthyroid Graves' disease treated preoperatively with carbimazole or propranolol. The ability of thyroid lymphocytes to secrete immunoglobulins, including thyroid microsomal or thyroglobulin autoantibodies, was markedly reduced in lymphocyte suspensions obtained from patients treated with carbimazole compared with suspensions from patients treated with propranolol. This effect (which was greater in individuals treated with carbimazole for longer periods) was attributable to a significant reduction in the number of viable lymphocytes present after the 14-day culture interval. In contrast, the type of preoperative therapy had little effect on cultures of lymphocytes obtained from lymph nodes draining the thyroid. Although it is not yet clear whether carbimazole exerts its effects in vivo by direct immunosuppression or indirectly by altering the thyroid microenvironment, our observations indicate that the fall in serum levels of thyroid autoantibodies that occurs during carbimazole therapy is related to an effect of the drug on lymphocytes within the thyroid.

Antibody Formation↗
PubMed1985

Thyrotropin-releasing hormone-induced contraction of urethral and vaginal muscle.

Pressure studies were carried out in 10 women to determine whether TRH stimulates muscular contractions in the genitourinary system. TRH (500 micrograms) or saline was administered iv as a bolus injection. Whereas saline had no effect, TRH increased intraurethral pressures in all women, vaginal pressure in 7, and bladder pressure in none. These findings suggest that TRH, acting centrally, peripherally, or both, may play a role in initiating muscular contractions in the female genitourinary tract.

Adult↗
PubMed1985

Isolated thrombocytopenia after allogeneic bone marrow transplantation: existence of transient and chronic thrombocytopenic syndromes.

Isolated thrombocytopenia after bone marrow transplantation was investigated in 65 fully engrafted patients surviving at least 60 days posttransplant. Twenty-four patients (37%) developed this complication, which occurred most frequently in patients receiving pretransplant preparation with total body irradiation or busulfan. Two distinct thrombocytopenic syndromes were identified: (1) transient thrombocytopenia (nine patients), in which a normal platelet count (greater than 100,000/microL) was initially established by day +40 but then diminished to less than 10,000 to 45,000/microL on day +40 to +70, with subsequent resolution of the thrombocytopenia by day +90; (2) chronic thrombocytopenia (15 patients), in which a platelet count greater than 100,000/microL was not achieved at any time during the first four months posttransplant, despite the simultaneous presence of normal granulocyte and reticulocyte counts. Although the transient syndrome did not adversely affect prognosis, the chronic syndrome carried a high mortality (21% actuarial survival at 1,000 days posttransplant compared with 67% survival for all patients, P less than .01) and had a high association with both severe (grades 3 to 4) acute graft-versus-host disease (GVHD) and chronic GVHD. In three of nine patients with transient thrombocytopenia, a temporal association with trimethoprim-sulfamethoxazole administration was observed, whereas in all other patients, no drug association could be found. Bone marrow biopsies in those patients with drug-associated thrombocytopenia showed decreased numbers of megakaryocytes, whereas biopsies in the remainder of the transiently thrombocytopenic patients demonstrated adequate numbers of platelet precursors, suggesting peripheral platelet destruction or ineffective thrombopoiesis. Biopsies in the chronic thrombocytopenic patients included those with and without adequate numbers of platelet precursors, although the association with chronic GVHD was strongest in patients demonstrating normal numbers of megakaryocytes. We conclude that isolated thrombocytopenia represents a significant complication of bone marrow transplantation, particularly in patients receiving hematopoietic ablative preparatory regimens, and that it is the chronic, not the transient, thrombocytopenic syndrome that is associated with an adverse patient prognosis.

Actuarial Analysis↗
PubMed1985

Natural killer lymphocytes in hairy cell leukemia: presence of phenotypically identifiable cells with defective functional activity.

