Showing papers by "University of Birmingham published in 1989"

Antibodies to CD3/T-cell receptor complex induce death by apoptosis in immature T cells in thymic cultures.

Abstract: The receptors found on most T lymphocytes bind to antigen presented on major histocompatibility complex proteins and consist of dimers of alpha- and beta-polypeptides associated with the invariant CD3 complex. A fully competent immune system requires a diverse array of T-cell antigen receptors (TCRs) with different specificities. This diversity is generated by rearrangement of TCR alpha- and beta-chain gene segments within the thymus where the receptors are first expressed. Any cells carrying self-reactive receptors must be eliminated, suppressed or inactivated so that destructive autoimmunity is avoided. Recently, compelling evidence has shown that one process involved in producing such self-tolerance is clonal deletion of autoreactive cells within the thymus by an as-yet-undefined mechanism. Here we show that engaging the CD3/TCR complex of immature mouse thymocytes with anti-CD3 antibodies produces DNA degradation and cell death through the endogenous pathway of apoptosis. Activation of this process in immature T cells by the binding of the TCR to self-antigens may therefore be the mechanism which produces clonal deletion and consequently self-tolerance.

Mechanism of antigen-driven selection in germinal centres.

Abstract: The high affinity of antibodies produced during responses to T-cell-dependent antigens is associated with somatic mutation in the variable region of the immunoglobulin. Indirect evidence indicates that: (1) this arises by a process of hypermutation, acting selectively on rearranged immunoglobulin variable-region genes, which is activated in centroblasts within germinal centres; and (2) centrocytes, the progeny of centroblasts, undergo selection on the basis of their ability to receive a positive signal from antigen. We have now performed experiments analysing this selection process, and found that, on culture, centrocytes isolated from human tonsil kill themselves within a few hours by apoptosis. This is not a feature of other tonsillar B cells. Centrocytes can be prevented from entering apoptosis if they are activated both through their receptors for antigen and a surface glycoprotein recognized by CD40 antibodies.

Actin accumulation at sites of bacterial adhesion to tissue culture cells: basis of a new diagnostic test for enteropathogenic and enterohemorrhagic Escherichia coli.

Abstract: Enteropathogenic Escherichia coli (EPEC) and enterohemorrhagic E. coli (EHEC) adhere to the intestinal mucosa and produce an attaching and effacing (AE) lesion in the brush border microvillous membrane; the AE lesion is characterized by localized destruction of microvilli and intimate attachment of bacteria to the apical enterocyte membrane. A similar lesion is seen when bacteria adhere in vitro to a variety of human tissue culture cell lines. In both cases, dense concentrations of microfilaments are present in the apical cytoplasm beneath attached bacteria. Using a fluorescein-labeled phallotoxin, we have shown that these microfilaments are composed of actin. Cells infected with EPEC and EHEC strains known from electron microscopic studies to produce the AE lesion all exhibited intense spots of fluorescence which corresponded in size and position with each adherent bacterium; cells infected with adherent E. coli strains known not to produce the AE lesion did not produce this striking pattern of fluorescence and were indistinguishable from uninfected control cells. These results indicate that such site-specific concentrations of cytoskeletal actin are characteristic of the AE membrane lesion and can form the basis of a simple, highly sensitive diagnostic test for EPEC and EHEC. Images

Real Exchange Rates, Devaluation, and Adjustment: Exchange Rate Policy in Developing Countries

