Epidural bupivacaine and diamorphine for postoperative analgesia.
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Analgesia, Epidural↗
Biomedical subjects
A Moriarty
Publications and source records attributed to A Moriarty.
Immunological characterization of hepatitis delta antigen.
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Amino Acid Sequence↗
Importance of subtype in the immune response to the pre-S(2) region of the hepatitis B surface antigen. II. Synthetic Pre-S(2) immunogen.
One purpose of this study was to examine the influence of viral subtype on in vivo antibody production to the pre-S(2) region of the hepatitis B surface Ag. Immunization with hepatitis B surface Ag particles containing the pre-S(2) region of the d or y subtypes identified the B10.M (H-2f) strain as an antibody nonresponder to the pre-S(2) and S regions after immunization with the y subtype, but as an antibody responder to the pre-S(2) and S regions after immunization with the d subtype. Both the S region and pre-S(2) region-specific antibody responses emanated from pre-S(2)/d-specific Th cell function because B10.M mice are T cell nonresponsive to the S region of both subtypes. Although responder/nonresponder status of the B10.M strain was dependent on the pre-S(2) subtype used for immunization, the anti-pre-S(2) antibody produced was totally cross-reactive on both subtypes. This is consistent with the conserved nature of the dominant pre-S(2) antibody-binding site and the highly polymorphic nature of the pre-S(2) sequence that represents the focus of T cell recognition. These data suggest that, to fully benefit from the inclusion of pre-S(2) region sequences, third generation hepatitis B virus vaccines should contain both the d and y subtype sequences of the pre-S(2) region to increase the frequency of pre-S(2) and S-specific antibody responses and to insure Th cell memory relevant to both viral subtypes. A second purpose of this study was to "design" a synthetic pre-S(2) immunogen based on combining the dominant B and T cell recognition sites into a single peptide. A composite peptide consisting of the dominant T cell recognition sequence p151-174 positioned N-terminal to the dominant B cell site p133-143 (i.e., p151-174(133-143] yielded an effective pre-S(2) synthetic immunogen. Interestingly, the orientation of the T and B cell determinants and the context of the T cell site within the larger composite peptide influenced both antibody fine specificity and T cell fine specificity.
Amino Acid Sequence↗
Hepatitis delta antigen. Antigenic structure and humoral immune response.
Hepatitis delta virus (HDV) is a small RNA virus that is dependent on helper functions provided by hepatitis B virus. The hepatitis delta Ag (HDAg) is the only protein known to be made from the viral genome, from an ORF with a coding capacity of 214 amino acids. The immunogenic epitopes of HDAg and the immune response to it were mapped by the use of synthetic peptides, antipeptide antibodies, and human mAb. Antipeptide sera covering approximately 60% of the linear sequence reacted with liver-derived HDAg. Antisera from HDV-infected humans, chimpanzees, and woodchucks reacted with from 2 to 13 of 15 peptides. The epitopes of two human anti-HD mAb were mapped to overlapping but distinct epitopes in the region around residues 106-123. Sera from infected humans, chimpanzees, and woodchucks were also tested by competition with the mAb. Use of the peptides and antipeptide sera defined one region in the sequence (residues 52-93) which is immunodominant in the immune response to HDAg. Reactivity of both peptides and antipeptide antibodies was very broad, covering most or all of the linear sequence. Competition assays also provided information on conformational epitopes, as well as the sequential epitopes defined by direct assays. The peptides and antipeptide antibodies should be useful in new assay development, in dissecting the anti-HD response in terms of chronic vs self-limited infection, and in studying the role of anti-HD in infection and recovery.
Amino Acid Sequence↗
Internalization of the human immunodeficiency virus does not require the cytoplasmic domain of CD4.
Binding of the human immunodeficiency virus (HIV) to infectable host cells, such as B and T lymphocytes, monocytes and colorectal cells, is mediated by a high-affinity interaction between the gp120 component of the viral envelope glycoprotein and the CD4 receptor. Upon binding, it is thought that the second component of the envelope, gp41, mediates fusion between the viral envelope and host cell membranes. However, the early steps of HIV infection have not yet been thoroughly elucidated. Viral entry was first reported to be mediated by pH-dependent receptor-mediated endocytosis; subsequent studies have shown entry to be pH-independent. Although direct fusion of virus to plasma membranes of infected cells has been observed by electron microscopy, it is still formally possible that the infectious path of the virus involves receptor-mediated endocytosis. To gain a better understanding of receptor function in viral entry, we have analysed the ability of several altered or truncated forms of CD4 to serve as effective viral receptors. Our results indicate that domains beyond the HIV-binding region of CD4 are not required for viral infection. Some of the altered forms of CD4 that serve as effective HIV receptors are severely impaired in their ability to be endocytosed. These experiments therefore support the notion that viral fusion to the plasma membrane is sufficient for infection.
