Biomedical subjects
D B Burlington
Publications and source records attributed to D B Burlington.
Use of prostate specific antigen assays.
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Introductory remarks to the biotechnology applications in biomaterials workshop.
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Conjugated estrogens: FDA's position.
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Methodological issues in AIDS clinical trials. Statutory and regulatory framework for drug approval.
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Public Health Service study of Reye's syndrome and medications. Report of the main study.
Between January 1985 and May 1986, following completion of a pilot study, a main study concerning the possible association between Reye's syndrome and salicylates was conducted. Twenty-seven patients with stage II or deeper Reye's syndrome whose diagnoses were confirmed by an expert panel and who had appropriate antecedent illnesses (chickenpox, respiratory illness, or gastrointestinal illness) prior to the onset of Reye's syndrome were compared with 140 controls matched for age, race (black or not black), and type and timing of onset of antecedent illness. Controls were selected from the same hospital, emergency room, or school as case-patients or were identified by random-digit telephone dialing. As in the pilot study, a strong statistical association with ingestion of salicylates during the antecedent illness and prior to the onset of Reye's syndrome was observed (odds ratio, 40; lower 95% confidence limit, 5.8). Analysis of the independent risk of aspirin and nonaspirin salicylates revealed a significant association with aspirin (odds ratio, 26; lower 95% confidence limit, 6.4); the independent risk of nonaspirin salicylates could not be assessed because only two cases were not exposed to aspirin. Assessment of epidemiologic issues of concern, including case-control differences in the severity of the antecedent illness, did not explain the high odds ratios that were observed. The high percentage of patients with Reye's syndrome exposed to salicylates (greater than or equal to 90%) in this and prior studies suggests that, though the reported incidence of Reye's syndrome has declined in recent years, concomitant with a decline in salicylate use among children, a majority of Reye's syndrome cases may be attributable to salicylate use.
Active synthesis of hemagglutinin-specific immunoglobulin A by lung cells of mice that were immunized intragastrically with inactivated influenza virus vaccine.
Intragastric inoculation with whole-virion vaccine of inactivated influenza virus resulted in production of hemagglutinin (HA)-specific immunoglobulin A (IgA) and IgG both in lung lavage fluids and in serum samples of mice. HA-specific IgA was the predominant isotypic antibody secreted in the lung lavage fluids (average IgA/IgG ratio, 13:1), whereas HA-specific IgG was the major antibody class in serum (average IgA/IgG ratio, 0.3:1). These responses were similar to the antibody responses stimulated by intranasal infection with live influenza virus. In vitro cultures of lymphoid cells from lungs and Peyer's patches, but not from spleens, in the presence of homologous antigen, from mice vaccinated intragastrically synthesized mostly HA-specific IgA. Mice immunized parenterally with inactivated influenza virus produced only IgG in lung lavage fluids and sera. Cultures of lymphoid cells from their spleens, but not their lungs, synthesized HA-specific IgG upon antigenic stimulation in vitro; neither synthesized IgA. These in vitro cell culture results, as well as the inverse relationship of IgA/IgG ratios in lung lavage fluids and sera, demonstrated that the IgA antibody in lung lavage fluids was actively synthesized locally in the lungs of intragastrically immunized mice. This finding was consistent with the migratory distribution of antigen-primed lymphoid cells from Peyer's patches to distant lymphoid tissue such as lung. Intragastric vaccination conferred protection against intranasal challenge with a lethal dose of virulent virus.
Effects of transforming growth factor beta on the functions of natural killer cells: depressed cytolytic activity and blunting of interferon responsiveness.
