The effect of treatment duration in the local control of cervix cancer.
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Female↗
Biomedical subjects
E Adams
Publications and source records attributed to E Adams.
T cell receptor-triggered activation of intraepithelial lymphocytes in vitro.
Intraepithelial lymphocytes (IEL) of the mouse small intestine were examined for their potential to respond to TCR signalling in vitro. Purified IEL subsets were activated using mAbs specific for CD3, TCR alpha beta or TCR gamma delta. Thy-1+ IEL, regardless of TCR type, proliferated equally well in response to anti-TCR mAb with or without exogenous IL-2. In contrast, Thy-1- TCR alpha beta, CD8 beta- IEL required exogenous IL-2 for proliferation. No such requirement was observed for Thy-1- TCR gamma delta IEL proliferation. IEL proliferation in the absence of added IL-2 was due to an IL-2 secretion/IL-2 receptor (IL-2R) autocrine pathway, since mAbs specific for IL-2 and IL-2R inhibited IEL proliferation. Thy-1+ CD8 beta- CD4+CD8+ IEL were unresponsive to TCR-induced proliferation but exhibited high levels of cytolytic activity upon TCR-triggering. Thy-1- non-cytolytic IEL were induced to express Thy-1 and cytolytic activity following activation in vitro. In addition, the involvement of the co-stimulatory molecule CD28 in IEL activation was tested. CD28 was weakly expressed by fresh IEL and anti-CD28 mAb had no effect on TCR-triggered proliferation. However, anti-TCR stimulation increased CD28 expression on a subset of TCR alpha beta IEL and the addition of anti-CD28 mAb resulted in increased IL-2 production, but not in increased proliferation. Our results indicate that IEL, including the purported extrathymic CD8 beta- subset, can respond to TCR-driven signals via proliferation and/or cytolytic activity.
Animals↗
Identification of human T cell epitopes in the Mycobacterium leprae heat shock protein 70-kD antigen.
In a number of pathogens, heat shock proteins (hsp) stimulate humoral and cellular immune responses despite significant sequence identity with host hsp. The 70-kD hsp of Mycobacterium leprae, which shares 47% identity with human hsp70 at the protein level, elicited a T cell response in most Myco. bovis (bacille Calmette-Guérin (BCG)) vaccinees as well as leprosy and tuberculosis patients and their contacts. In order to locate T cell epitopes, DNA fragments encoding portions of the 70-kD hsp were expressed in the vector pGEX-2T and tested for T cell reactivity in an in vitro proliferative assay. Cultures of peripheral blood mononuclear cells (PBMC) from BCG vaccinees indicated that the C-terminal half of the molecule contained multiple T cell epitopes, as the T cells from a majority of Myco. leprae hsp70-reactive individuals responded to C-344. Lower proportions of patients with paucibacillary leprosy (36%) and tuberculosis patients (16%) responded to C-344. The smaller C-142 fragment which includes the terminal 70 residues unique to Myco. leprae and is the target for the human antibody response elicited a cellular response in few patients and no vaccinees. In order to map T cell epitopes, two series of synthetic peptides encompassing the region 278-502 were prepared. Using overlapping 12mer and 20mer peptides, this region of the molecule was found to contain several potential T cell epitopes. The longer peptides gave a clearer indication of reactive sequences including regions of the molecule which were not identified with the 12mer peptides. Fine mapping of reactive peptide pools using the 12mer peptides identified two T cell epitopes. Although both were located in regions of the molecule shared with Myco. tuberculosis, one appeared to be cross-reactive with the equivalent human sequence, and thus has the potential to initiate autoimmune responses.
Amino Acid Sequence↗
Immunoglobulin M and D antigen receptors are both capable of mediating B lymphocyte activation, deletion, or anergy after interaction with specific antigen.
A series of immunoglobulin (Ig)-transgenic mice were generated to study the functional capabilities of the IgM and IgD classes of B lymphocyte antigen receptor in regulating both cellular development and responses to specific antigen. B cells from Ig-transgenic mice expressing either hen-egg lysozyme (HEL)-specific IgM or IgD alone were compared with B cells from mice that coexpressed IgM and IgD of the same anti-HEL specificity. In all three types of Ig-transgenic mice, conventional B cells specific for HEL exhibited exclusion of endogenous Ig expression and matured to populate the usual microenvironments in peripheral lymphoid tissues. These peripheral B cells could be stimulated by HEL through either IgM or IgD antigen receptors to generate T cell dependent antibody production in vivo or to enhance T cell independent proliferative responses to lipopolysaccharide in vitro. Conversely, when HEL was encountered in vivo as a self-antigen, B cells expressing HEL-specific IgM or IgD alone were both rendered tolerant. In each case this occurred by clonal anergy in response to soluble autologous HEL, and clonal deletion when HEL was recognized as a membrane-bound self-antigen. Taken together, these findings indicate that IgM and IgD antigen receptors expressed alone on conventional B cells can support normal differentiation, antigen-dependent activation, and induction of self-tolerance, the only overt difference lying in a greater degree of receptor downregulation for IgM relative to IgD after induction of clonal anergy by soluble HEL.