Antigens, Differentiation, T-Lymphocyte↗
Extramedullary disease in myelodysplastic syndromes.
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Aged↗
Hepatitis B synthetic immunogen comprised of nucleocapsid T-cell sites and an envelope B-cell epitope.
Previous studies located T-cell recognition of the nucleocapsid of the hepatitis B virus (HBcAg) to residues 120-140 in mice bearing the H-2s or H-2b haplotypes. Herein, we demonstrate that B10.S (H-2s) and B10 (H-2b) H-2 congenic strains recognize distinct T-cell sites within the p120-140 (a synthetic peptide corresponding to residues 120-140 of HBcAg) sequence defined by p120-131 and p129-140, respectively. Peptide p120-131 stimulates B10.S HBcAg-primed T cells, and reciprocally p120-131-primed T cells recognize HBcAg. Similarly, the p129-140 sequence is a T-cell recognition site relevant to the native HBcAg in the B10 strain. It is also shown that these 12-residue peptides efficiently prime T-helper cells, which are capable of eliciting antibody production to HBcAg in vivo. These observations prompted us to examine the ability of the HBcAg-specific p120-140 sequence to function as a T-cell carrier moiety as a component of a totally synthetic hepatitis B vaccine. For this purpose a synthetic B-cell epitope from the pre-S(2) region (p133-140) of the viral envelope was chosen because this sequence represents a dominant antibody-binding site of the envelope. Immunization of B10.S and B10 strains with the synthetic composite peptide c120-140-(133-140) elicited anti-peptide antibody production, which was crossreactive with the native viral envelope. Furthermore, c120-140-(133-140) immunization primed p120-131-specific T cells in the B10.S strain and p129-140-specific T cells in the B10 strain, which recognized HBcAg and provided T-helper cell function for anti-envelope antibody production in vivo. These results demonstrate the feasibility of constructing complex synthetic immunogens that represent multiple proteins of a pathogen and are capable of engaging both T and B cells relevant to the native antigens.
Animals↗
Immunologic monitoring of the cardiac transplant patient.
Peripheral blood lymphocyte morphology and cell surface markers were repeatedly evaluated in 49 orthotopic cardiac transplant patients over a period of three years to determine the utility of these parameters in predicting an episode of acute cardiac rejection. Lymphocytes were measured with a calibrated microscope and termed "activated" if greater than 10 mu in diameter. If a patient demonstrated greater than 30 activated lymphocytes/cu mm, the same lymphocytes were stained with monoclonal antibodies directed to T-cell subsets and B cells. These findings were retrospectively correlated with endomyocardial biopsy results. Absolute numbers of T-cell subsets and B cells were analyzed via Student's t test to identify significant differences during acute cardiac rejection. Of 347 biopsy specimens, 47 demonstrated histologic features of acute cardiac rejection. Simultaneous immune activation of lymphocytes occurred with 33 of 47 samples, while another 51 episodes of lymphocyte activation were detected without acute rejection. No statistically significant differences in absolute numbers of T-lymphocyte subsets were noted at the time of acute rejection.
Acute Disease↗
Immune response to hepatitis B virus core antigen (HBcAg): localization of T cell recognition sites within HBcAg/HBeAg.