Eleven patients with hairy cell leukemia (HCL) were studied to determine the number and function of circulating natural killer (NK) lymphocytes in this disorder using a well-defined surface marker of these cells (Mac-1), the fluorescence-activated cell sorter (FACS), and a standard 51Cr release assay to determine cytotoxicity against the K562 cell line. Four of these patients demonstrated normal numbers of phenotypic and morphological (large granular lymphocyte) NK cells in the blood, but these cells showed a severe functional deficiency in their ability to lyse the K562 target. Sorting experiments demonstrated that although all of the NK activity was contained within the phenotypically identifiable NK population, the defect in NK function persisted even when these cells were isolated from other cell populations. Of the remaining seven patients, two had normal numbers and function of NK cells and five showed a marked deficiency of both phenotypic NK cells in the blood and NK function. These data suggest that the marked in vitro functional deficiencies of NK activity that occur in a majority of patients with HCL are sometimes associated with the preservation of phenotypically identifiable NK cells that are qualitatively rather than quantitatively deficient.

Antibodies, Monoclonal↗
PubMed1985

Bone marrow transplantation for paroxysmal nocturnal hemoglobinuria: eradication of the PNH clone and documentation of complete lymphohematopoietic engraftment.

Paroxysmal nocturnal hemoglobinuria (PNH) involves the proliferation of an abnormal and possibly premalignant hematopoietic stem cell. Successful treatment of PNH by marrow grafting requires that the PNH clone be eradicated by the pretransplant conditioning regimen. Four patients with PNH-associated marrow aplasia were transplanted with marrow from their HLA-matched, MLR-nonreactive siblings. Three patients were conditioned with cyclophosphamide, procarbazine, and antithymocyte serum (CTX/PCZ/ATS), and one was conditioned with busulfan/CTX/PCZ/ATS. Persistent complete engraftment of myeloid, lymphoid, and erythroid cell lines was demonstrated in all four patients by DNA sequence polymorphism analysis or cytogenetics, and RBC typing. There was no recurrence of the abnormal clone of cells for up to five years after transplantation despite the use of a conditioning regimen in three of them, which is not usually associated with permanent marrow aplasia. Bone marrow transplantation is a curative therapy in patients whose illness is severe enough to warrant the risk.

Adult↗
PubMed1984

Circulating monoclonal B lymphocytes in non-Hodgkin's lymphoma.

Using a sensitive flow cytometric method ("kappa-lambda analysis"), we have found monoclonal B lymphocytes in the blood of 71 of 91 patients with non-Hodgkin's lymphoma. The presence of the B lymphocytes was independent of the histologic subclassification of the patient's disease. When we performed simultaneous analysis of the surface light-chain type in tumor tissue obtained by biopsy, the apparent light-chain type of the blood monoclonal cells corresponded with that of the tumor in 21 of 23 patients (P = 0.03). There was no correlation of the presence of these cells in the blood with morphologic evidence of bone-marrow involvement by lymphoma, but there was a strong correlation with clinical staging. Studies performed during prolonged clinical remission showed that whereas 16 of 25 patients with nodular non-Hodgkin's lymphoma had persistence of monoclonal lymphocytes, none of the 14 patients with diffuse histiocytic lymphoma in remission had these findings (P less than 0.005). Our analysis for B-cell clonal excess demonstrates the persistence of circulating monoclonal lymphocytes during complete remission in patients with forms of lymphoma that have a high probability of relapse, but we did not find these cells in patients in remission from categories of lymphoma in which prolonged remission is associated with cure. It is possible that the circulating monoclonal lymphocytes in patients with lymphoma are malignant cells, and their disappearance or persistence after remission may have prognostic importance.

B-Lymphocytes↗
PubMed1984

Forskolin, a potent adenylate cyclase activator, lowers rabbit intraocular pressure.

To our knowledge, this is the first report of a topically applied, specific adenylate cyclase activator that reduces intraocular pressure. Forskolin, a novel adenylate cyclase activator, is reported to increase cyclic adenosine monophosphate (AMP) in intact cells. Cyclic AMP levels are increased with various antiglaucoma agents. Intraocular pressure in rabbits was significantly reduced with two concentrations of forskolin, 0.1% and 0.05%. Ocular hypertension was noted with 0.05% and 0.2%. No change in IOP was noted with 0.01% forskolin. The IOP lowering with 0.1% and 0.05% forskolin lasted approximately six hours. Mild, transient conjunctival chemosis was noted in the doses that decreased IOP. The contralateral control eye showed decreases in IOP, but the differences between control and tested eyes were significant by the Student's paired t test.