Animals↗
Limiting dilution analysis in leprosy.
Peripheral blood mononuclear cells (PBM) obtained from leprosy patients and healthy controls were cultured with Mycobacterium leprae and the control antigens, BCG and SKSD. Parallel cultures were supplemented with additional interleukin-2 (IL-2). On the basis of the level of response to M. leprae, leprosy patients could be divided into low, intermediate and high responders. The addition of IL-2 resulted in enhanced proliferation to antigen only by cells from intermediate responders. This effect was neither antigen specific nor was it confined to cells from leprosy patients. When limiting dilution analyses were performed on cells from 26 patients across the leprosy spectrum, no M. leprae-reactive lymphocytes were detected in cells from subjects with lepromatous disease. The precursor frequency for cultures containing M. leprae plus IL-2 was no greater than that of cultures containing IL-2 alone, thereby excluding the possibility of clonal anergy reversible with IL-2. This was observed in both untreated patients and those on long-term treatment, which made sequestration of antigen-reactive cells within leprosy lesions an unlikely explanation. On the other hand, M. leprae-reactive lymphocytes were detected in patients with tuberculoid and borderline tuberculoid disease and in two subjects with borderline lepromatous leprosy in type I reversal reaction. IL-2 reactive cells were detected in all patients regardless of clinical classification. Three 'suppressor' curves were obtained but were not confined to cells from lepromatous patients. Taken together, these findings suggest that the non-responsiveness to M. leprae characteristic of the great majority of multibacillary patients is due to an absence of antigen-sensitive T cells.
Antigens, Bacterial↗
Breakdown of self-tolerance in anergic B lymphocytes.
Production of autoantibodies, which characterizes most autoimmune diseases, is normally avoided by active elimination or functional inactivation (anergy) of B and T lymphocytes bearing receptors for self antigens. The mechanisms leading to the escape of self-reactive clones from these normal tolerance mechanisms in autoimmune diseases nevertheless remain obscure. Here, we demonstrate that clonal anergy in B lymphocytes is a reversible process, and that silenced self-reactive B cells can be reactivated under particular conditions to give rise to vigorous antibody responses. Reactivation of anergic lymphocytes may explain many examples of transient autoimmune reactions in normal individuals, and may under pathological conditions be important in the development of chronic autoimmune disease.
Animals↗
Sequence and immunogenicity of the 70-kDa heat shock protein of Mycobacterium leprae.
The gene encoding the Mycobacterium leprae 70-kDa heat shock protein has been isolated from a cosmid library using a fragment of the clone JKL2. Southern blot analysis of a positive clone identified a 4.4-kb fragment containing the entire coding region of the gene plus 2.4 kb upstream. Sequencing revealed the gene to encode a 621-amino acid protein, bearing 56% identity with the Escherichia coli dnaK gene product and 47% and 46% identity with the human and Caenorhabditis elegans hsp70, respectively. Comparison with the C-terminal 203 amino acids of the Mycobacterium tuberculosis 71-kDa Ag yielded 70% identity. Recombinant M. leprae p70 was produced in E. coli as a fusion protein (rp70f) with a portion of the schistosomal glutathione-S-transferase, using the expression vector, pGEX-2T. Cleavage with thrombin resulted in the release of a 70.0-kDa protein (rp70c) from the glutathione-S-transferase. Examination of the proteins by immunoblotting demonstrated that anti-M. leprae mAb, L7, and sera from lepromatous leprosy patients bound to both the cleaved and fusion proteins. We compared the T cell reactivity of the M. leprae recombinant proteins with that of mAb affinity-purified bacille Calmette-Guerin (BCG) 70-kDa Ag using proliferation assays. PBMC of BCG vaccinees responded to both M. leprae cleaved and fusion p70, though more subjects responded to the rp70c (18 of 20) than to rp70f (13 of 20). Responses were generally higher to rp70c than to rp70f, however all responses to the M. leprae recombinant proteins were lower than to mAb affinity-purified BCG p70. Thus, the M. leprae 70-kDa heat shock protein elicits T and B cell responses in subjects exposed to mycobacteria, despite its homology with the human hsp70.