Hepatitis B virus nucleocapsid particles (HBcAg) can function as a T cell-independent antigen when injected into athymic mice. However, immunization of euthymic mice with HBcAg results in dramatically increased anti-HBc titers. Therefore we have examined the murine T cell response to HBcAg in terms of immunogenicity, the influence of H-2-linked genes, and the fine specificity of T cell recognition using synthetic peptide analogs. The HBcAg was shown to be an extremely efficient immunogen in terms of T cell activation as measured by the in vivo dose required to induce T cell sensitization (1.0 microgram), and the minimal in vitro concentration required to elicit interleukin 2 (IL 2) production (0.03 ng/ml). The degree of T cell immunogenicity of HBcAg and its ability to directly activate B cells most likely explain the enhanced humoral response to HBcAg in euthymic mice and HBV-infected patients. The influence of H-2-linked genes on the humoral response to HBcAg was discernable, and high responder (H-2k,s,d), intermediate responder (H-2b,f), and low responder (H-2p) haplotypes were identified. The H-2-linked regulation of the T cell response correlated with in vivo anti-HBc production. Examination of the fine specificity of T cell recognition revealed HBcAg-specific T cells from a variety of strains recognize multiple but distinct sites within the HBcAg/HBeAg sequence. T cell recognition sites were defined by small (16 to 21 residue) synthetic peptides. Each strain recognized a predominant T cell determinant, and the fine specificity of this recognition process was dependent on the H-2 haplotype of the responding strain. For example H-2s,b strains recognized p120-140, H-2f,q strains recognized p100-120, and H-2d mice recognized p85-100 predominantly. Because these sequences are common to both HBcAg and a nonparticulate form of the antigen termed HBeAg, these results indicate that HBcAg and HBeAg are highly cross-reactive at the T cell level although they are serologically distinct. These findings may have clinical relevance, because T cell sensitization to HBeAg and the subsequent seroconversion to anti-HBe status correlates with viral clearance during hepatitis B infection.
Animals↗
A single 10-residue pre-S(1) peptide can prime T cell help for antibody production to multiple epitopes within the pre-S(1), pre-S(2), and S regions of HBsAg.
The purpose of this study was to identify and characterize T cell and B cell recognition sites within the pre-S(1) region of HBsAg/p43, and to then analyze functional T cell-B cell interactions at the level of in vivo antibody production. The results indicate: three peptide sequences within the pre-S(1) region of HBsAg were identified which can induce and elicit HBsAg/p43-specific T cell proliferation; a 10-amino acid peptide, p12-21, defines one pre-S(1)-specific T cell recognition site, and residues 18 and 19 are critical to the recognition process; the p12-21 sequence can function as a T cell carrier for a synthetic B cell epitope within the pre-S(2) region; the p94-117 sequence contains at least two T cell recognition sites; five distinct, pre-S(1)-specific antibody binding sites were identified; synthetic pre-S(1) region T cell determinants can prime in vivo antibody production to multiple B cell epitopes within the pre-S(2) and S regions, as well as within the pre-S(1) region; the specificity of the primed T cell population can influence the specificity of the B cell response; and T cell recognition of pre-S(1) region peptides is regulated by H-2-linked genes.
Animals↗
Androgen regulates MMTV RNA in the short-term in S115 mouse mammary tumour cells.
This report demonstrates that androgens as well as glucocorticoids can regulate MMTV RNA production in the short term. In S115 mouse mammary tumour cells, MMTV RNA accumulation is regulated within hours by androgen, at a time before any increase in DNA synthesis can be detected, thus providing a marker of an early postreceptor molecular event in steroid action on these cells. Androgen acts via its own receptor and not by cross-binding to the glucocorticoid receptor. The effects are at transcription and not just on stabilisation of RNA because they are blocked by actinomycin D. However, the androgen action shows some partial dependence on simultaneous protein synthesis since cycloheximide is inhibitory. The androgen regulation of MMTV RNA is compared and contrasted with that by glucocorticoids in these cells.
Androgens↗
Dietary intake, energy metabolism, and excretory losses of adult male germfree Wistar rats.
Adult germfree rats excreted 87% more calories with the feces than comparable conventional rats, but this loss was compensated by an 18% higher intake. As a result, energy utilization of germfree and conventional rats was similar (148 and 143 kcal/kg/day, respectively), although the germfree rat metabolized only 71.9% of its dietary intake, versus the conventional rat's 80%. Germfree rats consumed 33% more water than conventional rats. Both excreted approximately 33% of water intake via feces and urine, but the germfree rat excreted 56% of this with the feces, the conventional rat only 15%. Cecectomy of the germfree rat reduced water loss via the feces, but the total daily excretion of fecal dry matter remained comparable to that of the intact germfree rat. The increase in fecal dry matter excretion demonstrated by the germfree rat can be largely accounted for in terms of water-soluble organic material. The data imply that the lower oxygen consumption of the germfree rat is not coupled to a reduction in metabolized energy, but may be an anomaly linked to cecal stasis and enlargement.
Animals↗