The removal of fibres of chrysotile asbestos from lung.
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Animals↗
Biomedical subjects
A Morgan
Publications and source records attributed to A Morgan.
Pancreatitis caused by a wandering spleen.
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Acute Disease↗
Individuals from different populations identify multiple and diverse T-cell determinants on mycobacterial HSP70.
The 70 kDa heat-shock protein (HSP) of Mycobacterium leprae stimulates both cellular and antibody responses in leprosy patients and subclinically infected individuals despite partial homology with host HSP70. Furthermore, mycobacterial HSP70 can act as a carrier protein in unprimed mice, suggesting the presence of widely shared T-cell determinants on this protein. In order to elucidate the frequency and genetic restriction of these T-cell epitopes, we have undertaken a systematic analysis of the proliferative responses to 20mer peptides encompassing the whole protein in different populations. Caucasian BCG vaccinees who responded to recombinant M. leprae HSP70 identified multiple scattered T-cell determinants, four of which were recognized by 60% of subjects in association with a variety of HLA-DR haplotypes. When a group of Nepali leprosy and tuberculosis patients were tested, significant differences in the pattern of peptide recognition were observed. The dominant peptides recognized by Caucasian subjects were infrequently reactive and other peptides were stimulatory, again in association with a variety of HLA-DR phenotypes. The C-terminal 70 residues of the M. leprae HSP70 are specific to M. leprae and sera from lepromatous leprosy patients bind to this region. However, few T-cell determinants were identified in these residues, indicating that this region is unhelpful as a diagnostic tool for detecting M. leprae-specific T-cell responses. When compared with the equivalent regions of the human HSP70, the commonly recognized peptides showed significant differences in amino-acid sequence. When taken in conjunction with the failure of human HSP70 to stimulate M. leprae HSP70-reactive T-cell clones (E. Adams et al., unpublished observations), this finding indicates that the human T-cell response to this protein is largely directed at mycobacterial-specific determinants. The presence of multiple T-cell epitopes on M. leprae HSP70 with varied patterns of HLA-DR association suggests that the whole protein is required for stimulating effective T-cell responses in genetically diverse populations.
Amino Acid Sequence↗
Photosensitization with a chlorin-thiobarbiturate conjugate.
The photobiologic properties of a chlorin-thiobarbiturate conjugate were examined. In addition to the characteristic 670 nm chlorin absorbance, the conjugate exhibited new absorbance bands at 517 and 743 nm, but these were not a part of the fluorescence emission spectra, nor was fluorescence observed at wavelengths > 670 nm. The action spectrum indicated that the long-wavelength absorbance of the conjugate was not involved in phototoxicity in cell culture, and that only irradiation at wavelengths associated with the chlorin moiety yielded a cytotoxic effect. In vivo cytotoxicity elicited by 745 nm irradiation is attributed to thermal effects.
Animals↗
Pharmacokinetics and safety of weekly dapsone and dapsone plus pyrimethamine for prevention of pneumocystis pneumonia.
The safety and pharmacokinetics of weekly dapsone and weekly dapsone plus pyrimethamine were examined in adult patients with human immunodeficiency virus infection who were at risk for pneumocystis pneumonia because of a prior episode or a CD4+ T-cell count less than 250 cells per mm3. Groups of patients received 100, 200, and 300 mg of dapsone as a single weekly dose. The maximum tolerated dose of weekly dapsone was established as 200 mg per week in patients receiving at least 500 mg of zidovudine concomitantly. This dose of dapsone was then found to be well tolerated when combined with pyrimethamine at 25 mg. Further patients were randomized to dapsone at 200 mg or dapsone at 200 mg plus pyrimethamine at 25 mg once weekly. Twenty-six patients each were followed for a median of 33 weeks on dapsone alone and 45 weeks on the combination. Seven patients in each group withdrew because of toxicity. Five patients receiving dapsone developed documented pneumocystis pneumonia, while four and two patients receiving dapsone plus pyrimethamine developed documented and presumptive pneumocystis pneumonia, respectively. To evaluate the tolerability of a higher dose of pyrimethamine, 11 patients had their regimen changed to dapsone at 200 mg plus pyrimethamine at 75 mg, which was well tolerated by 10 of the patients for a median period of 11 weeks. The pharmacokinetics of dapsone and pyrimethamine were examined by using a population pharmacokinetic model. Decreases in the apparent volume of the peripheral compartment were observed when multiple-dose regimens of dapsone were compared with single-dose dapsone and when multiple-dose regimens of dapsone with pyrimethamine were compared with multiple-dose dapsone alone. When administered weekly, dapsone at 200 mg and dapsone at 200 mg with pyrimethamine at 25 mg are both well-tolerated regimens. This preliminary study suggests that the efficacy of these regimens in preventing pneumocystis pneumonia, however, may be less than that of trimethoprim-sulfamethoxazole.