Adenylyl Cyclases↗
PubMed1984

Cefmenoxime. Clinical, bacteriologic, and pharmacologic studies.

Cefmenoxime, a new semisynthetic third-generation cephalosporin, was evaluated in 105 patients (45 men and 60 women) with the following infections: skin or skin structure (33), pulmonary (22), urinary tract (30), and septicemia (20). Forty-two infections were hospital-acquired, 85 patients had underlying diseases, 29 patients required concomitant surgery, and 32 patients had positive results of blood culture. Cefmenoxime dosages ranged from 4 to 12 g per day intravenously for one and a half to 51 days. Cultures revealed 183 organisms in the 105 patients. Minimal inhibitory concentrations were obtained for cefmenoxime, cefoperazone, cefotaxime, cefamandole, cefoxitin, and moxalactam. Cefmenoxime and cefotaxime exhibited nearly equivalent activities against all organisms tested and were the most active agents tested against all aerobic and facultative organisms except Staphylococcus aureus. Mean serum peak and trough levels obtained after 2 g every six hours were 84.1 micrograms/ml (peak), 8.3 micrograms/ml (trough); and after 2 g every four hours, 106 micrograms/ml (peak) and 10.9 micrograms/ml (trough). Of 105 infections, 86 were clinically cured, three were not cured, and 16 were not evaluable. Safety studies revealed 24 transient reactions in 23 patients including eosinophilia, diarrhea, leukopenia, rash, elevated liver enzyme levels, Antabuse effect, and phlebitis. On the basis of these clinical and in vitro results, cefmenoxime is a safe drug for the treatment of infections caused by gram-negative and gram-positive aerobic organisms.

Adult↗
PubMed1984

Metabolism and excretion of [3H]misonidazole by hypoxic rat liver.

Our investigation was initiated to determine if misonidazole's biological activity is related to hypoxia-dependent, reductive biotransformation to form reactive metabolites. This study was facilitated by the synthesis of [3H]misonidazole and by use of the isolated perfused rat liver as a model system for hypoxic tissue. The perfused rat liver was verified as an appropriate model system to study misonidazole (MISO) metabolism. This was done by demonstrating that the perfused liver produced the same metabolites as those isolated from rats given MISO, albeit reductive metabolism was much less in rats. Reductive metabolism of MISO by perfused livers was enhanced (estimated by measuring the rate of 1-[2-aminoimidazol-1-yl]-3-methoxy-2-propanol production) by hypoxic conditions. Formation of a MISO-derived glutathione conjugate (MISO-GSH) and covalent binding of MISO-derived radioactivity to tissue protein was also enhanced by hypoxia. Depletion of hepatic GSH with diethyl maleate increased the extent of covalent binding to protein under both aerobic and hypoxic conditions, and greatly diminished the formation of MISO-GSH. These results support the hypothesis that hypoxic conditions facilitate reductive metabolism of MISO to an alkylating agent, and that GSH plays an intervening role in the alkylation reaction.

Animals↗
PubMed1984

Diffusion of ceftriaxone into the cerebrospinal fluid of adults.

Fourteen adults, three recovering from bacterial meningitis, were given a single 2 g dose of ceftriaxone or three 2 g doses at 12-hourly intervals. The mean per cent penetration of drug into cerebrospinal fluid (CSF) across uninflamed meninges was 1.5%. These levels, although low, are bactericidal in vitro against most pathogens causing meningitis.

Adult↗
PubMed1984

Enterococcal superinfection and colonization with aztreonam therapy.

Patients were given aztreonam (SQ 26,776) parenterally for the treatment of various gram-negative infections. During or shortly after therapy, 8 (17.8%) of 45 patients became infected with or colonized by enterococcus. These eight cases included eight urinary tract isolates; one of these cases subsequently developed bacteremia. Five patients required further antimicrobial therapy directed against enterococcus. Patients receiving aztreonam are at risk for the development of enterococcal superinfection or colonization.

Anti-Bacterial Agents↗