Abstract: "Real Exchange Rates, Devaluation, and Adjustment "provides a unified theoretical and empirical investigation of exchange rate policy and performance in scores of developing countries. It develops a theory of equilibrium and disequilibrium real exchange rates, takes up the question of why devaluations are the most controversial policy measures in poorer nations, and discusses what determines their success or failure.In a lucid fashion, Edwards organizes vast amounts of data on exchange rates - both real and nominal - and discusses their effect on net trade balances, net asset positions, output growth, real wages, and rates of price inflation, analyzed both in time series and through cross country comparisons. Edwards's investigation singles out 39 major devaluation episodes for before and after comparative analyses while simultaneously isolating the separate effects of other important explanatory variables, such as bank credit expansion and changes in the terms of trade.The first part of the book focuses on theoretical models of devaluation and real exchange rate behavior in less developed countries. Special attention is paid to intertemporal channels in the transmission of disturbances. The second part uses a large cross country data set to analyze the way the real exchange rate has behaved in these nations. The data are also used to test the implications of several theories of real exchange rate determination. The third part analyzes actual devaluation experiences between 1962 and 1982. These chapters examine the events leading to a balance of payments crisis and to a devaluation, exploring the relation between macroeconomic disequilibrium, and the imposition of trade and exchange controls. They also investigate the effect of nominal devaluation on key variables such as the balance of payments, the current account, the real exchange rate, real output real wages, and income distribution.Sebastian Edwards is Professor of Economics at the University of California at Los Angeles and Research Associate at the National Bureau of Economic Research.

Expression of Epstein-Barr virus transformation-associated genes in tissues of patients with EBV lymphoproliferative disease.

Abstract: Epstein-Barr virus (EBV) has been associated with serious or fatal lymphoproliferative disease in immunocompromised patients. EBV nuclear protein 2 and latent membrane protein are characteristically expressed in B lymphocytes proliferating in vitro in response to growth transformation by EBV. These two proteins are thought to be effectors of lymphocyte growth since they increase the expression of B-lymphocyte activation (CD23) and cell-adhesion (LFA 3 and ICAM 1) molecules in vitro. Using monoclonal antibody-immune microscopy, we have demonstrated that these two EBV proteins and their associated B-lymphocyte activation or adhesion molecules are expressed in the infiltrating B lymphocytes in immunocompromised patients with EBV lymphoproliferative disease. These monoclonal antibodies should be useful in the early diagnosis of EBV lymphoproliferative disease and in distinguishing it from other B-lymphocyte cancers associated with EBV, such as Burkitt's lymphoma. The finding of EBV nuclear protein 2 and latent membrane protein and their associated activation or adhesion molecules provides a further pathophysiologic link between EBV and the proliferation of B lymphocytes in immunocompromised patients.

Narrative: A Critical Linguistic Introduction

Abstract: Contents Series Editor's Introduction to the Interface Series Preface Acknowledgements 1. Preliminary orientations 2. Basic story structure 3. The articulattion of narrative text I: time, focalization, narration 4. The articulation of narrative text II: character, setting, suspense, film 5. The articulation of narrative text III: representing character discourse 6. Narrative as socially situated: the sociolinguistic approach 7. Children's narratives 8. Narrative as political action Further Reading Notes and Exercises Bibliography Index

Evaluated kinetic and photochemical data for atmospheric chemistry: Supplement III

Abstract: Here we present the summary Table of reactions containing the recommended rate coefficients along with the assigned error limits. The reader is referred to the full article to obtain the data sheets for each reaction which contain the available experimental data upon which the recommendations are based

Specific Deficits in Component Reading and Language Skills: Genetic and Environmental Influences

Abstract: Phonological coding, measured by the oral reading of nonwords, and orthographic coding, measured by the discrimination of words from homophonic nonwords (e.g., rane, rain), were compared for pairs of older children with reading disabilities (RD) and younger nondisabled readers matched on word recognition. Phonological coding was substantially lower for most children with RD, indicating a unique developmental deficit in phonological coding rather than an equal developmental lag across all component reading skills. Data from identical and fraternal twins indicated that the phonological coding deficit of the children with RD was highly heritable and accounted for most of the heritable variance in their word recognition deficits. The deficits of the twins with RD in segmental language skills (rhyming and phoneme segmentation) were related to the heritable variance in their phonological coding deficits. Orthographic coding was not significantly heritable, and it accounted for much of the environmental variance in word recognition deficits. Implications of the results for the remediation of reading disability are discussed.