AIDS-Related Opportunistic Infections↗
In vivo evaluation of chemical biopersistence of man-made mineral fibers.
Techniques developed at the Harwell Laboratory for the determination of the biopersistence of man-made mineral fibers (MMMF) in vivo are described. Results obtained with samples of glass fiber with a range of compositions, and with a sample of rockwool, are summarized. With glass fibers the rate of dissolution of fibers in vivo depends not only on their chemical composition, but also on their length. Certainly, for all fibers exceeding 10 microns in length, the longer the fiber the more rapidly it dissolves. This effect is attributed to differences in the microenvironments to which long and short fibers are exposed. Although this phenomenon appears to operate with all glass fibers, it may not apply to other types of MMMF that dissolve more readily in environments with low pH. Finally, the article examines the validity of the intratracheal method of administration for studying the biopersistence of MMMF in vivo and the use of the rat for this purpose.
Animals↗
A guide to the diagnosis of learning disabilities in deaf and hard-of-hearing children and adults.
This article provides a guide to psychological tests and test procedures recommended for diagnosing learning disabilities in deaf and hard-of-hearing youth and adults. Tests are evaluated relative to their usefulness with deaf and hard-of-hearing persons in school and rehabilitation settings. These data provide the basis for recommendation of a battery of tests for use by school, vocational, and general psychologists in evaluating deaf and hard-of-hearing youth and adults for learning disabilities.
Adolescent↗
The behavior of glass fibers in the rat following intraperitoneal injection.
Potential carcinogenicity of fibers is believed to be determined by three factors: the dose, dimensions and durability of the fibers concerned. Currently there is considerable debate on the appropriateness of using results from intraperitoneal (i.p.) injection studies to predict the potential carcinogenicity of airborne fibers following inhalation. For ip results to have any significance to potential inhalation hazards, there should be some relation between the biopersistence, dose, and dose distribution of fibers in the serosal cavity and in the lung. Preliminary results on the durability of one experimental glass fiber in the peritoneal cavity suggest differences in dissolution when compared with durability in the lung. In the lung, the diameters of the long fibers (> 20 microns) were observed to decline at a rate consistent with their exposure to a neutral pH environment. The diameter of shorter fibers declined much more slowly, consistent with exposure to a more acidic environment such as is found in the phagolysosomes of alveolar macrophages. In the peritoneal cavity all fibers, regardless of length, dissolved at the same rate as short fibers in the lung. The effect of dose on the distribution of fibers in the peritoneal cavity was investigated using similar experimental glass fibers and compared with that of a powder made from ground fibers. For both materials at doses up to 1.5 mg, material was taken up by the peritoneal organs roughly in proportion to their surface area. This uptake was complete 1-2 days after injection. At higher doses, the majority of the material in excess of this 1.5 mg formed clumps of fibers (nodules) which were either free in the peritoneal cavity or loosely bound to peritoneal organs. These nodules displayed classic foreign body reactions with an associated granulomatous inflammatory response. The findings on both durability in the peritoneal cavity and the presence of two distinct populations of material following i.p. injection have implications for the justification of the use of i.p. injections to assess potential carcinogenicity of fibers following inhalation.
Animals↗
Anti-class II MHC antibodies prevent and treat EAE without APC depletion.
We have demonstrated that a murine IgG1 anti-class II major histocompatibility complex (MHC) antibody (OX6) is able both to prevent and treat experimental autoimmune encephalomyelitis (EAE) in the Biozzi AB/H mouse. We have confirmed that this antibody is poorly cytotoxic, allowing mechanisms of action other than depletion of antigen-presenting cells (APC) to be assessed. Despite its effect on disease, OX6 administration does not prevent priming of T cells in the draining lymph node, implying an alternative mechanism for regulation of the autoimmune disease process.
