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Biomedical subjects

J Lamb

Publications and source records attributed to J Lamb.

At least 91 records · Page 5Linked to original sources
PubMed1989

Detection of breakpoints in submicroscopic chromosomal translocation, illustrating an important mechanism for genetic disease.

A 3-year-old boy presented with alpha-thalassaemia, dysmorphic features, and mental handicap. His younger sister is also mentally retarded, but haematologically normal. High resolution cytogenetic analysis revealed a normal karyotype in all family members. However, a combination of DNA analysis and in situ hybridisation demonstrated that the mother has a previously unsuspected balanced reciprocal translocation between the tips of the short arms of chromosomes 1 and 16, and that the alpha-globin gene complex (which maps to the tip of chromosome 16) is included in the translocated segment. Both of her children have inherited one of the translocation chromosomes in an unbalanced fashion: the boy has the derived chromosome 16, and therefore has alpha-thalassaemia, whilst the girl has the derived chromosome 1. Such cytogenetically invisible subtelomeric translocations are probably an important and hitherto unrecognised cause of genetic disease.

Alpha-Globulins↗
PubMed1989

Molecular study of the T cell repertoire in family contacts and patients with leprosy.

The specificity of lymphocyte proliferative responses of 22 family contacts and 7 patients with leprosy were analyzed using Ag fractions from soluble extracts of Mycobacterium leprae and Mycobacterium tuberculosis. Fractions 10-100 kDa m.w. from each extract were separated by SDS-polyacrylamide gel electrophoresis, electroblotted to nitrocellulose membrane and solubilized for use in lymphocyte culture. The main immunogenic fractions for both contacts and patients had m.w. of 12,000 to 22,000, 35,000 to 40,000, and 65,000. Determinants which were either distinct or shared by the two extracts were active in each of the immunogenic fractions. Lymphocyte proliferation following stimulation with separated Ag was found also in five subjects who failed to respond to the whole soluble extracts. Stimulatory synthetic peptides were identified for the 65 kDa protein Ag. This technique has permitted the screening of the T cell immune repertoire for the identification of the immunodominant Ag which merit further purification and molecular characterization.

Adult↗
PubMed1989

Functional evidence for the recognition of endogenous peptides by autoreactive T cell clones.

The fine specificity of two human T cell clones responding to autologous HLA-DR1 expressing antigen-presenting cells (APC) in the absence of nominal antigen has been investigated using Epstein-Barr virus-transformed B cells (BCL) of known DR beta 1 domain sequence. It was found that responsiveness was markedly affected by changes in a limited number of residues in this domain. Substitution of the DR1 beta sequence at one residue, position 74, even conservatively, was found to be particularly significant. Located on the beta 1 domain alpha-helix, this residue is predicted to point into the antigen-binding groove and is therefore unlikely to make contact with the T cell receptor. This finding suggests that these T cells are specific for a bound endogenous peptide within the autologous major histocompatibility (MHC) binding groove. The autospecific T cell clones also responded to murine L cell transfectants expressing DR alpha DR1 beta as well as to transfectants expressing the mouse/human hybrid MHC molecule I-E alpha DR1 beta but not to the reciprocal combination DR alpha I-E beta, thus confirming the importance of the beta 1 domain to T cell recognition. In contrast to the autocytotoxicity observed with BCL, cytolysis of the murine L cells expressing the HLA-DR1 molecule was slight and only found at high effector-target ratios. In addition, although fixation enhanced the recognition of BCL, capacity of the murine L cells bearing the HLA-DR1 molecule to stimulate T cell clone proliferation was markedly reduced by aldehyde fixation. When taken together, these results suggest that the endogenous peptides recognized by these autoreactive T cells are of human origin.

Amino Acid Sequence↗
PubMed1989

Influence of cancer histology on the success of fine needle aspiration of the breast.

Fine needle aspiration (FNA) cytology carried out on 1318 primary breast cancers from 1980 to 1986 inclusive showed that 198 were well recognised, histological special types. These included medullary, mucoid, tubular, cribriform and lobular invasive cancers, and non-invasive cancers. Excluding these special histological types, the overall number successfully identified (malignant plus suspicious) by fine needle aspiration was 940 (84%), although in only 820 (73%) was malignancy definitely diagnosed. The results for the special types were variable, the mucoid and medullary cancers being consistently identified while the other types were not. For tubular and cribriform, lobular and non-invasive ductal cancers a malignant diagnosis was made in 30% to 40% of cases, although inclusion of suspicious results gave identification figures of 60% to 70%. Particular cytological patterns are characteristic of some special histological cancer types but lesion cellularity, size, and physical definition are all intrinsic factors influencing success of FNA diagnosis. About 10% of all primary breast cancers seem to have certain histological properties which further reduce the success of fine needle aspiration.