Synchroneity of climatic change and extinctions in the Late Triassic

Abstract: Although the Late Triassic was a time of widespread aridity, evidence exists for a significant increase in rainfall during the middle to late Carnian. Upper Triassic playa-lake sediments were interrupted by late Carnian fluviatile sandstones with erosive bases and high kao-linite/illite ratios. There was also an increase in the clastic component of marine sequences during this interval. Middle and upper Carnian marine carbonates show an extreme depletion in δ 13 C values, consistent with increased fresh-water influx. Large-scale karstic phenomena in limestone areas subaerially exposed during the Late Triassic are a further indication of increased rainfall. Important faunal and floral changes occurred during the Carnian-Norian interval; marine invertebrate turnover was greatest at the lower/middle Carnian boundary, and terrestrial extinctions were concentrated at the Carnian/Norian boundary. The cause of this Carnian pluvial episode may have been related to the rifting of Pangea, through disruption of atmospheric and oceanic circulation patterns, eustatic changes, or the effects of volcanism associated with rifting. A change in surface ocean temperature, salinity or pH, or habitat loss may have caused the decline of many shallow-marine invertebrates at the start of the middle Carnian; a return to arid conditions at the Carnian/Norian boundary would account for the turnover among terrestrial vertebrates and plants.

The polymerase chain reaction: a new epidemiological tool for investigating cervical human papillomavirus infection.

Abstract: The polymerase chain reaction is an in vitro method for primer directed enzymatic amplification of specific target DNA sequences. The technique was used to detect human papillomavirus types 11 and 16 simultaneously in cellular DNA recovered from cervical smears in 38 women referred for colposcopy to evaluate cytological abnormality and 10 women with no history of cytological abnormality. The polymerase chain reaction was shown to be both specific and sensitive in detecting human papillomavirus DNA such that a single human papillomavirus molecule was detected in 10(5) cells. Of the 38 women with cytological abnormality, all were positive for human papillomavirus on testing with the polymerase chain reaction; 36 were infected with human papillomavirus type 16 and 22 dually infected with human papillomavirus types 11 and 16. Seven of the 10 women with no cytological abnormality were also infected with human papillomavirus type 11 or 16. The use of the polymerase chain reaction will facilitate epidemiological investigation of the aetiological role of human papillomavirus in cervical neoplasia. This preliminary analysis suggests that the prevalence of human papillomavirus infection is greater than previously reported.

Response of patients in phase II studies of chemotherapy in ovarian cancer: implications for patient treatment and the design of phase II trials

Abstract: Results using the same drug in phase II studies of treatment in ovarian cancer vary widely. An analysis of five phase II studies with a total of 93 patients was carried out to determine whether factors other than the efficacy of the drug affect response. The drugs for the phase II studies were chosen on the basis of in vitro activity or previous activity in humans. Univariate analysis showed that several factors were of significance in predicting response. The most significant was interval from the end of previous treatment to entry into a phase II study. Others were the original presenting stage of the patient, the second line treatment given and the best previous response to therapy. In multivariate analysis, however, only two factors were shown to be of importance which were interval and the FIGO stage of the patient. Using these two variables the discriminant analysis predicted 89% of those who did not respond and 75% of those who did, with an overall correct prediction of 85%. The importance of interval is emphasised by the observation that the response rate for those patients who progressed on treatment or who relapsed within 3-6 months of primary therapy had a response rate of less than 10%. Future phase II studies should probably exclude patients in this category, since the chance of their responding is very low.

Depth of investigation of collinear symmetrical four-electrode arrays

Abstract: A study of collinear symmetrical four-electrode arrays and their tripotential variations indicates the existence of an electrode array for which all the tripotential arrangements have the same depth of investigation. Examination of computer-generated sounding curves confirms this result only when depth of investigation is defined as the median of the depth of investigation characteristic curve. The results lend support to this being the most practically useful definition of depth of investigation.