Acute Disease↗
Latent Epstein-Barr virus infection in cottontop tamarins. A possible model for Epstein-Barr virus infection in humans.
The association of Epstein-Barr virus (EBV) with a growing number of human malignancies underlines the importance of efforts aimed at preventing the infection with this potential carcinogen and of establishing animal models for human virus-associated tumors. Cottontop tamarins have been used in EBV vaccine studies because virus infection regularly induces lymphomas similar to those seen in human immunocompromised individuals. In recent years, several vaccines based on the gp340/220 envelope protein of EBV have been developed and shown to prevent the development of EBV-associated lymphomas in this model. Using in situ hybridization and immunohistology, we have characterized EBV infection in one nonimmunized and three immunized animals after challenge with a standard tumorigenic dose of EBV. In the nonimmunized animal, EBV-infected lymphoid cells were detected in numerous tissues showing no obvious lymphoma infiltration. Surprisingly, variable numbers of virus-carrying cells were also found in all three immunized animals that were protected against the development of virus-associated lymphoma. This observation demonstrates that vaccination does not induce sterilizing immunity against EBV infection in this model. Double labeling suggested a B cell phenotype of the majority of these cells. EBV infection of nonlymphoid cells was not observed. Analysis of viral gene expression in immunized animals suggested a restricted form of virus latency different from that seen in EBV-driven lymphomas in nonimmunized cottontop tamarins. These results raise the possibility that immunized cottontop tamarins protected against the development of EBV-driven lymphoma or animals exposed to a sublymphomagenic dose of virus may serve as a model for EBV infection in humans.
Animals↗
Changes in the rat lung after exposure to radon and its progeny: effects on incorporation of bromodeoxyuridine in epithelial cells and on the incidence of nuclear aberrations in alveolar macrophages.
The aim of this study was to investigate some responses of cells in the rat respiratory tract as a function of time after inhalation exposure to various levels of radon and its progeny. Rats were exposed to a constant concentration of radon and its progeny to give cumulative exposure levels of 120, 225, 440 and 990 working level months (WLM). An additional unexposed group of rats served as controls. The end points selected for investigation were (a) the incorporation of bromodeoxyuridine (BrdU) in epithelial cells of the conducting airways and of the alveolar region of the respiratory tract and (b) the incidence of alveolar macrophages with nuclear aberrations. After exposure, the incidence of epithelial cells incorporating BrdU--the labeling index--increased in all regions of the respiratory tract examined, but the increase occurred later in alveolar than in airway epithelial cells. The highest labeling index was found in bronchial epithelial cells, which probably received the highest radiation dose. After an initial induction period, the incidence of alveolar macrophages with nuclear aberrations also increased. The possibility of using the labeling index of alveolar and airway epithelial cells, and/or the incidence of nuclear aberrations in alveolar macrophages, to estimate the radiation dose to various regions of the respiratory tract after exposure of rats to radon and its progeny is discussed.
Animals↗
A synthetic peptide of the N-terminus of ADP-ribosylation factor (ARF) inhibits regulated exocytosis in adrenal chromaffin cells.
We have investigated the role of ADP-ribosylation factor (ARF) in regulated exocytosis in digitonin-permeabilized adrenal chromaffin cells by the use of a synthetic peptide, hARF1(2-17), based on the N-terminus of the protein. hARF1(2-17) inhibited Ca(2+)-dependent but not basal exocytosis, whereas equimolar levels of other synthetic peptides were ineffective. The inhibitory effect of hARF1(2-17) was dose-dependent and half-maximal at 12 microM. GTP gamma S-induced secretion in the presence of non-stimulatory CA2+ concentrations was also inhibited by hARF1(2-17). These results point to a hitherto unsuspected role for ARF in regulated exocytosis, and the potency of the hARF1(2-17) peptide suggests that ARF is essential for exocytosis in bovine adrenal chromaffin cells.
ADP-Ribosylation Factors↗
Identification of a key domain in annexin and 14-3-3 proteins that stimulate calcium-dependent exocytosis in permeabilized adrenal chromaffin cells.
