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Biomedical subjects

R A Johnson

Publications and source records attributed to R A Johnson.

At least 145 records · Page 8Linked to original sources
PubMed1991

Staging laparotomy in Hodgkin's lymphoma: 1979 to 1988.

A retrospective review of patients with Hodgkin's lymphoma undergoing staging laparotomy was done. Ninety-four patients were identified for analysis. Preoperative lymphangiography was performed in 86 patients, and computed tomography of the abdomen was performed in 53. Both proved to have an accuracy rate of 76%. Mortality and 30-day morbidity rates were 0% and 17%, respectively, when both major (8%) and minor (10%) complications were considered. Late complications (greater than 30 days) were noted in 5%. The results of the laparotomy required a change in staging in 28% of patients, with alterations in subsequent clinical management occurring in 18%. In selected patients, staging laparotomy is safe and remains a reliable means of determining the intra-abdominal extent of Hodgkin's lymphoma.

Adult↗
PubMed1991

Renal effects of ANF (95-126), a new atrial peptide analogue, in dogs with experimental heart failure.

Atrial natriuretic factor 95-126 [ANF (95-126)] is a novel 32 amino acid peptide which is thought to originate from the kidney. The systemic hemodynamic and renal effects of equimolar doses of intravenous synthetic ANF (95-126) and synthetic alpha ANF (99-126) were examined in normal dogs (n = 6) and in dogs with an arteriovenous (AV) fistula and chronic compensated high-output heart failure (n = 5). ANF (95-126) and alpha ANF (99-126) were infused at 5 and 10 pmol/kg/min for 75-min periods each. In the normal and AV fistula dogs the two peptides similarly decreased mean arterial pressures and right atrial pressures (P less than .05). Creatinine clearance and urinary volume excretion increased (P less than .05) in the normal dogs with both peptides, but only ANF (95-126) produced significant elevations (P less than .05) of these two parameters in the AV fistula animals. With the highest infusion dose, ANF (95-126) increased urinary sodium excretion to at least twice the levels observed with alpha ANF (99-126) in both groups of dogs (P less than .05). The decreases in plasma renin and aldosterone were comparable for the two peptides in both groups of animals. These results indicate that ANF (95-126) is more potent than alpha ANF (99-126) for the promotion of a natriuresis, particularly in AV fistula dogs with compensated high-output heart failure, in which the sodium excretory actions of alpha ANF (99-126) were attenuated markedly.

Animals↗
PubMed1991

Contribution of leukotriene B4 to airway inflammation and the effect of antagonists.

Inhalation of aerosols of ovalbumin in sensitized guinea pigs produced a marked, bronchoalveolar eosinophilia 24 hr after challenge. The lung eosinophilia was not prevented by the cyclooxygenase inhibitors, indomethacin or PAF antagonists (WEB-2086 and L-652731) but was inhibited by methylprednisolone, the 5-LO inhibitor, U-66858 and a series of structural analogs of LTB4, U-75302, U-77692, U-75485 and U-78489. The effectiveness of LTB4 antagonists but not PAF antagonists in vivo was consistent with in vitro studies in which LTB4 was shown to be far more chemotactic than PAF for guinea pig eosinophils. LTB4 elicited maximal directional migration of guinea pig eosinophils at concentrations from 10(-7) M to 10(-9) M while PAF showed no effect over the same concentration range. The structural analogs of LTB4 were shown to inhibit LTB4 induced chemotaxis of guinea pig eosinophils and produced a dose-related inhibition of binding of LTB4 to guinea pig eosinophil membranes. To add further proof to the hypothesis that LTB4 contributed to the antigen-induced lung eosinophilia we attempted to measure LTB4 release into BAL fluid immediately after and at various time points up to 24 hr after antigen inhalation. However, using a sensitive radioimmunoassay (detection limit 10 pg/ml) very low levels of LTB4 (24.9-67.9 pg/ml) or its metabolite, 20-OH LTB4 (24.9-98.2 pg/ml) were detected in BAL fluid and these levels did not increase significantly following antigen provocation. Inhalation of LTB4 aerosols in unsensitized Brown-Norway rats or inhalation of aerosols of ovalbumin in sensitized Brown-Norway rats also produced a marked "late-phase" eosinophil-rich influx of inflammatory cells into the lungs. The lung eosinophilia in the rat was prevented by two structurally unrelated leukotriene B4 (LTB4) antagonists, U-75302 and Ly255283. These data implicate LTB4 as a mediator of allergen-induced bronchopulmonary eosinophilia. Leukotriene B4 antagonists may provide leads for the development of compounds which inhibit the chronic airway inflammation associated with asthma in man.