Identification of susceptibility loci for insulin-dependent diabetes mellitus by trans-racial gene mapping

Abstract: INSULIN-dependent (type I) diabetes mellitus (IDDM) follows an autoimmune destruction of the insulin-producing β-cells of the pancreas1,2. Family and population studies indicate that predisposition is probably polygenic3. At least one susceptibility gene lies within the major histocompatibility complex and is closely linked to the genes encoding the class II antigens, HLA-DR and HLA-DQ (refs 3,4). Fine mapping of susceptibility genes by linkage analysis in families is not feasible because of infrequent recombination (linkage disequilibrium) between the DR and DQ genes. Recombination events in the past, however, have occurred and generated distinct DR–DQ haplotypes, whose frequencies vary between races4–6. DNA sequencing and oligonucleotide dot-blot analysis of class II genes from two race-specific haplotypes indicate that susceptibility to IDDM is closely linked to the DQA1 locus and suggest that both the DQB1 (ref. 7) and DQA1 genes contribute to disease predisposition.

Mental hospital admission rates of immigrants to England: A comparison of 1971 and 1981

Abstract: The present study compares admissions to mental hospitals in England in 1981 with comparable figures obtained for 1971. Patients were classified by place of birth and the two data sets reveal interesting similarities a decade apart. With schizophrenia the trend in 1981, as in 1971, is for the foreign born to have higher rates of admission in comparison to the native born; and as in 1971 the groups with the highest rate of admission are the Irish born and those born in the Caribbean and Poland. Overall rates of admission in 1981 for immigrants from India, Pakistan, Germany and Italy (like 1971) are lower than the native born rates. As in 1971 the Irish and Scots have extremely high rates of alcohol and drug related disorders, and although they also have high rates of personality disorders they are not as high as the 1971 rates. Those born in the Caribbean continue to show relatively low rates of admission for alcohol, drug and personality disorders. For Indian born males the 1981 figure for alcohol related admissions is twice that of 1971. There is an apparent increase in the rates of depression in 1981 compared to 1971 across all the groups which is affected by changes in recording procedures. There are other findings which are peculiar to only one sub-group, such as the very low re-admission rates for Pakistani women compared to the other groups. This paper provides some possible explanations to account for these variations in rates of admission.

Acylation of viral and eukaryotic proteins.

Abstract: This paper is a review article about post-transcriptionnal modification that occurs in viral and eukaryotic proteins. Acylation obviously plays a role in mediating protein-lipid interactions in targeting and binding polypeptide chains to different types of membrane, but it also seems to be important in mediating protein-protein interactions

Distinction between Epstein-Barr virus type A (EBNA 2A) and type B (EBNA 2B) isolates extends to the EBNA 3 family of nuclear proteins.

Abstract: The Epstein-Barr virus (EBV) nuclear antigens EBNA 3a, 3b, and 3c have recently been mapped to adjacent reading frames in the BamHI L and E fragments of the B95.8 EBV genome. We studied by immunoblotting the expression of the family of EBNA 3 proteins in a panel of 20 EBV-transformed lymphoblastoid cell lines (LCLs) carrying either type A (EBNA 2A-encoding) or type B (EBNA 2B-encoding) virus isolates. Certain human sera from donors naturally infected with type A isolates detected the EBNA 3a, 3b, and 3c proteins in all type A virus-transformed LCLs (with a single exception in which EBNA 3b was not detected) but detected only EBNA 3a in LCLs carrying type B isolates. These results were confirmed with human and murine antibodies with specific reactivity against sequences of the type A EBNA 3a, 3b, or 3c expressed in bacterial fusion proteins. Conversely, selected human sera from donors naturally infected with type B strains of EBV identified the EBNA 3a encoded by both types of isolates plus two novel EBNAs present only in type B, and not in type A, virus-transformed LCLs; these novel proteins appear to be the type B homologs of EBNA 3b and 3c. The distinction between type A and type B EBV isolates therefore extends beyond the EBNA 2 gene to the EBNA 3 family of proteins. This has important implications with respect to the evolutionary origin of these two EBV types and also places in a new light recent studies which identified differences between type A and type B transformants in terms of growth phenotype (A. B. Rickinson, L. S. Young, and M. Rowe, J. Virol. 61:1310-1317, 1987) and of detection by EBV-specific cytotoxic T cells (D. J. Moss, I. S. Misko, S. R. Burrows, K. Burman, R. McCarthy, and T. B. Sculley, Nature [London] 331:719-721, 1988).