Adenocarcinoma↗
PubMed1989

Clonal analysis of the cellular immune response to the house dust mite Dermatophagoides farinae.

A panel of human CD4+ T cell clones specific for the house dust mite was isolated from an atopic individual with perennial rhinitis. Soluble antigen specificity was defined using proliferation assays and subsequently the antigenic determinants recognized by some of these clones were mapped using nitrocellulose immunoblots of fractionated Dermatophagoides spp. Both cross-reactive and species-specific T cell clones were identified and in some instances their specificity could be mapped to the serologically defined Der f I, Der p I and Der f II allergens. In comparison, the serum antibody response showed additional specificity for Der f III. The antigen recognition by six of these clones was found to be restricted by HLA-DR gene products.

Allergens↗
PubMed1988

Structural and functional studies of HLA-DR restricted antigen recognition by human helper T lymphocyte clones by using transfected murine cell lines.

Murine L cells expressing the products of transfected HLA-DR1 genes functioned as APC for two influenza-specific, human Th cell clones with comparable efficiency to a DR1-expressing human lymphoblastoid cell line. In order to investigate the restriction specificity of the two Th clones, a transfectant expressing the species-mismatched MHC class II dimer DR1:I-E was tested as an APC. Both T cells showed no loss of Ag sensitivity due to substitution of the murine chain. One of the Th clones, TLC 72, showed even greater degeneracy by responding to Ag in the context of I-Ek. Taking into account the lower level of MHC class II expression on the I-Ek transfectant, there is remarkably little loss of efficiency of Ag-induced T cell activation due to the substitution of I-E for DR as restriction element. The Ag-specific responses of both clones were inhibited by anti-CD4 antibody when DR-transfected L cells or human lymphoblastoid cells were used as APC. This inhibition was also seen when Ag was presented to TLC72 by the I-Ek-expressing transfectant. Whether this inhibition is the result of negative signaling or of blocking an interaction between human CD4 and I-Ek is discussed. Similarly the inhibitory effects of mAb against the T cell accessory molecule LFA/1 were the same for both clones when either the transfectants or the lymphoblastoid cell line were used as APC, suggesting that L cells may express a molecule that is capable of acting as a ligand for human LFA/1. The results presented here further illustrate the value of transfectants in analyzing T cell recognition and accessory cell requirements. The patterns of degeneracy of MHC restriction exhibited by these clones provides a platform for a more detailed analysis of key residues involved in MHC class II-restricted T cell Ag recognition.

Amino Acid Sequence↗
PubMed1988

Viscoelasticity of F-actin and F-actin/gelsolin complexes.

Actin is the major protein of eukaryote peripheral cytoplasm where its mechanical effects could determine cell shape and motility. The mechanical properties of purified F-actin, whether it is a viscoelastic fluid or an elastic solid, have been a subject of controversy. Mainstream polymer theory predicts that filaments as long as those found in purified F-actin are so interpenetrated as to appear immobile in measurements over a reasonable time with available instrumentation and that the fluidity of F-actin could only be manifest if the filaments were shortened. We show that the static and dynamic elastic moduli below a critical degree of shear strain are much higher than previously reported, consistent with extreme interpenetration, but that higher strain or treatment with very low concentrations of the F-actin severing protein gelsolin greatly diminish the moduli and cause F-actin to exhibit rheologic behavior expected for independent semidilute rods, and defined by the dimensions of the filaments, including shear rate independent viscosity below a critical shear rate. The findings show that shortening of actin filaments sufficiently to permit reasonable measurements brings out their viscoelastic fluid properties. Since gelsolin shortens F-actin, it is likely that the effect of high strain is also to fragment a population of long actin filaments. We confirmed recent findings that the viscosity of F-actin is inversely proportional to the shear rate, consistent with an indeterminate fluid, but found that gelsolin abolishes this unusual shear rate dependence, indicating that it results from filament disruption during the viscosity measurements.(ABSTRACT TRUNCATED AT 250 WORDS)

Actins↗
PubMed1988

The inhibitory effects of mycobacterial lipoarabinomannan and polysaccharides upon polyclonal and monoclonal human T cell proliferation.

Lipoarabinomannan from Mycobacterium tuberculosis was able to inhibit antigen induced T cell proliferation of human CD4+ T cell clones specific for influenza virus. The inhibitory effect was also present when peripheral human T cells were stimulated with crude mycobacterial antigen extracts. Non-specific T cell stimulation, i.e. IL-2, PHA and anti-CD3 antibodies coupled to beads, was not affected. The inhibitory property was also found when arabinomannan and arabinogalactan of mycobacterial origin were tested but not with other unrelated polysaccharides used as controls. The effect appears to be related to the processing of the antigen by the antigen-presenting cells, since it was evident when T cell clones were stimulated with whole virus, whereas stimulation with a synthetic peptide containing the relevant epitope was not inhibitable.