Aerosols↗
PubMed1991

Adenosine stimulates phosphate and glucose transport in opossum kidney epithelial cells.

We have examined the effects of adenosine on sodium-coupled phosphate and glucose transport in cultured opossum kidney (OK) cells, a continuous cell line that resembles proximal tubule. Adenosine analogues R-(-)-N6-phenylisopropyladenosine (PIA) and 2',5'-dideoxy-adenosine (DDA) were employed as adenosine A1 receptor and P site-selective agonists, respectively. Sodium-dependent phosphate uptake activity (Na-Pi symport) increased by approximately 25% above both basal and parathyroid hormone (PTH)-inhibited levels in cells treated with PIA (0.1, 1 microM) but not in cells treated with DDA (100 microM). Adenosine (PIA) also stimulated sodium-coupled 3-O-methylglucose transport by approximately 40%. Intracellular adenosine 3',5'-cyclic monophosphate (cAMP) content was inversely related to Na-Pi symport activity in cells treated with PIA and PTH. However, changes in Na-Pi symport activity did not consistently relate to changes in intracellular cAMP. Protein kinase C was activated 15 s after treatment of OK cells with 1 microM PIA. Preincubation of cells with 3 microM staurosporine attenuated the effect of 1 microM PIA on phosphate uptake. These data suggest that Na-Pi and Na-glucose symport activities are stimulated by adenosine acting at a receptor coupled to more than one intracellular signal. It is likely that both protein kinases A and C are involved in these actions of adenosine.

Adenosine↗
PubMed1991

Serum-induced sensitization of cyclic AMP accumulation in 1321N1 human astrocytoma cells.

Exposure of 1321N1 human astrocytoma cells to fresh medium containing fetal bovine serum induced a marked increase in the subsequent ability of isoproterenol and forskolin to stimulate cAMP accumulation in intact cells, compared with cells exposed to fresh medium without serum. This "sensitization" of cAMP accumulation by serum was dose dependent, occurred rapidly, was maintained in the continuing presence of serum, and reversed rapidly upon removal of serum. Preliminary characterization of the sensitizing factor(s) in serum has been performed, but the factor(s) remain to be identified. Sensitization appeared to result from an increase in maximal response and not from changes in the potency of isoproterenol or forskolin. The protein kinase C inhibitor staurosporine inhibited serum-induced sensitization. Furthermore, down-regulation of protein kinase C almost completely eliminated the subsequent ability of serum to induce sensitization, indicating involvement of protein kinase C in the serum effect. Pretreatment of cells with pertussis toxin also markedly reduced subsequent sensitization induced by serum, suggesting involvement of a pertussis toxin-sensitive guanine nucleotide-binding protein in the pathway for serum-induced sensitization. The rate of cAMP degradation was not changed in sensitized cells, but some increase in adenylyl cyclase activity was retained in broken cell preparations from sensitized cells, suggesting increased synthesis of cAMP by adenylyl cyclase as the mechanism for sensitization.

1-Methyl-3-isobutylxanthine↗
PubMed1991

Cutaneous manifestations of human immunodeficiency virus infection. Part I.

The prevalence of dermatologic problems during the course of human immunodeficiency virus infection makes knowledge of these skin manifestations imperative to all practicing dermatologists. Detection of early infection is encouraged as effective therapy now exists both to delay the progression of human immunodeficiency virus-induced immunodeficiency and to prevent opportunistic infections. Skin manifestations of human immunodeficiency virus infection discussed in this article include the following groups: neoplastic, ie, Kaposi's sarcoma, lymphoma, and squamous cell carcinoma; infectious, ie, viral, bacterial, fungal, protozoal, and arthropod infestations; and a miscellaneous group including papulosquamous, papular, vascular, autoimmune, oral, and drug-related skin disorders.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Inhibition of Bordetella pertussis and Bacillus anthracis adenylyl cyclases by polyadenylate and "P"-site agonists.