Calcium-dependent secretion in digitonin-permeabilized adrenal chromaffin cells is stimulated by exogenous annexin II and 14-3-3 proteins. These proteins share a conserved domain that has been suggested to be involved in specific protein-protein interactions. We examined whether this domain was involved in secretion by using a synthetic peptide (P16) of sequence KGDYQKALLYLCGGDD corresponding to the C-terminus of annexin II. P16, but not truncated peptides, prevented the stimulation of secretion by 14-3-3 proteins and produced a partial inhibition of control secretion. These data suggest that the shared annexin/14-3-3 domain is important in the mechanisms controlling Ca(2+)-dependent secretion and may play a key role in protein-protein interactions during exocytosis.
14-3-3 Proteins↗
Identification of Exo2 as the catalytic subunit of protein kinase A reveals a role for cyclic AMP in Ca(2+)-dependent exocytosis in chromaffin cells.
Digitonin-permeabilized chromaffin cells secrete catecholamines by exocytosis in response to micromolar Ca2+ concentrations, but lose the ability to secrete in response to Ca2+ as the cells lose soluble proteins through the plasma membrane pores. We have previously shown [Morgan and Burgoyne (1992) Nature, 355, 833-836] that cytosol can retard this loss of secretory competence and that two distinct stimulatory activities (Exo1 and Exo2) are present in cytosol. Here we report that Exo2 behaved as a single peak of activity through purification on hydroxyapatite, ammonium sulfate precipitation and gel filtration and the activity correlated with a single polypeptide of approximately 44 kDa on SDS gels. Protein sequencing of this band revealed it to be the catalytic subunit of cyclic AMP-dependent protein kinase (PKA). Both cyclic AMP and the commercially available catalytic subunit of PKA stimulated exocytosis in a dose-dependent manner which was absolutely dependent on the presence of micromolar Ca2+. These data show that PKA (Exo2) regulates Ca(2+)-dependent exocytosis in bovine adrenal chromaffin cells.
Amino Acid Sequence↗
A radioactive tracer technique to determine in vivo the number of fibers in the lungs of rats following their administration by intratracheal instillation.
A radioactive tracer technique is described which enables the total number of fibers present in the lungs of rats to be estimated following administration of the fibers by intratracheal instillation. The glass fiber used in the study was irradiated with thermal neutrons to induce radioactive 24Na. A suspension of the radioactive fiber was administered to eight rats by intratracheal instillation and to two additional rats by intraesophageal instillation. The 24Na radioactivity in the rats was counted in vivo at 24 and 48 hr after administration, after which they were killed. The amounts of fiber in the lungs, in the gastrointestinal tracts, and excreted in feces were estimated radiometrically. On average 93% of the administered fiber was accounted for. The lungs were digested with sodium hypochlorite solution and aliquots of the resulting digest filtered through membrane filters which were clear for examination by phase-contrast optical microscopy (PCOM). The numbers of fibers in the lungs, estimated by PCOM, were well correlated with the in vivo counting rates at 48 hr, indicating that the latter can be used to provide an accurate index of the number of fibers retained in the lung at that time.
Administration, Inhalation↗
Identification of cytosolic protein regulators of exocytosis.
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14-3-3 Proteins↗
Distribution of glass fibers in the peritoneal cavity of the rat following administration by intraperitoneal injection.
The distribution of glass fibers in the peritoneal cavity of the rat was investigated at 2, 24, and 48 h following intraperitoneal injection of 1 mg of material using a radioactive tracer technique. At each time point the peritoneal cavities of the rats killed were lavaged with 20 ml of physiological saline to recover fibers not yet attached to tissue surfaces. At 2 h, 35% of the administered fiber could be recovered by lavage, but at 48 h this was reduced to 2%. At 48 h, the amount of fiber associated with the abdominal organs and the abdominal wall was roughly in proportion to their surface areas. The weight of fiber associated with the various tissues was in the following order: gastrointestinal tract > liver > carcass (abdominal wall) > diaphragm > urogenital tract > spleen > kidneys. Differential counts on cells recovered by lavage were made both on cytocentrifuge slides and by flow cytometry. Compared with controls, the numbers of cells recovered from treated rats at 24 and 48 h were increased by a factor of about 2, due mainly to an influx of neutrophils into the peritoneal cavity. There was a marked reduction in the proportion of mast cells compared to controls.
Animals↗