Antigen-Presenting Cells↗
PubMed1988

Novel uses of mass spectrometry in studies of adducts of alkylating agents with nucleic acids and proteins.

Several recent and major advances in the technology of mass spectrometry (MS) have greatly promoted use of this technique for the study of the interaction of alkylating agents with biomolecules. MS, in combination with gas chromatography (GC), may now be used to quantify adducts of carcinogens with proteins at levels down to 20 pmol/g protein. Soft ionization techniques have proved invaluable in determining the structure of carcinogen adducts with both DNA and proteins, and the newly developed tandem MS promises to be of considerable use in the characterization of complex carcinogen adduct mixtures.

Alkylating Agents↗
PubMed1987

The determination of urinary 3-methyladenine in humans as a potential monitor of exposure to methylating agents.

The determination of urinary 3-methyladenine has been explored as a potential monitor of exposure to methylating carcinogens. A method based on the use of high resolution gas chromatography--mass spectrometry has been developed for measuring this methylated base in human urine. Urine is extracted by XAD-2 column chromatography and the extract purified by reverse phase C18 h.p.l.c. Derivatization with N-(tert-butyldimethylsilyl)-N-methyltrifluoroacetamide yields the mono-tert-butyldimethylsilyl derivative of 3-methyladenine which has good gas chromatographic properties and is stable towards hydrolysis. The gas chromatographic separation was carried out using an SE-52 capillary column and quantitation made by electron impact selective ion monitoring mass spectrometry employing deuterium-labelled 3-methyladenine added initially to the urine as internal standard. Measurable levels (4.50-16.07 micrograms/24 h) of the methylated base have been found in control (i.e. nominally unexposed) human urines.

Adenine↗
PubMed1987

Role of fine needle aspiration cytology in breast cancer screening.

In a six year period up to the end of December 1985 fine needle aspiration cytology specimens of the breast were obtained from 562 apparently healthy women invited to participate in a breast cancer screening programme. Of these, 397 had a biopsy and 173 cancers were confirmed histologically. For the diagnosis of cancer, the procedure was less successful than in symptomatic cases. The main factors influencing success were the aspirator, the small size of many cancers, and the occult nature of the lesions seen only on mammography. Retrospective analysis of the figures shows that combining the results of FNA cytology in a triple assessment with physical and mammographical findings for restricted selection means that the number of benign biopsy specimens could be reduced considerably.

Biopsy, Needle↗
PubMed1987

Suppression of delayed hypersensitivity skin reactions to tuberculin by M. leprae antigens in patients with lepromatous and tuberculoid leprosy.

Delayed hypersensitivity skin reactions to tuberculin when injected alone or in mixture with antigens of M. leprae were examined in leprosy patients and in healthy controls. The tuberculin reaction was significantly inhibited in more than one half of both LL and BT patients by the soluble extract of M. leprae (leprosin), the leprosin derived 12 kD protein or leprosin depleted of the 12 kD antigen. However, suppression was not found in healthy controls from a leprosy endemic region. These results suggest that multiple M. leprae-specific antigens have an immunoregulatory function. Since suppression was demonstrable not only in LL (leprosin-anergic), but also in BT (leprosin-responder) patients it is of interest that the 'mixed' skin test can discriminate the immune status of at least certain BT patients from that of the infected but self-healing healthy controls. Corollary lymphocyte cultures failed to show any suppression by leprosing of the lymphoproliferative responses to tuberculin.

Antigens, Bacterial↗
PubMed1986

Comparative pathology of prevalent and incident cancers detected by breast screening. Edinburgh Breast Screening Project.

In the Edinburgh Breast Screening Project 210 cancers were detected from commencement in 1979 up to December, 1984. By this time the full initial cohort had completed at least 3 visits and a proportion had attended for up to 5 visits, so pathological characteristics for prevalent and incident cancers could be compared. The main differences are in distribution of histological type of cancer, detection of occult invasive disease, and lymph-node positivity among incident tumours. Only the first of these was statistically significant. This evaluation shows that cancer detection by screening in Edinburgh conforms with screening theory, in which detection of good prognosis tumours is favoured at the prevalence screens, and faster growing, aggressive tumours are found at the incidence screens. Qualitative histopathology may provide a better measure than standard quantitative judgments of size and lymph node status to compare the varieties of cancer detected by screening programmes and to understand the biology of the disease.

Aged↗