The case for sea-level change as a dominant causal factor in mass extinction of marine invertebrates

Abstract: A correlation between global marine regressions and mass extinctions has been recognized since the last century and received explicit formulation, in a model involving habitat-area restriction, by Newell in the 1960s. Since that time attempts to apply the species-area relation to the subject have proved somewhat controversial and promoters of other extinction models have called the generality of the regression-extinction relation into question. Here, a strong relation is shown to exist between times of global or regional sea-level change inferred from stratigraphic analysis, and times of high turnover of Phanerozoic marine invertebrates, involving both extinction and radiation; this is valid on a small and large scale. In many cases the most significant factor promoting extinction was apparently not regression but spreads of anoxic bottom water associated with the subsequent transgression. The sea-level-extinction relation cannot be properly understood without an adequate ecological model, and an attempt is made to formulate one in outline.

Antigen-induced apoptosis in developing T cells: a mechanism for negative selection of the T cell receptor repertoire

Abstract: Herein we have investigated the ability of antigen to induce thymocyte death by apoptosis on the basis that this may be the mechanism for the deletion of autoreactive cells during T cell development. We show that the ability of the bacterial "superantigen" staphylococcal enterotoxin B to cause specific depletion of V beta 8+ cells when added to thymus organ cultures is accompanied by DNA degradation into oligonucleosomal fragments, indicating that depletion involves apoptosis. Our results provide the first direct evidence that antigen-induced apoptosis can be triggered in developing T cells.

Epstein-Barr virus-infected B cells persist in the circulation of acyclovir-treated virus carriers.

Abstract: In this study, infectious Epstein-Barr virus (EBV) shedding in the oropharynx and numbers of virus-infected B cells in the blood have been monitored in long-term virus carriers receiving acyclovir (ACV) therapy for herpes zoster. Eleven patients on oral ACV were followed prospectively before, during and for 2 weeks after treatment. As expected, the low levels of EBV shedding in these virus carriers (measured as cord-blood lymphocyte transforming activity in throat washings) were eliminated during the period of ACV treatment and returned at later times. Over the same period, however, the frequency of virus-infected B cells in the blood (measured by spontaneous transformation in limiting dilution assay) remained completely unchanged. Regression assays showed that these same patients had normal levels of EBV-specific cytotoxic T-cell immunity, so that the in vivo persistence of virus-infected B cells could not be ascribed to a defect in T-cell surveillance. We infer that the in vivo half-life of the virus-infected B-cell pool in long-term virus carriers is measured in months rather than days. We further suggest that such persistence requires a novel form of virus: B-cell interaction distinct from the type of “latent” infection displayed by in vitro-transformed cells.

In vitro responses to a 65-kilodalton mycobacterial protein by synovial T cells from inflammatory arthritis patients.

Abstract: Bacterial Ag, especially those of mycobacteria, have been implicated in the pathogenesis of experimental inflammatory arthritis in rodents, while in man, reactive arthritis has a clear temporal relationship to infection with particular bacteria. To investigate the role of immune responses to bacterial Ag in inflammatory arthritis, we have examined the proliferative responses of paired synovial fluid and PBMC when stimulated with 1) suspensions of irradiated or heat-killed bacteria associated with reactive arthritis (ReA), 2) purified protein derivative, 3) a recombinant 65-kDa heat shock protein of Mycobacterium leprae. The 65-kDa Ag was stimulatory to synovial fluid mononuclear cells, but not PBMC, from patients with different arthropathies, including most of those with ReA, but also some with rheumatoid arthritis. Furthermore, the magnitude of these responses correlated more closely with responses to ReA-associated bacteria (such as Salmonella), than with responses to the mycobacterial Ag represented in purified protein derivative. These results suggest that the 65-kDa molecule, which is common to a wide range of bacteria, may be an important immunogen for the T cell-mediated immune responses within the joint in different clinically defined inflammatory arthropathies.