Type beta transforming growth factor (TGF-beta) is a unique polypeptide that has been isolated from a number of different tissues and can induce the phenotypic transformation of non-neoplastic fibroblasts as measured by the stimulation of their growth in soft agar. Recently, TGF-beta has been demonstrated to exert profound inhibitory effects on T and B lymphocyte proliferation. In this study, the effects of TGF-beta on natural killer (NK) cell function were investigated. After 20 hr of culture in the presence of TGF-beta, the NK activity of peripheral blood lymphocytes (PBL) was significantly reduced compared with PBL cultured in medium alone. Similarly, TGF-beta produced a significant depression in the cytolytic activity of highly enriched large granular lymphocytes (LGL). This effect of TGF-beta appeared to be mediated directly on the effector cells, because cultivation of the K562 target cells in TGF-beta did not affect target cell susceptibility to lysis. Binding studies with 125I-TGF-beta indicated that LGL possess approximately 1400 high-affinity (Kd = 1PM) receptors/cell, which represents a considerably higher affinity receptor for TGF-beta than that found on fibroblasts. Culturing of PBL and LGL in TGF-beta resulted in a marked blunting of the boosting of NK cytolysis by interferon-alpha but not by interleukin 2, which suggested that TGF-beta may down-regulate interferon-alpha receptors on NK cells. These results, indicate that in addition to inhibitory effects on T and B cells, TGF-beta also inhibits NK cell function. Although the in vivo role of TGF-beta is presently undefined, it may be an important immunoregulatory protein that has a negative influence on lymphocyte activation.
Public Health Service study on Reye's syndrome and medications. Report of the pilot phase.
Between February and May 1984, we conducted a pilot study to examine the methods for a larger study of a previously reported relation between Reye's syndrome and medications. Thirty patients with Reye's syndrome, whose diagnosis was confirmed by an expert panel, and 145 controls were matched for age, race (black or not black), and antecedent illness (respiratory infection, chickenpox, or diarrhea) and selected from the same hospital, emergency room, or school, or identified by random digit dialing. Significantly more cases (93 per cent, 28 of 30) than members of each of the four control groups or all controls combined (46 per cent, 66 of 145) had received salicylates during matched antecedent illnesses (odds ratio of all 30 cases vs. all controls = 16.1; lower 95 per cent confidence limit = 4.6). The prevalence and mean severity score of signs, symptoms, and selected events during the antecedent illness tended to be lower among cases than controls. Thus, differences in the severity of this illness between cases and controls did not explain differences in medication exposures. This pilot study suggests an association between Reye's syndrome and the use of salicylates during an antecedent illness.
Development of subtype-specific and heterosubtypic antibodies to the influenza A virus hemagglutinin after primary infection in children.
Children undergoing primary infection with an H1N1 or H3N2 influenza A virus developed subtype-specific hemagglutination inhibition antibodies and enzyme-linked immunosorbent assay antibodies to purified hemagglutinin (HA) of the infecting virus subtype. They also developed lower titered ELISA antibodies to the noninfecting H1 or H3 HA and to H8 (an avian strain) HA. Thus, after primary infection with an influenza A virus, children develop enzyme-linked immunosorbent assay, but not hemagglutination inhibition, antibodies reactive with heterosubtypic HAs. These heterosubtypic antibodies could influence the response to infection with other wild-type or attenuated vaccine strains of influenza A virus.
Large granular lymphocytes provide an accessory function in the in vitro development of influenza A virus-specific cytotoxic T cells.
We report that large granular lymphocytes (LGL) have an accessory function in the development of cytotoxic T cells (Tc) through the production of soluble factor(s). LGL and T cells were separated on Percoll gradients and the ability of the separated and of the recombined LGL and T cells to generate influenza A virus-specific Tc activity was measured. When stimulated by virus-infected, irradiated, adherent cells, neither LGL nor T cells cultured separately produced Tc activity. When they were co-cultured, however, even if separated by a 0.22-micron pore size membrane, Tc responses were readily generated from the small T cell precursors and natural killer activity was maintained in the LGL. Thus, LGL were required as accessory cells for Tc responses to occur and the effect was mediated by a soluble factor(s). alpha-Interferon (IFN) was produced in cultures containing LGL and/or stimulating adherent cells, whereas gamma-IFN was only produced in cultures containing both LGL and T cells. Therefore, neither alpha- nor gamma-IFN appeared to be the LGL produced soluble factor that mediated the accessory effect of LGL on Tc responses.
Anti-influenza A activity of combinations of amantadine and ribavirin in ferret tracheal ciliated epithelium.