Amino Acid Sequence↗
Normal sequence of the gonadotropin-releasing hormone gene in patients with idiopathic hypogonadotropic hypogonadism.
Idiopathic hypogonadotropic hypogonadism (IHH) results from absent or greatly diminished secretion of GnRH. Defects in the GnRH gene have been identified in an animal model of IHH and have been hypothesized as a possible basis for GnRH deficiency in humans. In this study, we used the polymerase chain reaction to clone and sequence the coding regions, promoter, and 3' untranslated tract of the GnRH genes from both alleles of four unrelated patients with IHH. One of the patients studied is a member of a kindred in which X-linked inheritance has been excluded by father-to-son transmission of the disease. No DNA sequence mutations were found. We conclude that most cases of IHH in humans do not involve mutations in the GnRH gene and are presumably caused by mutations at one or more other genetic loci that are required for normal function of GnRH-producing neurons.
Adolescent↗
Self tolerance in the B-cell repertoire.
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Animals↗
The prediction of dentists' work behaviour; factors affecting choice or intention in the treatment of special need patients.
The present study was undertaken as part of an overall strategy to develop a co-ordinated dental health care programme for special need patients between general dental practitioners and the community dental service. The beliefs, attitudes and work behaviours of the practitioners were examined, using the theory of reasoned action, in order to highlight perceived difficulties associated with treating this particular patient group as well as to find those dentists willing to treat and carry out domiciliary dental care for them. The results demonstrated that those dentists who had previous experience of treating special need patients and carrying out a variety of domiciliary dental treatments intended to provide dental care for this group. Furthermore, the dentists differed in their evaluations with regard to beliefs and attitude. Those dentists who intended to provide dental care appeared to have more positive attitudes and were able to assess and perceive the relevance as well as the reality of their own beliefs in the light of their previous working behaviours.
Adult↗
Portrait of a hospital. Boston's Massachusetts General.
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Attitude of Health Personnel↗
Intrinsic B-cell hyporesponsiveness accounts for self-tolerance in lysozyme/anti-lysozyme double-transgenic mice.
In double-transgenic mice expressing a gene construct encoding hen egg lysozyme as well as rearranged anti-lysozyme antibody genes, large numbers of anti-lysozyme B cells are present in peripheral lymphoid tissues but are profoundly tolerant. The cellular basis for this form of non-deletional self-tolerance was explored. The tolerant anti-lysozyme B cells from double-transgenic mice were found to produce much less antibody than nontransgenic controls in T-cell-dependent antigen-specific responses, in adoptive transfer in vivo, and in hanging-drop cultures in vitro, as well as in response to stimulation with the nonspecific mitogen lipopolysaccharide. The diminished responsiveness of the tolerant B cells was not due to a reduction in the number of responding B-cell precursors per se nor were suppressor cells detected in titration, depletion, or mixing experiments. Nondeletional tolerance in this model, therefore, appears to result from an intrinsic functional change in the self-reactive B cells themselves.
Animals↗
T cell reactivity to the purified mycobacterial antigens p65 and p70 in leprosy patients and their household contacts.
T cell reactivity to the 70 and 65 kD (p70 and p65) protein antigens derived from Mycobacterium bovis BCG strain was studied by measuring the proliferative responses of peripheral blood mononuclear cells from members of an isolated Aboriginal community resident in the Torres Straits islands. In the nine index leprosy cases the pattern of responsiveness to the purified antigens paralleled that to whole sonicates from M. leprae and BCG. In the 40 contacts of the index cases, a high correlation was observed between the responses to p70 and p65 as well as to the crude sonicates. Significant T cell responses to the purified antigens, as well as the crude sonicates, were obtained with cells from the majority of contacts. Limiting dilution analysis of precursor frequencies in the contacts confirmed the immunogenicity of the purified antigens and excluded both a mitogenic component and the presence of suppressor cells in those moderate or low responders whose blood contained sufficient precursors to be tested. p70 appeared to be more potent in stimulating a proliferative response than p65 at equivalent protein concentrations. No correlation between responder status to either antigen and disease type was detected in families. These findings provide confirmation of the importance of p70 and p65 as major T cell immunogens in man and indicate that they are both potential candidates for inclusion in a bivalent vaccine for leprosy and tuberculosis.