Inhibition of adenylyl cyclases from Bacillus anthrasis and Bordetella pertussis by polyadenylate and by the most potent "P"-site agonists was investigated. These bacterial adenylyl cyclases differed in their sensitivity to inhibition by nominal "P"-site agents and in the effect of divalent cations on this inhibition. The enzyme from Bordetella pertussis was relatively insensitive to inhibition by "P"-site agonists, exhibiting a rank order of potency of 2'd3'AMP greater than 3'-AMP greater than 2',5'-ddAdo approximately Ado approximately 2'-dAdo, with IC50 values for 2'd3'AMP and 3'-AMP of 1-3 mM. Inhibition by 2'd3'AMP, however, was not affected by divalent cation, making it distinct from "P"-site-mediated inhibition of most mammalian adenylyl cyclases. The sensitivity to these nucleosides was comparable with potency for inhibition of bovine sperm adenylyl cyclase but was 3 orders of magnitude less potent than for activated enzyme from bovine or rat brain. The Bordetella pertussis enzyme was similarly insensitive to inhibition by polyadenylate, with 16 microM inhibiting less than 20%. By comparison, Bacillus anthrasis adenylyl cyclase was more potently inhibited by 2'd3'AMP (IC50 approximately 85 microM) but not by the other nucleosides (less than 15% inhibition at 1 mM), and inhibition by 2'd3'AMP was optimally enhanced by 5-10 mM Mg2+ or Mn2+, as is typical for inhibition by "P"-site agonists. The Bacillus anthrasis enzyme was potently inhibited by polyadenylate (IC50 approximately 0.3 microM), comparable to inhibition of brain adenylyl cyclases. Sensitivity of Bacillus anthrasis adenylyl cyclase to poly(A) was diminished somewhat by Ca2+/calmodulin (to IC50 approximately 1 microM) although Ca2+/calmodulin was without effect on inhibition by 2'd3'AMP. In contrast to inhibition of mammalian adenylyl cyclases via the "P"-site, inhibition of both bacterial adenylyl cyclases by 2'd3'AMP was competitive with respect to substrate MgATP. The data indicate basic differences in susceptibilities of these bacterial adenylyl cyclases to inhibition by poly(A), by adenosine analogs, and the effects of divalent cations. Although the potency of 2'd3'AMP and the metal-dependent nature of inhibition of Bacillus anthrasis adenylyl cyclase shared characteristics of "P"-site-mediated inhibition, the fact that inhibition of both bacterial adenylyl cyclases was competitive with respect to substrate strongly suggests that this inhibition was at the catalytic site and that these bacterial enzymes do not contain a distinct "P"-site.

Adenosine↗
PubMed1990

Irreversible inactivation of adenylyl cyclase by the "P"-site agonist 2',5'-dideoxy-,3'-p-fluorosulfonylbenzoyl adenosine.

2',5'-Dideoxy,3'-p-fluorosulfonylbenzoyl Adenosine (2',5'-dd3'-FSBA) was synthesized and found to be an agonist and affinity label for the "P"-site of adenylyl cyclase. This compound irreversibly inactivated both a crude detergent-dispersed adenylyl cyclase from rat brain and the partially purified enzyme from bovine brain. The irreversible inactivation by 100 to 200 microM 2',5'-dd3'-FSBA was blocked in a concentration-dependent manner by several established P-site inhibitors of adenylyl cyclase, 2',5'-dideoxyadenosine, 2'-d3'-AMP, adenosine, and 2'-deoxyadenosine, but not by inosine, N6-(phenylisopropyl)adenosine, adenine, 2'-d3':5'-cAMP, or 5'-AMP, agents known not to act at the P-site. Moreover, irreversible inactivation by 2',5'-dd3'-FSBA occurred in the presence of ATP at concentrations up to 3 mM, making it unlikely that inactivation was due to an effect on the enzyme's catalytic site. Adenylyl cyclase was also irreversibly inactivated by 5'-FSBA, although modestly (less than 20%) and apparently nonspecifically. Dithiothreitol protected the enzyme from irreversible inactivation by 2',5'-dd3'-FSBA, but reversible inhibition of the enzyme was still observed, although with reduced potency. When 2 mM dithiothreitol was added after a 30-min preincubation with 2',5'-dd3'-FSBA, the rat brain enzyme was partially (approximately 80%) reactivated. The data suggest that 2',5'-dd3'-FSBA may irreversibly inactivate adenylyl cyclase by reacting with a cysteinyl moiety in proximity to the P-site domain of the enzyme. These data together with results of studies of P-site inhibition kinetics published elsewhere (Johnson, R. A., and Shoshani, I. (1990) J. Biol. Chem. 265, 11595-11600) strongly suggest that the P-site and catalytic site are distinct domains on the enzyme. 2',5'-dd3'-FSBA, and especially its radiolabeled analog, should prove to be a useful probe for structural studies of adenylyl cyclase, particularly with regard to the P-site.