The anti-influenza A activities of amantadine and ribavirin were investigated separately and in combination. Ferret tracheal ciliated epithelium was continuously exposed to the drugs at concentrations (0.25, 0.5, and 1 mg/l) comparable to those found in human serum after oral administration. Each drug alone produced a modest delay in A/Alaska/6/77 (H3N2) induced cytopathic effect. The combination of drugs synergistically delayed cytopathic effect. At 1 mg/l of each, cytopathic effect was prevented in 75% of rings for the 28-day duration of the experiment. This effect was greater than that of 32 mg/l of amantadine or 64 mg/l of ribavirin as single antiviral drugs. Peak virus production was suppressed 4.4 log-fold by the combination of 1 mg/l of each drug. This is in contrast to amantadine alone which suppressed peak virus production by 1 log-fold and ribavirin along which at 1 mg/l suppressed peak virus production by 1.9 log-fold. At lower concentrations, the drugs were at least additive in suppression of virus production.
Hemagglutinin-specific antibody responses in immunoglobulin G, A, and M isotypes as measured by enzyme-linked immunosorbent assay after primary or secondary infection of humans with influenza A virus.
The isotype-specific antibody responses to purified hemagglutinin of adults undergoing either primary or secondary infection with an influenza A virus were characterized by using an enzyme-linked immunosorbent assay. Twenty-eight military recruits undergoing primary infection with A/USSR/92/77 (H1N1)-like virus had serum antibody rises in the immunoglobulin M (IgM) (86%), IgG (100%), and IgA (96%) isotypes. In contrast, 19 adult volunteers undergoing secondary infection with A/Peking/2/79 (H3N2) wild-type virus had serum antibody titer rises largely restricted to the IgG (68%) and IgA (74%) classes, with only 1 volunteer having a serum IgM antibody titer rise. Nasal wash hemagglutinin-specific antibody responses in the adults undergoing secondary infection were predominantly in the IgA class (74%). There was a correlation between the presence of and the magnitude of nasal wash and serum hemagglutinin-specific IgA antibody responses in these adults. This suggested that there was a common source for the hemagglutinin-specific local IgA antibody and serum IgA antibody produced after infection. The recruits undergoing primary H1N1 influenza virus infection had H1 hemagglutinin-specific enzyme-linked immunosorbent assay antibody in each of the IgA, IgG, and IgM isotypes in their acute-phase serum. However, no role for this cross-reactive antibody in modifying the severity of illness experienced by the recruits could be demonstrated.
Anti-influenza A virus activity of amantadine hydrochloride and rimantadine hydrochloride in ferret tracheal ciliated epithelium.
The activities and toxicities of amantadine hydrochloride and rimantadine hydrochloride against influenza A/Alaska/6/77 (H3N2) and A/Bangkok/1/79 (H3N2) viruses were compared in organ cultures and ferret tracheal ciliated epithelium. Pretreatment of cultures with concentrations (0.5 and 1 micrograms/ml) comparable to those found in human serum after oral administration of amantadine revealed that rimantadine produced significantly longer protection than amantadine against virus-induced cytopathic effects. Correspondingly, rimantadine produced a comparable protective effect at four- to eight-fold-lower concentrations than amantadine. Both drugs produced increasing and similar effects at higher concentrations, which were comparable to those reported in nasal washings after aerosol administration of amantadine. At the concentrations tested, amantadine was nontoxic. However, at concentrations of 16 and 32 micrograms/ml, rimantadine was toxic to the ciliated epithelium after 10 to 21 days of continuous exposure. When the drugs were added 24 h or more after infection, protection against cytopathic effects decreased markedly. Both drugs moderately suppressed virus production at concentrations of 0.5 to 16 micrograms/ml. However, no dose response or difference between the drugs was observed. Because of comparable antiviral activity at lower concentrations and greater activity at similar concentrations, rimantadine may be more useful than amantadine for oral prophylaxis and therapy of influenza.
Toxicity of amantadine and rimantadine for the ciliated epithelium of ferret tracheal rings.
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