Specific antibodies reveal ordered and cell-cycle-related use of histone-H4 acetylation sites in mammalian cells.

Abstract: Antibodies specific for the acetylated forms of histone H4 (H4) were produced in rabbits with a synthetic peptide corresponding to the 18 N-terminal residues of tetra-acetylated H4 (i.e. with acetyllysine at positions 5, 8, 12 and 16). Specificity was determined by inhibition assays using four additional peptides, each acetylated at only a single site. Using an antiserum (R6) specific for the acetylation site at Lys-5 we have estimated the proportion of Lys-5 sites acetylated in the mono-, di- and tri-acetylated forms of H4 from randomly growing human HL-60 cells. The values obtained (7%, 29% and 61% respectively) differ from those expected if acetylation were random (i.e. 25%, 50% and 75%) or if site usage followed a set order for all H4 molecules (i.e. a jump from 0% to 100%). Antibodies from a second animal (R5) bound preferentially to peptides acetylated at Lys-12 and also bound to mono-acetylated H4 relatively weakly in several cell types. In contrast, mono-acetylated H4 from metaphase HeLa cells labelled more strongly with both antisera, indicating significant acetylation at Lys-5 and Lys-12. We conclude that (1) the sites at Lys-5 and Lys-12 are under-used in mono-acetylated H4 from a variety of mammalian cell types and Lys-8 and/or Lys-16 are therefore the first to be acetylated, (2) more than one order of site usage is possible and (3) there is a metaphase-specific shift in site usage. These results suggest that H4 acetylation plays a role in the modulation of chromatin structure in mammalian cells.

Production of lymphokine mRNA by CD45R+ and CD45R- helper T cells from human peripheral blood and by human CD4+ T cell clones.

Abstract: The expression of lymphokine mRNA by human CD4+CD45R+ and CD4+CD45R- Th cells was assessed after mitogen stimulation. These Ag have previously been shown to relate closely to virgin and primed T cells, respectively. CD4+CD45R+ (virgin) and CD4+CD45R- (primed) cell fractions were isolated by sorting double-labeled cells with a fluorescence-activated cell sorter. CD4+CD45R+ cells produced high levels of IL-2 mRNA when stimulated with either PMA together with calcium ionophore, or with PHA, but they expressed only trace quantities of mRNA for IL-4 or IFN-gamma. In contrast, CD4+CD45R- cells produced high levels of mRNA for IL-2, IL-4, and IFN-gamma. After 14 days of continuous culture, CD4+CD45R+ Th cells lost expression of the CD45R Ag, but gained high level expression of CDw29, such that they were indistinguishable from the cell population which originally expressed this Ag. At the same time, they acquired the ability to synthesize IL-4 mRNA. It seemed likely that the broad lymphokine profile of primed Th cells might mask clonal heterogeneity. Analysis of 122 CD4+ T cell clones showed that all of them synthesized IL-2 mRNA. One clone failed to express IL-4 mRNA, but did produce those for IL-2 and IFN-gamma. A total of 34 of the clones was investigated to determine expression of IFN-gamma mRNA; two of these clones were negative for IFN-gamma mRNA, and both expressed IL-2 and IL-4 message. These data suggest that while fresh virgin and primed peripheral blood T cells show a clear resolution of lymphokine production, a simple subdivision of human CD4+ T cell clones on the basis of their lymphokine production (such as that reported for mouse Th cell clones) is not possible.