Adenylyl Cyclase Inhibitors↗
PubMed1990

Kinetics of "P"-site-mediated inhibition of adenylyl cyclase and the requirements for substrate.

The kinetics of "P"-site-mediated inhibition of adenylyl cyclase was studied with the detergent-solubilized enzyme from rat brain. Mn2(+)-activated adenylyl cyclase exhibited typical noncompetitive inhibition by 2'-d3'-AMP or 2',5'-dideoxyadenosine (2',5'-ddAdo). However, enzyme that was preactivated with guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S) or proteolytically with ninhibin (+ GTP gamma S) exhibited apparently uncompetitive inhibition with either 2'-d3'-AMP or 2',5'-ddAdo and with either MgATP or MgApp(NH)p (adenosine 5'-(beta gamma-imino)triphosphate) as substrate. Inhibition increased with increasing substrate concentration, consistent with distinct domains for catalysis and the P-site and the formation of a 2'-d3'-AMP.C.MgATP complex. This conclusion was supported by the kinetics of product inhibition. For both cAMP and inorganic pyrophosphate (MgPPi) inhibition was mixed, suggesting that product release is likely random sequential. Although MgPPi enhanced inhibition in the presence of P-site agonist, it did not affect the dissociation constant for P-site agonist. The uncompetitive character of P-site-mediated inhibition and the independence of inhibition by MgPPi and P-site agonist imply that the P-site binding domain is distinct from the substrate binding domain. Given the structural requirements for catalysis and for P-site-mediated inhibition, these domains would be expected to be homologous. Sensitivity to P-site-mediated inhibition was also dependent on the structure of ATP, with the following IC50 values for 2'-d3'-AMP: ATP approximately 2'-dATP (approximately 1 microM); adenosine 5'-O-(3-thiotriphosphate) (approximately 5 microM); App(NH)p (approximately 30 microM); adenosine 5'-(beta gamma-methylene)triphosphate (approximately 300 microM). The differing effectiveness of the ATP analogs to support P-site inhibition was not due to their binding at the P-site. This effect of substrate was also observed with the platelet enzyme and was independent of the means by which the enzyme was activated, whether by Mn2+ or proteolytically by ninhibin/GTP gamma S, suggesting it is a general characteristic of P-site-mediated inhibition. The data suggest a structure for activated adenylyl cyclase such that one nucleotide binding domain, selective for ATP vis-à-vis other ATP analogs, allosterically modulates a proximate P-site domain.

Adenosine Triphosphate↗
PubMed1990

Alloimmunization in sickle cell anemia and transfusion of racially unmatched blood.