Antigens, Bacterial↗
Human papillomavirus associated with adenocarcinoma and adenosquamous carcinoma of the cervix: analysis by in situ hybridization.
The incidence of adenocarcinoma of the cervix appears to be increasing. Recent reports have demonstrated an association between adenocarcinoma of the cervix and human papillomavirus (HPV) by Southern blot hybridizations. In situ deoxyribonucleic acid (DNA) hybridization was performed on paraffin-embedded specimens to localize the source of HPV DNA. In pure adenocarcinoma five of six specimens were positive for HPV DNA. Four specimens contained HPV type 18 and one HPV type 16. Only one of three adenosquamous lesions was positive and it contained both HPV types 16 and 31. These findings suggest an association between HPV and adenocarcinoma of the cervix.
Adenocarcinoma↗
Inhibition of human lymphoproliferative responses by mycobacterial phenolic glycolipids.
The effect of mycobacterial phenolic glycolipids from Mycobacterium leprae, M. bovis BCG, and M. kansasii on in vitro proliferative responses by human blood mononuclear cells from healthy BCG vaccinees was investigated. All three phenolic glycolipids inhibited proliferation in a concentration-dependent manner. Inhibition was independent of the stimulus used and involved neither antigen-presenting cells nor antigen-specific CD8+ suppressor T cells. It was concluded that the phenomenon may be a general property of mycobacterial phenolic glycolipids, perhaps analogous to the growth-modulating properties of gangliosides. Despite the lack of specificity of inhibition in vitro, de facto specificity may occur in vivo by virtue of the localization of glycolipid in the leprosy lesions.
Antigen-Presenting Cells↗
Faculty practice: nurse educators' views and proposed models.
Faculty practice is an issue that has been extensively debated, yet no consensus about its definition, purposes, or implementation has yet been achieved among nurse educators. This nationwide survey of a random sample of 909 AD and BSN educators was designed to elicit concepts of faculty practice and to find how and why faculty are implementing practice. Sixty percent of the sample are practicing nursing; the reason most frequently given was to maintain clinical skills. The 40% not practicing stated lack of time as the primary reason. Responses demonstrated no differences between AD and BSN educators regarding definition, implementation, and motivation for faculty practice. As a result of the survey, a definition of faculty practice has been formulated and conceptual models of faculty practice delineated. The models that have been developed are the Nurse-Researcher Model, Nurse-Clinician Model, and Nurse-Consultant Model.
Humans↗
Indicators of impact of services on persons with developmental disabilities: issues concerning data-collection mandates in P.L. 100-146.
Public Law 100-146 requires the Administration on Developmental Disabilities to report to the Congress in 1990 on the status of services to persons with developmental disabilities. Considerable effort has been devoted by the National Association of Developmental Disabilities Councils to providing a national methodology for characterizing state services and for surveying consumer satisfaction with these services; but these data alone will not be sufficient to adequately characterize all variables required by the 1990 report. Definitional, conceptual, and methodological issues related to measurement of scope and extent of services, documenting eligibility and accessibility, and estimating the effectiveness of services was reviewed. A framework was suggested for integrating data-collection with consumer satisfaction survey efforts already underway.
Consumer Behavior↗
Intraindividual variability in theophylline pharmacokinetics in subjects with mild/moderate asthma.
Intrasubject variability in theophylline pharmacokinetics was assessed in six subjects with mild/moderate asthma. On four occasions, each separated by a minimum of 3 weeks, a 6 mg/kg intravenous aminophylline dose was infused during 30 minutes, and multiple blood samples were obtained thereafter. The pharmacokinetic parameters of clearance (Cl), volume of distribution, and half-life were determined by noncompartmental analysis. There was evidence for within-subject variability in these parameters. In comparison to the first study day, Cl changed by greater than 15% in all but one subject and by greater than 25% in two of six subjects. Changes in half-life exceeding 25% of the value observed on the first study day occurred in three of six subjects. Within-subject coefficient of variation for Cl was 14.9% (range 3.9% to 33.3%) and 14.4% (range 5.8% to 24.3%) for half-life. Volume of distribution, however, was a more stable parameter with a within-subject coefficient of variation of 7.2% (range 2.3% to 11.1%). Thus, within-subject changes in the pharmacokinetics of theophylline do exist over time. These data suggest that close monitoring of patients receiving theophylline is warranted, particularly when theophylline concentrations are maintained at either extreme of the therapeutic range.
Adult↗