Transfusion therapy for sickle cell anemia is limited by the development of antibodies to foreign red cells. To evaluate the frequency and risk factors associated with such alloimmunization, we determined the transfusion history, red-cell phenotype, and development of alloantibodies in 107 black patients with sickle cell anemia who received transfusions. We compared the results with those from similar studies in 51 black patients with sickle cell disease who had not received transfusions and in 19 nonblack patients who received transfusions for other forms of chronic anemia. We assessed the effect that racial differences might have on the frequency of alloimmunization by comparing the red-cell phenotypes of patients and blood-bank donors (n = 200, 90 percent white). Although they received transfusions less frequently, 30 percent of the patients with sickle cell anemia became alloimmunized, in contrast to 5 percent of the comparison-group patients with other forms of anemia (P less than 0.001). Of the 32 alloimmunized patients with sickle cell anemia, 17 had multiple antibodies and 14 had delayed transfusion reactions. Antibodies against the K, E, C, and Jkb antigens accounted for 82 percent of the alloantibodies. Comparison of red-cell phenotypes in the three study groups (the patients with sickle cell anemia, the patients with other forms of anemia, and the blood donors) revealed statistically significant differences between the patients with sickle cell anemia and the donors but not between the patients with other forms of anemia and the donors. These differences are most likely racial. We conclude that alloimmunization is a common, clinically serious problem in sickle cell anemia and that it is partly due to racial differences between the blood-donor and recipient populations.

Adolescent↗
PubMed1990

Inhibition of adenylate cyclase by polyadenylate.

The effects of ribo- and deoxyribonucleic acids on the activity of detergent-dispersed adenylate cyclases from rat and bovine brain were examined. Mn2+ (10 mM)-activated adenylate cyclase was inhibited by micromolar concentrations of poly(A) (IC50 congruent to 0.45 microM). This inhibition was directly due to poly(A) and was not mediated by: (a) protein contamination of the poly(A) preparation, (b) metal chelation, (c) formation of an acid-soluble inhibitor of adenylate cyclase, (d) effects on the specific activity of [alpha-32P]ATP, (e) competition with MnATP for binding to adenylate cyclase, or (f) diversion of substrate to an alternate polymerase reaction. Inhibition of adenylate cyclase by poly(A) was on the enzyme's catalytic unit, as purified preparations of the enzyme from bovine brain were inhibited by poly(A). This inhibition by poly(A) was not likely mediated via the enzyme's "P"-site, through which activated forms of the enzyme are selectively inhibited by specific adenosine phosphates. In contrast with inhibition by the "P"-site agonist 3' AMP, inhibition of adenylate cyclase by poly(A) was slow in onset and was not reversible by dilution and showed a different metal-dependence. Inhibition of adenylate cyclase was relatively specific for poly(A) as poly(U) caused less than 50% inhibition and deoxyribonucleic acids had no effect. The potency and specificity of the inhibition of adenylate cyclase by poly(A) imply a biochemically interesting interaction that is possibly also of physiological significance.

Adenylyl Cyclase Inhibitors↗
PubMed1990

Measurement of Hispanic ethnicity in the U.S. census: an evaluation based on latent-class analysis.

"Two models, the U.S. census model and the latent-class model, are compared in their application to evaluating measurements of ethnicity. Although the census approach assumes that the response categories of a questionnaire item correspond to groups in the population, the latent-class approach seeks to assess whether any set of response categories can represent observed ethnic heterogeneity. Data collected using the 1990 census Hispanic-origin question and other instruments for measuring ethnicity suggest that the latent-class approach is superior whenever the response categories are not known to be valid. In particular, using the latent-class model, this article rejects the census model's assumption of a single dimension of meaning underlying responses to the Hispanic-origin question."

Americas↗
PubMed1990

Use of coded mortality data to assess area cancer rates: impact of residence reporting and coding errors.

In spite of their limitations, mortality data are used in many epidemiologic and public health settings. In this investigation, the authors examined the extent to which community cancer mortality rates were affected by incorrect reporting or coding of residence on death certificates. Observed and expected cancer mortality for two adjacent communities in northern rural Minnesota for the periods 1970-1974 and 1980-1984 were obtained from computerized state mortality data. Using statewide rates to obtain expected values, standardized mortality ratios for total cancers for both periods combined were 138 for men (101 observed deaths) and 148 for women (86 observed deaths). These excesses were statistically significant (p less than 0.05). However, after review of data from the actual death certificates, city maps, and information from city officials, 44 of the 187 total cancer deaths (24%) were found to have had an incorrectly reported or coded residence status. After removal of these cases, the standardized mortality ratio for total cancers for males went from 138 to 107, and for females the standardized mortality ratio went from 148 to 111. No standardized mortality ratios remained statistically significant. These findings may have implications for those who use mortality data for assessing cancer rates in communities in rural areas.

Death Certificates↗